Meiosis error and subsequent genetic and epigenetic alterations invoke the malignant transformation of germ cell tumor.

Germ cell tumors (GCTs) are thought to arise from primordial germ cells (PGCs) that undergo epigenetic reprogramming. To explore the mechanisms of GCT formation, we analyzed single-nucleotide polymorphism array comparative genomic hybridization patterns and the methylation status of 15 tumor suppressor genes (TSGs) and differentially methylated regions (DMRs) of two imprinted genes, H19 and SNRPN, in 28 children with GCTs. Three GCTs with 25-26 segmental uniparental disomies (UPDs), heterozygous centromeric regions, and a highly methylated SNRPN DMR may have occurred through meiosis I error. Three other GCTs with whole UPD and homozygous centromeric regions of all chromosomes may have occurred through endoreduplication of a haploid set in an ovum or testis. The other 22 GCTs had heterozygous centromeric regions of all chromosomes and no or a small number of segmental or whole UPDs and may have developed from premeiotic PGCs before imprint erasure or a reestablishment of imprinting. Gain and amplification of 3p24-p22 and 20q13-q13, and loss and UPD of 1p36-p35, 4q21-q21, 5q11-q13, and 6q26-qter were found in five or more tumors. 1p36-p35 loss was frequent, and found in 19 tumors; RUNX3 residing at 1p36 was methylated in the promoter regions of 16 tumors. Two yolk sac tumors with many segmental UPDs or whole UPD of all chromosomes had gain of 20q13-q13 and loss of 1p36-p35, and seven or eight methylated TSGs. These genetic and epigenetic alterations may have caused malignant transformation because they were rarely found in teratomas with segmental or whole UPDs.

Successful alternative treatment containing vindesine for acute lymphoblastic leukemia with Charcot-Marie-Tooth disease.

Peripheral neuropathy is a well-known side effect of vincristine (VCR), a microtubule inhibitor commonly used to treat malignancies. Severe neurological adverse events can occur in patients with Charcot-Marie-Tooth disease (CMT) treated with VCR. Vindesine is also a microtubule inhibitor, which, like VCR, is widely used to treat malignancies. The case of an 11-year-old female patient with CMT type 1A who developed severe peripheral neuropathy induced by VCR given for her acute lymphoblastic leukemia is reported. Alternative treatment containing vindesine instead of VCR led to a successful outcome without a relapse of leukemia or neurological worsening of CMT.

Development of germinoma during the treatment of systemic-onset juvenile idiopathic arthritis with infliximab.

We report a 19-year-old patient with systemic-onset juvenile idiopathic arthritis (JIA) who developed a mediastinal germinoma during treatment with infliximab. Although the cancer risk of infliximab is controversial, this agent may have accelerated the growth of the germinoma. We conclude that the indications for tumor necrosis factor (TNF) inhibitors should be strictly decided and that a nationwide cohort study is necessary to assess the risk of cancer in patients with JIA exposed to biologics.

Piperacillin/tazobactam versus cefozopran for the empirical treatment of pediatric cancer patients with febrile neutropenia.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of piperacillin/tazobactam (PIP/TAZO) and cefozopran (CZOP) monotherapy in pediatric cancer patients with febrile neutropenia (FN). PROCEDURE: A total of 119 febrile episodes in 49 neutropenic pediatric cancer patients (20 females and 29 males) with a median age of 6.8 years (range, 0.3-18.4 years) received randomized treatment either with PIP/TAZO 125 mg/kg every 8 hr or CZOP 25 mg/kg every 6 hr. Clinical response was determined at completion of therapy. Durations of fever and neutropenia, the need for modification of the therapy, and mortality rates were compared between the two groups. RESULTS: The frequency of success without modification of treatment was not significantly different between PIP/TAZO (59.6%) and CZOP (53.2%). Durations of fever and antibiotic therapy did not differ between the treatment groups, and no major side effects were observed in either group. CONCLUSIONS: PIP/TAZO and CZOP monotherapy were both effective and safe for the initial empirical treatment of pediatric cancer patients with FN.

Higher urinary excretion of inorganic phosphate during early induction chemotherapy predicts a good prognosis in childhood acute leukemia.

The rapidity of response to induction therapy is emerging as an important prognostic factor in children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Urine inorganic phosphate (IP) and uric acid (UA) may increase in patients with acute leukemia who undergo their induction chemotherapy, owing to the breakdown of tumor cells. The crystallization of UA or calcium phosphate in renal tubules can result in acute tumor lysis syndrome (ATLS). Some reports indicate that patients who experience ATLS have a better prognosis than those who do not. We investigated the relationship between urinary IP and UA excretion and treatment outcome in children with acute leukemia. Participants included 93 patients with ALL and 31 patients with AML. Urine samples were collected and measured for the first 3 days of induction chemotherapy. Among patients with ALL, urinary IP excretion was significantly higher in patients without relapse than in those with relapse and correlated with long-term outcome. Among patients with AML, urinary IP excretion was significantly higher in patients without induction failure (IF) than those with IF. We propose that higher urinary IP excretion could be a useful prognostic marker for determining favorable outcomes in patients with acute leukemia.

The clinical feature of invasive fungal infection in pediatric patients with hematologic and malignant diseases: a 10-year analysis at a single institution at Japan.

