Search

Background The percentage of blasts in the bone marrow in the early stage of remission induction therapy for acute myeloid leukemia (AML) has been reported to affect not only remission rate, but also long-term prognosis. If early post-treatment response to therapy was determined to affect prognosis, this finding could be a basis for selection of a proactive treatment such as hematopoietic stem cell transplantation; however, the proper assessment period and the percentage of blast cell survival vary among reports. Therefore, we retrospectively analyzed the relationship between prognosis and the percentage of blasts in the bone marrow in the early post-treatment stage in cases registered for the AML201 study conducted by the Japan Adult Leukemia Study Group (JALSG). Patients and Methods The JALSG AML201 study was a multicenter randomized study in which 1064 patients with newly diagnosed AML patients were registered between December 2001 and December 2005. For remission induction therapy, we compared standard-dose idarubicin or high-dose daunorubicin in combination with cytarabine. For consolidation therapy, we compared standard-dose multiagent chemotherapy or high-dose cytarabine alone, and no apparent differences were observed in overall survival (OS) between both treatment groups. The percentage of blasts in the bone marrow on day 15 was strongly associated with remission; using the receiver operating characteristic curve as a reference, we divided patients into a ≥5% and a Results Among the 1064 patients registered for the JALSG AML201 study, 600 patients for whom bone marrow examination was performed on Day 15 were selected as subjects for the present study. The patients consisted of 375 men and 225 women with a median age of 47 years (15-64 years). A total of 377 patients (62.8%) had Conclusion As an early assessment of bone marrow following remission induction therapy, having Disclosures Fujita: Chugai Pharmaceutical CO.,LTD.: Honoraria. Kiyoi:Novartis Pharma K.K.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; Celgene Corporation: Consultancy; Nippon Shinyaku Co., Ltd.: Research Funding; Alexion Pharmaceuticals: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; MSD K.K.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding. Naoe:Amgen Astellas BioPharma K.K.: Honoraria; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Pfizer Inc.: Research Funding; CMIC Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Celgene K.K.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; Bristol-Myers Squibb: Honoraria; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding.

Introduction: Acute myeloid leukemia (AML) with hyperleukocytosis is considered to have a poor prognosis due to a high early death rate secondary to complications such as disseminated intravascular coagulation (DIC), tumor lysis syndrome (TLS), and leukostasis. The usefulness of pre-treatment reduction of leukemic cells is controversial. We reviewed the clinical characteristics and outcome of adult patients with newly diagnosed AML with or without hyperleukocytosis registered to the Japan Adult Leukemia Study Group (JALSG) AML201study and examined whether early death in induction therapy for this AML subtype influenced the outcome. Methods: We retrospectively reviewed the records of 1,022 patients enrolled in the JALSG AML201 study, which was a phase 3 clinical trial for AML newly diagnosed from December 2001 to December 2005. The JALSG AML201 study administered cytarabine from day 1 to 7 as the induction therapy combined with idarubicin or daunorubicin (Ohtake S, et al. Blood. 2011, 24;117:2358-65.). None of the patients received pre-treatment with oral hydroxyurea or leukapheresis. Patients with performance status (PS) of 4 or severe comorbidities such as septic shock were excluded. Patients' characteristics and outcomes such as rate of early death (defined as death occurring within the first thirty days of treatment), achievement of complete remission (CR), overall survival (OS) rate and cumulative incidence of recurrence (CIR) were compared between patients with hyperleukocytosis and those without hyperleukocytosis. Result: We analyzed retrospectively the records of 1,057 patients with AML registered with the JALSG AML201 study and excluded 35 patients whose leukocyte count or outcome was not recorded. We found 113 AML patients with an initial leukocyte count greater than 100 × 109L−1 (HiLC group). There were 66 males and 47 females, and the median age was 45 years (range: 16-64). Median of leukocyte count before treatment was 160 × 109L−1 (range: 102-382 × 109L−1). According to the French-American-British (FAB) classification, there were four as M0, thirty-four as M1, fifty-six as M2, thirty as M4, and nineteen as M5. Cytogenetic analysis was performed in 107 patients. Eight patients had favorable karyotype, 90 had intermediate karyotype, and nine had unfavorable karyotype. Fifteen percent of patients with hyperleukocytosis had PS of two or greater. We compared the outcome of this AML subset with 909 patients with a leukocyte count lower than 100 × 109L−1 (median count: 10,900, range: 0.77-99.5× 109L−1) who received the same induction chemotherapy as the JALSG AML201 protocol (LoLC group). There was no significant difference between the two groups for age and sex; median age of the patients in LoLC group was 47 years (range: 15-64) with 542 males and 367 females. The frequency of the patients with a favorable karyotype or PS of 0 or 1 was lower in HiLC group than in LoLC group, whereas the rate of FAB M4 or M5 was higher in HiLC as compared to LoLC group. Eighty-two patients (72.5%) in HiLC group and 714 patients (78.5%) in LoLC group achieved CR. Sixty (53%) and twenty-two (19.5%) achieved CR after one and two cycles of treatment, respectively. In contrast, 577 (63%) and 137 (15%) in LoLC group achieved CR after one and two cycles of chemotherapy, respectively. The rate of CR was not significantly different between two groups (p=0.118). However, 5 year OS was significantly lower in HiLC as compared to LoLC group (26.9% vs. 49.4%, p < 0.001). Interestingly, the rate of early death was not different between the two groups (1.65% vs. 1.77%, p = 1.0), although the rate of severe complications, such as DIC, was higher in HiLC compared to LoLC group (32% vs. 10%, p < 0.001). The frequency of brain hemorrhage (1% vs. 1%, p = 1.0) and gastrointestinal hemorrhage (4% VS. 3%, p = 0.294) was not different between two groups. One patient died of brain hemorrhage and one of DIC in HiLC group, whereas five patients died of brain hemorrhage, four of sepsis, and three of pneumonia in LoLC within the first thirty days of treatment. CIR was higher in HiLC (64.7%) as compared to LoLC group (51.6%) (p = 0.0048). Conclusion: We conclude that hyperleukocytosis on presentation did not significantly affect the rate of early mortality during the induction phase of the treatment. It is considered that intensive chemotherapy without pre-treatment would be possible if appropriate supportive cares were given to manage fatal complications such as DIC. Disclosures Kiyoi: MSD K.K.: Research Funding; Alexion Pharmaceuticals: Research Funding; AlexionpharmaLLC.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Phizer Japan Inc.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Zenyaku Kogyo Co.LTD.: Research Funding; Kyowa-Hakko Kirin Co.LTD.: Research Funding; Celgene Corporation: Consultancy; Chugai Pharmaceutical Co. LTD.: Research Funding. Naoe:Amgen Astellas BioPharma K.K.: Honoraria; CMIC Co., Ltd.: Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Bristol-Myers Squibb: Honoraria; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Celgene K.K.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties.

