Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia.

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 (DNMT3AR882 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 DNMT3AR882 mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3AR882 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: DNMT3AR882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3AR882 mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3AR882 /FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3AR882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3AR882 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.

[Perforated upper gastrointestinal ulcers potentially attributable to mycophenolate mofetil after allogeneic hematopoietic stem cell transplantation].

A 46-year-old man with myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable underwent myeloablative bone marrow transplantation from an HLA-DR-1-antigen-mismatched related donor while receiving tacrolimus and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. However, grade III acute GVHD of the gut occurred on day 20 and was treated with prednisolone (PSL) and oral beclomethasone dipropionate while continuing MMF. Subsequently, he presented with progressive epigastric pain. Endoscopy demonstrated multiple stomach and duodenal deep ulcers. The ulcers were suspected to be GVHD; thus, the PSL dose was increased and infliximab was administered; however, the ulcers exacerbated, resulting in repeated perforations and hemorrhagic shock. Furthemore, MMF was suspected as the cause of refractory ulcers and was discontinued on day 156, which resolved the ulcers after 6 months. MMF-induced gastrointestinal (GI) injury resembles anti-inflammatory drug-related ulcers and upper and lower GI tract GVHD, respectively. MMF-induced GI injury has been reportedly resolved after discontinuing or reducing the MMF dose. Several reports suggested that refractory upper GI ulcers and rectal sparing colitis were associated with MMF toxicities rather than GVHD in hematopoietic stem cell transplantations. Physicians should be aware that MMF can induce severe GI injury.

Clinical characteristics and incidence of toxoplasmosis after autologous hematopoietic stem cell transplantation: A retrospective study and literature review.

BACKGROUND: Toxoplasmosis is a rare but life-threatening infection occurring in immunocompromised hosts, including allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. However, thus far, the clinical features and incidence of toxoplasmosis in autologous HSCT (auto-HSCT) recipients remain unknown. This retrospective survey aimed to analyze 152 patients who received auto-HSCT between 1998 and 2017. METHODS: Serological tests for Toxoplasma gondii-specific IgG were performed on 109 (71.7%) recipients, and 12 pre-HSCT recipients (11%) were Toxoplasma seropositive. Among the 12 recipients, three who did not receive trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis developed cerebral, pulmonary or disseminated toxoplasmosis due to reactivation after auto-HSCT and died despite treatment. RESULTS: The incidences of toxoplasmosis were 2% and 25% among 152 auto-HSCT recipients (five recipients received auto-HSCT two times) and 12 pre-HSCT Toxoplasma seropositive recipients, respectively. Further, we conducted a literature review and identified 21 cases of toxoplasmosis following auto-HSCT. In these previous cases, the mortality rate was high, especially for pulmonary and disseminated toxoplasmosis. Our findings suggest that, similar to toxoplasmosis after allo-HSCT, toxoplasmosis after auto-HSCT is a fatal complication. CONCLUSIONS: Serial screening of T. gondii-specific IgG before HSCT could contribute to the detection of Toxoplasma reactivation and allow for prompt diagnosis and treatment. The present study is the first to reveal the incidence of toxoplasmosis after auto-HSCT among seropositive patients in Japan.

Kinetics and clinical significance of human herpesvirus 6 DNA shedding in saliva after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Little is known about the kinetics and clinical significance of saliva human herpesvirus-6 (HHV-6) DNA after hematopoietic stem cell transplantation (HSCT). METHODS: In this observational study, we quantified HHV-6 DNA in serially collected plasma and saliva from allogeneic HSCT recipients. Associations between the status of salivary HHV-6 DNA and the development of HHV-6 encephalitis, depression, and oral mucosal graft-versus-host disease (GVHD) were retrospectively analyzed. RESULTS: A total of 787 plasma and 434 saliva samples were collected from 56 patients. The cumulative incidence of HHV-6 DNA in plasma and saliva at 60 days after transplantation was 51.8% and 83.9%, respectively. The peak level of salivary HHV-6 DNA was significantly higher in patients who displayed plasma HHV-6 DNA than in those who did not (median, 51,584 copies/mL vs 587 copies/mL; P < .0001). Salivary HHV-6 DNA levels increased after positive plasma HHV-6 DNA was detected and remained high during observation period. Despite the frequent occurrence of positive salivary HHV-6 DNA, no patient developed depression. Positivity of salivary HHV-6 DNA was not significantly associated with the development of HHV-6 encephalitis (P = 1.00, Fisher's exact test) or oral mucosal GVHD (P = .71, Grey's test). No significant relationship between salivary HHV-6 DNA and these diseases was found even when comparing higher HHV-6 DNA loads in saliva. CONCLUSION: Salivary HHV-6 DNA levels increased after HHV-6 DNA was detected in the blood. However, no epidemiological evidence was shown to support a role of salivary HHV-6 in the development of HHV-6 encephalitis, depression, and oral mucosal GVHD.

