Bone involvement in childhood acute lymphoblastic leukaemia

Three cases of major vessel injuries referred to Mendi Hospital during 1993-1994 are reported. All three vessels were repaired successfully. The surgical management of these cases is described.     

Morphology and cytochemistry of acute lymphoblastic leukaemia

A total of 88 consecutive new women patients were surveyed on an adult psychiatric inpatient unit which did not have a specific program for the treatment of alcoholics. Those with a self-reported history of physical and/or sexual abuse had significantly higher scores on the Michigan Alcoholism Screening Test (MAST) than those with no such history. Former drinkers and teetotalers were more likely to have been both physically and sexually abused than the others. Thirty-three patients (38%) reported a history of alcohol problems measured by scores of seven or more on the MAST, but only 20 had a diagnosis of alcohol abuse or alcohol dependence made by a psychiatrist.     

Stomatococcus mucilaginosus septicemia in a patient with acute lymphoblastic leukaemia

A 16-year-old patient with acute lymphoblastic leukaemia which had relapsed for the third time developed clinical signs and symptoms of septicemia during a period of neutropenia. The patient had signs of oral mucositis, and Stomatococcus mucilaginosus was isolated from blood cultures. The patient responded well to antibiotic therapy. The biochemical characteristics and antimicrobial susceptibility patterns of 68 other pharyngeal isolates of Stomatococcus mucilaginosus from immunocompromised patients are presented.     

Measles inclusion-body encephalitis in a child with treated acute lymphoblastic leukaemia

A child with acute lymphoblastic leukaemia, being treated in the UKALL II Trial, had while in remission an attack of measles and made a normal recovery. Four months later she developed an acute encephalopathy and died within two weeks. The brain showed mild inflammatory features and widespread inclusion bodies in neurones and glial cells. Immunofluorescence proved an infection with measles virus. Similar cases have been called SSPE; reasons are given for preferring the term "measles inclusion-body encephalitis".     

Treatment of childhood acute lymphoblastic leukaemia with the BFM regimen

This study was undertaken to further characterize the secretory response of the rat pancreas after reserpine treatment. Rats were given reserpine (1 mg kg-1 day-1 i.p.) or vehicle for 7 days. To distinguish between specific effects of reserpine and those related to secondary malnutrition caused by the drug, the secretory response of a group of pair-fed (PF) animals to reserpine was also investigated. Amylase release from dispersed pancreatic acini, prepared from control (C), PF and reserpine-treated (R) rats were used to evaluate functional secretory capacity. Reserpine and pair-feeding caused reduced responses of pancreatic acini to secretin. The pair-feeding-altered secretin response was greatly improved by increasing extracellular Ca2+ concentration, whereas a slight improvement was noticed in the R group. Reserpine significantly reduced the secretory response to the ionophore A23187 at concentrations above 5 x 10(-7) M in 1.25 mM Ca2+; in 2.5 mM Ca2+, the response to the ionophore was significantly higher in the R group than in C at all ionophore concentrations. Furthermore, at 2 x 10(-7) M ionophore, the secretory response to secretin in the R group became significantly higher than that in the C group but comparable to that of the control+ionophore. In conclusion, reserpine affects the secretory response to secretin as did pre-exposure of pancreatic acini to a high concentration of carbamylcholine. The modified secretory response to the ionophore following reserpine treatment indicates that reserpine may act as a 'Ca2+ entry mechanism' antagonist which may explain the partial reduction in the secretin response.     

Urticaria-pigmentosa-like lesions in acute lymphoblastic leukaemia (2 cases)

A patient with an obstructed femoral hernia and intercurrent respiratory failure was successfully anaesthetised with a continuous spinal technique. The technique provided excellent intra-operative anaesthesia and early postoperative analgesia, whilst avoiding further respiratory compromise. Disconnection of the catheter hub from the catheter prevented prolonged provision of postoperative analgesia by this route. Fixing of both the catheter and the hub to the patient are advocated to avoid this problem.     

