Prospective observational study on the first 51 cases of peripheral blood stem cell transplantation from unrelated donors in Japan.

The Japan Marrow Donor Program (JMDP) has facilitated unrelated peripheral blood stem cell transplantation (URPBSCT) since 2010. We conducted a prospective multicenter observational study to evaluate the feasibility of such transplantation. Between 2011 and 2014, 51 patients underwent URPBSCT from 8/8 allele-matched donors for hematological malignancies. The median age of the patients was 50 years; 21 had high-risk disease. Myeloablative conditioning regimens were used in 31 patients, and tacrolimus based graft-versus-host disease (GVHD) prophylaxis was used for all patients. The cumulative rate of engraftment was 96%. With a median follow-up period of 610 days for survivors, 100-day and 1-year overall survival rates were 86 and 59%, respectively. The cumulative incidence of non-relapse mortality and relapse at 1 year were 14 and 35%, respectively. The incidence of grade II to IV acute GVHD at 100 days and extensive type of chronic GVHD at 1 year were 25 and 32%, respectively. The probability of overall survival was comparable with that of bone marrow transplantation from HLA matched-unrelated donors in Japan, although the incidence of chronic GVHD was higher. Further follow-up with more patients is clearly warranted to establish the optimal use of URPBSCT together with the approaches of minimizing chronic GVHD.

Comparison of cord blood transplantation with unrelated bone marrow transplantation in patients older than fifty years.

We retrospectively compared the transplantation outcomes for patients 50 years or older who received umbilical cord blood transplantation (UCBT) with those who received unrelated bone marrow transplantation (UBMT) for hematologic malignancies. A total of 1377 patients who underwent transplantation between 2000 and 2009 were included: 516 received 8/8 HLA allele-matched UBMT, 295 received 7/8 HLA allele-matched UBMT, and 566 received 4/6 to 6/6 HLA-matched UCBT. Adjusted overall survival (OS) was significantly lower in those who underwent UCBT than those who underwent 8/8 HLA-matched UBMT but was similar to that of 7/8 HLA-matched UBMT (the 2-year OS after 8/8 HLA-matched UBMT, 7/8 HLA-matched UBMT, and UCBT were 49% [95% confidence interval (CI), 45% to 55%], 38% [95% CI, 32% to 45%], and 39% [95% CI, 34% to 43%], respectively). However, adjusted OS was similar between 8/8 HLA-matched UBMT and UCBT receiving ≥.84 × 10(5) CD34(+) cells/kg among those with acute myeloid leukemia and those with acute lymphoblastic leukemia (the 2-year OS was 49% [95% CI, 43% to 55%], and 49% [95% CI, 41% to 58%], respectively). These data suggest that UCB is a reasonable alternative donor/stem cell source for elderly patients with similar outcomes compared with UBM from 8/8 HLA-matched unrelated donors when the graft containing ≥.84 × 10(5) CD34(+) cells/kg is available.

Phase I/II study of decitabine in patients with myelodysplastic syndrome: a multi-center study in Japan.

The management of myelodysplastic syndrome (MDS) remains challenging. We performed a phase I/II study to evaluate the safety and efficacy of decitabine in patients with MDS in Japan. Patients with MDS with red cell transfusion dependence or 5-30% blasts in marrow and with an International Prognostic Scoring System score of intermediate-1 or higher were eligible. Patients received intravenous decitabine at 15 or 20 mg/m(2) daily for 5 days every 4 weeks. A total of 37 patients were enrolled. Three patients received 15 mg/m(2) and experienced no dose limiting toxicity during the first cycle. Thirty-four patients received 20 mg/m(2) . Grade 3 or greater non-hematologic toxicities included cerebral infarction (n = 1), subdural hematoma (n = 1), elevated blood glucose (n = 1), and pulmonary hypertension (n = 1). At 20 mg/m(2) , complete response, partial response, and hematologic improvement were observed in 7 (20.6%), 2 (5.9%), and 7 (20.6%) patients, respectively. Complete cytogenetic response was observed in 30% of evaluable 20 patients. The median number of cycles to clinical response was 4 (range 4-8), and duration of remission was 474+ days (range 294-598+). The 2-year rate of acute myeloid leukemia-free survival was 52%. Correlative studies revealed hypomethylation in multiple genes in peripheral blood cells after treatment. Hypomethylation was generally more profound in CD15 + peripheral blood cells, which reflects myeloid cells, than in peripheral blood mononuclear cells. In summary, decitabine was safe and demonstrated efficacy in Japanese patients with high-risk MDS. This trial was registered at ClinicalTrials.gov (NCT00796003).

