Clinical Efficacy and Safety of Arbekacin against Pneumonia in Febrile Neutropenia: A Retrospective Study in Patients with Hematologic Malignancies.

BACKGROUND: Arbekacin (ABK) is an aminoglycoside that exhibits anti-methicillin-resistant Staphylococcus aureus (MRSA) and anti-Pseudomonas aeruginosa activities. Therefore, for patients with febrile neutropenia (FN) and concurrent pneumonia suspected to be caused by MRSA, ABK may be sufficiently effective even as a single agent. MATERIALS AND METHODS: Patients with hematologic malignancies treated with ABK who met the following criteria were included: 1) fever during neutropenia or functional neutropenia, 2) FN complicated by pneumonia, and 3) possible infection by antimicrobial-resistant Gram-positive cocci. RESULTS: This study encompassed 22 episodes involving 19 patients, of which, 15 (68.2%) were successfully treated with ABK. Of the nine episodes showing inadequate response to other anti-MRSA drugs, eight were successfully treated with ABK. Grade 2 or worse adverse events included acute kidney injury (13.6%) and increased transaminase levels (9.1%). CONCLUSION: The present study demonstrated that ABK is effective and safe in patients with FN and concurrent pneumonia caused by antimicrobial-resistant Gram-positive cocci. ABK may also be effective in patients who are unresponsive to other anti-MRSA drugs. Therefore, ABK may be beneficial in the treatment of pneumonia caused by antimicrobial-resistant Gram-positive cocci in patients with FN.

Prognostic impact of trisomy 21 in follicular lymphoma.

The chromosomal abnormalities associated with follicular lymphoma (FL) prognosis are not fully elucidated. Here, we evaluated the pattern of chromosomal abnormalities in FL, and clarified the correlations between the cytogenetic features and clinical outcome. Cytogenetic analysis was performed using standard methods of Giemsa-banding at diagnosis for 201 FL patients admitted to our hospitals between 2001 and 2013. The identified chromosomal abnormalities were: t(14;18)(q32;q21) (59·2%), +X (17·9%), del(6)(q)/-6 (16·9%), +7 (14·4%), abnormality of 1q12-21/1q (12·9%), del(13)(q)/-13 (11·9%), abnormality of 3q27 (10·4%), abnormality of 10q22-24 (10·0%), +12/dup(12)(q) (10·0%), abnormality of 1p21-22/1p (9·0%), +18 (9·0%), del(17)(p)/-17 (5·0%), and a complex karyotype (54·7%). Patients with trisomy 21 had a significantly shorter progression-free survival (P = 0·00171) and overall survival (OS) (P < 0·001) than those without trisomy 21; additionally, patients with trisomy 21 in the rituximab-treated cohort also had a significantly shorter OS (P = 0·000428). Multivariate analysis identified trisomy 21 as an independent risk factor in our cohorts with or without t(14;18) (P = 0·015). In conclusion, the presence of trisomy 21 was an independent risk factor for in FL. Chromosomal analysis of FL patients at diagnosis can provide useful information about their expected survival.

Randomized phase II study of a bendamustine monotherapy schedule for relapsed or refractory low-grade B-cell non-Hodgkin lymphoma or mantle cell lymphoma (RABBIT-14).

The aim of this randomized phase II study was to improve the treatment delays and discontinuations associated with bendamustine use by comparing the effect of Benda-14 (intravenous bendamustine, 120 mg/m2 on days 1 and 15, repeated every 4 weeks for a total of 6 cycles) with those of the standard treatment in relapsed indolent lymphoma and/or mantle cell lymphoma. Forty-six patients were randomly assigned to the treatments from September 2012 to February 2016. Treatment accomplishment rate and median relative dose intensity were similar in both arms: 38 and 63.4% in the Benda-14 arm and 41 and 66.3% in the standard treatment arm, respectively. The overall response rate and median progression-free survival, respectively, were 83% and 21.0 months for Benda-14, and 77% and 15.5 months for the standard treatment. Benda-14 induced favorable responses with less frequent hematological toxicities.

