Haemophagocytic lymphohistiocytosis in children.

OBJECTIVE: To evaluate the clinical and diagnostic features of children presenting with haemophagocytic lymphohistiocytosis (HLH), evolution of the disease and outcomes in response to treatment. METHODOLOGY: The medical records of 12 children, aged 5 weeks to 13 years at diagnosis, with HLH managed at a single institution were reviewed. RESULTS: Presenting features were fever, hepatosplenomegaly, pancytopenia and hypertriglyceridemia or hypofibrinogenemia. Nine patients (75%) developed central nervous system (CNS) disease. Only one child with CNS disease survived. Five children had complete responses to therapy (42%), but all relapsed at a median of 1.5 months after starting treatment (range 2 weeks to 5 months). Two of the children treated are long-term survivors (17%), both after allogeneic bone marrow transplantation. All deaths occurred in the context of active disease. CONCLUSIONS: Haemophagocytic lymphohistiocytosis is a disease with a poor prognosis. Central nervous system complications are common and response to treatment usually is transient. This study provides support for the use of immunomodulatory therapy for remission introduction followed by consideration of allogeneic bone marrow transplantation.

Molecular detection of acute lymphoblastic leukaemia in boys with testicular relapse.

AIMS: To determine the role of polymerase chain reaction (PCR) based minimal residual disease (MRD) detection of leukaemia specific DNA in testicular relapse in childhood acute lymphoblastic leukaemia. METHODS: DNA was obtained from archival testicular and bone marrow samples from boys with acute lymphoblastic leukaemia who relapsed in the testes. Overlapping DJH clone specific primers derived from clonal immunoglobulin heavy chain (IgH) gene rearrangement in each case were used to analyse testicular or bone marrow DNA. RESULTS: Histologically normal end of treatment testicular biopsies in the five patients in longterm remission were all MRD negative, but MRD positive in three of six boys with subsequent testicular relapse. Histologically normal bone marrow samples taken at the end of treatment were MRD negative in five of seven cases, but MRD positive in all cases at the time of isolated testicular relapse. Three boys with unilateral testicular relapse underwent unilateral orchidectomy, rather than bilateral testicular irradiation, as part of their treatment. Two of these boys were MRD positive in the histologically uninvolved testes, and both had subsequent relapses either in the testes or the bone marrow, while the MRD negative patient has not had a testicular relapse. CONCLUSIONS: The presence of MRD in testicular tissue can be assayed with a PCR based method to detect clone specific antigen receptor gene rearrangements. In this setting, PCR is more sensitive than conventional testicular histology for predicting clinical outcomes. MRD assays might be useful in the management of boys at the time of isolated testicular relapse, to confirm the presence of unilateral testicular disease.

The experience of a single Australian paediatric oncology unit. 1000 patients 1964-1987.

OBJECTIVE: To determine the survival for children with malignant disease diagnosed in the period 1964-1987 and treated in a single paediatric oncology unit. DESIGN: Records of patients treated by the Department of Haematology and Oncology at the Prince of Wales Children's Hospital were reviewed to determine the survival of children with cancer according to decade of diagnosis and diagnostic group. PATIENTS: Patients were eligible for the study if referred for treatment at or soon after diagnosis of malignancy. One thousand patients were treated during the study period. There were 363 with acute lymphoblastic leukaemia (ALL), 126 with tumours of the central nervous system (CNS), 86 with acute non-lymphoblastic leukaemia (ANLL), 81 with lymphoma, 79 with neural crest tumours, 69 with renal tumours, 66 with bone sarcomas, 53 with soft tissue sarcomas, and 77 with various other diagnoses. Age range was one day to 20.75 years. INTERVENTIONS: Treatment included surgery, radiotherapy and chemotherapy in a variety of protocols. RESULTS: Ten-year survival for the 1960s, 1970s and 1980s was 15%, 51% and 64% respectively (P < 0.001), excluding tumours of the CNS. From 1985 onwards, actual survival at five years has been 79%. Survival from Wilms' tumour and Hodgkin's disease remained high throughout the study period, and significant improvement in survival occurred with ALL, non-Hodgkin's lymphoma (NHL) and osteogenic sarcoma. Survival remained poor with neuroblastoma and ANLL. CONCLUSIONS: Significant improvement in outcomes for childhood malignancy has been achieved over the last three decades, with five-year survival currently at 79% (excluding tumours of the CNS). Some diagnostic groups have had only small improvements in outcome and require new strategies.

