Second and third malignant solid tumor in a girl with ovarian Sertoli-Leydig tumor.

We report a Sertoli-Leydig cell (SLC) tumor of the right ovary in a 10-year-old girl, which was dealt with surgical removal. Three months after resection, she presented with a new episode of acute abdomen because of an abdominal mass, which histologically was compatible with an undifferentiated embryonal rhabdomyosarcoma. Chemotherapy, according to SIOP-??? 89 protocol, was administered additionally to radiotherapy (3,960 cGy). Three years after completing treatment, the patient developed a painful swelling at her left upper arm. The diagnosis was Ewing sarcoma of the humerus, which was confirmed by identification of the typical 11; 22 translocation on cytogenetic and molecular analysis of the tumor tissue. The patient died 14 months from Ewing diagnosis due to progressive disease.

Infections in a pediatric patient cohort with acute lymphoblastic leukemia during the entire course of treatment.

GOALS: To assess the type, frequency, severity, and outcome of all infectious episodes in a pediatric patient cohort with acute lymphoblastic leukemia (ALL) from a single institution during the entire length of leukemia treatment. PATIENTS AND METHODS: Eighty-six patients were treated according to a modified ALL Berlin-Frankfurt-Munster protocol. Retrospective analysis of all types of infections according to the treatment phase and the degree of neutropenia is presented. RESULTS: A total of 610 infectious episodes were recorded. Most infections were documented during maintenance (57%), followed by the induction phase (20.3%). During maintenance, 347 episodes were encountered, with nonspecific viral upper respiratory tract infections (URIs) being the commonest diagnosis (40.0%). Additionally, 38 of 58 total specific viral infections occurred during maintenance: 16 herpes simplex, 7 varicella, 10 herpes zoster infections [varicella-zoster virus (VZV), 45%]. The majority of bacteremia and fever of unknown origin occurred during induction (20%). The number of Gram-negative bacteremia was 50% of the total (26 of 52). The majority of the infections (59.5%) occurred without neutropenia [absolute neutrophil count (ANC) >1,000 microl(-1)]. Fewer infections (9.3%) were recorded with concurrent very severe neutropenia (ANC <100 microl(-1)), although 38.5% of positive blood cultures were documented with severe neutropenia. No infection-related fatality occurred. CONCLUSIONS: Most of the severe infections occurred during induction. Gram-positive bacteremia and Gram-negative bacteremia were almost equal. URIs were the commonest infections during the entire treatment and during maintenance. Specific viral infections represented a smaller percentage of the total (VZV was the commonest pathogen). Infectious complications represented a significant morbidity factor, but notably, mortality was negligible.

Classic transient erythroblastopenia of childhood with human parvovirus B19 genome detection in the blood and bone marrow.

The etiology of transient erythroblastopenia of childhood (TEC) remains unknown, although an association with viral infections has been proposed. The authors describe a 3.5-year-old girl with classic TEC concomitantly with human parvovirus B19 (HPV) infection. The infection was evident by detection of HPV genome in the blood and the bone marrow by polymerase chain reaction. Viral genome was no longer detected when the TEC resolved clinically. The patient was immunocompetent and the anemia has not recurred. To the authors' knowledge, this is one of the few documented cases of classic TEC attributable to HPV infection.

Decrease of CD4+ and B-lymphocyte populations is not associated with severe infectious complications in children with acute lymphoblastic leukemia during maintenance.