[Bone disease in multiple myeloma].

Osteolytic bone disease in multiple myeloma (MM) affects more than 80% of patients. Bone disease results in severe bone pain, pathologic fractures, and hypercalcemia. These complications have not only a negative impact on quality of life but also effect in overall survival. MM bone lesions arise from the altered bone remodeling due to both increased osteoclast activation and decreased osteoblast differentiation. Myeloma cells directly stimulate the osteoclast formation, and induce various cells in the marrow microenvironment to produce factors that stimulate osteoclast formation and suppress osteoblast formation. Furthermore many factors produced by marrow stromal cells and osteoclast promote tumor growth through direct action on myeloma cells. Therefore, novel agents targeting bone disease are also promising therapeutic strategies for the treatment of MM.

Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma.

Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is extremely rare, and the etiology of disease is not fully understood. We present herein the case of a primary hepatic MALT lymphoma with Helicobacter pylori and hepatitis C virus infection. A 71-year-old male was admitted to our institution to undergo a precise evaluation of a hepatic tumor incidentally detected during a computed tomography (CT) scan for chest examination. Dynamic CT showed faint enhancement during the arterial phase. The gadoxetate disodium-enhanced magnetic resonance imaging showed a hyper-intensity on the arterial phase and low intensity during the late and hepatocyte phases. Liver biopsy specimen showed small to intermediate size atypical lymphocytes with positive CD20 immunohistochemical staining. It was finally diagnosed as primary hepatic MALT lymphoma. FDG-PET/CT showed faintly increased uptake with a maximum standardized uptake value of 4.6, and did not show other pathological uptake. We present the rare case of primary hepatic MALT lymphoma and discussed the etiology of this disease.

Atypical lymphoplasmacytic and immunoblastic proliferation of autoimmune disease : clinicopathologic and immunohistochemical study of 9 cases.

Atypical lymphoplasmacytic immunoblastic proliferation (ALPIB) is a rare lymphoproliferative disorder (LPD) associated with autoimmune disease (AID). To further clarify the clinicopathologic, immunohistological, and genotypic findings of ALPIB in lymph nodes associated with well-documented AIDs, 9 cases are presented. These 9 patients consisted of 4 patients with systemic lupus erythematosus, 3 patients with rheumatoid arthritis, and one case each with Sjögren's syndrome and dermatomyositis. All 9 patients were females aged from 25 to 71 years with a median age of 49 years. Four cases presented with lymphadenopathy as the initial manifestation. In 4 patients, immunosuppressive drugs were administered before the onset of lymph node lesion. However, none of the 9 patients received methotrexate therapy. The present 9 cases were characterized by : (i) prominent lymphoplasmacytic and B-immunoblastic infiltration ; (ii) absence of pronounced arborizing vascular proliferation ; (iii) absence of CD10(+) "clear cells" ; (iv) presence of hyperplastic germinal center in 7 cases ; (v) immunohistochemistry, flow cytometry, and polymerase chain reaction demonstrated a reactive nature of the T- and B-lymphocytes ; and (vi) on in situ hybridization, there were no Epstein-Barr virus -infected lymphoid cells in any of the 9 cases. Overall 5-year survival of our patients was 83%. The combination of clinical, immunophenotypic, and genotypic findings indicated that the present 9 cases can be regarded as having an essentially benign reactive process. Finally, we emphasized that ALPIB should be added to the differential diagnostic problems of atypical LPDs, particularly lymph node lesions of IgG4-related diseases.

Hodgkin lymphoma presenting with various immunologic abnormalities, including autoimmune hepatitis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, and immune thrombocytopenia.

Immunologic abnormalities have been described in patients with Hodgkin lymphoma, including autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). In this report, we describe a rare case of a 59-year-old woman who had autoimmune-mediated hepatitis and Hashimoto's thyroiditis at initial presentation of Hodgkin lymphoma. She was treated with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine), which induced a complete remission. One year later, she developed a sudden Coombs-positive hemolytic anemia and immune thrombocytopenia. She was diagnosed with Evans syndrome and was treated with prednisolone and intravenous immunoglobulin. However, the response of the therapies was poor; she died of progressive thrombocytopenia. The autopsy revealed the relapse of Hodgkin lymphoma of cervical lymph nodes. Although autoimmune disorders are described in Hodgkin lymphoma, our case shows a rare instance of a patient who had various immunologic abnormalities, including autoimmune-mediated hepatitis, Hashimoto's thyroiditis, AIHA, and ITP.