Correlations of cytokine levels in cerebrospinal fluid and peripheral blood with outcome of HHV-6B encephalitis after hematopoietic stem cell transplantation.

BACKGROUND: Human herpesvirus (HHV)-6B encephalitis has been recognized as a serious complication after allogeneic hematopoietic cell transplantation (allo-HCT). Little is known about the pathogenic mechanism for its progression. STUDY DESIGN: We retrospectively evaluated the 16 kinds of cytokines and chemokines in cerebrospinal fluid (CSF) and plasma in patients who developed HHV-6B encephalitis. Among a total of 20 patients, 12 were categorized as the poor prognosis group (died of encephalitis; n = 8 and retained sequelae; n = 4), and other eight patients were categorized as the good prognosis group (complete recovery; n = 8). RESULTS: Concentrations of CSF IL-6 and IL-8 at the onset of encephalitis were significantly higher in the poor prognosis group than in the good prognosis group (median CSF IL-6, 28.27 pg/mL vs 14.32 pg/mL, P = .004; median CSF IL-8, 128.70 pg/mL vs 59.43 pg/mL, P = .043). Regarding plasma, the concentration of each cytokine at the onset of encephalitis was not significantly different between the two groups, except IL-5. However, higher levels of IL-6, IL-7, and MCP-1 and lower levels of IL-12 were observed 1 week before the development of encephalitis in patients with poor prognosis (median IL-6; 464.17 pg/mL vs 47.82 pg/mL, P = .02; median IL-12; 1.63 pg/mL vs 6.57 pg/mL, P = .03). CONCLUSION: We found that one week before onset of HHV-6B encephalitis, poor prognosis patients had high plasma concentrations of IL-6, IL-7, and MCP-1 and low concentrations of IL-12. At the onset of encephalitis, high concentrations of IL-6 and IL-8 in CSF were more common in the poor prognosis group, consistent with other evidence that IL-6 can have a role in CNS disturbances. Our findings show that specific cytokine status is associated with severe brain damage in patients with HHV-6B encephalitis, demonstrate prognostic value of plasma IL-6 concentrations, and suggest evaluation of anti-cytokine therapeutics in patients with HHV-6B encephalitis.

Usefulness of BCOR gene mutation as a prognostic factor in acute myeloid leukemia with intermediate cytogenetic prognosis.

BCOR gene is a transcription regulatory factor that plays an essential role in normal hematopoiesis. The wider introduction of next-generation sequencing technology has led to reports in recent years of mutations in the BCOR gene in acute myeloid leukemia (AML), but the related clinical characteristics and prognosis are not sufficiently understood. We investigated the clinical characteristics and prognosis of 377 de novo AML cases with BCOR or BCORL1 mutation. BCOR or BCORL1 gene mutations were found in 28 cases (7.4%). Among cases aged 65 years or below that were also FLT3-ITD-negative and in the intermediate cytogenetic prognosis group, BCOR or BCORL1 gene mutations were observed in 11% of cases (12 of 111 cases), and this group had significantly lower 5-year overall survival (OS) (13.6% vs. 55.0%, P = 0.0021) and relapse-free survival (RFS) (14.3% vs. 44.5%, P = 0.0168) compared to cases without BCOR or BCORL1 gene mutations. Multivariate analysis demonstrated that BCOR mutations were an independent unfavorable prognostic factor (P = 0.0038, P = 0.0463) for both OS and RFS. In cases of AML that are FLT3-ITD-negative, aged 65 years or below, and in the intermediate cytogenetic prognosis group, which are considered to have relatively favorable prognosis, BCOR gene mutations appear to be an important prognostic factor.

