Yutaka Shimazu

Central nervous system event in patients with diffuse large B-cell lymphoma in the rituximab era

Central nervous system (CNS) events, including CNS relapse and progression to CNS, are known to be serious complications in the clinical course of patients with lymphoma. This study aimed to evaluate the risk of CNS events in patients with diffuse large B‐cell lymphoma in the rituximab era. We performed a retrospective survey of Japanese patients diagnosed with diffuse large B‐cell lymphoma who underwent primary therapy with R‐CHOP chemoimmunotherapy between September 2003 and December 2006. Patients who had received any prophylactic CNS treatment were excluded. Clinical data from 1221 patients were collected from 47 institutions. The median age of patients was 64 years (range, 15–91 years). We noted 82 CNS events (6.7%) and the cumulative 5‐year probability of CNS events was 8.4%. Patients with a CNS event demonstrated significantly worse overall survival (P < 0.001). The 2‐year overall survival rate after a CNS event was 27.1%. In a multivariate analysis, involvement of breast (relative risk [RR] 10.5), adrenal gland (RR 4.6) and bone (RR 2.0) were identified as independent risk factors for CNS events. We conclude that patients with these risk factors, in addition to patients with testicular involvement in whom CNS prophylaxis has been already justified, are at high risk for CNS events in the rituximab era. The efficacy and manner of CNS prophylaxis in patients for each involvement site should be evaluated further. (Cancer Sci 2012; 103: 245–251)

Human herpesvirus-6 encephalitis during hematopoietic stem cell transplantation leads to poor prognosis

Indications for the application of hematopoietic stem cell transplantation (HSCT) from alternative donors have remarkably broadened in scope; however, the incidence of infections that lead to failure of HSCT, such as human herpesvirus‐6 (HHV‐6) encephalitis, has also increased.

Graft‐Versus‐Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal/Stem Cell‐Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations

A substantial proportion of patients with acute graft‐versus‐host disease (aGVHD) respond to cell therapy with culture‐expanded human bone marrow mesenchymal stromal/stem cells (BM‐MSCs). However, the mechanisms by which these cells can ameliorate aGVHD‐associated complications remain to be clarified. We show here that BM‐MSC‐derived extracellular vesicles (EVs) recapitulated the therapeutic effects of BM‐MSCs against aGVHD. Systemic infusion of human BM‐MSC‐derived EVs prolonged the survival of mice with aGVHD and reduced the pathologic damage in multiple GVHD‐targeted organs. In EV‐treated GVHD mice, CD4+ and CD8+ T cells were suppressed. Importantly, the ratio of CD62L‐CD44+ to CD62L + CD44‐ T cells was decreased, suggesting that BM‐MSC‐derived EVs suppressed the functional differentiation of T cells from a naive to an effector phenotype. BM‐MSC‐derived EVs also preserved CD4 + CD25 + Foxp3+ regulatory T cell populations. In a culture of CD3/CD28‐stimulated human peripheral blood mononuclear cells with BM‐MSC‐derived EVs, CD3+ T cell activation was suppressed. However, these cells were not suppressed in cultures with EVs derived from normal human dermal fibroblasts (NHDFs). NHDF‐derived EVs did not ameliorate the clinical or pathological characteristics of aGVHD in mice, suggesting an immunoregulatory function unique to BM‐MSC‐derived EVs. Microarray analysis of microRNAs in BM‐MSC‐derived EVs versus NHDF‐derived EVs showed upregulation of miR‐125a‐3p and downregulation of cell proliferative processes, as identified by Gene Ontology enrichment analysis. Collectively, our findings provide the first evidence that amelioration of aGVHD by therapeutic infusion of BM‐MSC‐derived EVs is associated with the preservation of circulating naive T cells, possibly due to the unique microRNA profiles of BM‐MSC‐derived EVs. Stem Cells 2018;36:434–445

The standard international prognostic index for predicting the risk of CNS involvement in DLBCL without specific prophylaxis

