Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence.

Endocrine dysfunction and parameters of metabolic syndrome were assessed in 91 patients aged 4.3-32.5 years who underwent allogeneic or autologous BMT in childhood. Final short stature, found in five of the 35 patients who attained final height, was associated with the underlying disease (specifically, Fanconi anemia) (P=0.0013), previous cranial irradiation (P=0.0007), type of conditioning irradiation (P<0.05) and allogeneic BMT (P=0.05). Growth hormone deficiency (n=10) was associated with previous cranial irradiation (P<0.005) and conditioning total body irradiation (P<0.001). Twelve patients had primary hypothyroidism, one had hyperthyroidism and one papillary thyroid carcinoma. Hypothyroidism was associated with neck/mediastinal (P<0.005) and conditioning irradiation (P<0.05). Primary gonadal failure was found in 24 of the mature patients (62.5% females). Hypogonadism was associated with the underlying disease (especially hematological malignancies) (P<0.05), pretransplant treatment (P<0.05), irradiation conditioning (P<0.001), older age (P<0.005) and advanced pubertal stage at BMT (P<0.05). Obesity (body mass index >2 s.d.) was found in 4.4% and type II diabetes and impaired glucose tolerance in 3.3% each. Dyslipidemia was found in 27.9% of the 43 patients tested. These findings emphasize the need for long-term follow-up of endocrine and metabolic parameters in young patients after BMT in order to offer proper treatment and improve quality of life.

Molecular variants of the ATM gene in Hodgkin's disease in children.

Ataxia telangiectasia is an autosomal recessive disease with a striking predisposition of lymphoid malignancies. ATM mutations have been reported in adult sporadic lymphoma and leukaemia. The aim of this study was to investigate the possible involvement of the ATM gene in the carcinogenesis of Hodgkin disease in children. Tumours were obtained from 23 patients and were subjected to mutation screening and loss of heterozygosity analysis. Eight base substitutions were identified in seven patients. Of them, Y54Y, a silent change, was observed in two patients and a known polymorphism, D1853N, in three patients. Of the other two patients, one harboured a combined genotype P604S/F1463C, identified previously in two patients with Hodgkin lymphoma, and the other a novel missense mutation, V595A. The alterations were present in the germ line, and both had a more aggressive disease. In all, 100 matched normal ethnic controls were screened for these mutations and P604S/F1463C was identified in one healthy control. Loss of heterozygosity was identified in four patients and in three of them it was located centromeric to the ATM gene, and, in one, it spanned a large region, indicating the involvement of other tumour-suppressor genes in this disease. Missense variants of the ATM gene are a rare event in childhood Hodgkin disease.

Association between telomerase activity and outcome in patients with nonmetastatic Ewing family of tumors.

PURPOSE: Telomerase is considered a molecular marker for malignancy. The aim of this study was to determine telomerase activity (TA) as a prognostic factor at diagnosis and as a marker for minimal residual disease during therapy and follow-up in nonmetastatic Ewing family of tumors (EFT). PATIENTS AND METHODS: Primary tumor specimens and 97 peripheral blood (PBL) samples from 31 EFT patients were analyzed for TA by the Telomeric Repeat Amplification Protocol (TRAP assay). The telomerase catalytic subunit (human telomerase reverse transcriptase [hTERT]) gene expression was evaluated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and telomere length was determined by Southern blotting. The presence of the EFT chimeric transcripts was analyzed by RT-PCR. Correlations with progression-free survival were evaluated. RESULTS: At diagnosis, TA in primary tumors did not correlate with outcome. During therapy and follow-up, highly significant correlation was observed between high TA in PBL samples and adverse prognosis (P <.0001). None of the patients harboring low TA progressed, with a long follow-up (median, 60 months) and a progression-free survival (PFS) of 100%. In nine patients, high TA actually could predict relapse, long before overt clinical relapse. The group of patients with high TA and positive RT-PCR had the most adverse outcome; PFS of 20% (P =.0025). TA was found to be a better prognostic factor than RT-PCR and histopathologic response at surgery. CONCLUSION: The results suggest that TA is a significant prognostic variable, superior to the established clinical prognostic parameters during therapy and tumor surveillance. It could be used in combination with RT-PCR for a new risk classification.

Significance of residual abdominal masses in children with abdominal Burkitt's lymphoma.

