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Leukemias and lymphomas occurring in a series of families with Wilms' tumor (WT) are described. One surviving case developed a large cell anaplastic Ki-1 lymphoma at age 20 years, and 23 second- and higher degree relatives were affected. In two instances leukemia/lymphoma occurred in the context of Li-Fraumeni syndrome (LFS) and two other families showed striking clusters of unusual and early-onset malignancies. In several cases, children had genitourinary abnormalities of the type associated with the WT1 gene on chromosome 11p13. Some of these families may provide important subjects for study of WT genes in hematologic disease and lymphomas and for investigation of interaction between different tumor-suppressor genes, e.g., WT1 and other candidate WT genes, and p53.

Distribution of miscarriages, stillbirths and infant deaths in the families of a population-based series of children with soft-tissue sarcoma was examined in relation to index case histology (rhabdomyosarcoma or other soft-tissue sarcoma) and to the possible presence of genetic predisposition to cancer in the families (Li-Fraumeni syndrome or neurofibromatosis). Reproductive loss was not related to index histology (miscarriages, p = 0.3; all losses, p = 0.6) but was significantly higher in "genetic" rather than "sporadic" families (miscarriages, p = 0.02; all losses, p = 0.01). However, excess reproductive loss was not a feature of families with the Li-Fraumeni syndrome, but appeared to be concentrated in the families affected by neurofibromatosis.

The adolescent growth pattern of eight boys, who had puberty induced with androgen replacement therapy following radiation-induced Leydig cell failure, was studied from induction of puberty at a mean age of 13.1 years (range 11.6-14.5) to final height at mean age of 18.8 years (range 17.7-20.3). The mean gains during puberty (SD) for standing height, sitting height, and sub-ischial leg length were 18.56 cm (3.98), 10.46 cm (2.39), and 8.1 cm (2.01) respectively, which were significantly reduced compared with normal Tanner standards (P < .001). The peak velocity for each parameter occurred in the 1st year of induced puberty in contrast to the pattern in normal adolescence, although the mean peak velocity for each auxological parameter was not significantly different from the normal Tanner standards. The mean adult standing height (SD), 167.5 cm (9.88), and mean adult leg length (SD), 80.8 cm (6.19), were not significantly different from the normal Tanner standards, whereas the mean adult sitting height (SD), 86.7 cm (4.78), was shorter (P < .001). Three of the eight patients had a leg length standard deviation score less sitting height standard deviation score in excess of +2.96 suggesting the presence of significant skeletal disproportion. Seven of the eight boys reached target genetic height, though in six, the final height was below mid-parental height (P < .05). The modest loss in height potential was mainly due to radiation-induced skeletal dysplasia attenuating the growth of the spine. The families of boys with radiation-induced Leydig cell failure requiring androgen replacement therapy can be reasonably optimistic about height prognosis as seven of the eight boys reached target genetic height.

Aims: To report the clinical features and pathology of four childhood cases of primary mediastinal non-Hodgkin's lymphoma of non-lymphoblastic pathology., Methods: Biopsy material was fixed in formol-saline and routinely processed and stained. Immunohistochemical staining was performed on paraffin wax embedded sections using the alkaline phosphatase anti-alkaline phosphatase method., Results: The four patients presented with a large mediastinal mass and symptoms consistent with superior vena cava syndrome secondary to lymphoma. None of the patients had any clinically important disease outside the mediastinum. The four tumours had a histological appearance similar to diffuse large cell non-Hodgkin's lymphoma with sclerosis. Immunohistochemical staining showed that these tumours were of B cell origin. One patient died from infection during treatment and two patients died with progressive disease. The remaining patient remained well 43 months off all treatment., Conclusions: These four cases further illustrate the heterogeneity of paediatric large cell lymphomas. Clinically, they seem to be equivalent to the B cell lymphoma of the mediastinum, sclerosing type, that is seen in young (predominantly female) adults. The clinical and biological features of this type of tumour in childhood are largely unknown. Using standard treatment protocols, this tumour seems to have a poor prognosis and its optimal treatment therefore requires further clarification.

