Yoichi Tatsumi

Expression of CCL28 by Reed-Sternberg Cells Defines a Major Subtype of Classical Hodgkin’s Disease with Frequent Infiltration of Eosinophils and/or Plasma Cells

Classical Hodgkins disease (HD) is characterized by rare neoplastic Hodgkin and Reed-Sternberg (H-RS) cells within abundant reactive cellular backgrounds. In most cases, H-RS cells originate from the B-cell lineage, but their immunophenotypes are unusual. Here we newly found frequent expression of chemokine receptors CXCR6 and CCR10 and their respective ligands CXCL16 and CCL28 in HD-derived cell lines. CCR10 is known to be selectively expressed by plasma cells, whereas CCL28 attracts eosinophils via CCR3 and plasma cells via CCR10 and CCR3. Therefore, we examined their expression in HD tissues by immunohistochemistry. We found that H-RS cells in 15 of 19 cases were positive for CCL28. Among them, seven cases were also positive for CCR10, suggesting a potential autocrine effect. In situ hybridization confirmed the expression of CCL28 mRNA in H-RS cells. The CCL28 positivity in H-RS cells did not significantly correlate with that of LMP-1, CCL17, CCL22, or CCL11. However, it significantly correlated with the background accumulation of eosinophils, plasma cells, and CCR10+ cells. Thus, the production of CCL28 by H-RS cells may play a major role in tissue accumulation of eosinophils and/or plasma cells in classical HD. The frequent expression of CCR10 in H-RS cells themselves also supports their close relationship to plasma cells.

Prognostic implication of types of tumor-associated macrophages in Hodgkin lymphoma

To evaluate roles of tumor-associated macrophages (TAMs) for prognosis of classical Hodgkin lymphoma (CHL). Expression of markers for TAMs, CD68, HLA-DR, CD163, HLA-DR/CD68 (M1), and CD163/CD68 (M2) was immunohistochemically examined in 82 cases with CHL. Positively stained cells were counted and correlation of number of TAMs and patients’ survival time was analyzed. Number of CD163+ cells and M2 cells was significantly correlated with shorter overall survival (P < 0.05), while it was marginally significant for CD68+ cells (P = 0.0827). HLA-DR + cells and M1 cells showed no significant correlation with overall survival. When confined to mixed cellularity subtype, number of M1 cells was correlated with favorable prognosis (P < 0.05), while M2 did not (P = 0.7). Older age and male sex were unfavorable factors for prognosis. At multivariate analysis, number of CD163+ cells, M2+ cells, and age were independent factors for poor overall survival (P = 0.03, 0.02, and 0.01, respectively). CD163+ cells and M2 cells might work to be tumor promotive in CHL. M1 cells might be tumor suppressive in mixed cellularity type.

Tumour-associated macrophages in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group.

Wada N, Zaki M A A, Hori Y, Hashimoto K, Tsukaguchi M, Tatsumi Y, Ishikawa J, Tominaga N, Sakoda H, Take H, Tsudo M, Kuwayama M, Morii E & Aozasa K 
(2012) Histopathology 60, 313–319 
Tumour‐associated macrophages in diffuse large B‐cell lymphoma: a study of the Osaka Lymphoma Study Group

A novel lipopolysaccharide inducible C-C chemokine receptor related gene in murine macrophages

To identify genes induced in activated macrophages, we screened a cDNA library prepared from the lipopolysaccharide (LPS)‐treated cell line, RAW264, using the suppression subtractive hybridization technique. One of the clones isolated was dramatically induced by LPS in macrophages. The predicted protein sequence of this gene contains the domain unique to seven transmembrane receptors, and shows similarity with mouse C‐C chemokine receptor 5 (CCR5). Therefore, we designated it LPS inducible C‐C chemokine receptor related gene (L‐CCR). Northern blot analysis revealed that L‐CCR was specifically expressed in differentiated macrophages after LPS stimulation. These results show that L‐CCR is a novel C‐C chemokine receptor related gene induced by LPS in macrophages and may play an important role in inflammatory responses.

