Long-term survival after adrenalectomy for asynchronous metastasis of bladder cancer to the bilateral adrenal glands.

Isolated adrenal metastasis of bladder cancer, particularly the bilateral, is quite rare. Systemic chemotherapy is the treatment of choice for metastatic urothelial carcinoma. However, despite initially promising response rates of approximately 45%-71%, most tumors eventually show progression, and the median survival time following chemotherapy regimen is approximately 14-15 months. Recently, favorable results of surgery for metastatic urothelial carcinoma have been reported. Here, we report a rare case of asynchronous metastasis of bladder cancer to the bilateral adrenal glands with long-term survival after bilateral adrenalectomy. A 69-year-old man underwent radical cystoprostatectomy and ileal conduit urinary diversion for invasive bladder cancer. Ten months later, left adrenalectomy was performed for a left adrenal tumor, revealing metastatic urothelial carcinoma. After adjuvant chemotherapy, a tumor in the right adrenal gland was detected. Right adrenalectomy was done, and the tumor was also found to be metastatic urothelial carcinoma. The patient had an uneventful recovery after starting steroid replacement therapy. Three years later, he was doing well and had no evidence of recurrence. Adrenalectomy for isolated adrenal metastasis of urothelial carcinoma may be a reasonable option, even if such metastases are bilateral.

Expression and production of aberrant PAX5 with deletion of exon 8 in B-lineage acute lymphoblastic leukaemia of children.

Summary We investigated PAX5 expression in childhood B-lineage acute lymphoblastic leukaemia (ALL). Seven of 21 children with B-lineage ALL had multiple PAX5 variants, while 14 children and healthy controls showed full-length (FL) and one variant PAX5. By Western blotting, healthy controls displayed Pax5-FL, while one short Pax5, derived from the deletion of exon 8 (Pax5-DeltaE8) was produced in 90% of ALL samples, as well as in ALL cell lines. PAX5-DeltaE8 lacked more than 50% of the transactivation domain, indicating that aberrant Pax5 production might lead to the arrest of B-cell differentiation, contributing to the pathogenesis of B-lineage ALL.

Changes in the awareness of oral health among new students newly enrolled at the University of Tokyo over the past 15 years.

OBJECTIVE: The aim of this study was to examine changes in awareness of oral health among Japanese university students. METHODS: Between 1990 and 2004, a total of 51,650 students newly enrolled at the University of Tokyo responded to an annual written questionnaire on oral health. RESULTS: (i) Approximately 60% of the students brushed their teeth twice a day. Female students brushed more frequently than male students. (ii) The percentage of students who brushed for 2-3 min per time decreased, while the percentage who brushed four or more minutes increased. (iii) The number of students who had learned how to brush properly increased. This trend was particularly clear-cut among male students, although the proportion of female students who had learned to brush properly remained higher than that of male students. (iv) The percentage of female students who sought treatment for malocclusion was higher than that of male students. The percentage of students who underwent orthodontic treatment increased from 11.6 to 19.7%. The percentage of female students who received orthodontic treatment was approximately twofold that of male students. (v) The percentage of students who had temporomandibular disorders was 0.7% in males and 1.5% in females. (vi) More than 40% of the students had periodontal diseases, with a higher prevalence among male students than female students. (vii) Approximately 20% of the students wanted to consult our service centre. CONCLUSIONS: The awareness of oral health among new undergraduates at the University of Tokyo has improved over the past 15 years.

Polymorphisms of transforming growth factor-beta1 and transforming growth factor-beta1 type II receptor genes are associated with acute graft-versus-host disease in children with HLA-matched sibling bone marrow transplantation.

The aim of this study was to determine whether the gene polymorphisms of Th1/Th2 and immunoregulatory cytokines were associated with aGVHD in Japanese children receiving allogeneic bone marrow transplantation (allo BMT). We investigated polymorphisms of genes encoding interleukin (IL)-4, IL-4 receptor (IL-4 R), IL-10, transforming growth factor (TGF)-beta1, TGF-beta1 type II receptor (TGF-beta1 RII), interferon (IFN)-gamma, IFN-gamma type 2 receptor (IFN-gamma R2), and IFN regulatory factor (IRF)-1. Sixty-seven patients were treated with allo BMT from HLA-identical siblings, and aGVHD was observed in 38. TGF-beta1 codon 10 leucine (Leu) /proline (Pro) polymorphism in donors was associated with the development of aGVHD. Patients having donors with the Pro allele had aGVHD more frequently than those without Pro allele (30/45 vs 8/20, odds ratio = 3.00; P = 0.04). TGF-beta1 RII 1167 C/T polymorphism in recipients was also associated with the development of aGVHD. The incidence was significantly higher in recipients with T allele than in those without T allele (21/27 vs 16/35, odds ratio = 4.16; P = 0.01). In conclusion, genetic backgrounds of TGF-beta1 and TGF-beta1 RII may be involved in the development of aGVHD in HLA-matched sibling BMT in Japanese children.