PURPOSE: To evaluate the natural history of children with abdominal Burkitt's lymphoma who had complete clinical remission and residual abdominal mass after treatment. MATERIAL AND METHODS: The charts and imaging findings of all children with abdominal Burkitt's lymphoma treated and followed at our medical center between 1988 and 1999 were reviewed for the presence, management, clinical course, and prognosis of residual mass. RESULTS: Only children who achieved complete clinical remission were included. The study group consisted of 33 children (20 boys and 13 girls) aged 2.6-17.6 years (mean 7.2 years). Of these, seven (20.6 %) were found to have a residual abdominal mass. Two underwent second-look operation with no evidence of viable tumor on histology. The remaining five were followed by imaging studies for 2.2-9.1 years (mean 6.1 years); none relapsed. CONCLUSION: Residual mass is not uncommon in children with abdominal Burkitt's lymphoma. The presence of residual mass in a child with complete clinical remission does not alter the long-term prognosis. Therefore, in children with Burkitt's lymphoma and residual mass with no other signs of disease activity, expectant watching may be appropriate.

Treatment of alpha-fetoprotein secreting hepatoblastoma by response of serum alpha-fetoprotein levels: a new concept.

Hepatoblastoma, the commonest primary malignant liver tumor in infants and children, is usually associated with elevated serum alpha-fetoprotein (AFP) levels. The authors sought to determine if AFP levels can be used to modify treatment, thereby avoiding the wait for formal imaging studies and prolonged suboptimal treatment and limiting the use of effective but toxic chemotherapy. From April 1984 to December 1997, 8 children were diagnosed with AFP-secreting hepatoblastoma. Serum AFP levels were measured weekly. If AFP levels failed to improve, or increased on at least 2 successive examinations, the chemotherapy protocol was changed. When an excellent response was achieved, less toxic chemotherapy was substituted. Six patients (75%) were disease-free for at least 2 years, some with high-risk or metastatic disease. Two patients died. Six of the 7 nonmetastatic patients (86%) remain disease-free (only one had a resectable tumor). Chemotherapy changes resulted in reduced AFP levels in 7 patients. This study supports the use of AFP monitoring to modify treatment in hepatoblastoma responding to therapy with less toxic drugs and the use of nonstandard therapy when suboptimal responses are obtained.

Methotrexate treatment protocols and the central nervous system: significant cure with significant neurotoxicity.

Methotrexate can influence the central nervous system through several metabolic toxic pathways. These effects can be categorized as immediate, acute to subacute, or chronic neurologic syndromes. The acute to subacute syndrome occurs frequently in acute lymphoblastic leukemia treatment protocols, generally manifesting with focal neurologic signs and changes seen on magnetic resonance imaging and single photon emission computed tomography. While in some patients the neurotoxicity is transient and benign and allows for continuation of chemotherapy, in others it can be quite severe and debilitating, leading to permanent neurologic deficits. The need to modify the treatment protocols when neurotoxicity appears is not fully established. It is also unknown whether the use of sufficient amounts of leucovorin can overcome the toxic effects of the drug.

Improved outcome in childhood B-cell lymphoma with the intensified French LMB protocol.

BACKGROUND: During the last 20 years, 120 children with B cell lymphoma were treated at the National Pediatric Hematology/Oncology Center of Israel. Until 1986, 63 patients received an institutional protocol (BMC), and thereafter 57 patients received a modified French LMB protocol. We report the results of a retrospective analysis comparing the results of these two protocols. PROCEDURE: Patient characteristics were similar in both groups except for stage of disease and lactate dehydrogenase (LDH) levels. Significantly more patients in the LMB group had higher stage disease, and the LDH levels also were higher (<600 microg/ml). RESULTS: Fifty-four of fifty-seven children on the modified LMB protocol are alive, disease-free, with an overall event-free survival of 94% (median follow-up of 73 months). Event-free survival for stages I, II, and III patients is 100%, and for stage IV 77%, whereas the overall event-free survival was 58% among 63 children treated previously, and for stage IV patients only 10%. Severe marrow suppression and neutropenic enterocolitis were the major complications of this intensive protocol. CONCLUSIONS: Intensive chemotherapy with a modified LMB protocol and modern supportive care result in a high cure rate of childhood B cell lymphoma even in patients with advanced disease.

High frequency of loss of heterozygosity for 1p35-p36 (D1S247) in Wilms tumor.

We analyzed the loss of heterozygosity (LOH) for 1p in 18 Wilms tumors using a panel of 11 polymorphic markers. Loss of heterozygosity was identified in 56% of the tumors. The smallest region of overlap was defined for marker D1S247, underlying the 1p35-1p36.1 locus. This is the highest LOH frequency for 1p, or for the well-defined 11p13 and 11p15.5 loci. Based on the fact that tumors of all stages, with both favorable and unfavorable histology, exhibited LOH, we suggest that the 1p35-1p36.1 locus is involved in the etiology of Wilms tumor.

