Empirical voriconazole therapy for febrile neutropenic patients with hematological disorders: a prospective multicenter trial in Japan.

An open-label, prospective, multicenter study was conducted between October 2006 and March 2010 to assess the efficacy and safety of intravenous voriconazole (VRCZ) as empirical therapy for antibiotic-refractory febrile neutropenia in Japanese patients with hematological disorders. In addition, to find the patient groups that may benefit from antifungal therapy, the definition of invasive fungal infection proposed by EORTC/MSG (2002) was assessed in this study. Plasma (1-3)-ß-D-glucan and Aspergillus PCR in blood were also measured to improve the diagnostic accuracy. A total of 103 patients (median age, 59 years), including 25 undergoing induction chemotherapies and 19 allogeneic hematopoietic cell transplants, were evaluable. Sixty-nine percent of the patients achieved resolution of clinical symptoms and 31% achieved treatment success, defined as fulfilling the previously described five-part composite endpoint. Although VRCZ was discontinued in 9.7% of the patients because of adverse effects, all the patients recovered soon after discontinuation of VRCZ. The treatment success rate of VRCZ appeared to be higher in patients categorized as "not classified" compared with "possible invasive fungal disease" according to the EORTC/MSG criteria. Moreover, six "not classified" patients were positive for either plasma (1-3)-ß-D-glucan (n = 5) or Aspergillus PCR in blood (n = 2). The present study demonstrates that empirical VRCZ therapy is safe and effective in Japanese patients. Additionally, (1-3)-ß-D-glucan and Aspergillus PCR tests were expected to provide additional information on the diagnosis of invasive fungal infections.

Clinical evaluation of WT1 mRNA expression levels in peripheral blood and bone marrow in patients with myelodysplastic syndromes.

A study to evaluate WT1 mRNA expression levels in peripheral blood (PB) and bone marrow aspirate (BM) was conducted in 172 patients, including 115 with myelodysplastic syndromes (MDS), in Japan. The level of WT1 mRNA expression was evaluated according to the French-American-British (FAB) and World Health Organization (WHO) classifications (2001, 2008) and using the International Prognostic Scoring System and the WHO Prognostic Scoring System scales. WT1 mRNA expression levels in PB and BM were well correlated (r = 0.85), and they tended to increase with disease stage progression and in those at higher risk of leukemic transformation. WT1 mRNA expression can be a useful marker for the diagnosis and risk evaluation of MDS.

Epstein-barr virus in diffuse large B-Cell lymphoma in immunocompetent patients in Japan is as low as in Western Countries.

According to previous reports, the frequency of Epstein-Barr virus (EBV) positivity in diffuse large B-cell lymphoma is higher in East Asia (approximately 9%) than in Western countries. The presence of the EBV genome was examined in diffuse large B-cell lymphoma patients registered with the Osaka Lymphoma Study Group (OLSG) in Osaka, Japan, situated in East Asia. The EBV-positive rate was examined with in situ hybridization (ISH) in 484 immunocompetent diffuse large B-cell lymphoma patients registered with OLSG. The male-to-female ratio was 1.29, with ages ranging from 16 to 95 (median, 68) years. ISH with EBV-encoded small RNAs (EBER) probes revealed positive signals in the nuclei of tumor cells: the frequency of positively stained cells among all tumor cells was almost none in 458 cases, 5-10% in 5, 10-20% in 5, 20-50% in 11, and >50% in 5. When the frequency was >20% or >50%, the EBV-positive rate in the present series (3.3% or 1.0%) was rather similar to that reported in Western cases. Careful evaluation of patient backgrounds, including age distribution, type of lymphomas, exclusion of immunocompromised patients, and establishment of definite criteria for EBV positivity (>20%, >50%, or almost all tumor cells) are essential in comparing geographical differences.

Efficacy of rituximab monotherapy for an elderly hemodialysis patient with primary cardiac lymphoma.

We report a case of primary cardiac lymphoma (PCL) occurring in a 76-year-old man during maintenance hemodialysis. Chest computed tomography (CT) revealed a tumor with pericardial effusion in the left ventricular posterior wall. Cytological examination of the pericardial fluid revealed monotonous lymphoid cells positive for B-cell markers, and clonal immunoglobulin heavy chain gene rearrangement was detected, indicating B-cell lymphoma. Rituximab monotherapy was administered biweekly at the therapeutic level on hemodialysis. The follow-up chest CT showed tumor disappearance with pericardial fluid after two courses of therapy. Rituximab monotherapy was effective for an elderly hemodialysis patient with PCL.

