A tricky fetal case of isolated transposition of great arteries without the I-shaped sign.

Isolated transposition of the great arteries (TGA) is a congenital heart disease that presents with severe cyanosis after birth and a fetal diagnosis is crucial for the preservation of life. The I-shaped sign (I-sign) is useful as a fetal screening method for TGA. We herein present a tricky fetal case of isolated TGA with a side-by-side position of the great arteries and no I-sign. Severe cyanosis immediately after birth necessitated urgent interventions. A potentially fatal outcome was prevented by a prenatal diagnosis. In the fetal diagnosis of isolated TGA, it is important to not only detect the I-sign, but also conventionally examine the ventricular outflow tract.

Persistent clonal chromosomal abnormalities in a chronic myeloid leukemia patient.

Clonal cytogenetic abnormalities (CCA) in Philadelphia chromosome (Ph)-negative cells have been reported in a small population of adult chronic myelogenous leukemia (CML) patients during the clinical course, but CCA in pediatric CML patients are rarely reported. We herein report the case of an 8-year-old boy from the onset of CML. Although he had relapse after unrelated bone marrow transplantation when 9 years old, he has since been in complete molecular response on imatinib mesylate treatment. Surprisingly, various CCA have been observed in this patient, including several reciprocal chromosomal translocations in Ph-negative cells for >12 years. Although dysplasia in the bone marrow cells was identified, no overt transformation to myelodysplastic syndrome or acute myeloid leukemia has been observed. The cause of the CCA remains unknown in this patient, and careful observation is required.

A Long-term Survivor after Congenital Acute Myeloid Leukemia with t(8 ; 16)(p11 ; p13).

The treatment of patients with congenital leukemia is difficult and often results in a poor prognosis. We present here the case of a female child with congenital acute myeloid leukemia (AML) with t(8 ; 16) (p11 ; p13) who received chemotherapy and survived for more than 10 years without relapse. A novel MOZ-CBP chimera was found in her diagnostic sample. Although adult AML patients with MOZ-CBP have mainly been reported as having therapy-related AML and showed poor prognoses, the present case supports the idea that AML with MOZ-CBP in the pediatric population might show better prognoses.

Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia.

BACKGROUND: Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, a pro-survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B-precursor acute lymphoblastic leukemia (B-pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P-Akt) in pediatric B-pre ALL. PROCEDURE: We evaluated the activation status of Akt in bone marrow samples from 21 children with newly diagnosed B-pre ALL and correlated the expression level of P-Akt with clinicopathologic and prognostic features. Additionally, we transfected the myristoylated Akt cDNA into the B-pre ALL cell line, Nalm-6, and examined the effect, in vitro, of Akt activation on the response to antitumor drugs. RESULTS: P-Akt expression in B-pre ALL blast cells at diagnosis was associated significantly with poor response to induction chemotherapy including prednisolone, dexamethasone, vincristine, and adriamycin in B-pre ALL patients. Both overall survival and relapse-free survival in patients with P-Akt expression were reduced significantly more than in patients without P-Akt expression. Activation of Akt reduced the extent of apoptosis induced by the antitumor drugs in Nalm-6 listed above. Activation of Akt did not induce expression of P-glycoprotein, a drug transporter that is capable of conferring multidrug resistance. CONCLUSION: These results support the contention that Akt activation is a mechanism of chemotherapeutic resistance in B-pre ALL and suggest that Akt can be a therapeutic target for the treatment of relapsed or refractory pediatric B-pre ALL.

[A phase III study of the efficacy and safety of meropenem in patients with febrile neutropenia].