The suppression of lymphopoiesis and immune competence during the maintenance phase in children with acute lymphoblastic leukemia (ALL) and the occurrence of infectious complications remain an unexplored area. In this study we assessed lymphocyte subpopulation disturbances during maintenance for childhood ALL along with the incidence, type, and severity of infections that occur during that period in the absence of neutropenia. Twenty-eight children (13 boys, 15 girls) with ALL aged 3-14 years (median 7 years) and treated according to the ALL-BFM 90/95 protocol were studied during maintenance for ALL. Complete white blood cell (WBC) counts and peripheral blood lymphocyte (PBL) analyses were performed. Major lymphocyte subsets (CD19+, CD3+CD4+, CD3-CD8+, CD3-CD16+CD56+, CD45RA-, CD45RO+) and markers of T-cell activation (CD25, CD38, CD69, HLA-DR) were analyzed with flow cytometry. Serum immunoglobulin G (IgG), IgA, and IgM levels were measured by a nephelometric assay. All infectious episodes during the study period were recorded in detail. Additionally, 41 age-matched immunocompetent children were used as controls. Absolute WBC counts (median, 3627/microL) and PBL counts (median, 1206/microL) were significantly below the age-adjusted control values (7400/microL and 2673/microL, respectively; P < .0001). B-lymphocyte, total CD4+, and memory CD4+ (CD4+CD45RO+) subsets were also significantly decreased (33/microL versus 377/microL [P < .0001], 531/microL versus 1045/microL [P < .01], and 80/microL versus 299/microL [P < .001], respectively). Significantly lower immunoglobulin levels were found in all patients. Twenty-two of the 28 patients presented with 74 episodes of a variety o minor infections (mostly respiratory viral [39], skin [7], and gastrointestinal [3]), none demanding prolonged hospital treat ment. Our findings demonstrate a profound immunosuppression throughout maintenance therapy in children with ALL tha has no major clinical impact in terms of increased incidence or severity of systemic infections.

Osteosarcoma as a second tumor after treatment for primary non-Hodgkin's lymphoma in a child with ataxia-telangiectasia: presentation of a case and review of possible pathogenetic mechanisms.

Patients with ataxia-telangiectasia (A-T) and cancer are exposed to additional toxicity due to their underlying inability to repair chemotherapy-induced DNA damage. The authors report the development of osteosarcoma as a second neoplasia in a child with A-T who was treated, without being irradiated, for non-Hodgkin's lymphoma as a primary malignancy. This is the first report of osteosarcoma associated with A-T. The authors postulate that the mechanisms of carcinogenesis are common and independent of the different histopathology categories of these two neoplasias, and the underlying "canvas" of the A-T mutated gene was further triggered by chemotherapy, leading to the development of a second malignancy.

Nasopharyngeal carcinoma in childhood and adolescence: a single institution's experience with treatment modalities during the last 15 years.

Pediatric nasopharyngeal carcinoma (NPC) represents a locally advanced undifferentiated tumor with widely varying epidemiological features and with a high cure rate when combined modality treatment is provided. Both local and systemic treatment is necessary, and additional treatment with biologic modifiers seems promising. In this study, clinical experience and therapeutic results of 10 children with newly diagnosed NPC, treated in a single pediatric hematology/oncology institution in Athens over a period of 15 years, are analyzed. Results from Greece on NPC in young patients are reported for the first time. Ten patients (6 male, 4 female) 7-14 years old (median = 12.5) with a nasopharyngeal tumor were retrospectively evaluated. Disease extent was staged according to the TNM system. EBV-DNA, EBERs, and LMP-1 from paraffin-embedded tissues were studied in 8 patients. All patients received both local and systemic treatment. All cases were classified as type WHO-3. The presence of EBV-DNA and expression of EBER 1-2 mRNAs was demonstrated in the 8 tumors examined, while LMP-1 protein was expressed in 4/8 of the studied cases. Disease stage was III in 4 and IV in 6 patients. Time from the onset of symptoms to diagnosis ranged from 4 to 24 weeks (mean 8 weeks). All patients received preradiation chemotherapy and radiotherapy, and 5/10 received postradiation chemotherapy due to either resistant or advanced disease. In 9/10 patients, complete locoregional control was achieved. In addition to chemotherapy and radiotherapy the latest patient of this series was treated with recombinant IFN-beta (10(5) IU/Kg i.v. 3 times a week) for 6 months and at 18 months remains in continuous complete remission. One patient was lost to follow-up 3 years after cessation of treatment while remaining in complete remission. Of the remaining 9 patients, 7 are alive for a median follow-up of 54 months (range 18-186); 5/7 are free of disease, and 2/7 are with disease but stable. The median time for first relapse was 17 months. The data confirm the good results of combined chemo-radiotherapy treatment for high-risk NPC in young patients. The documented EBV latency underlying this tumor, which possibly critically mediates its pathogenesis, justifies the use of biological modifiers with antiviral and immunoregulatory activity, like the IFNs, which may offer better therapeutic results in the future.