Extramedullary blast crisis derived from 2 different clones in the central nervous system and neck during complete cytogenetic remission of chronic myelogenous leukemia treated with imatinib mesylate.

We describe a patient with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who developed an extramedullary blast crisis in the central nervous system (CNS) and then a subcutaneous tumor of the neck during treatment with imatinib mesylate. Administered 400 mg of imatinib mesylate after the diagnosis of chronic-phase CML, the patient achieved a complete cytogenetic remission 4 months later. However, he developed a mixed myeloid/B-cell blast crisis with additional karyotype abnormalities only in the CNS during a complete cytogenetic remission in the bone marrow. Several doses of intrathecal chemotherapy and whole-brain irradiation were effective in treating the blast crisis in the CNS. After 7 months of complete cytogenetic remission, the patient experienced a subcutaneous tumor in the right neck. A biopsy of the tumor revealed a mixed myeloid/T-cell blast crisis. The cytogenetic analysis showed that the blast crisis clone in the neck tumor was different from that of the CNS. An increased dose of imatinib mesylate was ineffective in treating the neck tumor. Irradiation to the right neck was therefore undertaken. This case suggests that the development of a clone resistant to imatinib mesylate is not always detected in the bone marrow and that multiple Ph-positive clones have the potential to become transformed into a blast crisis.

Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large b-cell lymphoma

Purpose Rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy is the standard of care in previously untreated diffuse large B-cell lymphoma (DLBCL). Obinutuzumab (G) is a glycoengineered, type II, anti-CD20 monoclonal antibody. GOYA was a randomized phase III study that compared G-CHOP with R-CHOP in patients with previously untreated advanced-stage DLBCL. Methods Patients (N = 1,418) were randomly assigned to receive eight 21-day cycles of G (n = 706) or R (n = 712), plus six or eight cycles of CHOP. Primary end point was investigator-assessed progression-free survival (PFS). Results After median observation of 29 months, the number of investigator-assessed PFS events was similar between G (201; 28.5%) and R (215; 30.2%), stratified hazard ratio was 0.92 (95% CI, 0.76 to 1.11; P = .39), and 3-year PFS rates were 70% and 67%, respectively. Secondary end points of independently reviewed PFS, other time-to-event end points, and tumor response rates were similar between arms. In exploratory subgroup analyses, patients with germinal-center B cell-like subtype had a better PFS than did patients with activated B cell-like subtype, irrespective of treatment. Frequencies of grade 3 to 5 adverse events (AEs; 73.7% v 64.7%, respectively) and serious AEs (42.6% v 37.6%, respectively) were higher with G-CHOP compared with R-CHOP. Fatal AE frequencies were 5.8% for G-CHOP and 4.3% for R-CHOP. The most common AEs were neutropenia (G-CHOP, 48.3%; R-CHOP, 40.7%), infusion-related reactions (G-CHOP, 36.1%; R-CHOP, 23.5%), nausea (G-CHOP, 29.4%; R-CHOP, 28.3%), and constipation (G-CHOP, 23.4%; R-CHOP, 24.5%). Conclusion G-CHOP did not improve PFS compared with R-CHOP in patients with previously untreated DLBCL. AEs reported with G were consistent with the known safety profile. Biomarker analyses may help define a future role for G in DLBCL.

Fluorodeoxyglucose uptake in the bone marrow after granulocyte colony-stimulating factor administration in patients with non-Hodgkinʼs lymphoma

