Batya Stark

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. (J Child Neurol 2000;15:573-580).

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.

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 (1–5mg/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.

Synovial sarcoma of bone delineated by spectral karyotyping

Representative karyogram of a metaphase after spectral karyotyping (SKY) after hybridisation with a 24-chromosome-specific DNA probe cocktail The chromosomes are visualised in pseudocolours according to their spectrum signatures. Note presence of t(X;18) (arrows) and der (1)t(1;22) (arrow head). nucleoli. There was a lobular growth pattern and evidence of a few Homer-Wright rosettes with a fibrillary intercellular background. Spindle cells were noted in many areas. Immunohistochemical staining was positive for MIC-2 neuron-specific enolase, keratin, synaptophysin and vimentin, and focally positive for S-100. Cells were negative for smooth muscle actin, muscle actin (HHF-35), desmin, LCA, EMA, Leu-7, and PAS. Electron microscopy showed no glycogen particles and sheets of fusiform cells with scanty cytoplasm, rudimentary cell junctions and cytoplasmic (neuritic) processes that contained microtubules and dense neurosecretory-type core granules of average diameter 100 nm. Findings were consistent with a primitive neuroectodermal variant of Ewing sarcoma. Conventional chromosome analysis showed a karyotype of 45 chromosomes with an unbalanced translocation from chromosome 22 to the short arm of chromosome 1 (confirmed by FISH) and unidentified chromosomal material on the short arm of chromosome X. SKY on 15 metaphase spreads unequivocally confirmed the presence of der (1)t(1;22) and the unidentified extra material added to the short arm of chromosome X was a balanced translocation t(X;18)(p;q11), typical of synovial sarcoma (figure). The karyotype was defined as 45, Y, t(X;18) (p11;q11), der (1)t(1;22)(p13;q12?), –22. The 583 base pair SYT/SSX chimeric transcript resulting from the t(X;18)(p11.2;q11.2) was identified by molecular techniques, but the EWS-FL-1 and EWS-ERG transcripts of Ewing sarcoma were not. No evidence of the typical Ewing sarcoma translocations t(11;22), t(21;22), or t(7;22) was found. The t(X;18)(p11.2;q11.2) translocation disclosed by SKY and confirmed by molecular biology has only been found in synovial-cell sarcomas, a tumour that occurs primarily in para-articular regions, commonly in the area of the knee in young adults but never previously described as a bone tumour.

Parental occupational exposure and the risk of acute lymphoblastic leukemia in offspring in Israel.

Objective: Parental employment in occupations that have potential exposures to organic solvents or pesticides could be associated with the risk of childhood acute lymphoblastic leukemia (ALL) in their offspring. Methods: We explored this hypothesis by studying the association with respect to exposure time windows. Our case–control study included 224 children, 112 diagnosed with ALL and 112 matched controls. Results: A significantly higher odds ratio (OR) was found between childhood ALL and reported parental occupational exposures. Analysis of exposures of both parents by exposure time windows revealed significant OR during the preconception and postnatal periods separately. Conclusions: The results provide support to the association between parental occupational exposures and ALL in their children. These results should be interpreted cautiously because of the small numbers, biases characterizing case–control studies, and the use of hospital-based controls.

Prognostic relevance of genetic alterations in the p32 region of chromosome 1 in neuroblastoma

Thirty-six neuroblastomas were analysed for chromosome 1p alterations and their prognostic relevance. In 72% (26/36) of the patients, 1p alterations were identified in the tumours using 24 polymorphic loci ranging 1p22-1p36.3. LOH was identified in 25 children, and in 10 additional allelic imbalance was identified. In 1 child allelic imbalance was the sole alteration. Imbalance was termed as gain in intensity of one allele with or without reduction of the second allele (< 50%). The imbalance was identified in adjacent regions to the LOH. Two distinct regions of LOH were identified: 1p36.1-p36.3 and 1p31-p32. The common imbalance regions overlapped the common LOH regions. The children with LOH and imbalance had improved survival (100%) compared to the children with LOH only (26%) after 48 months of follow-up. The imbalance had an advantageous effect that is reflected by the improved outcome in children with other unfavourable clinical features.

Hodgkin's 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, blemycin, 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%) recieved 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.

The mystery of electroencephalography in acute lymphoblastic leukemia.

The aim of the study was to evaluate changes in electroencephalogram (EEG) recordings during the course of acute lymphoblastic leukemia (ALL) in children. The study group consisted of 48 children with ALL who underwent a total of 72 EEGs at various stages of the disease. The medical files were reviewed for pertinent clinical data, and the EEGs were evaluated for changes in brain activity. Abnormal background activity was noted in 52.2% of the EEGs done at 1-10 days of therapy, in 43.5% of those done at 10-60 days, and only 4.3% of those done at later stages (p=0.037). These findings, together with earlier reports, suggest that early-stage ALL, even before treatment, may be associated with excessive slow EEG activity, which improves over time. The EEG changes, by themselves, are not an indication of central nervous system leukemia or a predictor of later seizures or other central nervous system involvement.