Multiple cystic brain lesions in a patient with pilocytic astrocytoma.

Pilocytic astrocytomas are usually present as solitary posterior cranial fossa tumours. An unusual case of pilocytic astrocytoma in a 3 year and 8 month old boy is presented. The patient presented over the course of 10 months with intermittent headaches, vomiting, gait ataxia and drowsiness. After extensive investigations magnetic resonance imaging (MRI) revealed widespread lesions throughout the central nervous system, including multiple cystic cerebral grey matter lesions. A brain biopsy was performed and pathological studies revealed pilocytic astrocytoma. The literature pertaining to neuraxis dissemination of pilocytic astrocytomas in the paediatric population is reviewed. There are only a very limited number of reports of pilocytic astrocytoma ca using multiple brain lesions, with no publications of multiple cystic brain lesions. We believe this to be a unique case of pilocytic astrocytoma presenting with widespread cystic lesions throughout the brain.

Comparison of methods for assessment of minimal residual disease in childhood B-lineage acute lymphoblastic leukemia.

The level of minimal residual disease (MRD) early in treatment of acute lymphoblastic leukemia (ALL) strongly predicts the risk of marrow relapse. As a variety of methods of varying complexity have been separately used for detecting and quantifying MRD, we compared the prognostic utility of three methods measurement of blast percentage on day 14 of treatment, detection of monoclonality on day 14 or day 35, and measurement of MRD by PCR-based limiting dilution analysis on day 14 or day 35. The study group comprised 38 children aged 1-15 with Philadelphia-negative B-lineage ALL who were uniformly treated and followed until relapse or for a minimum of 5 years. We also studied some of the technical factors which influence the ability to detect MRD. Measurement of blast percentage on day 14 by an expert morphologist, detection of monoclonality on day 35, and PCR-based measurement of MRD levels on days 14 and 35 all showed significant ability to divide patients into prognostic groups. Measurement of blast percentage on day 14 by routine morphology or detection of monoclonality on day 14 were not useful. The quality of DNA samples varied greatly, as determined by amplifiability in the PCR. However, virtually all amplifiable leukemic targets in a sample were detectable which suggests that the level of detection achieved by limiting dilution analysis is essentially determined by the amount of DNA which it is practicable to study. We conclude that quantification of MRD at the end of induction provides the full range of prognostic information for marrow relapse but is complex; detection of monoclonality on day 35 is simple and has good positive predictive value; and quantification of MRD on day 14 merits further study. PCR-based methods for measurement of MRD levels should incorporate a correction for variation in DNA amplifiability.

Early resistance to therapy during induction in childhood acute lymphoblastic leukemia.

Many patients with acute lymphoblastic leukemia (ALL) are not cured by current therapy because of the development of drug resistance. It is not clear when resistance develops during the growth of the leukemic clone and whether resistant cells are already present at diagnosis or develop later during treatment. Twenty-two uniformly treated children with ALL were studied throughout induction treatment. The size of the leukemic clone in blood and marrow was estimated by limiting dilution PCR analysis, using the rearranged immunoglobulin heavy chain gene as a molecular marker. The decline in the number of leukemic cells was biphasic in virtually all patients. For both marrow and blood, the logarithmic mean of the number of leukemic cells fell by approximately four orders of magnitude during the first 2 weeks, one order of magnitude during the third week, and not at all during the last two weeks of induction treatment. For marrow, the median of the fraction of leukemic cells in each patient that survived per week of treatment was 0.008 for the first 2 weeks, 0.12 for the third week, and 1.4 for the last 2 weeks; for blood, the corresponding figures were 0.003, 0.14, and 0.69, respectively. In individual patients, the results for marrow and blood showed good correlation. The biphasic decline of leukemic cell number suggests that most leukemic cells were sensitive to treatment and were rapidly killed, leaving behind a minor but substantial population of drug-resistant cells. The most likely explanation for this phenomenon is that these resistant cells were already present at diagnosis, their resistance having originated from genetic or epigenetic mutations during prior growth of the leukemic clone.

Childhood cancer: a 4-year prospective study of the psychological adjustment of children and parents.