Ovarian function was assessed in 40 long term survivors who had received standard United Kingdom Acute Lymphoblastic leukaemia (UKALL) protocols and were in first clinical and haematological remission. A menstrual and pregnancy history was taken (median age at assessment: 18.8 (12-34.7) years) and the acquisition of adult secondary sexual characteristics confirmed in each patient. Basal bloods were taken for follicle stimulating hormone (FSH), luteinizing hormone (LH), and serum oestradiol estimations. Serum progesterone concentration was measured in those patients who were in the luteal phase of their menstrual cycle at assessment. In addition, menstrual cycle profiles of salivary progesterone concentrations were derived from daily samples in 12 patients. All patients achieved adult sexual development; median age at menarche was early at 12.4 (9.0-14.6) years and 37 of them have regular menses. Ten patients have had 14 live births, and evidence of ovulation was seen in a further 11 patients assessed in the luteal phase of the menstrual cycle. Four patients had damaged ovaries, two of whom show evidence of ovulation; three of the four received craniospinal irradiation and one received cyclophosphamide as part of her chemotherapy regimen. None of these patients has yet developed total ovarian failure or required sex steroid replacement therapy. The medium term outlook for ovarian function is good for the majority of childhood ALL survivors. The spinal component of craniospinal irradiation is a major risk factor for ovarian damage, and cyclophosphamide may be a contributory factor. A premature menopause remains a possibility if significant follicular depletion has occurred at the time of cytotoxic treatment.

Objective: We aimed to investigate the effect of low dose (1800 cGy) prophylactic cranial irradiation on physiological growth hormone secretion., Design: We performed an analysis of 24-hour serum GH profiles using 20-minute sampling., Patients: Forty-four children were studied, of whom 21 were long-term survivors of acute lymphoblastic leukaemia and 23 were normal children. They were further subdivided into prepubertal, pubertal and post-pubertal groups., Measurements: GH profiles were analysed by autocorrelation, Fourier transformation and spectral analysis of stationarized data, and peak detection using the Pulsar peak detection program. RESULTS In the normal children, there was a significant increase in the median (range) area under the curve (AUC) of the GH profile between the prepubertal and pubertal groups (62 (11-124) and 137 (142-158) IU/I/h respectively, (P less than 0.01)). There was also a change in the spectral analysis through puberty. The dominant frequencies were spread widely in the prepubertal and post-pubertal groups but sharply focused in the pubertal group. In the cranially irradiated children there was no significant increase in AUC between the prepubertal (62(13-110) IU/I/h) and pubertal groups (92 (14-163) IU/I/h). The wide range of dominant frequencies persisted in the pubertal cranially irradiated group due to the presence of additional high frequency pulses. The impression of a disturbance of the periodicity of GH secretion in the cranially irradiated pubertal group was further supported by the finding that the autocorrelation function in this group alone was not significantly different from that which would arise from random data., Conclusions: A novel form of GH insufficiency has been observed after low dose irradiation in childhood in which an abnormality of periodicity and a quantitative reduction in GH secretion appears restricted to puberty.

Absence from school during the first year after starting major treatment for cancer or chronic or orthopaedic conditions was examined. Retrospective data were collected on 72 children and obtained from hospital records, school registers, and interviews with parents and teachers. Median initial absences caused by treatment were 91, 29-5, and 15 days for cancer, chronic, and orthopaedic patients respectively. The mean proportions of the remaining school time in the year occupied by absences caused by treatment and those not caused by treatment were respectively 17% and 17% for oncology patients, 8% and 12% for chronic patients, and 2% and 11% for orthopaedic patients. The only significant factor associated with the amount of absence caused by treatment was the type of illness. Increased absence not caused by treatment was associated with the amount of treatment time and the patient being a girl. The proportion of absence not caused by treatment decreased if the mother was educated beyond the age of 18. The possible reasons for and effects of excess absence are discussed.