We have measured electron energy spectra and asymmetry parameters of Ar clusters and Xe clusters illuminated by intense x-rays at 5 and 5.5 keV. A velocity map imaging spectrometer was developed for this purpose and employed at an x-ray free-electron laser facility, SACLA in Japan. The cluster size dependence and the peak fluence dependence of the electron spectra and asymmetry parameters are discussed.

We report here an acute myelocytic leukemia (AML-M2) patient with trisomy 13 as the sole cytogenetic anomaly, who had relapse of AML with a normal karyotype and developed multiple myeloma. Fluorescence in situ hybridization analysis using the RB gene probe revealed the plasma cells of multiple myeloma (MM) to have monosomy 13 anomaly, whereas relapsed blast cells of AML carried disomy of chromosome 13. To our knowledge, this is the first case showing clonal evolution of trisomy 13 AML and monosomy 13 MM, which might be derived from the leukemic clone at relapse.

Efficacy, safety and pharmacokinetics of meropenem (MEPM) were assessed when 1 g (40 mg/kg for some of the pediatric patients) t.i.d. was administered every 8hours to 101 adult and 6 pediatric patients with febrile neutropenia (FN) as diagnosed based on the Japanese guideline for FN treatment. The efficacy rate evaluated as antifebrile effect up to Day 4 of treatment was 40.0% (40/100) in adult and 66.7% (4/6) in pediatric patients. The antifebrile effect in adult patients was analyzed after stratifying them according to their neutrophil counts up to Day 4. Treatment with MEPM produced an antifebrile effect not only in patients with higher neutrophil counts (or = 500/mm3) but also in those with lower counts (100/mm3), and the efficacy rate was comparable between the two groups: 38.2% in the100/mm3 group and 29.4 to 55.6% in theor = 500/mm3 group. The bacteriological efficacy of MEPM evaluated as disappearance rate on Days 3 to 5 and Day 7 was both 100% (8/8 and 4/4, respectively). The time above minimal inhibitory concentration (% TMIC) in the treatment interval was greater than 90% in 9 out of 10 patients for whom likely causative organism was isolated and identified after MEPM treatment or for whom causative organism emerging after treatment was isolated and identified. The incidence of adverse events was 93.1% in adult and 83.3% in pediatric patients. There were three deaths and one serious adverse event reported among the adult patients; however, all these cases were assessed as not related to the study medication. The incidence of adverse drug reactions was 45.5% and 66.7%, respectively. All the observed adverse drug reactions were mild or moderate in severity and none of them was severe. Adverse drug reactions which were unknown from the previous MEPM clinical studies and investigation of the results of clinical experience include 'chest discomfort', 'blood uric acid decreased', 'lymphocyte deformation', 'blood uric acid increased', 'abnormal funduscopy', 'hypesthesia' and 'hemorrhagic cystitis'. All these events were mild or moderate in severity and resolved without requiring any action or after providing symptomatic treatment. There was no unknown adverse drug reaction that resulted in treatment discontinuation. No nervous system disorders such as convulsion and impaired consciousness were reported. The results show that monotherapy of MEPM 1 g (or 40 mg/kg for some of the pediatric patients) t.i.d. every 8 hours was effective, and was also safe and well tolerated in adult and pediatric patients with FN. Therefore, MEPM monotherapy is expected to be useful as the initial treatment for Japanese patients with FN.