PURPOSE: The objective of this 4-year prospective study was to assess the psychological adjustment of children treated for cancer and their parents. PATIENTS AND METHODS: Children aged 2 to 12 years with cancer diagnosed and their parents and families (n = 39) were assessed immediately after their diagnosis and then annually for the next 4 years. At each assessment, the psychological adjustment of the children and their families was compared with the adjustment of a cohort of children and families in the general community (n = 49). RESULTS: Immediately after the diagnosis of cancer in the children, the children and their parents had significantly more psychological problems than children and parents in the community. However, at subsequent assessments, there was no difference in the number of psychological problems experienced by children and parents in the two groups. CONCLUSIONS: In the longer term, the prevalence of psychological problems experienced by children treated for cancer and their parents does not differ from that found in children and parents in the general community. Future research should give greater attention to other aspects of the lives of children treated for cancer and their parents, including their broader health-related quality of life.

Neuroblastoma associated with seizures and arrested development.

Two unrelated cases of childhood peripheral neuroblastoma associated with infantile seizures and developmental problems (but without opsoclonus-myoclonus) are presented. The considerable body of evidence supporting the view that the opsoclonus-myoclonus syndrome associated with neuroblastoma has an immunologic basis is reviewed. Patients with neuroblastoma and opsoclonus-myoclonus syndrome commonly have subsequent developmental problems and, rarely, may have seizures. The authors postulate that the seizures and developmental problems in their two patients may result from an immunologic mechanism similar to that suggested for the opsoclonus-myoclonus syndrome of neuroblastoma. The only laboratory evidence to support an immunologic mechanism in these two patients was the presence of raised cerebrospinal fluid immunoglobulins in Patient 2. Specific antineuronal antibody tests in Patient 2 were negative. It is therefore possible that the association reported in these two unrelated cases is coincidental. However, reasonably extensive investigations did not uncover an alternative etiology for the presence of the seizures and developmental delay.

Longitudinal follow-up of the intellectual and academic functioning of children receiving central nervous system-prophylactic chemotherapy for leukemia: a four-year final report.

This longitudinal investigation extends our prospective study of the intellectual and academic functioning of children treated for cancer to 4 years after diagnosis. In the longer term, the children who received central nervous system (CNS) chemotherapy experienced greater neurocognitive deficits, particularly in the area of academic achievement, than did the children who did not receive CNS chemotherapy. Specifically, the CNS chemotherapy-treated children scored lower on academic tests of reading at 3 and 4 years after diagnosis. The results suggest that CNS chemotherapy prophylaxis may adversely effect the development of higher-order mental abilities and cognitive skills during the late-effects period and may also impair academic achievement.

High incidence of treatment failure with vincristine, etoposide, epirubicin, and prednisolone chemotherapy with successful salvage in childhood Hodgkin disease.

BACKGROUND AND PROCEDURE: In an attempt to further reduce the long-term toxicity of chemotherapy for childhood Hodgkin disease (HD), the Australian and New Zealand Children's Cancer Study Group between 1990 and 1996 enrolled 53 children with biopsy-proven and imaging-staged HD into a chemotherapy-only treatment regimen using 5-6 courses of vincristine, etoposide, epirubicin, and prednisolone (VEEP). RESULTS: There were 23 events in these children with 3 progressive disease (PD), 8 partial remissions (PR), and 12 relapses. In the stage I patients, there were 8 events (35%). There was no association between the number of events and the stage of HD. Massive mediastinal disease at diagnosis was present in 16 patients, 11 of whom had an event with 3 PD, 3 PR, and 5 relapses. For all patients with an event at 6-24-month follow-up, all but two patients were salvaged with either alkylating agent-based chemotherapy alone or with irradiation and chemotherapy. The event-free survival for the whole group with median follow-up of 33 months was 59%, but only 31% for massive mediastinal disease. Disease-free survival was 78% and overall survival at 60 months was 92%, with one death due to drug-induced aplasia and another from acute myeloid leukemia. CONCLUSIONS: We conclude that VEEP chemotherapy in childhood HD used as the only treatment modality has an unacceptably high treatment failure rate in patients with massive mediastinal disease and 35% incidence of treatment failure in stage I disease.

A comparison of parent and adolescent reports describing the health-related quality of life of adolescents treated for cancer.