[Miliary tuberculosis with markedly elevated soluble interleukin-2 receptor levels mimicking intravascular large B-cell lymphoma].

An 81-year-old woman with type 2 diabetes mellitus presented to our hospital due to anorexia, leg edema, and respiratory distress. Laboratory results revealed anemia, thrombocytopenia, elevated lactate dehydrogenase, and markedly elevated soluble interleukin-2 receptor levels. Computed tomography showed ground-glass opacities and consolidation in both lung fields, but no lymphadenopathy was noted. Intravascular large B-cell lymphoma (IVLBCL) was considered as a differential diagnosis; therefore, bone marrow and random skin biopsy were performed. Her respiratory condition deteriorated, with the occurrence of acute respiratory distress syndrome, disseminated intravascular coagulation, hemophagocytic syndrome, and further alveolar hemorrhage. Methylprednisolone pulse therapy was performed, but did not improve the patient's condition. On hospital day 6, the acid-fast bacterial smear of the sputum using the Gaffky scale was 2, and on the next day, tuberculosis DNA was detected in the polymerase chain reaction. In the bone marrow biopsy, multiple epithelioid cell granulomas were found; thus, the patient was diagnosed with miliary tuberculosis. Although anti-tuberculosis therapy was started immediately, she died on hospital day 22. The soluble interleukin-2 receptor level increased up to 19,400 U/ml. The differential diagnosis should be cautiously made because miliary tuberculosis can mimic IVLBCL.

[Successful cord blood transplantation for myelodysplastic syndrome with Behçet disease-like refractory stomatitis and multiple ileocecal ulcerations].

A 12-year-old boy was diagnosed with aplastic anemia. He was followed as an outpatient without medication, and his cytopenia improved after several years. When he was 26 years old, an annual medical checkup revealed leukocytopenia, and at the age of 31 years, he was diagnosed with myelodysplastic syndrome (MDS), refractory cytopenia with multilineage dysplasia. Chromosomal analysis of his bone marrow cells revealed trisomy 8. Ten months after being diagnosed with MDS, he developed refractory stomatitis. Two months later, he experienced abdominal pain and bloody stool, and simple punched-out ulcers similar to intestinal Behçet's disease (BD) were noted in the terminal ileum on colonoscopy. Steroids, mesalazine, and adalimumab were ineffective. Nineteen months after the MDS diagnosis, he underwent cord blood transplantation from an HLA 1-locus mismatched unrelated donor in accordance with a non-myeloablative pretransplant conditioning regimen. The patient's stomatitis and ileocecal ulcers improved following the transplantation. Currently, both MDS and BD-like symptoms are in complete remission at 36 months post transplantation, and the patient continues to take low-dose oral tacrolimus for chronic skin GVHD. Allogeneic hematopoietic stem cell transplantation could become a therapeutic choice for MDS associated with BD, even if refractory intestinal BD symptoms are present.

Effects of Prophylactic Foscarnet on Human Herpesvirus-6 Reactivation and Encephalitis in Cord Blood Transplant Recipients: A Prospective Multicenter Trial with an Historical Control Group.

