Radiation therapy has been playing important roles in the treatment of childhood acute leukemia since the 1970s. The first is the preventive cranial irradiation for central nervous system therapy in acute lymphoblastic leukemia. The second is the total body irradiation as conditioning before bone marrow transplantation for children with acute myeloid leukemia in first remission and with acute lymphoblastic leukemia in second remission. Although some late effects have been reported, a part of them could be overcome by technical improvement in radiation and salvage therapy. Radiation therapy for children might have a successful outcome on a delicate balance between efficiencies and potential late toxicities. The role of radiation therapy for childhood acute leukemia was reviewed from the standpoint of basic and clinical radiation oncology in this paper.

View full abstract

Early after stem cell transplantations (SCT), nine patients were given foscarnet (FCN) for treatment or as prophylaxis against CMV. Of the nine patients, one patient had ganciclovir resistant CMV infection, four were given treatment due to CMV-antigenemia early post SCT, and another four were given FCN prophylaxis, because they were at increased risk for CMV infection. Only one patient out of the four who were given asymptomatic treatment developed fatal CMV interstitial pneumonia. Three out of the 9 patients had transient increases in creatinine. No patient experienced myelotoxicity, and eight evaluable patients had engraftment. We suggest that FCN can safely be administered with acceptable toxicity for treatment of asymptomatic CMV infection or prophylaxis early after SCT.

View full abstract

Drug resistance continues to be a serious problem in cancer therapy. To analyze the gene expression profile in doxorubicin-resistant human leukemia cell lines, we established a doxorubicin-resistant phenotype through continuous exposure of the suspension culture of K562 leukemia cells to increasing doxorubicin concentrations. The resistant cell line K562/ADM was more resistant to doxorubicin than the parent cells (K562/P) and also exhibited cross-resistance to vincristine. P-glycoprotein expression in the resistant cell line was significantly higher than the parent line. Using the microarray method to investigate the resistant cell line, we detected many unexpected differences in gene expression in comparison with the parent cell line. We also investigated the doxorubicin-induced variations in the gene expression profiles of K562 parent cells. Cyclooxygenase-1 and heat shock protein 90 kDa showed increased expression in both K562/ADM cells and 8-hour doxorubicin-treated K562/P cells when compared to expression levels in non-treated K562/P cells by microarray as well as northern analysis. We concluded that DNA microarray would be an effective tool to discover new drug resistance mechanisms.

View full abstract

We retrospectively analyzed the outcome of children who did not achieve remission with induction therapy and discussed the effectiveness of salvage therapy in CCLSG AML 9805 protocol. Seventy-five children were treated with CCLSG AML 9805 protocol from May 1998 to December 2001. Fifteen (20%) out of 75 failed to achieve complete remission with the induction regimen. Thirteen of these children were then treated with salvage protocol (9805 IF protocol) and 71% (10 cases) of them subsequently could achieve complete remission. Stem cell transplantation (SCT) was performed for 5 children during or after completing 9805 IF protocol and three of them are disease-free without complication. Three children were treated with IF protocol without SCT ; however, all of them developed bone marrow relapse within several months after completion of the chemotherapy. Two patients treated with protocols other than 9805 IF are disease-free after unrelated cord blood transplantation. Three-year event-free survival of fifteen cases who failed to achieve remission was 46.7% and that of thirteen cases treated with 9805 IF protocol was 38.5%. 9805 IF protocol was considered to an effective salvage therapy for AML children with induction failure. However, SCT is mandatory to maintain remission for these patients.

View full abstract

Recent studies have suggested an association of Helicobacter pylori (H. pylori) and iron-deficiency anemia (IDA). This is a report of 15 cases of IDA in adolescents without evidence of gastrointestinal bleeding, but associated with H. pylori gastritis. Fifteen patients with IDA were studied (9 boys and 6 girls; mean age 13.6years; range 13-16 years). Ten patients had a medical history of long-standing IDA (6 months to 4 years) and of oral iron supplementation at outpatient clinics. The anemia recurred after the iron therapy had been discontinued. An extensive work-up was ordered that included technetium-99 m (^99mTc) scans for Meckel's diverticulum, total colonoscopy and gastrointestinal endoscopy. After biopsy-based H. pylori test results were confirmed to be positive, anti-H. pylori therapy was administered. In 14 patients, H. pylori was successfully eradicated and normalization of iron status has been maintained. In one patient who failed in bacterium eradication, IDA relapsed but was reversed by a second successful eradication therapy. H. pylori infection may be involved in cases of IDA in adolescents of unknown origin, and eradication of H. pylori can be associated with the resolution of anemia.