Our objectives were to compare adolescent and parent ratings of the health-related quality of life (HRQL) of adolescents treated for cancer, to compare the HRQL of adolescents who were on treatment vs. the HRQL of those who were off treatment following their diagnosis with cancer and to assess the HRQL of adolescents who were at different points of time following their diagnosis with cancer. The HRQL of 70 adolescents (aged 10 to 18 years) consecutively attending the Women's and Children's Hospital Oncology Clinic in South Australia was assessed by means of standard questionnaires. Parents completed the Child Health Questionnaire, the Functional Status II(R) Questionnaire and the Impact-on-Family Scale. Adolescents completed the self-report version of the Child Health Questionnaire. In general, there was good agreement between parent and adolescent reports. However, parents of adolescents receiving active treatment for cancer reported that their illness was having a greater impact on the adolescents' physical functioning than was reported by the adolescents. The psycho-social functioning of adolescents in single-parent families was reported also by parents to be worse than that of adolescents in 2-parent families. The physical functioning of adolescents had only a weak relationship with parental status but a significant relationship with treatment status. Despite generally good agreement between parent and adolescent reports describing the HRQL of adolescents treated for cancer, it cannot be assumed that reports from parents are always an accurate reflection of the views of the adolescents. Studies examining the influence of independent factors on adolescents' HRQL must take into account differences in reports from these 2 informants and the possibility that key independent variables have differing relationships with the various domains which comprise adolescents' HRQL.

Granulocyte colony-stimulating factor (G-CSF) dose-dependent efficacy in peripheral blood stem cell mobilization in patients who had failed initial mobilization with chemotherapy and G-CSF.

For 10 consecutive patients in our unit who did not show a significant rise in blood progenitor cells within 14 days following chemotherapy and G-CSF, we increased the G-CSF dose from 5 to 10 microg/kg/day (n = 9) or from 10 to 15 microg/kg/day (n = 1). As a result, there were significant increases in total yield as well as yield per apheresis of mononuclear cells, CD34+ cells and CFU-GM (P < 0.025, <0.01 and <0.005, respectively). After G-CSF dose escalation, six of the 10 patients had sufficient CD34+ cells for performing transplantation. These results demonstrate a dose-dependent response of progenitor cell mobilization by G-CSF when used in combination with chemotherapy. Moreover, increasing the dose of G-CSF as late as the third week of mobilization may still provide sufficient cell yield even with patients who did not show a significant mobilization with conventional doses of G-CSF.

Minimal residual disease in childhood acute lymphoblastic leukaemia quantified by aspirate and trephine: is the disease multifocal?

The level of minimal residual disease (MRD) in marrow early in treatment strongly predicts outcome in childhood acute lymphoblastic leukaemia (ALL). Using PCR we studied 30 pairs of aspirates and trephines taken during induction treatment. Consensus PCR primers showed a monoclonal gene rearrangement in eight pairs, polyclonal rearrangement in 18 pairs and a monoclonal rearrangement only in the trephine in four pairs. MRD was quantified by leukaemia-specific primers in 22 pairs. There was a linear relationship between the logarithms of MRD levels of aspirate and trephine, with a residual variance which increased as the level of MRD fell. The mean level of MRD in the trephines was 4.1-fold greater than that in the aspirates, probably due to greater dilution of the aspirates with peripheral blood. The high variance at low levels of MRD could not be explained by measurement variation, which had an MRD-independent value of 0.42 log10 units, and was attributed to sampling variation due to patchiness of disease at low MRD levels. The magnitude of the variation was such that predictions of outcome could well be confounded for many patients. We suggest that MRD sampling variability could be minimized either by taking multiple marrow samples or by measuring MRD in peripheral blood.

Influence of parental and family adjustment on the later psychological adjustment of children treated for cancer.

OBJECTIVE: To examine the relationship between parental adjustment and family adjustment during the period after the children's diagnosis of cancer and the psychological adjustment of children 2 years after their diagnosis. METHOD: The study used a prospective design. Children aged 2 to 5 years with cancer and their parents and families (n = 38) were assessed immediately after the children's diagnosis and again 2 years after the diagnosis. Path analysis was used to investigate the relationship between parental and family adjustment during the period after diagnosis and the psychological adjustment of the children 2 years after their diagnosis. RESULTS: Maternal adjustment during the period after the children's cancer was diagnosed had a significant relationship with the children's psychological adjustment 2 years after diagnosis. In contrast, the adjustment of fathers and family adjustment appeared to have a more limited impact on the later psychological adjustment of the children. CONCLUSION: The level of distress experienced by mothers after the children's diagnosis may have an important influence on the later psychological adjustment of the children. It is possible that this is due to the impact of maternal distress on the capacity of mothers to care for their children during the children's treatment for cancer.

Postoperative chemotherapy in children less than 4 years of age with malignant brain tumors: promising initial response to a VETOPEC-based regimen. A Study of the Australian and New Zealand Children's Cancer Study Group (ANZCCSG).

