A case of autoimmune encephalitis in a patient with a solitary intracranial plasmacytoma.

A 65-year-old woman presented with fever and abnormal behavior. Magnetic resonance imaging showed swelling of the left medial temporal lobe and an intracranial extra-axial occipital tumor. While her neurological symptoms improved after the administration of corticosteroid therapy under the suspicion of autoimmune encephalitis, the occipital tumor unexpectedly shrank, and the diagnosis of a solitary plasmacytoma was confirmed by biopsy. Additional examinations revealed elevated anti-glutamate receptor antibodies in the cerebrospinal fluid. The patient was diagnosed with autoimmune encephalitis concurrent with an intracranial solitary plasmacytoma. Central nervous system involvement can be considered a neurological complication in patients with a solitary plasmacytoma.

Outcomes of transplant-eligible patients with myelodysplastic syndrome with excess blasts registered in an observational study: The JALSG-CS11-MDS-SCT.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the sole curative therapy for myelodysplastic syndrome (MDS). However, whether bridging therapy (BRT) including azacitidine (AZA) and combination chemotherapy (CCT) prior to allo-SCT should be performed is unclear. We analyzed BRT and the outcomes of patients with myelodysplastic syndrome with excess blasts (MDS-EB) who were ≤ 70 years old at the time of registration for a prospective observational study to clarify the optimal allo-SCT strategy for high-risk MDS. A total of 371 patients were included in this study. Among 188 patients (50.7%) who were considered for allo-SCT, 141 underwent allo-SCT. Among the patients who underwent allo-SCT, 64 received AZA, 29 received CCT, and 26 underwent allo-SCT without BRT as the initial treatment. Multivariate analysis identified BRT as an independent factor influencing overall survival (AZA vs. without BRT, hazard ratio [HR] 3.33, P = 0.005; CCT vs. without BRT, HR 3.82, P = 0.003). In multivariate analysis, BRT was independently associated with progression-free survival (AZA vs. without BRT: HR, 2.23; P = 0.041; CCT vs. without BRT: HR, 2.94; P = 0.010). Transplant-eligible patients with MDS-EB should undergo allo-SCT when clinically acceptable, and upfront allo-SCT without BRT may be superior to AZA or CCT.

Real-world data of AML in Japan: results of JALSG clinical observational study-11 (JALSG-CS-11).

This report covers acute myeloid leukemia (AML) results from a multicenter, prospective observational study of AML, myelodysplastic syndromes, and chronic myelomonocytic leukemia in Japan. From August 2011 to January 2016, 3728 AML patients were registered. Among them, 42% were younger than 65, and the male-to-female ratio was 1.57:1. With a median follow-up time of 1807 days (95% confidence interval [CI]: 1732-1844 days), the estimated 5-year overall survival (OS) rate in AML patients (n = 3707) was 31.1% (95% CI: 29.5-32.8%). Trial-enrolled patients had a 1.7-fold higher OS rate than non-enrolled patients (5-year OS, 58.9% [95% CI: 54.5-63.1%] vs 35.5% [33.3-37.8%], p < 0.0001). Women had a higher OS rate than men (5-year OS, 34% [95% CI; 31.4-36.7%] vs 27.7% [25.7-29.7%], p < 0.0001). The OS rate was lower in patients aged 40 and older than those under 40, and even lower in those over 65 (5-year OS for ages < 40, 40-64, 65-74, ≥ 75: 74.5% [95% CI; 69.3-79.0%] vs 47.5% [44.4-50.6%] vs 19.3% [16.8-22.0%] vs 7.3% [5.5-9.4%], respectively). This is the first paper to present large-scale data on survival and clinical characteristics in Japanese AML patients.

Real-world data of MDS and CMML in Japan: results of JALSG clinical observational study-11 (JALSG-CS-11).

