Isao Yoshida

Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV‐8‐negative multicentric Castleman disease

Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi‐organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus‐8 (HHV‐8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV‐8‐negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese‐born and two US‐born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23–72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed. Am. J. Hematol. 91:220–226, 2016.

Severe bleeding tendency caused by leukemic infiltration and destruction of vascular walls in chronic neutrophilic leukemia

Bleeding is reportedly one of the major causes of death in patients with chronic neutrophilic leukemia (CNL), but thrombocytopenia, abnormal platelet functions, or coagulopathy has been confirmed to be the cause of the bleeding tendency in only a small proportion of the patients. We report the case of a 49-year-old woman with CNL who experienced episodes of cutaneous and recurrent multiple cerebral hemorrhages without severe thrombocytopenia,detectable abnormal platelet functions, or coagulating dysfunction. Histological examination of specimens obtained at autopsy showed extensive infiltration and destruction of vascular walls by leukemic cells, which could explain her severe bleeding tendency.This study is the first to clearly show that the infiltration and destruction of vascular walls by leukemic cells can cause fatal bleeding episodes without warning from laboratory findings. Further studies are needed to elucidate the mechanism of the infiltration and destruction of blood vessels by CNL cells and to develop effective measures to control the growth and infiltration of CNL cells.

Transient respiratory disturbance by granulocyte–colony‐stimulating factor administration in healthy donors of allogeneic peripheral blood progenitor cell transplantation

BACKGROUND:  Allogeneic peripheral blood progenitor cell (PBPC) transplantation requires granulocyte–colony‐stimulating factor (G‐CSF) administration to mobilize PBPCs in healthy donors. The effects of G‐CSF on pulmonary functions, however, have not been clearly elucidated in PBPC donors.

Antisense oligodeoxynucleotides to latent membrane protein 1 induce growth inhibition, apoptosis and Bcl-2 suppression in Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cells, but not in EBV-positive natural killer cell lymphoma cells.

Epstein‐Barr virus (EBV)‐encoded latent membrane protein 1 (LMP‐1) is essential for immortalization of B cells by EBV, protects the infected cells from apoptotic cell death and induces Bcl‐2 expression. Suppression of LMP‐1 expression by antisense oligodeoxynucleotides (AS‐oligo) to LMP‐1 inhibits proliferation, promotes apoptosis and suppresses Bcl‐2 expression in EBV‐transformed B cells. However, the function of LMP‐1 expression in EBV‐positive natural killer (NK) cell lymphoma cells has not been reported previously. We examined the function of LMP‐1 in two EBV‐positive NK cell lymphoma cell lines (NK‐YS and YT) through suppressing LMP‐1 expression by AS‐oligo to LMP‐1. The AS‐oligo to LMP‐1 suppressed LMP‐1 mRNA and protein expression in two EBV‐positive NK cell lymphoma cell lines, as well as in an EBV‐transformed B‐cell line (CMG‐1). Proliferation was inhibited, apoptosis was induced and Bcl‐2 expression was suppressed in CMG‐1 cells, but none of these events were observed in NK‐YS or YT cells. These results suggest that proliferation, inhibition of apoptosis and Bcl‐2 expression in EBV‐positive NK cell lymphoma cells are not directly regulated by LMP‐1 as in EBV‐transformed B‐cell lines, but are probably mediated through other signal transducing systems.

The prophylactic effect of itraconazole capsules and fluconazole capsules for systemic fungal infections in patients with acute myeloid leukemia and myelodysplastic syndromes: A Japanese multicenter randomized, controlled study

We performed a randomized, controlled study comparing the prophylactic effects of capsule forms of fluconazole (n = 110) and itraconazole (n = 108) in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) during and after chemotherapy.There were 4 cases with possible systemic fungal infection in the itraconazole group, and there were 8 possible and 3 probable cases in the fluconazole group. Adverse events did not significantly differ in the 2 groups. In patients with MDS or in the remission-induction phase of chemotherapy, the numbers of cases with probable or possible infections were lower in the itraconazole group than in the fluconazole group, whereas no difference was seen in patients with AML or in the consolidation phase of therapy. In patients with neutrophil counts of <0.1 * 109/L lasting for more than 4 weeks, the frequency of infection in the fluconazole group (5 of 9 patients) was significantly higher than in the itraconazole group (0 of 7 patients; P = .03). Our results suggest that both drugs were well tolerated in patients with AML or MDS who received chemotherapy and that the efficacy of itraconazole for prophylaxis against systemic fungal disease is not inferior to that of fluconazole.