PURPOSE: Postoperative chemotherapy with indefinite postponement of radiation therapy in children < 4 years old with brain tumors was investigated in a multi-institutional study. PATIENTS AND METHODS: From 1991 to 1995, 42 patients aged 3 to 47 months (median 20) with brain tumors were enrolled in a 2-phase chemotherapy protocol: 16 patients had medulloblastoma (MB); 8 had supratentorial primitive neuroectodermal tumor (PNET); 14 had ependymoma; and 4 had other tumors. The initial phase was comprised of 4 courses of the 3-drug regimen: vincristine (VCR), etoposide (VP-16), and intensive cyclophosphamide (CPA) in a previously reported schedule (VETOPEC). The continuation phase was comprised of 2-drug courses: A, CPA + VCR; B, cisplatin + VP-16; and C, carboplatin + VP-16, for a total duration of 64 weeks. RESULTS: Response to VETOPEC was evaluable in 28 patients with postresection residual (25) and/or metastatic (1 M2, 6 M3) tumor. There were 9 complete responses (CR) and 9 partial responses (PR) with a combined CR + PR of 64% (95% confidence interval [CI] 44 to 81). In 12 evaluable patients with MB, CR + PR was 82% (48 to 98); in 6 patients with PNET, 50% (12 to 88); and, in 8 patients with ependymoma, 86% (42 to 99). Of 40 patients eligible for further analysis, 6 remain progression-free at a median of 30 months, 14 are alive at a median of 38 months, 29 have progressed at a median of 7 months (range, 2 to 37 months), and 26 have died. The progression-free and overall survival rates at 36 months are estimated to be 11% (95% CI 1 to 22) and 34% (18 to 50), respectively. CONCLUSIONS: The initial response to the VETOPEC regimen is encouraging and warrants study of further dose escalation. Survival remains poor with current strategies in this high-risk population.

Allogeneic CD34 selected peripheral stem cell transplant for Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI): rapid haemopoietic and biochemical reconstitution.

Severe Maroteaux-Lamy syndrome is usually fatal in teenage or early adult life. Until recently, allogeneic bone marrow transplantation was the only form of enzyme replacement. We report the first successful transplant using CD34 selected, mobilised allogeneic blood cells for an inborn error of metabolism. A busulphan, cyclophosphamide, melphalan and antithymocyte globulin conditioning regimen was used as myeloablative therapy. Allogeneic CD34 selected granulocyte colony-stimulating factor (G-CSF)-mobilised blood cells from a HLA-identical sibling were used for the transplant. Haemopoietic reconstitution occurred on day 10 post-transplant with normal N-acetylgalactosamine-4-sulphatase levels. Infectious and graft-versus-host disease (GVHD) complications were minimal. We suggest that CD34 selected, mobilised allogeneic blood cells are a safe form of enzyme replacement therapy in Maroteaux-Lamy syndrome and should be considered in other metabolic diseases where the benefits of haemopoietic transplantation are proven.

Improvement in outcome of children with Wilms' tumour in South Australia over the last 30 years.

OBJECTIVE: To evaluate the outcome of children with Wilms' tumour over the last 30 years in South Australia. To compare the outcome of children treated before and after 1982, when standard treatment protocols were introduced. METHODOLOGY: Management approaches, survival rates and side-effects of treatment were identified from case notes. Pathology slides were reviewed to ensure all children were correctly diagnosed with Wilms' tumour. RESULTS: Children treated for Wilms' tumour prior to 1982 had an overall survival rate of 54%. Since 1982 there has been a significant improvement in outcome and the current survival rate is now 85%. Children treated since 1982 have also experienced fewer treatment related side-effects than children treated prior to 1982. CONCLUSIONS: There has been substantial improvement in survival from childhood Wilms' tumour over the past 30 years in South Australia. This is likely to be due to a combination of factors including standardization of treatment, tailoring of treatment to stage and histology, improved perioperative care, enhanced radiological techniques and higher levels of collaboration between relevant specialists.

Monitoring minimal residual disease in peripheral blood in B-lineage acute lymphoblastic leukaemia.