Abstract Central nervous system (CNS) involvement is a serious complication in patients with diffuse large B-cell lymphoma (DLBCL) and evaluating CNS risk is an important issue. Using the standard international prognostic index (IPI) and CNS-IPI, a recently proposed model including IPI risk factors and adrenal/kidney involvement, we assessed CNS risk in 1220 untreated DLBCL patients who received R-CHOP without prophylaxis. According to the standard IPI, the cumulative incidences of CNS involvement at 2 years were 1.3, 4.6, 8.8, and 12.7% in the low-, low-intermediate-, high-intermediate-, and high-risk groups, respectively (p <.001). This result is comparable with that of the CNS-IPI. Patients with breast involvement tended to have lower risk according to the standard IPI but showed frequent CNS involvement, similar to patients with testis involvement. The standard IPI is also a useful predictor of CNS involvement. Patients with breast/testis involvement would be candidates for prophylaxis regardless of the standard IPI risk.

Acute pancreatitis as a side effect of anagrelide hydrochloride hydrate: a case report.

Dear Editor, A 79-year-old Japanese woman was admitted to our clinic with thrombocytosis. No medical history for other chronic diseases or alcohol intake was noted. Platelet count was 1144 × 10/L. Bone marrow aspiration and biopsy showed normal cellularity and an increased number of megakaryocytes of normal size and morphology. The platelet production was vigorous, which was compatible with essential thrombocytosis (ET). JAK2 mutation (V617F) was positive. Treatment with hydroxycarbamide (500 mg/day) and aspirin was started. Doses were adjusted and thrombocytosis was well under control. Two and a half years later, her thrombocytes increased to 434 × 10/L. Due to general malaise, a possible side effect of hydroxycarbamide, she refused to have the doses adjusted. Instead, she chose to take oral anagrelide hydrochloride 0.5 mg capsule two times daily. Three weeks later, she was admitted to the hospital because of mild abdominal pain with rebound tenderness. Computed tomography of the abdomen showed diffuse swelling of the pancreas and turbid surrounding fat tissue with ascites. Blood tests showed a total white cell count of 4.6 × 10/ L, hemoglobin level of 111 g/L, and platelet count of 121 × 10/ L. C-reactive protein level was 1.8 mg/L, and amylase level was elevated to 917 U/L. She was diagnosed with acute pancreatitis (Ranson score of 2 points) and hospitalized. All the medications (anagrelide and aspirin) were discontinued. She received about 2 L of fluid transfusion, gabexate mesilate, antibiotics, and a proton pomp inhibitor. She recovered completely without any complications. Amylase level decreased to normal levels 4 days after admission. Her platelet count increased to 406× 10/L at day 7, and hydroxycarbamide and aspirin were readministered. Her thrombocytosis was well control led by treatment with adjusted doses of hydroxycarbamide. She did not show any exacerbation of pancreatitis during more than 1.5 years of outpatient clinic follow-up. Anagrelide is an inhibitor of phosphodiesterase III (PDE3) activity and has been used for the treatment of ET [1–3]. Headache (44%) and palpitation (26%) are common side effects of anagrelide. Other gastrointestinal side effects include diarrhea (26 %), abdominal pain (17 %), nausea (17 %), and vomiting (10 %). Previously, pancreatitis as a side effect of anagrelide has been reported in only one case report [4]. However, in the previous case, the etiology of thrombocytosis was unknown, and amylase level was not elevated during the pancreatitis period, which is atypical in drug-induced pancreatitis [5]. Because abdominal pain was frequently reported as a side effect, pancreatitis might be underdiagnosed in clinical studies. The diagnosis of drug-induced pancreatitis is often challenging to the clinician. Although rechallenging the doubtable drug is the gold standard to confirm a casual association, the diagnosis is usually based on excluding all other causes [5–7]. In our case, we concluded that anagrelide was the cause of pancreatitis by excluding other causes. We treated the patient following Japanese guidelines for acute pancreatitis treatment [7]. In conclusion, we should be alert to the possibility of acute pancreatitis as a rare but severe side effect of anagrelide. * Yutaka Shimazu shimazuy@frontier.kyoto-u.ac.jp