Diffuse large B-cell lymphoma in the spinal epidural space: A study of the Osaka Lymphoma Study Group.

Diffuse large B-cell lymphoma (DLBCL) involving spinal epidural space (SEDLBCL) is relatively rare, constituting 1.8% of DLBCLs in Osaka, Japan. The aim of this study was to analyze SEDLBCL cases for their clinical and histopathologic findings, including an association with Epstein-Barr virus (EBV) and immunohistochemical characteristics. We analyzed the clinicopathologic findings of 27 SEDLBCL cases. They consisted of 16 males and 11 females, their age ranging from 37-86 years (median 64 years). Eight patients had stage I disease, 3 had stage II, 5 had stage III, and 11 had stage IV. Based on the staining pattern for anti-CD10, bcl-6, and MUM-1, the cases were categorized into 17 cases of the germinal center B-cell (GCB) type and nine of the non-GCB type. There was a 4%-positive rate for EBV in the tumor cells. When compared to nodal DLBCL, the frequency of patients with a high performance status (PS) is higher in SEDLBCL. Compared to the DLBCL of the central nervous system (CNS), the frequency of cases with high stage, 2 or more extranodal lesions, high international prognostic index (IPI), and GCB-type is higher in SEDLBCL. There were no significant differences in the histologic features between SEDLBCL and nodal/CNS DLBCL. Univariate analysis revealed that advanced stage was an unfavorable factor for overall survival (P=0.060). SEDLBCL is different from nodal and CNS DLBCL, but an association with EBV is unlikely in every group.

Comparative analysis of remission induction therapy for high-risk MDS and AML progressed from MDS in the MDS200 study of Japan Adult Leukemia Study Group.

A total of 120 patients with high-risk myelodysplastic syndrome (MDS) and AML progressed from MDS (MDS-AML) were registered in a randomized controlled study of the Japan Adult Leukemia Study Group (JALSG). Untreated adult patients with high-risk MDS and MDS-AML were randomly assigned to receive either idarubicin and cytosine arabinoside (IDR/Ara-C) (Group A) or low-dose cytosine arabinoside and aclarubicin (CA) (Group B). The remission rates were 64.7% for Group A (33 of 51 evaluable cases) and 43.9% for Group B (29 out of 66 evaluable cases). The 2-year overall survival rates and disease-free survival rates were 28.1 and 26.0% for Group A, and 32.1 and 24.8% for Group B, respectively. The duration of CR was 320.6 days for Group A and 378.7 days for Group B. There were 15 patients who lived longer than 1,000 days after diagnosis: 6 and 9 patients in Groups A and B, respectively. However, among patients enrolled in this trial, intensive chemotherapy did not produce better survival than low-dose chemotherapy. In conclusion, it is necessary to introduce the first line therapy excluding the chemotherapy that can prolong survival in patients with high-risk MDS and MDS-AML.

Polymorphous lymphoproliferative disorder: a clinicopathological analysis.

Lymphoproliferative disorder (LPD) with polymorphous composition of proliferation (polymorphous LPD), containing large lymphoid cells together with small lymphocytes, plasma cells, macrophages, and/or eosinophils, is found in individuals with immunodeficiency conditions. Clinicopathological findings in 19 cases of polymorphous LPD registered with the Osaka Lymphoma Study Group, Osaka, Japan, were analyzed; they represented 0.4% of the registered cases. In six cases, there was a history of rheumatoid arthritis; five of them had received immunosuppressive agents. There were no acquired immunodeficiency syndrome cases or organ transplant recipients. Southern blotting and/or polymerase chain reaction (PCR)-based clonality analysis revealed monoclonal B cell and T cell proliferation in eight and six cases (B- and T-LPD), respectively, and polyclonality in one. In B-LPD, there was polymorphous proliferation, containing large B-lymphoid cells, while medium-to-large T lymphoid cells with occasional eosinophilic infiltration were seen in T-LPD. Epstein-Barr virus (EBV) was detected in three of eight B-LPD, four of six T-LPD, and one of one polyclonal LPD. The prognosis was not favorable; the 3-year overall survival rate was 49.7 +/- 17.3%. Thus, polymorphous LPD is relatively rare in Japan and is a heterogeneous disease with monoclonal proliferation of B or T cells; additionally, it is occasionally EBV-associated, and behaves as an aggressive lymphoma.