[Successful treatment of azole-refractory Candida guilliermondii fungemia with a combination therapy of micafungin and liposomal amphotericin B].

Candida guilliermondii (C. guilliermondii) are uncommon, representing approximately 1% of all Candida infections, but have been reported to show a higher rate of drug-resistance and mortality rate than C. albicans. Current guidelines for treatment of non-albicans candidemia in neutropenic patients now recommend the use of amphotericin B or voriconazole (VRCZ). We describe here the successful treatment for a 58-year-old male with azole-refractory C. guilliermondii fungemia by combination with liposomal (L-AmB) and micafungin (MCFG) therapy. He was diagnosed as having mantle cell lymphoma, and treatment with HyperCVAD (Rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) was started. Despite prophylactic treatment with fluconazole, he developed fungemia due to C. guilliermondii 41 days after the start of chemotherapy. Positive blood culture and high levels of (1-->3)-beta-D-glucan persisted despite changing the treatment from fluconazole to voriconazole. Although L-AmB was also added to VRCZ, the clinical symptoms worsened. When MCFG was combined with L-AmB, the symptoms and data dramatically improved. Thus, combination therapy consisting of MCFG and L-AmB might be more effective against candidemia that is refractory to azole than combination therapy with VRCZ and L-AmB.

[Splenic marginal zone B-cell lymphoma with bilateral renal invasion after splenectomy].

A 61-year-old woman presented with hepatosplenomegaly, systemic lymphadenopathy, anemia, and thrombocytopenia. Peripheral blood and bone marrow examination showed atypical lymphoid cells with villi. Immunophenotyping of these cells was CD19+CD20+CD5-CD10-CD23-, and light chain restriction (kappa) was positive. To confirm the diagnosis histologically, we performed a splenectomy and diagnosed the patient's disease as splenic marginal zone lymphoma (SMZL). She rapidly recovered normal hematological parameters and gallium-67 citrate scan showed no increased uptake. Two months after the splenectomy, however, she was readmitted with findings of 15% blasts in the peripheral blood and massive infiltration of the bone marrow by large blastoid cells. Laboratory evaluations were positive for monoclonal IgM-kappa protein. Under acute renal dysfunction, we performed a CT scan that showed bilateral enlargement of the kidneys with features suggestive of an infiltrative process besides systemic lymph node enlargement. A kidney biopsy established the diagnosis of lymphoma with renal infiltration. SMZL is characterized by an indolent clinical course, and no previous report has described SMZL with bilateral renal invasion. Complete remission was obtained after 3 cycles of chemothreapy (R-CHOP). She is undergoing 3 more courses and remains in remission 6 months after the rapid progress of her illness.

Prevalence and clinical characteristics of acute myeloid leukemia associated with disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is one of the important complications to develop in patients with acute myeloid leukemia (AML). While acute promyelocytic leukemia (APL) is a strong risk factor for DIC, other clinical features have not been fully defined. We retrospectively analyzed 161 consecutive adult patients with de novo non-APL AML. DIC was diagnosed in 52 patients (32%); 28 patients at diagnosis and 24 soon after the initiation of induction chemotherapy. Leukocyte counts, C-reactive protein, and lactate dehydrogenase were significantly higher in the DIC+ group. Negative expressions of CD13, CD19, CD34, and HLA-DR were more prevalent in the DIC+ group. On multivariate logistic-regression analysis, variables that were independently associated with the development of DIC were high C-reactive protein, high leukocyte count, negative expressions of CD13 and HLA-DR, and cytogenetics with a normal karyotype or 11q23 abnormality. Although DIC is considered to be associated with serious morbidity and occasional mortality, we did not find any significant differences in the complete remission rate, overall or disease-free survival between DIC+ and DIC- groups. This study is the first to define the clinical characteristics associated with DIC in patients with non-APL AML, but exactly how and when DIC should be treated remains to be determined.

