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Standard therapy for idiopathic thrombocytopenic purpura (ITP) has not been established. We are conducting a multicenter, prospective trial to determine the efficacy and safety of short-term, high-dose dexamethasone therapy in ITP patients aged 18-80 years with platelet counts of more...

A 48-year-old man developed general fatigue, dyspnea, and fever at an altitude of 1562 m from the morning of the first day of a 3-day hike. Despite pharyngeal discomfort and mild general fatigue, he felt that the symptoms were not sufficient to abandon his plan. He usually required 1.5 hours to reach Tokusawa (6.4 km from the starting point at an altitude of 1500 m), but this time he required 2.5 hours and slept briefly upon arrival at Tokusawa due to extreme fatigue and respiratory discomfort. His symptoms became aggravated, so he presented at a mountain clinic with oxygen saturation at 80% and body temperature of 37.6ºC. He was diagnosed with hypoxemia due to pneumonia and/or other disease(s) and was evacuated to a hospital where a chest computed tomography scan revealed ground glass opacity and infiltrative shadows. He was treated for pneumonia, but another doctor discovered during follow-up that the patient had sprayed 300 mL of a waterproofing aerosol on mountain equipment in a nonventilated, enclosed area of his home on the night before starting out on the hike. Therefore, waterproofing spray was considered to have caused pulmonary damage. Self-reporting or appropriate questionnaires are the only means of identifying this type of injury. The differential diagnosis of pulmonary problems in an outdoor setting should include toxic aerosol exposure from waterproofing spray. more...

Chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD-NK) is a rare disease with an indolent clinical course, which is characterized by persistent increase in large granular lymphocytes of NK-cell type. A somatic mutation in signal transducer and activator transcription 3 (STAT3) has been reported in patients with CLPD-NK; however, the details of the mutational profiles and their clinical significance remain unclear. We performed mutation analyses of the STAT3, STAT5B, and TNF-alpha-induced protein 3 (TNFAIP3) genes for mononuclear cell-derived DNA in 17 CLPD-NK patients using allele-specific polymerase chain reaction and amplicon sequencing. Mutations in STAT3 and TNFAIP3 were found in 29% (5/17) and 6% (1/17) of cases, respectively. All patients were negative for STAT5B mutations. In all three STAT3-mutation (+) patients studied, STAT3 mutations were restricted to sorted NK cells. STAT3 mutation (+) patients had a lower hemoglobin level (6.6 g/dL vs. 13.9 g/dL, P = 0.0044) and showed a trend toward reduced neutrophil counts (1.22 × 109/L vs. 3.10 × 109/L, P = 0.070) compared with the STAT3 mutation (−) patients. No mutations in these genes were found in patients with neuropathy. These results suggest that heterogeneity of CLPD-NK and STAT3-mutated NK cells may play a significant role in cytopenia in CLPD-NK patients. more...

Hypoxia induces innumerable changes in humans and other animals, including an increase in peripheral red blood cells (polycythemia) caused by the activation of erythropoiesis mediated by increased erythropoietin (EPO) production. However, the elevation of EPO is limited and levels return to normal ranges under normoxia within 5–7 days of exposure to hypoxia, whereas polycythemia continues for as long as hypoxia persists. We investigated erythropoiesis in bone marrow and spleens from mouse models of long-term normobaric hypoxia (10 % O2) to clarify the mechanism of prolonged polycythemia in chronic hypoxia. The numbers of erythroid colony-forming units (CFU-E) in the spleen remarkably increased along with elevated serum EPO levels indicating the activation of erythropoiesis during the first 7 days of hypoxia. After 14 days of hypoxia, the numbers of CFU-E returned to normoxic levels, whereas polycythemia persisted for >140 days. Flow cytometry revealed a prolonged increase in the numbers of TER119-positive cells (erythroid cells derived from pro-erythroblasts through mature erythrocyte stages), especially the TER119 (high) CD71 (high) population, in bone marrow. The numbers of annexin-V-positive cells among the TER119-positive cells particularly declined under chronic hypoxia, suggesting that the numbers of apoptotic cells decrease during erythroid cell maturation. Furthermore, RT-PCR analysis showed that the RNA expression of BMP-4 and stem cell factor that reduces apoptotic changes during erythroid cell proliferation and maturation was increased in bone marrow under hypoxia. These findings indicated that decreased apoptosis of erythroid cells during erythropoiesis contributes to polycythemia in mice during chronic exposure to long-term hypoxia. more...