View full abstract

A retrospective study was conducted at our institute to assess the efficacy of the carbapenem-based empirical therapy for febrile neutropenia during chemotherapy or stem cell transplantation. We investigated 34 pediatric cancer patients with 36 bacteremia episodes from 1999 to 2001. Isolated pathogens were 20 gram-positive cocci, 3 gram-positive bacilli, 9 gram-negative bacilli, and 2 fungi. The mean duration of neutropenia (neutrophil counts of <500 and 100/μl) at the onset of bacteremia was 8.5 and 5.6 days, respectively. Ciprofloxacin or second-generation cephalosporin was prophylactically administered to 18 patients during afebrile neutropenia. Not only gram-positive cocci, but also gram-negative bacilli were isolated from the second-generation cephalosporin group. On the other hand, gram-positive cocci were predominantly isolated from the ciprofloxacin group. The success rate without the modification of empirical therapy until defervescence was 83%. Thus, carbapenem-based empirical therapy seems to be effective. A further prospective study is warranted.

View full abstract

We evaluated the reliability and validity of the quality of life (QOL) questionnaires which were developed by the QOL committee of the Japan Association of Childhood Leukemia Study group. 1. Reliability : The internal consistency and reproducibility were proved by Spearman's rank correlation analysis and test-retest method, respectively. 2. Validity : The criterion-based validity was examined by comparison between the new questionnaires and the other established ones (QLQ-C30, QOL-ACD and FACT-G). The correlation coefficients were high (0.79-0.81) between the new questionnaires for a patient and the other established ones, but low (0.38-0.49) between the new questionnaires for a family and the other established ones. The clinical validity (sensitivity and responsibility) was demonstrated by the change of total scores for each therapy phases. The factor analysis showed the validity of the set domain. It demonstrated the reliability and validity of the newly developed questionnaires. We plan to do the QOL study by using the new questionnaires.

View full abstract

We conducted a the prospective QOL study from a parental viewpoint using a new questionnaire developed by the QOL Committee of the Japan Association of Childhood Leukemia Study Group. We collected 906 questionnaires in March 2002. 1) Parent-rating QOL scores were not associated with the age of the patients, but parent-rating emotional well-being QOL scores were lower for female patients as compared to male patients. 2) Parent-rating total QOL scores depended on the treatment protocol, and improved as treatment progressed in the SR, IR and HR groups. 3) Parents thought that bone marrow and lumbar puncture were the most stressful examinations and lumbar puncture and L-asparaginase injection were the most stressful treatments for their children. 4) The most supportive activities were hobbies, religion and work, and the most supportive persons were family members, friends and partners. It is useful to measure childhood QOL by parent-rating questionnaires using anonymous answer forms.

View full abstract

We conducted a prospective QOL study from the patient's viewpoint using a new questionnaire developed by the QOL Committee of the Japan Association of Childhood Leukemia Study Group, and compared the patients' and their parents' ratings regarding QOL. We collected 191 questionnaires in March 2002. 1) The collection rate of patient-rating questionnaires was 37.0% at induction, 23.9% at post-intensification, 18.5% at maintenance, and 5.4% at end of treatment, respectively. 2) Patient-rating family well-being QOL scores were lower for the female patients as compared to male patients (p=0.0009). 3) Patient-rating total QOL scores did not depend on the treatment protocol, but improved as treatment progressed. 4) There were some differences between patient-rating QOL and parent-rating QOL with the exception of total score and physical well-being domain. This suggests that we should evaluate the QOL of the children with acute lymphoblastic leukemia from many viewpoints.

View full abstract

We present a case of 17-year-old male with myelodysplastic syndrome who died of a sudden cardiorespiratory arrest on the 24th day after an unrelated HLA matched bone marrow transplantation. In autopsy findings, there was hemorrhagic necrosis in the lung, heart, and large vessels due to the direct tissue invasion of mucor. The cause directly leading to death was regarded as left coronal artery embolism caused by the lump of mucor. It is said that a diagnosis of mucormycosis is difficult before a patient's death, regardless of diagnostic progress of fungal infection. In this case, long-term usage of steroid, an iron excess state from frequent blood transfusion, and administration of deferoxamine to remove iron may have become a motive of mucormycosis in addition to primary disease. It is necessary to recognize that mucor readily forms a thrombus/embolus and therefore develops various clinical manifestations.

View full abstract

Bleeding due to idiopathic thrombocytopenic purpura (ITP) is usually associated with mucocutaneous bleeding. A hemorrhagic ovarian cyst, that rarely progress into intraperitoneal bleeding, is one of the gynecological diseases leading to acute abdomen. We report here a girl with chronic ITP who developed intraperitoneal hemorrhage caused by hemorrhagic ovarian cyst at the luteal phase. We suggest that ovarian hemorrhage should be added as one of the differential diagnosis in a girl with thrombocytopenia who presents with acute abdominal pain. Careful follow-up is required because ovarian hemorrhage has a tendency to recur.

