Japanese Society of Clinical Oncology clinical practice guidelines 2010 for antiemesis in oncology: executive summary.

The purpose of this article is to disseminate the standard of antiemetic therapy for Japanese clinical oncologists. On the basis of the Appraisal of Guidelines for Research and Evaluation II instrument, which reflects evidence-based clinical practice guidelines, a working group of the Japanese Society of Clinical Oncology (JSCO) reviewed clinical practice guidelines for antiemesis and performed a systematic review of evidence-based domestic practice guidelines for antiemetic therapy in Japan. In addition, because health-insurance systems in Japan are different from those in other countries, a consensus was reached regarding standard treatments for chemotherapy that induce nausea and vomiting. Current evidence was collected by use of MEDLINE, from materials from meetings of the American Society of Clinical Oncology National Comprehensive Cancer Network, and from European Society of Medical Oncology/Multinational Association of Supportive Care in Cancer guidelines for antiemesis. Initially, 21 clinical questions (CQ) were selected on the basis of CQs from other guidelines. Patients treated with highly emetic agents should receive a serotonin (5-hydroxytryptamine; 5HT3) receptor antagonist, dexamethasone, and a neurokinin 1 receptor antagonist. For patients with moderate emetic risk, 5HT3 receptor antagonists and dexamethasone were recommended, whereas for those receiving chemotherapy with low emetic risk dexamethasone only is recommended. Patients receiving high-emetic-risk radiation therapy should also receive a 5HT3 receptor antagonist. In this paper the 2010 JSCO clinical practice guidelines for antiemesis are presented in English; they reveal high concordance of Japanese medical circumstances with other antiemetic guidelines that are similarly based on evidence.

PI3K/p110{delta} is a novel therapeutic target in multiple myeloma.

In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110delta signaling in multiple myeloma (MM). Knockdown of p110delta by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110delta specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines and patient MM cells, associated with inhibition of Akt phosphorylation. In contrast, CAL-101 did not inhibit survival of normal peripheral blood mononuclear cells. CAL-101 overcame MM cell growth conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cell coculture. Interestingly, inhibition of p110delta potently induced autophagy. The in vivo inhibition of p110delta with IC488743 was evaluated in 2 murine xenograft models of human MM: SCID mice bearing human MM cells subcutaneously and the SCID-hu model, in which human MM cells are injected within a human bone chip implanted subcutaneously in SCID mice. IC488743 significantly inhibited tumor growth and prolonged host survival in both models. Finally, combined CAL-101 with bortezomib induced synergistic cytotoxicity against MM cells. Our studies therefore show that PI3K/p110delta is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.

Biologic sequelae of I{kappa}B kinase (IKK) inhibition in multiple myeloma: therapeutic implications.

Nuclear factor-kappaB (NF-kappaB) has an important role in multiple myeloma (MM) cell pathogenesis in the context of the bone marrow (BM) microenvironment. In NF-kappaB signaling cascades, IkappaB kinase alpha (IKKalpha) and IKKbeta are key molecules that predominantly mediate noncanonical and canonical pathways, respectively. In this study, we examined the biologic sequelae of the inhibition of IKKalpha versus IKKbeta in MM cell lines. All MM cell lines have constitutive canonical NF-kappaB activity, and a subset of MM cell lines shows noncanonical NF-kappaB activity. Adhesion to BM stromal cells further activates both canonical and noncanonical NF-kappaB activity. IKKbeta inhibitor MLN120B blocks canonical pathway and growth of MM cell lines but does not inhibit the noncanonical NF-kappaB pathway. Although IKKalpha knockdown induces significant growth inhibition in the cell lines with both canonical and noncanonical pathways, it does not inhibit NF-kappaB activation. Importantly, IKKalpha down-regulation decreases expression of beta-catenin and aurora-A, which are known to mediate MM cell growth and survival. Finally, IKKbeta inhibitor enhances the growth inhibition triggered by IKKalpha down-regulation in MM cells with both canonical and noncanonical NF-kappaB activity. Combination therapy targeting these kinases therefore represents a promising treatment strategy in MM.

SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK.

Heat-shock protein 90 (Hsp90) acts as a molecular chaperone required for maintaining the conformational stability of client proteins regulating cell proliferation, survival, and apoptosis. Here we investigate the biologic significance of Hsp90 inhibition in multiple myeloma (MM) and other hematologic tumors using an orally available novel small molecule inhibitor SNX-2112, which exhibits unique activities relative to 17-allyamino-17-demethoxy-geldanamycin (17-AAG). SNX-2112 triggers growth inhibition and is more potent than 17-AAG against MM and other malignancies. It induces apoptosis via caspase-8, -9, -3, and poly (ADP-ribose) polymerase cleavage. SNX-2112 inhibits cytokine-induced Akt and extracellular signal-related kinase (ERK) activation and also overcomes the growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. Importantly, SNX-2112 inhibits tube formation by human umbilical vein endothelial cells via abrogation of eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation of ERK/c-fos and PU.1. Finally, SNX-2112, delivered by its prodrug SNX-5422, inhibits MM cell growth and prolongs survival in a xenograft murine model. Our results indicate that blockade of Hsp90 by SNX-2112 not only inhibits MM cell growth but also acts in the bone marrow microenvironment to block angiogenesis and osteoclastogenesis. Taken together, our data provide the framework for clinical studies of SNX-2112 to improve patient outcome in MM and other hematologic malignancies.

Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells.

Bortezomib is a proteasome inhibitor with remarkable preclinical and clinical antitumor activity in multiple myeloma (MM) patients. The initial rationale for its use in MM was inhibition of nuclear factor (NF)-kappaB activity by blocking proteasomal degradation of inhibitor of kappaBalpha (IkappaBalpha). Bortezomib inhibits inducible NF-kappaB activity; however, its impact on constitutive NF-kappaB activity in MM cells has not yet been defined. In this study, we demonstrate that bortezomib significantly down-regulated IkappaBalpha expression and triggered NF-kappaB activation in MM cell lines and primary tumor cells from MM patients. Importantly, no inhibition of p65 (RelA) nuclear translocation was recognized after bortezomib treatment in a murine xenograft model bearing human MM cells. Bortezomib-induced NF-kappaB activation was mediated via the canonical pathway. Moreover, other classes of proteasome inhibitors also induced IkappaBalpha down-regulation associated with NF-kappaB activation. Molecular mechanisms whereby bortezomib induced IkappaBalpha down-regulation were further examined. Bortezomib triggered phosphorylation of IkappaB kinase (IKKbeta) and its upstream receptor-interacting protein 2, whereas IKKbeta inhibitor MLN120B blocked bortezomib-induced IkappaBalpha down-regulation and NF-kappaB activation, indicating receptor-interacting protein 2/IKKbeta signaling plays crucial role in bortezomib-induced NF-kappaB activation. Moreover, IKKbeta inhibitors enhanced bortezomib-induced cytotoxicity. Our studies therefore suggest that bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-kappaB activity in MM cells.

The proteasome inhibitor bortezomib inhibits FGF-2-induced reduction of TAZ levels in osteoblast-like cells.