Invasive fungal infections (IFI) are an important complication in hematologic malignancies and stem-cell transplantation (SCT). However, there are limited data characterizing IFI in children. The clinical feature of IFI after chemotherapy and SCT were analyzed in 334 pediatric patients treated at Hokkaido University Hospital from 1997 to 2006. The cumulative incidence of IFI was 6.9%; this comprised cases of proven, probable and possible IFI at rates of 1.2%, 3.0%, and 2.7%, respectively. The infected lesions were lung in 14 patients, liver in 5 patients, brain in 3 patients, fungemia in 2 patients, kidney in 1 patient, and endophthalmitis in 1 patient. The mortality of IFI was 48.2%, excluding patients who died due to relapse and interstitial pneumonitis; in particular, 71.4% patients with a lung lesion (10/14) died due to IFI. Fifty-nine pediatric patients died in our institution over the 10-year period of the study and IFI was the direct cause of death in 18.6% (11/59) of the patients. Risk factors for IFI with chemotherapy and SCT were also analyzed. Univariate analysis showed that age at diagnosis older than 10 years, relapse of original disease, long-term administration of broad-spectrum antibiotics, and acute myelogenous leukemia (AML) were the risk factors for IFI. All patients with IFI received long-term antibiotic therapy. AML was most strongly associated using a multivariate analysis. The prognosis of IFI has been expected poor; therefore, prevention of this condition, especially for older patients with AML, would be important.

[Huge brain abscess and invasive pulmonary disease by fungal infection during chemotherapy for infantile acute myeloid leukemia].

The authors encountered a 7-year-old girl with a huge brain abscess and invasive pulmonary lesion due to fungus, who had been treated for acute myelogenous leukemia (AML). Although she was administered voriconazole to prevent fungal infection, she developed partial seizure and paralysis of the left side because of the huge brain abscess. Fungus culture and serum fungal markers, including Aspergillus antigen, were all negative. She underwent drainage and surgical resection of necrotic tissue after antifungal agents, including liposomal amphotericin B (L-AMB). Resection pathology revealed localized fungal infection, suspected as due to zygomycosis. The cerebral lesion reduced after the operation and the pulmonary lesion also vanished. We discontinued AML treatment because of the severe fungal infection; however, she has remained in continuous remission. Although Lipo-AMPH and itraconazole are comparatively effective for zygomycosis, progressive disseminated zygomycosis is extremely intractable. Our case underlines the feasibility and successful application of combined conventional antifungal agents and surgical resection in such a patient.

[Clinical evaluation of urinary leukotriene e4 levels in children with respiratory syncytial virus infection].

The levels of leukotriene E4 (LTE4) of the urine were determined in 24 pediatric patients with infectious diseases due to respiratory syncytial virus (RSV), i.e., bronchitis, pneumonia, and bronchiolitis, and compared with those in controls without allergic disease. The level for LTE4 of the acute-phase urine was 620+/-562 pg/mg. cr in the pediatric patients infected with RSV, being significantly higher than 190+/-67 pg/mg. cr in controls (P<0.005). The levels for LTE4 of the urine in the recovery phase showed a tendency toward decrease, as compared to those in the acute phase. However, there was no significant difference in the level for LTE4 of the acute-phase urine between the presence and the absence of each of the following conditions: expiratory wheezing; the association of pneumonia; family history of allergic diseases; the association of atopic dermatitis; and a past history of expiratory wheezing. An allergological study also revealed that there was no significant difference in LTE4 level between the presence and the absence of peripheral eosinophilia or between the presence and the absence of the high total level for IgE of the serum or positivity for the specific IgE level in the serum. These results suggest that LT is involved with the pathological conditions of RSV infection, but there are no direct relation between atopic diathesis or expiratory wheezing and the amounts of LT production.

Current approaches to management of cerebral fungal infection in pediatric patients with hematologic disorders.

We report 2 pediatric cases of cerebral fungal infection. A patient with severe aplastic anemia developed an Aspergillus species brain abscess and pulmonary aspergillosis after peripheral blood stem cell transplantation. Despite administration of micafungin, amphotericin B, and flucytosine, the patient died 2 months after the transplantation because of underlying pulmonary aspergillosis. Another patient with acute myelogenous leukemia developed a huge brain abscess with histopathologic findings suspicious of mucormycosis. This patient was cured with combination therapy of antifungal agents and intensive surgery, without sequelae. It is important to perform aggressive multimodality treatment, when indicated, including surgical intervention, even if in myelosuppression.

Evaluation of risk factors for invasive fungal infection after allogeneic stem cell transplantation in pediatric patients.

Invasive fungal infections (IFIs) are a significant cause of morbidity and mortality after stem cell transplantation (SCT). The incidence, outcome, and risk factors for IFI after allogeneic SCT were analyzed in 149 pediatric patients treated at Hokkaido University hospital from 1988 to 2006. The cumulative incidence of IFI after allogeneic SCT was 8.1%; this comprised cases of proven, probable, and possible IFI at rates of 0.7%, 4.0%, and 3.4%, respectively. Only 1 patient complicated with IFI in the 100 days after SCT, excluding cases with rejection. Antifungal drugs were effective in 3 of the 12 patients with IFI, but the other 9 patients died because of IFI and relapse of original diseases. Nonrelapse mortality was markedly higher for patients with IFI than for those without IFI (60.0% vs. 20.0%, P=0.0204). Univariate analysis showed that age at transplant, chronic graft-versus-host disease (GVHD), and a corticosteroid dose >2 mg/kg or 60 mg/d for 10 days or longer were possible risk factors for IFI. Of these factors, chronic GVHD was the only factor associated with IFI in a multivariate analysis. Treatment of IFI is very difficult and, therefore, prevention of this condition is important, especially upon occurrence of chronic GVHD.