We report here a case of a 37-year-old man with human immunodeficiency virus (HIV) infection followed by JC virus (JCV) infection and primary central nervous system lymphoma (PCNSL). The patient had been infected with HIV type 1 due to blood products for hemophilia A during infancy. He had progression of nervous symptoms and was diagnosed with progressive multifocal leukoencephalopathy (PML) clinically at the age of 36, when his CD4-positive lymphocyte counts ranged between 350 and 450/μl. Oral mefloquine, intravenous methylprednisolone pulse therapy, and intravenous immunoglobulin were not effective for the PML, and the patient entered a vegetative state. Brain biopsy revealed JCV infection without pathological findings of PML. Eight months after the clinical diagnosis of PML, he developed respiratory failure and brain magnetic resonance imaging revealed a mass lesion in the brain stem. The patient died 19 months after the diagnosis of PML. Autopsy findings were compatible with PCNSL. EBV-encoded small RNA-1-positive cells were not detected. We present a case of JCV-positive PCNSL with HIV infection complicated with clinical PML. more...

We report a 68-years-old woman with systemic sclerosis and interstitial pneumonia (IP). She had developed subacute progressively encephalopathy and dementia while treated with oral cyclophosphamide and prednisolone. She admitted to our hospital because of syncope. Laboratory tests indicated slight elevated cerebrospinal fluid protein, and levels of serum C-reactive protein (CRP), levels of soluble IL-2 receptor was normal. But, magnetic resonance imaging (MRI) of the brain showed multiple infarct-like lesions mainly in the white matter, which mimics progressive multiple leukoencephalopathy (PML). Twenty days after admission, the retested MRI of the brain disclosed initial lesions progressively enlarged and numbers of the lesions were increased. The polymerase chain reaction (PCR) for JC virus of cerebrospinal fluid was negative. To make diagnosis, brain biopsy was performed. Microscopic examination revealed that small vessels were filled with lymphoma cells (CD20+, CD79+, CD3-), and intravascular lymphoma (IVL) was diagnosed. She treated with regimens of R-CHOP. After chemotherapy her consciousness and dementia were gradually improved. IVL of central nerve system (CNS) is a rare disease, and its common symptoms are ischemia, infarction and dementia. Diagnosis of IVL of CNS is difficult when the lesion mimics PML, and patient with similar laboratory examinations and radiographic findings of PML should undergo brain biopsy detected malignant cell in small vessels, which is a value of diagnosis. more...

We herein report the case of an 80-year-old man with malignant lymphoma who became persistently infected with influenza A virus. Although he was repeatedly treated with NA inhibitors, such as oseltamivir or peramivir, nasal cavity swab tests for influenza A antigen continued to be positive for more than 2 months. Virological analyses revealed that he was infected with the NA inhibitor-resistant A (H3N2) virus possessing an R292K substitution in the NA protein. These findings suggest that a drug-resistant influenza virus strain might selectively survive antiviral therapy in elderly patients with refractory malignant lymphoma undergoing multiple chemotherapies. more...

Multiple osteolysis and hypercalcemia are rare conditions accompanying diffuse large B-cell lymphoma (DLBCL). There have been no reports demonstrating the protein expression of osteoclast-activating factors in such cases. Herein, we report a case of a 38-year-old man with DLBCL, who initially presented with hypercalcemia, multiple osteolysis and renal insufficiency that mimicked multiple myeloma with poor outcome. Immunohistochemical analysis was conducted to examine the expression of macrophage inflammatory protein (MIP)-1α, MIP-1β and receptor activator of NF-kappa B ligand (RANKL) in a lymph node that was obtained at diagnosis. Compared with a control DLBCL sample, we observed increased expression of MIP-1α in lymphoma and vascular endothelial cells and MIP-1β in stromal cells in our case. RANKL expression was not observed in either our case or control cases. MIP is likely associated with the development of osteolysis and hypercalcemia in some lymphoma cases. more...

