Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group.

The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR-ABL-negative ALL. Patients aged 15-24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58-75%) and 73% (95% CI 64-80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR-ABL-negative ALL.

Air-leak syndrome following allo-SCT in adult patients: report from the Kanto Study Group for Cell Therapy in Japan.

We retrospectively investigated air-leak syndrome (ALS), including pneumothorax and mediastinal/s.c. emphysema, following allogeneic hematopoietic SCT. Eighteen patients (1.2%) developed ALS among 1515 undergoing SCT between 1994 and 2005 at the nine hospitals participating in the Kanto Study Group on Cell Therapy. The median onset of ALS was at 575 days (range: 105-1766) after SCT and 14 patients (77.8%) had experienced late onset noninfectious pulmonary complications (LONIPC) before ALS. Chronic GVHD (cGVHD) was the strongest risk factor for ALS (odds ratio 13.5, P=0.013 by multivariate analysis). Repeat SCT, male sex and age <38 years at the time of transplantation were also significant risk factors for ALS. Patients with ALS had a significantly worse survival rate than those without ALS (61.5 vs 14.9% at 3 years; P=0.000). The main cause of death was respiratory complications in 8 of the 18 patients. In conclusion, ALS is a rare complication of SCT that is more likely to occur in relatively young male patients with cGVHD and/or LONIPC. It is possible that better understanding and treatment of LONIPC may lead to prevention of ALS.

Myeloablative hematopoietic stem cell transplantation for myelodysplastic syndrome in patients younger than 55 years: impact of comorbidity and disease burden on the long-term outcome.

We retrospectively investigated 31 myelodysplastic syndrome (MDS) patients receiving myeloablative hematopoietic stem cell transplantation (HCT) and focused on prognostic factors affecting the long-term outcome. Patients were classified according to the French-American-British classification and the HCT-comorbidity index was determined. Cytosine arabinoside or thiotepa combined with cyclophosphamide and total body irradiation was used as myeloablative conditioning in eight and 23 patients respectively. After a follow-up period of 0.8-14.2 years from transplantation (median: 6.4 years), 23 patients were alive in complete remission, and the 5-year overall survival (OS) and disease-free survival (DFS) rates were 79% and 72% respectively. The cumulative nonrelapse mortality (NRM) rate was 22% at 5 years. According to multivariate analysis, > or =20% blasts in the bone marrow and an HCT-comorbidity score > or = 3 were significantly associated with poor OS and DFS. Patients with a high HCT-comorbidity score and male patients receiving transplantation from female donors were significantly more likely to have a higher NRM according to the univariate, but not the multivariate analysis. These data suggest that comorbidity and the tumor burden at the time of transplantation may be useful variables for predicting the outcome in MDS patients receiving myeloablative HCT.

Thiotepa/cyclophosphamide/TBI as a conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome.

In all, 18 patients (30-56 years; median 49) with MDS underwent allogeneic HSCT from related (n=12) or unrelated (n=6) donors after a conditioning regimen comprising thiotepa, cyclophosphamide, and TBI. GVHD prophylaxis consisted of cyclosporine (n=15) or tacrolimus (n=3) with short-course methotrexate. Four patients had low-risk disease (refractory anemia or complete remission after chemotherapy) and 14 patients had high-risk disease (RAEB, RAEB-t, or AML). Grade II-IV acute GVHD developed in six patients and chronic GVHD in 10. With a median follow-up of 31 months, the 2-year survival probability is 75% for low-risk patients and 57% for high-risk patients. One patient died of leukemia and six of treatment-related causes. This conditioning regimen requires further study in patients with MDS.

Therapy-related CD7+ acute myeloid leukemia with trisomy 8 following acute monocytic leukemia.

We report a patient who developed CD7+ therapy-related acute myeloid leukemia (t-AML) with trisomy 8 after chemotherapy for AML.

[Feasibility of early tapering and discontinuation of cyclosporine to intensify the graft-versus-leukemia effect in patients with advanced hematologic neoplasms].

Twenty patients with advanced hematological malignancies at high risk of relapse who had each received a bone marrow transplant from a matched sibling were registered between October 1996 and January 2000. Cyclosporine (CSP) was tapered on day 40 and stopped on day 50 in 10 patients without prior grade II-IV acute graft-versus-host disease (GVHD), relapse or active infection. These patients were eligible for early tapering of CSP. Although grade II/III acute GVHD was observed in three patients and chronic GVHD in eight patients after CSP tapering, no patients died of GVHD. Three patients died due to disease relapse and one patient died of idiopathic interstitial pneumonia while in remission. The probability of event-free survival at 2 years was 60%. These result indicate that early tapering and withdrawal of CSP is feasible and may provide a graft-versus-leukemia effect in patients with advanced leukemia.

Immune reconstitution assessed during five years after allogeneic bone marrow transplantation.