We have investigated multiphoton multiple ionization dynamics of argon and xenon atoms using a new x-ray free electron laser (XFEL) facility, SPring-8 Angstrom Compact free electron LAser (SACLA) in Japan, and identified that highly charged Xe ions with the charge state up to +26 are produced predominantly via four-photon absorption as well as highly charged Ar ions with the charge state up to +10 are produced via two-photon absorption at a photon energy of 5.5 keV. The absolute fluence of the XFEL pulse, needed for comparison between theory and experiment, has been determined using two-photon processes in the argon atom with the help of benchmark ab initio calculations. Our experimental results, in combination with a newly developed theoretical model for heavy atoms, demonstrate the occurrence of multiphoton absorption involving deep inner shells., 5 pages, 5 figures

It has been known empirically that the odor evolved from human hair and scalp is different from the odor from body or foot.We tried to identified the volatile compounds evolved from human hair and scalp using headspace sampling method and extraction by acetone.By the headspace method, over eighty of compounds were detected and almost thirty subsequently identified. The latter belong to various chemical classes such as alkanes, alkenes, alcohols, aldehydes, and acids. we tried to reconstitute of the odor according to the result of analysis and using the sense of perfumers.Moreover, the changing of volatile compounds and increasing of scalp resident bacteriars during three days were investigated.

Summary. We encountered a patient with Philadelphia-negative chronic myeloid leukaemia, witht(7;11)(p15;p15), in whom acute leukaemia phase (acute myeloid leukaemia-M2 morphology) developed within a short period. We detected a novel gene fusion between NUP98 and HOXA11 both in the chronic phase and in the acute leukaemia phase in this case. Although it is well known that a fusion of NUP98–HOXA9 in myeloid malignancies is created by the t(7;11)(p15;p15), this case suggests the possibility that HOXA11 might be another partner gene for NUP98 in t(7;11)(p15;p15) leukaemia.

The magnetic dipole-dipole interaction between nanomagnets having huge magnetic moments can have a strength comparable to that of the van der Waals interaction between them, and it can be manipulated by applying an external magnetic field of conventional strength. Therefore, the cooperation between the dipole-dipole interaction and the applied magnetic field allows the magnetic moments of nanomagnets to be aligned and organized in an ordered manner. In this work, a network of magnetic nanoparticles connected with flexible long-alkyl-chain linkers was designed to develop a "magnetic sponge" capable of absorbing and desorbing guest molecules with changes in the applied magnetic field. The magnetization of the sponge with long-alkyl-chain bridges (30 C atoms) exhibited a 500% increase after cooling in the presence of an applied field of 7 T relative to that in the absence of a magnetic field. Cooling in a magnetic field leads to anisotropic stretching in the sponge due to reorganization of the nanomagnets along the applied field, in contrast to the isotropic organization under zero-field conditions. Such magnetic-responsive organization and reorganization of the magnetic particle network significantly influences the gas absorption capacity of the nanopores inside the material. The absorption and desorption of guests in an applied magnetic field at low temperature can be regarded as a fascinating "breathing feature" of our magnetic sponge.

Cardiac dysfunction due to transfusional iron overload is one of the most critical complications for patients with transfusion-dependent hematological disorders. Clinical parameters such as total red blood cell (RBC) transfusion units and serum ferritin level are usually considered as indicators for initiation of iron chelation therapy. We used MRI-T2*, MRI-R2* values, and left ventricular ejection fraction in 19 adult patients with blood transfusion-dependent hematological disorders without consecutive oral iron chelation therapy, and propose possible formulae of cardiac function using known parameters, such as total RBC transfusion units and serum ferritin levels. We found a positive correlation in all patients between both R2* values (reciprocal values of T2*) and serum ferritin levels (r = 0.81) and also total RBC transfusion volume (r = 0.90), but not when we analyzed subgroups of patients whose T2* values were over 30 ms (0.52). From the formulae of the R2*, we concluded that approximately 50 Japanese units or 2,900 pmol/L ferritin might be the cutoff value indicating possible future cardiac dysfunction.

Nanoisland films prepared by annealing thin gold films at high temperatures were imaged using scanning electron microscopy (SEM) and atomic force microscopy, and optically characterized through absorption spectroscopy. Thin gold films of effective thicknesses 2, 5 and 7 nm annealed at 500, 700 and 900 degrees C were fabricated and studied experimentally. The measured absorption characteristics in support of theoretical calculations showed that the shapes of gold islands were partial spheres. The position of the peak absorption wavelength measured with s-polarized light or at normal incidence confirmed that the island shape grew from a near-hemisphere towards a sphere with increasing annealing temperature. The SEM images confirmed that the size of islands increased from 15 nm in diameter to 40 nm in diameter as film thickness increased from 2 to 5 nm. The affect of the index of the substrate material on absorption characteristics were also studied by comparing the absorption spectra of gold island films on quartz and LaSF15 glass substrates. The use of gold nanoisland films for preparing localized surface plasmon resonance substrates was suggested as they held advantages over the gold colloid films.

By using a “finite-segment” model for an ion-exchange column, breakthrough curves of ternary cation components—lysine, ammonium, and hydrogen—on a column of a cation-exchange resin of the ammonium form are calculated as a function of limited parameters such as the selectivity coefficients and the dissociation constant of the amino acid. Experimental breakthrough curves on a fixed column packed with Diaion SK-IB (nominal DVB 8%) are simulated and analyzed by the calculated results. Within a limited flow rate of the liquid phase, the model is valid for experimental results, including dependencies on the pH and the ratio of lysine to ammonium, when the conditions of electroneutrality are obeyed.

The JAK2V617F mutation is an activating kinase that is constitutively expressed in the vast majority of patients with polycythemia vera and approximately half of those with essential thrombocythemia (ET).1 The significance of the association between JAK2V617F mutation in ET and thrombosis is still controversial: we have shown that ET patients with JAK2V617F had more frequent thrombotic episodes compared with those with wild-type JAK2, whereas the platelet count at the initial ET diagnosis did not differ between wild-type ET and JAK2V617F-positive ET.2 On the basis of this evidence, we retrospectively sought and evaluated thrombotic episodes in ET patients to obtain more insight into the risk factors of thrombosis in ET patients.