Existence of JAK2 mutation 19 years prior to the development of overt polycythemia vera

A 54‐year‐old Japanese man was admitted to Yamato Koriyama Hospital with anemia. He had undergone a total gastrectomy for gastric cancer at the age of 46. He had been taking only valproic acid for epilepsy from the age of 47. Blood tests on admission showed megaloblastic anemia: red blood cell (RBC) count 1.89 × 10/L, hemoglobin 8.6 g/dl, mean corpuscular volume 130.8 fl, white blood cell (WBC) count 7.1 × 10/L and platelet count 190 × 10/L. Other laboratory tests revealed lactate dehydrogenase 660 IU/L (normal range 120‐230), serum B12 91 pg/mL (normal range 233‐914), and folic acid 7.2 ng/mL (normal range 3.6‐12.9). He was examined as having vitamin B12‐deficient megaloblastic anemia. He was repeatedly treated with intramuscular vitamin B12. His reticulocytes and hemoglobin recovered to a satisfactory level. Twelve years later, at the age of 65, the patient’s RBC and WBC started to increase. When he became 67, his RBC count was elevated to 6.24 × 10/L, hemoglobin was 15.7 mg/dl, the WBC count was 13.6 × 10/L, and the platelet count was 401 × 10/L. The serum erythropoietin level was not elevated. Bone marrow aspiration showed trilineage hyperplasia with no obvious dysplasia. JAK2 mutation (V617F) was positive. He was examined as having polycythemia vera (PV), and hydroxycarbamide (500 mg/day) was started. His PV was well controlled by the administration of hydroxycarbamide. Vitamin B12‐deficient megaloblastic anemia can be caused by several factors: gastric abnormalities such as those due to a gastrectomy or chronic atrophic gastritis (Type A), intestinal disorders, medications, and hereditary causes. Pernicious anemia (PA) is caused by a lack of intrinsic factors, mainly due to autoimmune disease, leading to vitamin B12 deficiency. Since 1927, approx. 40 cases in which PV occurred secondary to PA have been reported, and in most of the cases, PV occurred a few months after the treatment of PA, so it is suggested that the PV existed before the PA. No casual relation between PA and PV has been identified. There is a single report of myeloproliferative disease (MPD) complicated by megaloblastic anemia. In our patient’s case, there were no signs of PV when his vitamin B12‐deficient megaloblastic anemia was diagnosed. We analyzed the DNA from a gastrectomy tissue sample and identified the JAK2 mutation (V617F). Since JAK2 mutation (V617F) is not observed in gastric cancer or in the germ line, we interpreted this result as showing that

Non-severe form of severe fever with thrombocytopenia syndrome (SFTS)