Immune reconstitution is an important component of successful allogeneic bone marrow transplantation. Immune reconstitution was evaluated for 5 years after transplantation. While the number of CD8+ T cells and CD56+ cells recovered early post transplantation, a low number of CD4+ and CD4+ CD45RA+ T cells and reversal of the CD4/CD8 ratio continued up to 5 years. Although early recovery of IgG and IgM was seen at day 100 post transplantation, serum concentration of IgA was below the normal range at 6 months and increased gradually up to 5 years. Development of acute GVHD did not affect the numbers of CD4+, CD8+, CD4+ CD45RA+ and CD4+ CD29+ T cells, but the number of CD56+ cells in patients who developed grades II-IV acute GVHD was low. The number of CD4+ CD29+ T cells had a tendency to be higher in the patients with extensive chronic GVHD than in those without chronic GVHD 2 years after transplantation whereas the number of CD4+ CD45RA+ T cells was low in spite of the absence of chronic GVHD. Serum concentration of IgA was lower in patients with extensive chronic GVHD than in those without chronic GVHD at 180 days. The number of CD4+ CD45RA+ cells in 10-19-year-old patients was higher than that in 40-49-year-old patients. Response to the Con A and PHA in 10-19-year-old patients was higher than that in older patients at 1 and 2 years. There was no significant difference in the ability of immune reconstitution between related transplant recipients and unrelated transplant recipients. These results suggest that chronic GVHD and age of patients affected immune reconstitution post transplant.

[Complete cytogenetic response obtained with unrelated donor lymphocyte infusion for relapse of chronic myeloid leukemia in blastic crisis after allogeneic bone marrow transplantation].

A 35-year-old man with chronic myeloid leukemia (CML) in blastic crisis (BC) received an allogeneic bone marrow transplant from an unrelated donor in October 1998 after three cycles of chemotherapy. BC relapse developed on day 349 after transplantation. After one cycle of chemotherapy and treatment with interferon, the patient received donor lymphocyte infusion (DLI), and this resulted in a complete cytogenetic response 21 days later. Grade III acute graft-versus-host disease developed on day 25 after DLI, but this was resolved after administration of prednisolone. Disease relapse occurred at extramedullary sites on day 162 after DLI, and the patient died of sepsis after receiving chemotherapy. This case illustrates that unrelated DLI can induce remission successfully in patients with relapse of CML in BC through a graft-versus-leukemia effect.

Nucleotide sequence analysis of the binding site on the inositol 1,4,5-trisphosphate type-1 receptor in bipolar disorder -- a negative study.

Pharmacological studies of bipolar disorder suggest that dysfunction of calcium mobilization via phosphatidylinositol-mediated transduction may be involved in its pathogenesis. The present study tests the hypothesis that dysfunction of calcium mobilization in bipolar disorder is due to the mutation of the nucleotide sequence in the FKBP12 binding site on the inositol 1,4,5-trisphosphate type-1 receptor (IP(3)R1). Nucleotide sequence analysis of the FKBP12 binding site on IP(3)R1 was performed using reverse transcription-polymerase chain reaction and DNA sequencing. The nucleotide sequence in this region was preserved in all subjects. This finding suggests that IP(3)R1 dysfunction through the FKBP12 binding site is not involved in the pathogenesis of bipolar disorder.

[Sequential analysis of p210- and p190-bcr-abl by RT-PCR after allogeneic bone marrow transplantation for p210/p190-bcr-abl double positive acute lymphoblastic leukemia].

In patients with both p210-bcr-abl (p210) and p190-bcr-abl (p190)-positive acute lymphoblastic leukemia, the number of p190 transcripts is lower than that of p210 transcripts. It is speculated that the p190 transcript occurs as a consequence of alternative splicing or missplicing events in the BCR gene. Four patients with both p210- and p190-positive acute lymphoblastic leukemia were studied for expression of p210 and p190 by RT-PCR before and after allogeneic bone marrow transplantation. p190 negativity was documented in all four patients, followed by p210 negativity one to two months later in three patients. These results suggest that negativity for p190 indicates an ongoing decrease in the small number of residual leukemic cells. In one patient p190 appeared transiently in spite of prolonged negativity for p210 18 months after bone marrow transplantation. We conclude that analysis of p210 and p190 is useful for following up patients with both p210- and p190-positive acute lymphoblastic leukemia.

Influence of restraint stress on the expression and the serine/threonine phosphatase activity of calcineurin in the rat brain.

To investigate the role of calcineurin (CaN) in the pathogenesis of stress-related psychiatric disorders, we examined the expression of CaN A mRNA and the serine/threonine phosphatase activity of CaN in the rat brain following various restraint stress paradigms. Northern blot analysis revealed no significant changes in the levels of CaN A mRNA expression, in either the frontal cortex or the hippocampus, in response to a single restraint stress for either 15, 45, or 90 min. In addition, no significant change in the levels of CaN A mRNA was found 3 or 6 h after a single restraint stress for 90 min. In situ hybridization analysis revealed that a single restraint stress for 45 min had no influence on CaN A mRNA expression in the CA1 and CA3 pyramidal cell layers or in the dentate gyrus granule cell layer of the hippocampus. However, serine/threonine phosphatase activity was significantly increased in both regions in response to a single restraint stress for either 45 or 90 min. These results demonstrate that the single restraint stress paradigms used in this study increase the activity of CaN without any changes in the expression of CaN, suggesting that the activation of calmodulin and the increased levels of heat shock proteins in response to the restraint stress may upregulate the activity of CaN in the rat brain.

