Kotaro Arita

Recurrence of IgG4-related disease following treatment with rituximab

A 54-year-old woman with suspected low-grade B-cell lymphoma of mucosa-associated lymphoid tissue type of the eyelids underwent rituximab-containing chemotherapy. She initially responded to the rituximab therapy, but later experienced two recurrences over a 3-year period. Biopsy specimens and a review of her previous histology revealed that she had had immunoglobulin G4-related disease at the initial presentation. Although IgG4-related disease seems to respond well to rituximab therapy, long-term follow up, including disease monitoring, is needed to evaluate disease remission.

Molecular Characterization of Chronic-type Adult T-cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type-1-induced neoplasm with four clinical subtypes: acute, lymphoma, chronic, and smoldering. Although the chronic type is regarded as indolent ATL, about half of the cases progress to acute-type ATL. The molecular pathogenesis of acute transformation in chronic-type ATL is only partially understood. In an effort to determine the molecular pathogeneses of ATL, and especially the molecular mechanism of acute transformation, oligo-array comparative genomic hybridization and comprehensive gene expression profiling were applied to 27 and 35 cases of chronic and acute type ATL, respectively. The genomic profile of the chronic type was nearly identical to that of acute-type ATL, although more genomic alterations characteristic of acute-type ATL were observed. Among the genomic alterations frequently observed in acute-type ATL, the loss of CDKN2A, which is involved in cell-cycle deregulation, was especially characteristic of acute-type ATL compared with chronic-type ATL. Furthermore, we found that genomic alteration of CD58, which is implicated in escape from the immunosurveillance mechanism, is more frequently observed in acute-type ATL than in the chronic-type. Interestingly, the chronic-type cases with cell-cycle deregulation and disruption of immunosurveillance mechanism were associated with earlier progression to acute-type ATL. These findings suggested that cell-cycle deregulation and the immune escape mechanism play important roles in acute transformation of the chronic type and indicated that these alterations are good predictive markers for chronic-type ATL.

Clonal heterogeneity of mantle cell lymphoma revealed by array comparative genomic hybridization

Mantle cell lymphoma (MCL) is an aggressive B‐cell non‐Hodgkin lymphoma (NHL) characterized by the translocation t(11;14)(q13;q32). This lymphoma exhibits a poor prognosis and remains incurable with standard chemotherapy approaches. Recently, we have shown that a majority of patients with acute‐type adult T‐cell leukemia/lymphoma (ATLL) have multiple subclones that were likely produced in lymph nodes. We investigated whether MCL has multiple subclones as identified in ATLL by high‐resolution oligo‐array comparative genomic hybridization (CGH). Eleven of 20 (55%) evaluable MCL cases had a log2 ratio imbalance, suggesting the existence of multiple subclones in MCL. Based on the proportion of every subclone relative to the main clone, we were able to speculate clonal evolution in each MCL case with multiple subclones. Our analysis gave new insights into the clonal heterogeneity quantitatively and accurately. Furthermore, genomic copy number alterations are not hierarchical events and not necessarily the initial or later events for cells to become MCL.

Comprehensive gene expression profiles of NK cell neoplasms identify vorinostat as an effective drug candidate

NK cell neoplasms are lymphoid malignancies with an aggressive clinical course. In the present study, we analyzed gene expression profiling of NK cell neoplasms and attempted to identify important molecular pathways and new effective drugs. Pathway analysis of gene expression profiles suggested the important roles of the JAK-STAT pathway, NF-κB pathway or Wnt pathways in NK cell neoplasms. Notably, western blot analysis revealed that STAT3 was expressed and phosphorylated at a higher level in NK cell lines than in normal NK cells or other cell lines. These findings indicate the occurrence of JAK-STAT activation in NK cell neoplasms. Connectivity Map (CMAP) analysis of gene expression profiles identified candidate drugs against NK cell neoplasms. Among the drugs suggested by CMAP analysis, we focused on puromycin, phenoxybenzamine, LY294002, wortmannin, vorinostat and trichostatin A because they exhibited high enrichment scores. We added these drugs to NK cell lines and other cell lines. Among the drugs, vorinostat suppressed NK cell line proliferation at a significantly lower concentration compared to other cell lines. Suppression of the JAK-STAT pathway appeared to contribute to this effect. Vorinostat may be a good candidate for use in the therapy against NK cell neoplasms.

Effects of different types of tooth movement and force magnitudes on the amount of tooth movement and root resorption in rats

OBJECTIVE To investigate differences in the amount of tooth movement and root resorption that occurred after tipping and bodily movement of the maxillary first molar in rats. MATERIALS AND METHODS Ten-week-old female Wistar rats were divided into two groups according to type of tooth movement and subdivided into four subgroups according to the magnitude of applied force. Nickel-titanium closed-coil springs exerting forces of 10, 25, 50, or 100 g were applied to the maxillary left first molars to induce mesial tooth movement. We designed a novel orthodontic appliance for bodily tooth movement. Tooth movement distance and root resorption were measured using microcomputed tomography and scanning electron and scanning laser microscopy. RESULTS The amount of tooth movement in the bodily tooth movement group was less than half that in the tipping tooth movement group. The greatest amount of tooth movement occurred in the 10-g tipping and 50-g bodily tooth movement subgroups, and the amount of tooth movement decreased with the application of an excessive magnitude of force. Conversely, root resorption increased when the heavier orthodontic force was applied in both groups. Root resorption in the tipping tooth movement group was approximately twice that in the bodily tooth movement group. CONCLUSIONS Root resorption in the tipping tooth movement group was more pronounced than that in the bodily tooth movement group. Although the amount of tooth movement decreased when extremely heavy forces were applied, root resorption increased in both the tipping and bodily tooth movement groups in rats.

