Downregulation of Cap43 gene by von Hippel-Lindau tumor suppressor protein in human renal cancer cells

We previously identified 9 genes (i.e., thymosin beta4, secreted protein acidic and rich in cysteine, Cap43, ceruloplasmin, serum amyloid A, heat shock protein 90, LOT1, osteopontin and casein kinase Igamma) that are more highly expressed in cancerous regions than in noncancerous regions in human renal cancers. In our study, we considered the possibility that the von Hippel-Lindau (VHL) tumor suppressor gene might be able to affect the expression of these 9 genes in renal cancer cells. We first established 2 VHL-positive cell lines, 786/VHL-1 and 786/VHL-2, after the introduction of wild-type VHL into VHL-negative renal cancer 786-O cells. Of these 9 genes, expression of the Cap43 gene was specifically downregulated by VHL. Expression of Cap43 was also much lower in 4 other VHL-positive renal cancer cell lines than in VHL-negative 786-O cells. Cap43 promoter assays with several deletion or mutation constructs demonstrated that the Sp1 site in the element from -286 base pairs (bp) to -62 bp was partly responsible for VHL-induced suppression of the Cap43 gene. Immunostaining analysis with human specimens of renal cancers demonstrated that the Cap43 protein was expressed in most cancer cells and macrophages. We also observed a marked and specific increase of Cap43 mRNA levels in response to hypoxia or nickel in all VHL-positive cell lines. Cellular expression of Cap43 mRNA in response to hypoxia or nickel thus is closely associated with VHL gene expression in renal cancer cells. Although the function of the Cap43 protein remains unclear, the expression of Cap43 protein could be a molecular marker closely associated with VHL in renal cancer.     

ABVD chemotherapy for Hodgkin lymphoma at a single institute

Fifty-eight newly diagnosed patients with Hodgkin lymphoma were treated with ABVD chemotherapy at Yokohama City University Hematology group from October 1996 to June 2005. The median age of patients age was 41 years old and ranged from 15 to 75. Thirty-eight patients were in the early stage and 20 patients were in the advanced stage. Patients in the early stage received 3 cycles of ABVD chemotherapy and involved-field radiation therapy, while those in the advanced stage received 6 cycles of ABVD chemotherapy. The overall response rate in patients was 100% (CR 87%, PR 13%) in the early stage and 95% in the advanced stage. With a median follow-up of 44 months, the 3-year progression-free survival and overall survival were 89% and 95% in the early stage, and 70% and 81% in the advanced stage, respectively. The results of this study were similar to those previously reported in Western countries.     

Trial of front-line intensive chemotherapy followed by peripheral blood stem cell transplantation in high-intermediate and high risk non-Hodgkin's lymphoma patients

High-intermediate (HI)- and high (H)-risk non-Hodgkin lymphoma was treated with front-line intensive chemotherapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT). Twenty-eight cases were enrolled after obtaining informed consent, from November, 1998 to October, 2003. Initial treatment was 2 or 3 cycles of CHOP-V regimen, followed by three high-dose therapy, one each of cyclophosphamide, methotrexate and etoposide. The final high-dose therapy was a combination of ranimustine, ifosphamide and etoposide, which was followed by auto-PBSCT. Patients with a bulky mass received involved-field radiation therapy (IF-RT) after auto-PBSCT. Complete remission (CR) was achieved in 16 cases (57%) and partial remission (PR) in 9 cases (32%), after auto-PBSCT The final responses after IF-RT were CR in 20 cases (71%) and PR in 5 cases (18%). Overall survival of cases with 2 cycles of CHOP-V regimen was 56% after a median observation time of 30 months, compared with 82% in cases with 3 cycles (p = 0.0732). The results suggested that the reduction of tumor size with the initial CHOP-V treatment was most important. In all cases, progression-free survival was 64% and the overall survival was 74% after a median observation time of 30 months, which showed a good outcome compared with that of HI- and H-risk group defined by the age-adjusted international prognostic index reported by Shipp et al.     

Pretransplant serum ferritin is associated with bloodstream infections within 100 days of allogeneic stem cell transplantation for myeloid malignancies

We retrospectively studied the association between iron overload and bloodstream infections (BSI) in the 100-day period following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia or myelodysplastic syndromes. Serum ferritin was measured before transplantation to evaluate iron overload. Of 114 adult patients who underwent transplantation between 2000 and 2008, 36 (32%) developed BSI. Of the 44 isolates, 63% were Gram-positive bacteria, 32% were Gram-negative bacteria, and 4% were fungi. The median time to the onset of the first BSI was day 28 (range day 0-95) after transplantation. Univariate analysis revealed a significantly higher incidence of BSI in the high (≥ 1,000 ng/ml, n = 57) than in the low (< 1,000 ng/ml, n = 57) ferritin group (42.1 versus 21.1%, respectively, P = 0.017). Peripheral blood stem cell transplantation (PBSCT) (n = 23) showed a greater protective effect against BSI compared with bone marrow (n = 71) and cord blood (n = 20) transplantation. Pretransplantation serum ferritin (HR = 2.844, 95% CI: 1.180-6.859, P = 0.020) and PBSCT (HR = 0.135, 95% CI: 0.025-0.717, P = 0.019) were significant factors on multivariate analysis. In conclusion, pretransplantation serum ferritin significantly predicts BSI within the 100-day period after allo-HSCT.     