To study long-term testicular function following the treatment of acute lymphoblastic leukaemia (ALL) in childhood, 37 young adult males were assessed at two separate time points. The initial assessment was made by a wedge testicular biopsy after completion of treatment (median 9.7 years; range 4.1-16.3 years) and the subsequent assessment (median 18.6 years; range 15.4-26.8 years) consisted of the clinical examination of pubertal stage, measurement of serum gonadotrophins and testosterone and, in 19 patients, semen analysis. All 37 men completed pubertal development normally and had a testosterone concentration within the normal adult range. Six men showed evidence of severe damage to the seminiferous epithelium, five were azoospermic and one, who did not provide semen for analysis, had a reduced mean testicular volume (11 mls; normal greater than or equal to 15 mls) and a raised basal FSH level (13 UI 1-1; normal less than or equal to 6 IU 1-1). All six men with germ-cell damage had received either cyclophosphamide or both cyclophosphamide and cytosine arabinoside as part of their chemotherapy regimen. Approximately 10.7 years earlier all 37 men had undergone a testicular biopsy after completion of their chemotherapy. Morphological damage to the seminiferous epithelium had been calculated by estimating the tubular fertility index (TFI), which is the percentage of seminiferous tubules containing identifiable spermatogonia (age-matched normal = 100%).(ABSTRACT TRUNCATED AT 250 WORDS)

The respiratory status of 47 patients surviving childhood Wilms' tumor was studied. The group that had received flank irradiation (which impinges on the lower lung) (n = 17) had a significantly lower mean percent predicted for forced expiratory volume in one second, residual volume, and total lung capacity when compared to those who had received no irradiation (n = 23). Those patients who had received whole-lung irradiation (n = 3) had significantly lower transfer factor for carbon monoxide and gas transfer per unit lung volume when compared to the nonirradiated group (n = 23). There was no significant difference in the prevalence of respiratory symptoms between the three groups. Patients receiving any form of radiotherapy for Wilms' tumor may have abnormalities of pulmonary function and should have pulmonary function tests performed as part of their long-term follow-up.

Three hundred eighty-one children with Wilms' tumor were treated in the United Kingdom Children's Cancer Study Group WT1 Study (1982 to 1986). Seventy-one patients had relapses during or after treatment with surgery and chemotherapy, and radiation therapy, depending on stage and histologic characteristics. Forty-nine patients were evaluable for disease response to second-line chemotherapy alone. Evaluation of response to chemotherapy was impossible in the remaining patients because either surgery or radiation therapy was used at the time of relapse. With second-line combination chemotherapy (which included ifosfamide, etoposide/VM26, cisplatin/carboplatin, bleomycin, melphalan, and Thiotepa [Lederle Laboratories, Pearl River, NY]), there were five complete responses and 12 partial responses. In patients with favorable histologic findings, six of nine with Stage I, five of ten with Stage II, none of 11 with Stage III, three of 16 with Stage IV, and one of five with Stage V disease survived. Two survivors were treated with chemotherapy alone; the others received combined treatment with chemotherapy, radiation therapy, and/or surgery. For those with unfavorable histologic findings of any stage, only two of 20 survived. The authors conclude that, even for patients with localized disease with favorable histologic findings, the "salvage" rate is little more than 50%, and for all other stages and histologic findings the likelihood of cure after relapse is remote. There is clearly a need for additional effective chemotherapeutic agents for these patients.

Three hundred and eighty one children with Wilms' tumour were treated on the United Kingdom Children's Cancer Study Group WT1 Study (1980/6). Seventy one patients relapsed during or after treatment, which included surgery and chemotherapy, with irradiation depending on stage and histology. Despite treatment with various combinations of chemotherapy, surgery, and radiotherapy there were only 17 survivors. For unfavourable histology, any stage, only two of 20 survive. We conclude that, after relapse, even for patients who have had localised disease and favourable histology, the 'salvage' rate is little more than 50% and for all others the likelihood of cure is very small. Three of 41 children who relapsed less than 12 months from diagnosis survive, compared with 14 of 30 who relapsed later. It is essential that even with this 'good prognosis' tumour initial treatment is optimal and given by centres experienced in management of children's cancer. Furthermore, there is a clear need for additional effective chemotherapeutic agents for relapsed patients.