The use of peripheral blood rather than marrow has potential advantages for monitoring minimal residual disease during the treatment of leukaemia. To determine the feasibility of using blood, we used a sensitive polymerase chain reaction method to quantify leukaemia in the blood and marrow in 35 paired samples from 15 children during induction treatment. Leukaemic cells in the blood ranged from 1.1 x 10(-2) to < 9.4 x 10(-7) leukaemic cells/total cells, corresponding to 1.3 x 10(7) to < 2 x 10(3) leukaemic cells/l. In 15 paired samples, leukaemia could be quantified in both tissues and in 20 paired samples, leukaemia was not detected in one or both tissues so that only upper level limits could be set. In the former 15 pairs, the level of leukaemia in peripheral blood was directly proportional to that in marrow but was a mean of 11.7-fold lower. Leukaemia in blood was detected in 10/12 pairs in which the level in marrow was > 10(-4), but in only two of 13 pairs in which the level in marrow was < 10(-5). Patients studied at multiple time-points showed parallel declines in the number of leukaemic cells in both tissues. The results showed that leukaemia could be monitored in peripheral blood during induction therapy, and quantitative considerations based on the results suggest that monitoring of blood during post-induction therapy may be of value in detecting molecular relapse.

Childhood cancer: a two-year prospective study of the psychological adjustment of children and parents.

OBJECTIVE: To follow prospectively the psychological adjustment of young children, parents, and families during the first 2 years after the children's diagnosis of cancer. METHOD: Children aged 2 to 5 years with cancer diagnoses and their parents and families (n = 38) were assessed immediately after diagnosis, 1 year after diagnosis, and 2 years after diagnosis. At each assessment, the psychological adjustment of the children and their families was compared with the adjustment of a cohort of children and families in the general community (n = 39). RESULTS: Children with cancer and their parents experienced significantly more emotional distress than children and parents in the community during the period immediately after diagnosis. However, the number of problems experienced by the children with cancer and their parents declined during the first year after the children's diagnosis and stabilized at a level comparable with that found among children and parents in the general community. CONCLUSION: Although the results are consistent with reports that suggest that in the longer term the prevalence of psychological problems among children with cancer is similar to that found among children in the general community, they also highlight the considerable distress experienced by children and parents during the period immediately after the children's diagnosis.

Effect of the Philadelphia chromosome on minimal residual disease in acute lymphoblastic leukemia.

The Philadelphia translocation is associated with a poor prognosis in adults and children with acute lymphoblastic leukemia, even though the majority of patients achieve remission. To test the hypothesis that the translocation leads to drug resistance in vivo, we studied 61 children and 20 adults with acute lymphoblastic leukemia and used the level of minimal residual disease at the end of induction as the measure of drug resistance in vivo. In children the presence of the translocation was associated with a significant increase in residual disease, indicating higher drug resistance in vivo; five of seven Philadelphia-positive children but only five of 54 Philadelphia-negative children had a minimal residual disease level >10(-3), a level which is associated with a high risk of relapse in childhood acute lymphoblastic leukemia of standard risk. By contrast, in adults, residual disease and hence drug resistance was already higher than in children, and the presence of the Philadelphia translocation in seven patients had no obvious additional effect. We conclude that the Philadelphia chromosome may increase resistance to drugs in vivo in children, but not detectably in adults.

Granulocyte-macrophage colony-stimulating factor in association with high-dose chemotherapy (VETOPEC) for childhood solid tumors: a report from the Australia and New Zealand Children's Cancer Study Group.

PURPOSE: Combination chemotherapy with vincristine, etoposide, and high-dose, escalating cyclophosphamide (VETOPEC) is an effective regimen in pediatric patients with high-risk solid tumors. The toxicity of the regimen is predominantly haematologic. This study addressed the role of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) following each cycle of chemotherapy in decreasing neutropaenia, incidence of fever/ hospitalization, and/or increasing chemotherapy dose-intensity. PATIENTS AND METHODS: Twenty-nine children with recurrent solid tumors were treated with the VETOPEC regimen. Sequential cohorts of patients received no GM-CSF (Group I), or GM-CSF in a dosage of 5 micrograms/kg/day (Group II) or 10 micrograms/kg/day (Group III) on days 4-18 of each chemotherapy cycle. Up to four cycles of chemotherapy were analysed with respect to haematopoietic recovery, clinical parameters, and dose intensity. RESULTS: Neutrophil recovery was significantly more rapid in patients treated with GM-CSF. Time to achieving an absolute neutrophil count (ANC) over 0.5 x 10(9)/L in Groups I, II, and III were 21, 18, and 16 days, respectively (P < 0.0001). Time to achieving an absolute neutrophil count (ANC) over 1.0 x 10(9)/L in Groups I, II, and III were 24, 19, and 17 days, respectively (P < 0.0001). There was no significant difference in the incidence of febrile neutropaenia between the three groups. Febrile neutropaenia occurred following 42, 68, and 62% of chemotherapy cycles in Groups I, II, and III, respectively (P = 0.27). Chemotherapy dose intensity was not different between the three groups. GM-CSF was associated with pericarditis and myalgias in one patient, and transient hypoxia/hypotension in another. CONCLUSION: GM-CSF led to significantly more rapid neutrophil recovery following VETOPEC chemotherapy, but did not lead to any demonstrable clinical benefit, either in reducing febrile events, or in increasing chemotherapy dose intensity.