OBJECTIVES: Bortezomib (PS-341; Velcade), a proteasome inhibitor, is used as a therapeutic agent for multiple myeloma. Bortezomib has been shown to strongly induce osteoblast differentiation and elevate the levels of osteoblast-related differentiation markers in the serum of patients with myeloma. Bortezomib also reportedly increases the activity of the transcription factor, Runx2. However, the mechanism of action by which bortezomib-elevated Runx2 activity mediates osteoblast differentiation remains unclear. On the other hand, fibroblast growth factor 2 (FGF-2) is found at high levels in patients with multiple myeloma. We previously reported that FGF-2 reduces the levels of the transcriptional coactivator with PDZ-binding motif (TAZ). We therefore investigated the effects of bortezomib on TAZ protein levels in the presence of FGF-2. METHODS: Osteoblastic MC3T3-E1 cells were treated with different concentrations of bortezomib in the presence or absence of FGF-2 and various biologic responses were investigated by immunoblotting, RT-PCR, quantitative PCR, and alizarin red staining. RESULTS: We found that bortezomib inhibited FGF-2-induced reduction of TAZ levels through a pathway other than that used for proteasome inhibition, while maintaining TAZ function, which in turn, enhanced the expression of Runx2-transcribed osteogenic differentiation markers. Bortezomib also suppressed the antimineralization effect of FGF-2. CONCLUSIONS: These findings suggest that bortezomib inhibited FGF-2-induced reduction of TAZ and consequently stimulated osteogenic differentiation independently of proteasome inhibition. These findings may contribute to elucidate the osteolytic mechanism in multiple myeloma, and to the development of new drugs for multiple myeloma and other osteolytic diseases.

Fatty acid synthase is a novel therapeutic target in multiple myeloma.

This study investigated the biological significance of the inhibition of fatty acid synthase (FAS) in multiple myeloma (MM) using the small molecule inhibitor Cerulenin. Cerulenin triggered growth inhibition in both MM cell lines and MM patient cells, and overcame the survival and growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. It induced apoptosis in MM cell lines with only modest activation of caspase -8, -9, -3 and PARP; moreover, the pan-caspase inhibitor Z-VAD-FMK did not inhibit Cerulenin-induced apoptosis and cell death. In addition, treatment of MM cells with Cerulenin primarily up-regulated apoptosis-inducing factor/endonuclease G, mediators of caspase-independent apoptosis. Importantly, Cerulenin induced endoplasmic reticulum stress response via up-regulation of the Grp78/IRE1alpha/JNK pathway. Although the C-Jun-NH(2)-terminal kinase (JNK) inhibitor SP600215 blocked Cerulenin-induced cytotoxicity, it did not inhibit apoptosis and caspase cleavage. Furthermore, Cerulenin showed synergistic cytotoxic effects with various agents including Bortezomib, Melphalan and Doxorubicin. Our results therefore indicate that inhibition of FAS by Cerulenin primarily triggered caspase-independent apoptosis and JNK-dependent cytotoxicity in MM cells. This report demonstrated that inhibition of FAS has anti-tumour activity against MM cells, suggesting that it represents a novel therapeutic target in MM.

p38 mitogen-activated protein kinase inhibitor LY2228820 enhances bortezomib-induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications.

The interaction between multiple myeloma (MM) cells and the bone marrow (BM) microenvironment induces proliferation and survival of MM cells, as well as osteoclastogenesis. This study investigated the therapeutic potential of novel p38 mitogen-activated protein kinase (p38MAPK) inhibitor LY2228820 (LY) in MM. Although cytotoxicity against MM cell lines was modest, LY significantly enhanced the toxicity of bortezomib by down-regulating bortezomib-induced heat shock protein 27 phosphorylation. LY inhibited interleukin-6 secretion from long term cultured-BM stromal cells and BM mononuclear cells (BMMNCs) derived from MM patients in remission. LY also inhibited macrophage inflammatory protein-1alpha secretion from patient MM cells and BMMNCs as well as normal CD14 positive osteoclast precursor cells. Moreover, LY significantly inhibited in vitro osteoclastogenesis from CD14 positive cells induced by macrophage-colony stimulating factor and soluble receptor activator of nuclear factor-kappaB ligand. Finally, LY also inhibited in vivo osteoclatogenesis in a severe combined immunodeficiency mouse model of human MM. These results suggest that LY represents a promising novel targeted approach to improve MM patient outcome both by enhancing the effect of bortezomib and by reducing osteoskeletal events.