Outcome of allogeneic stem cell transplantation in patients older than 50 years of age

Because of progress in supportive therapies, the upper limit of age for conventional allogenic stem cell transplantation (allo-SCT) is rising. We retrospectively evaluated the impact of age on transplant outcomes in patients older than 50 years of age who underwent conventional allo-SCT in 8 institutions in Japan. The median age was 52-years old (range 50 to 65). The underlying diseases included severe aplastic anemia (n = 3), acute myelogenous leukemia (n = 20), acute lymphoblastic leukemia (n = 10), chronic myelogenous leukemia (n = 11), myelodysplastic syndrome (n = 18), and non-Hodgkin lymphoma (n = 3). Forty two patients (67%) with hematological malignancies received allo-SCT in an advanced disease stage at the time of transplant. The two-year overall survival and disease-free survival rate were 50.1% and 43.6%, respectively. In patients with hematological malignancies, the two-year probability rates of survival were 54.3% with standard risk patients, and 45.9% with poor risk patients. The severity of acute GVHD, the kind of grafts, and age (> or = 55) were related to poor prognosis. Our data suggest that prophylaxis of acute GVHD and selection of the graft is more important for older patients, and that patients less than 55-years old can be candidates for conventional allo-SCT.     

Outcome of medium-dose VP-16/CY/TBI superior to CY/TBI as a conditioning regimen for allogeneic stem cell transplantation in adult patients with acute lymphoblastic leukemia

The choice of conditioning regimen before allogeneic stem cell transplantation (SCT) in patients with acute lymphoblastic leukemia (ALL) is important. We retrospectively compared outcomes of medium-dose VP-16/cyclophosphamide/total body irradiation (VP/CY/TBI) regimen and CY/TBI. Five hundred and twenty-nine patients (VP/CY/TBI: n = 35, CY/TBI: n = 494) who met all of the following criteria were compared: first time for SCT, aged 15-59 years; first or second complete remission at SCT; bone marrow or peripheral blood as stem cell source; and HLA phenotypically matched donor. Median age of the patients was 34 years, and patients who received VP/CY/TBI were younger (28 vs. 34 years, P = 0.02). Cumulative incidences of relapse and non-relapse mortality (NRM) were higher for patients who received CY/TBI (P = 0.01 for relapse, P < 0.01 for NRM). After a median follow-up period of 36.9 months, 5-year overall survival (OS) rates were 82.2% in the VP/CY/TBI group and 55.2% in the CY/TBI group. OS, and disease-free survival (DFS) in the VP/CY/TBI group were shown to be significantly better by multivariate analysis [hazard ratio: 0.21 (95% confidence interval: 0.06-0.49) for DFS, hazard ratio: 0.25 (95% confidence interval: 0.08-0.59) for OS]. VP/CY/TBI was associated with a lower relapse rate and no increase in NRM, resulting in better survival than that in CY/TBI for adult ALL patients.     

Impact of age on outcomes of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in elderly patients with acute myeloid leukemia

Previous studies have repeatedly reported that increasing age is a significant risk factor for worse outcomes after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) among patients with acute myeloid leukemia (AML). However, more recent studies reported conflicting results regarding the association between age and outcomes in elderly patients. Therefore, we conducted a large‐scale, nationwide retrospective study to examine the impact of age on outcomes of allo‐HSCT with reduced intensity conditioning (RIC) for AML patients who were older than 50 years. Of the 757 patients, 89 patients (11.8%) were 50–54, 249 patients (32.9%) were 55–59, 301 patients (39.8%) were 60–64 and 118 patients (15.6%) were ≥65 years old. The 3‐year overall survival (OS) (47.8, 45.2, 37.9, and 36.6% for patients aged 50–54, 55–59, 60–64, and ≥65 years, respectively, P = 0.24) and nonrelapse mortality (NRM) (24.0, 22.8, 29.2, and 27.6% for patients aged 50–54, 55–59, 60–64, and ≥65 years, respectively, P = 0.49) were not significantly different among the four age groups. Multivariate analysis revealed that increased age had no significant effect on OS or NRM after adjusting for covariates. These results suggested that advanced patient age is not a contraindication for RIC allo‐HSCT in elderly AML patients. Am. J. Hematol. 91:302–307, 2016. © 2015 Wiley Periodicals, Inc.     

Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older

Older recipient and donor age were associated with higher incidences of severe graft‐versus‐host disease (GVHD) and mortality after allogeneic hematopoietic stem cell transplantation from matched sibling donors (MSDs) and matched unrelated donors. Since a lower incidence of severe GVHD is advantageous in unrelated cord blood transplantation (CBT), a higher incidence of GVHD using older MSDs could be overcome using cord blood for older patients. We retrospectively analyzed Japanese registration data of 2,091 patients with acute myeloid leukemia, acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome aged 50 years or older who underwent MSD bone marrow transplantation (BMT) (n = 319), MSD peripheral blood stem cell transplantation (PBSCT) (n = 462), or unrelated CBT (n = 1,310) between 2007 and 2012. Median age of MSD was 56 (range, 38–74) years. Compared with CBT, the risk of developing extensive chronic GVHD was higher after BMT (hazard ratio [HR], 2.00; P = 0.001) or PBSCT (HR, 2.38; P < 0.001), and transplant‐related mortality was lower after BMT (HR, 0.61; P < 0.001) or PBSCT (HR, 0.63; P < 0.001). Relapse rates were not significant difference between three groups. Although overall mortality was lower after BMT (HR, 0.67; P < 0.001) or PBSCT (HR, 0.75; P = 0.002) compared with CBT, the rates of a composite endpoint of GVHD‐free, relapse‐free survival (GRFS) were not significant difference between three groups. These data showed that MSDs remain the best donor source for older patients, but CBT led to similar GRFS to BMT and PBSCT. Am. J. Hematol. 91:E284–E292, 2016. © 2016 Wiley Periodicals, Inc.     

Acute Myelomonocytic Leukemia with Dysplastic Bone Marrow Eosinophils Showing t(5;17)(q13;q11) and a Secondary Chromosomal Aberration, inv(16)(p13q22)

inv(16)(p13q22) is associated with de novo acute myelomonocytic leukemia with dysplastic bone marrow eosinophils (AMML Eo), which has a relatively favorable clinical course with a longer remission duration and better survival prospects. On the other hand, t(5; 17)(q13;q11), although relatively rare, has been reported to be a component of complex chromosomal abnormalities in myelodysplastic syndromes and secondary acute myeloid leukemia (AML). We treated a 29-year-old woman with the first reported case of de novo AMML Eo with inv(16)(p13q22) in addition to t(5; 17)(q13;q11). Although she attained complete remission (CR) immediately after induction therapy, the disease recurred 1 year after the completion of consolidation therapies. She underwent HLA-matched unrelated allogeneic bone marrow transplantation (UBMT), together with a myeloablative conditioning regimen, after achieving a second CR and has survived without a recurrence for more than 24 months since UBMT. In general, certain secondary chromosomal abnormalities are associated with the phenotype of the disease, which retains its essential biologic characteristics established by the primary abnormality. Accordingly, the primary nature of the leukemic cells in this case differs from the findings for core-binding factor AML with inv(16)(p13q22). We believe this report is the first of de novo AMML Eo with t(5; 17)(q13;q11) showing as a secondary chromosomal aberration with inv(16)(p13q22).     

Hematopoietic stem cell transplantation in the second or later complete remission in acute promyelocytic leukemia initially treated with all-trans retinoic acid

Despite the use of all-trans retinoic acid (ATRA) as the first-line treatment for acute promyelocytic leukemia (APL), relapse occurs in about 20% of cases. Most relapsing APL patients can achieve second remission (CR2) following ATRA combined with chemotherapy or arsenic trioxide. Stem cell transplantation (SCT) has been widely adopted in CR2, but optimal SCT (auto- or allo-SCT) remains controversial. We analyzed the outcomes for 8 APL patients initially treated using ATRA, who relapsed, achieved CR2 and underwent auto-SCT (n = 4) or allo-SCT (n = 4). The mean age of patients who underwent allo-SCT was 39 years. Minimal residual disease (MRD) just prior to SCT was positive in 1 patient and negative in 3. Engraftment was achieved in all patients, but 2 patients died of transplantation-related complications within 6 months. Complete molecular remission has been maintained in the remaining 2 patients. The mean age of patients who underwent auto-SCT was 48 years. MRD just prior to SCT was negative in all 4 patients. Complete molecular remission has been maintained in all 4 patients (mean follow-up, 3 years 9 months). The results for auto-SCT are favorable in patients with MRD-negative APL.