Cefozopran, meropenem, or imipenem–cilastatin compared with cefepime as empirical therapy in febrile neutropenic adult patients: A multicenter prospective randomized trial

We conducted an open-label, randomized study to evaluate the clinical efficacy of cefozopran, meropenem or imipenem-cilastatin using cefepime as a control in febrile neutropenia (FN) patients. Three hundred and seventy-six patients received cefepime, cefozopran, meropenem or imipenem-cilastatinas initial therapy for FN. The primary endpoint was the non-inferiority of response rates including modification at day 7 in cefozopran, meropenem or imipenem-cilastatin patients compared with cefepime in the per-protocol population (delta = 10%). The response rates for cefozopran, meropenem and imipenem-cilastatin were not significantly different compared with cefepime (cefozopran: 54/90 (60%), meropenem: 60/92 (65%), and IPM/CS: 63/88 (72%) versus cefepime: 56/85 (66%) (p = 0.44, 1.0 and 0.51, respectively)), and the differences in treatment success for cefozopran, meropenem and imipenem-cilastatin compared with cefepime were -5.9% (95% confidence interval (CI): -20.1-8.4), -0.7% (95% CI: -14.6-13.3), and 5.7% (95% CI: -8.1-19.4), respectively. The same tendency was seen in the modified intention-to-treat population. Based on the evaluation of initial drug efficacy performed on days 3-5, there was no significant difference between the four drugs. In the subgroup with an absolute neutrophil count ≤ 100 × 10(6)/L for longer than seven days, there was significantly better efficacy in the carbapenem arm compared to 4th generation beta-lactams (52% versus 27% at days 3-5, p = 0.006, and 76% versus 48% at day 7, p = 0.002). Our results suggest that the effects of these four drugs as empiric therapy were virtually the same for adult FN patients, although non-inferiority was shown only in imipenem-cilastatin compared with cefepime (clinical trial number: UMIN000000462).

Pharmacokinetics of a standard dose of cytarabine in a patient with acute promyelocytic leukemia undergoing continuous ambulatory peritoneal dialysis

Dose setting for drugs to treat acute leukemia in patients undergoing dialysis therapy is a critical problem that is complicated by incomplete knowledge of the underlying pharmacokinetics of antileukemic agents in this setting, especially in continuous ambulatory peritoneal dialysis (CAPD) [1]. Because impaired renal function, permeability of the peritoneal membrane, the protein-binding ratio of the drug, and the CAPD schedule, along with other factors, are likely to influence plasma drug concentrations, the pharmacokinetics of individual antileukemic drugs must be evaluated. We report pharmacokinetic observations for a standard dose of cytarabine, the key drug for treating myeloid leukemia, in a patient with acute promyelocytic leukemia (APL) who was undergoing CAPD.

Dose-adjusted EPOCH chemotherapy for untreated peripheral T-cell lymphomas: A multicenter phase II trial of West-JHOG PTCL0707

The standard CHOP therapy for peripheral T-cell lymphoma has resulted in unsatisfactory outcomes and it is still not clear what is the optimal front-line therapy. We conducted a multicenter phase II study of dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone (EPOCH) for untreated peripheral T-cell lymphoma patients. In this prospective study, 41 patients were treated with dose-adjusted-EPOCH as initial therapy: peripheral T-cell lymphoma-not otherwise specified, n=21; angioimmunoblastic T-cell lymphoma, n=17; anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, n=2; and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, n=1. Median patient age was 64 years (range: 32–79 years). According to the International Prognostic Index criteria, 51.2% were at high-intermediate or high risk. The overall response and complete response rates were 78.0% [95% confidence interval (CI): 62.4–89.4%] and 61.0% (95%CI: 44.5–75.8%), respectively. At the median follow up of 24.0 months, the 2-year progression-free survival and overall survival were 53.3% (95%CI: 36.4–67.5%) and 73.2% (95%CI: 56.8–84.1%), respectively. The younger patients (≤ 60 years old) had a high response rate (overall response 94.1% and complete response 70.6%) and survival rate (progression-free survival 62.5% and overall survival 82.4%). The most common grade ≥ 3 adverse events were neutropenia (74.5%), anemia (40.8%), thrombocytopenia (22.0%), and febrile neutropenia (9.0%). Dose-adjusted-EPOCH had a high response rate with a tolerable toxicity profile. Our results indicate that dose-adjusted-EPOCH is a reasonable first-line approach for peripheral T-cell lymphoma patients and may improve outcomes.

Correction to: Multicenter phase 1/2 study of forodesine in patients with relapsed peripheral T cell lymphoma

The original version of this article contained a mistake in Fig. 4. The horizontal axis should be 36 instead of 60.

Phase II study of intensified rituximab induction and maintenance for low grade B cell lymphoma

Abstract Rituximab has markedly improved the outcomes of B cell lymphoma, and its maintenance has been shown to be beneficial in low grade B cell lymphoma (LGBCL). We conducted a multicenter, phase II trial of intensive rituximab induction and maintenance therapy for LGBCL to optimize the rituximab monotherapy. Patients with newly diagnosed or rituximab naïve relapsed LGBCL received 8 weekly rituximab as induction, then continued maintenance therapy with rituximab for 4 weeks at 6-month intervals. The primary endpoint was the overall response rate (ORR). Forty-five patients were enrolled from 2005 to 2009 and 36 were eligible. The ORR was 83.3% (30/36) with a complete response rate of 72.2% (26/36). The 3-year progression-free survival (PFS) was 76.7% with a median follow-up of 43.0 months. Five grade three toxicities were observed (no grade 4). Our findings suggest that this regimen demonstrates high activity with durable PFS and minimal toxicity in LGBCL patients.