Yoshiko Okikawa

Clinical significance of sIL-2R levels in B-cell lymphomas.

Elevated soluble interleukin-2 receptor (sIL-2R) in sera is observed in patients with malignant lymphoma (ML). Therefore, sIL-2R is commonly used as a diagnostic and prognostic marker for ML, but the mechanisms responsible for the increase in sIL-2R levels in patients with B-cell lymphomas have not yet been elucidated. We first hypothesized that lymphoma cells expressing IL-2R and some proteinases such as matrix metalloproteinases (MMPs) in the tumor microenvironment can give rise to increased sIL-2R in sera. However, flow cytometric studies revealed that few lymphoma cells expressed IL-2R α chain (CD25) in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), and most CD25-expressing cells in the tumor were T-cells. Distinct correlations between CD25 expression on B-lymphoma cells and sIL-2R levels were not observed. We then confirmed that MMP-9 plays an important role in producing sIL-2R in functional studies. Immunohistochemical (IHC) analysis also revealed that MMP-9 is mainly derived from tumor-associated macrophages (TAMs). We therefore evaluated the number of CD68 and CD163 positive macrophages in the tumor microenvironment using IHC analysis. A positive correlation between the levels of sIL-2R in sera and the numbers of CD68 positive macrophages in the tumor microenvironment was confirmed in FL and extranodal DLBCL. These results may be useful in understanding the pathophysiology of B-cell lymphomas.

Clinical and genetic features of therapy-related myeloid neoplasms after chemotherapy for acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a highly curable disease with excellent complete remission and long-term survival rates. However, the development of therapy-related myeloid neoplasms (t-MN) is being reported with increasing frequency in patients successfully treated for APL. We attempted to clarify the different clinical features and hematologic findings between t-MN and relapse cases, and to identify gene alterations involved in t-MN. We compared 10 relapse and 11 t-MN cases that developed in 108 patients during their first complete remission from APL. At APL diagnosis, t-MN patients had lower white blood cell counts than did relapse patients (P = .048). Overall survival starting from chemotherapy was significantly worse in t-MN patients than in relapse patients (P = .022). The t-MN cases were characterized as CD34(+)/HLA-DR(+) and PML-RARA(-), and 4 RUNX1/AML1 mutations were detected. T-MN is easily distinguished from APL relapse by evaluating these hematologic features, and it may originate from primitive myeloid cells by chemotherapy-induced RUNX1 mutations.

Connective tissue growth factor is an indicator of bone involvement in multiple myeloma, but matrix metalloproteinase-9 is not.

Bone disease (BD) in multiple myeloma (MM) is because of the activation of osteoclasts and impairment of osteoblast differentiation. Connective tissue growth factor (CTGF) is known to participate in the differentiation of mesenchymal stem cells to committed osteoprogenitor cells. We analysed the concentration of circulating CTGF in 35 MM patients and 22 malignant lymphoma (ML) patients and 14 normal individuals. CTGF is protease‐sensitive and thus is found as both an N‐terminal half fragment (N‐half CTGF) and whole (W‐CTGF). Serum levels of W‐CTGF and N‐half CTGF + W‐CTGF were determined by separate sandwich enzyme‐linked immunosorbent assays. The level of W‐CTGF was significantly lower (P < 0·005) in MM patients compared with ML patients and normal individuals, while N‐half + W‐CTGF was similar in all groups. Furthermore, W‐CTGF was significantly lower in MM patients with BD compared with those without BD (P < 0·005) and this was independent of previous treatment. Matrix metalloproteinase (MMP)‐9 is produced by myeloma cells and is thought to be related to BD in MM. However, MMP‐9 does not cleave CTGF and serum MMP‐9 level was not related to BD in MM. Thus, CTGF is an indicator of BD in MM; its metabolism and function in MM should be clarified.

The Maturation of Myeloma Cells Correlates with Sensitivity to Chemotherapeutic Agents

We analyzed both morphologic and phenotypic findings of myeloma cells before and after chemotherapy in 21 patients with multiple myeloma. The morphologic analysis was based on the Greipp classification, and phenotypic analysis was performed by 3-color flow cytometry using the CD38 plasma gating method (Marrow plasma 38). Results with flow cytometry using a combination of MPC1, CD49e, and CD45 supported the morphologic findings for the myeloma cells. Treatment with 3 or 4 cycles of VAD (vincristine, doxorubicin, and dexamethasone) therapy was effective in reducing the total numbers of myeloma cells, but the proportion of immature myeloma cells increased after this treatment. However, the immature myeloma cells were reduced by high-dose melphalan (HD-Mel) therapy followed by autologous stem cell transplantation (ASCT). High-dose cyclophosphamide treatment for stem cell harvesting did not show an effect on the residual immature myeloma cells after VAD treatment. In addition, thalidomide was not effective in reducing the numbers of immature myeloma cells. These results suggest that VAD (3 or 4 cycles) therapy plus HD-Mel followed by ASCT is a reasonable treatment for multiple myeloma and that Marrow plasma 38 analysis is a useful method for monitoring the response of multiple myeloma to chemotherapy.