5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells.

In this study, we investigated the cytotoxicity of 5-azacytidine, a DNA methyltransferase inhibitor, against multiple myeloma (MM) cells, and characterized DNA damage-related mechanisms of cell death. 5-Azacytidine showed significant cytotoxicity against both conventional therapy-sensitive and therapy-resistant MM cell lines, as well as multidrug-resistant patient-derived MM cells, with IC(50) of approximately 0.8-3 micromol/L. Conversely, 5-azacytidine was not cytotoxic to peripheral blood mononuclear cells or patient-derived bone marrow stromal cells (BMSC) at these doses. Importantly, 5-azacytidine overcame the survival and growth advantages conferred by exogenous interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or by adherence of MM cells to BMSCs. 5-Azacytidine treatment induced DNA double-strand break (DSB) responses, as evidenced by H2AX, Chk2, and p53 phosphorylations, and apoptosis of MM cells. 5-Azacytidine-induced apoptosis was both caspase dependent and independent, with caspase 8 and caspase 9 cleavage; Mcl-1 cleavage; Bax, Puma, and Noxa up-regulation; as well as release of AIF and EndoG from the mitochondria. Finally, we show that 5-azacytidine-induced DNA DSB responses were mediated predominantly by ATR, and that doxorubicin, as well as bortezomib, synergistically enhanced 5-azacytidine-induced MM cell death. Taken together, these data provide the preclinical rationale for the clinical evaluation of 5-azacytidine, alone and in combination with doxorubicin and bortezomib, to improve patient outcome in MM.

Purification and characterization of C-terminal truncated forms of histone H2A in monocytic THP-1 cells.

Histones are key components of chromatin. We investigated histone H2A-immunoreactive proteins in acute monocytic leukemia THP-1 cells using three polyclonal antibodies raised against peptides corresponding to distinct regions of H2A. Two unknown immunoreactive proteins (9- and 12-kDa proteins), H2A (14kDa) and ubiquitinated H2A (23kDa) were found in the cell lysates prepared by immediate direct addition of SDS-PAGE sample buffer to the cells as well as in the nuclear and chromatin fractions. However, they were not found in the cytoplasmic fraction. The unknown proteins were successfully purified by immunoaffinity chromatography from the cell nucleus extract and identified as 9-kDa H2A(1-87) and 12-kDa H2A(1-114), suggesting that both were produced by limited proteolysis of intact H2A(1-129). The truncated forms of H2A probably persisted as chromatin constituents, since the stability of H2A(1-87) in the chromatin fraction was sensitive to treatment with micrococcal nuclease, and H2A(1-114) was solubilized with lower ionic strength from the chromatin fraction obtained by micrococcal nuclease treatment. Truncated H2A proteins in THP-1 cells were transiently increased in amount by short-term treatment with phorbol 12-myristate 13-acetate or all-trans-retinoic acid, both of which induce macrophage-like differentiation. Furthermore, these increases were suppressed by preceding treatment with carbobenzoxy-l-leucyl-l-leucyl-l-leucinal (MG132) but not with carbobenzoxy-l-isoleucyl-gamma-t-butyl-l-glutamyl-l-alanyl-l-leucinal (PSI), both of which are generally known as proteasome inhibitors. Our results suggest that histone H2A is cleaved at least at two sites by protease(s) that remain obscure, and might affect chromatins in the early stage of THP-1 cell differentiation.

[Pseudoleukocytosis and pseudothrombocytosis caused by fragmentation of leukemic cells in tumor lysis syndrome].

