We previously reported that children in the UKALL XI ALL trial with HLA-DP 1 and -DP 3 supertypes had significantly worse event-free survival (EFS) than children with other DP supertypes. As DP 1 and DP 3 share two of four key antigen-binding amino-acid polymorphisms (aspartic acid84–lysine69), we asked whether Asp84-Lys69 or Asp84 alone were independent prognostic indicators in childhood acute lymphoblastic leukemia (ALL). We analysed EFS in 798 UKALL XI patients, stratified by Asp84-Lys69 vs non-Asp84-Lys69, for a median follow-up of 12.5 years. Asp84-Lys69 was associated with a significantly worse EFS than non-Asp84-Lys69 (5-year EFS: Asp84-Lys69: 58.8% (95% CI (confidence of interval): 52.7–64.9%); non-Asp84-Lys69: 67.3% (63.4–71.2%); 2P=0.007). Post-relapse EFS was 10% less in Asp84-Lys69 than non-Asp84-Lys69 patients. EFS was significantly worse (P=0.03) and post-relapse EFS marginally worse (P=0.06) in patients with Asp84 compared with Gly84. These results suggest that Asp84-Lys69 predicted adverse EFS in the context of UKALL XI because of Asp84, and may have influenced post-relapse EFS. We speculate that this may be due to the recruitment of Asp84-Lys69-restricted regulatory T cells in the context of this regimen, leading to the re-emergence of residual disease. However, functional and molecular studies of the prognostic value of this and other HLA molecular signatures in other childhood ALL trials are needed.
childhood ALL; HLA-DP supertype; DP molecular signature; event-free survival; relapse
Hermansky–Pudlak syndrome (HPS) is a rare disorder characterised by oculocutaneous albinism, a bleeding tendency, and lipofuscinosis. This retrospective study reviews the clinical history and haematological features of 23 cases of HPS. Information was gathered from patient notes and by direct interview. Thirteen of the 23 children were of Turkish origin, 12 being members of four kindreds from the Turkish/Kurdish border. Four children originated from Pakistan. Haemorrhage was uncommon; two experienced significant bleeding (intracranial and retinal haemorrhage in one and menorrhagia in another), and twelve minor symptoms. Results of laboratory evaluation of platelet function were not predictive of bleeding; in particular the PFA-100 analyser was not sensitive to the HPS defect. The most sensitive test of platelet fuction was quantitation of platelet nucleotides. The occurrence of Turkish and Pakistani kindreds with HPS is novel and follow up for long term complications described in Puerto Rican patients as well as genetic analysis is ongoing.
AIMS—To examine the clinical and
biological features of acute lymphoblastic leukaemia in children with
Down's syndrome (DS), to compare their survival with other children,
and to determine if entry to trials and survival has improved.
METHODS—Examination of presenting
features and response to treatment in patients treated in two
consecutive national trials, MRC UKALL X and XI.
RESULTS—The proportion of children
with DS was significantly higher in UKALL XI (1.9%) than UKALL X
(0.9%). Children with DS tended to be under 10 years and to have the
common ALL subtype. Cytogenetic analysis showed that favourable
features, such as high hyperdiploidy and t(12;21) were less frequent
but also that there was a lack of translocations associated with a poor
prognosis. Children with DS showed no increase in risk of relapse at
any site but their survival and event free survival were inferior to
other children. These results were caused by an increased number of
infective deaths during remission (11% compared to 2%). At five years
overall survival was 73% in DS children compared with 82% in other
children; event free survival was 53% compared to 63% in non-DS children.
CONCLUSIONS—Entry of children with
DS to national trials has increased and survival has improved. However
they remain at risk of relapse and also of treatment related mortality.
These findings emphasise the need for both intensive chemotherapy and
optimal supportive care.