Ineffective erythropoiesis underlies the clinical heterogeneity of congenital dyserythropoietic anemia type II (CDA II).

BACKGROUND: Congenital dyserythropoietic anemia type II (CDA II) is an autosomal recessive disease, and is the most common CDA. The qualitative and quantitative defects of erythropoiesis in CDA II, as estimated by the hematological and biochemical parameters at the time of diagnosis, may not reflect the heterogeneity of the disease course of each patient. METHODS: Three pediatric patients with CDA II are herein presented, having an heterogeneous clinical course. In addition to bone marrow morphology, Ham test and SDS-PAGE of erythrocyte membrane protein, the present study also examined erythroid marrow activity, by measuring serum Erythropoietin (Epo), soluble Transferrin Receptors (sTfR) concentrations and Reticulocyte Production Index (RPI). RESULTS: All patients demonstrated the same pattern of ineffective erythropoiesis, having increased Epo (350-389 IU/L), sTfR concentrations (6.2-7.8 mg/L) and low RPI values (0.8-1.3). Erythron expansion was expressed by RPI values nearly twofold higher than normal values in parallel to raised sTfR and high Epo production. Despite the same degree of ineffective erythropoiesis seen in all patients, the severity of the clinical course was diverse in terms of frequency and clinical relevance of transfusion needs. CONCLUSION: An analysis of the parameters expressing ineffective erythropoiesis in CDA II can provide a better understanding of the degree of dyserythropoiesis, however it is not useful for predicting the clinical course of disease in patients, because the underlying genetic heterogeneity of this disorder remains obscure.

Correlation of cerebrospinal fluid beta-glucuronidase activity with plasma methotrexate concentrations in leukemic children receiving high-dose methotrexate.

BACKGROUND: The activity of lysosomal enzymes is increased in body fluids during inflammation, in which cellular malfunction and cellular death occurs. Because chemotherapy also causes cell malfunction and death, for identifying a neurologic effect, we studied the activity of beta-glucuronidase in the cerebrospinal fluid (CSF) of leukemic children during treatment. PROCEDURE: The beta-glucuronidase activity in CSF was determined in 13 patients with B-precursor acute lymphoblastic leukemia (ALL) treated with the medium risk arm of ALL Berlin-Frankfurt-Munster (BFM) 95 protocol. Plasma methotrexate (MTX) levels were determined at 24 and 48 hr after the infusion of high-dose (5 g/m(2)/24 hr) MTX (MCA phase). RESULTS: The mean (SD) beta-glucuronidase activity prior to the onset of chemotherapy was 19.9 (5.6) nmoles/4-methylumbelliferone/ml/hr. No significant changes in activity were noted during the phases of the protocol except of the MCA3. The activity was 24.4 (6.8) on MCA2, 28.4 (9.3) on MCA3, and 24.1 (9.5) on MCA4. The beta-glucuronidase activity was positively correlated with the plasma MTX levels at both 24 hr (r = 0.483, P = 0.006) and 48 hr (r = 0.676, P < 0.0001). No progressive changes were noted during the different phases of the protocol. The greatest beta-glucuronidase activity was measured in two patients with neurotoxicity. CONCLUSIONS: The beta-glucuronidase activity is increased in the CSF of leukemic children receiving high-dose MTX and particularly in neurotoxicity. It is positively correlated with plasma MTX levels. No cumulative effect of the chemotherapy was observed. The increased beta-glucuronidase activity is most likely due to enzyme leakage through the cell membranes caused mainly by a toxic effect of MTX on the cells of the central nervous system (CNS).