Clinical relevance of molecular diagnosis in childhood rhabdomyosarcoma.

Rhabdomyosarcoma may be divided into three subtypes--embryonal, alveolar, and undifferentiated sarcoma--which can be distinguished by molecular analysis. The authors applied reverse transcriptase-polymerase chain reaction analysis (RT-PCR) to analyze tumor samples from 14 children with rhabdomyosarcoma for the presence of the chimeric PAX3-FKHR transcript resulting from the translocation t(2;13)(q35,q14). Both fresh and paraffin-embedded tissues were used. In only nine specimens was the RNA intact for the analysis. The chimeric transcript was identified in seven samples: four alveolar type, one embryonal type, and two undifferentiated sarcoma. Histologic review was performed in the three samples with discordance between the molecular and histologic findings. A sample from a patient with a diagnosis of embryonal rhabdomyosarcoma on presentation and expression of PAX3-FKHR fusion transcript yielded a small focus of alveolar rhabdomyosarcoma and was reclassified as alveolar rhabdomyosarcoma. One of the samples from a patient with undifferentiated sarcoma was redefined as alveolar subtype; the diagnosis of the second undifferentiated sarcoma remained unchanged, in accordance with the histologic diagnosis. These findings further support the recommendation that molecular analysis be included in the diagnostic workup of childhood small round cell tumors to reach a more accurate diagnosis for tailoring of specific treatment.

Home intravenous antibiotic treatment for febrile episodes in immune-compromised pediatric patients.

The purpose of this work was to assess the feasibility of home intravenous antibiotic treatment (HIAT) for febrile episodes in immune-compromised (neutropenic, splenectomized), low-risk pediatric patients. Thirty hematology-oncology patients who presented to our emergency room from January 1993 to January 1995 and who suffered from a febrile episode and were considered at low risk for septic complications were immediately discharged on HIAT. Patients were followed for at least 3 weeks after recovery. Patients and parents were retrospectively questioned about adverse effects and about their degree of satisfaction with home treatment. Patients who required hospitalization during this period were considered unresponsive to HIAT and were analyzed for causes and adverse effects. Thirteen out of 60 (22%) febrile episodes, or eight out of 42 (19%) episodes of fever and neutropenia eventually led to hospitalization. Pseudomonas species infections were associated with the highest rate of unresponsiveness (88%). A central venous catheter infection developed in two cases following HIAT (two cases out of 640 days of therapy). No other complications were identified. No infection-related morbidity was observed. Patients and parents were highly satisfied with HIAT and wanted to use it again, if necessary. Immediate discharge on HIAT for low-risk pediatric immune-compromised patients suffering from a febrile episode is feasible, safe, and well accepted by patients and families. Patients who are found to have Pseudomonas infections should probably be hospitalized. Our results are preliminary and must be confirmed by a prospective, randomized trial before definite recommendations can be made.

A novel germ line p53 mutation in intron 6 in diverse childhood malignancies.

Screening for p53 mutations in exons 5 to 8 in 124 pediatric malignancies identified 18 abnormal shifts using single strand conformation polymorphism: 12 were missense mutations and in 6, no mutation was detected in the exon or in the splice donor acceptor sequences. Sequencing was then performed in the adjacent introns, revealing a G to A base substitution at 39 base pairs upstream to exon 7. This mutation was identified in the germ line of five of the patients, and also in the father of one, whose parents were available. For comparison, of the 184 normal controls similarly screened, only one had this mutation (P=0.036). Positive staining of p53 protein was observed in three of the paraffin embedded tissues that were available: brain tumor, rhabdomyosarcoma, and lymphocytes from a normal lymph node from the rhabdomyosarcoma patient. All tumors with the identified intron mutation were Li-Fraumeni syndrome tumors. Sequencing of all exons including splice sites was performed and revealed no mutation. We suggest that this mutation in intron 6 of the p53 gene stabilizes the wild type p53 protein, resulting in its abnormal accumulation. Mutations in the noncoding region of p53 should be further studied.

Additional chromosome 1q aberrations and der(16)t(1;16), correlation to the phenotypic expression and clinical behavior of the Ewing family of tumors.

The cytogenetic hallmark of the Ewing family of tumors is t(11,22)(q24;q12) in its simple, complex or variant forms and/or its molecular equivalent EWS/FLI, EWS/ERG rearrangement. Additional secondary consistent chromosomal aberrations include the der(16)t(1;16) and frequently, other chromosome 1q abnormalities leading to 1q overdosage. We studied whether these secondary cytogenetic changes are correlated to clinical features and phenotypic expression which may have a prognostic impact. Successful cytogenetic evaluation was performed in eight patients with a Ewing family tumor. In four of these, in addition to the primary aberration, chromosome 1q overdosage (including two with der (16)t(1;16)) was noted. Out of these four patients, two had metastatic disease at the time of evaluation, while in the other four, disease was localized. Morphologically, the tumors with the additional 1q aberration, revealed the pPNET subtype more frequently than the typical Ewing. They also expressed a higher degree of neural differentiation by neural marker immunocytochemistry, in comparison to tumors without the 1q aberration. Determination of the prognostic significance of this finding requires a longer follow-up with a larger group of patients.