Cord blood transplantation (CBT) is a distinct risk factor for human herpesvirus-6 (HHV-6) reactivation and HHV-6 encephalitis. In a prospective multicenter trial we investigated the effects of prophylactic foscarnet (90 mg/kg i.v. infusion from days 7 to 27 after CBT) on the occurrence of HHV-6 reactivation, HHV-6 encephalitis, and acute graft-versus-host disease (aGVHD) in CBT recipients. Between 2014 and 2016, 57 patients were included in a foscarnet-prophylaxis group. Outcomes were compared with an historical control group who received CBT between 2010 and 2014 (standard-treatment group, n = 63). The cumulative incidence of high-level HHV-6 reactivation, defined as plasma HHV-6 DNA ≥ 104 copies/mL, at 60 days after CBT was significantly lower in the foscarnet-prophylaxis group than in the standard-treatment group (18.3% versus 57.3%, P < .001). Multivariate analysis revealed that myeloablative preconditioning and standard treatment were significant risk factors for high-level HHV-6 reactivation. The cumulative incidence of HHV-6 encephalitis at 60 days after CBT was not different between the groups (foscarnet-prophylaxis group, 12.4%; standard-treatment group, 4.9%; P = .14). The cumulative incidences of grades II to IV and grades III to IV aGVHD at 60 days after CBT were not different between the groups (grades II to IV aGVHD: foscarnet-prophylaxis group, 42.0%; standard-treatment group, 40.5%; P = .96; grades III to IV aGVHD: foscarnet-prophylaxis group, 14.5%; standard-treatment group, 14.5%; P = 1.00). In the setting of this study foscarnet significantly suppressed systemic HHV-6 reactivation in CBT recipients but failed to prevent the development of HHV-6 encephalitis. Suppression of HHV-6 reactivation by foscarnet did not show any effects against the incidence of aGVHD.

Full-length mutation search of the TP53 gene in acute myeloid leukemia has increased significance as a prognostic factor.

TP53 gene abnormality has been reported to be an unfavorable prognostic factor in acute myeloid leukemia (AML). However, almost all studies of TP53 gene abnormality so far have been limited to mutation searches in the DNA binding domain. As there have been few reports examining both mutation and deletion over the full-length of the TP53 gene, the clinical characteristics of TP53 gene abnormality have not yet been clearly established. In this study, TP53 gene mutation was observed in 7.3% of the total 412 de novo AML cases (33 mutations in 30 cases), with mutation outside the DNA binding domain in eight cases (27%). TP53 gene deletion was observed in 3.1% of 358 cases. All cases had monoallelic deletion with TP53 gene mutation on the opposite allele. Multivariate analysis demonstrated that TP53 gene mutation in the DNA binding domain and outside the DNA binding domain was an independent poor prognostic factor for overall survival and relapse-free survival among the total cohort and it is also an unfavorable prognostic factor in FLT3-ITD-negative AML cases aged 70 years or below with intermediate cytogenetic prognosis. In stratified treatment, full-length search for TP53 gene mutation is therefore very important.

[Successful treatment with mecobalamin in a pernicious anemia patient presenting with false-normal serum vitamin B12].

An 81-year-old woman presented to our hospital with anemia. Complete blood counts revealed macrocytic anemia; however, serum vitamin B12 and folate levels were normal. Bone marrow aspiration revealed multilineage dysplasia, and the patient was initially diagnosed with refractory cytopenia and multilineage dysplasia subtype of myelodysplastic syndrome. However, blood smear revealed hypersegmented neutrophils and bone marrow aspiration showed remarkable megaloblastic changes of erythroid cells. Based on these findings, the patient was administered 1,500 µg mecobalamin per day on a trial basis. Three weeks after initiating mecobalamin, macrocytic anemia improved. Her hemoglobin levels were also normalized along with immediate resolution of peripheral blood dysplasia. The final diagnosis was pernicious anemia (PA) based on anti-intrinsic factor positivity and the efficacy of mecobalamin. Use of automated analyzers may be associated with falsely normal or falsely elevated vitamin B12 levels in the presence of anti-intrinsic factor antibodies. Our case suggests that trial administration of mecobalamin may be an important step to correctly diagnose PA associated with falsely normal or falsely elevated vitamin B12 levels, particularly when typical morphological features of PA are present.

[Clinical characteristics of vascular adverse events and significance of peripheral artery disease as a risk factor in chronic myeloid leukemia patients treated with nilotinib].