Tumor lysis syndrome (TLS) is a severe complication of chemotherapy brought about by the rapid destruction of tumor cells. TLS is usually diagnosed by elevation of intracellular enzymes and no specific abnormality is found in complete blood counts. We present a 22-year-old woman with acute lymphoblastic leukemia (ALL) complicated with TLS, in whom elevation of leukocytes and platelet count was observed due to fragmented leukocytes. The day after initiating chemotherapy, a rapid increase in intracellular enzymes was found and a diagnosis of TLS was made. Her leukocyte and platelet counts increased from 8,400/ml to 42,600/ml. and from 43,000/ml to 231,000/ml, respectively. Many fragmented leukocytes were found in her peripheral blood picture. The automated hematology analyzer counted these fragments as leukocytes or platelets, with resulting pseudo-leukocytosis and pseudo-thrombocytosis. When evaluating laboratory data of TLS, it is necessary to focus on the peripheral blood picture to avoid misunderstanding the blood cell counts.

[Pulmonary cryptococcosis occurring 6 months after cladribine therapy for relapsed follicular lymphoma].

We report a case of follicular lymphoma in which pulmonary cryptococcosis occurred with cladribine therapy. The case involved a 72-year-old man. He was diagnosed as having follicular lymphoma, grade 1, clinical stage IVA from a tongue tumor biopsy in January 2003. A total of 6 courses of R-CHOP therapy was performed, but no clear effect was found. A new cervical lesion appeared, so he was treated with a total of 2 courses of R-EPOCH therapy, and the effect was classed as stable disease. We started cladribine therapy (0.09 mg/kg, seven days of continuous infusion) from February 2004, and complete remission was achieved after 4 courses of cladribine therapy. In January 2005, an abnormal nodular shadow in the right S10 area was found on chest CT images which was diagnosed as pulmonary cryptococcosis by serum antigen and a trans-bronchial lung biopsy. We started fluconazole (200 mg a day, initially intravenous drip infusion, followed by oral intake), following which both the pulmonary shadow and serum antigen improved. Afterward, the fifth course of cladribine therapy and local radiation therapy were performed against a relapse of lymphoma, but cryptococcosis did not reappear. The prolonged bone marrow suppression after cladribine therapy was considered to be a severe adverse event. These findings suggest that it is very important to pay attention to any opportunistic infection such as pulmonary cryptococcosis.

Long-term follow-up high-dose chemotherapy (drug-only program) followed by autologous stem cell transplantation for aggressive non-Hodgkin's lymphomas.

PURPOSE: To investigate the feasibility of high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) for aggressive non-Hodgkin's lymphoma (NHL), we conducted HDCT with ASCT using a drug-only protocol without total body irradiation. Previously untreated and treated adult patients with aggressive lymphoma were enrolled onto this study. For the HDCT protocol, we developed the AECC regimen, a drug-only regimen consisting of etoposide, carboplatin, cyclophosphamide, and nimustine (ie, ACNU). Mobilized peripheral blood stem cells were used mainly as a source for ASCT and were used based on collection rates of CD34 cells. PATIENTS AND METHODS: Fifty-six patients were enrolled and assessed for this study. The median length of follow-up was 6.5 years, with a range of 0.2-12.5 years. Retrospective immunophenotypic examination indicated that the majority of the patients were diagnosed with B-cell lymphoma. RESULTS: Before HDCT, 37 patients still had disease (26 partial responses [PRs] and 11 cases of no response), and 19 patients exhibited a complete response (CR) before HDCT with ASCT. Among 56 patients, 37 (66%) exhibited a CR, including patients continuing their first CR and those experiencing a second or further CR, and 11 patients (19.6%) exhibited PR on HDCT with ASCT. Outcomes of patients without CR were significantly poorer than those of the patients with CR, and 7-year overall survival rates of patients with and without CR were 63% and 27.2%, respectively. No patients developed a second malignancy, including leukemia or myelodysplastic syndrome. CONCLUSIONS: High-dose chemotherapy followed by ASCT is one of the available consolidation therapies for aggressive NHL, and additional involved-field irradiation could play a role in the management of patients with NHL who do not exhibit a CR after treatment with HDCT containing a drug-only program.