Hodgkin disease in children: reduced tailored chemotherapy for stage I-II disease.

PURPOSE: Between January 1982 and January 1994, 46 children with stage I-II Hodgkin disease were treated with a tailored regimen to maintain a high cure rate while reducing toxicity. PATIENTS AND METHODS: Forty-six previously untreated children with stage I-II Hodgkin disease received four to six courses of cyclophosphamide, oncovin, procarbazine, and prednisone (COPP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), tailored according to clinical response. Staging was based on various imaging modalities and gallium scan, but surgical staging was not performed. Radiotherapy was given only to bulky mediastinal disease. RESULTS: The median age at diagnosis was 13 years (range 4-18) and only 4 of 46 children had B symptoms. The majority (31 of 46) had stage II disease; 10 had bulky mediastinal disease. Nodular sclerosis histology predominated (32 of 46). Gallium scan was positive in 66% of the patients who were evaluated. Forty-three patients (93%) achieved complete remission after planned therapy. Thirty-six patients (78%) received chemotherapy alone, and 10 (22%) received combined-modality treatment. Fifteen children (33%) completed treatment with only four courses of COPP/ABVD. Overall freedom from relapse was 87% and overall survival was 98% with a median follow-up of 5 1/2 years. Long-term treatment-related morbidity was found mainly in patients receiving radiotherapy. CONCLUSION: Comprehensive clinical staging combined with tailored COPP/ABVD therapy according to response results in excellent disease control and may reduce toxicity.

Oral ondansetron: an effective ambulatory complement to intravenous ondansetron in the control of chemotherapy-induced nausea and vomiting in children.

One hundred children with non-central nervous system malignancies received ondansetron at initiation of chemotherapy and every 8 hours for 5 days after cisplatin-containing therapy and for 3 days after other chemotherapy. Ondansetron was administered orally except with the intravenous chemotherapy. For the chemotherapy days, 72 of 93 children (76%) had complete or major control of vomiting on their worst day, 25% with cisplatin-containing protocols, 60% with ifosfamide-containing protocols, and 82% with other protocols. For the overall period, 71 of 93 children (76%) reported complete or major control of vomiting on the worst day, 14% with cisplatin, 60% with ifosfamide, and 83% with other chemotherapy. All had mild or no nausea. Of the 355 chemotherapy days, 228 children (64%) were emesis free, 40% with cisplatin, 60% with ifosfamide, and 68% with other regimens. Of the overall period (541 days), 393 days were emesis free, 45% with cisplatin, 71% with ifosfamide, and 86% with other regimes. Sixty-nine patients were not hospitalized, and oral ondansetron was given when chemotherapy was completed. Of the 241 ambulatory chemotherapy days, 178 (74%) were emesis free. No significant toxicity was encountered. Oral ondansetron reduced hospitalization without reducing antiemetic efficiency in children.

Chronic childhood idiopathic thrombocytopenia purpura: long-term follow-up.

An understanding of the natural history of childhood chronic idiopathic thrombocytopenia purpura (ITP) could contribute to a rational therapeutic approach to its treatment, which remains controversial. In our retrospective study of 92 children with ITP, 22 had a chronic course and were followed for 3-14 years (median 8.6 years). Treatment, when indicated, was individualized: 4 patients (18.2%) did not receive any treatment, 14 (63.6%) received steroids only, while 4 (18.2%) were treated with steroids and one of the following: high-dose gamma globulin (4 patients), splenectomy (2 patients) or immunosuppressive therapy (2 patients). During follow-up, 14 patients (63.6%) achieved complete remission, 5 (22.7%) partial remission and only 3 (13.5%) remained severely thrombocytopenic, with minimal bleeding tendency. Eleven patients (50%) responded to the initial prednisone course (1-5 mg/kg/day), but showed a marked decrease in platelet count when steroids were tapered off. In view of the high rates of complete and partial remission and the mild course of the few non-responding patients, it is suggested that with adequate supportive therapy, follow-up problems and fatalities can be kept to a minimum. We believe that aggressive therapy, such as splenectomy, should be reserved for the rare symptomatic and severely thrombocytopenic patient.