We conducted a multicenter, prospective observational study of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML) in Japan. From August 2011 to January 2016, we enrolled 6568 patients. Herein, we report the results for MDS (n = 2747) and CMML (n = 182). The percentage of patients aged 65 years or older was 79.5% for MDS and 79.7% for CMML. The estimated overall survival (OS) rate and cumulative incidence of AML evolution at 5 years were 32.3% (95% confidence interval: 30.2-34.5%) and 25.7% (23.9-27.6%) for MDS, and 15.0% (8.9-22.7%) and 39.4% (31.1-47.6%) for CMML. Both diseases were more common in men. The most common treatment for MDS was azacitidine, which was used in 45.4% of higher-risk and 12.7% of lower-risk MDS patients. The 5-year OS rate after treatment with azacitidine was 12.1% (9.5-15.1%) for of higher-risk MDS patients and 33.9% (25.6-42.4%) for lower-risk patients. The second most common treatment was erythropoiesis-stimulating agents, given to just 20% of lower-risk patients. This is the first paper presenting large-scale, Japanese data on survival and clinical characteristics in patients with MDS and CMML.

[Development of autoimmune hemolytic anemia after BNT162b2 mRNA COVID-19 vaccination].

A 75-year-old woman with a history of postoperative chemotherapy for lung adenocarcinoma and a history of Helicobacter pylori eradication for idiopathic thrombocytopenic purpura (ITP) was admitted to the department of hematology and oncology for the treatment of anemia 2 weeks after BNT162b2 mRNA COVID-19 vaccination. Her blood examination revealed direct and indirect Coombs test-positive hemolytic anemia and elevation of serum LDH and indirect bilirubin levels. No obvious trigger other than BNT162b2 mRNA COVID-19 vaccination was found. She was diagnosed with autoimmune hemolytic anemia (AIHA), and oral prednisolone therapy was administered. The anemia improved soon after the administration of prednisolone. Although vaccination is considered to be very important for suppressing the spread of COVID-19, there have been reports of increasing risk of ITP development and deterioration caused by BNT162b2 mRNA COVID-19 vaccination. Because the number of vaccinated people is increasing rapidly, hematologists must be vigilant to the development of AIHA after BNT162b2 mRNA COVID-19 vaccination although case reports of this phenomenon have been very rare thus far.

Comparison of Transplantation Outcomes after Foscarnet and Ganciclovir Administration as First-Line Anti-Cytomegalovirus Preemptive Therapy.

Ganciclovir (GCV) and foscarnet (FCN) are effective anti-cytomegalovirus (CMV) preemptive therapies; however, the impact of the 2 agents on various clinical outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) remains unclear. We retrospectively analyzed data on 532 patients undergoing allogeneic HSCT from unrelated donors and administered FCN (n = 86) or GCV (n = 446) as first-line anti-CMV preemptive therapy. Overall survival, relapse, and nonrelapse mortality (NRM) did not differ between the FCN and GCV groups, whereas the GCV group had a higher risk of chronic graft-versus-host disease (cGVHD) (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.28 to 4.39; P = .006) and extensive cGVHD (HR, 3.94; 95% CI, 1.43 to 10.9; P = .008). All 13 patients with cGVHD in the FCN group survived. Switching to the other agent was done mainly due to hematologic adverse events in the GCV group and mainly due to insufficient efficacy in the FCN group. The incidence of end-organ CMV disease was similar in the 2 groups. Selection of FCN or GCV as first-line preemptive anti-CMV therapy did not affect survival, relapse, or NRM. Physicians can select either of the agents, depending on the clinical situation; however, the selection may influence the cGVHD-related clinical course in HSCT recipients.

[Pneumocystis pneumonia prophylaxis with low-dose trimethoprim/sulfamethoxazole during rituximab-containing chemotherapy].

Although Pneumocystis pneumonia (PCP), a life-threatening infection, has been reported in patients with non-Hodgkin B-cell lymphoma (BNHL) who were treated with rituximab-containing chemotherapies (R-CTX), the PCP prophylaxis regimen awaits establishment to date. This study reports a retrospective analysis of the efficacy and safety of a low-dose trimethoprim/sulfamethoxazole (TMP/SMX) in patients with BNHL receiving R-CTX. We retrospectively analyzed 156 patients newly diagnosed with BNHL who received R-CTX at our institute from 2010 to 2015. We collected patients' clinical and laboratory data, including lymphocytes count, IgG level, PCP prophylaxis regimens, and adverse events (AEs). Patients were categorized into the following two groups based on the TMP/SMX regimen: group A (33 patients; 80 mg/400 mg×3/week) or group B (65 patients; 160 mg/800 mg×2/week). Both lymphocytes count and IgG level declined during R-CTX. No patient developed PCP. Patients in group B exhibited a significantly higher incidence of AEs (18.2% vs. 63.1%; p<0.05) and increased AST (6.1% vs. 26.6%; p<0.05), compared with those in group A. Thus, TMP/SMX (80 mg/400 mg×3/week) effectively prevents PCP and is preferable because of the lower rates of AEs.