To study the effect of abdominal irradiation on spinal growth in childhood we have measured final height, sitting height, and leg length in 30 male survivors of a Wilms' tumor. Twenty-one patients received whole abdominal irradiation by either megavoltage therapy (MV: n = 11) or orthovoltage therapy (OV: n = 10); the remainder received flank irradiation. To examine the effect of the adolescent growth spurt on the irradiated spine we have followed prospectively seven patients who received whole abdominal irradiation and nine patients who received flank irradiation through puberty. Compared to a normal population there is a modest reduction in median final standing height SDS (H.SDS: -1.15) accompanied by a marked reduction in median final sitting height SDS (S.HT SDS: -2.41) with no apparent effect on median subischial leg length SDS (SILL.SDS: 0.04). This reduction in spinal growth is reflected by a strongly positive disproportion score (DPS; [SILL SDS-S.HT SDS] + 2.81). The incidence of scoliosis after abdominal irradiation has been low (10%). During puberty there is a significant fall in median sitting height SDS after both whole abdominal (median fall: -0.9, P = 0.02) and flank irradiation (median fall: -1.85, P = 0.01), and this is reflected in a significant increase in disproportion (DPS: whole abdominal; median rise +1.4, P = 0.02: flank, median rise +1.34, P = 0.01). After MV irradiation there is a significant correlation between the degree of disproportion and the age at treatment (P less than 0.0005). The younger the patient is at treatment the more severe is the restriction on spinal growth and the shorter and more disproportionate they become as an adult. The estimated eventual loss in potential height from abdominal irradiation at the age of one is 10 cm and at five years is 7 cm.

Great advances have been made in recent years in the treatment of children's cancers. Consequently, increasing numbers are now returning to school. The pilot study described in this paper looks at the problems experienced by some of these children, their teachers and parents, and some of the solutions which have been found, with a view to eventually taking some action to help the situation. The results are based on detailed studies of 16 children who had all been off treatment for two or more years and had therefore returned to school on a normal full-time basis. Parents and teachers were interviewed. The preparation for the return to school, reintegration problems including general physical, academic, psychological and behavioural ones, schoolmates' reactions, siblings' reactions, and the teachers, and parents, suggestions for how these might be alleviated are considered. Five important factors emerged especially clearly: Children whose treatment absence was right at the start of their schooling had particularly severe problems in integrating into school. Children at secondary schools had special anxieties about their school-work, especially Mathematics, which leads to consideration of the whole problem of teaching during absence from school. Some children are having severe problems in obtaining efficient prostheses. Whilst classmates were usually welcoming or unconcerned, much teasing was experienced from children in other classes, particularly in secondary schools. Whilst attention is focused on the sick child, siblings are developing severe problems of their own which need special attention. Most teachers and parents would have welcomed advice on or help with these problems and it is hoped that, when a larger scale study has clarified the finer points, some systems for helping will be devised.

Six peroxidase conjugated lectins were used to compare their ability to bind to formalin fixed paraffin embedded tissue sections of childhood renal tumours (Wilms' tumour, mesoblastic nephroma, renal carcinoma, rhabdoid renal tumour, and bone metastasising renal tumour of childhood (BMRTC) with fetal and normal children's kidney. Lectins were found to be helpful in the differential diagnosis of renal tumours. Another important finding was that the mesenchyme of renal tumours showed differences in its reactivity among various types of kidney tumours. The results of lectin binding were not helpful in establishing the origin of kidney tumours.

Eighty-four children with acute lymphoblastic leukaemia (ALL) who had relapsed in bone marrow were studied to assess whether treatment would be more successful if relapse was detected before the disease became clinically evident. Patients whose relapse was detected by routine bone marrow examination before the disease became apparent were compared with those whose relapse was suspected from clinical examination or peripheral blood findings. In the former there was a lower percentage of blast cells in the marrow (p less than 0.02) and the patients suffered less from complications of the disease, but there was no difference in the incidence or duration of second remissions between the two groups.