Relationship between expression of mutant type glutathione S-transferase theta-1 gene and reactivity of rapamycin in myelodysplastic syndrome.

We previously reported mRNA expression of glutathione S-transferases theta (GSTT)-1, wild type (623 bp) and mutant (500 bp), in patients with myelodysplastic syndrome (MDS). The deletion of 123 bp creates a sequence that is homologous to the mammalian target of rapamycin (mTOR). To analyze the function of mutant GSTT-1 gene, stable transformants for the mutant and wild-type GSTT-1 gene, respectively, were established. In this study, the expression of the wild and mutant type of the GSTT-1 gene of those stable transformants in cell lines and in bone marrow cells from MDS patients by reverse-transcription polymerase chain reaction (RT-PCR) was observed in the presence or absence of rapamycin. Significant growth inhibition by rapamycin was observed among stable transformants for the mutant GSTT-1 gene, but not wild type GSTT-1 gene, and was indicative of typical apoptosis.

Diffuse large B-cell lymphoma with a high number of epithelioid histiocytes (lymphoepithelioid B-cell lymphoma): a study of Osaka Lymphoma Study Group.

The aim of this study was to clarify whether diffuse large B-cell lymphoma (DLBCL) with a high number of epithelioid histiocytes (DLBCL-EH) could have distinctive clinicopathological characteristics. Clinicopathological findings in 22 cases with DLBCL-EH and, as a control, 96 cases with ordinary type of DLBCL were analyzed. There were ten men and 12 women with ages ranging from 38 to 91 (median, 64) years. The primary site was lymph node in 16 cases, extranodal organs in three, and unknown in three. Stage of disease was I in five cases, II in three, III in nine, and IV in five. Histologically, there was a diffuse proliferation of large lymphoid cells admixed with numerous clusters of epithelioid histiocytes sprinkling throughout the lesions. Immunohistochemically, the large lymphoid cells were CD20(+), CD15(-), and CD3(-) and positive for CD10, bcl-6, and MUM1 in nine (41%), eight (36%), and 12 (55%) of 22 cases, respectively. Epstein-Barr virus positive rate was higher in DLBCL-EH (23.8%) than that in ordinary DLBCL (4.5%; P<0.05). Clonality analysis revealed monoclonal bands in all of the examined 20 cases with DLBCL-EH. Multivariate analysis revealed the prominent epithelioid reaction to be an independent factor for favorable prognosis. These findings suggest that DLBCL-EH could be a specific morphological variant of DLBCL associated with a better prognosis.

[Diffuse large B-cell lymphoma presenting with hypoglossal nerve palsy and great occipital neuralgia].

A 74-year-old man was hospitalized with hypoglossal nerve paralysis and severe great occipital neuralgia. Enhanced MRI of the head showed tumor on the left petrous bone, which compressed the medulla oblongata. Soluble IL-2 receptor was elevated and malignant lymphoma was clinically diagnosed. PET-CT demonstrated a single hot spot on the spleen. After radiation therapy to the lesion on the petrous bone, splenectomy was performed. Pathological findings established a diagnosis of diffuse large B-cell lymphoma. After chemotherapy consisting of rituximab and THP-COP, complete remission was achieved.

Efficacy and safety of micafungin, an echinocandin antifungal agent, on invasive fungal infections in patients with hematological disorders.

The study was conducted as a prospective multicenter trial to evaluate the efficacy and safety of micafungin in patients with invasive fungal infections (IFIs) in hematological disorders. A total of 277 patients was registered, and 197 were assessed for clinical efficacy. The mean dosage and duration of micafungin were 170.7 mg/day and 22.0 days, respectively. The efficacy rates were 87.5% (7/8) for patients with candidiasis, 44.7% (17/38) for probable IFIs, 61.9% (39/63) for possible IFIs and 80.7% (71/88) for those who failed to respond to antibacterials. In patients with febrile neutropenia (below 500 microL), despite broad-spectrum antibacterial treatment over 2 days, 86.3% (44/51) of patients had a favourable response to micafungin. The incidence of adverse events related to micafungin was 14.1% (39/277), but most of them were mild and reversible. These data indicate the usefulness of micafungin as a novel therapeutic drug for both empirical and targeted therapy for IFIs.