Purification of N-terminally truncated histone H2A-monoubiquitin conjugates from leukemic cell nuclei: probable proteolytic products of ubiquitinated H2A.

To gain insight into the significance of nuclear ubiquitinated proteins, two serial extracts prepared from various leukemic cells were analysed by western blotting with anti-ubiquitin antibody. Two previously unidentified ubiquitinated proteins with molecular masses of 10 and 17 kDa were found in 8 M urea-soluble extracts, obtained from Tris-buffer-insoluble materials, of acute myeloid leukemia OCI/AML 1a cells and the cells from the leukemia patients. Both proteins were successfully purified from the OCI/AML 1a cells and identified as monoubiquitin-truncated H2A conjugates, the 10 kDa ubiquitinated H2A(115-129) and the 17 kDa ubiquitinated H2A(54-129), suggesting that both proteins were produced by limited proteolysis of an intact form (23 kDa) of ubiquitinated H2A(1-129). The 17 kDa protein as well as the 23 kDa ubiquitinated histone H2A were localised in chromatin fractions of the OCI/AML cells and released by high concentrations of salt in a micrococcal nuclease-sensitive manner, suggesting their association with chromatin. In contrast, the 10 kDa protein remained insoluble even when the nuclei were treated with nuclease under high salt concentrations, presumably due to binding to the nuclear matrix. An antibody recognising H2A(70-81) also detected the 17 kDa protein in anti-ubiquitin immunoprecipitates obtained from the OCI/AML cell nuclei. In addition, the 17 kDa protein levels in THP-1 cells were transiently increased, concomitant with a decrease in the 23 kDa ubiquitinated H2A, by treatment with phorbol 12-myristate 13-acetate or all-trans-retinoic acid, both of which induce differentiation. This is the first report of probable proteolytic products of ubiquitinated H2A, which might have a role in nuclear functions.

Intensified daunorubicin in induction therapy and autologous peripheral blood stem cell transplantation in postremission therapy (Double-7 protocol) for adult acute myeloid leukemia.

To investigate whether an intensified dose of daunorubicin (DNR) in induction therapy and autologous peripheral blood stem cell transplantation (PBSCT) in the postremission period are effective treatments, we used a Double-7 protocol to treat adult patients with de novo acute myeloid leukemia (excluding M0 and M3). Induction therapy consisted of 40 mg/m2 of DNR intravenous drip infusion for 7 days and 200 mg/m2 of ara-C by continuous infusion for 7 days (7 + 7 DC regimen). Patients who achieved complete remission (CR) were given high-dose chemotherapy with autologous PBSCT in postremission therapy. Of the 22 assessable patients, 16 attained CR (73%). Disease-free survival (DFS) and overall survival (OS) at 3 years were 61.2% and 48.1%, respectively. Nine of the CR patients underwent PBSCT without therapy-related mortality. Patients in a favorable cytogenetic group (n = 7) attained 100% CR and long-term survival (71.4% DFS and 85.7% OS at 3 years). Thus, intensified DNR administration of 280 mg/m2 (40 mg/m2 per day for 7 days) in induction therapy for adult patients younger than 60 years of age might be optimal or at least comparable with the new anthracyclines such as idarubicin. In addition, autologous PBSCT in postremission therapy might improve DFS and OS, at least for patients in a favorable cytogenetic group, such as those with a t(8;21) abnormality.

Successful combination therapy with trastuzumab and Paclitaxel for adriamycin- and docetaxel-resistant inflammatory breast cancer.