Objective Bacillus cereus (B. cereus) septicemia is a cause of life-threatening infection in patients with hematologic diseases. However, preventing a fatal prognosis in patients with B. cereus infection has not yet been achieved due to insufficient clinical investigations. To discover more optimal treatment strategies, we analyzed B. cereus septicemia in patients with hematologic diseases. Methods At our institution, we observed 13 cases of B. cereus septicemia in 12 patients with hematologic diseases between January 2001 and September 2010. The susceptibility of B. cereus strains to antibiotics was also analyzed. Results Of 12 patients, four died of B. cereus septicemia. In this study, the delayed administration of appropriate antibiotics (starting >24 hours after presentation), the presence of liver dysfunction and evidence of central nervous system (CNS) involvement tended to result in a fatal prognosis. All of the bacterial strains were found to be susceptible to vancomycin and quinolones (such as ciprofloxacin and levofloxacin), whereas many strains were resistant to clindamycin (76.9%) and imipenem (30.8%). In seven of 10 patients, central venous (CV) catheter tips were removed and routinely cultured. Catheter tip cultures were positive for B. cereus in three of seven patients. Conclusion Although not specific to B. cereus bacteremia, patients who died of B. cereus tended to present with CNS symptoms and/or liver dysfunction. Our clinical data suggested that carbapenem and clindamycin are no longer appropriate choices for treating B. cereus. In addition, B. cereus septicemia was found to frequently originate from CV catheters. Constant attention must be paid to update assessments of antibiotic susceptibility and careful management must be applied to CV catheters in patients with hematologic diseases. more...

Abstract 4855 Background: Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of non-Hodgkin lymphomas, often resulting in poor prognoses. The CHOP chemotherapy regimen, which includes cyclophosphamide, doxorubicin, vincristine, and prednisone, had been used previously to treat other types of lymphomas. Here, we examined the efficacy and safety of a dose-intensified CHOP regimen (Double-CHOP), which was followed by autologous stem-cell transplantation (ASCT) or high-dose methotrexate (HDMTX), in PTCL patients. Patients and Methods: Twenty-eight PTCL patients, who received 3 courses of Double-CHOP at our institution, were retrospectively studied from 1996 to 2012. Patients with anaplastic lymphoma-kinase-positive anaplastic large-cell lymphoma (ALK+–ALCL) were excluded from this study. The Double-CHOP regimen consisted of 3 courses of intravenous (iv) administration of cyclophosphamide (750 mg/m2, days 1–2, over 2 h), doxorubicin (50 mg/m2, days 1–2, over 30 min), vincristine (1.4 mg/m2, day 1, max 2 mg/Kg body weight), and per os (p.o.) prednisone (50 mg/m2, days 1–5). For patients aged >60, cyclophosphamide and doxorubicin doses were modified. The third cycle of Double-CHOP regimen was used for stem cell mobilization. Consolidating high-dose therapy (HDT) regimen consisted of cyclophosphamide (60 mg/kg, day 6 and 7, iv, over 3 h), etoposide (500 mg/m2; day 4, 5, and 6; iv; over 6–8 h), and ranimustine (250 mg/m2, day 2 and 3, iv, over 1 h). ASCT was performed on day 0 and G-CSF administered from day 1 until neutrophil engraftment. As an alternative to HDT/ASCT, HDMTX (8 g/m2, day 1, iv, over 4 h) was indicated for patients who could not yield a sufficient number of stem cells or were ineligible for HDT/ASCT. Results: Patients' median age was 58 years (range: 17–69). They had low-intermediate (n = 11), high-intermediate (n = 10), or high (n = 7) risk according to the International Prognostic Index (IPI). The overall complete remission (CR) rate following Double-CHOP treatment was 68%. Of all the CR patients, 10 could successfully tolerate a consolidated HDT followed by ASCT, and 7 received HDMTX. Only a single case of treatment-related mortality was recorded during the study. On a median 31-month follow-up, the estimated 3-year overall survival (OS) rate and 3-year relapse-free survival (RFS) rate after CR were 68% and 60%, respectively. Conclusion: Although this study included elderly and excluded low-risk IPI and ALK+–ALCL patients, both RFS and OS results were superiorly favorable, indicating the efficacy of this Double-CHOP regimen and Double-CHOP followed by ASCT/HDMTX consolidations is safe and may achieve prolonged EFS, especially in patients with poor prognostic factors. However, an effective treatment strategy for refractory or relapsing patients needs to be validated and established. Disclosures: No relevant conflicts of interest to declare. more...