Thirty-three children aged between 1 month and 16 years (median 1 year, 7 months), were treated for stage II neuroblastoma with surgery, radiotherapy, or chemotherapy, alone or in combination. After 3 years 70% were living, 6 children had died from the disease, and 4 had died as a result of treatment. Patient characteristics (age, gender) and tumour characteristics primary site, presence of lymph node involvement, catecholamine excretion, histology) were reviewed in an attempt to determine prognostic features. While age under 1 year at diagnosis was, as expected, favourable in this series, the most important prognostic variable was the presence or absence of regional lymph node involvement. No patient with uninvolved nodes died of neuroblastoma and the difference in the 3-year survival rate between these patients and those with positive nodes was statistically significant. Although this study of patients treated between 1970 and 1977 provided no clear evidence that either postoperative radiotherapy or contemporary chemotherapy was of benefit, our findings suggest that subclassification of stage II patients into 'node-positive' and 'node-negative' groups will help to define those who might benefit from improved adjuvant postsurgical treatment.

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.

Twenty-eight children were treated for various cancers with protocols that included dichlorodiamine platinum (cisplatin). Sixteen children were given intravenous magnesium after the administration of cisplatin, and 12 were given intravenous magnesium before and after administration of cisplatin. Serum magnesium concentration levels were monitored before, during, and after the full course of treatment and found to be lower in the first group of patients than in the second group. We recommend that magnesium supplements be given to patients receiving cisplatin during the precisplatin hydration period to prevent hypomagnesemia.

Two neck tumours in young children with similar clinical features were compared using light and electron microscopy. Both tumours consisted of uniform sheets of epithelial-like cells and there were scattered stromal elements in one. Tonofilaments in sheets or bundles reminiscent of squamous epithelium were striking in the epithelial cells. Intercellular junctions were frequent but true desmosomes were not seen. Most cells contained a few secretory droplets. Occasional secretory cells, foam cells and cilia were observed. Since these tumours were not sited superficially they are unlikely to have been derived from skin epithelium. An origin in branchial sinus remnants capable of differentiation towards squamous and ciliated epithelia is suggested.

Five normal children, four children on chemotherapy, and two children who had completed chemotherapy within a year were studied using 13C-leucine breath test. 13C-Leucine was administered on an empty stomach and a single breath was collected sequentially over 3 h. The cumulative dose of 13C in expired gas was measured and found to be lower in children who had had chemotherapy than in the normal children. These results suggest that chemotherapy may lead to a reduction in leucine catabolism.

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).

Twenty children who were in unmaintained full haematological remission after treatment for acute lymphoblastic leukaemia (ALL) showed a significantly lower incidence of granulocyte-macrophage progenitor cells (GM-CFC) in the bone marrow compared to controls. This low incidence lasted for up to at least 3 years after the cessation of chemotherapy. There was no tendency to higher values with longer times after treatment, and the low incidence was not predictive of relapse. Long-term cultures from ALL bone marrows and from controls achieved similar levels of production of mature cells through the whole period of culture (6 weeks). However, cultures from patients' bone marrow had on average about 5 times lower numbers of GM-CFC, indicating that the level of mature cell production was achieved by a higher level of post-GM-CFC amplification than needed in the controls. This is taken to be due to compensatory mechanisms operative during stressed haemopoiesis which appears to be a long-lasting effect after current chemotherapy of ALL.

Pituitary-function tests have been done in twenty-seven patients at various times after treatment in childhood for intracranial tumours not directly involving the hypothalamic-pituitary region. Impaired growth hormone (G.H.) responses to hypoglycaemia and 'Bovril' were found in ten children. There seeems to be progressive impairment in G.H. production with time after treatment. During the first 3 months after neurosurgery no child was found to be G.H. deficient, but the peak G.H. response of this group seemed to be blunted when compared with a control group of children who had been treated for abdominal tumours. The rest of anterior-pituitary function in G.H.-deficient children seems quite normal except for a significantly greater basal thyroid-stimulating hormone (T.S.H.) level and T;S.H. response after thyrotrophin-releasing hormone. Two girls have developed secondary amenorrhoea, and one is G.H. deficient.