Association between birthweight and body mass index at 3 years of age.

BACKGROUND: Obesity in children is one of the risk factors for adulthood obesity, which then leads to the development of chronic diseases such as hypertension, hyperlipidemia and diabetes. In this study, we identified significant factors associating with the body mass index (BMI) at 3 years of age from the perinatal characteristics of children. METHODS: A total of 588 children were included in the study. The BMI at 3 years of age was examined in conjunction with the possible variables such as parents' smoking status during pregnancy, parents' age at birth, gestational age, sibling number and live birth order, sex, birthweight, BMI at 1 month of age, weight gain during the first month of life and feeding method at 1 month of age. RESULTS: Univariate analysis showed that birthweight (P<0.0001), weight gain during the first month of life (P=0.0012) and BMI at 1 month of age (P<0.0001) were significantly associated with the BMI at 3 years of age. Of these factors, birthweight and weight gain during the first month of life were the independent factors correlating with the BMI at 3 years by multivariate analysis (P<0.0001 and P=0.0095, respectively). CONCLUSIONS: Infants with higher birthweight and/or greater weight gain during the first month of life may have a risk of being overweight at 3 years of age.

High expression of platelet-derived growth factor and transforming growth factor-beta 1 in blast cells from patients with Down Syndrome suffering from transient myeloproliferative disorder and organ fibrosis.

To determine whether platelet-derived growth factor (PDGF) and transforming growth factor-beta 1 (TGF-beta 1) are involved in organ fibrosis in patients with transient myeloproliferative disorder (TMD) in Down syndrome, the expression of PDGF and TGF-beta 1 mRNA in blast cells of TMD was investigated using real-time quantitative reverse transcription polymerase chain reaction. Blasts and liver tissue from TMD patients with hepatic fibrosis showed a significantly elevated expression of PDGF gene. The expression of TGF-beta 1 gene was higher in TMD and acute megakaryoblastic leukaemia than in the control group. These results suggest that PDGF in combination with TGF-beta 1 plays a role in organ fibrosis of TMD.

Role of thymidine phosphorylase in biomodulation of fluoropyrimidines.

Thymidine phosphorylase (TP) is a key enzyme in the activating pathway of 5'DFUR and capecitabine. On the other hand, TP is identical to platelet-derived endothelial cell growth factor (PD-ECGF) which is known to be an angiogenic factor. Recent studies show TP expression is increased in various malignancies compared with the surrounding normal tissues. These reports demonstrate that elevated TP expression indicates a predisposition for aggressive disease and/or poor prognosis. Therefore, it is a reasonable strategy to target TP in cancer treatment by using fluoropyrimidines including 5-fluorouracil (5FU), 5'DFUR and capecitabine. TP-mediated biomodulation of fluoropyrimidines to enhance their anti-tumor effects has been investigated. TP up-regulators including cytokines, anti-tumor drugs and X-ray irradiation significantly increase cytotoxicity of fluoropyrimidines. Also, transfection of TP cDNA significantly enhances cytotoxicity of fluoropyrimidines. Biomodulation of fluoropyrimidines is clinically successful in treating some malignancies. We report a review on roles of TP in biomodulation of fluoropyrimidines.

[A case showing effective radiotherapy for a radiation-induced glioblastoma].

Radiation-induced glioblastoma is usually resistant to all treatments. We report a case with radiation-induced glioblastoma, in which radiotherapy was remarkably effective. A 14-year-old female with a history of acute lymphoblastic leukemia, at the age of 7, underwent 15 Gy of radiotherapy to the whole brain. She was admitted to our department due to the development of headache and nausea. Magnetic resonance imaging showed an irregularly enhanced mass in the left frontal lobe. Partial removal of the mass was performed and histological examination showed it to be glioblastoma with a high MIB-1 index. The patient underwent 40 Gy of local radiotherapy and chemotherapy with ACNU and Interferon-beta for 2 years. The residual tumor disappeared after the radiotherapy, and her status is still "complete remission", 29 months after the onset.