Efficacy, safety and pharmacokinetics of meropenem (MEPM) were assessed when 1 g (40 mg/kg for some of the pediatric patients) t.i.d. was administered every 8hours to 101 adult and 6 pediatric patients with febrile neutropenia (FN) as diagnosed based on the Japanese guideline for FN treatment. The efficacy rate evaluated as antifebrile effect up to Day 4 of treatment was 40.0% (40/100) in adult and 66.7% (4/6) in pediatric patients. The antifebrile effect in adult patients was analyzed after stratifying them according to their neutrophil counts up to Day 4. Treatment with MEPM produced an antifebrile effect not only in patients with higher neutrophil counts (> or = 500/mm3) but also in those with lower counts (< 100/mm3), and the efficacy rate was comparable between the two groups: 38.2% in the < 100/mm3 group and 29.4 to 55.6% in the > or = 500/mm3 group. The bacteriological efficacy of MEPM evaluated as disappearance rate on Days 3 to 5 and Day 7 was both 100% (8/8 and 4/4, respectively). The time above minimal inhibitory concentration (% T > MIC) in the treatment interval was greater than 90% in 9 out of 10 patients for whom likely causative organism was isolated and identified after MEPM treatment or for whom causative organism emerging after treatment was isolated and identified. The incidence of adverse events was 93.1% in adult and 83.3% in pediatric patients. There were three deaths and one serious adverse event reported among the adult patients; however, all these cases were assessed as not related to the study medication. The incidence of adverse drug reactions was 45.5% and 66.7%, respectively. All the observed adverse drug reactions were mild or moderate in severity and none of them was severe. Adverse drug reactions which were unknown from the previous MEPM clinical studies and investigation of the results of clinical experience include 'chest discomfort', 'blood uric acid decreased', 'lymphocyte deformation', 'blood uric acid increased', 'abnormal funduscopy', 'hypesthesia' and 'hemorrhagic cystitis'. All these events were mild or moderate in severity and resolved without requiring any action or after providing symptomatic treatment. There was no unknown adverse drug reaction that resulted in treatment discontinuation. No nervous system disorders such as convulsion and impaired consciousness were reported. The results show that monotherapy of MEPM 1 g (or 40 mg/kg for some of the pediatric patients) t.i.d. every 8 hours was effective, and was also safe and well tolerated in adult and pediatric patients with FN. Therefore, MEPM monotherapy is expected to be useful as the initial treatment for Japanese patients with FN.

Identification of the HERV-K gag antigen in prostate cancer by SEREX using autologous patient serum and its immunogenicity.

The prostate cancer HERV-K gag-related NGO-Pr-54 antigen was identified by SEREX analysis using autologous patient serum. NGO-Pr-54 mRNA was observed to be faintly expressed in normal prostate and strongly expressed in a variety of cancers, including ovarian cancer (5/8), prostate cancer (6/9), and leukemia (5/14). A phage plaque assay showed that a strong reaction was constantly observed with clone ZH042 in which the 5' end of NGO-Pr-54 is deleted, suggesting that it contained the sequence coding for the protein product. A TI-35 mAb was produced using a recombinant protein (438 aa) deduced from the sequence of ZH042. Transfection of clone ZH042 into 293T cells resulted in the production of an approximately 50-kDa molecule visualized by Western blotting. Natural production of the molecule was confirmed in a SK-MEL-23 melanoma cell line. An indirect immunofluorescence assay showed that NGO-Pr-54 protein was expressed on the cell surface as well as in the cytoplasm. Cell surface expression was confirmed by flow cytometry using the TI-35 mAb. The antibody response against NGO-Pr-54 was observed in patients with bladder (5.1%), liver (4.1%), lung (3.4%), ovarian (5.6%), and prostate (4.2%) cancer, as well as with malignant melanoma (13.2%).

[Complications in the central nervous system during chemotherapy for childhood acute lymphoblastic leukemia: JACLS ALL-02 study].

