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Two hundred and nine children presenting consecutively with acute lymphoblastic leukaemia to a regional paediatric oncology unit were investigated to determine the prognostic significance of various factors at diagnosis. There was a strong positive correlation between the pretreatment haemoglobin level and the percentage of bone marrow blast cells in S phase of the cell cycle as assessed by flow cytometry. Patients with T- and B-cell leukaemia had significantly higher haemoglobin levels than non-B non-T patients. In patients with total white cell counts less than 20 X 10(9)/l, aged less than 13 years, and no mediastinal mass, there was no association of haemoglobin with length of first remission. However, among those with white blood counts greater than 20 +/- 10(9)/l there was a strong positive trend towards shorter remission with higher haemoglobin levels. Children with high white blood counts at diagnosis and low haemoglobin levels may have a better prognosis than predicted by the white blood count alone.

Circulating immune complexes have been measured using the (125I)C1q binding test in 216 sera from 135 children with acute lymphoblastic leukaemia. Increased circulating immune complexes were detectable in 10.7% of the sera and 10.4% of the children. There was no correlation between the presence of circulating immune complexes and prognosis, but a strong correlation with a history of recent infection.

Pretreatment marrow blast cells were studied in 38 boys and 27 girls (aged 1-14) with acute lymphoblastic leukaemia by flow cytometry after staining with propidium iodide.The percentage of blast cells in the S phase of the cell cycle ranged from 1% to 40% (median 6%). A correlation was found between the percentage of cells in S and the morphological classification of the French American British Cooperative Group (FAB), presence of T or B cell markers, haemoglobin concentration, blast size, bone pain, platelet count, and an inverse correlation with coarse granule and block staining with Periodic-acid-Schiff (PAS).63 of the 65 children attained complete remission. During the first 24 months of follow up there were fewer relapses (P = 0·054), and deaths (P = 0·004) in those children with 6% or fewer blasts in S phase. The difference was most marked in the first 12 months with 4 relapses out of 33 in the group with 6% or fewer cells in S compared with 13/30 in the group with > 6% cells in S.In order to investigate the prognostic significance of the pretreatment proliferative studies in greater detail, remission duration was correlated with 17 presenting features. Each feature was correlated individually and then the simultaneous effect of all the features was assessed by stepwise multiple regression.Only 3 features of the disease at diagnosis were individually correlated with duration of remission. These were% cells in S (P < 0·001), log white cell blood count (WBC) (P < 0·01) and the presence of T- or B-cell surface markers (P < 0·05). However, the multiple regression analysis showed that cell markers were not an independent prognostic feature, whereas the percentage cells in S and log WBC were independently and significantly correlated with duration of first remission (P < 0·001 in each case).

We have assessed testicular function with luteinising hormone-releasing hormone (LH-RH) and human chorionic gonadotrophin stimulation tests in 44 boys previously treated with, or currently receiving, chemotherapy for acute lymphoblastic leukaemia (ALL). At the same time a testicular biopsy was performed in each boy and the morphology was studied. Histologically the chemotherapy appeared to damage the tubular system in particular, and the degree of damage was assessed by estimating the tubular fertility (TF) index which is defined as the percentage of seminiferous tubules containing identifiable spermatogonia. The mean TF index in all 44 biopsies was 51%. Only 2 of the 44 boys showed an absent or blunted testosterone response to human chorionic gonadotrophin. This suggests that Leydig cell function is rarely impaired by such chemotherapy and that most of the boys, similarly treat for ALL, will undergo normal pubertal maturation. Apart from the basal luteinising hormone (LH) levels in the prepubertal group which could not be compared, the median basal serum follicle-stimulating hormone (FSH), LH, and testosterone concentrations, the median peak FSH and LH responses to LH-RH, and the mean plasma testosterone responses to human chorionic gonadotrophin stimulation did not differ between the prepubertal, early pubertal, and late pubertal groups compared with normal boys of similar pubertal maturation. Three of 32 prepubertal ALL boys, and 5 of 12 pubertal ALL boys showed abnormalities of gonadotrophin secretion. The increased frequency of abnormalities of FSH secretion in the pubertal ALL boys compared with the prepubertal ALL boys could not be explained by more severe tubular damage in the former group. We conclude that moderately severe damage to the tubular system of the testis unassociated with Leydig cell impairment may not be detected in the prepubertal boy with current tests of testicular function.