Outcome of acute lymphoblastic leukemia in children with AL90 regimen: impact of response to treatment and sex difference on prognostic factors.

BACKGROUND: In our previous studies, the outcome of high-risk ALL was still poor. In the present study, all children with ALL were classified into three groups and treated with a new regimen (AL90). PATIENTS AND METHODS: Between 1990 and 1996, 220 children with ALL, treated with the AL90 regimen, were classified into three risk groups: low, intermediate, and high: LR, IR, and HR, respectively. The protocol consisted of three- to five-drug induction, consolidation with intermediate-dose methotrexate and/or cytarabine, mercaptopurine and cyclophosphamide, four-drug intensification, and sequential maintenance therapies. Only intrathecal chemotherapy was used for CNS prophylaxis in the LR group, whereas cranial irradiation was added for the IR and HR groups. RESULTS: The number of eligible patients was 91: LR group, 71: IR group, and 58: HR group. Complete remission (CR) was obtained in > 98% of the LR and IR groups, while only 88% achieved CR in the HR group. The 5-year event-free survival (EFS) rate was 67.4% in all patients: 70.4% in the LR group, 71.7% in the IR group, and 57.5% in the HR group. With respect to the previous study, EFS in the HR group who showed positive residual leukemia at 14 days was improved, whereas EFS in boys versus girls was significantly lower (48.8% : 85.7%, P = 0.02). CONCLUSIONS: In high-risk ALL, the rate of induction failure was high and boys had a worse outcome, calling for improvements in induction therapy and a specific approach for boys.

Quantitative monitoring of circulating Epstein-Barr virus DNA for predicting the development of posttransplantation lymphoproliferative disease.

Epstein-Barr virus (EBV)-DNA was quantitatively measured to assess posttransplantation virus reactivation by real-time polymerase chain reaction (PCR). In the first retrospective analysis of a 7-year-old boy with lymphoproliferative disease (LPD) after an unrelated cord blood transplantation, serum EBV-DNA progressively increased to 4 x 10(5) copies/mL. EBV load was then prospectively monitored in peripheral blood from posttransplantation patients. The second case was an 8 year-old boy with aplastic anemia who received a CD34+ cell transplantation. This patient died of LPD with the progression of pulmonary nodules. EBV-DNA increased to 4 x 10(4) copies/mL after the control of cytomegalovirus reactivation. On the other hand, EBV-DNA was undetectable (<200 copies/mL) in the series of all 58 samples from 10 patients who did not develop LPD after hematopoietic stem cell transplantation. Sequential monitoring of circulating EBV-DNA by quantitative PCR may be a useful indicator for predicting the development of posttransplantation LPD.

Long-term outcome of treatment with protocols AL841, AL851, and ALHR88 in children with acute lymphoblastic leukemia: results obtained by the Kyushu-Yamaguchi Children's Cancer Study Group.

We analyzed the long-term outcome and late effects of treatment in 187 patients with childhood acute lymphoblastic leukemia (ALL) diagnosed between 1984 and 1990. Overall survival and event-free survival rates were 68.2% +/- 3.7% and 63.2% +/- 3.6% at 15 years, respectively. Of 55 patients who relapsed after achieving the first complete remission (CR), only 17.4% were rescued by salvage therapy. The advantage of stem cell transplantation over chemotherapy was observed only in those patients with bone marrow relapse during therapy. The SD for score height in patients maintaining the first CR significantly decreased at the time of final follow-up compared with that at diagnosis: 0.059 to -0.800 (P < .0001). The decrease was remarkable in patients younger than 5 years at diagnosis. Other late effects included mild liver dysfunction in 18% and hepatitis C virus infection in 9%. Congestive heart failure was observed in only 2.9% of patients despite the high cumulative dose of daunorubicin (450 mg/m2). Although the survival rates of patients on our protocols were comparable to those of other study groups, some modification, including reduction in dose of cranial irradiation and/or anticancer drugs, should be considered to reduce late adverse effects in survivors of childhood ALL.