PurposeTo clarify the change in the fluorodeoxyglucose (FDG) uptake by the bone marrow over time after administration of granulocyte colony-stimulating factor (G-CSF), we evaluated the correlation between the interval from the last day of administration of G-CSF to positron emission tomography/computed tomography (PET/CT) study and spinal bone marrow accumulation in patients with non-Hodgkins lymphoma. MethodsA total of 127 patients with confirmed non-Hodgkins lymphoma who underwent FDG PET within 60 days from the last administration of G-CSF were retrospectively reviewed. Thirty age-matched and sex-matched healthy controls were also included to evaluate physiological FDG uptake. PET/CT examinations were retrospectively reviewed, and maximum standardized uptake value (SUVmax) was measured by placing volumetric regions of interest over each thoracic and lumbar vertebra on PET images referring to CT images. Bone marrow SUV was defined as the mean SUVmax of the vertebra. The correlation between the interval after G-CSF and the bone marrow SUV was plotted and analyzed with polynomial approximation. ResultsIn controls, physiological bone marrow SUV of the spine was determined. In patients with lymphoma, bone marrow SUV decreased over time and reached a plateau at about 14 days after G-CSF administration, and this was higher by 5% than the plateau at 10 days. SUV declined to the ‘physiological range’, that is, mean+1 standard deviation of patients, at about 7 days. ConclusionFor a PET/CT study, an interval of 10 days after G-CSF administration is recommended to minimize the influence of G-CSF on the bone marrow when evaluating treatment response in patients with non-Hodgkins lymphoma.

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

Abstract We previously reported that all-trans retinoic acid (ATRA) inhibited growth in HTLV-l-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-l-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-l-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-l 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-l proviral DNA load. Finally, we conclude that ATRA may be a potential therapeutic agent for HIV infection.

Follicular Lymphoma in Osaka, Japan : Histological Features and Chronological Change

Follicular lymphoma (FL) is defined as a neoplastic proliferation of follicle center cells with varying follicular areas. To learn the time trend of FL in the Osaka area, an adult T-cell leukemia/lymphoma (ATL) nonendemic area of Japan, we examined the frequency of FL among all non-Hodgkin ’s lymphomas (NHLs) during the period 1964 to 1987 (n = 1000) and 1999 to 2001 (n = 659). The frequency of FL with varying follicular areas increased from 1964-1987 to 1999-2001. There was a significant difference in frequency of total cases of FL (14.2% versus 18.8%) (P < .05) and FL with no to 25% follicular area (2.3% versus 5.0%) (P < .01). According to the Berard criteria, cytologic grade of FL was defined by counting the number of centroblasts (CB) in 10 neoplastic follicles as follow: ≤ CB per high power field (HPF), grade 1; 6-15 CB, grade 2; >15 CB, grade 3. Immunohistochemical staining with monoclonal antibodies for bcl-2 and CD10 was performed. There was an inverse correlation between follicular area and cytological grade (P < .0001) and bcl-2 expression and cytological grade (P < .01). That is, the larger the follicular area in cases with a lower cytological grade, the stronger was bcl-2 expression in a lower cytological grade. There was a significant correlation between follicular area and stage of disease (P < .05). That is, the follicular area was larger in cases in an advanced stage. This study showed the increase in frequency of FL in Osaka, Japan. Change of lifestyle in Japan may be one of the causative factors for the increase.Int J Hematol. 2002;76:333-337.

Inhibition of growth and induction of apoptosis by all‐trans retinoic acid in lymphoid cell lines transfected with the PML/RARα fusion gene

The interaction of an exogenous PML/RARα fusion gene associated with acute promyelocytic leukaemia, with all‐trans retinoic acid (ATRA) was examined in two lymphoid cell lines. L1210 and MOLT‐4 cells were transfected with PML/RARα cDNA in the expression vector pGD and stable transformants (L1210PML/RARα and MOLT‐4PML/RARα) were selected with G418. ATRA inhibited the growth of these stable transformants, as assessed by [3H]thymidine incorporation, in a dose‐dependent manner, but had no effect on the growth of control cells stably transformed with neomycin resistant gene alone. ATRA also induced apoptosis, as assessed by fragmentation of genomic DNA, in L1210PML/RARα and MOLT‐4PML/RARα cells but not in control cells. The exogenous PML/RARα fusion gene therefore probably mediates the effects of ATRA on cell growth and apoptosis in these cell lines.