Successful Treatment of γ-Heavy-Chain Disease with Rituximab and Fludarabine

An 84-year-old Japanese man was admitted because of pancytopenia. The bone marrow was hypoplastic with a predominance of abnormal small lymphocytes and grape cells, which were positive for CD19 and CD20, and partially for the surface ?-light chain. Systemic CT scanning showed neither lymph node swelling nor hepatosplenomegaly. Serum immunoelectrophoresis and rocket immunoselection assays showed the presence of monoclonal IgG protein without a corresponding light chain and faint IgM? monoclonal protein. Histologic analysis of the clot preparation of the bone marrow aspirate facilitated a diagnosis of lymphoplasmacytic lymphoma (LPL). PCR analysis of the marrow cells demonstrated a clonal rearrangement of the immunoglobulin heavy-chain gene. From these results, we made a final diagnosis of γ-heavy-chain disease (γ-HCD) with underlying LPL localized in the bone marrow. We performed only a single course of immunochemotherapy (rituximab and fludarabine) in view of severely impaired hematopoiesis, which resulted in marked reduction of lymphoma cells and improvement of hematopoiesis. This report suggests the efficacy of rituximab plus fludarabine therapy for LPL-associated γ-HCD.     

AAV8 vector expressing IL24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice

Mixed-lineage leukemia (MLL)/AF4-positive acute lymphoblastic leukemia (ALL) is a common type of leukemia in infants, which is associated with a high relapse rate and poor prognosis. IL24 selectively induces apoptosis in cancer cells and exerts immunomodulatory and antiangiogenic effects. We examined the effects of adeno-associated virus type 8 (AAV8) vector-mediated muscle-directed systemic gene therapy in MLL/AF4-positive ALL using IL24. In a series of in vitro studies, we examined the effects of AAV8-IL24-transduced C2C12 cell-conditioned medium. We also examined the effects of AAV8-IL24 in MLL/AF4 transgenic mice. The results revealed the effects of AAV8-IL24 in MLL/AF4-positive ALL both in vitro and in vivo. With regard to the mechanism of therapy using AAV8-IL24 in MLL/AF4-positive ALL, we demonstrated the antiangiogenicity and effects on the ER stress pathway and unreported pathways through inhibition of S100A6 and HOXA9, which is specific to MLL/AF4-positive ALL. Inhibition of S100A6 by IL24 was dependent on TNF-α and induced acetylation of p53 followed by activation of the caspase 8-caspase 3 apoptotic pathway. Inhibition of HOXA9 by IL24, which was independent of TNF-α, induced MEIS1 activation followed by activation of the caspase 8-caspase 3 apoptotic pathway. Thus, gene therapy using AAV8-IL24 is a promising treatment for MLL/AF4-positive ALL.     

Nighttime Home Blood Pressure and the Risk of Hypertensive Target Organ Damage

In ambulatory blood pressure (BP) monitoring, nighttime BP has a superior ability to predict hypertensive target organ damage than awake BP. We evaluated whether nighttime BP, assessed by a home BP monitor, was associated with hypertensive target organ damage. We measured clinic BP, out-of-clinic BP including nighttime home BP, and the urinary albumin:creatinine ratio (UACR) in 854 patients who had cardiovascular risk factors. Nighttime home BP was measured at 2:00, 3:00, and 4:00 am, in addition to clinic, awake ambulatory, nighttime ambulatory, and awake home BP. Nighttime home systolic BP (SBP) was slightly higher than nighttime ambulatory SBP (difference, 2.6 mm Hg; P<0.001). Clinic (r=0.186), awake ambulatory (r=0.173), nighttime ambulatory (r=0.194), awake home (r=0.298), and nighttime home (r=0.311) SBPs were all associated with log-transformed UACR (all P<0.001). The correlation coefficient for the relationship between nighttime home SBP and log-transformed UACR was significantly greater than that for the relationship between nighttime ambulatory SBP and log-transformed UACR (P<0.001). The goodness of fit of the association between SBP and UACR was improved by adding nighttime home SBP to the other SBPs (P<0.001). Nighttime home diastolic BP also improved the goodness-of-fit of the association between diastolic BP and UACR (P=0.001). Similar findings were observed for the left ventricular mass index in the subgroup (N=594). In conclusion, nighttime home BP is slightly different from (but comparable to) nighttime ambulatory BP. The addition of nighttime home BP to other BP measures improves the association of BP with hypertensive target organ damage.