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 of0.1 x 10(9)/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.

The deletion of the long arm of chromosome 20, or del(20q), is a common cytogenetic abnormality in various myeloid disorders and is known to be a favorable prognostic factor in myelodysplastic syndromes (MDS) when it is the sole change. However, del(20q) occurs with one or more cytogenetic changes when it is associated with disease progression. Here, we analyzed 33 patients with MDS and del(20q) to ascertain the risk factors in MDS. We categorized del(20q) into two groups: one with the del(20q) clone (or =50% marrow metaphases), corresponding to genomic integrity, and the other with a late appearance of a minor del(20q) clone (50% metaphases) with additional cytogenetic changes, representing genomic instability. Of the MDS patients with del(20q) at initial presentation, the negative factors in predicting prognosis on survival are (i) INT-2/High risk according to the International Prognostic Scoring System, (ii) any additional cytogenetic changes, or (iii) minor del(20q) clone. The late appearance of del(20q) at any phase is linked to a significantly unfavorable prognosis, thus indicating the clinical and biological heterogeneity of del(20q) in MDS.

Mutations of N-RAS , FLT3 and p53 genes are not involved in the development of acute leukemia transformed from myeloproliferative diseases with JAK2 mutation

We describe a patient with hepatosplenic 33 T-cell lymphoma who showed pancytopenia and myelodysplasia. A 35-year-old man was admitted with fever, pancytopenia, and hepatosplenomegaly but with no lymphadenopathy. We also found trilineage myelodysplasia in the bone marrow on his first admission. The patient had high fever and anemia but no evidence of infection and was tentatively treated with prednisolone. This treatment resulted in a transient improvement of the cytopenia and a reduction of spleen size. However, 10 months after the first manifestation, progression of the splenomegaly and fever became apparent, and a splenectomy was performed. The pathologic findings for the spleen showed diffuse and disseminated infiltration of medium- to large-sized T-lymphocytes in the splenic red pulp. These cells were immunohistochemically positive for CD3, CD5, CD7, CD8, CD16, CD56,T-cell receptor 33 (TCR33),T-cell intracellular antigen 1, and granzyme B but were negative for CD4, CD30, CD57, and TCR33. These data suggested a diagnosis of hepatosplenic 33 T-cell lymphoma. A Southern blot analysis revealed gene rearrangement of the TCR 3-chain gene but not the immunoglobulin heavy chain gene in the spleen cells. An in situ hybridization analysis for the Epstein-Barr virus revealed negative results. The patient received 8 courses of combination chemotherapy and achieved a partial remission; however, the dysplastic features of the marrow cells persisted after the partial remission was obtained. Additional treatment with allogeneic bone marrow transplantation resulted in a transient complete remission; however, the patient relapsed 11 months later. Because he had experienced no lymphadenopathy and showed dysplastic features in the bone marrow, the diagnosis was highly dependent on the pathologic findings for the resected spleen.

Myelofibrosis is usually observed in myeloproliferative disorders, such as chronic myeloid leukemia. However, there are only a few reports showing an association between T-cell lymphoma and myelofibrosis. We report a case of peripheral T-cell lymphoma, unspecified (diffuse large cell) type, involving the bone marrow that was associated with severe myelofibrosis. In the present case, the plasma concentration of transforming growth factor-beta1 (TGF-beta1) was increased to 8.95 ng/ml (normal range: 1.56-3.24 ng/ml). No lymphadenopathy or skin lesions were observed during the entire clinical course. Although the mechanism of secondary myelofibrosis is still unclear, elevated plasma TGF-beta1 might be involved in the pathogenesis of bone marrow fibrosis in the present case.

(2005). Simultaneous occurrence of der(1;7)(q10;p10) and t(14;18)(q32;q21) in non-Hodgkin's lymphoma: der(1;7) will appear as a secondary change in lymphoid neoplasia. Leukemia & Lymphoma: Vol. 46, No. 6, pp. 949-950.

Leukemic transformation or myelofibrosis is a major concern in managing patients with chronic myeloproliferative disorders, including essential thrombocythemia (ET). We analyze the relationship between cytogenetic changes and the transformation in 89 patients with ET; 8 patients experienced transformation, including 2 patients with acute leukemia following myelofibrosis, 3 with acute leukemia, and 3 with myelofibrosis. Among the eight patients showing transformation, two patients developing myelofibrosis derived from a group with normal cytogenetics, but the remaining six were categorized as showing de novo appearance of cytogenetic changes. Two leukemia patients had de novo cytogenetic changes at the time of leukemia diagnosis, whereas two patients with acute leukemia following myelofibrosis showed der(1;7) during their myelofibrosis period. Moreover, patients with der(1;7) did not receive any cytotoxic agents before the appearance of der(1;7), indicating that detection of der(1;7) may have predictive value for not only leukemic transformation but also unfavorable prognosis.