Ewing's sarcoma: long-term follow-up in 49 patients treated from 1967 to 1989.

PURPOSE: Review of long-term results of therapy for Ewing's sarcoma in terms of survival, local tumor control, distant failure and complications rates. METHODS AND MATERIALS: Retrospective review of the records of patients with Ewing's sarcoma of bone and soft tissues treated at The Prince of Wales Children's and Prince of Wales Hospitals, Sydney, between 1967 and 1989 and followed-up to July 1991. RESULTS: There were 49 patients with median age 16 years (range 3-33 years) and average potential follow-up time 12.3 years (range 2-24 years). Forty patients presented with localized disease (three with regional lymph node involvement) and nine with distant metastases. Local therapy for the primary was by amputation in three patients, by resection and postoperative radiotherapy in five, and by definitive radiotherapy in 41 (median dose 50 Gy). Forty-four patients received adjuvant multi-agent chemotherapy. The overall actuarial survival rate was 33% (SE = 7%) at 5 years and 30% (SE = 7%) at 10, 15, and 20 years. The factors predictive of shorter survival were distant metastases at diagnosis (p = 0.036) and older age (p = 0.025). The actuarial local control rate for all 49 patients was 75% (SE = 8%) at 5, 10, 15, and 20 years. The only factor predictive of local failure was an inadequate target volume irradiated (p = 0.003). In 40 patients who presented with localized disease only, the actuarial rate of freedom from distant failure at 5 years was 44% (SE = 8%) and at 10, 15, and 20 years was 40% (SE = 8%). Seven patients experienced severe or fatal complications (defined as requiring investigation and treatment in hospital), namely stress fracture in two, fatal osteogenic sarcoma in one, fatal cardiotoxicity in one and severe hemorrhagic cystitis in three. The rate for severe or fatal complications at 5 years was 19% (SE = 8%), at 10 years was 29% (SE = 12%) and at 15 and 20 years was 53% (SE = 21%). CONCLUSION: Survival to 5 years appears to confer probable cure and one third of our patients have achieved this. Long-term follow-up also reveals that an increasing number of patients experience treatment-related complications, the majority of which, however, can be corrected.

Local failure in childhood rhabdomyosarcoma and undifferentiated sarcoma: prognostic factors and implications for curative therapy.

In this retrospective review, the risk factors for local failure in childhood rhabdomyosarcoma and undifferentiated sarcoma were assessed in 49 patients managed by a multi-disciplinary team at the Prince of Wales Children's Hospital, Sydney, between 1970 and 1988. Average follow-up time was 6.1 years. Sixteen of 49 patients experienced local failure defined as local recurrence after complete excision (5/20) or progressive local disease following incomplete resection (11/29). Fourteen of 16 patients who experienced local failure have died. Using logrank analysis of time to local failure, we found significantly increased risk with "non-embryonal" histology (P = 0.032), residual tumour (P = 0.052, higher IRS group (P = 0.088), "inadequate radiotherapy" for residual tumour (P = 0.001), delay in definitive local treatment (P = 0.038) and Adriamycin-containing chemotherapy (P = 0.017). When these factors were examined by multivariate analysis (Cox regression), only the presence of residual tumour after resection, "inadequate radiotherapy" for residual tumour (P < 0.001), and delay in definitive local therapy (P < 0.037) were shown to have independent significant association with local failure. We conclude that local failure may be avoided by prompt local treatment by either complete surgical resection or adequate radiotherapy.

Antiemetic therapy for chemotherapy-induced vomiting: metoclopramide, benztropine, dexamethasone, and lorazepam regimen compared with chlorpromazine alone.