Gonadal function was studied in 15 patients 12 pubertal or postpubertal, and three prepubertal, who had been treated during childhood for nonmetastatic osteosarcoma of the long bones by chemotherapy regimens that included cis-platinum and adriamycin. Of seven postpubertal female patients assessed (mean age at diagnosis 16.5 years), three were amenorrhoeic and showed evidence of ovarian damage with raised gonadotrophin levels and a low serum oestradiol concentration. One patient who had regular periods had a raised luteal-phase follicle-stimulating hormone (FSH) concentration suggestive of gonadal dysfunction. Severe oligospermia or reduced testicular volumes in the presence of raised gonadotrophin levels were observed in three of the five pubertal males (mean age at diagnosis 13.25 years). A reliable assessment of gonadal function was not possible in three male patients who remained prepubertal at the time of study. The median total dose of cis-platinum received by those patients with gonadal damage (median dose, 490 mg) was significantly higher than in those patients with normal gonadal function (median dose, 300 mg) (P = 0.01). In the boys the damage to the testes was primarily directed at the germinal epithelium. Leydig cell function was intact and the males progressed spontaneously through puberty. In the girls, unlike the boys, there was evidence of reversibility of gonadal damage with time. This is the first study to show gonadal dysfunction due to cis-platinum and adriamycin therapy in childhood.

Ovarian function has been studied sequentially since 1975 in 19 patients treated in childhood for an intra-abdominal tumour with surgery and whole abdominal radiotherapy (total dose 30 Gy). Eleven patients received chemotherapeutic agents that are not known to cause gonadal dysfunction. All but one patient have developed ovarian failure with persistently elevated gonadotrophin levels (FSH and LH greater than 32 IU/litre) and low serum oestradiol values (less than 40 pmol/litre) before the age of 16 years. The majority (n = 12) did not progress beyond breast stage 1 without sex steroid replacement therapy. As the number of oocytes within the ovary declines exponentially by atresia from approximately 2,000,000 at birth to approximately 2000 at the menopause, we have been able to estimate that the LD50 for the human oocyte does not exceed 4 Gy.

The annual incidence of leukaemia among children aged up to 14 years as estimated by the Manchester Children's Tumour Registry has been analysed for the 24 years 1954-1977. A significant increase in acute lymphoid leukaemia (ALL) was found, while the incidence of acute myeloid leukaemia (AML) remained constant. Other types of leukaemia were too rare to be analysed separately. The increase in ALL was concentrated among boys in the 1--5-year age group. Analysis with respect to initial white-cell count showed the increase to be more pronounced in children with initial white cell counts of 1-5 x 10(4)/microliters. The proportion of cases presenting in Lancashire compared with Greater Manchester did not change during the study period. The distribution of cases with respect to social class and socio-economic group of the parents also remained constant. Due to advances in the treatment of childhood ALL survival improved considerably during the study period and no increase in mortality was seen.

In 24 children with acute leukaemia a low serum albumin concentration (31 g/l or less) and a median weight:height ratio of less than 0.95 on admission were indicators of severe weight loss.

From November 1977 to July 1983, 82 children with T leukaemia/lymphoma entered a randomised trial of combination chemotherapy and radiotherapy. Twenty-five were designated T lymphoma and 57 T leukaemia, 28 having greater than 100 x 10(9)1(-1) blasts in peripheral blood at diagnosis. Twenty-seven patients with mediastinal primaries who were treated on the companion non-Hodgkin lymphoma (NHL) trial were comparable in all respects to the T lymphoma patients and the results of treatment were therefore combined and analysed together. Overall 4-year survival (48-53%) and failure-free survival (FFS) (37-40%) were similar in all groups except the 28 with T leukaemia and WCC greater than 100 X 10(9)1(-1) (20% and 13%). There was a significant advantage in FFS for patients randomised to receive low dose mediastinal radiation, and this was most marked in patients with T lymphoma (66% vs 18%, P = 0.006).