A 31-year-old woman was given a diagnosis of aplastic anemia (AA) in 2000 and was treated with anti-thymocyte globulin (ATG) (horse serum), cyclosporine and granulocyte-colony stimulating factor (G-CSF). In 2002, she came to our hospital. The laboratory data revealed severe cytopenia according to the criteria by Camitta. A cytogenetic study revealed a normal female karyotype. We demonstrated CD55-negative and CD59-negative clones in her erythrocytes and granulocytes. HLA-DR 1501 was negative. After corticosteroid pulse therapy, the del(13q) (7/21 cells) was noted in her marrow cells. She was re-treated with ATG (rabbit serum), cyclosporine and G-CSF without particular cytogenetic changes after the therapy. Deletion of the 13q anomaly is rarely detected in patients with AA and its clinical significance in this disease is not well known. In the literature, AA patients with the del(13q) responded well to immunosuppressive therapy, irrespective of the timing of the appearance of the del(13q) anomaly. Further investigation will be needed to clarify the significance of del(13q) in AA.

A 60-year-old male was referred to our hospital because of cervical lymphadenopathy and a left hilar abnormal shadow seen on chest X-ray in May 1999. The pathological findings of the cervical lymph nodes revealed that the patient had a malignant lymphoma, of the diffuse large B cell type, at clinical stage IIIB. Immunohistochemistry demonstrated that the lymphoma cells were positive for CD11a, CD19, CD20, CD23, CD25, CD45, IgM, IgD and lambda, but negative for CD5. Although a complete remission was obtained after 8 courses of CHOP therapy, the patient relapsed 32 months later. Two courses of a half dose of CHASE therapy consisting of CPM, ara-C, VP-16 and dexamethasone, followed by rituximab (600 mg/week x4) resulted in a transient re-induction of complete remission. However, multiple cutaneous tumors became apparent just 10 days after the last rituximab therapy. Immunohistochemistry of the cutaneous tumors revealed infiltration of CD20-negative lymphoma cells. A series of chemotherapy including high-dose MTX was ineffective, and the patient died in August 2003. Autopsy findings revealed the systemic intra-capillary infiltration of CD20 negative-lymphoma cells into multiple organs, including the lungs, liver, and kidneys. A CD20 negative-clone selected by rituximab therapy appeared to have expanded in this case.

The roles of matrix metalloproteinases (MMPs) in chronic obstructive pulmonary disease (COPD) have been studied. Macrophages are considered to release MMPs in the lung tissue. We measured intracellular collagenase activity in intact CD14(+)CD45++ cells from the bronchoalveolar lavage fluid (BALF) of patients with obstructive ventilatory impairment and other respiratory diseases. Collagenase activity in current smokers was significantly lower than those in non-smokers (3.25+/-0.54 versus 5.48+/-0.55; P=0.006), and also lower than those in ex-smokers (versus 6.54+/-1.54; P=0.019). We found a lower activity of collagenase in patients with FEV1/FVC below 70% than those with 70% or higher (2.68+/-0.59 versus 4.51+/-0.44; P=0.034). Mean value of FEV1/FVC in patients with collagenase activity of 4 or higher was significantly elevated as compared to those with the activity lower than 4 (83.3+/-3.3 versus 71.8+/-4.9; P=0.021). The discrepancy between increased release of MMPs by previous reports and decreased intracellular activity in our results, may be explained by the production of inactive form of MMPs is relatively increased in COPD. Our study may provide the future direction in investigating the mechanism of COPD. In clinics, this measurement in patients with smoking habits may be helpful to advise them to stop smoking, and to avoid progression to the irreversible obstructive disease.

The development of various kinds of autoimmune disease as a result of interferon-alpha (IFN-alpha) therapy has been reported among chronic myeloproliferative disorders(CMPD) including chronic myeloid leukemia(CML). Therefore, we investigated the frequency of autoimmune disorders in 33 patients with hematopoietic diseases treated with IFN-alpha in our department. Thirty-three patients (12 females, 21 males) included cases of CML (n = 23), essential thrombocythemia (ET) (n = 1), multiple myeloma (n = 8), and hypereosinophilic syndrome (HES) (n = 1). Autoantibodies (ANA, dsDNA, and RAPA), thyroid grand functions, and coagulant functions were examined. Twenty-five out of 33 patients were treated with natural IFN-alpha, and 8 patients were treated with recombinant IFN-alpha 2b (rIFN alpha-2b). Three patients were treated with IFN and anticancer agents. Antinuclear antibodies were detected in 2 of 33 patients. RAPA and anti-thyroglobulin antibody became positive in 3 and 4 patients, respectively. Ten patients showed low serum levels of either free T3 and/or free T4. However, none of them showed any clinical symptoms for developing autoimmune diseases. In addition, circulating anticoagulant antibodies were detected in 3 of 23 patients with CML treated with rIFN alpha-2b, but in no cases treated with natural IFN-alpha. Although none of the patients developed autoimmune diseases, we concluded that patients receiving IFN therapy should be carefully monitored for clinical signs and symptoms of autoimmune disorders.

A patient with myeloid/natural killer (NK) cell precursor acute leukemia who was also homozygous for protein C deficiency was treated and showed a complete remission while he simultaneously received low molecular weight heparin. He presented with fever spikes, lymphadenopathy, and a bulky tumor of the anterior mediastinum. A bone marrow aspirate showed the infiltration of immature lymphoblastoid cells. The patient's diagnosis was determined to be myeloid/NK cell precursor acute leukemia by morphologic and immunophenotypic analysis (CD7(+)CD33(+)CD34(+)CD56(+)). The patient developed a thrombosis in his jugular vein on cannulation of the internal jugular vein. An examination of the serum levels and the activities of proteins C and S demonstrated a slight decrease in the protein C level but an undetectable protein C activity. The patient received the diagnosis of homozygous protein C deficiency, because both parents were found to have heterozygous protein C activity. Treatment of the patient's leukemia included induction chemotherapy (Ara-C and idarubicin) with concomitant administration of low molecular weight heparin for his homozygous protein C deficiency. He achieved a complete remission without expressing any thrombosis during the course of chemotherapy. To our knowledge, this is the first case ever described in which acute myeloid leukemia was complicated with homozygous protein C deficiency.