[Clinical features of intravascular large B-cell lymphoma: a single-institute retrospective analysis].

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of extranodal non-Hodgkin's lymphoma, and the absence of specific findings makes ante-mortem diagnosis difficult. This study was conducted to identify the clinical findings useful for timely diagnosis of IVLBCL. Ten patients who were diagnosed with IVLBCL in our institute between 2005 and 2017 were retrospectively analyzed. Eight of the 10 cases had fever and 7 cases presented with respiratory symptoms, including cough, sputum, and dyspnea. Cytopenias were noted in all patients, and serum lactate dehydrogenase levels were elevated in 9 of the 10 patients. Arterial partial pressures of oxygen were <80 mmHg in 6 of the 7 patients examined. Computed tomography scanning detected hepatosplenomegaly and chest abnormalities in 7 and 9 cases, respectively. These results suggest that IVLBCL has a higher frequency of lung involvement than those reported previously. Physicians must therefore be vigilant in the identification of IVLBCL in patients who demonstrate respiratory symptoms or hypoxemia of uncertain origin, because early diagnosis can decrease the severity and prevent mortality.

Successful Treatment of a Case of Late-onset Colitis after Umbilical Cord Transplantation with Metronidazole: A Case Report and Literature Review.

Diarrhea after hematopoietic stem cell transplantation (HSCT) can be life-threatening, and its etiology includes conditioning regimens, graft-versus-host disease (GVHD), infections, and transplantation-associated microangiopathy (iTAM). Cord colitis syndrome (CCS) has been described as a syndrome of culture-negative and antibiotic-responsive persistent watery and non-bloody diarrhea of uncertain pathogenesis and occurs in umbilical cord blood transplantation (UCBT) recipients. We encountered a case similar to CCS that developed severe watery diarrhea after UCBT without any signs of GVHD or infection and responded well to metronidazole (MNZ) treatment. Since CCS is very rare, we herein describe a case of MNZ-effective diarrhea after UCBT.

Low signal intensity lesions on brain susceptibility-weighted MRI in a patient with intravascular large B-cell lymphoma.

A 71-year-old man was admitted to our hospital because of abnormal behavior and generalized convulsion. Brain MRI revealed no abnormalities upon admission. Levels of serum lactate dehydrogenase and soluble interleukin-2 receptors were significantly elevated, whereas the initial bone marrow puncture and random skin biopsy findings were non-malignant. On the tenth day of admission, brain MRI revealed dot and strip-shaped low signal intensity lesions on susceptibility-weighted images (SWI) disseminated mainly within the cerebral cortex. Administration of high dose methyl-prednisolone improved neither his condition nor these MRI findings. Ground-glass opacities within the bilateral lungs later emerged on the chest CT. The results of a transbronchial lung biopsy and second bone marrow puncture were consistent with a diagnosis of intravascular large B-cell lymphoma (IVLBCL). Despite the lack of histopathological confirmation, the low signal intensities on brain SWI in this case were also considered IVLBCL lesions, reflective of micro-hemorrhagic changes.

Interdigitating dendritic cell sarcoma successfully treated with ABVD therapy in which serum CEA levels correlated with disease activity.