[Retrospective analysis of posterior reversible encephalopathy syndrome after allogeneic stem cell transplantation].

Posterior reversible encephalopathy syndrome (PRES) is one of the serious adverse side effects of calcineurin inhibitors, which are used for the prophylaxis of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). We retrospectively analyzed 12 patients who developed PRES after allo-SCT aiming to clarify the clinical features, risk factors, and prognosis of PRES. Median onset of PRES is 17 days after allo-SCT. The most frequent primary symptom was high blood pressure, followed by headache and visual disturbance. Nine of our patients subsequently developed systemic seizure. Sites of PRES by MRI were detected in the frontal, temporal, and parietal lobes, basal ganglia, and brain stem in addition to occipital lobe. Serum creatinine that had increased two-fold from the baseline value was identified as the only risk factor for developing PRES after allo-SCT. The incidence of acute GVHD (grade II-IV) in patients with PRES and those without were 88.9% and 48.7%; respectively (P<0.001), and most of these patients died of GVHD or GVHD-related causes. The 2-year overall survival of patients with PRES and those without were 16.7% and 72.4%, respectively (P<0.001). These data suggested the importance of early intervention for PRES and exploitation of optimal GVHD prophylaxis after developing PRES.

Possible association between obesity and posttransplantation complications including infectious diseases and acute graft-versus-host disease.

Both obesity and malnutrition are considered risk factors for complications after bone marrow transplantation (BMT). To elucidate the impact of pretransplantation body mass index (BMI) on clinical outcome, we performed a retrospective cohort study with registration data from the Japan Marrow Donor Program (JMDP). Between January 1998 and December 2005, a total of 3935 patients received unrelated BMT through the JMDP; of these, 3827 patients for whom pretransplantation height and weight data were available were included in the study. Patients were stratified according to pretransplantation BMI values (low BMI: BMI < 18 kg/m(2), n = 295; normal BMI: 18 < or = BMI < 25 kg/m(2), n = 2906; overweight: 25 < or = BMI <30 kg/m(2), n = 565; obese: 30 kg/m(2) < or = BMI, n = 61). In a univariate analysis, pretransplantation BMI was associated with a significantly greater risk of grade II-IV acute graft-versus-host disease (GVHD; P = .03). Multivariate analysis showed that pretransplantation BMI tended to be associated with an increased risk of grade II-IV acute GVHD (P = .07). Obesity was associated with an increased risk of infection compared with normal BMI (odds ratio = 1.9; 95% confidence interval = 1.1 to 3.2; P = .02). Our findings demonstrate a correlation between pretransplantation BMI and posttransplantation complications. Although BMI depends strongly on multiple factors, the effect of obesity on clinical outcome should be evaluated in a prospective study.

Japanese phase II study of 90Y-ibritumomab tiuxetan in patients with relapsed or refractory indolent B-cell lymphoma.