Bone marrow necrosis, an uncommon finding in acute lymphoblastic leukaemia, has previously been regarded as a poor prognostic feature. It has been associated with difficulty in establishing the diagnosis, a low rate of remission as well as short remission duration. We report a case of bone marrow necrosis in a girl with acute lymphoblastic leukaemia and good prognostic features who attained complete remission uneventfully and will discuss previous reports of this association in the literature.

Thirty-two variables at diagnosis of acute lymphoblastic leukaemia (ALL) were studied in an unselected population-bases series of 209 children. Twelve variables had individually a statistically significant effect on the duration of first remission. A multivariate analysis using data on the 199 children who went into complete remission showed that all significant variation in remission times could be explained by only 3 variables acting simultaneously. These were the total white blood count (WBC) at diagnosis, the Franco-American-British (FAB) classification of blast morphology and the percentage of lymphoblasts with PAS+ coarse granules or blocks. A simple scoring system (for WBC add 1 if less than 20 X 10(9)/1, add 2 if 20 - 50 X 10(9)/1, add 3 if greater than or equal to 50 X 10(9)/1; for L2 or L3 leukaemia add 1; for PAS+ less than 5% add 1) separated patients into risk groups with widely different median lengths of first remission. Application of the risk score improves the prediction of the outcome of treatment, and the clinical trials, allows more accurate stratification, less extensive data collection and simpler analysis.

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.

A single-film intravenous pyelogram was performed on 87 children with acute lymphoblastic leukemia at presentation. The kidney size was measured and a standard deviation score based on patient height was calculated. There was a tendency of renal enlargement, with 21 patients (24%) having scores of over 1 SD and 6 (7%) over 2 SD. A trend of shorter duration of first remission with increasing renal size was shown to be statistically significant (P = 0.036). This trend was not quite statistically significant (P = 0.087) whenthe analysis was confined to 54 "better-risk" patients (WBC less than 20 X 10(9)/liter and no mediastinal mass), and was much weaker and not significant in 33 "poor-risk" patients (P = 0.62).

Full skeletal survey was performed on 193 consecutive children presenting over a 6-year period with acute lymphoblastic leukaemia (ALL). A record was made of the degree of bone pain in these patients and 60 others presenting immediately prior to the availability of skeletal surveys. Bone pain was present in 76 out of 253 patients (30%) and radiological bone changes characteristic of leukaemia in 125 out of 193 (65%). A significant correlation was found between the severity of bone pain and the number of bones involved on X ray (r = 0.25, P = less than 0.001), but not between initial white cell counts and bone score (r = -0.14, P = 0.08). There was no significant correlation between the degree of bone pain and survival or length of first remission (P = 0.29 and 0.86). Similarly, the extent of radiological bone disease was of no prognostic significance with relation to survival (P = 0.41) or length of first remission (P = 0.21).

A prospective study of bone marrow fibrosis was made in a group of 40 children with acute lymphoblastic leukaemia to see whether it affected the prognosis or course of the disease. Secondary myelofibrosis (SMF) was present at diagnosis in 57% of the cases. It was not statistically significantly related to the prognosis or course of the disease. Thus, although trephine biopsy occasionally provided useful information in different diagnosis and when aspiration was difficult, it provided little information of use for management.

The morphological classification of ALL based on the FAB co-operative group's criteria is capable of identifying 10-15% of children with L2 disease who, given similar treatment, will fare less well than the 85-90% with the L1 variant. The significant features defining L2 morphology are a low cellular nuclear: cytoplasmic ratio and the presence of nucleoli. Children with L2 disease do not have higher leucocyte counts but are older, have "common" ALL less frequently, and more often have well-preserved marrow function at diagnosis. Their poor outlook is manifest not only by their higher relapse rate but also by a higher proportion failing to remit in the first instance. L2 morphology does not necessarily "breed true" and can arise in a small proportion of patients with previous L1 disease at the time of relapse. Other striking morphological features of lymphoblasts, including azurophil granules, vacuoles and "hand mirror" cells, have yet to have their significance defined, though the latter feature may be an unfavourable finding.