[Polyclonal B-cell lymphocytosis with hairy cell appearance: hairy B-cell lymphoproliferative disorder].

A 72-year-old woman was referred to our hospital for evaluation of leukocytosis revealed by a medical examination. Her physical examination demonstrated no splenomegaly and no palpable lymph nodes. Her white cell count was 10,900/microl with atypical lymphocytosis (84.5%). Her hemoglobin concentration was 10.4 g/dl, and platelet count 151,000/microl. On peripheral blood smears, the atypical lymphocytes had a hairy cell-like appearance, and phase-contrast microscopic and transmission electron microscopic findings revealed the lymphocytes had many long surface microvilli. Flowcytometric analysis of peripheral blood lymphocytes identified expanded B-lymphocytes as having the IgG+, CD5- CD10- CD11c+ CD19+ CD20+ CD23- CD25- and CD103- cell surface phenotype. Serum electrophoresis disclosed polyclonal elevation of IgG and IgM (2620 mg/dl and 840 mg/dl, respectively). No light-chain restriction and a polyclonal VH gene rearrangement pattern indicated the polyclonal proliferation of B cells. The patient was a nonsmoker and had HLA-DR4, as in previous reports which have suggested an association between hairy B-cell lymphoproliferative disorder (HBLD) and HLA-DR4. No chromosome 3 abnormality was observed. These findings were consistent with the characteristics of HBLD, but differed in some respects from those of persistent polyclonal B-cell lymphocytosis (PPBL). Therefore, we diagnosed this patient as having HBLD.

JAK2-V617F mutation analysis of granulocytes and platelets from patients with chronic myeloproliferative disorders: advantage of studying platelets.

There have been conflicting reports over the JAK2-V617F mutation status of platelets in chronic myeloproliferative diseases (CMPDs). The aim of this study was to analyse JAK2-V617F status, not only in granulocytes but also in platelets. The JAK2-V617F mutation was analysed in both granulocytes and platelets in 115 patients with CMPDs using direct sequencing. JAK2-V617F was detected in granulocytes from 71 of those patients, all 71 of whom also had platelet JAK2-V617F expression. The remaining 44 patients showed negative JAK2-V617F expression on granulocytes, but positive JAK2-V617F expression was detected on the platelets from nine of the 33 essential thrombocythaemia (ET) patients, one of the eight polycythaemia vera patients, and two of the three primary myelofibrosis patients. When ET patients were divided into three groups according to granulocyte and platelet JAK2-V617F status (both-positive, platelets-only positive and both-negative), the both-positive and platelets-only positive groups shared the clinical features of higher white blood cell count and frequent thrombosis. These results suggest that analysis of platelets is a more sensitive approach for detecting JAK2-V617F in CMPD patients than analysis of granulocytes. They also suggest that previous reports of the incidence of JAK2-V617F in CMPD patients, obtained using only analysis of granulocytes, could be underestimations.

[Acquired hemophilia A developed at relapse of minimal change nephrotic syndrome].

We present a case of a 74-year-old male, who had a relapse of minimal change nephrotic syndrome (MCNS) as the initial presentation of acquired hemophilia A. MCNS had been maintained in remission with prednisolone 10 mg for 15 years. In early December 2005, the patient developed edema of the right leg, was admitted to a local general hospital, and was diagnosed as having a relapse of MCNS based on massive proteinuria (urine protein 6.1 g/day). One week later, severe anemia (hemoglobin 4.4 g/dl) and acute renal failure (creatinine 2.0 mg/dl) developed, and a CT scan of the abdomen revealed a hematoma in the left iliopsoas muscle. He was referred to our hospital with bleeding tendency. Laboratory examination revealed prolonged APTT 80.5 seconds), reduced factor VIII activity (<1%) and thepresence of factor VIII inhibitor at a titer of 19 Bethesda units/ml, based on which he was diagnosed as having acquired hemophilia A. With recombinant activated FVII, hemostasis was obtained and prednisolone administration 60 mg/day (1 mg/kg) was started. Both the acquired hemophilia A and MCNS responded well to the treatment with prednisolone. Six weeks after initiation of the treatment, factor VIII inhibitor and urine protein disappeared. This patient is considered to be a rare case; to the best of our knowledge, this is the third report of acquired hemophilia A with nephrotic syndrome.