Long-term sequelae of therapy for childhood acute lymphoblastic leukaemia

Childhood ALL has provided the model for basic therapeutic principles in the past and now provides the model for late effects studies. Common threads which run throughout the literature in this area of clinical research are the importance of young age with increased vulnerability to long-term treatment induced sequelae and the relatively large contribution of radiation as compared with chemotherapy in the pathogenesis of adverse sequelae. Previous retrospective studies of long-term childhood ALL survivors focused on neuropsychologic changes and anatomic changes in the CNS after cranial irradiation. More recent retrospective studies have made the following new observations: (i) the high frequency of significant short adult stature in those less than 6 years of age at diagnosis who received 24 Gy cranial irradiation; (ii) actuarial risk of 2.5% of developing a second malignancy with approximately one-half of secondary malignancies occurring in the CNS in children 5 years of age or less who received cranial irradiation; (iii) the association of secondary ANLL with epipodophyllo-toxin use, and (iv) delayed cardiac toxicity despite anthracycline dosage reduction. Current therapy regimens, especially in high-risk patients, are both more successful and more intensive than those used in the past. While it will be another decade before many of the long-term sequelae begin to emerge, one can anticipate, based on current experience, some of the problems that will occur.     

Quantitative flow cytometry can predict childhood acute lymphoblastic leukaemia presenting with aplasia

Acute lymphoblastic leukaemia (ALL) presenting as a transient pancytopenia is known to occur in children and less commonly in adults. The period of pancytopenia usually resolves after about 5-38 weeks, to be followed by overt ALL. The pathogenesis is not known and there are no specific cytogenetic abnormalities. Diagnosis is often difficult during the period of bone marrow hypoplasia. Quantitative flow cytometry can help to establish early diagnosis, and can be used on more patients presenting in a similar way.     

Transformation of essential thrombocythaemia to T cell acute lymphoblastic leukaemia

Leukaemic transformation of essential thrombocythaemia is a rare event and is usually associated with previous treatment with either alkylating agents or radioactive phosphorous. We describe a patient with essential thrombocythaemia who developed an acute leukaemia of T cell phenotype following hydroxyurea therapy. The T cell phenotype of the blasts suggests the target cell for leukaemic transformation was a pluripotential stem cell.     

Expression of cell adhesion molecules and common acute lymphoblastic leukaemia antigen in hepatoblastoma

Hepatoblastoma is an embryonal tumour of the liver, which often contains tissue components with multidirectional differentiation. The occurrence of cell surface antigens in this tumour has not been studied systematically, and we therefore investigated 20 hepatoblastomas for the expression of common acute lymphoblastic leukaemia antigen (CALLA) and cell adhesion molecules (CAMs) in their different tissue components. Epithelial tumour cells of fetal differentiation contained E-cadherin. This protein did not occur in tumour areas with embryonal or mesenchymal differentiation. In contrast, immature embryonal and anaplastic cells expressed CALLA and the hyaluronate receptor (HCAM, CD44). Both fetal and embryonal areas stained irregularly positive for ICAM-1, which, in contrast, was not present on anaplastic cells. Immature fibrous tissue did not contain any of these molecules except for ICAM-1. However, some cells adjacent to, or enclosed in, osteoid were positive for HCAM and NCAM. Like small undifferentiated hepatoblastoma cells, primitive mesenchymal spindle-shaped cells also expressed CALLA, HCAM, and the polysialylated embryonic form of NCAM strongly. This last is not present on other epithelial or mesenchymal tumour cells. Hepatoblastoma cells of varying differentiation express distinct patterns of CAMs and CALLA. Our results give further insight into their histogenesis and cellular interactions and may explain their variable ability for invasive growth and formation of metastases.     

Detection of clonal immunoglobulin gene rearrangements in the PBPC harvests of patients with acute lymphoblastic leukaemia

We have used a fluorescently based PCR technique to detect rearrangements in the immunoglobulin heavy chain (IgH) gene in the presentation BM of five patients with adult ALL and have looked for similar rearrangements in their PBPC. Using this approach we have been able to demonstrate clonal rearrangements in the PBPC of two of five patients. Remission BM samples taken 6-12 weeks prior to leucapheresis failed to show a clonal rearrangement in either patient. The significance of these results is discussed.     