A dose-intensive, cyclophosphamide-based regimen for the treatment of recurrent/progressive or advanced solid tumors of childhood: a report from the Australia and New Zealand Children's Cancer Study Group.

BACKGROUND: Children with solid tumors that progress or recur after conventional multimodality therapies have a very poor prognosis. In a pilot study, vincristine, etoposide, and dose-escalated cyclophosphamide (VETOPEC) was shown to be a promising salvage regimen. Continued accrual of patients and increased duration of follow-up has resulted in substantial experience with VETOPEC. METHODS: Between May 1991 and March 1994, 56 pediatric patients from 6 centers were enrolled in this study; 44 had recurrent or progressive tumors (Group A) and 12 had newly diagnosed, advanced tumors with a very poor prognosis (Group B). The VETOPEC regimen was comprised of vincristine, 0.05 mg/kg, on Days 1 and 14; etoposide, 2.5 mg/kg, on Days 1, 2, and 3; and fractionated, dose-escalated cyclophosphamide on Days 1, 2, and 3. The initial cyclophosphamide dose was 90 mg/kg (2.7 g/m2)/cycle with an escalation of 15 mg/kg/cycle in each subsequent cycle, to a maximum (over 6 cycles) of 165 mg/kg (5.0 g/m2)/cycle. Tumor response was evaluated every two to three cycles and included central review of imaging. RESULTS: The combined and partial response rates for Groups A and B were 66% (25 of 38 patients) and 91% (10 of 11 patients), respectively. In Group A, best evaluable responses and event free (EF) survivors were observed with: brain tumors (7 of 9 patients; 2 EF at 39 and 45 months [mos], respectively), Wilms' tumor (6 of 7 patients; 3 EF at 37-49 mos), and lymphoma (4 of 4 patients; 2 EF at 52 and 59 mos, respectively); in Group B best evaluable responses and EF were observed with: neuroblastoma (5 of 6 patients; 1 disease free at 57 mos) and rhabdomyosarcoma (4 of 4 patients; no survivors). Hematologic toxicity was limiting despite support with myeloid growth factors in 33 patients. Four deaths in Group A and one in Group B were directly associated with this toxicity. Specifically, no cases of drug-related myocardial toxicity or pneumonitis were observed. CONCLUSIONS: This chemotherapy regimen with its intense scheduling produced a high response rate and appreciable survival in patients with a variety of recurrent, progressive, or advanced solid tumors of childhood.

The use of monoclonal gene rearrangement for detection of minimal residual disease in acute lymphoblastic leukemia of childhood.

Sensitive quantification of minimal residual disease (MRD) using the polymerase chain reaction (PCR) is strongly predictive of outcome in childhood acute lymphoblastic leukemia (ALL), with MRD levels at the end of induction therapy of >10(-3) predicting a poor outcome. Methods for sensitive quantification are, however, complicated and time-consuming. Detection by PCR of monoclonal immunoglobulin heavy chain (IgH) and T cell receptor (TCR) gene rearrangements is simple and can be used in routine laboratories but is non-quantitative and of lower but uncertain sensitivity. The aim of this study was to determine the value of detection of monoclonality in identification of different levels of MRD. We looked for monoclonality in 64 bone marrow aspirates which had been obtained from 31 patients with B lineage ALL at various times during induction therapy and for which levels of MRD had been determined by limiting dilution analysis using patient-specific PCR primers. Detection of monoclonality identified levels of MRD of > or =10(-3) during induction with a sensitivity of 78% and a specificity of 93%. The positive and negative predictive values were 0.86 and 0.88, respectively. The sensitivity of detection of a monoclonal IgH rearrangement was greater than that for the TCRgamma locus during induction as an IgH rearrangement was detected more often than a TCRgamma rearrangement in patients who had both IgH and TCRgamma rearrangement at diagnosis. Detection of monoclonality is therefore a simple and quick test applicable to the majority of patients with ALL and it may be useful in identifying high-risk patients at the end of induction and in identifying relapsing patients later during therapy.