There is no data about the efficacy and safety of radioimmunotherapy with 90Y-ibritumomab tiuxetan in patients with relapsed or refractory indolent B-cell lymphoma pretreated with rituximab-containing chemotherapy. We focused on this in a Japanese phase II study. Radioimmunotherapy with 90Y-ibritumomab tiuxetan (11.1 and 14.8 MBq) was evaluated in patients with 100-149x10(9) and >150x10(9) platelets/L, respectively. The primary endpoint was the overall response rate. Forty patients were treated with 90Y-ibritumomab tiuxetan (18 with 11.1 MBq/kg and 22 with 14.8 MBq/kg). Thirty-five patients (88%) had been pretreated with rituximab, including 27 (68%) pretreated with rituximab-containing chemotherapy. The overall response rate was 83% (33/40; 95% confidence interval, 67-93%), and the complete response rate was 68% (27/40; 95% confidence interval, 51-81%). The overall response rates in patients pretreated with rituximab-containing chemotherapy and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were 83% (19/23) and 94% (17/18), respectively. The median progression-free survival time of the 40 patients who received 90Y-ibritumomab tiuxetan was 9.6 months. Toxicity was primarily hematological and mostly transient. No grade 4 non-hematological toxicity was observed. In conclusion, radioimmunotherapy with 90Y-ibritumomab tiuxetan is safe and highly effective in patients with relapsed or refractory indolent B-cell lymphoma, including those pretreated with rituximab-containing chemotherapy. (ClinicalTrials.gov number NCT00220285).

Single-institute phase 2 study of thalidomide treatment for refractory or relapsed multiple myeloma: prognostic factors and unique toxicity profile.

We previously reported a pilot study of thalidomide monotherapy for Japanese patients with refractory or relapsed multiple myeloma. In the present work, we have extended this clinical trial to a single-institute phase 2 study with a larger number of patients and longer follow-up time. New information on the optimal dose and prognostic factors as well as the correlation of toxicities with treatment schedule was obtained. Fifteen of 56 (27%) patients achieved a partial response, including three cases with near-complete remission. Most patients suffered toxicities at a dose of 400 mg per day, but there was no clear dose-response relationship. Thus, a lower dose such as 200 mg per day or less is considered optimal. Multivariate analyses identified only lack of response to therapy as an adverse prognostic factor for progression-free survival. Chromosomal abnormality, C-reactive protein >10 mg/L, and more than six previous courses of chemotherapy were significantly associated with shorter overall survival. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 23 and 11% of patients, respectively. Grade 4 interstitial pneumonia and grade 5 pulmonary hypertension were observed; however, no patient suffered deep vein thrombosis, which has frequently been observed in other studies. Duration of therapy was closely related to the development of peripheral neuropathy. The efficacy and prognostic factors of this treatment were confirmed in long-term observation. However, special attention should be paid to toxicities such as hematological and pulmonary complications as well as peripheral neuropathy in long-term users.

Ossifying choroid plexus papilloma recurring with features of atypical papilloma.

A case of ossifying choroid plexus papilloma (CPP) with an unusual clinical course is reported. The patient was a 46-year-old woman who underwent surgery for a 3-cm tumor occupying the fourth ventricle. The tumor showed typical histopathological features of CPP, and the formation of psammoma bodies and mature bone trabeculae was prominent in the stroma. The tumor recurred locally after a dormant period of 15 years, and the recurrent lesion showed invasion of the cerebellum as well as increased cellularity, cellular stratification, nuclear atypism, and mitotic activity, all of which were consistent with a diagnosis of "atypical" CPP. The recurrent tumor did not show ossification of the stroma, although many psammoma bodies were found. There have been very few reported cases of ossifying CPP, and all of the previous cases behaved in a benign fashion. The present case is the first report of ossifying CPP that showed postoperative recurrence with progression to atypical CPP after an unusually long dormant period.

Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208.