Simplified strategies for minimal residual disease detection in B-cell precursor acute lymphoblastic leukaemia

We have developed a simplified fluorescent run-off (FluRO) based IgH PCR strategy in order to facilitate follow-up of large numbers of B-cell precursor (BCP) acute lymphoblastic leukaemias (ALL) in a routine molecular diagnostic laboratory. DNA samples from 26 BCP-ALL and one B-cell line were amplified using IgH FR1 and FR2 consensus primers and analysed in parallel either by ethidium bromide non-denaturing PAGE or, after rendering the PCR products fluorescent with an internal JH consensus primer, by high-resolution analysis on an automated fragment analyser. The latter led to a minimum of one log increase in sensitivity of detection in 62% of alleles from 19 samples (16/28 in FR1; 11/15 in FR2) tested in parallel on log DNA dilutions, and to at least a 10(-2) level of sensitivity of detection in 15/19. The improved resolution allowed an approximate 20% increase in the number of clonal alleles detected, and consequently doubled the incidence of oligoclonality (6/26; 23%). Using these strategies, 6/17 (35%) of children analysed prospectively showed residual IgH positivity in the post induction complete remission bone marrow sample. Both early deaths occurred within this subgroup of patients and of the three of four surviving patients tested, two remained positive 2-3 months later. Although this simplified strategy is, as expected, less sensitive than anti-V-D-J junction specific strategies, it enables detection of a category of 'slow-remitters' which may have prognostic significance at a stage where therapeutic decisions are taken.     

Immunophenotypic and clinical features of T-cell receptor gammadelta+ T-lineage acute lymphoblastic leukaemia

The immunophenotypic and clinical features of TCR-gammadelta+ T-lineage acute lymphoblastic leukaemia (T-ALL) were prospectively analysed in 52 children with membrane CD3+ T-ALL. We observed a relatively high incidence of TCR-gammadelta+ T-ALL (26/52 patients). Leukaemic blasts from 22 children demonstrated TCR-alphabeta positivity, and simultaneous expression of the TCR-beta and -delta chain was found in four children. Clinical and haematological features of TCR-alphabeta and gammadelta+ T-ALL did not differ significantly, except that haemoglobin levels were significantly lower in TCR-gammadelta+ cases. Event-free survival at 4 years was significantly better in TCR-gammadelta+ compared with TCR-alphabeta+ T-ALL, but expression of TCR molecules did not emerge as an independent prognostic factor in multivariate analysis.     

Prolonged but reversible neutrophil dysfunctions differentially sensitive to granulocyte colony-stimulating factor in children with acute lymphoblastic leukaemia

Treatment of average-risk acute lymphoblastic leukaemia (ALL) in children consists of 6 months of intensive chemotherapy followed by 18 months of maintenance therapy. Polymorphonuclear leucocyte (PMN) functions from children with ALL were studied in order to evaluate and compare the toxicity of the initial intensive treatment with the toxicity of the subsequent less intensive maintenance treatment. H2O2 and O2- production, evaluated by chemiluminescence, were significantly decreased during the intensive period but returned to normal values when maintenance therapy began. In contrast, bactericidal activity against Gram-positive and Gram-negative microorganisms remained at low levels throughout the treatment but returned to normal values in patients off chemotherapy. PMN from patients on maintenance therapy exhibited an excess of morphological changes associated with apoptosis. This was confirmed by standard two-colour flow cytometry which revealed an increase in the number of hypodiploid cells, and increased expression of membrane phosphatidylserine together with a drastic reduction in the expression of the Fcgamma receptor IIIB (CD16). These defective PMN were differentially sensitive to the effects of granulocyte colony stimulating factor (G-CSF): G-CSF induced similar increase in chemiluminescence in control and patient PMN; GSF partially corrected the defective bactericidal activity; G-CSF did not affect the accelerated PMN apoptosis. These observations indicate that ALL children undergoing chemotherapy present PMN defective functions which are partially sensitive or even resistant to G-CSF.     

