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The BCL10 gene was identified at the breakpoint region of the t(1;14)(p22;q32) translocation in mucosa-associated lymphoid tissue lymphoma. Initially, mutations in the BCL10 gene were reported to occur at a high frequency in various types of lymphomas and solid tumors. However, subsequent studies showed that the mutations were rarely recognized. To evaluate the frequency and spectrum of its mutations in B-cell non-Hodgkin's lymphoma (B-NHL), we screened 56 cases with B-NHL by mutation analysis of exons 2 and 3 of the gene. In addition to 2 polymorphisms, a frame-shift mutation and a missense mutation were identified in 2 cases (3.6%): 1 with diffuse large B-cell lymphoma and the other with mantle cell lymphoma. Both cases showed mutations within exon 3, resulting in a C-terminal truncation in the former and a C-terminal amino acid substitution in the latter. Reverse transcriptase-polymerase chain reaction analysis of the former case revealed that both the mutated and the wild-type alleles were transcribed with or without a sequence modification. Our results, together with recent reports, indicate that BCL10 gene mutations take place in a small population of B-NHL and are not associated with specific histological subtypes. [ABSTRACT FROM AUTHOR]

A correction to the article "Chronic Idiopathic Myelofibrosis Expressing a Novel Type of TEL-PDGFRB Chimaera Responded to Imatinib Mesylate Therapy," that was published in the 2007 issue is presented.

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated AML. Although patients with NPM1-mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3A R882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1-mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3A R882 mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3A R882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3A R882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3A R882 mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3A R882 /FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3A R882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3A R882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Recent studies have reported that measurable residual disease (MRD) analysis using NPM1 mutations helps determine whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in acute myeloid leukemia (AML) patients. However, the optimal timing and cutoff value for measuring MRD using genomic DNA remain undetermined. This study aimed to investigate the optimal timing and cutoff value to ascertain the value of NPM1 mutation in MRD assessment. NPM1-mutated MRD was quantified by real-time polymerase chain reaction of bone marrow samples from 56 patients with NPM1-positive AML who achieved hematological remission. The area under the receiver-operating characteristic curve was greatest when MRD was assessed after two courses of post-remission therapy with a cutoff value of 0.010% (specificity, 68.4%; sensitivity, 87.0%). Patients whose MRD was below the cutoff value throughout the course of treatment had significantly better overall survival and relapse-free survival rates. Of the 33 patients who did not undergo transplantation during the first remission, all of the 11 who were never MRD-negative at any point experienced a relapse. Evaluating MRD with a cutoff value of 0.010% after two courses of post-remission therapy helps predict prognosis and determine the indication for allo-HSCT., (© 2022. Japanese Society of Hematology.)

Mutations of CCAAT/enhancer-binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P < .001), better overall survival (OS; P < .001) and a lower risk of relapse (P < .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P < .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

A 56-year-old man who sustained a right waist injury 1 month ago, reported to our department complaining of pain in the right waist and femur for 1 day. In a computed tomography examination, hematoma of the right iliopsoas muscle was revealed, and arterial embolization was immediately performed but was not effective. Laboratory findings showed hemoglobin levels as 5.4 g/dl, platelet of 20.2×10 4 /µl, prothrombine time of 13.1 s, partial thromboplastin time (APTT) of 81.1 s, and a convex upward curve of the APTT cross-mixing test. The activity of the coagulation factor VIII was <1.0%, but its amount was 120%, and the level of factor VIII inhibitor was 130 Bethesda Unit/ml. Disseminated intravascular coagulation was not noted. Under the diagnosis of acquired hemophilia A, treatment with prednisolone and recombinant activated factor VII was initiated. However, APTT remained prolonged, and intubation and mechanical ventilation were required because of right hemothorax. After steroid pulse therapy and plasma exchange, APTT returned to its normal range, and the inhibitor disappeared. Thus, we finally succeeded in extubation. This case indicated that intensive care may be necessary in the early phase treatment for acquired hemophilia A.

