Hirotaka Takasaki

Affixin interacts with α-actinin and mediates integrin signaling for reorganization of F-actin induced by initial cell–substrate interaction

The linking of integrin to cytoskeleton is a critical event for an effective cell migration. Previously, we have reported that a novel integrin-linked kinase (ILK)–binding protein, affixin, is closely involved in the linkage between integrin and cytoskeleton in combination with ILK. In the present work, we demonstrated that the second calponin homology domain of affixin directly interacts with α-actinin in an ILK kinase activity–dependent manner, suggesting that integrin–ILK signaling evoked by substrate adhesion induces affixin–α-actinin interaction. The overexpression of a peptide corresponding to the α-actinin–binding site of affixin as well as the knockdown of endogenous affixin by small interference RNA resulted in the blockade of cell spreading. Time-lapse observation revealed that in both experiments cells were round with small peripheral blebs and failed to develop lamellipodia, suggesting that the ILK–affixin complex serves as an integrin-anchoring site for α-actinin and thereby mediates integrin signaling to α-actinin, which has been shown to play a critical role in actin polymerization at focal adhesions.

Monitoring of Hepatitis B Virus (HBV) DNA and Risk of HBV Reactivation in B-Cell Lymphoma: A Prospective Observational Study

BACKGROUND There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). METHODS We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥ 11 IU/mL. RESULTS With a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of <10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P < .001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis. CONCLUSIONS Monthly monitoring of HBV DNA is useful for preventing HBV reactivation-related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299).

Peripheral blood absolute lymphocyte/monocyte ratio as a useful prognostic factor in diffuse large B-cell lymphoma in the rituximab era

The tumor microenvironment, including tumor‐infiltrating lymphocytes and myeloid‐derived cells, is an important factor in the pathogenesis and clinical behavior of malignant lymphoma. However, the prognostic significance of peripheral lymphocytes and monocytes in lymphoma remains unclear.

Pretransplant serum ferritin is associated with bloodstream infections within 100 days of allogeneic stem cell transplantation for myeloid malignancies

We retrospectively studied the association between iron overload and bloodstream infections (BSI) in the 100-day period following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia or myelodysplastic syndromes. Serum ferritin was measured before transplantation to evaluate iron overload. Of 114 adult patients who underwent transplantation between 2000 and 2008, 36 (32%) developed BSI. Of the 44 isolates, 63% were Gram-positive bacteria, 32% were Gram-negative bacteria, and 4% were fungi. The median time to the onset of the first BSI was day 28 (range day 0–95) after transplantation. Univariate analysis revealed a significantly higher incidence of BSI in the high (≥1,000 ng/ml, n = 57) than in the low (<1,000 ng/ml, n = 57) ferritin group (42.1 versus 21.1%, respectively, P = 0.017). Peripheral blood stem cell transplantation (PBSCT) (n = 23) showed a greater protective effect against BSI compared with bone marrow (n = 71) and cord blood (n = 20) transplantation. Pretransplantation serum ferritin (HR = 2.844, 95% CI: 1.180–6.859, P = 0.020) and PBSCT (HR = 0.135, 95% CI: 0.025–0.717, P = 0.019) were significant factors on multivariate analysis. In conclusion, pretransplantation serum ferritin significantly predicts BSI within the 100-day period after allo-HSCT.

Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan

Enteropathy-associated T-cell lymphoma (EATL) is a rare primary T-cell lymphoma of the digestive tract. EATL is classified as either Type I, which is frequently associated with and thought to arise from celiac disease and is primarily observed in Northern Europe, and Type II, which occurs de novo and is distributed all over the world with predominance in Asia. The pathogenesis of EATL in Asia is unknown. We aimed to clarify the histological and genomic profiles of EATL in Japan in a homogeneous series of 20 cases. The cases were characterized by immunohistochemistry, high-resolution oligonucleotide microarray, and fluorescence in situ hybridization (FISH) at five different loci: 1q21.3 (CKS1B), 6q16.3 (HACE1), 7p22.3 (MAFK), 9q33.3 (PPP6C), and 9q34.3 (ASS1, CARD9) using formalin-fixed paraffin-embedded sections. The histological appearance of EATL ranged from medium- to large-sized cells in 13 cases (65%), small- to medium-sized cells in five cases (25%), and medium-sized in two cases (10%). The immunophenotype was CD2+ (60%), CD3ɛ+ (100%), CD4+ (10%), CD7+ (95%), CD8+ (80%), CD56+ (85%), TIA-1+ (100%), Granzyme B+ (25%), T-cell receptor (TCR)β+ (10%), TCRγ+ (35%), TCRγδ+ (50%), and double negative for TCR (six cases, 30%). All cases were EBER−. The genomic profile showed recurrent copy number gains of 1q32.3, 4p15.1, 5q34, 7q34, 8p11.23, 9q22.31, 9q33.2, 9q34.13, and 12p13.31, and losses of 7p14.1. FISH showed 15 patients (75%) with a gain of 9q34.3 with good correlation with array comparative genomic hybridization. EATL in Japan is characterized by non-monomorphic cells with a cytotoxic CD8+ CD56+ phenotype similar to EATL Type II. The genomic profile is comparable to EATL of Western countries, with more similarity to Type I (gain of 1q and 5q) rather than Type II (gain of 8q24, including MYC). The 9q34.3 gain was the most frequent change confirmed by FISH irrespective of the cell origin of αβ-T-cells and γδ-T-cells.

R-CHOP therapy alone in limited stage diffuse large B-cell lymphoma

Long‐term observation has identified a pattern of continuing relapse in limited stage diffuse large B‐cell lymphoma (DLBCL) treated by three cycles of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved‐field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R‐CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full‐dose R‐CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R‐CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5‐year progression‐free survival and 5‐year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the ‘standard’ strategy of three cycles of R‐CHOP followed by involved‐field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R‐CHOP alone.

Serum ferritin and disease status at transplantation predict the outcome of allo-SCT in patients with AML or myelodysplastic syndrome

Serum ferritin and disease status at transplantation predict the outcome of allo-SCT in patients with AML or myelodysplastic syndrome

Fasciitis and myositis: An analysis of muscle-related complications caused by chronic GVHD after allo-SCT

The muscle-related complications of fasciitis and myositis, caused by chronic GVHD after Allo-SCT are relatively rare, but at times will severely impair a patients quality of life (QOL). We performed a retrospective analysis in Japanese Allo-SCT recipients to identify the incidence, risk factors and clinical features of fasciitis and myositis. In 1967 patients who underwent Allo-SCT between January 1994 and March 2005 and survived beyond 90 days post transplantation, eight patients developed fasciitis and nine patients developed myositis, with a 5-year cumulative incidence of 0.55% and 0.54%, respectively. The median time from SCT to the development of fasciitis and myositis was 991 and 660 days, respectively. PBSCT was a risk factor for developing fasciitis, but no risk factors were found for myositis. The response to immunosuppressive treatment was better in patients with myositis than fasciitis, and the overall survival after developing these symptoms was better in patients with myositis than those with fasciitis. An early diagnosis by a biopsy, which includes fascia and muscle or magnetic resonance imaging (MRI) and prompt treatment may be important to prevent an impairment of the patients QOL with persistent disability.

Involvement of Central Nervous System in Prolymphocytoid Transformation of Chronic Lymphocytic Leukemia

We report a rare case of involvement of the central nervous system (CNS) by chronic lymphocytic leukemia (CLL). A 68-year-old man with prolymphocytic variant of B-CLL (CLL/PLL), develops CNS involvement with headache and vomiting. Computed tomography of the head showed no abnormalities. The cerebrospinal fluid (CSF) revealed numerous lymphocytoid cells of prolymphocytic appearance consistent with findings on the peripheral blood smear. Immunophenotypic analysis demonstrated that the leukemic B cells were positive for CD19, CD20, and HLA-DR, but CD5 was difficult to detect. The patient was treated with intrathecal methotrexate, cytarabine, and hydrocortisone and had improvement in symptoms and CSF findings. Although CNS involvement is an unusual manifestation in CLL, one should be aware of the possibility of this complication in cases presenting with neurological symptoms.

Comparison of peripheral T-cell lymphomas and diffuse large B-cell lymphoma.

Peripheral T‐cell lymphomas (PTCLs) are a biologically heterogeneous subgroup of lymphomas with poor prognosis. In this study, the authors analyzed the clinical behaviors of PTCLs and diffuse large B‐cell lymphoma (DLBCL).