ALL R-87 protocol in the treatment of children with acute lymphoblastic leukaemia in early bone marrow relapse

Seventy-three children with acute lymphoblastic leukaemia (ALL) in first bone marrow (BM) relapse, occurring within 30 months from complete remission (CR), were enrolled in an Italian cooperative study (ALL R-87 protocol). This treatment programme consisted of an induction phase with intermediate-dose cytarabine (IDARA-C) plus idarubicin (IDA) and prednisone (PDN), followed by a multidrug consolidation therapy and bone marrow transplant (BMT). 55/73 children achieved CR (75.3%); 15 (20.5%) failed to respond and three (4.2%) died during induction. The response rate was significantly higher for children with a first CR duration > or = 12 months (P=0.0005) and for those with a white blood cell (WBC) count at relapse < 20 x 10(9)/l (P=0.004). The estimated disease-free survival (DFS +/- SE) at 82 months was 0.18 +/- 0.05 for all responders, and 0.70 +/- 0.14 for allotransplanted patients versus 0.05 +/- 0.05 for those autografted (P=0.001). The estimated probabilities of survival +/- SE and event-free survival (EFS +/- SE) at 83 months were 0.16 +/- 0.07 and 0.13 +/- 0.04, respectively. for all enrolled children. Univariate analysis showed that age < 10 years at initial diagnosis and B-lineage immunophenotype favourably influenced both DFS (P=0.001) and EFS probabilities (P=0.0014 and P=0.012, respectively), whereas a first CR duration > or = 12 months and a WBC count at relapse < 20 x 10(9)/l were associated only with a better EFS rate (P=0.026 and P=0.004, respectively). Our results show the efficacy of the IDA plus IDARA-C schedule used in the ALL R-87 protocol in high-risk relapsed ALL children. Allogeneic BMT proved effective for patients with an HLA sibling donor. In a multivariate analysis, age > or = 10 years at initial diagnosis (P=0.016) and WBC count at relapse > or = 20 x 10(9)/l (P=0.048) were independently associated with a worse disease outcome.     

Clonal stability in late-relapsing childhood lymphoblastic leukaemia

We report stability of a clonal immunoglobulin heavy chain (IgH) gene rearrangement in a case of childhood acute lymphoblastic leukaemia (ALL) relapsing 17 years after completion of first-line therapy. Clonal stability was shown by polymerase chain reaction amplification of the hypervariable CDRIII region of IgH gene. Identically sized products from the original diagnostic and the second presentation samples were obtained and direct sequencing confirmed complete sequence homology. Absence of clonal evolution together with recent reports of persistent minimal residual disease in patients in long-term complete remission, suggests that 'cure' of childhood ALL may be critically dependent on effective immune surveillance to keep such disease below clinically significant levels.     

The clinical indications for identical pathogenesis of isolated and non-isolated testicular relapses in acute lymphoblastic leukaemia

In the present population-based study, we compared the clinical data of testicular relapses with and without concurrent bone marrow relapse and clinical data of the relapses in other locations among boys with acute lymphoblastic leukaemia (ALL), in order to study the possible evidence of early sequestration and local regulation of leukaemic lymphoblast in the testis of humans. The results suggest that the pathogenesis of isolated testicular relapse (T) and testicular relapse with a concurrent bone marrow relapse (T + BM) is likely to be similar. Isolated and non-isolated testicular relapses appeared late after the achievement of remission (T 34 +/- 16 months, T + BM 32 +/- 15 months) in ALL compared to relapses in other locations (CNS 23 +/- 11 months, BM 25 +/- 19 months). The better prognosis after testicular relapses (estimated second event free survival probability, 2-EFS: T 0.63, T + BM 0.32) compared to bone marrow relapse (2-EFS: BM 0.13) further suggests that testicular relapse with a concurrent bone marrow relapse possibly originates from the isolated testicular relapse, and that the isolated testicular relapse is a separate entity and not a manifestation of systemic recurrence. Higher frequencies of isolated and non-isolated testicular relapses (T 9%, T + BM 5%) were observed among boys with onset of ALL in early puberty (10-12 y) compared to those among younger (T 4%, T + BM 2%) and older (T 0%, T + BM 0%) boys. The late occurrence, the possible association with hormonal maturation and the good prognosis after testicular relapses suggest a possible local regulation of the residual leukaemic lymphoblast in human testis.