Dear Editor, A 78-year-old Japanese womanwas referred to our hospital due to neutropenia and thrombocytopenia. She had experienced a high fever (39–40 °C) for 1 week before admission. She had received antibiotic orally or intravenously for 1 week at other clinic, without effect. Because of the patient’s neutropenia and thrombocytopenia, she was transferred to our hospital with the suspicion of sepsis. She had a > 10-year history of hypertension and had taken antihypertensive drugs. She was admitted to our hematological department for further investigation. The physical exam upon admission showed blood pressure 102/65 mmHg, heart rate 77/min, body temperature 36.6 °C, respiratory rate 24/min, and SpO2 95% at room air with clear consciousness. There were no apparent tick-bite site and any lymphadenopathy. Blood tests showed severe leukocytopenia and thrombocytopenia: red blood cell (RBC) count 4.42 × 10/L, hemoglobin 13.9 g/dL, white blood cell (WBC) count 0.8 × 10/L (reference range [r.r.] 40–70), and platelet count 42 × 10/L (r.r. 15–40). Atypical lymphocytes (11% among WBCs) and defect of granules in granulocytes were observed in her peripheral blood smear. Other laboratory tests revealed elevated aspartate aminotransferase 133 U/L (r.r. 5–40), alanine aminotransferases 48 U/L (r.r. 5–35), lactate dehydrogenase 384 IU/L (r.r. 106–211), total bilirubin level 0.5 mg/dL, serum creatinine 0.63 mg/dL, c-reactive protein 0.01 mg/dL, and mild elevated ferritin level 240.8 ng/mL (r.r. 10–60). As she showed bicytopenia, a bone marrow aspiration was performed to rule out possible hematological malignancies. Bone marrow examination revealed an increase of atypical lymphocytes (approx. 40% of total nucleated cell count (6000/μL)) but there was no evidence of hematological malignancy or hemophagocytosis. From these results, virus infection was suspected; however, hepatitis type B virus, hepatitis C type virus, human immunodeficiency virus, human T cell leukemia virus type 1, and herpes simple virus were all negative. The blood testing for cytomegalovirus and Epstein-Barr virus showed a prior infection pattern. The patient’s fever continued after admission. Other than fever, she was doing well. We performed blood culture tests and treated her with NSAIDs without using antibiotics. Her family members told us that she was living in a house with wild mice, and that she frequently worked outside on farmland. From this medical history, we suspected that she had possible zoonosis. As severe thrombocytopenia and leukocytopenia without anemia were detected, the diagnosis of severe fever with thrombocytopenia syndrome (SFTS) was suspected, and we had performed a polymerase chain reaction analysis for SFTS virus using peripheral blood. Her fever was sustained for one more day, after which she was de-fevered. The test for SFTS virus revealed a positive result, confirming the diagnosis of * Yutaka Shimazu yshimazu@kankyo.ne.jp

Hyponatremia in a multiple myeloma patient treated with bortezomib.

Hematologists often encounter electrolyte disturbances such as hyponatremia during chemotherapy. Hyponatremia can be elicited by several mechanisms: renal or extra‐renal sodium loss, fluid hyper‐ infusion or excessive water intake, and endocrine disorders such as hypothyroidism, adrenal insufficiency, and syndrome of inappropriate antidiuretic hormone (SIADH), which may be associated with pulmonary infection or tumor, disorders in the central nervous system, and concomitant medication. Severe hyponatremia can lead to life‐threatening events. Here, we report marked hyponatremia in a patient being treated with bortezomib. A 64‐year‐old Japanese man was admitted to our clinic with recurrent costal bone fractures. One month before admission, he developed appetite loss and lost 3 kg of weight. His body mass index on admission was 14.9. He had a history of retinitis pigmentosa with blindness. On admission, laboratory findings showed hemoglobin 8.2 g/dL, albumin 4.3 g/dL, creatinine 1.77 mg/dL, sodium 130 mEq/L (normal range: 135‐148 mEq/L), calcium 9.5 mg/dL, IgG 5,568 mg/dL (normal range: 870‐1700mg/dL). Protein electrophoresis showed amonoclonal peak, and β2‐microglobulin was 18.4 mg/L (normal range: 0.9‐1.9). A bone marrow examination revealed that 90% of nucleated cells were myeloma cells with unbalanced κ‐ and λ ‐type immunoglobulin. We diagnosed the IgG‐κ type of multiple myeloma stage III disease (International Staging System) with symptoms. He was treated with bortezomib (1.3 mg/m on days 1, 4, 8 and 11) and oral dexamethasone (20 mg on days 1, 4, 8 and 11). Because of the patients thrombocytopenia, the administration of bortezomib and dexamethasone scheduled for day 11 was canceled. During the 1st course of treatment, the serum sodium level decreased to 125 mEq/L, and the patient had appetite loss. He was treated with fluid intake restriction (800 mL/day) and sodium chloride supplementary intake (12 g/day). The 2nd course of bortezomib was started on day 35 after the patient had recovered from the bone marrow suppression. On the second day after the patient was discharged, he was hospitalized again due to fever. The laboratory testing showed white blood cells 5.9 × 10/L, creatinine 0.57 mg/dL, sodium 110 mEq/L, potassium 3.2 mEq/L, and C‐reactive protein 0.5 mg/L. Liver function was normal. Other specific test results were as follows: blood osmolality 248 mOsm/kgH2O, thyroid function normal, non‐suppressed ADH levels (2.4 pg/mL) and normal brain natriuretic peptide (15.2 pg/mL). A urine examination revealed elevated osmolality (525 mOsm/kgH2O)