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP (i.e., R-CHOP)] is considered to be the standard regimen for treating localized, primary gastric diffuse large B-cell lymphoma (PG-DLBCL). However, few studies have reported the long-term efficacy of R-CHOP therapy in the management of localized PG-DLBCL. In the present study, we performed a retrospective analysis of 11 patients with localized PG-DLBCL, who were treated with R-CHOP at Nihon University Itabashi Hospital and Kasukabe Municipal Hospital (Japan) from 2001 to 2008. Limited stage cancer was defined as stage I/II according to the Lugano staging system for gastrointestinal (GI) lymphomas. The relative dose intensity (RDI) of CHOP therapy was calculated for each patient. The median age of the patients was 68 years (range, 48–82). Gastralgia and anemia were common symptoms at initial presentation. All patients except 1 received 6 cycles of R-CHOP treatment without consolidative radiation therapy or prior surgery. RDI was maintained at over 80% in 9 out of 11 patients. All patients achieved complete remission and the estimated overall survival with a median follow-up of 54 months (range, 39–103) was 100%, without relapse or significant GI adverse effects, such as perforation or bleeding during R-CHOP treatment. No long-term adverse effects of rituximab were recorded during the observation period. Helicobacter pylori infection was diagnosed in 72.7% (8 cases) of the patients, but was eradicated in a limited number of patients. Our data suggest the feasibility and effectiveness of the addition of rituximab to conventional CHOP therapy in the management of localized PG-DLBCL. more...

Background Recent studies have shown that the concurrent expression of MYC and BCL2 protein evaluated by immunohistochemistry (IHC) in patients with de novo diffuse large B-cell lymphoma (DLBCL) is associated with worse survival when treated with standard R-CHOP, but the effect of intensive chemotherapies for such patients is unknown. Thus, we evaluated the impact of the co-expression of MYC and BCL2 protein among patients with advanced DLBCL, who were treated with a dose-intensive immunochemotherapy followed by up-front autologous stem cell transplantation (ASCT). Patients and Methods This is a retrospective analysis of patients with de novo DLBCL, who were categorized into high/high-intermediate risk by the age-adjusted International Prognostic Index (aaIPI). They were consecutively treated with the R-Double-CHOP regimen, consisting of rituximab (375 mg/m2, day -2), cyclophosphamide (750 mg/m2, day 1, 2), doxorubicin (50 mg/m2, day 1, 2), vincristine (1.4 mg/m2 [maximum 2.0 mg/body], day 1) and prednisolone (50 mg/m2, day 1-5) followed by consolidative high-dose chemotherapies at our institution from 2001 to 2013. MYC and BCL2 protein were measured by IHC assay using formalin-fixed paraffin-embedded tissue specimens for all available cases. Cut-off values of positivity for MYC and BCL2 protein were set as 40% and 50% of stained tumor cell, respectively. Lymphomas showing concurrent positivity for MYC and BCL2 protein were defined as "Double expressor lymphoma (DEL)". Results A total of 40 patients with a median 53-years (range 19-68) of age were analyzed. Twenty-one patients were at high risk and the other 19 patients were at high-intermediate risk by aaIPI. Cell of origin (COO) subtypes classified by Hans algorithm consisted of 14 germinal center B-cell (GCB) type and 26 non-GCB type. Totally, 10 (25%) patients were categorized into DEL. The overall response (OR) and the complete response (CR) rates to R-Double-CHOP for all patients were 93% and 83%, respectively. The OR and the CR rates were not significantly different between the DEL group and the non-DEL group (100% vs 90%, and 80% vs 83%, respectively). The proportion of patients proceeding to ASCT was not significantly different among these groups (50% vs 60%). With a median 52 months (range 3-155) of follow-up, the 3-year progression-free survival (PFS) and the overall survival (OS) rates for all patients were 55% and 72%, respectively (Figure a, b). Both the PFS and the OS were significantly worse in the DEL group than in the non-DEL group (Figure c, d). As for aaIPI and COO subtyping, either high/high-intermediate risk or GCB/non-GCB subtype were not significantly associated with the outcome of PFS or OS. Conclusion The concurrent expression of MYC/BCL2 protein in advanced DLBCL was associated with shorter remission duration and worse survival despite similar susceptibility to the treatment when a dose-intensive immunochemotherapy was applied. Our findings suggest that patients with advanced DEL may not benefit from dose-intensified therapies, and therefore need highly discrete strategies. Disclosures Miura: Astellas Pharma Inc.: Honoraria; Celgene K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; CHUGAI PHARMACEUTICAL CO. LTD: Honoraria; Kyowa Hakko Kirin CO., Ltd, Japan: Honoraria; Meiji Seika Pharma: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Hatta:Kyowa Hakko Kirin CO., Ltd, Japan: Honoraria; CHUGAI PHARMACEUTICAL CO. LTD: Honoraria; Celgene K.K.: Honoraria. Iriyama:Brystol-Myers K.K.: Honoraria. Takei:Kyowa Hakko Kirin CO., Ltd, Japan: Research Funding; Bristol-Myers K.K.: Research Funding; Nippon Kayaku Co.: Research Funding; Shionogi & Co.: Research Funding; Meiji Seika Pharma: Research Funding; Astellas Pharma Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; TEIJIN PHARMA LIMITED: Research Funding; CSL Behring K.K: Research Funding; Japan Blood Products Organization: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; TORII, PHAMACEUTICAL CO: Research Funding; Alexion Pharmaceuticals: Research Funding; YAKULT HONSHA CO., Ltd.: Research Funding; Taisho Toyama Pharmaceutical Co., Ltd.: Research Funding; TAIHO PHARMACEUTICAL CO., Ltd.: Research Funding; CHUGAI PHARMACEUTICAL CO. LTD: Research Funding. more...