The existence of isolated cytopenia in myelodysplastic syndrome (MDS) has been described, however, the exact clinico-hematologic features of such MDS patients are still obscure. The aim of this study was to provide additive clinico-hematologic information on MDS patients with isolated thrombocytopenia in comparison with idiopathic thrombocytopenic purpura (ITP). We searched for MDS with isolated thrombocytopenia in 146 sequential patients with MDS and evaluated their clinical features at the time of MDS diagnosis. We found 13/146 (8.9%) patients with MDS showing isolated thrombocytopenia. These patients were male predominant (10:3) and were all diagnosed as refractory anemia after reassessment of marrow findings, however, two of them had an initial diagnosis of ITP. Leukemic transformation was rarely noted (1/13 patients), but 1 patient developed myelofibrosis. Cytogenetic study demonstrated that 3 patients had del(20q), 2 had t(1;7)(q10;p10), and 5 showed normal karyotypes. The most prominent morphologic feature in the megakaryocytes was the presence of micromegakaryocytes (5/13) and 8/13 had hypogranulated neutrophils, whereas pseudo-Pelger nuclear anomaly was rarely detectable. Of note is that 7/13 patients had an increased number of megakaryocytes in the marrow. Most patients survived for more than 2 years. Approximately 9% of MDS patients showed isolated thrombocytopenia and most of them had a favorable prognosis. Some MDS patients with isolated thrombocytopenia have been mistakenly diagnosed as having ITP, since approximately 50% of our MDS patients with isolated thrombocytopenia had an increased number of megakaryocytes with low grade dysplasia. Therefore, careful attention to differential diagnosis is recommended for these patients.

Helicobacter pylori has recently been postulated to play a role in the pathogenesis of autoimmune diseases, including idiopathic thrombocytopenic purpura (ITP). We investigated the prevalence of H pylori infection and the effects of its eradication in 61 patients with ITP. H pylori infection was found in 50 patients (83%), an incidence significantly higher than not only healthy volunteers in Japan (60%) but also subjects in other reported ITP series (approximately 43%-71%). In our study, the mean age of H pylori-positive ITP patients (58.0 years) was significantly higher than that of H pylori-negative ITP patients (40.5 years). Bacterium eradication efforts were performed in 29 infected ITP patients and succeeded in 27 patients (93%). The 29 patients with eradicated H pylori infections showed significant increases in platelet counts compared with patients with uneradicated infections or who were H pylori-negative. During the follow-up period (median, 11.0 months), 16 (55%) of 29 patients achieved a major or a minor response. The patients who achieved a major response had not received previous prednisolone therapy, suggesting a relationship between prednisolone therapy and the response to eradication efforts. The assessment of H pylori infection and its eradication should be attempted in cases of ITP, because this approach may be a good new strategy for treating some ITP patients, especially elderly Japanese patients. Some regional factors have been suggested as causes of H pylori-associated ITP.

To evaluate the retinal thickness of the macula in healthy subjects with different axial lengths.Included were 203 healthy subjects (116 males and 87 females). The axial length of the eyes ranged from 22.68 to 30.22 mm. Four optical coherence tomograms were obtained in a radial spoke pattern centered on the central fovea. Retinal thickness was calculated from the inner and outer retinal boundaries. The average retinal thickness in three circular areas surrounding the central fovea (350, 1,850, and 2,850 microm in diameter) was determined.The retinal thickness in the three circular areas was not significantly correlated with the axial length of the eye (P = 0.10, P = 0.39, and P = 0.12). There also was no statistically significant difference found between the average thickness in emmetropic and low myopic, mildly myopic, and highly myopic eyes in the three circular areas (P = 0.35, P = 0.38, and P = 0.14).When eyes with pathologic myopia were excluded, the axial length of the eye was found not to influence the average retinal thickness in the macular area.

We report here an acute myelocytic leukemia (AML-M2) patient with trisomy 13 as the sole cytogenetic anomaly, who had relapse of AML with a normal karyotype and developed multiple myeloma. Fluorescence in situ hybridization analysis using the RB gene probe revealed the plasma cells of multiple myeloma (MM) to have monosomy 13 anomaly, whereas relapsed blast cells of AML carried disomy of chromosome 13. To our knowledge, this is the first case showing clonal evolution of trisomy 13 AML and monosomy 13 MM, which might be derived from the leukemic clone at relapse.

