Summary We examined serum levels of the angiogenic factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF), in normal donors for allogeneic peripheral blood stem cell (PBSC) transplantation. Granulocyte colony‐stimulating factor (G‐CSF) (filgrastim 400 μg/m2/d) was administered to 23 donors for 5 d and aphereses were performed on days 4 and 5. Although bFGF remained at similar levels after G‐CSF treatment, serum VEGF and HGF levels increased 1·5‐fold (n = 13; P = 0·02) and 6·8‐fold (n = 23; P < 0·0001) respectively. The serum HGF level before G‐CSF administration on day 1 correlated inversely with mobilized CD34+ cell numbers. Time course kinetics of HGF showed that on the day after G‐CSF administration (day 2), serum HGF levels increased to 3678 pg/ml. For auto PBSC mobilization with chemotherapy and G‐CSF 200 μg/m2/d (n = 8), we observed similar HGF elevation, which appeared to be dose‐dependent on the G‐CSF administered.

Summary:Acute graft-versus-host disease (GVHD) increases posttransplant mortality and morbidity, but exerts a potent graft-versus-leukemia (GVL) effect. To clarify the impact of GVHD on outcome after transplant in aggressive diseases, patients with acute myeloid or lymphoblastic leukemia (AML, n ¼ 366 or ALL, n ¼ 255) in nonremission states, or chronic myelogenous leukemia (CML, n ¼ 180) in accelerated phase (AP) or blastic crisis (BC), who received allogeneic hematopoietic stem cell transplantation (HSCT) from a related donor between 1991 and 2000, were analyzed. Significant improvement in overall and disease-free survival (DFS) was detected with grade I acute GVHD in AML (P ¼ 0.0002 for overall survival and 0.0009 for DFS, respectively) and in CML (P ¼ 0.0256 and 0.0366, respectively), while the trend towards improved survival was observed in ALL. Relapse rate was lower in grade I acute GVHD than in grade II in all three diseases, suggesting that treatment for grade II GVHD may compromise the GVL effect associated with GVHD. Chronic GVHD was found to suppress relapse in CML and ALL, but not in AML, although no improvement in survival was observed in any disease category. Our results suggest that treatment for grade II acute GVHD may need to be attenuated in transplant for refractory leukemias. Refractory or relapsed acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML) in accelerated phase (AP) or blastic crisis (BC) have poor prognosis, and conventional salvage chemotherapy does not yield satisfactory survival benefit for patients with these refractory and/or advanced leukemias. If a suitable donor for allogeneic hematopoietic stem cell transplantation (HSCT) is available and the patient's general condition permits, high-dose chemoradiotherapy followed by allogeneic HSCT is indicated for the advanced stage of these diseases. In spite of high incidence of transplant-related mortality (TRM) and morbidity, including regimen-related toxicity (RRT), infection, and other complications, 1,2 allogeneic HSCT during the nonremission state seems to contribute toward prolonged disease-free survival (DFS). Indeed, clinical

In an earlier report, we demonstrated overexpression of a short isoform of Helios, Hel-5, which lacks three of four N-terminal zinc fingers, in patients with adult T-cell leukemia/lymphoma. Here, we characterized Hel-5 using immunoprecipitation, and gel shift and luciferase promoter assays, and found that Hel

The effectiveness of vandetanib, an agent that targets RET, VEGFR and EGFR signaling, against EGFR-mutant lung cancer cells with PTEN loss was investigated. Two EGFR mutant non-small cell lung cancer (NSCLC) cell lines, PC-9 (PTEN wild type) and NCI-H1650 (PTEN null), were used. We transfected an intact PTEN gene into H1650 cells and knocked down PTEN expression in PC-9 cells using shRNA. The effectiveness of gefitinib and vandetanib was assessed using a xenograft model. While PC-9 cells were more resistant to vandetanib than gefitinib, H1650 cells were more sensitive to vandetanib than gefitinib. Both gefitinib and vandetanib suppressed the activation of EGFR and MAPK in H1650 cells, although phosphorylated AKT levels were not affected. In an H1650 cell xenograft model, vandetanib was also more effective than gefitinib. Although PTEN-transfected H1650 cells did not show restoration of sensitivity to gefitinib in vitro, the xenograft tumors responded to gefitinib and vandetanib. Knockdown of PTEN in PC-9 cells caused resistance to gefitinib. In conclusion, vandetanib might be effective in NSCLC with EGFR mutations that lack PTEN expression. The contribution of PTEN absence to vandetanib activity in NSCLC cells harboring EGFR mutations should be further examined.

We report a chronic myelogenous leukemia (CML) patient in chronic phase (CP) who developed multiple sclerosis (MS) in association with interferon-alpha (IFN-a) administration. In our patient, recombinant IFN-a2b therapy induced hematologically complete and cytogenetically major partial response for CML ®rst, and sequential central nervous system dysfunction evolved, which subsided shortly after the cessation of its administration. Restarting IFN-a therapy by changing to a natural type of IFN-a resulted in rapid exacerbation of MS. The patient's neurological symptoms progressed gradually, but partial hematologic response persisted without any IFN-a derivatives or anti-cancer agents until a matched unrelated donor transplant procedure was performed. Myeloablative therapy led to lasting stable state of MS and ®nally to complete cytogenetic remission of CML. This patientÕs presenting clinical course and laboratory data suggest that both exertion of anti-leukemic activity and autoimmune process of MS might be mediated by mutual mechanisms, such as enhancement of speci®c cellular immunity induced by IFN-a. Am.