Introduction Patients with hematological malignancies are at high-risk for severe infections with drug-resistant gram-positive bacteria, as typified by methicillin-resistant staphylococcus aureus (MRSA). Vancomycin (VCM) is widely used as empirical therapy for these high-risk infections, but the global decline in their susceptibilities to VCM is at issue. Arbekacin sulfate (ABK), a unique aminoglycoside with anti-MRSA activity, has not yet been evaluated in this setting. Patients and methods This is a phase 4 study to evaluate the efficacy and safety of ABK for adult patients with hematological malignancies complicated with infections including febrile neutropenia, who are at high-risk for MRSA. All participant provided written informed consent and this study was approved by the institutional review board of the hospital. ABK was administered intravenously at a dose of 100–400mg every 24–48 hours based on the patients’ body weight and the renal function. Therapeutic drug monitoring (TDM) using Habekacin TDM software (Meiji Seika Pharma, Tokyo, Japan) was performed 48–96 hours after the initiation of ABK. The clinical response was rated as “effective” if the symptoms of infection disappeared or significantly improved, taking into account the vital signs, the serum C-reactive protein (CRP) concentration, and other clinical parameters at baseline and after completion/discontinuation of the treatment. Results From December 2010 to June 2012, 35 eligible patients were treated with ABK up to 4 times with intervals of at least 2 weeks. Consequently, a total of 54 febrile or infectious episodes were registered. The median age, serum creatinine concentration, absolute neutrophil count, axillary temperature, and serum CRP concentration for all cases at baseline were 59 (range 34–77) years, 0.64 (range 0.34–1.31) mg/dl, 0.2 X 109/L (range 0–15.1), 38.4°C (range 37.2–40.5), and 8.2 mg/dl (range 0.7–40.6), respectively. Primary diseases consisted of 34 cases of acute myeloid leukemia, 12 cases of relapsed/advanced non-Hodgkin lymphoma, 3 cases of acute lymphoblastic lymphoma/leukemia, 3 cases of myelodysplastic syndrome/aplastic anemia, and 2 cases of multiple myeloma. Diagnosis of infections consisted of 26 cases of febrile neutropenia, 18 cases of septicemia (methicillin-resistant coagulase negative staphylococci in most cases), 7 cases of pneumonia (MRSA pneumonia in one case), 2 cases of cellulitis, and 1 case of neutropenic colitis. Fifty-two cases (96%) had already received oral prophylaxis using fluoroquinolones and/or intravenous therapy with broad-spectrum antibacterials, and 47 (87%) had received cytotoxic chemotherapies. ABK was initiated with a median of 2 days (range 0–14) after the onset of fever/infection, concomitantly with a variety of broad-spectrum beta-lactams. Overall, 43 cases (80%) attained afebrile states with the absence of symptoms and rated as “effective” at the end of treatment with a median of 10 days (range 4–35). All grade renal toxicity was observed in 6 cases (11%), but they were generally mild and reversible. There were 3 deaths within 30 days of the treatment, but all of them were associated with the progression of the primary disease. Conclusion This study demonstrated for the first time the high efficacy of ABK for persistent or high-risk infections in patients with hematological malignancies. Further evaluations­—e.g. randomized controlled trials comparing ABK with VCM for these populations—are therefore warranted. Disclosures Miura: Meiji Seika Pharma: Consultancy, Research Funding. Iriyama:Meiji Seika Pharma: Research Funding. Kobayashi:Meiji Seika Pharma: Research Funding. Hatta:Meiji Seika Pharma: Research Funding. Takei:Meiji Seika Pharma: Research Funding. more...