Change of CD20 Expression in Diffuse Large B-Cell Lymphoma Treated with Rituximab, an Anti-CD20 Monoclonal Antibody: A Study of the Osaka Lymphoma Study Group.

Change of CD20 expression was examined in cases of diffuse large B-cell lymphoma (DLBCL). CD20 expression after treatment with anti-CD20 antibody (rituximab, Rx) for DLBCL was examined in 23 cases who received serial biopsy by immunohistochemistry (IHC) and flow cytometry (FCM). CD20- by IHC and/or FCM was defined as CD20-. Four cases were CD20- at initial biopsy but became CD20+ after chemotherapy with Rx (CH-R) (group A). Recurrent tumors in three group A cases became resistant to CH-R. Initial and recurrent tumors were CD20+ before and after CH-R in 17 cases (group B). Tumors before CH-R were CD20- in two cases (group C) and continued to be CD20- in one and turned CD20+ in the other with survival time after the relapse of 8 and 23 months, respectively. Evaluation of CD20 expression with immunohistochemical and flow cytometric methods is used for the prediction of responsiveness of relapsed DLBCL for CH-R.

Hypersensitivity of Ph-positive lymphoid cell lines to rapamycin: Possible clinical application of mTOR inhibitor.

The BCR/ABL tyrosine kinase inhibitor, imatinib mesylate, has shown substantial effects in chronic myelogenous leukemia (CML) and Ph-positive acute lymphoblastic leukemia (Ph(+)ALL). However, most patients relapse after an initial clinical response, indicating that drug resistance is a major problem in patients on imatinib. It is a serious problem that effective treatment choices to T315I, in the ABL kinase domain that shows a strong tolerance in imatinib do not exist clinically. In this study, we propose a new therapeutic approach to Ph(+)ALL with the T315I. Here, we report that the serine/threonine kinase mTOR (the mammalian target of rapamycin) inhibitor, rapamycin, inhibits the growth of not only the Bcr-Abl-positive lymphoid leukemic cell line, SU-Ph2, established from Ph(+)ALL patients, but also the imatinib-resistant cell line, SU/SR, that has acquired T315I. Rapamycin significantly inhibits cell growth in both these cell lines, and easily induces apoptosis at the same dose, thereby acting as an immunosuppressive agent. Our result suggested that the mTOR-signaling pathway has become an important therapeutic target for Ph-positive leukemias in the future, and at the same time, it is also becoming a very effective tool for the treatment of Ph(+)ALL with T315I.

Influence of Epstein-Barr virus infection in adult T-cell leukemia.

The involvement of adult T-cell leukemia (ATL) cells in organs such as the skin and lymph nodes is observed in about 50% of cases of ATL. Epstein-Barr virus (EBV) infection has often been observed in the clinical course of ATL. In this study, we established two B-cell lines from peripheral blood of patients with ATL. EBV DNA, proviral DNA for HTLV-1 and Tax mRNA were detected in both lines. As part of the characterization of these cells, an enhanced expression of intercellular adhesion molecule-1 (ICAM-1) (CD54) or ICAM-3 (ICAM-3) (CD50), lymphocyte function-1 (LFA-1) (CD11a/CD18), and Mac-1 (CD11b/CD18) was observed. To investigate the role of the interaction of these viruses, we transfected EBV and/or HTLV-1 into a healthy donor's lymphocytes, an EBV-infected B cell line, Raji, and a HTLV-1 negative T-cell line, Jurkat. Enhanced expression of adhesion molecules was also observed in double transfectants (EBV and HTLV-1). In the clinical course of ATL, LMP-1, EBNA-2, CD50 and CD54 were detected in lymph nodes and skin specimens by immunohistochemical staining. Furthermore, high levels of interleukin-4 (IL-4) were detected in these cell lines and transfectants. The results indicated that coinfection with HTLV-1 and EBV may induce aggressive organ involvement through the enhanced expression of adhesion molecules via IL-4 signaling. A new mechanism of ATL involvement is discussed.