Twenty-six children aged 4 to 15 years who were to receive cancer chemotherapy were enrolled in a double-blind, randomized, crossover trial that compared the antiemetic efficacy of a four-drug regimen (the MBDL regimen: metoclopramide, 8 mg/kg; benztropine, 0.04 mg/kg; dexamethasone, 0.7 mg/kg; lorazepam, 0.1 mg/kg), given over 24 hours, with the efficacy of chlorpromazine, 3.3 mg/kg, given in four doses over 24 hours. The MBDL regimen was more effective than chlorpromazine in both objective and subjective measures of antiemetic control. Of 26 children, 23 (89%) had less vomiting on the MBDL regimen, and 20 (77%) of 26 patients or parents preferred this regimen (p less than 0.01). The MBDL regimen reduced the number of vomiting episodes by a mean of 4.0 (p less than 0.01) and reduced the duration of vomiting by a mean of 3.7 hours (p less than 0.01). A moderate level of sedation was documented at some stage in the 24-hour period of observation in 27% on the MBDL regimen and in 35% receiving chlorpromazine. Dystonia was seen in 1 (4%) of 26 children. We conclude that the MBDL regimen is safe in children and more effective than chlorpromazine.

Bone-marrow transplantation for haematological malignancy in childhood.

Twenty-three children with haematological malignancies and a poor prognosis underwent bone-marrow transplantation. Thirteen children had acute lymphoblastic leukaemia, eight had acute nonlymphoblastic leukaemia, one had chronic myeloid leukaemia and one had malignant histiocytosis. One child was in relapse at the time of transplant and 22 were in first or subsequent remission. Before transplantation all patients received cyclophosphamide (60 mg/kg) on two consecutive days followed by total body irradiation given as a single dose of 10 Gy at 0.18 Gy/min (one patient) or 0.07 Gy/min (three patients), or as a fractionated dose of 10-12 Gy at 0.07-0.1 Gy/min (19 patients). One child with malignant histiocytosis also received two doses of etoposide (5 mg/kg). Methotrexate was given after transplantation to prevent or modify graft-versus-host disease (GVHD). One patient who received a transplant in relapse died early from overwhelming bacterial sepsis. Twenty-two patients engrafted, and of these 11 developed acute GVHD; five developed chronic GVHD; seven developed interstitial pneumonitis, with four deaths; and five relapsed between three and 12 months after transplantation, with three deaths. Fifty-nine per cent (13/22) of patients who received a transplant during remission remain in continuous complete remission and 68% (15/22) have survived for a median of 18 months (range, four to 73 months). Bone-marrow transplantation that is undertaken during remission of disease offers a prolonged disease-free survival in selected childhood malignancies.

Determination of serum methotrexate and 7-hydroxymethotrexate concentrations. Method evaluation showing advantages of high-performance liquid chromatography.

The use of large doses of methotrexate (MTX), greater than 3 g/m2, for the treatment of some malignant disorders requires careful monitoring of serum concentrations. A simple and sensitive method for the separation of MTX and 7-hydroxymethotrexate (7-OH-MTX) by reversed-phase high-performance liquid chromatography (HPLC) is described. The method involves deproteinizing the serum sample on a Sep-Pak C18 cartridge, followed by separation on a C18 column and detection at 313 nm. The extraction efficiency of free MTX from serum is 70% and the maximum sensitivity is 2.2 X 10(-8) M. A high degree of correlation was obtained between the HPLC method of serum MTX determination and an enzyme multiplied immunoassay technique. The HPLC method separates MTX from its analogues, or drugs which may be administered concomitantly with MTX. Concentrations of MTX and 7-OH-MTX achieved over a 24-h period during high-dose therapy, (500-1000 mg/m2), and over 48 h for very-high-dose methotrexate therapy (8-12 g/m2) are described. A significant observation is the presence of 7-OH-MTX in sera of patients 6 h after commencement of infusion. This method was also utilized for monitoring cerebrospinal fluid MTX concentrations.

Acute leukemia characterized by trisomy 8 in Down's syndrome.

Of the myeloproliferative disorders which develop in Down's syndrome, acute leukemia associated with trisomy 8 has distinct characteristics. It is non-lymphoblastic in type and has a preleukemia phase in which thrombocytopenia is a prominent feature. One case occurring in a 20 mth-old girl is reported and 3 other similar cases reviewed. Acquired trisomy 8 in Down's syndrome is linked to leukemogenesis and confers non-lymphoblastic differentiation.

Methotrexate megadosage followed by folate rescue. I. A study in clearance patterns.

Plasma clearance rates of methotrexate (MTX) have been determined in five patients given an infusion of 3,000 mg of MTX over six hours, followed by folate rescue 24 hours after the commencement of infusion. Results presented indicate that maintenance of high MTX concentrations and potential toxicity could not be related to age, body weight or surface area.