A 70-year-old man visited our emergency department, whose laboratory test results revealed leucocytosis, anaemia, thrombocytopenia and high levels of serum lactate dehydrogenase. In addition, the peripheral blood smear revealed neutrophilic granulocytes with nuclear hypolobation (pseudo-Pelger-Hüet anomaly), hypogranulation and no myeloperoxidase reactivity. Genetic testing of the peripheral blood sample was as follows: G-band, 46XY,t(9;22)(q34;q11.2) (20/20); fluorescence in situ hybridisation BCR/ABL fusion signal, 97%; and analysis of exons 5-9 of the p53 gene, mutation (Pro72Arg) in exon 4 protein. On the basis of these findings, the patient was diagnosed with chronic myelogenous leukaemia (CML) in chronic phase with a p53 mutation and treated with hydroxyurea, dasatinib and nilotinib. Neutrophilic granulocytes with the anomalies were no longer observed after achieving cytogenetic remission. To the best of our knowledge, this is the first report of CML case with the anomalies, in which a p53 mutation without chromosome 17 abnormalities was identified., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Certain autoimmune conditions are associated with an increased risk of lymphoid malignancy. We report a 65-year old patient with autoimmune hemolytic anemia (AIHA) complicated by a follicular lymphoma (FL) in situ and other B-cell clones in the spleen. This diagnosis was made by immunohistochemistry, flow cytometry, and Southern blot analysis of the B-cell receptor. Chromosomal analysis revealed 46,XX,t(14;18)(q32;q21) 2/20, 46,XX,del(7)(q?),del(11)(q?) 2/20, and 46,XX 16/20. It has been speculated that these preneoplastic conditions do not progress to overt FL and other lymphomas without a second lymphomagenic insult. However, AIHA confers a 27.4-fold higher risk of such an insult leading to lymphoma compared with the normal healthy population. Without any therapy after splenectomy, our current study patient remained healthy with no lymphoma development for 28 months. Based on this case, we discuss the pathophysiology of lymphomagenesis in a spleen with AIHA and the roles of a splenectomy for preventing further lymphomagenesis in AIHA patients., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Objectives: This analysis was conducted to clarify risk factors for severe adverse effects and treatment-related deaths reported during a postmarketing survey of irinotecan., Methods: The survey covered all patients treated with irinotecan in Japan between April 1995 and January 2000. The patient background data and adverse drug reactions were collected through case report forms. Univariate and multivariate logistic regression analyses including 14 explanatory variables were performed to determine the risk factors for grade 3-4 leukopenia, thrombocytopenia and diarrhea for all patients and subgroups with five major cancers. Treatment-related deaths were also analyzed., Results: Case report forms of 13 935 patients (94.1% of 14 802 patients registered) treated with irinotecan-based chemotherapy were collected. Major grade 3-4 adverse drug reactions were leukopenia (34.8%), thrombocytopenia (12.4%) and diarrhea (10.1%). Multivariate analysis revealed that the risk factors (odds ratio ≥1.5) common for all these three adverse drug reactions were performance status (≥3), infection and renal dysfunction before starting irinotecan therapy. Additionally, the risk factors for leukopenia were being female and prior radiotherapy, those for thrombocytopenia were age (≥65 years), while those for diarrhea were pleural effusion and watery stool. The risk factors in each cancer were also identified. The incidence of treatment-related death was 1.3% (176). Myelosuppression-related deaths accounted for 70% and interstitial lung disease for 11% of all treatment-related deaths. Being male, age, performance status ≥3, massive ascites and infection and renal dysfunction were identified as risk factors for treatment-related death., Conclusions: To ensure the safety of irinotecan therapy, it is important to select appropriate patients by considering the risk factors.

We report a 69-year-old male with CD3-positive peripheral T-cell lymphoma, not otherwise specified (PTCL-nos). Interestingly, tumor cells slightly expressed CD20 as well. Southern analyses of the tumor cells showed rearrangement for only the T cell receptor gene but not the immunoglobulin genes. This patient achieved partial remission with a treatment regimen of THP-COP excluding prednisolone, but died of pneumonia. Although CD20-positive PTCL is rare, a review of the reported cases suggests that CD20-positive PTCL has a poor prognosis and that bone marrow infiltration of tumor cells results in a poorer prognosis in CD20-positive PTCL than in usual PTCL. By accumulating cases of this rare entity of lymphoma, we need to clarify the biological nature of the tumor cells and usefulness of rituximab combined with standard chemotherapy.