View full abstract

This paper reports a case of mild hemophilia A in which the lack of appropriate hemostatic management after tibial fracture caused subperiosteal hematoma formation, thus necessitating open reduction. A 6-year-old boy, diagnosed as having a fractured right tibia, received two doses of desmopressin acetate (DDAVP) and his broken leg was splinted and plastered at another hospital on the day the injury occurred. Dislocation found in the lesion three weeks after the fracture was treated only with local cooling at the time of follow-up and the patient was discharged. He came to our hospital with persistent pain in the fractured area, which was then diagnosed as posttraumatic displacement in the lesion with subperiosteal hematoma. Since conservative treatment did not achieve synostosis, we conducted open reduction with removal of the hematoma while controling hemostasis by continuous administration of factor VIII preparation. The patient recovered after a favorable postoperative course without any complications. This case suggests the necessity for conducting appropriate hemostasis for patients with mild hemophilia because even if obvious subperiosteal hematoma is not found immediately after fracturing, it could be generated later, which might delay synostosis and induce pseudotumor formation.

View full abstract

Childhood idiopathic thrombocytopenic purpura (ITP) is a common hemorrhagic disorder characterized by very low platelet count and relatively mild mucocutaneous bleeding, for which no minimal essential treatment strategy has been established. This is chiefly because most childhood ITP is resolved shortly after the onset irrespective of whether specific intervention is induced, and partly because there is no evidence that initial treatment diminishes mortality or morbidity. Even for the remaining patients who become chronic as defined by persistent thrombocytopenia, high rates of subsequent remission are also predicted. This makes it difficult to clarify the appropriate indication for splenectomy for those with symptomatic chronic ITP, where more than two-thirds of the patients achieve a platelet count of 50, 000/, μ1 or higher. Because of the generally benign outcome in childhood ITP, as well as limited efficacy of treatment, the management strategy for ITP is still controversial.

View full abstract

Idiopathic thrombocytopenic purpura (ITP) is considered an autoimmune disease that lowers blood platelets due to autoantibody infiltration against the platelets. The precise cause of this is unclear, but in recent years a high prevalence of Helicobacter pylori (HP) infection has been reported in adult patients with ITP. Furthermore, the platelet count increases after HP eradication in many HP-infected ITP patients, suggesting that HP is involved as a causative agent in 20-40% of adult ITP cases. The present study therefore examined HP infection in chronic childhood ITP cases. Serum anti-HP IgG antibody, anti-HP IgG antibody in urine, stool HP antigen and ¹³C urea breath test were measured in 40 subjects, but HP infection was verified in only a small percentage (two subjects; 5.0%). Neither of these subjects underwent bacterium eradication therapy in the survey stage, so the relationship with ITP pathology remains a topic for future study. In the diagnosis and treatment of HP infection in children, it is necessary to fully bear in mind the low sensibility to serum anti-HP IgG antibody testing and the ¹³C urea breath test, as well as the prevalence of clarithromycin-resistant HP as compared to adults.

View full abstract

We report the case of a 5-year-old girl who developed ITP following primary immunodeficiency (CD4-positive lymphocytopenia). She was treated with steroids and high-dose intravenous immunoglobulin (HD-IVGG), but the efficacy of this standard treatment for ITP was transient. The administration of steroids, other immunosuppressive agents, and splenectomy are undesirable in this patient with immunodeficiency, because they increase the susceptibility to infection of patients who are already immunocompromised. In Western countries, the administration of anti-D immunoglobulin is one of the standard treatments for ITP and not immunosuppressive. A similar efficacy of anti-D immunoglobulin was observed in ITP patients infected with human immunodeficiency virus (HIV), as compared with other ITP patients. Therefore, the patient was treated with anti-D immunoglobulin and showed a transient increase in platelet count. At present in Japan, anti-D immunoglobulin is not a standard therapy for ITP. However, we may need to re-examine its use for ITP because of its effectiveness, safety, cost benefits, and non-immunosuppressive characteristics.

View full abstract

We announce how to take formalin-fixed material from an aspirated bone marrow clot by bedside. On histological specimen, we can not only recognize cellularity, but also know the extent of fibrosis and the existence of tumor proliferation. On the other hand, a bone marrow smear shows whether or not there are dysplastic cells. We can also count the cells in the bone marrow smear in order to learn the cell ratio (myelogram). In this way, the histological specimen and bone marrow smear have different benefits and play compensatory roles. We can use both specimens not only to make a diagnosis, but also to learn the disease stage, which is then followed by the decision of treatment direction.

View full abstract