A randomized controlled trial was conducted to evaluate the efficacy of high-dose chemotherapy (HDC) as consolidation of the treatment of high-risk postoperative breast cancer. Patients under 56 years of age with stage I to IIIB breast cancer involving 10 or more axillary lymph nodes were eligible. The primary endpoint was relapse-free survival (RFS). Between May 1993 and March 1999, 97 patients were enrolled, and two patients became ineligible. The median age of the 97 patients was 46 years (range 27-55 years), and 72 (74%) were premenopausal. The median number of involved axillary nodes was 16 (range 10-49). All patients had undergone a radical mastectomy. Major characteristics were well balanced between the treatment arms. Forty-eight patients in the standard-dose (STD) arm received six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen. Forty-nine patients were assigned to undergo HDC with cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen; however, 15 of these patients (31%) did not undergo HDC. HDC was well tolerated without any treatment-related mortality. At a median follow-up of 63 months, the 5-year RFS of 47 eligible patients in the STD arm and 48 eligible patients in the HDC arm was 37% and 52% on an intent-to-treat basis, respectively (P = 0.17). Five-year overall survival of all randomized patients was 62% for the STD arm and 63% for the HDC arm (P = 0.78). Although the prespecified values of the two arms were not so accurate as to allow detection of the observed difference, no advantage of HDC was observed in terms of RFS or overall survival.

Intraventricular meningioma with anaplastic transformation and metastasis via the cerebrospinal fluid.

We report a surgical case of intraventricular meningioma that arose in the trigone of the right lateral ventricle of a 61-year-old woman. Local recurrence and metastasis (dissemination) via the CSF to the fourth ventricle developed about 52 months postoperatively. Further subarachnoid dissemination in the pontine base and spinal cord occurred 6 months later. The tumor exhibited a histopathological appearance of transitional meningioma without cellular atypism in the original specimen, but in the metastatic nodules in the fourth ventricle and spinal subarachnoid space the histopathology was that of typical anaplastic meningioma. Only four cases of anaplastic intraventricular meningioma that developed metastasis via the CSF have been reported. This report presents the fifth case, which is also the second case in which progression from ordinary low-grade meningioma to anaplastic meningioma was demonstrated histopathologically.

Fulminant Epstein-Barr virus (EBV)-associated T-cell lymphoproliferative disorder with hemophagocytosis following autologous peripheral blood stem cell transplantation for relapsed angioimmunoblastic T-cell lymphoma.

Post-transplant lymphoproliferative disorder (PTLD) is a complication that can develop after either solid-organ or hematopoietic stem cell transplantation (HSCT). T-cell PTLD is a rare disorder, especially following autologous HSCT. Here we report a case of T-cell PTLD which occurred after autologous peripheral blood stem cell transplantation (PBSCT) for relapsed angioimmunoblastic T-cell lymphoma (AILT). Three months after the transplant, the patient developed fever with elevated plasma Epstein-Barr virus (EBV)-PCR values. The patient subsequently developed pneumonitis, hepatomegaly and marked pancytopenia due to hemophagocytosis. The patient died of multi-organ failure, despite antiviral and steroid pulse therapy. Our post-mortem study confirmed the marked proliferation of EBV-infected T-cells that differed from the original AILT clone and macrophages/histiocytes were observed in the marrow, liver, lymph nodes and lungs. Phagocytosis was most evident in the bone marrow. The patient's AILT remained in complete remission. To the best of our knowledge, this is the first case of fulminant EBV-associated T-cell lymphoproliferative disorder (LPD) following autologous HSCT.

Effect of cobalt on the liver glycogen content in the streptozotocin-induced diabetic rats.

Cobalt decreases blood glucose in diabetic rats but the mechanisms involved are unclear. To determine the contribution of glycogen metabolism to glycemia-lowering effect, glycogen contents of liver and muscle in the streptozotocin-induced diabetic rats were determined. The liver glycogen was depleted in diabetic rats. But when cobalt was administered to the rats, the glycogen returned to the level of healthy rats, concomitantly with the decrease in blood glucose. The cobalt treatment had no effect on the muscle glycogen in the diabetic rats. The tissue-specific responses of glycogen metabolism suggest the involvement of suppressed glucagon signaling due to cobalt treatment.

[Acute myeloid leukemia presenting with obstructive jaundice and granulocytic sarcoma of the common bile duct].

