Ryuko Cho

Late-onset noninfectious pulmonary complications after allogeneic stem cell transplantation are significantly associated with chronic graft-versus-host disease and with the graft-versus-leukemia effect

Late-onset noninfectious pulmonary complications (LONIPCs) occurring beyond 3 months after allogeneic stem cell transplantation (allo-SCT) have become recognized as life-threatening complications, and they reduce the recipients quality of life. However, the pathogenesis and optimal treatment for LONIPCs are still unclear. In this study, we retrospectively analyzed the incidence and outcome of LONIPCs among allo-SCT recipients. Between October 1993 and September 2001, 96 patients underwent allo-SCT and 76 patients who survived and were free of disease for more than 3 months after SCT were enrolled. Among the 76 patients, 18 patients (23.7%) developed LONIPCs at a median interval of 227 days after allo-SCT (range, 91-1105 days). The patients with LONIPCs were subclassified into those with bronchiolitis obliterans (BO) (6 patients), with interstitial pneumonia (IP) (11 patients), or with both BO and IP (1 patient). The presence of extensive chronic graft-versus-host disease (GVHD) was significantly associated with the development of LONIPCs (P =.0008). Liver or skin involvement in chronic GVHD was not associated, but sicca syndrome was significantly associated with the development of LONIPCs (P <.0001). Most of the IP patients (58.3%) responded well to immunosuppressive treatment, while BO patients did not respond to the therapy. Eight of the 18 patients with LONIPCs died. The major cause of death was respiratory failure (62.5%). The relapse rate of primary malignant disease in the LONIPC patients was significantly lower than that of non-LONIPC patients (1 of 17 [5.9%] versus 16 of 52 [30.8%]; P =.0387). These results indicate that the development of LONIPCs was strongly associated with chronic GVHD and especially with sicca syndrome and the graft-versus-leukemia (GVL) effect.

Autologous peripheral blood stem cell transplantation for POEMS syndrome

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome is a rare multisystem disorder. Overproduction of vascular endothelial growth factor (VEGF) by plasmocytoma could be responsible for the symptoms. The authors treated four patients with high-dose chemotherapy and autologous peripheral blood stem cell transplantation. Within 6 months, symptoms associated with rapid normalization of serum VEGF levels improved.

Chronic graft-versus-host disease after allogeneic bone marrow transplantation from an unrelated donor: incidence, risk factors and association with relapse. A report from the Japan Marrow Donor Program

Chronic graft‐versus‐host disease (GVHD) remains the major cause of late morbidity and mortality after allogeneic stem cell transplantation. We retrospectively analysed 2937 patients who underwent bone marrow transplantation from an unrelated donor (UR‐BMT) facilitated by the Japan Marrow Donor Program (JMDP) and survived beyond day 100 after transplantation. The cumulative incidence of chronic GVHD (limited + extensive) or extensive chronic GVHD at 5 years post‐transplant was 45·8% and 28·2%, respectively. On multivariate analysis, seven variables predicting chronic GVHD were identified: recipient age over 20 years, donor age over 30 years, primary diagnosis of chronic myeloid leukaemia, human leucocyte antigen (HLA)‐A or ‐B mismatch, total body irradiation‐containing regimen, platelet count not having reached 50 × 109/l by day 100, and prior acute GVHD. Among 2609 patients with haematological malignancy, overall survival was significantly higher in patients with limited chronic GVHD but lower in patients with extensive chronic GVHD compared with those without chronic GVHD. The cumulative incidence of relapse among patients with limited or extensive chronic GVHD was significantly lower than that among patients without chronic GVHD. Our results suggest that limited chronic GVHD provides a survival benefit to patients with haematological malignancies by reducing the risk of relapse without increasing the risk of death from chronic GVHD.