Abstract 1039 Background: The association between increase in body mass index (BMI) and development of acute promyelocytic leukemia (APL) has been reported. Interaction of APL cells with bone marrow adipocytes in vitro induces phosphorylation of STAT3 and MAPK, resulting in an anti-apoptotic effect in APL cells. However, the influence of obesity on the prognosis of APL is not well understood. Materials and Methods: To evaluate the effect of obesity on the prognosis of adult APL, we retrospectively analyzed 62 patients under the age of 65 with newly diagnosed APL. Patients who could not be administered intensified chemotherapy, because of either poor performance status or adverse events of chemotherapy, were excluded. Results: Median age of patients was 40 years (range, 14–63). Twenty-five were male and 37 were female. Median follow-up period was 646 days (range, 3–12,558). Median BMI was 22.7 (range, 16.0–33.0). Twenty-six patients diagnosed with APL between 1970 and 1992 had been treated with chemotherapy alone (chemotherapy group), and 36 patients diagnosed between 1995 and 2010 had been treated with all-trans retinoic acid (ATRA) ± chemotherapy (ATRA group). In both groups, the outcome was compared between high-BMI (BMI ≥ 24) and low-BMI (BMI < 24) patients. Eight out of 26 in the chemotherapy group and 16 out of 36 in the ATRA group were high-BMI patients. In the chemotherapy group, complete remission (CR) was obtained in 13 out of 18 (72.2%) low-BMI patients and in only 3 out of 8 (37.5%) high-BMI patients. By day 498, all 3 CR patients with high BMI had relapsed, whereas only 6 out of 13 (46.2%) low-BMI CR patients had relapsed. The 2-year relapse-free survival (RFS) rate, event-free survival (EFS) rate, and overall survival (OS) rate in high-BMI versus low-BMI patients were 0% v 50.5%, 0% v 61.1%, and 12.5% v 42.8%, respectively. Although the relapsed patients were salvaged with ATRA, arsenic trioxide, or allogeneic bone marrow transplantation, OS was significantly worse in high-BMI patients. On the contrary, in the ATRA group, prognosis between high-BMI and low-BMI patients was not statistically different. Rates of CR, relapse, 2-year RFS, EFS, and OS in high-BMI versus low-BMI patients were 87.5% v 94.7%, 35.7% v 38.9%, 73.3% v 46.2%, 55.0% v 52.5%, and 87.5% v 81.1%, respectively. The initial white blood cell (WBC) and platelet counts have been previously reported to be prognostic factors in APL; however, they were not associated with BMI in our study. A WBC count of >10 × 109/L and a platelet count of ≤40 × 109/L were observed in 4 (10.5%) and 28 (73.8%) out of 38 low-BMI, and 4 (16.5%) and 19 (79.2%) out of 24 high-BMI patients, respectively. Conclusions: Our results demonstrate that obesity at diagnosis is a poor prognostic factor in APL, especially in patients not administered ATRA. ATRA overcomes the anti-apoptotic effect of adipocytes for APL cells. Disclosures: No relevant conflicts of interest to declare. more...

Background Speciation of arsenic trioxide (ATO) metabolites in clinical samples such as peripheral blood (PB) from acute promyelocytic leukemia (APL) patients has been conducted. However, speciation of arsenicals in bone marrow (BM) has not yet been performed. Profiles of arsenic speciation in plasma of BM were thus investigated and compared with those of PB plasma from a relapsed APL patient. The total arsenic concentrations in high molecular weight fraction (HMW-F) of BM and PB plasma were also determined. Methods Response assessment was evaluated by BM aspirate examination and fluorescence in situ hybridization analysis. The analyses of total arsenic concentrations and speciation were preformed by inductively coupled plasma mass spectrometry (ICP-MS), and high-performance liquid chromatography (HPLC)/ICP-MS, respectively. Results Response assessment showed that the patient achieved complete remission. The total arsenic concentrations in BM plasma increased with time during the consecutive administration. The PB plasma concentrations of methylated arsenic metabolites substantially increased after the start of administration, while those of inorganic arsenic were still kept at a low level, followed by substantially increase from day-14 after administration. The arsenic speciation profiles of PB plasma were very similar to those of BM plasma. Furthermore, the total arsenic concentrations of HMW-F in BM plasma were much higher than those in PB plasma. Conclusions The behaviors of arsenic speciation suggested for the first time that arsenic speciation analysis of PB plasma could be predicative for BM speciation, and showed relatively higher efficiency of drug metabolism in the patient. These results may further provide not only significance of clinical application of ATO, but also a new insight into host defense mechanisms in APL patients undergoing ATO treatment, since HMW proteins-bound arsenic complex could be thought to protect BM from the attack of free arsenic species. more...