We previously tested a less toxic CAG regimen consisting of low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor for the treatment of patients with relapsed or refractory myeloid malignancies or elderly patients with untreated ones, obtaining a satisfactory complete remission rate of 62%. Gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody conjugated to calicheamicin, has recently been approved as a single agent in Japan for the treatment of relapsed/refractory CD33-positive acute myelogenous leukemia (9 mg/m(2) on days1 and 15). Complete remission rate was reported as 30% in a phase 2 trial in Japan. In this study, effectiveness and safety of combining dose-attenuated gemtuzumab ozogamicin (3 mg/m(2) on day5) and original CAG regimen were assessed in nine patients with relapsed/refractory CD33-positive acute myelogenous leukemia and a median age of 70 years. Rate of complete remission with or without platelet recovery was 44% (4/9). The median duration of complete remission and overall survival were 5.5 and 16 months, respectively. Reversible myelosuppression and liver toxicity were the main adverse events, but no regimen-related death was recorded. Although only a small number of cases were included in this preliminary study, this CAG-GO regimen was found to be feasible and useful even in high-risk relapsed or refractory patients.

Objective: The actual condition of drug utilization and the adverse drug reactions profile of irinotecan hydrochloride hydrate (irinotecan), an antitumor drug, were examined on the basis of all the case survey results from April 1995 to January 2000., Methods: Drug utilization and the adverse drug reactions profile of irinotecan were figured out by checking of the patient conditions at the start of therapy and monitoring during on-therapy period in this survey., Results: Among the 13 935 patients investigated, 32% had non-small cell lung cancer, 16% had colorectal cancer, 15% had ovarian cancer and 14% had small cell lung cancer, all principal cancers in which irinotecan was domestically approved for use. Most frequent regimens of each cancer were concomitant use with cisplatin for non-small cell lung cancer and small cell lung cancer (38 and 46%, respectively), concomitant use with cisplatin or mitomycin for ovarian cancer (each 30%) and irinotecan alone for colorectal cancer (51%). The major (grade 3 or more) adverse drug reactions were myelosuppressions such as leukopenia (23.8 and 38.3% for lone and concomitant use, respectively) thrombocytopenia (6.5 and 14.3%) and gastrointestinal tract disorders such as diarrhea (10.2 and 10.0%)., Conclusions: It was reconfirmed that the incidences of serious leukopenia, thrombocytopenia and diarrhea were high among the patients with contraindication or careful administration of its use prescribed in the drug package insert. Therefore, for proper use of irinotecan, it is important to discriminate the patient on the basis of risk status.

It is well known that patients with rheumatoid arthritis (RA) have a higher risk of developing malignant lymphoma (ML) than the general population. Most of these lymphomas occur in patients receiving immunosuppressive (IS) agents such as methotrexate (MTX). Spontaneous regression of tumors is often observed after the discontinuation of IS drugs, especially in patients with Epstein-Barr virus-positive lymphoma. Here we encountered an RA patient who developed extranodal NK/T-cell lymphoma, nasal type during treatment of RA with MTX and etanercept. Despite the discontinuation of MTX and etanercept, the tumor did not show any regression. Complete response was achieved after treatment with concurrent chemoradiotherapy. ML of NK-cell origin is extremely rare, while the majority of ML cases associated with RA are of B-cell origin. This report describes extranodal NK/T-cell lymphoma, nasal type case associated with RA. Such cases should be accumulated to evaluate the mechanism of onset and clinical characteristics of NK/T-cell lymphoma associated with RA.