CD44 and hyaluronan engagement promotes dexamethasone resistance in human myeloma cells

Dexamethasone (Dex) is an effective therapeutic agent against multiple myeloma (MM); however, resistance to it often becomes a clinical issue. CD44 is an adhesion molecule that serves as a cell surface receptor for extracellular matrix components, including hyaluronan (HA). HA is an extracellular matrix component that is involved in survival and progression in MM. In the present report, we describe isolation of a CD44‐expressing population from a Dex‐sensitive MM cell line, RPMI8226, in which the CD44‐high population had a significantly higher potential to resist Dex than did the CD44‐low population. Furthermore, we demonstrate that CD44 engagement by an anti‐CD44 monoclonal antibody (mAb) or HA protects MM cells from Dex‐induced growth inhibition. The activity of HA was partially inhibited by blocking its binding to CD44, indicating that CD44 mediates HA activity promoting MM cell survival. CD44 engagement by an anti‐CD44 mAb led to phosphorylation and degradation of IκB‐α, thus preventing its Dex‐induced up‐regulation. Our data suggest that CD44 is not only an important mediator for the survival activity of HA, but it may also contribute to MM cell resistance to Dex.

Successful combination treatment with bevacizumab, thalidomide and autologous PBSC for severe POEMS syndrome

Successful combination treatment with bevacizumab, thalidomide and autologous PBSC for severe POEMS syndrome

Restrictive usage of monoclonal immunoglobulin λ light chain germline in POEMS syndrome

POEMS syndrome is a rare plasma cell disorder characterized by peripheral neuropathy, monoclonal gammopathy, and high levels of serum vascular endothelial growth factor, the pathogenesis of which remains unclear. A unique feature of this syndrome is that the proliferating monoclonal plasma cells are essentially lambda-restricted. Here we determined complete nucleotide sequences of monoclonal immunoglobulin lambda light chain (IGL) variable regions in 11 patients with POEMS syndrome. The V-region of the Ig lambda gene of all 11 patients was restricted to the V lambda 1 subfamily. Searching for homologies with IGL germlines revealed that 2 germlines, IGLV1-44*01 (9/11) and IGLV1-40*01 (2/10), were identified, with an average homology of 91.1%. The IGLJ3*02 gene was used in 11 of 11 re-arrangements with an average homology of 92.2%. These data suggest that the highly restricted use of IGL V lambda 1 germlines plays an important role in the pathogenesis of POEMS syndrome.

Zoledronate has an antitumor effect and induces actin rearrangement in dexamethasone-resistant myeloma cells

New strategies are needed to overcome the resistance of multiple myeloma (MM) to dexamethasone (Dex). Several recent in vitro studies demonstrated the antitumor effect of nitrogen‐containing amino‐bisphosphonates (N‐BPs) in various tumor cell lines. Inhibition of the prenylation of small G proteins is assumed to be one of the principal mechanisms by which N‐BPs exert their effects. There have been few reports on N‐BP treatment of MM cells that are resistant to Dex. Additionally, it is not known how small G proteins are altered in N‐BP‐treated MM cells. In this study, we evaluated the effect of the most potent N‐BP, zoledronate (ZOL), on a Dex‐resistant human MM cell subline (Dex‐R) that we established from the well‐documented RPMI8226 cell line. ZOL reduced the viability and induced apoptosis of Dex‐R cells. Some of the ZOL‐treated RPMI8226 cells and ZOL‐treated Dex‐R cells were elongated; however, elongated cells were not seen among the Dex‐treated RPMI8226 cells. Furthermore, we found that portions of the small G proteins, Rho and Rap1A, were unprenylated in the ZOL‐treated MM cells. Geranylgeraniol reduced the above‐mentioned ZOL‐induced effects. These findings suggest that ZOL may be beneficial for the treatment of Dex‐resistant MM by suppressing the processing of RhoA and Rap1A.

Second cord blood transplantation (CBT) with reduced-intensity conditioning for graft failure after the first CBT for AML.

Second cord blood transplantation (CBT) with reduced-intensity conditioning for graft failure after the first CBT for AML

Successful engraftment by second cord blood transplantation with reduced-intensity conditioning after graft rejection due to hemophagocytic syndrome following initial CBT

Successful engraftment by second cord blood transplantation with reduced-intensity conditioning after graft rejection due to hemophagocytic syndrome following initial CBT

Successful matched unrelated BMT for secondary AML which developed simultaneously with relapsed Hodgkin's lymphoma

Successful matched unrelated BMT for secondary AML which developed simultaneously with relapsed Hodgkins lymphoma