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare neoplasm of spindle to ovoid cells with phenotypic features similar to those of interdigitating dendritic cells. No standard therapy for advanced IDCS has yet been established. According to past reports, CHOP-like regimens are often chosen as primary therapy. Herein, we report a case with advanced IDCS, for which ABVD achieved remarkable clinical improvement and serial CEA levels correlated with disease status. A 76-year-old man presented with general fatigue and pancytopenia with CEA elevation. Colonoscopy showed erosion and polyps in the colon. FDG-PET showed marked abnormal accumulation throughout the bone marrow. Pathologically, polyps of the colon and IDCS of the bone marrow were diagnosed. Although the patient received CHOP as initial therapy, clinical improvement was not significant. Subsequently, six cycles of ABVD resulted in remarkable regression of both the colonic polyps and the bone marrow infiltration. Moreover, the patient was transfusion-free after ABVD. In addition to these clinical responses, serial CEA levels normalized. Our case highlights the efficacy of ABVD for IDCS and serial CEA measurements might reflect treatment efficacy.

Drug-induced interstitial pneumonitis in essential thrombocythemia treated with anagrelide.

Anagrelide, a phospholipase A2 inhibitor, is widely used in the management of essential thrombocythemia. To date, anagrelide has only rarely been reported to be associated with the development of drug-induced interstitial pneumonitis. We herein report two cases of anagrelide-associated interstitial pneumonitis. The patients were a 67-year-old woman and a 75-year-old man, both with essential thrombocythemia. Both cases developed interstitial pneumonitis at 8 weeks after administration of anagrelide. Because anagrelide-induced interstitial pneumonitis was suspected from CT scan and bronchoalveolar lavage fluid findings, anagrelide-therapy was discontinued and corticosteroid administration was initiated. Anagrelide withdrawal and corticosteroid administration resulted in marked symptom amelioration. A lymphocyte stimulation test using anagrelide was positive in both cases. As interstitial pneumonitis is a rare adverse event during anagrelide-therapy administration, physicians must be vigilant in identifying drug-induced interstitial pneumonitis in patients treated with anagrelide because early detection can decrease the severity and prevent mortality.

Molecular response to nilotinib in a patient with imatinib-intolerant e19a2-positive chronic myeloid leukemia.

The BCR-ABL1 fusion gene is the molecular marker of chronic myeloid leukemia (CML). The e19a2 transcript is a rare variant associated with various clinical presentations and courses of CML. We herein present a case of e19a2-positive CML who was intolerant to initial treatment with imatinib and successfully responded to subsequent nilotinib therapy. She achieved a major molecular response and has since be able to sustain it. According to the literature, achieved molecular response by imatinib monotherapy has not yet been reported in e19a2-positive CML patients. Second generation tyrosine kinase inhibitors may therefore be a more effective treatment for e19a2-positive CML patients.

Y654 of ß-catenin is essential for FLT3/ITD-related tyrosine phosphorylation and nuclear localization of ß-catenin.

ß-Catenin plays a dual role as a key effecter in the regulation of adherens junctions as well as a transcriptional co-activator. Tyrosine phosphorylation of ß-catenin affects the cell adhesion, migration, and gene transcription in many types of human cancer cells, including acute myeloid leukemia cells with FLT3 internal tandem duplication (FLT3/ITD-AML). Here, we investigated the relationship between three tyrosine residues (Y86, Y142, and Y654) in ß-catenin and oncogenic FLT3/ITD kinase. In the experiments using COS-7 cells expressing FLT3/ITD and Wt or mutant ß-catenin, FLT3/ITD phosphorylated Y654, and this residue was essential for ß-catenin's nuclear localization by FLT3/ITD. Promoter-reporter assays demonstrated that Y654 phosphorylation of ß-catenin was closely related to TCF transcriptional activity. In vitro kinase assays, using recombinant FLT3 and biotinylated ß-catenin peptide including Y654 showed that FLT3 directly phosphorylated Y654 of ß-catenin. These results explain how FLT3/ITD affects the tyrosine phosphorylation, nuclear localization, and transcriptional activity of ß-catenin. Targeting Y654 phosphorylation may lead to the development of novel approaches to therapy for FLT3/ITD-AML.

Expanded distribution of the T315I mutation among hematopoietic stem cells and progenitors in a chronic myeloid leukemia patient during imatinib treatment.