We evaluated central nervous system (CNS) complications treated under the ALL-02 protocol of the Japan Association of Childhood Leukemia Study (JACLS) from April 2002 to March 2005. According to NCI Toxicity Criteria, 17 events of grade 3 and 4 CNS complications were reported in 15 out of 541 patients. Out of these CNS complications, leukoencephalopathy was seen in 5 patients; seizure in 5; cerebrovascular disease in 3; conscious disturbance in 2; and hypertensive encephalopathy and reversible posterior leukoencephalopathy syndrome in one patient each. The complications were intensively observed during induction therapy and the last of the early phase chemotherapy. The protocol treatment was stopped or modified in most patients after CNS complications. MRI imaging demonstrated no improvement in one patient with leukoencephalopathy who developed an isolated CNS relapse, while other patients were alive and remain in their first complete remission without any neurological sequelae. Further studies will be required to analyze risk factors for CNS complications during chemotherapy not accompanied by irradiation and to establish alternative treatments after the appearance of such CNS complications.

ABL kinase mutation and relapse in 4 pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia cases.

The tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL), which had showed poor prognosis before the dawn of IM treatment. However, if Ph-ALL patients showed IM resistance due to ABL kinase mutation, second-generation TKI, dasatinib or nilotinib, was recommended. We treated 4 pediatric Ph-ALL patients with both IM and bone marrow transplantation (BMT); however, 3 relapsed. We retrospectively examined the existence of ABL kinase mutation using PCR and direct sequencing methods, but there was no such mutation in all 4 diagnostic samples. Interestingly, two relapsed samples from patients who were not treated with IM before relapse did not show ABL kinase mutation and IM was still effective even after relapse. On the other hand, one patient who showed resistance to 3 TKI acquired dual ABL kinase mutations, F359C at the IM-resistant phase and F317I at the dasatinib-resistant phase, simultaneously. In summary, Ph-ALL patients relapsed with or without ABL kinase mutation. Furthermore, ABL kinase mutation was only found after IM treatment, so an IM-resistant clone might have been selected during the IM treatment and intensive chemotherapy. The appropriate combination of TKI and BMT must be discussed to cure Ph-ALL patients.

Successful chemotherapy for congenital malignant gliomas: a report of two cases.

We describe the cases of 2 patients with a congenital malignant glioma that responded to chemotherapy. In the first case, a 2-month-old boy had a conjugate deviation to the right side and nystagmus. A T(1)-weighted gadolinium-enhanced magnetic resonance image showed a large tumor in his right frontal lobe. The tumor was partially resected, and the histological diagnosis was malignant ganglioglioma. The child then underwent 6 cycles of chemotherapy (mainly carboplatin and etoposide), and the residual tumor shrank. The tumor was then partially resected during a second operation, after which the patient underwent 5 cycles of chemotherapy (a combination of carboplatin, etoposide, vincristine, ifosfamide, cisplatin and cyclophosphamide). The tumor has not recurred in more than 8.5 years. In the second case, a 2-month-old boy had bulging of the anterior fontanel. The T(1)-weighted gadolinium-enhanced magnetic resonance image showed a large suprasellar tumor. The tumor was partially resected, and the histological diagnosis was anaplastic astrocytoma. The patient underwent 8 cycles of chemotherapy (MCNU, carboplatin and etoposide) and the tumor has not recurred in more than 7.5 years. Our experience indicates that, if surgical removal and chemotherapy are done aggressively for malignant gliomas in neonates and infants, long-term survival is possible.

The role of virus-specific immunoglobulin E in airway hyperresponsiveness.

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis during infancy and is associated with subsequent wheezing and asthma, but the nature of this association is not fully understood. We investigated the role of RSV-specific IgE antibodies in the pathophysiology of virus-induced airway dysfunction in a mouse model. Lung infection with RSV resulted in significant increases in mRNA expression for IgE and both of its high- and low-affinity receptors. In serum, virus-specific IgE antibodies reached peak levels by Day 21 after infection. Data from in vitro experiments show that RSV can induce mast cell degranulation, but only if these cells are sensitized with specific IgE. When passively sensitized in vivo with virus-specific IgE, mice developed exaggerated airway responsiveness to methacholine on airway infection, an effect that required the high-affinity receptor of IgE. These data suggest that RSV-specific IgE may contribute to the pathophysiology of airway dysfunction in children who develop this class of specific antibody.