A 55-year-old man presented with jaundice and edema of the right leg. Tests of the peripheral blood and bone marrow showed leukocytopenia with 6% blasts and 38.3% of myeloperoxidase-positive blasts, respectively. Computed tomography (CT) scanning disclosed thickening of the common bile duct wall. Granulocytic sarcomas were also found at the left chest wall and the pelvic floor. Endoscopic retrograde cholangiopancreatography confirmed the narrowing of the common bile duct. Biopsy specimens of the common bile duct and pelvic masses revealed myeloblastic infiltration. After placement of a naso-biliary drainage tube, chemotherapy consisting of cytarabine (100 mg/m2/ day for 7 days) and idarubicin (12 mg/m2/ day for 3 days) was commenced. The dose of idarubicin was not modified. No serious complications, including delayed hematopoietic recovery, were observed after chemotherapy, and a complete remission was obtained 35 days later. Jaundice and liver dysfunction also gradually improved. The patient continues to receive consolidation therapy and remains in remission 8 months after the onset of his illness.

Rapid and efficient generation of lentivirally gene-modified dendritic cells from DC progenitors with bone marrow stromal cells.

Since dendritic cells (DC) play pivotal roles in both innate and adaptive immunity, DC can be a good target for immuno-gene therapy. However, the optimal generation method for gene-modified DC has not yet been well exploited. CD34+ cells from cord blood (CB), bone marrow (BM), or peripheral blood (PB) were expanded in a medium containing stem cell factor (SCF), flt 3 ligand (Flt3L) and thrombopoietin (TPO) with or without HESS-5, a murine BM stromal cell line, for 2 weeks (the first expansion step), then differentiated to DC in a medium containing granulocyte-macrophage colony-stimulating factor (GM-CSF), flt 3 ligand (Flt3L), stem cell factor (SCF), tumor necrosis factor-alpha (TNF-alpha), IL-4, and lipopolysaccharide (LPS) for 9 days (the second differentiation step). DC progenitors were transduced with human immunodeficiency virus (HIV) vectors at different time points during the second step. Use of HESS-5 during the first step resulted in more DC generation than without it (cell expansion: CB, 10,461 vs. 354-fold; BM, 962 vs. 225-fold; peripheral blood mononuclear cell (PBMC), 8,506 vs. 240-fold; %DC: CB, 83.4% vs. 76.9%; BM, 83.6 vs. 69.8%; PBMC, 85.9 vs. 60.5%). Gene transduction to the in vitro expanded DC progenitors at day 3 during the second step, resulted in better final yield of the gene-modified DC than that to those at day 0 or day 6 (as much as 44% of DC expressed green fluorescence protein (GFP) as a transgene) and the transduction efficiency correlated with endocytic ability and percent of S phase. DC transduced with an HIV vector encoding a melanoma antigen, MART-1, were adequately recognized by specific anti-MART-1 CTL. The two-step culture method with HESS-5 is useful for rapid expansion of DC progenitors and subsequent lentiviral gene transduction to DC.

Imatinib mesylate has limited activity against the central nervous system involvement of Philadelphia chromosome-positive acute lymphoblastic leukaemia due to poor penetration into cerebrospinal fluid.

A 32-year-old woman with relapsed Philadelphia chromosome-positive acute lymphoblastic leukaemia was treated with imatinib mesylate (formerly STI571), a selective inhibitor of BCR/ABL tyrosine kinase. Although the initial marrow response was good and stably maintained, she subsequently relapsed with extensive infiltration of leukaemic cells into the central nervous system (CNS). After controlling her CNS disease with additional intrathecal chemotherapy, we measured the concentration of imatinib in cerebrospinal fluid (CSF) and blood simultaneously. The concentration of imatinib in CSF was about 92-fold lower than that in blood. These results suggest that imatinib poorly penetrates the blood-brain barrier and has limited activity against CNS leukaemia.