We present a case of adriamycin-and docetaxel-resistant inflammatory breast cancer (IBC) in which partial response was achieved with combination therapy using trastuzumab and paclitaxel. A 48-year old woman noticed a lump in her right breast. She was diagnosed with IBC and the disease was staged as T4d N1 M0, stage III B. The patient was started on neoadjuvant chemotherapy with adriamycin (50 mg/m2) and docetaxel (60 mg/m2) administered every three weeks. Six courses were performed and the response was evaluated as no change. After one month, contralateral breast swelling indicated bilateral IBC. Bilatera1 mastectomy using the Halsted method was performed. The immunohistochemical results of the Hercep Test was strongly positive (3+). After the mastectomy, right pleural effusion appeared, and cytological examination revealed the cells to be classV(adenocarcinoma). To treat the clinically advanced breast cancer, combination therapy with trastuzumab (initially 4 mg/kg followed by two or more cycles of 2 mg/kg) and paclitaxel (80 mg/m2) were given intravenously every week for eight cycles and then every two weeks thereafter. A total of 32 courses of therapy were performed, the pleural effusion completely disappeared and partial response was maintained for a duration of 482 days. The adverse reactions were mild, and it was possible for her to be treated as an outpatient with high quality of life. This report suggests that weekly combination therapy of trastuzumab and paclitaxel was useful for treatment of adriamycin-and docetaxel-resistant metastatic breast cancer.

[Progressive outer retinal necrosis in a patient with malignant lymphoma].

A 29-year-old man with diffuse large B-cell lymphoma treated by radiotherapy for his relapsed lesion followed by 4 doses of weekly rituximab was admitted to our hospital with interstitial pneumonia. After steroid pulse therapy, he had contraction of the left visual field. He was diagnosed as having progressive outer retinal necrosis due to a varicella-zoster virus that was detected from the left vitreous sample. Systemic antiviral treatment failed to prevent rapid development of whole layer necrosis of the left retina. Vitrectomy with silicone oil tamponade saved his final visual acuity. This unusual event might be related to rituximab causing deterioration of humoral immunity.

[Intravascular large B cell lymphoma with migratory local high density shadow by chest CT and diagnosed by transbronchial lung biopsy].

The intravascular large B cell lymphoma (IVL) is a rare subtype characterized by the presence of lymphoma cells in the lumina of small vessels. Reported here is the case of a 68-year-old woman with a high-grade fever uncontrolled by antibiotics or antipyretic drugs, and elevation of the serum LDH and sIL-2R levels. After she was admitted, dyspnea, hypoxia, and severe body weight gain with leg edema gradually developed. Chest computed tomography (CT) revealed a characteristic migratory local high density area typical of atelectasis. A diagnosis of IVL was made with a transbronchial lung biopsy (TBLB) and immunohistochemical analysis. The patient was treated with combination chemotherapy (modified CHOP), and her symptoms of dyspnea, hypoxia, pyrexia and leg edema were quickly resolved. The level of LDH and sIL-2R returned to normal, and a complete response was obtained. Although diagnosis of IVL is difficult, an early and appropriate diagnostic procedure (biopsy of tissue with vessels, such as lung and skin, is required) will improve the prognosis of IVL.

[Successful induction of complete cytogenetic response with high-dose imatinib mesylate and subsequent allogeneic stem cell transplantation for CML blastic crisis].

A 29-year-old man was referred to our hospital with leukocytosis on March 7th, 2002. The white blood cell count was 132.9 x 10(3)/microliter with 42.0% blast cells. We diagnosed Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in a blast crisis and started imatinib mesylate therapy at a dose of 800 mg/day on March 9th, 2002. The patient's peripheral blood blasts had disappeared by March 22nd, 2002, and the percentage of blasts in the bone marrow was 0.6% on May 2nd, 2002. The patient achieved a complete cytogenetic response on May 13th, 2002, and underwent allogeneic peripheral blood stem cell transplantation from his HLA-identical sibling donor on May 30th, 2002. Although adverse reactions such as grade 3/4 of hematological events (leukopenia, anemia, thrombocytopenia and neutropenia) and grade 1/2 of non-hematological events (hyperbilirubinemia, dermatitis and edema) were observed, these adverse reactions were clinically managed. This case suggested the usefulness of imatinib mesylate in the management of the CML-associated blast crisis.