Identification of multiple subclones in peripheral T-cell lymphoma, not otherwise specified with genomic aberrations

Peripheral T‐cell lymphoma, not otherwise specified (PTCL, NOS) with genomic aberrations has been shown to resemble lymphoma‐type adult T‐cell leukemia/lymphoma (ATLL) in terms of its genomic aberration patterns, histopathology, and prognosis. We have shown recently that a majority of patients with acute‐type ATLL have multiple subclones that were likely produced in lymph nodes. In this study, we analyzed whether PTCL, NOS with genomic aberrations also has multiple subclones as found in ATLL by means of high‐resolution oligo‐array comparative genomic hybridization (CGH). Thirteen cases of PTCL, NOS were available for 44K high‐resolution array CGH analysis. The results showed that 11 (84.6%) of the 13 cases had a log2 ratio imbalance, suggesting that multiple subclones exist in PTCL, NOS with genomic aberrations. In order to analyze the association between multiple subclones and prognosis, we used previous bacterial‐artificial chromosome (BAC) array analyses for 29 cases and found that the existence of multiple subclones was associated with a poor prognosis (P = 0.0279).

Clonal heterogeneity of lymphoid malignancies correlates with poor prognosis.

Clonal heterogeneity in lymphoid malignancies has been recently reported in adult T‐cell lymphoma/leukemia, peripheral T‐cell lymphoma, not otherwise specified, and mantle cell lymphoma. Our analysis was extended to other types of lymphoma including marginal zone lymphoma, follicular lymphoma and diffuse large B‐cell lymphoma. To determine the presence of clonal heterogeneity, 332 cases were examined using array comparative genomic hybridization analysis. Results showed that incidence of clonal heterogeneity varied from 25% to 69% among different types of lymphoma. Survival analysis revealed that mantle cell lymphoma and diffuse large B‐cell lymphoma with clonal heterogeneity showed significantly poorer prognosis, and that clonal heterogeneity was confirmed as an independent predictor of poor prognosis for both types of lymphoma. Interestingly, 8q24.1 (MYC) gain, 9p21.3 (CDKN2A/2B) loss and 17p13 (TP53, ATP1B2, SAT2, SHBG) loss were recurrent genomic lesions among various types of lymphoma with clonal heterogeneity, suggesting at least in part that alterations of these genes may play a role in clonal heterogeneity.

The effect of bone morphometric changes on orthodontic tooth movement in an osteoporotic animal model.

OBJECTIVE To elucidate the effect of bone morphometric changes on orthodontic tooth movement (OTM) in zoledronic acid-treated ovariectomized rats. MATERIALS AND METHODS Twenty-one 10-week-old female Wistar rats were divided into ovariectomy (OVX), OVX with zoledronic acid administration (OVX + ZOL), and sham operation (control) groups. Two weeks after OVX, ZOL administration was initiated. Twelve weeks after OVX, a nickel-titanium closed-coil spring of 25-g force was applied mesially to the maxillary left first molar. In vivo micro-computed tomography (CT) of the left proximal tibia was performed for bone morphometric analysis every 2 weeks after OVX. In addition, OTM was investigated using micro-CT at 0, 12, and 14 weeks after OVX. RESULTS There were significant differences in the bone mineral content (BMC), bone volume (BV), BMC to tissue volume ratio (BMC/TV), and BV to TV ratio of trabecular bone between the control and OVX groups and also between the OVX + ZOL and OVX groups. In the OVX + ZOL group, increased BMC and BV in the cortical bone and increased bone mineral density (BMD) in the trabecular bone were observed. Interestingly, OTM in the OVX group was almost two times more than that in the control and OVX + ZOL groups. Moreover, OTM was correlated with BMD, BMC, BV, and BMC/TV in the trabecular bone. CONCLUSIONS OVX accelerated OTM, while ZOL suppressed it. OTM demonstrated a significant negative relationship with trabecular bone mass.

Hepatic Sinusoidal Obstruction Syndrome Induced by Non-transplant Chemotherapy for Non-Hodgkin Lymphoma

Hepatic sinusoidal obstruction syndrome (SOS), a serious complication that mainly occurs after hematopoietic-stem cell transplantation (HSCT), is caused by damage to the sinusoidal endothelial cells after the obstruction of the sinusoid. Recently, hepatic SOS was reported to occur after non-HSCT chemotherapies. This report describes a patient who experienced hepatic SOS after non-HSCT chemotherapy for non-Hodgkin lymphoma. A liver biopsy showed the slight dilatation of the hepatic sinusoid, which may be indicative of hepatic SOS. Hepatic SOS should be included in the differential diagnosis of patients with severe liver injury following the administration of chemotherapy regimens that are toxic to the vascular endothelial cells.

Synergy of Myc, cell cycle regulators and the Akt pathway in the development of aggressive B-cell lymphoma in a mouse model

Synergy of Myc, cell cycle regulators and the Akt pathway in the development of aggressive B-cell lymphoma in a mouse model