Progressive myeloma after thalidomide therapy in a patient with immature phenotype of myeloma (plasma) cells.

In our experience with thalidomide treatment for refractory multiple myeloma (MM), most patients with progressive disease (PD) did not show an increase in M-protein despite the tumor burden of myeloma cells. This finding led us to suspect that proliferation of immature myeloma cells showing MPC-1-/CD49e- phenotype may be a sign of PD. We report the results of consecutive analysis of the phenotype of myeloma (plasma) cells in an MM patient with PD during treatment with thalidomide. The myeloma cells decreased by thalidomide therapy were mature (MPC-1+/CD49e+) and intermediate (MPC-1+/CD49e-) types. When the patient was in the PD state, extramedullary plasmacytoma was recognized without proliferation of myeloma cells in the bone marrow (BM). The phenotype of myeloma (plasma) cells in both of these locations was that of immature myeloma cells (MPC-1-/CD49e-), and they showed decreased intensity of CD38 expression. The level of immunoglobulin G (IgG) in serum was decreased, and myeloma (plasma) cells in BM did not increase in PD. Although these clinical features may not be specific to MM patients in PD undergoing treatment with thalidomide, we suggest that immature myeloma cells may be resistant to thalidomide.

High early death rate in elderly patients with acute promyelocytic leukemia treated with all-trans retinoic acid combined chemotherapy

In a recent article in Cancer Science, Ono et al. [1] reported that elderly patients (60–70 years) with acute promyelocytic leukemia (APL) showed a higher induction death rate and non-relapse mortality during consolidation therapy, resulting in a significantly inferior overall survival rate. Many APL clinical trials have found that intensive chemotherapy combined with all-trans retinoic acid (ATRA) dramatically improved patient outcomes. Therefore, it has been generally thought that even elderly APL patients should be treated aggressively to increase the likelihood of curing the disease. However, most clinical trials have excluded elderly patients. Indeed, the German Acute Myeloid Leukemia Cooperative Group showed that 30 % of their newly diagnosed APL patients were age C60 years, and of these, 25 % were ineligible for the therapeutic study due to death before therapy, reduced performance status, comorbidity, or concomitant malignancy [2]. Moreover, elderly patients show lower tolerance to chemotherapy, resulting in a higher incidence of early death during chemotherapy [3]. To determine the responses to therapy in all relevant patient groups, we investigated all APL cases in our hospitals. Unselected patients with newly diagnosed APL were consecutively enrolled at Hiroshima University Hospital and its affiliated hospitals between 1996 and 2008. The patients received front-line intensive treatment consisting of ATRA and anthracycline/cytarabine-based chemotherapy with dose adjustment to WBC counts, as per the recommendations of the Japan Leukemia Study Group studies. Patients 70 years or older received a dose reduction of 30 % in order to prevent severe adverse effects. Patients were examined as approved by the Institutional Review Board at Hiroshima University. We identified a total of 124 patients and conducted a follow-up study [4]. The patient ages were: 10 patients \30 years, 22 patients 30–39 years, 21 patients 40–49 years, 25 patients 50–59 years, 27 patients 60–69 years, 16 patients 70–79 years and three patients 80 years or older. Thirty-two (26 %) patients 65 years or older were regarded as elderly; two of them received ATRA without chemotherapy. Differential clinical outcomes between younger and elderly patients with APL were compared. Complete remission (CR) for patients age C65 years was 78 %, which was lower than that for the whole population (95 %) and for patients age \65 years (100 %). The 5-year overall survival (OS) rate for the whole population was 76 %. The 5-year OS rate of J. Imagawa H. Harada (&) Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan e-mail: herf1@hiroshima-u.ac.jp; hharada@juntendo.ac.jp

The Progression of Esophageal Mucosa-associated Lymphoid Tissue Lymphoma after Helicobacter pylori Eradication Therapy: A Case Report and Discussion of Therapeutic Options

A 50-year-old woman with epigastric discomfort was referred to our hospital. Esophagogastroduodenoscopy showed flat, elevated, submucosal tumor-like lesions in the esophagus. Extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) of the esophagus was diagnosed based on the examination of an endoscopic biopsy specimen. Computed tomography showed the enlargement of a lymph node in the gastric cardia. The present case showed disease progression despite Helicobacter pylori eradication therapy and achieved partial remission after rituximab monotherapy. The patient remained in partial remission for 20 months. This case suggests that esophageal MALT lymphoma with lymph node involvement does not respond to H. pylori eradication therapy and that it requires systemic treatment.