A 73-year-old woman with chronic myeloid leukemia was treated with interferon-alpha, hydroxyurea, and busulfan before imatinib mesylate treatment. The leukocyte count was 8,400/; hemoglobin concentration, 12.0 g/; and platelet count, 19.7 x 10(4)/. She received 400 mg of imatinib mesylate for 17 days before the agent was discontinued because of pancytopenia. A bone marrow biopsy on the 87th day after the last imatinib mesylate administration demonstrated severe hypocellularity. She needed many RBC and Plt transfusions and filgrastim administration. Grade 4 neutropenia continued for 35 days and Grade 3 thrombocytopenia continued for over 122 days. Imatinib mesylate, an agent targeting BCR-ABL, is expected to be useful as an effective therapeutic agent for chronic myeloid leukemia. However the present case suggests that its appropriate dose is individually variable and we should carefully consider the former treatment, and the clinical stage of the disease before initiating imatinib treatment.

It is well known that some patients with monopathic thrombocytopenia in myelodysplastic syndrome (MDS) show clinico-hematologic features resembling chronic idiopathic thrombocytopenic purpura (ITP). This study examined the monoclonal nature of ITP to obtain a further insight into patients with borderline ITP and monopathic thrombocytopenia in MDS, using polymorphic trinucleotide CAG repeats in the X-linked human androgen receptor (HUMARA) gene. In this study, we separated peripheral neutrophils and mononuclear cells (MNCs) from 18 patients with chronic ITP, and analyzed them in comparison with those from normal or MDS female subjects by PCR-based HUMARA assay. All normal controls showed a polyclonal pattern of the HUMARA gene, whereas some MDS patients had monoclonality in MNC and/or neutrophils. Among ITP patients, two had a nonrandom inactivation pattern of the HUMARA gene in neutrophils, which was considered to be derived from hematopoietic cells of clonal origin, whereas no ITP patient had MNC of clonal nature. Two ITP patients with a monoclonal pattern in the neutrophil fraction were refractory to ordinary treatment. This approach may provide further information in patients with borderline hematologic disorders between chronic ITP and refractory thrombocytopenia of MDS.

We report a 26-year-old man with Coats' disease associated with premacular fibrosis. As an initial treatment, the peripheral exduative area was treated with argon laser photocoagulation. Six weeks later, the premacular fibrosis was peeled off and the posterior vitreous membrane was also detached. The patient's visual acuity improved to 20/20. We also observed a change of the vitreous component before and after the treatment that was similar to posterior vitreous detachment (PVD). This is the first reported case in which a distinct vitreous change was observed after premacular fibrosis peeling in Coat's disease.

It has been demonstrated that the chromosomal translocation t(7;11)(p15;p15) in patients with human acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) invariably involves fusion of the nucleoporin gene, NUP98, on chromosome 11 and the class 1 HOX gene, HOXA9, on chromosome 7, and that the fusion gene NUP98-HOXA9 is an important gene in myeloid leukemogenesis. Here are reported 2 novel chromosome 7p15 targets of the t(7;11)(p15;p15) chromosomal translocation in 2 patients with CML and myelodysplastic syndrome (MDS). Southern blot and polymerase chain reaction (PCR) analyses of leukemia cell DNA failed to show rearrangement of HOXA9,whereas NUP98 was found to be rearranged in both cases. Reverse transcription-PCR analysis using a NUP98 primer and a degenerate primer corresponding to the third helix of the homeodomain of HOXA demonstrated that NUP98 was fused in-frame to HOXA11 in the patient with CML and toHOXA13 in the patient with MDS. The chromosomal breakpoints on 7p15 were located within introns of HOXA11 orHOXA13 genes. In both patients chimericNUP98-HOXA9 transcripts were also observed. These findings suggest that AbdB-type HOXA genes are common targets of t(7;11)(p15;p15) chromosomal translocations and that a single translocation can produce more than oneNUP98-HOXA fusion gene, presumably because of altered splicing.

Multiple myeloma (MM) is one of the common hematological malignancies and is a uniformly fatal disorder of B cells characterized by accumulation of abnormal plasma cells in the bone marrow. Proteasome inhibitor, bortezomib, and immunomodulatory drugs such as thalidomide and lenalidomide play important roles in the treatment of MM patients. Although novel agents including, e.g. bortezomib, have significantly improved the response and survival of patients with MM, a large number of patients eventually have relapsed. For the patients who relapse after treatment with novel agents, the prognosis is still poor. Thus circumstanced, alternative strategies are required for continued disease control. Phosphoinositide 3-kinases (PI3Ks) are a family of proteins involved in the regulator of cell growth, metabolism and proliferation. PI3K signaling pathway also plays a critical regulatory role in MM pathology, including survival, cellular proliferation, migration and angiogenesis. Therefore, PI3K signaling pathway may present attractive targets for MM treatment. Copanlisib also known as BAY80-6946 is a potent and highly selective reversible PI3K inhibitor. Copnalisib is currently investigated in a pivotal phase 2 clinical trial against hematological malignancy such as malignant lymphoma. We hypothesized that treatment with PI3K inhibitor and proteasome inhibitors together would result in enhanced therapeutic activity in MM cells. In this study, we investigated the efficacy of copanlisib by using the MM cell lines, RPMI8226, MM1.S and MM1.R and primary sample. 72 h treatment of copanlisib exhibits cell growth inhibition of MM cell lines in a dose dependent manner. The treatment of proteasome inhibitors, bortezomib and carfilzomib exhibits cell growth inhibition partially against RPMI8226 cells in the presence of feeder cell line, HS-5. We examined the intracellular signaling in the presence of HS-5. Phosphorylation of Akt and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) was partially reduced by carfilzomib or bortezomib in the presence of HS-5. We found that the treatment of copanlisib abrogated the protective effects of HS-5 in RPMI8226 cells. We examined the intracellular signaling after treatment of copanlisib. Activity of caspase 3 and poly (ADP-ribose) polymerase (PARP) was increased after copnlisib treatment in a dose dependent manner. Because PI3K signaling pathway regulates MM cell migration, we next evaluated the chemotactic response of MM cells to stromal cell-derived factor 1α (SDF-1α). We found that 4 h treatment of SDF-1α significantly induced the migration of MM cells compared to control medium. Treatment of copanlisib inhibited SDF-1α-stimulated chemotaxis in a dose dependent manner. We found that phosphorylation of Akt was reduced after copanlisib treatment suggesting that intracellular PI3K signaling pathway may play the important role in SDF-1α induced chemotaxis of MM cells. We investigated the copanlisib activity against MM cells. Combined treatment of MM cells with proteasome inhibitor, carfilzomib or bortezomib, and copanlisib caused significantly more cytotoxicity than each drugs alone. Phosphorylation of Akt was reduced and cleaved PARP was increased after copanlisib with or without proteasome inhibitor. We also found that copanlisib which was combinaed with carfilzomib or borteomib exhibited cell growth inhibition against MM primary sample. Data from this study suggested that administration of the PI3K inhibitor, copanlisib may be a powerful strategy against stroma-associated drug resistance of MM cells and enhance cytotoxic effects of proteasome inhibitors in those residual MM cells. Disclosures No relevant conflicts of interest to declare.