[Iron deficiency anemia].

Iron deficiency anemia (IDA) is defined as a disease of the reduced erythrocyte production with low content of hemoglobin, because of the lack of iron which is the most important constituent of hemoglobin. The main cause of the deficiency is blood loss including the mensturation and hemorrhage. The frequency of IDA is as high as 9.1% among 10 to 19 years cohort of apparently healthy women in metropolitan area of Japan. The pathophysiology of the deficiency, clinical features, laboratory findings, diagnosis and treatment are discussed as well as the basic findings of iron absorption mechanism in which the newly found factors such as DMT-1 and hepcidin are involved.

The expression of anamorsin in diffuse large B cell lymphoma: possible prognostic biomarker for low IPI patients.

Anamorsin is a cell-death-defying factor, which was originally isolated as a molecule that conferred resistance to apoptosis induced by growth factor starvation. In order to evaluate anamorsin expression levels in malignant lymphoma, we immunostained paraffin-embedded sections with anti-anamorsin monoclonal antibodies. About 40% (89/234) of sections from patients with diffuse large B cell lymphoma (DLBCL) showed strong anamorsin expression. Comparing the level of anamorsin expression in DLBCL patients with their clinical features (i.e., overall survival rate, International Prognostic Index (IPI) parameters, and treatment response) revealed no significant correlation between anamorsin expression levels and these clinical features. However, anamorsin expression in DLBCL patients with a low IPI was shown to be an unfavorable biomarker, especially in the patients who received chemotherapy without rituximab. It is suggested that anamorsin might play some roles in the abnormal growth of DLBCL.

Clinical efficacy of all-trans retinoic acid for treating adult T cell leukemia.

PURPOSE: We previously reported that all-trans retinoic acid (ATRA) inhibited growth in human T-cell leukemia virus type I (HTLV-I)-positive T-cell lines and in fresh cells from patients with adult T cell leukemia (ATL). Here, we confirmed the clinical effects of ATRA in 20 patients with ATL. MATERIALS AND METHODS: The 20 patients (n = 20) with a median age of 56 (range 35-73) years who were diagnosed with ATL received ATRA orally. RESULTS: The efficacy of treatment was as follows: no complete response (CR), a partial response (PR) in 40% of the patients, no change (NC) in 45% of the patients, and a progressive disease (PD) in 15% of the patients. In seven acute-type ATL patients, a PR was achieved in two (28.5%), NC was observed in two (28.5%), and a PD was observed in three (42.8%). In three lymphoma-type ATL patients, a PR (100%) was achieved. Among four chronic-type ATL patients, a PR was achieved in one (25%) and NC was observed in the remaining three (75%). In six smoldering-type ATL patients, a PR was achieved in two (33.3%) and NC was observed in four (66.6%). The major side effects were headache (n = 5), transient liver dysfunction (n = 2), hyperlipidemia (n = 2), and anorexia (n = 1). CONCLUSION: These results indicated that ATRA might be a useful agent for the safe treatment of ATL.

All-trans retinoic acid attacks reverse transcriptase resulting in inhibition of HIV-1 replication.

We previously reported that all-trans retinoic acid (ATRA) inhibited growth in HTLV-1-positive T-cell lines and fresh cells from patients with adult T-cell leukemia. Interestingly, ATRA significantly inhibited reverse transcriptase (RT) activity similar to azidothimidine (AZT) in HTLV-1-positive T-cell lines. To clarify whether ATRA has an inhibitory effect on the replication of HIV, we examined HIV proviral DNA in a HIV-1-positive cell line (8E5) using real time PCR. ATRA as well as AZT reduced the proviral DNA load of 8E5 in a dose-dependent manner. These results suggest that there is a common element of ATRA signaling in both HTLV-1 and HIV. Furthermore, we examined the effects of ATRA on viral replication in primary lymphocytes of three individuals infected with HIV. ATRA reduced viral replication significantly similar to AZT. These findings suggested that ATRA acts as a RT inhibitor, reducing the HIV-1 proviral DNA load. Finally, we conclude that ATRA may be a potential therapeutic agent for HIV infection.