Vascular adverse events (VAEs) in chronic myeloid leukemia (CML) patients treated with nilotinib (NIL) has become a; however, studies on strategies to prevent VAEs remain limited. Therefore, the present study investigated VAEs in 19 CML patients treated with NIL at our hospital. The median age of the patients was 65 years and median follow-up period was 55 months after the initiation of NIL. VAEs occurred in 8 patients (peripheral artery disease (PAD), n=6; cerebral infarction (CI), n=3; coronary artery disease (CAD), n=4). The median elapsed time from the initiation of NIL to VAEs was 42 months. The 4-year cumulative incidence of VAEs was 23.5%. Majority of the patients with VAEs were smokers (P=0.074). All the six patients with PAD were diagnosed on the basis of the ankle-brachial index (ABI<0.9) in the asymptomatic phase; 4 of these patients had other VAEs (CI, n=1; CAD, n=2; CI and CAD, n=1). However, antecedent asymptomatic PAD was diagnosed even before CAD was diagnosed in two patients. Nevertheless, in cardiology, extensive studies have indicated that asymptomatic PAD is a risk factor for the development of cardiovascular events. In conclusion, for the effective management of CML patients treated with NIL, a routine screening with ABI to diagnose asymptomatic PAD may be beneficial in preventing severe VAEs.

[Neurolymphomatosis due to enteropathy-associated T-cell lymphoma clinically diagnosed by FDG-PET/CT and subsequently confirmed by autopsy].

A 59-year-old man who complained of abdominal pain was referred to our hospital. Computed tomography (CT) revealed mesenteric lymph node swelling and intestinal perforation. Histopathological study of the resected ileum and lymph node demonstrated diffuse proliferation of medium-sized atypical lymphocytes. Immunohistochemistry results were positive for cluster of differentiation (CD) 3, CD8, and CD56 cells, negative for CD5 and CD4 cells, and negative for Epstein-Barr virus-encoded RNA-fluorescent in situ hybridization (EBER-FISH). It also revealed the expression of γδ T-cell receptors. On the basis of these findings, enteropathy-associated T-cell lymphoma (EATL) was diagnosed. Although the patient received two courses of cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) therapy, facial nerve and lower limb paralysis manifested. Magnetic resonance imaging (MRI) and lumbar puncture revealed central nervous system invasion of the EATL. Despite intrathecal chemotherapy and high-dose cytarabine therapy, the patient's neurological symptoms deteriorated. Fluorodeoxyglucose positron emission tomography (FDG-PET) /CT scan showed the accumulation of FDG along both median and sciatic nerves, and he was diagnosed with neurolymphomatosis (NL). He died on day 120 after admission. Autopsy specimens exhibited infiltration of lymphoma cells in the median and sciatic nerves. Although only one case of suspected NL in a patient with type 2 EATL has been previously reported, we clinically diagnosed NL using FDG-PET/CT and confirmed the diagnosis by autopsy. This case is valuable in terms of the pathological diagnosis of NL.

D816 mutation of the KIT gene in core binding factor acute myeloid leukemia is associated with poorer prognosis than other KIT gene mutations.

The clinical impact of KIT mutations in core binding factor acute myeloid leukemia (CBF-AML) is still unclear. In the present study, we analyzed the prognostic significance of each KIT mutation (D816, N822K, and other mutations) in Japanese patients with CBF-AML. We retrospectively analyzed 136 cases of CBF-AML that had gone into complete remission (CR). KIT mutations were found in 61 (45%) of the patients with CBF-AML. D816, N822K, D816 and N822K, and other mutations of the KIT gene were detected in 29 cases (21%), 20 cases (15%), 7 cases (5%), and 5 cases (4%), respectively. The rate of relapse-free survival (RFS) and overall survival (OS) in patients with D816 and with both D816 and N822K mutations was significantly lower than in patients with other or with no KIT mutations (RFS: p < 0.001, OS: p < 0.001). Moreover, stratified analysis of the chromosomal abnormalities t(8;21)(q22;q22) and inv(16)(p13.1q22), t(16;16)(p13.1;q22) showed that D816 mutation was associated with a significantly worse prognosis. In a further multivariate analysis of RFS and OS, D816 mutation was found to be an independent risk factor for significantly poorer prognosis. In the present study, we were able to establish that, of all KIT mutations, D816 mutation alone is an unfavorable prognostic factor.

Successful management of intraperitoneal bleeding with platelet apheresis and von Willebrand factor supplementation in a patient with essential thrombocythemia and acquired von Willebrand syndrome.

