Treatment of advanced neuroblastoma.
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Biomedical subjects
Publications and source records attributed to M M Reid.
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This report describes the cloning and sequencing of the breakpoint of a deletion of approximately 166 bp in the 5' region of a rearranged T-cell receptor gamma (TCRG) V gamma 2 gene from the disease cells of a patient with T-cell ALL. This abnormal rearrangement was not detected in a biopsy taken during clinical remission. Sequence analysis indicated that the deletion breakpoint occurred at a position immediately upstream of sequences found in the germline V gamma 2 gene that are closely related to known heptamer and nonamer recombination signal sequences. Furthermore, the rearrangement was found to have non-germline nucleotides (N-region) in between otherwise intact V and J segments. These data indicate that this structure may be the result of an aberrant rearrangement event in common with the frequently occurring chromosomal abnormalities found in T-cell ALL. This event could either be one directly associated with the leukaemic transformation or one occurring during normal lymphocyte development but which is coincidental with leukaemic transformation. This represents the first molecular genetic evidence for an abnormality specifically involving the TCRG locus in ALL.
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AIMS: To test the hypothesis that the abnormal fibrous stroma of bone marrow found after treatment of disseminated neuroblastoma represents traumatic scarring. METHODS: Twenty six restaging bone marrow biopsy specimens from 14 children with disseminated neuroblastoma were compared with 37 from 37 children with acute lymphoblastic leukaemia. They were assessed independently by two observers for the presence of abnormal fibrous stroma. All biopsies were performed 23 to 50 days after the initial diagnostic biopsy, and from the same iliac crest. A further nine restaging bone marrow biopsy specimens from previously unbiopsied iliac crests from four children with neuroblastoma were examined and the appearances of the diagnostic bone marrow specimens in those with neuroblastoma recorded. Between diagnostic and restaging biopsies, the children received combination chemotherapy regimens. RESULTS: In neuroblastoma abnormal stromal material was observed in 17 of 26 rebiopsied iliac crests as opposed to only 9 of 37 of those with acute lymphoblastic leukaemia (p < 0.005). In addition, four of nine restaging biopsy specimens taken from previously unbiopsied crests in patients with neuroblastoma contained abnormal stroma. All 11 children with neuroblastoma whose restaging specimens contained abnormal stroma had similar abnormalities in one or more biopsy specimens at diagnosis. CONCLUSIONS: Abnormal fibrous stromal material in restaging marrow biopsy specimens of previously biopsied iliac crests occurs much more frequently in neuroblastoma than in acute lymphoblastic leukaemia. We suggest that factors other than traumatic scarring are responsible. This is supported by finding similar abnormalities in previously unbiopsied iliac crests and in the diagnostic biopsy specimens of children with neuroblastoma.
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Data on all patients aged 60 or older in whom a diagnosis of acute lymphoblastic leukemia (ALL) was made in the Northern Health Region of the United Kingdom, over a period of 8 1/2 years, were studied to determine the incidence and range of biological subtypes, and the outcome of a variety of therapeutic approaches. Forty-nine cases were diagnosed (31% of all adult ALL), giving an incidence of 0.9 per 100,000 age-specific population (ASP). Immunophenotyping was performed in 41 patients. Eighteen had common, two T-ALL, 10 null, and 7 B-ALL. Four were biphenotypic with both lymphoid and myeloid markers. One patient refused treatment and four were considered too frail for chemotherapy. Twenty-two were treated palliatively. Aggressive "curative" treatment was planned for 22, but three died before it started. The actuarial survival for the whole group was 4%. The median survival of the palliatively treated group was 1 month, compared with 3 months for those given aggressive treatment. Only two patients (aged 74 and 67) survived more than 2 years in complete remission (CR), both having been treated aggressively. We conclude that the prognosis for those over 60 years of age is extremely poor, but that for a small number of patients a useful prolongation of good quality life may be achieved. Age should not, by itself, be a bar to treatment intended to induce remission. Patients and their relatives should be made aware of the overall poor prognosis and advised of the therapeutic goals when decisions regarding management are being made.