Hodgkin lymphoma accompanied by aplastic anemia and polyclonal expansion of large granular lymphocytes.

Immunologic abnormalities have been described in patients with Hodgkin lymphoma, including autoimmune hemolytic anemia and immune thrombocytopenic purpura. The concurrent diagnoses of Hodgkin lymphoma and acquired aplastic anemia, however, is extremely rare. We report a 56-year-old Japanese female patient with severe aplastic anemia and increased large granular lymphocytes prior to the recurrence of Hodgkin lymphoma. After being in remission for 10 years from Hodgkin lymphoma, she developed progressive pancytopenia. The large granular lymphocytes (expressed CD3+ CD8+ TCRalphabeta+) had a polyclonal distribution, the serum-soluble FasL concentration was significantly elevated, and bone marrow biopsy showed severely hypocellular bone marrow without infiltration of abnormal lymphocytes. No lymphadenopathy was observed that would suggest a relapse of Hodgkin lymphoma. A diagnosis of aplastic anemia was made, and treatment with corticosteroids and cyclosporine was initiated. Two months later, she suddenly developed celiac and mediastinal lymphadenopathy. She underwent one cycle of chemotherapy before she died of progressive pancytopenia. Autopsy revealed the recurrence of Hodgkin lymphoma, nodular sclerosis in the lymph nodes and markedly hypocellular bone marrow. Although autoimmune disorders are described in Hodgkin lymphoma, our case shows a rare instance of a patient who had aplastic anemia as the first manifestation of a relapse of Hodgkin lymphoma.

Transjugular intrahepatic portosystemic shunt for the treatment of portal hypertension due to idiopathic myelofibrosis.

A 59-year-old man was diagnosed to have idiopathic myelofibrosis (IMF) in November 2001. In April 2004, massive ascites and esophageal varices were found. IMF was considered to be the cause of portal hypertension (ascites and esophageal varices). Since ascites tend to be intractable with diuretic drugs, a transjugular intrahepatic portosystemic shunt (TIPS) was inserted in May 2004. Before TIPS, his waist measured 98 cm. On day 74 after TIPS, his waist measured 68 cm as a result of the administration of diuretic drugs alone. He eventually died due to hepatic failure on day 168 after TIPS. The autopsy findings suggest that sinusoidal fibrosis caused portal hypertension.

Sacroiliitis as an initial manifestation of acute myelogenous leukemia.

Sacroiliitis is the most pathognomonic and earliest manifestation of ankylosing spondylitis. We herein report a 28-year-old female patient who presented with sacroiliitis as an initial manifestation of acute myelogenous leukemia (AML). She had a 3-month history of anemia and walking difficulty. Bone marrow findings revealed an increase of blasts with trilineage dysplasia. Although she was initially diagnosed with myelodysplastic syndrome (MDS), blasts rapidly increased and AML developed 1 month after the diagnosis of MDS with Sacroiliitis. Induction chemotherapy failed to induce a complete remission of AML, but it did effectively treat the sacroiliitis. However, the sacroiliitis relapsed when the leukemia cells progressed thereafter. Oral corticosteroids helped ameliorate the sacroiliitis. She underwent bone marrow transplantation (BMT) from an HLA-identical sister during a nonremission period; however, the leukemic cells began to rapidly increase from day 30 after BMT. The close relationship between the occurrence of sacroiliitis and AML suggested that autoimmune sacroiliitis was a paraneoplastic phenomenon of AML in this patient. Although autoimmune disorders develop in a substantial number of MDS patients, they are rarely observed in de novo AML. No previous report has described sacroiliitis as the initial manifestation of de novo AML.