Glomerular filtration rates (GFR) were estimated in 168 children (227 estimates) before treatment for haematological
malignancies with high dose, intravenous methotrexate. Clinical
management was altered on the basis of GFR in only two cases, both of
whom had tumour lysis syndrome. Routine estimations of GFR do not
contribute to management.
the clinical features, treatment, and outcome of children in the UK
with Down's syndrome and acute myeloid leukaemia (AML).
study of 59 children with Down's syndrome and AML presenting between
1987 and 1995. Data were obtained from hospital case notes, trial
records, and by questionnaire.
were unusually young (median age, 23 months) with a predominance of
megakaryoblastic AML. Two of the seven infants who presented with
abnormal myelopoesis aged 2 months or younger achieved complete
spontaneous remission. Most of the older children with AML (32 of 52)
were treated on recognised intensive protocols but 13 received
individualised treatment and seven symptomatic treatment alone. Only
four received a bone marrow transplant (BMT) in first remission. For
the 45 older children who received chemotherapy the overall survival
was 55% (median follow up 4.5 years). Patients on individualised
protocols had a similar overall survival and toxic death rate but
marginally higher relapse rate than those on standard (intensive)
protocols. Children with Down's syndrome treated on the national AML
10 trial had a similar overall survival (70%
v 59%) at five years to children of
comparable age without Down's syndrome: their improved relapse risk
(12% v 38%) offset the slight increase in
deaths as a result of treatment toxicity (19%
with Down's syndrome and abnormal myelopoesis may achieve spontaneous
remission, and older children with Down's syndrome and AML can be
treated successfully with intensive chemotherapy, without BMT.
This study compared the prognosis of patients treated for
aplastic anaemia at Great Ormond Street Hospital for Children from 1973-88 (group A; n = 38) with a more recent cohort from 1989-96 (group B; n = 37). The two groups were similar in terms of clinical history, age, and severity of aplasia. The main treatment differences included the use of androgen treatment in group A (21 of 38 patients) but not in group B, and the addition of cyclosporin A to
immunosuppressive treatment for 14 patients in group B. Actuarial
survival at eight years' follow up was significantly better for group
B (84%; 95% CI, 68% to 93%) than for group A (45%; 95% CI, 30%
to 60%), because of improved outcome for both immunosuppressive
treatment (86% v 39%) and bone marrow
transplantation (93% v 56%). There was no
evidence for late clonal disorders or secondary malignancies in
survivors in either group. The prognosis for aplastic anaemia has
improved greatly in recent years so that over 80% of children are long
OBJECTIVE—To investigate the prevalence of
currently recognised inherited prothrombotic states in a population of
children with arterial stroke.
METHODS—Children with arterial stroke presenting
to a tertiary level paediatric neurology centre between 1990 and 1996 were investigated for inherited prothrombotic states.
RESULTS—Sixty seven children with arterial stroke
were investigated. Abnormalities were initially identified in 16 patients; however, only eight children (12%) had an inherited
prothrombotic state. This was type 1 protein S deficiency in one
patient, the factor V Leiden mutation in six, and activated protein C
resistance (without the factor V Leiden mutation) in one. The
prevalence of the factor V Leiden mutation was not significantly higher
in children with arterial stroke (12%) than in a control population of
children without thrombosis attending the same institution (5.2%;
Fisher's exact test, p=0.19; difference in prevalence between patients and controls (95% confidence interval)=6.8% (−2.78% to 16.8%)).
CONCLUSIONS—Currently recognised inherited
prothrombotic tendencies were rarely associated with stroke in this
group of children, although larger numbers of patients would be needed
to confirm this. Age appropriate normal values should be used when
interpreting the results of a prothrombotic screen. Prothrombotic
abnormalities seen acutely are as often transient as inherited.
Longitudinal assessment and family studies are required before low
concentrations of an anticoagulant protein found acutely can be
attributed to an inherited abnormality.