Seven of the 25 children with acute leukemia were malnourished on admission. Of the 11 children who presented with fever, 6 had protein energy malnutrition and a bacterial infection was confirmed. They had a lower total leucocyte count. Out of 18 well-nourished children, 5 presented with a fever and the causative organism was isolated in 1 patient. There were more patients with a palpable liver in the malnourished group, and they had a high morbidity due to infections during remission induction.

Ovarian function has been reviewed sequentially since 1975 in 53 patients treated in childhood between 1942 and 1985 for an intraabdominal tumour with surgery and external abdominal radiotherapy (XRT). Of 38 patients who received whole abdominal XRT (20-30 Gy), 27 failed to undergo or complete pubertal development (pubertal failure) and a premature menopause (median age 23.5 years) occurred in a further ten. Of 15 patients who received flank XRT (20-30 Gy), ovarian function (median age at last assessment 15.2 years) was normal in all but one in whom pubertal failure occurred. In only one patient, who developed pubertal failure after whole abdominal XRT and required sex steroid replacement therapy (HRT) to achieve normal secondary sexual characteristics, has there been evidence of reversibility of ovarian function with a documented conception at the age of 22.7 years. Five patients who developed pubertal failure required bilateral augmentation mammoplasties despite sex steroid replacement therapy. Four patients have had documented conceptions, all received whole abdominal XRT (20-26.5 Gy) and subsequently developed a premature menopause. There have been no live births, with all miscarriages occurring in the second trimester. The outlook for normal ovarian function following whole abdominal XRT is poor, flank XRT introduced intermittently from 1972, has resulted in less pubertal failure but the possibility of a premature menopause may with time become a reality.

The effect of testicular irradiation on Leydig cell function has been studied in a group of boys irradiated between 1 and 5 years earlier for a testicular relapse of acute lymphoblastic leukaemia. Six of the seven boys irradiated during prepubertal life had an absent testosterone response to HCG stimulation. Two of the four boys irradiated during puberty had an appropriate basal testosterone level, but the testosterone response to HCG stimulation was subnormal in three of the four. Abnormalities in gonadotrophin secretion consistent with testicular damage were noted in nine of the 11 boys. Evidence of severe Leydig cell damage was present irrespective of whether the boys were studied within 1 year or between 3 and 5 years after irradiation, suggesting that recovery is unlikely. Androgen replacement therapy has been started in four boys and will be required by the majority of the remainder to undergo normal pubertal development.

Growth was assessed in 82 children with acute lymphoblastic leukaemia (ALL) who achieved complete continuous first remission following treatment. 34 received prophylactic cranial irradiation at a total dose over 2000 cGy (group I) and 48 at a dose of 1800 cGy (group II). Chemotherapy was given over two or three years and was more intense in group II. Both groups showed a similar significant decrease in height standard deviation score (SDS) over four years (group I -0.31, group II -0.39). 15 children in group I were followed to ten years and continued to show restricted growth with a mean height SDS decrease of -0.84 (range 0 to -1.7). The greatest reduction in yearly decrements in height SDS occurred in the first year after diagnosis. In both groups height SDS increased significantly on completion of chemotherapy. Thus chemotherapy protocols contribute to growth retardation in ALL. In most of these children the mean loss of height over ten years was not sufficiently great to justify long-term growth hormone (GH) therapy.

We have studied granulocyte-macrophage progenitor cells (GM-CFC) in serial bone marrow aspirates from 43 children who had been treated for acute lymphoblastic leukaemia (ALL). All patients were in full remission, not receiving anti-leukaemic therapy and 42 out of the 43 had normal peripheral blood counts. Thirty-seven patients have received standard amounts of chemotherapy and 6 have received additional therapy for relapses occurring in the first treatment-free interval. In the former group estimation of GM-CFC incidence did not provide evidence of long-term residual bone-marrow damage. In the latter, however, the mean incidence of GM-CFC was significantly reduced. This reduction was also apparent when the incidence of GM-CFC was related to the incidence of non-haemopoietic progenitor cells within the marrow (CFU-F).