Idiopathic hypereosinophilic syndrome manifesting with eosinophilic cholecystitis and recurrent gastroenteritis

Dear Editor, A 75-year-old Japanese woman was admitted to our hospital with epigastric pain. Prior to the admission, she had experienced flu-like symptoms for 1 week. She also had a history of hypertension and hyperlipidemia diagnosed when she was 60 years old, and she was treated with an αβ blocker and statin. Blood laboratory tests on admission showed marked eosinophilia: white blood cell (WBC) count 16.8 × 10/L and eosinophil count 2.8 × 10/L. Other tests revealed lactate dehydrogenase (LDH) 251 IU/L (normal range 120–230) and C-reactive protein 4.6 mg/L (normal range 0–0.3). We diagnosed infectious enteritis and treated the patient with fluid replacement. On the third day of fluid administration, an upper gastrointestinal endoscopy was performed. Chronic gastritis was observed in the body of the stomach, and a biopsy revealed marked infiltration by eosinophils. The patient had eosinophilic gastroenteritis. On the eighth day, her WBC and eosinophil count further increased to 28.8 × 10 and 23.6 × 10/L, respectively. A bone marrow biopsy revealed a significant increase of eosinophilic cells (63% of all granulocytes), but myeloblasts accounted for only 0.6% of the granulocytes. Fusion of Fip1-like1 (FIP1L1) and platelet-derived growth factor receptor alpha (PDGFRA) genes was not detected by fluorescence in situ hybridization. We did not investigate other infrequent genemutations such as PDGFß, FGF, and bcr/abl. Other condit ions that could lead to secondary hypereosinophilia such as drug hypersensitivity reactions, helminth infection, and paraneoplastic syndromes were excluded. IgG4-related disease with eosinophilia was less likely, since the serum levels of IgG was normal and there were scanty infiltration by IgG4-positive plasma cells in the gastric specimens. She was diagnosed as having idiopathic hypereosinophilic syndrome (HES). Her eosinophilia persisted but her symptoms spontaneously resolved, and she was thus discharged without treatment. As her symptoms resolved, the eosinophilia gradually decreased (Fig. 1). Ten months later, she developed recurrent eosinophilic gastroenteritis with sustained diarrhea. Prior to the diarrhea, she had flu-like symptoms. The diarrhea recovered spontaneously without treatment. Three years later, she was admitted to our hospital for fever. Blood laboratory tests showed hypereosinophilia:WBC count 49.9 × 10/L and eosinophil count 42.4 × 10/L. Other tests revealed LDH 660 IU/L, aspartate aminotransferase alanine 57 IU/L (normal range 13–30), aminotransferase 117 IU/L (normal range 6–30), alkaline phosphatase 959 IU/L (normal range 115–340), and C-reactive protein 8.1 mg/L. Subserosal edema of the gallbladder wall was detected by an abdominal computed tomographic scan. She was diagnosed as having acute necrotizing cholecystitis, and an emergency cholecystectomy was performed. After the surgery, the patient’s symptoms gradually resolved and her WBC and eosinophilic count decreased to 7.9 × 10 and 1.4 × 10/L, respectively (Fig. 1). The pathological diagnosis was eosinophilic cholecystitis. Four months * Yutaka Shimazu shimazuy@frontier.kyoto-u.ac.jp