From July 1990 to March 1996, 112 children with stage III or IV B-cell non-Hodgkin's lymphoma (B-NHL) with up to 70% FAB L3-type blasts (n= 42) in the bone marrow without central nervous system (CNS) disease were treated on the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol (identical to the French LMB 84). The median age was 8.3 years. There were 81 boys and 31 girls. According to the extent of the primary disease, patients were sub-staged into three groups: IIIA with unresectable abdominal tumour (n= 39); IIIB with abdominal multiorgan involvement (n= 57) and IIIX with extra-abdominal primary lymphoma often presenting as pleural effusion (n= 16). Univariate and multivariate analyses were carried out to evaluate the prognostic significance of lactate dehydrogenase (LDH) level at diagnosis, the sub-stage and the time to achieve complete remission (CR). With a median follow up of 48 months (range 12–92), the overall and event free survival (EFS) is 87% (95% confidence interval (CI) 79.2–92.1%) and 83.7% (95% CI 76.3–89.2%) respectively. Six patients (5.4%) never achieved CR, of whom one is alive following high-dose therapy. Eight patients (7.1%) relapsed after achieving CR, three are alive after second-line therapy. There were three early toxic deaths (2.7%), mainly from infection, and one late death from a second cancer. There was no significant difference in EFS according to LDH level at diagnosis, the sub-stage or the time to CR. This study confirms the overall good prognosis and low rate of toxic deaths in patients with advanced B-NHL treated with this intensive regimen. No significant difference in EFS according to the sub-stage, the time to achieve CR or LDH level at diagnosis making it difficult to identify a group that should not receive intensive therapy. © 2000 Cancer Research Campaign
childhood; B-cell non-Hodgkin's lymphoma; advanced stage III and IV; UKCCSG 9002 protocol
AIMS--Children in a United Kingdom national trial for relapsed non-B lymphoblastic leukaemia (ALL) had their diagnostic and relapse marrow cytomorphology compared to see what changes occur during the evolution of the disease. METHODS--Each relapse slide was assessed blindly for French American British (FAB) type and other morphological features by a panel of three independent microscopists without reference to each other or any diagnostic material. Diagnostic slides had been assessed by the same panel on an earlier occasion. RESULTS--A total of 134 consecutive children was studied. Six (5%) were classified as FAB type L2 at diagnosis, compared with 18 (13%) at relapse (a difference of 9%). Twenty two (16%) changed their FAB type, 17 (13%) from L1 to L2 and five (4%) from L2 to L1. The FAB score fell at relapse in 34 children and rose in 14, a difference of 14%. Cell size was the commonest feature to change (increasing in 22 and diminishing in nine) followed by prominent nucleoli (appearing in 21 and disappearing in six). Forty four (33%) children had vacuolated blasts at diagnosis, compared with 48 (36%) at relapse. Twenty five changed their vacuole score substantially, 14 gaining > 10% and 11 falling < 10%. CONCLUSIONS--These findings reflect the variability of lymphoblast cytomorphology, but also show a trend for cells to have more prominent nucleoli and greater size at relapse. Factors controlling these features of the FAB type are unknown, but they may simply be related to the growth fraction of a particular disease and not to any lineage specific biological feature.
AIM: To assess the results of supportive treatment with intravenous immunoglobulin (IVIG) and antibiotic prophylaxis in combination with splenectomy in patients with Wiskott-Aldrich syndrome. STUDY DESIGN: Retrospective review of case records of 21 patients from March 1984 to February 1996. RESULTS: Thrombocytopenia was cured in 14 of 15 patients who had splenectomy, but it recurred intermittently in three. Mean platelet volume (MPV) was normal transiently in some patients, but all MPV values were subnormal 8-23 months after splenectomy. Antibiotic and IVIG prophylaxis may have contributed to the lack of a detectable increase in the number of severe acute bacterial infections in the 451 months after splenectomy. Four patients died in 2205 months of observation before and after splenectomy (median 82, range 16-248): two of cerebral B cell lymphoma, one of progressive multifocal leucoencephalopathy, and one with severe chronic chest disease of pneumonia. CONCLUSION: Adequate supportive treatment with IVIG and antibiotic prophylaxis together with splenectomy enables good survival and quality of life in the short and medium term in patients with Wiskott-Aldrich syndrome. Persistence of infection, bleeding, and vasculitic and allergic symptoms in a significant minority and the risk of development of lymphoma, however, suggest that bone marrow transplantation may be indicated if an HLA identical donor is available.