Background: The inhibition of BCR-ABL1 kinase with tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis of chronic myeloid leukemia (CML). Recently, it has been recognized that some CML patients with a complete molecular response (CMR) are able to maintain treatment-free remission (TFR) after discontinuation of TKIs. However, no predictive prognostic factors for successful discontinuation of the treatment have yet been identified. We set out to further clarify the role of predictive biomarkers in molecular relapse and non-relapse after ABL TKI discontinuation. Materials and methods: Patients in sustained CMR (MR 4.5) undergoing TKI therapy were eligible for inclusion in the study. Molecular relapse was defined as loss of major molecular response (MMR) of at least one point. Genomic DNA was obtained from whole blood using a DNA Extractor WB Kit (Wako, Osaka, Japan), and was subjected to polymerase chain reaction (PCR) amplification using primers designed to detect a deletion site (2903 bp) in intron two of the BCL2L11 gene (forward: 5′-AATACCACAGAGGCCCACAG-3′; reverse: 5′-GCCTGAAGGTGCTGAGAAAG-3′) and JumpStart RedAccuTaq LA DNA polymerase (Sigma Aldrich, St. Louis, MO, USA). Results: 32 CML patients (17 men, 15 women, median age 58.4 years) were included in this study (Sokal category; low 24, intermediate 7, high 1). Six patients were treated with IFNα before TKI treatment, and 3 were treated with IFNα after stopping TKI. Median duration from TKI initiation to discontinuation was 79.3 months (range; 22 to 138 months); median duration of CMR before TKI discontinuation was 47.3 months (range; 5 to 97 months). Seven patients showed loss of MMR; 6 relapsed within 6 months and one showed late relapse at 25 months after discontinuation. The cumulative incidence of MMR loss was estimated as 18.8% at 12 months and at 24 months. Fluctuation of BCR-ABL transcript levels below the MMR threshold (> two consecutive positive values) was observed in 6.25% of patients at 24 months after ABL TKI discontinuation. Treatment-free remission was estimated as 81.2% at 12 months and at 24 months. The median period of restoration of second CMR was 6.0 months in re-treated patients. No patient died during the follow-up period. TKI-free remission was estimated as 78.1% at 30 months. There was only a significant difference in BCL2L11 (BIM) deletion polymorphism between the patients who maintained and those who lost MMR (p = 0.0253). No significant difference was observed in prior IFNα therapy, time to complete cytogenetic response (CCyR), time to MMR, and time to CMR between relapsing and non-relapsing patients. Conclusion: Our study shows a specific association between BCL2L11 (BIM) deletion polymorphism and clinical outcome after ABL TKI discontinuation in patients with long-lasting molecular undetectable residual disease. BCL2L11 (BIM) deletion polymorphism may predict relapse after ABL TKI discontinuation, which may have an impact on future ABL TKI discontinuation trials. These results further illustrate the importance of single nucleotide polymorphisms in successful long-term treatment of CML. Disclosures Ohyashiki: Bristol-Myers Squibb KK : Research Funding, Speakers Bureau; Novartis KK: Research Funding, Speakers Bureau.

We have investigated multiphoton multiple ionization of Ar and Xe atoms irradiated by intense X-ray pulses using the new X-ray free electron laser facility SACLA. The experimental results are compared with theoretical results.

We have studied charge migration and dissociation in iodine-substituted methane molecules using extremely intense and short 5.5 keV free electron laser pulses from the SACLA XFEL facility. Multiple core ionization down to I 2p subshells creates highly charged molecular states, the fragmentation of which was studied by ion momentum imaging multiparticle coincidence technique. We report experimental and modeling results on various dissociation pathways, fragment momentum correlations, and kinetic energy releases.

We used flow cytometry to measure the activities of cathepsin G and elastase. The activity of elastase in neutrophils from patients with myelodysplastic syndrome (MDS) was significantly lower than that in neutrophils from the control group (P

Uncontrolled thrombocytosis in polycythemia vera is a risk for thrombosis, regardless of JAK2 V617F mutational status