Peripheral blood lymphocytes incubated with tumour cells or extracts may undergo blastogenesis. This is the basis of a technique studied in children with acute lymphoblastic leukaemia (ALL) in childhood in an attempt to predict relapse. Samples of peripheral blood and bone marrow from 82 children with varying degrees of ALL were analysed. Cultures were prepared by incubating a lymphocyte suspension with an autologous bone-marrow suspension. Final ratios of lymphocytes to bone-marrow cells (L: BM) were 1: 1 and 2: 1. Control wells received bone-marrow or lymphocyte suspension only. Cultures were incubated for 72, 96, and 120 hours. All were pulse-labelled with (3)H-TdR and radioactivity was measured by scintillation counting. Results were expressed as the stimulation index, calculated by dividing the mean counts per minute (cpm) of wells containing both lymphocytes and bone-marrow cells by the sum of the mean cpm for control wells. If the stimulation index exceeded 1 at 72, 96, or 120 hours at either L: BM ratio a positive response was recorded.Seventy-six children were in clinical remission at the time of testing (group A) and six were in clinical relapse (group B). In group A 24 patients showed stimulation and relapsed later at a mean time of 3.8 months (21 with marrow disease, two with testicular infiltration, and one with lung infiltration). Sixteen patients showed stimulation and had up to 4% blasts in their bone marrow but remained in remission. Nineteen other patients showed a positive response and several factors may have contributed to this: two underwent a "rebound" lymphocytosis after stopping treatment, nine had current or intercurrent infections, two had persistent unexplained bone-marrow lymphocytosis, but six had no causative symptoms and thus their responses were "true false-positives." Seventeen patients from group A showed no response and remained in remission for a mean of 22.9 months after testing. None of the six children in group B responded, and at testing had 17-85% blasts in their bone marrow.During the study no patient relapsed who had not shown a positive response. The technique merits further study as a guide to the presence of leukaemic cells.

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.

A consecutive series of 209 children with acute lymphoblastic leukaemia (ALL) presenting to a regional referral unit between 1970 and 1977 was studied. The following morphological features in the initial bone marrow were recorded: blast size, percentage periodic acid-Schiff (PAS) and oil-red-O (ORO) positivity, percentage of blasts with vacuoles, and acid phosphatase positivity. The blasts were also coded according to the FAB (L13) classification. When analysed separately, increasing blast size was significantly related to the length of first remission (P = 0.01). However, this was almost entirely due to its association with the FAB L2 type of disease which also had a highly significant influence on length of first remission (P less than 0.0001) independent of all other factors. Patients with L3 disease had blasts with heavy vacuolation, ORO positivity and displayed monoclonal surface immunoglobulin and their prognosis was very poor. The percentage of vacuolated blasts and ORO positivity otherwise showed no influence on prognosis. Fine granularity of PAS staining in lymphoblasts showed no prognostic value but the trend of longer remission duration with increase in percentage of PAS coarse granularity and blocks, was statistically significant (P = 0.006). This relationship was partly due to a correlation with the presence of mediastinal mass and L2 disease, but was still independent of all other prognostic factors. In a smaller number (39) of the series of patients on whom cell surface markers were available, we were unable to demonstrate a correlation between T-derived blasts and the L1 and L2 classification; but there was a strong correlation with polar acid phosphatase positivity in T-derived blasts.

Examination of surface markers on leukaemic blasts from 51 children with ALL revealed that ALL is a heterogeneous disease. The majority (68%) of patients with ALL lack surface markers (null leukaemia); 28% could be classed as T cell as they form rosettes with sheep RBC and 4% have been shown to possess surface immunoglobulins and hence are classed as B cells. The children with null cell leukaemia have a better prognosis than T and B cell types.

A study of testicular histology has been made in 44 boys treated with combination chemotherapy for acute lymphoblastic leukaemia. At the time of testicular biopsy 21 boys were still receiving cytotoxic drugs and 23 had completed their chemotherapy some time earlier. Evidence of leukaemic infiltration was seen in 5 (11%), interstitial fibrosis in 24 (55%), and basement-membrane thickening in 6 (14%). The mean tubular fertility index in the 44 biopsies was 50% of that in age-matched controls, and 18 of the biopsies had a severely depressed tubular fertility index (40% or less). Three variables had a highly significant effect on the tubular fertility index: previous therapy with cyclophosphamide or cytosine arabinoside (greater than 1 g/m2) depressed the tubular fertility index, whereas with increasing time after completion of chemotherapy the tubular fertility index improved. The prognosis for fertility in these subjects is not known. Long-term surveilance is necessary.