There appears to be an increase in imported cases of visceral leishmaniasis in Northern Europe; many are children infected on holiday in the Mediterranean. Making the diagnosis in young children can be difficult especially when an adequate travel history is not obtained at presentation. Two infants with visceral leishmaniasis are presented who were initially felt to have alternative diagnoses and who subsequently responded dramatically to a short course of liposomal amphotericin B (AmBisome).
An immunohistological study of paraffin wax embedded tissue from three cases of plasmacytoid monocyte neoplasms, using a panel of antibodies which react with fixation resistant leucocyte markers, is reported. This neoplasm was found to have a distinctive antigenic profile, being negative for CD3 and elastase, but positive for CD43 and CD68. This immunological phenotype, coupled with its characteristic morphological features, should facilitate the recognition of this rare neoplasm in routinely processed tissue. Furthermore, the term "plasmacytoid monocyte sarcoma" is proposed to designate it because it is inappropriate to refer to it as a lymphoma. As all cases have been associated with a myeloproliferative disorder (usually an acute or chronic myeloid leukaemia), these tumours probably represent the accumulation in lymphoid tissue of neoplastic cells which have differentiated along the plasmacytoid monocyte pathway.
Forty-four children aged 3-13 years with Murphy stage III B cell non-Hodgkin's lymphoma were treated between May 1986 and December 1989. All have been followed up for at least 12 months. The primary site was the abdomen in 37 children, 24 of whom had involvement of other organs or nodal disease outside the abdomen. Twenty-eight received a standard dose regimen (regimen 1) and 16 had a more intensive regimen (regimen 2--MACHO). Fourteen patients (87%) who received MACHO had extensive multi-organ disease compared to 15 (53%) on regimen 1. Most of the latter had only pleural effusions. Thirty-four children are alive relapse free and considering the early relapse pattern in this disease are probably cured (actuarial event free survival = 76%). There has been one relapse (6%) after MACHO, but three toxic deaths. Six patients (21%) on the less intensive regimen have relapsed. Morbidity was high in terms of infection and need for haematological support and hospitalisation in the one third of children electively given the more intensive regimen. It is concluded that the vast majority of children with stage III disease who have disease limited to lymph nodes are curable with a moderately intensive regimen. Those with multiorgan involvement probably require more intensive treatment. It is therefore of importance to clarify prognostic factors in these patients to determine who can be cured with a less intensive regimen and who requires further dose intensification.
Over 15 years, 42 children aged 2-14 years were diagnosed as having acquired aplastic anaemia. Adequate clinical details were available for 38 children who were categorised as very severe (n = 13), severe (n = 16), or nonsevere (n = 9) by the modified Camitta criteria. Treatment varied over the study period. Seven children received a bone marrow allograft from a full match family donor and three a matched unrelated donor transplant after failed treatment with antilymphocyte globulin. The remainder were treated with antilymphocyte globulin (n = 11), antilymphocyte globulin and oxymetholone (n = 4), oxymetholone with or without prednisolone (n = 12), or supportive treatment alone (n = 1). With a minimum follow up of one year since treatment, the five year survival was 70% for bone marrow transplantation with a family donor, 30% for antilymphocyte globulin, and 25% for oxymetholone. All three children with a matched unrelated donor transplant died. The prognosis of acquired aplastic anaemia remains poor for most children and new approaches to treatment are urgently required.