Malignant lymphoma (ML) is frequently associated with several forms of collagen diseases such as Sjören syndrome, systemic lupus erythematodes, and rheumatoid arthritis. However, the occurrence of ML in systemic sclerosis (SSc) patients has rarely been reported. Here we report an SSc patient who developed mediastinal (thymic) large B-cell lymphoma (MLBCL). A 31-year-old woman was diagnosed as having SSc in August 2007. The patient was treated with low-dose prednisolone (10 mg/day) without any effect. One year after the diagnosis, chest computed tomography-scan demonstrated thymic tumor in the anterior mediastinum. Thymectomy was performed, and a pathohistological diagnosis of MLBCL was established. Immunohistochemical analysis demonstrated that the tumor cells were positive for CD45 and CD20, but negative for CD30 and EBV-encoded RNA. The patient was treated with 6 courses of CHOP regimen, resulting in complete remission of lymphoma. This report describes the first SSc patient associated with MLBCL. SSc patients occasionally develop ML after a relatively short interval. Our case suggests that intensive monitoring for the development of ML is needed in newly diagnosed SSc patients.

A 63-year-old male presented with fever and general malaise in June 2004. On admission hepatosplenomegaly was apparent, but without lymphadenopathy. The laboratory examination revealed pancytopenia and increased levels of lactate dehydrogenase, direct bilirubin and soluble interleukin-2 receptor. Histological analysis of the bone marrow biopsy specimen demonstrated proliferation of atypical lymphoid cells positive for CD20 in the small capillaries, leading to the diagnosis of the Asian variant of intravascular large B-cell lymphoma (AIVL). The presence of rearrangement of the immunoglobulin gene confirmed the diagnosis. The patient responded well to CHOP therapy followed by seven courses of rituximab-combined CHOP therapy and has remained in complete remission up to the present. This case implies that bone marrow biopsy could be a useful examination for diagnosing AIVL and that rituximab-combinedchemotherapy could improve survival in patients with the disease.

A 63-year-old female was diagnosed as having Philadelphia chromosome-positive acute myelomonocytic leukemia in June 2002. The patient received monotherapy with imatinib mesylate or combination therapy with DCM and idarubicin/cytarabine, both of which failed in attaining disease remission. However, the second imatinib administration plus CAG therapy resulted in disappearance of the Philadelphia chromosome-positive clone and increase of Philadelphia chromosome-negative cells. During a therapy-withholding period due to fungal infection, the Philadelphia chromosome-positive clone expanded and the patient died of cerebral hemorrhage in February 2003. The transient suppression of the Philadelphia chromosome-positive clone may have brought about amplification of the Philadelphia chromosome-negative cells after the secondary imatinib treatment.

A 26-year-old woman was diagnosed as having autoimmune hemolytic anemia in September 2002. Her eosinophil count was already high (2,190/microliter) at that time. She received prednisolone therapy with a good response and was released from the treatment in April 2003. Eosinophil numbers were within the normal range under the prednisolone administration. However, they began to increase after its completion. No underlying causes for the eosinophilia were evident. When the eosinophil count reached 5,474/microliter, the patient developed massive pleural effusion as well as palpebral swelling and myalgia, leading to a diagnosis of hypereosinophilic syndrome. Re-administration of prednisolone resulted in the disappearance of these symptoms and eosinophilia. Her eosinophils seemed to have reactivated after cessation of the prednisolone therapy and infiltrated into her organs.

A 29-year-old woman was diagnosed as having pure red cell aplasia (PRCA) in 1983. Her serum and IgG inhibited erythroid colony formation of bone marrow cells from a normal individual, suggesting antibody-mediated suppression of erythropoiesis. She was first successfully treated with corticosteroids, azathiopurine and cyclophosphamide. However, she relapsed in 1995 and her anemia became refractory to immunosuppressive therapy. In 1998, she developed systemic lymph node enlargement and was diagnosed as having B-cell small lymphocytic lymphoma. Combination chemotherapy resulted in regression of the lesion, but failed to improve the anemia. In this patient's case, we can speculate that B cells producing autoantibodies against erythroid cells have undergone transformation, or alternatively that the immunosuppressive state caused by the PRCA therapy promoted generation of a neoplastic B cell clone.