Enhancement of sensitivity to capecitabine in human renal carcinoma cells transfected with thymidine phosphorylase cDNA.

The purpose of the present study was to examine directly the role of thymidine phosphorylase (TP) in the sensitivity of renal cell carcinoma (RCC) to a novel fluoropyrimidine carbamate, capecitabine. TP cDNA-transfected RCC are used in these experiments to provide a basis for improved therapeutic benefit in chemoimmunotherapy. Human RCC line KU2 cells were transfected with pcDNA3.1/zeo(+) with or without human TP cDNA by the lipofectin method. We established a clone transfected with pcDNA3.1/zeo(+)/TP (KU2-TP15) and a clone transfected with pcDNA3.1/zeo(+) as a control (KU2-C1). TP expression levels (mean +/- SD) examined by enzyme-linked immunosorbent assay (ELISA) were 1.3 +/- 0.14 U/mg protein in KU2, 1.6 +/- 0.57 U/mg protein in KU2-C1 and 216 +/- 25.6 U/mg protein in KU2-TP15. Immunohistochemical staining of subcutaneous tumors established in Balb/c nu/nu mice showed that KU2-TP15 was strongly positive for TP expression, whereas KU2 and KU2-C1 were negative. Sensitivities in vitro to 5-fluorouracil (5FU), 5'-deoxy-5-fluorouridine (5'DFUR) and capecitabine in KU2-TP15 were significantly enhanced compared with those in KU2 or KU2-C1. A moderate but statistically significant bystander effect was observed in vitro. KU2-TP15 tumors showed significant increase in the in vivo sensitivities to 5'DFUR and capecitabine as compared with the vehicle alone while KU2-C1 tumors did not. The difference in tumor-free rate in mice bearing KU2-TP15 at 2 months after the cessation of treatment was statistically significant between the capecitabine treatment group and the controls, the 5FU treatment group and the 5'DFUR treatment group. The present study clearly provides direct evidence for the role of TP in mediating the sensitivity of RCC to capecitabine.

Unrelated cord blood transplantation for an infant with chemotherapy-resistant progressive Langerhans cell histiocytosis.

The authors describe a patient successfully treated with unrelated cord blood transplantation (CBT) for chemotherapy-resistant progressive Langerhans cell histiocytosis (LCH). An 8-month-old boy had LCH diagnosed based on the histologic examination of skin lesions. Despite intensive chemotherapy and immunotherapy, the disease was progressive, with organ dysfunction. He received unrelated CBT after a conditioning regimen consisting of total body irradiation, etoposide, and melphalan. He was in complete remission 12 months after the transplantation. The authors suggest that CBT could be considered in the treatment of patients with chemotherapy-resistant progressive LCH, especially if there are no available human leukocyte antigen-matched family donors.

Membranous tissue under the flexor carpi ulnaris muscle as a cause of cubital tunnel syndrome.

Membranous tissue under the flexor carpi ulnaris (FCU), hypertrophy and fascia of the FCU were examined in 90 patients with cubital tunnel syndrome; it (submuscular membrane) was found in all patients, excluding five whose data were incomplete. Impressions on the nerve under the FCU were noted in 75 patients. In 43 patients, the submuscular membrane was judged to be the cause of neural compression. These 75 patients included 60 and 15 cases whose fascia of the FCU were judged to the thick and thin, respectively. Among the 58 with a thick submuscular membrane, 56 patients had an impression under the membrane. Fifteen patients had a flat impression on the nerve in the proximal compartment of the FCU, which was formed by ligamentous and bony floor and thick fascia of the FCU. It is believed that increased pressure in the compartment is the cause of a flat impression. Slight compression of the nerve under the FCU with compressions in proximal and distal part of the nerve can cause symptoms of the nerve compression by multiple crush effect.

Treatment of childhood acute myelogenous leukemia with allogeneic and autologous stem cell transplantation during the first remission: a report from the Kyushu-Yamaguchi Children's Cancer Study group in Japan.