OBJECTIVE--To assess the need for formal psychotherapeutic intervention in children attending a children's haemophilia clinic after some of them had been diagnosed as positive for HIV. DESIGN--Comparison of haemophiliac children with matched control groups of diabetic and healthy children. SETTING--The West of Scotland Children's Haemophilia Centre, Glasgow. PATIENTS--43 Children aged 3 to 16 years with mild, moderate, and severe clotting disorders were matched with control groups of 46 diabetic children and 42 physically healthy children. INTERVENTIONS--Parents of children aged 3-5 years were interviewed with the behaviour screening questionnaire. Children aged 6 to 16 were assessed by parental and teacher report using standardised questionnaires and self report using a computerised depression inventory. All were scored numerically according to the presence of symptoms of emotional and behavioural problems. MAIN OUTCOME MEASURES--The groups were compared for mean scores on each rating device and for number of children achieving scores within the pathological range. RESULTS--In the 6-16 age group five haemophiliac children, five diabetic children, and three healthy children scored in the pathological range on the parent questionnaire, as did two, three, and five respectively on the teacher questionnaire and four, four, and eight on the depression inventory. There was no significant difference across the three groups. Analysis of mean scores similarly showed no significant difference across groups. In contrast, the single measure used for younger children showed an increase in behavioural difficulties among the diabetic children. CONCLUSION--Haemophiliac children attending the West of Scotland Centre were no more disturbed than their diabetic or healthy peers despite the identification of HIV infection within the clinic and the widespread adverse publicity associated with AIDS and HIV infection.
Human neuroblastoma cells grown as tumour spheroids were briefly incubated with a conjugate of 131I and an anti-human neuroectodermal monoclonal antibody UJ13A. Unbound 131I was removed by washing and the spheroids observed in culture conditions for up to 4 weeks. Spheroid response to irradiation was evaluated as time to reach 10x treatment volume and proportion of spheroids sterilised. Spheroid growth was found to be affected by both the activity of 131I-UJ13A and the duration of the incubation. Na[131I], 131I-HSA, 131I labelled non-specific antibody and unlabelled antibody were found to be relatively ineffective compared to 131I-UJ13A. The tumour spheroid model has applications in the evaluation of antibodies or antibody fragments and different radionuclides which may be considered for radioimmunotherapy of micrometastases.
Measles is a major cause of mortality and morbidity in children receiving treatment for leukaemia. A review was made of all the documented cases of measles in children in first remission from acute lymphoblastic leukaemia at four major treatment centres in 1974-84. Over the 11 years reviewed 1043 children with acute lymphoblastic leukaemia were referred to these centres. Fifty one (4.9%) died while in first remission and 15 (29.4%) of these deaths were due to measles or its complications: 12 cases of pneumonia, 10 of them fatal; and six cases of encephalitis, five of them fatal and the sixth child left severely handicapped. These children would have had at least a 50% chance of long term survival. The severity of measles in the immunocompromised patient reinforces the need to improve the poor uptake of measles immunisation in Britain.
As part of the Medical Research Council Leukaemia Trial UKALL VIII, 738 unselected children with acute lymphoblastic leukaemia (ALL) had the morphology of their marrow blast cells reviewed by a panel of three haematologists. Ninety four (13%) showed appearances classifiable as type L2 by the French American and British (FAB) cooperative group's criteria, five (0.7%) were typed L3, and the remaining 639 (86%) as L1. Disregarding the patients classified as L3, those with the L2 variant showed an inferior disease free survival to that of the remainder (p less than 0.01), and more of them failed to remit after receiving "standard" remission induction treatment (p less than 0.01). They included an excess of older children (p less than 0.01) with less profound marrow failure at diagnosis, and fewer of them expressed the common ALL antigen (p = 0.05). There was no association between L2 morphology and the diagnostic white cell count, sex, or the presence of a mediastinal mass. These findings confirm earlier reports that FAB L2 ALL is associated with a poor prognosis and that it occurs more commonly in older children. The high remission failure rate is a recent observation and indicates that alternative early treatment may be appropriate for such patients.
In the west of Scotland use of a single intragenic restriction fragment length polymorphism (F9(VIII)/TaqI) allowed definitive genetic counselling for 45% of females at risk of being carriers for haemophilia B. Two further intragenic RFLPs, F9(VIII)/XmnI) and F9(VIII)/DdeI, have been applied to this population and by using all three polymorphisms the carrier status could be determined in 68% of females at risk. Linkage disequilibrium was apparent between these three RFLPs, and in the west of Scotland the single most clinically useful polymorphism was F9(VIII)/TaqI followed by F9(VIII)/DdeI and then F9(VIII)/XmnI. Overall, prenatal diagnosis by DNA analysis could be offered to 31 of 37 (84%) carriers (obligate and detected) in these families.