Whether very-low birthweight (VLBW less than or equal to 1500 gm) children differ from normal birthweight (NBW greater than 2500 gm) children with respect to social (as opposed to intellectual) competence has been a relatively neglected issue. The social competence at school age of 183 VLBW children was therefore compared with that of 183 NBW children born at the same hospital matched for age, gender, social class, parity, and maternal age. A multi-informant, multidefinitional approach to social competence was adopted involving teacher, (same-gender) peer, and self-ratings of the 366 children's levels of social maladjustment, social skill, and peer acceptance. VLBW children from the upper, middle, and lower social classes received significantly higher mean sadness/unhappiness scores (even with IQ covaried) than their NBW counterparts. Mean scores for the VLBW group were also higher for social withdrawal, and lower for both social skill and peer acceptance. Possible antecedents and consequences of such group differences in affect and sociability are suggested.
Bone marrow cells from a child with chronic myelomonocytic leukemia showed an acquired, non-Robertsonian translocation between chromosomes 13 and 14, t(13;14)(q12.?2;q32.?3). This rearrangement has not previously been reported in childhood myeloproliferative or myelodysplastic disorders.
In a high-dose schedule for disseminated neuroblastoma, eight courses of chemotherapy were administered every 10 days, regardless of myelosuppression, to eradicate tumour cells rapidly and reduce emergence of drug-resistant clones. Relatively non-myelotoxic vincristine and cisplatin were alternated with high-dose cisplatin-etoposide and cyclophosphamide-etoposide. Of 12 evaluable patients, there were 1 complete (CR), 3 very good partial (VGPR), 5 partial (PR) and 3 mixed responses (MR) 100 days after starting treatment. 6 out of 9 achieved a bone marrow CR at 40 days. 9 of 11 primary tumours were completely resected, after which 4 patients had CR, 3 VGPR (bone scan alone being abnormal), 4 PR and 1 mixed response (MR). Myelotoxicity was the major adverse effect. The only death was due to fungal infection. Clinically important renal dysfunction occurred in 3 patients. 4 had convulsions and 4 temporary hypertension. This schedule produced a rapid response and its toxicity, though serious, was manageable. Further evaluation is warranted.
16 unselected patients with advanced neuroblastoma were given high-dose consolidation chemotherapy with vincristine, melphalan, etoposide and carboplatin over 5 h followed by autologous bone marrow rescue. 3 patients died from treatment-related toxicity, 2 from disease, 1 is alive with disease and 10 are alive and disease-free a median of 12.5 months (range 2-38 months) after bone marrow rescue. All had bone marrow toxicity, most mucositis and 6 had seizures. Renal failure was unexpectedly severe. In the last 3 patients, administration of carboplatin was delayed by 18 h in an attempt to reduce renal damage. The results show that this regimen produces significant morbidity and has a high mortality. Although the overall outcome is encouraging, too few patients have been studied to gauge its efficacy. Whether such aggressive consolidation is necessary in heavily pretreated children with neuroblastoma remains unknown.
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The biology of Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) is the subject of much interest. We present a case of Ph+ ALL with a minor breakpoint cluster (mBCR) rearrangement who subsequently relapsed with Ph+ mBCR+ acute myeloid leukaemia and later with Ph+ mBCR+ acute stem cell leukaemia. This case provides further evidence that Ph+ ALL with a mBCR rearrangement may arise from a pluripotent stem cell with similar potential to that of chronic granulocytic leukaemia to undergo blastic crises with differing lineage characteristics.
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A baby with unilateral cleft lip, midline cleft palate and hypertelorism developed meningitis in the first 48 h of life. Examination of the nasopharynx showed a soft tissue mass, which was confirmed as a basal encephalocele by computed tomography. There was also congenital hydrocephalus and the corpus callosum was absent. Surgical treatment included repair of the anterior basal skull defect, repair of the lip and palate, and ventriculo-peritoneal shunt. There is currently evidence of developmental delay and right-sided visual impairment due to Morning Glory syndrome. This case demonstrates that basal encephalocele should be considered in any baby with midline facial deformity who develops meningitis.
Corticosteroids were used to treat two children with presumed idiopathic thrombocytopenic purpura and one with juvenile rheumatoid arthritis without examination of the bone marrow. Of the two with presumed idiopathic thrombocytopenic purpura, one had Fanconi's anaemia and the other may have had aplastic anaemia. The third child had acute lymphoblastic leukaemia. The diagnosis of Fanconi's anaemia was delayed. A diagnostic and therapeutic dilemma was caused in the second case. In the third, delayed diagnosis and, perhaps, compromised outlook resulted. These three cases re-emphasize the well aired caveats about the diagnosis of idiopathic thrombocytopenic purpura and juvenile rheumatoid arthritis and provide further support for the arguments of those who believe that if corticosteroids are to be used to treat such children, their bone marrow should be examined first.
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