Severe cardiac toxicity in hematological stem cell transplantation: predictive value of reduced left ventricular ejection fraction.

Eighty patients receiving hematological stem cell transplantation (HCT) with a preparative regimen consisting of total body irradiation (12.5 Gy), cyclophosphamide (4000 or 4500 mg/m2), and thiotepa (400 mg/m2) were evaluated for the development of cardiac toxicity. Patients in whom the pretransplant cumulative dose of anthracycline was more than or equal to 300 mg/m2 showed a lower left ventricular ejection fraction (EF) before HCT compared to patients with less than 300 mg/m2 (0.61 +/- 0.09 vs 0.67 +/- 0.06, P = 0.0010). Patients who had undergone more than or equal to six courses of chemotherapy showed a decreased EF before HCT compared to those after less than six courses (0.67 +/- 0.05 vs 0.63 +/- 0.09, P = 0.03). Three of seven patients (43%) whose pretransplant EF had been less than or equal to 0.55 developed severe cardiac toxicity, characterized by congestive heart failure (CHF) compared with none of 83 patients (0%) whose pretransplant EF had been more than 0.55 (P = 0.00026). Of the three patients who developed severe cardiac toxicity, two were given more than 300 mg/m2 of cumulative anthracycline and underwent 23 courses and six courses of chemotherapy, while the other patient received only two courses of chemotherapy with a total dose of 139 mg/m2 of anthracycline. These results indicate that an increased cumulative dose of anthracycline and number of chemotherapy treatments are correlated with a decrease of the EF and that the EF before HCT is useful for predicting the risk of cardiac complications for recipients who have received chemotherapy.

Antigens of monoclonal antibody NB3C4 are novel markers for oligodendrocytes.

We produced NB3C4, a novel monoclonal antibody specific for oligodendrocytes, using human neuroblastoma IMR-32 cells. NB3C4 specifically recognized oligodendrocytes in the CNS, although it bound to neuroblastoma IMR-32 cells and oligodendrocytes in vitro. Double immunofluorescence staining of rat brain using NB3C4 and anti-GST-pi, anti-glial fibrillary acidic protein (GFAP), or anti-neurofilament 200 (NF) antibody revealed that anti-GST-pi antibody identified an oligodendrocyte marker recognizing NB3C4-positive cells, while both anti-GFAP and anti-NF antibody did not. Western blotting of rat brain homogenates showed that NB3C4 bound three proteins of 22-28 kDa, while the anti-GST-pi recognized a 27 kDa protein. Therefore, antigens recognized by NB3C4 could be novel markers for oligodendrocytes.

Regulation of phosphorylation of cyclic AMP response element-binding protein by paroxetine treatments.

The present study was undertaken to examine the effect of paroxetine, a selective serotonin reuptake inhibitor, on the phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) in the rat brain. Single administration of paroxetine significantly induces the phosphorylation of CREB in the rat frontal cortex and hippocampus in a time-dependent manner. Repeated administration of paroxetine attenuates CREB phosphorylation in response to acute paroxetine challenge. These findings suggest that the enhancement of intracellular signal transduction after the activation of serotonin receptors may be attenuated after chronic paroxetine treatment, and this attenuation may be, at least in part, involved in the therapeutic efficacy of paroxetine.

[CD16+ CD56- indolent, NK cell-lineage granular lymphocyte proliferative disorder with autoimmune hemolytic anemia].

A 64-year-old man was given a diagnosis of CD16+ CD56- natural killer cell-lineage granular lymphocyte proliferative disorder (NK-GLPD) with Coombs-negative autoimmune hemolytic anemia (AIHA). Two courses of 1,000 mg intravenous methylprednisolone for 3 days were transiently effective for both AIHA and NK-GLPD. On the recurrence of AIHA, NK-GLPD also re-appeared. The same treatment was effective in controlling both diseases again. This was a rare case of NK-GLPD combined with autoimmune disease.

[Anesthetic management of bilateral lung lavage for pulmonary alveolar proteinosis--comparison between sevoflurane and propofol].

A 55-year-old man with pulmonary alveolar proteinosis underwent lung lavage under general anesthesia using sevoflurane three years ago. Although transient hypoxia occurred postoperatively, there were no complications. Because of the recent deterioration of his symptoms, he was rescheduled for lung lavage. Anesthesia was induced with propofol 120 mg and fetanyl 0.2 mg. Vecuronium 7 mg was administered to facilitate tracheal intubation using a double-lumen tube. Anesthesia was maintained with propofol 4 mg.kg-1.h-1. Electrocardiogram, blood pressure, SPO2, EtCO2 and rectal temperature were monitored intraoperatively. We also checked PaO2 when necessary. Although transient hypoxia occurred after the procedure, it receded spontaneously. Since inhalation anesthetics inhibit hypoxic pulmonary vasoconstriction, intravenous anesthetics may be more useful for patients with severe pulmonary alveolar proteinosis.