A total of 64 newly diagnosed acute myelogenous leukemia patients (except FAB M3 and/or Down syndrome) under 18 years of age were consecutively enrolled into the study. Patients having an HLA-identical sibling (allo group) were assigned to undergo allogeneic bone marrow transplantation (allo BMT) in the first complete remission (CR). Others (non-allo group) were assigned to undergo autologous peripheral blood stem cell transplantation (PBSCT) or autologous BMT (auto BMT). Conditioning regimen was busulfan + melphalan for all transplantation. Of 64 patients (allo group 24; non-allo group 40), 59 (92.2%) achieved a CR. Eighteen relapses occurred (allo group 4; non-allo group 14) and 6 died during the first CR. The 5-year event-free survival (EFS) rate was 53.3 +/- 6.4% at a median follow-up period of 45 months. The 5-year EFS rates of allo and non-allo groups were 70.8 +/- 9.3% and 43.0 +/- 8.1%, respectively (p = .08). The EFS rates at 5 years post-transplant for allo BMT from an HLA-identical sibling (n = 18), PBSCT (11), and auto BMT (6) were 88.1 +/- 7.9%, 41.6 +/- 19.7%, and 83.3 +/- 15.2%, respectively. The outcome of allo BMT was superior to that of autograft. Auto BMT rather than PBSCT might contribute to a long-term survival in case of no available HLA-identical siblings.

Genomic imprinting of insulin-like growth factor-2 in infant leukemia and childhood neuroblastoma.

BACKGROUND: Loss of imprinting (LOI) of insulin-like growth factor-2 (IGF-2) has been implicated in the pathogenesis of certain human cancers and tumor-predisposing overgrowth disorders, such as Beckwith-Wiedemann syndrome. In a previous study, the authors revealed that certain patients with childhood acute leukemia and neuroblastoma had had rapid somatic growth after birth, suggesting the involvement of growth factor(s) in tumorigenesis. In the current study, the authors examined whether relaxation of IGF-2 imprinting occurred in infant leukemia and childhood neuroblastoma. METHODS: The genomic DNA of infant leukemia, childhood neuroblastoma, and control individuals was amplified by polymerase chain reaction (PCR). Patients who had heterozygous genotype were selected as informative cases using Apa I polymorphism in exon 9 of the IGF-2 gene. Total RNA was isolated from informative cases, followed by cDNA synthesis. cDNA was amplified by PCR, and direct sequence was performed for determining allele specific transcription. RESULTS: Twenty of 22 infant leukemia blasts and all of 16 neuroblastoma cells showed normal monoallelic expression of IGF-2 as well as 23 controls. The height and weight of two acute lymphoblastic leukemia patients with LOI were within normal ranges for Japanese children. CONCLUSIONS: The current study revealed that the imprinting status of IGF-2 was generally maintained in infant leukemia and confirmed that it was maintained in childhood neuroblastoma. The results suggest that LOI of IGF-2 does not play a major role in the carcinogenesis of these diseases or in rapid physical growth of the patients.

[Stage pT1 signet ring cell carcinoma of the urinary bladder: a case report].

A case of primary signet ring cell carcinoma of the urinary bladder is described. A 59-year-old man presented with microscopic hematuria, and cystoscopy revealed a white nonpapillary tumor. Histopathological examination of the resected tumor revealed signet ring cell carcinoma and transitional cell carcinoma. Histological depth of invasion was pT1. No adjuvant therapy was performed. Primary signet ring cell of the urinary bladder is a rare tumor with 37 cases reported to date in Japan. We investigated previously reported cases and discussed adjuvant therapies of superficial signet ring cell carcinoma of the urinary bladder.

Epstein-Barr virus-associated lymphoproliferative disease after a cord blood transplant for Diamond-Blackfan anemia.

A 7-year-old boy with Diamond-Blackfan anemia (DBA) developed lymphoproliferative disease (LPD) after a cord blood transplant (CBT). 3.1 x 107/kg mononuclear cells from an HLA one-locus mismatched CB were transplanted after conditioning with total body irradiation (8 Gy), cyclophosphamide (200 mg/kg) and antithymocyte globulin (10 mg/kg). Complete engraftment occurred on day 33 post transplant. Despite the resolution of grade II graft-versus-host disease (GVHD), he died of lymphoma on day 130 post transplant. The tumor was of donor origin, indicating clonal proliferation of Epstein-Barr virus (EBV)-infected B cells. This is the first report of EBV-LPD after CBT. Post-transplant LPD can be a serious EBV-associated complication of CB grafts. Bone Marrow Transplantation (2000) 25, 209-212.