T315I mutation of the ABL-kinase domain in chronic myeloid leukemia (CML) confers resistance to imatinib (IM) as well as second-generation tyrosine kinase inhibitors (TKIs). We report a chronic-phase CML patient undergoing IM treatment, who showed the overt existence of the T315I mutation after 15 months. We retrospectively analyzed the distribution of the T315I mutation using the invader assay and direct DNA sequencing among FACSAria-sorted populations from bone marrow cells: total mononuclear cells (TMC), hematopoietic stem cells (HSC)/Thy-1(+), HSC/Thy-1⁻, common myeloid progenitors (CMP), granulocyte macrophage progenitors (GMP), and megakaryocyte erythroid progenitors (MEP), at 0, 3, 6, 9, and 12 months after IM treatment. T315I was barely detectable by 12 months in TMC, but detectable in 19.2% of HSC/Thy-1⁻ and 46.4% of MEP at diagnosis, and finally expanded into all populations. These results suggest that the monitoring of gene mutations in HSC and progenitors at diagnosis might be helpful for the early detection of TKI-resistant CML patients and facilitate appropriate therapeutic decision.

Azithromycin-related agranulocytosis in an elderly man with acute otitis media.

Azithromycin (AZM) is widely used for respiratory tract infections and otitis media because of its activity against Haemophilus influenzae and atypical pathogens, and its ease of administration. Although leukopenia is the one of the most frequent AZM-related laboratory abnormalities in children, agranulocytosis has not been reported in adults. Here, we present the case of an 81-year-old man with agranulocytosis following AZM-treatment for acute otitis media. He developed febrile neutropenia and granulocyte colony-stimulating factor and cefepim were administered. All his symptoms and absolute neutrophil counts were recovered within 7 days after admission. Physicians must be vigilant in identifying drug-induced neutropenia in AZM-treated patients because early detection can decrease the severity and prevent mortality.

KIT regulates tyrosine phosphorylation and nuclear localization of beta-catenin in mast cell leukemia.

Gain-of-function mutations in the proto-oncogene c-kit that induce constitutive kinase activity of its product, KIT protein, are characteristic of human mast cell disease and are believed to play a central role in mast cell leukemia oncogenesis, proliferation and survival. Nuclear overexpression of the Wnt effector beta-catenin and deregulated beta-catenin nuclear signaling can promote malignant transformation in solid tumors and hematologic malignancies. However, a role for beta-catenin in mast cell leukemia has not been described. Nuclear accumulation of beta-catenin is upregulated by its tyrosine phosphorylation, a process that can be exacerbated by deregulated expression of oncogenic tyrosine kinases. Here, we investigated the relationship between activated KIT and beta-catenin signaling in mast cell leukemia. Beta-catenin was tyrosine-phosphorylated in cells with KIT activated by either gain-of-function mutation or incubation with the KIT ligand stem cell factor. Beta-catenin tyrosine phosphorylation depended on KIT activity but not on PI3K-AKT activation. Tyrosine phosphorylation of beta-catenin was associated with its nuclear localization and enhanced transcription of target genes c-myc and cyclin D1. Endogenous KIT and beta-catenin were found to associate in mast cell leukemia cells, and in vitro kinase assay demonstrated that active KIT phosphorylates tyrosine residues of beta-catenin directly. Aberrant beta-catenin-driven transcription caused by deregulated KIT may represent a significant new target for treatment of mast cell leukemia.

Increased oxidative DNA products in patients with acute promyelocytic leukemia during arsenic therapy.

Arsenic trioxide (ATO) has been used to treat acute promyelocytic leukemia (APL), but the oxidative DNA damage occurring in patients has not been fully elucidated. We measured 8-hydroxy-2'-deoxyguanosine (8-OHdG), one of the most abundant oxidative products of DNA, by enzyme-linked immunoassay, and reactive oxidative species (ROS), by luminol- and luminol-H2O2 chemiluminescence, in the plasma of four APL patients treated with ATO. After six courses of ATO therapy, the plasma 8-OHdG concentration had increased from 45.6+/-22.8 ng/mL to 310.2+/-239.6 ng/mL. The plasma chemiluminescence level did not change significantly. These findings suggest that ATO generates intracellular oxidative DNA damage, but this is not correlated with the plasma ROS level. The clinical significance of 8-OHdG during and after ATO therapy warrants further study.