A 36-year-old woman with essential thrombocythemia (ET) was admitted to our hospital for acute lower abdominal pain. Given no family history of bleeding disorder, she was diagnosed with acquired von Willebrand syndrome. Despite having a medical history of venous thrombosis, she had never been treated for ET because of her preferences. On admission, CT scan revealed massive hemorrhage in the ascending colon with the leakage of a contrast agent. Furthermore, a delayed enhancement of fluid collection in the Douglas fossa followingcontrast CT indicated bloody ascites. Laboratory data revealed elevated platelets (1,569×103/µl) and reduced von Willebrand factor (VWF) :RCo (32%) and VWF:Ag (48%). Platelet apheresis was initiated, combined with the infusion of VWF-containing concentrates and cytoreductive therapy with hydroxyurea. Three days after admission, her platelet count decreased to 992×103/µl after the second round of platelet apheresis. CT scan revealed no hemorrhage, which implied hemostasis. Because of the absence of symptoms, she was discharged 23 days after admission. These results suggest that platelet apheresis, combined with infusion of VWF-containing concentrates and cytoreductive therapy with hydroxyurea, is an effective approach for the treatment of acquired von Willebrand syndrome characterized by emergent bleeding concomitant with ET.

Cyclic thrombocytopenia synchronizing with the menstrual cycle showing periodic phases of thrombocytopenia and rebound thrombocytosis.

A 37-year-old woman was admitted to our hospital for purpura involving the extremities and thrombocytopenia. Prednisolone (PSL) was administered based on a diagnosis of idiopathic thrombocytopenic purpura (ITP), but was not effective for maintaining her platelet count within the normal range, which showed cyclic fluctuation corresponding to the menstrual cycle. Therefore, we discontinued PSL, and cyclic thrombocytopenia (CTP) was diagnosed. CTP is a rare disease which is usually treated as ITP but with no response. Although the exact cause of CTP is uncertain, in our case, a hormonal mechanism may be responsible for fluctuating platelet count.

Multicentric Castleman's disease with multiple hepatic mass lesions mimicking malignant liver tumors.

Multicentric Castleman's disease (MCD) is a rare, non-malignant lymphoproliferative disorder. We report a case of MCD with multiple liver masses. A 26-year-old woman presented with asymptomatic anemia and hypoalbuminemia. Laboratory tests detected high CRP levels and findings indicative of polyclonal gammopathy. Abdominal CT revealed multiple hepatic large masses (≤10 cm) and partial calcification in the right lobe. Multiple enlarged lymph nodes were also identified in the cardiophrenic angle and porta hepatis. We suspected hepatic malignancy, but pathological examinations of the liver and lymph nodes demonstrated polyclonal plasma cell infiltration and fibrosis. IL-6 staining was positive for plasma cell infiltration of lymph nodes. A few plasma cells were positive for IgG4, and tests for HIV and HHV-8 were negative. Serum IL-6 and plasma VEGF levels were both elevated (45 and 536 pg/ml, respectively). The patient was diagnosed with plasma cell type MCD. We started treatment with PSL 1 mg/kg/day, which led to improvement of anemia, hypoalbuminemia, and high CRP levels. Marginal regression of liver masses was also observed. At the last follow-up, the patient had been progression-free for 18 months. To our knowledge, this is the first report of a plasma cell type MCD with liver masses.

Decision Analysis of Postremission Therapy in Cytogenetically Intermediate-Risk Acute Myeloid Leukemia: The Impact of FLT3 Internal Tandem Duplication, Nucleophosmin, and CCAAT/Enhancer Binding Protein Alpha.