Ten patients with acute myelogenous leukemia or high risk myelodysplastic syndrome who had achieved complete remission following treatment with the CAG regimen were monitored for peripheral blood WT1 expression mRNA levels. Induction therapy with the CAG regimen did not seem to be enough to lower WT1 expression levels to the normal range. In comparison with patients who received intensive chemotherapy for post-remission therapy, those who received only CAG therapy showed higher levels of WT1 expression and more easily relapsed. These data suggest that CAG therapy alone might not be sufficient to maintain complete remission and WT1 monitoring could be useful in the choice of appropriate post-remission therapy after achieving remission with the CAG regimen.

A 25-year-old man was admitted to our hospital because of hematuria, anemia and thrombocytopenia. Laboratory examinations revealed an increased number of bone marrow megakaryocytes and an increased level of platelet-associated immunoglobulin G, suggesting immune thrombocytopenia. Computed tomography of the abdomen showed enlargement of the bilateral kidneys with multiple low-density areas, although neither lymphadenopathy nor hepatosplenomegaly was evident. After amelioration of the thrombocytopenia by prednisolone therapy, open renal biopsy was performed and a diagnosis of diffuse large B-cell non-Hodgkin's lymphoma was made. The patient achieved complete remission after CHOP therapy. This was thought to be a rare case of primary renal non-Hodgkin's lymphoma initially presenting as immune thrombocytopenia, which was treated successfully by chemotherapy.

We report a rare case of hypereosinophilic syndrome (HES) that developed to acute myeloblastic leukemia (AML). The patient, a 34-year-old man, presented with eosinophilia of unknown origin (white blood cells 38,200/microliter with 74% eosinophils) and pericardial effusion, and was diagnosed as having HES with a normal karyotype. He received four cycles of combination chemotherapy including cyclophosphamide, cytosine arabinoside and vindesine, and thereafter remained in remission. After 12 years, he was referred to our hospital because of fever and malaise. On admission, CBC showed white blood cells 3,000/microliter with 70% myeloblasts and 3% eosinophils. The bone marrow was hypercellular with 95% blasts, which were negative for myeloperoxidase (MPO) staining. Immunophenotype analysis revealed that the cells were positive for CD13, CD19, CD34, HLA-DR and cytoplasmic MPO. CD19-positive AML was diagnosed. Cytogenetic analysis showed 46, XY, t(6;21)(q13;q22), add(7)(q11) in 19 of 20 metaphase spreads. Rearrangement of the AML1 gene at 21q22 and fusion of the BCR/ABL gene could not be detected by fluorescence in situ hybridization analysis. The patient received combination chemotherapy and achieved a complete remission. Chromosome aberrations involving 7q as well as 21q22 suggested that the initial chemotherapy for HES might have been implicated in the pathogenesis of acute leukemia in this case.

We used the CAG regimen (low-dose cytarabine [10 mg/m2 per 12 hours, days 1-14], aclarubicin [14 mg/m2 per day, days 1-4], and granulocyte colony-stimulating factor [200 micrograms/m2 per day, days 1-14]) for the treatment of patients with primary resistant acute myelogenous leukemia (AML) and previously untreated elderly patients with AML, secondary AML, and refractory anemia with excess blasts in transformation (RAEB-T) in addition to relapsed AML. Forty-three of 69 (62%) patients achieved complete remission (CR), including 29 of 35 (83%) patients with relapsed AML, 1 of 8 patients with primary resistant AML, 5 of 8 elderly patients with previously untreated AML, and 8 of 18 patients with previously untreated secondary AML or RAEB-T. Ten of 22 (45%) patients > or = 65 years old achieved CR. The patients who achieved CR received at least 1 course of modified CAG therapy as the first consolidation therapy, followed by various second consolidation and intensification therapies. The median disease-free survival and overall survival were 8 and 15 months, respectively, for relapsed AML; 11 and 8 months for the elderly patients; and 8 and 17 months for secondary AML and RAEB-T. Myelosuppression was mild to moderate, and other than fever, severe nonhematologic toxicity was rare. CAG as the induction therapy seems promising for the treatment of various categories of poor-prognosis AML.