Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia.

BACKGROUND: Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, a pro-survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B-precursor acute lymphoblastic leukemia (B-pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P-Akt) in pediatric B-pre ALL. PROCEDURE: We evaluated the activation status of Akt in bone marrow samples from 21 children with newly diagnosed B-pre ALL and correlated the expression level of P-Akt with clinicopathologic and prognostic features. Additionally, we transfected the myristoylated Akt cDNA into the B-pre ALL cell line, Nalm-6, and examined the effect, in vitro, of Akt activation on the response to antitumor drugs. RESULTS: P-Akt expression in B-pre ALL blast cells at diagnosis was associated significantly with poor response to induction chemotherapy including prednisolone, dexamethasone, vincristine, and adriamycin in B-pre ALL patients. Both overall survival and relapse-free survival in patients with P-Akt expression were reduced significantly more than in patients without P-Akt expression. Activation of Akt reduced the extent of apoptosis induced by the antitumor drugs in Nalm-6 listed above. Activation of Akt did not induce expression of P-glycoprotein, a drug transporter that is capable of conferring multidrug resistance. CONCLUSION: These results support the contention that Akt activation is a mechanism of chemotherapeutic resistance in B-pre ALL and suggest that Akt can be a therapeutic target for the treatment of relapsed or refractory pediatric B-pre ALL.

Successful treatment of unresectable advanced hepatoblastoma: living liver transplantation after surgical removal of lung metastasis.

Hepatoblastoma is a rare malignant tumor of the liver in children. Intensive combination chemotherapy has increased the number of surgically resectable cases and improved prognosis markedly. However, unresectable cases and cases with residual metastasis, including lung metastases, have a poor prognosis. In these refractory cases, treatment strategy has not been established. On the other hand, living liver transplantation has been shown to be effective in cases of advanced hepatoblastoma, but its effectiveness in cases with residual distant metastases after chemotherapy remains unclear. We report one successful case of advanced unresectable hepatoblastoma with multiple lung metastases. Intensive chemotherapy consisting of high-dose chemotherapy with autologous hematopoietic stem cell transplantation was not effective. We performed living liver transplantation after surgical resection of residual lung metastases, which were histologically viable. After liver transplantation, the level of tumor marker decreased gradually. The patient experienced no severe complications. This case suggested that living liver transplantation could be effective in cases of advanced refractory hepatoblastoma after control of distant metastases.

Two cases of chronic active Epstein-Barr virus infection in which EBV-specific cytotoxic T lymphocyte was induced after allogeneic bone marrow transplantation.

CAEBV is a high mortality and morbidity disease with life-threatening complications. Nevertheless, the treatment regimens for CAEBV have not yet been established. Although some reports have described CAEBV therapy involving treatments such as antiviral drugs, immunomodulatory agents, and immunochemotherapy, none of these treatments have been demonstrated to be effective. The only treatment reported to be effective is allogeneic SCT. However, the complications of SCT are severe, so treatment results have been poor. Recently, immunotherapy has been devised, but this is still in the developmental stage. In this report, two cases of CAEBV in which allogeneic SCT was performed soon after diagnosis are reported. In both cases, a high EBV genome titer in the peripheral blood was detected at onset. After SCT, the EBV genome titer decreased as CTL activity gradually increased. This fact suggested that not only high-dose chemotherapy as a preconditioning treatment of SCT but also increased CTL activity which could eliminate virus-infected cells might be effective, although additional cases should be studied in order to establish effective treatments.