We performed a decision analysis comparing allogeneic hematopoietic cell transplantation (allo-HCT) versus chemotherapy in first complete remission for patients with cytogenetically intermediate-risk acute myeloid leukemia, depending on the presence or absence of FLT3-internal tandem duplication (ITD), nucleophosmin (NPM1), and CCAAT/enhancer binding protein alpha (CEBPA) mutations. Adjusted means of the patient-reported EQ-5D index were used as quality-of-life (QOL) estimates. In 332 patients for which FLT3-ITD status was available, FLT3-ITD was present in 60. In 272 patients without FLT3-ITD, NPM1 mutations were present in 83. CEBPA biallelic mutations were detected in 53 patients. For patients harboring FLT3-ITD, allo-HCT improved life expectancy (LE) (52 versus 32 months during 10-year observation) and QOL-adjusted life expectancy (QALE, 36 versus 21). Monte-Carlo simulation identified allo-HCT as the favored strategy in 100% of simulations. In patients without FLT3-ITD, allo-HCT improved LE/QALE with or without NPM1 mutations. However, sensitivity analyses showed that the results were not robust enough. For patients harboring CEBPA biallelic mutations, chemotherapy was favored (LE, 53 versus 84; QALE, 37 versus 59), whereas, for patients with monoallelic mutations or wild-type CEBPA, allo-HCT was favored (LE, 68 versus 54; QALE, 48 versus 37). Sensitivity analyses did not change the results in either group. In conclusion, based on a Markov decision analysis, allo-HCT was a favored postremission strategy in patients with FLT3-ITD, and chemotherapy was favored in patients with biallelic CEBPA mutations. A prospective study is warranted to determine the value of allo-HCT, especially in FLT3-ITD-negative patients.

Clinical characteristics and prognosis of acute myeloid leukemia associated with DNA-methylation regulatory gene mutations.

In recent years, it has been reported that the frequency of DNA-methylation regulatory gene mutations - mutations of the genes that regulate gene expression through DNA methylation - is high in acute myeloid leukemia. The objective of the present study was to elucidate the clinical characteristics and prognosis of acute myeloid leukemia with associated DNA-methylation regulatory gene mutation. We studied 308 patients with acute myeloid leukemia. DNA-methylation regulatory gene mutations were observed in 135 of the 308 cases (43.8%). Acute myeloid leukemia associated with a DNA-methylation regulatory gene mutation was more frequent in older patients (P<0.0001) and in patients with intermediate cytogenetic risk (P<0.0001) accompanied by a high white blood cell count (P=0.0032). DNA-methylation regulatory gene mutation was an unfavorable prognostic factor for overall survival in the whole cohort (P=0.0018), in patients aged ≤70 years, in patients with intermediate cytogenetic risk, and in FLT3-ITD-negative patients (P=0.0409). Among the patients with DNA-methylation regulatory gene mutations, 26.7% were found to have two or more such mutations and prognosis worsened with increasing number of mutations. In multivariate analysis DNA-methylation regulatory gene mutation was an independent unfavorable prognostic factor for overall survival (P=0.0424). However, patients with a DNA-methylation regulatory gene mutation who underwent allogeneic stem cell transplantation in first remission had a significantly better prognosis than those who did not undergo such transplantation (P=0.0254). Our study establishes that DNA-methylation regulatory gene mutation is an important unfavorable prognostic factor in acute myeloid leukemia.

[Discordant lymphoma of duodenal EBV-positive peripheral T-cell lymphoma not otherwise specified and ileal diffuse large B-cell lymphoma].

A 79-year-old woman was admitted with a 5-kg weight loss and anorexia. Computed tomography showed diffuse lymphadenopathy, and thickening of the duodenal and ileal walls. The patient then underwent biopsy of these sites. Pathological examination revealed duodenal Epstein-Barr virus (EBV)-positive peripheral T cell lymphoma-not otherwise specified (PTCL-NOS) and EBV-negative ileal diffuse large B-cell lymphoma (DLBCL) to be present simultaneously. Combination chemotherapy including rituximab produced a reduction of the duodenal EBV-positive PTCL-NOS lesion, but had no effect on the EBV-negative ileal DLBCL lesion. Thereafter, new lymphadenopathy, high fever, and lactate dehydrogenase (LD) elevation developed, complicated by pneumonia. The patient died due to rapid deterioration of the lymphoma and pneumonia on day 108 after initiation of treatment. EBV-positive PTCL-NOS is reportedly rare and the prognosis is poor. Moreover, EBV-negative ileal DLBCL was diagnosed simultaneously. This case is considered to have had an extremely rare discordant lymphoma, although the exact etiology of its development remains unknown. We speculate that age-related disorders of the immune system and HCV infection may have been associated with the pathogenic mechanism of lymphomagenesis in this case.