Genome-wide loss of maternal alleles in a nephrogenic rest and Wilms' tumour from a BWS patient.

A patient with Beckwith-Wiedemann syndrome (BWS) presented with Wilms' tumour. Examination of the nephrectomy specimen showed, in addition to the tumour, the presence of nephrogenic rests. Nephrogenic rests are thought to be precursor lesions from which a Wilms' tumour may develop. A molecular analysis examining the loss of constitutional heterozygosity (LOCH), initially for chromosome 11, was performed on peripheral blood, the normal kidney, nephrogenic rest and tumour material. The study was extended to include markers from all 23 chromosomes. At each informative, locus, LOCH of the maternal allele was shown in the nephrogenic rest and tumour material. In addition, the normal kidney displayed allele imbalance. It would appear from these results that either extensive LOCH across the genome was an early genetic event in the development of malignancy in this patient or that the tumour and rest developed from cells containing no maternal chromosomes. The apparent LOCH seen in the normal kidney sample implies that full reduction to homozygosity is consistent with a histologically normal appearance. Putative mechanisms to explain this phenomenon are discussed.

Results of the United Kingdom Children's Cancer Study Group first Wilms' Tumor Study.

PURPOSE: The first United Kingdom Children's Cancer Study Group (UKCCSG) Wilms' Tumor Trial (UKW1) applied treatment regimens stratified by stage and histology in accordance with National Wilms' Tumor Study (NWTS) criteria, seeking to reduce treatment of low-stage, favorable-histology (FH) tumors without impairing survival and to improve prognosis of stage III and IV (FH) and unfavorable-histology (UH) tumors with more intensive chemotherapy. PATIENTS AND METHODS: Three hundred eighty-four consecutively diagnosed patients with Wilms' tumor were recruited from the 20 UKCCSG centers and Oslo, Norway, between January 1980 and June 1986. The regimen for stage I patients was vincristine (Vcr) only, while stage II patients received Vcr and dactinomycin (Act-D). Stage III patients received three-drug therapy and stage IV and UH patients four-drug regimens. Act-D was given as pulsed doses of 1.5 mg/m2 every 3 or every 6 weeks. No lung irradiation was used in stage IV patients. No randomized comparisons were attempted. End points were survival and event-free survival (EFS). RESULTS: Survival at 6 years in FH patients was 96% for stage I, 93% for stage II, 83% for stage III, 65% for stage IV, and 50% for UH patients of all stages. CONCLUSION: Vcr alone is as effective for stage I FH tumors as the two-drug regimen used in the NWTS and International Society of Pediatric Oncology (SIOP) studies. Fractionation of Act-D is unnecessary. The poorer results for stage IV FH and UH patients compared with the NWTS may be due to treatment differences, such as the use of lung irradiation for stage IV FH patients in NWTS3, and/or to case selection bias.

Leukemia, lymphoma, and related disorders in families of children diagnosed with Wilms' tumor.

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.

Foetal loss and infant deaths in families of children with soft-tissue sarcoma.

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.

Pubertal growth in response to testosterone replacement therapy for radiation-induced Leydig cell failure.

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.

Childhood B cell lymphomas arising in the mediastinum.

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 following the treatment of childhood acute lymphoblastic leukaemia.

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.

Detection of bone marrow metastases in neuroblastoma using a short term tissue culture technique.

AIMS: To improve detection of neuroblastoma metastases in the bone marrow: morphological evaluation of bone marrow is a routine and important component of the clinical staging of neuroblastoma and it depends on the successful identification of tumour cells which may only be present at extremely low levels. METHODS: Bone marrow mononuclear cells from patients with neuroblastoma were incubated in a simple suspension culture and examined regularly using an inverted objective microscope. In some cases cytospins of the cultured cells were examined further using morphological and immunocytological techniques. RESULTS: In some cultures spheroidal clumps of cells could be seen growing after only a few days. If the marrow was cultured for a longer period these spheroids continued to increase in size, became adherent to the stromal cell layer on the culture flask floor, and put out long characteristic processes (neurites). Morphological and immunocytological examination of cytospins from these cultures confirmed these cells as neuroblasts. CONCLUSIONS: This method has provided the sole evidence of marrow metastases in several newly diagnosed cases of neuroblastoma in which the bone marrow had shown no evidence of tumour using standard morphological and fluorescent immunocytological techniques. Although negative cultures do not preclude the presence of neuroblastoma, this method is a useful adjunct to the standard techniques.

A novel variant of growth hormone (GH) insufficiency following low dose cranial irradiation.

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 related to cancer and other chronic conditions.

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.

Male fertility in long-term survivors of childhood acute lymphoblastic leukaemia.

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)

Pulmonary function in survivors of Wilms' tumor.

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.

Response rates in relapsed Wilms' tumor. A need for new effective agents.

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.

How curable is relapsed Wilms' tumour? The United Kingdom Children's Cancer Study Group.

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.

Short duration, high dose, alternating chemotherapy in metastatic neuroblastoma. (ENSG 3C induction regimen). The European Neuroblastoma Study Group.

Fifty-one children, aged from 15 months to 13 years 5 months with metastatic neuroblastoma presenting sequentially at the participating institutions received four 3 to 4 weekly courses of high dose multiagent chemotherapy. High dose cisplatin (200 mg m-2) combined with etoposide (500 mg m-2), HIPE, was alternated with ifosfamide (9 g m-2), vincristine (1.5 mg m-2), and adriamycin (60 mg m-1), IVAd. Disease status was re-evaluated 3 to 4 weeks after the fourth course and the response classified according to the International Neuroblastoma Response Criteria (INRC). The overall response rate in evaluable patients was 55% and response rates by site were: bone marrow 67% (complete response 47%); bone scan 68%; primary tumour 61%, and urinary catecholamine metabolites (VMA/HVA) 95%. Serial 51Cr EDTA renal clearance studies showed a glomerular filtration rate (GFR) decline in 40% of patients but in only seven cases to below 50% of the pretreatment value. There was no instance of renal failure during induction, though two patients developed severe renal failure following 'megatherapy' given to consolidate remission. Serial audiometry showed a significant decline in hearing at frequencies above 2,000 Hz in 37% of children but at or below 2,000 Hz in only 17%. Neutropenia and thrombocytopenia were severe and intravenous antibiotics were required after 30% of courses. Each of two treatment-related deaths occurred during pancytopenia following courses of IVAd. Complete, or greater than 90%, removal of primary site tumour was possible in 70% of cases following this induction regimen and 75% of patients proceeded to elective megatherapy within a median time of 24 weeks after diagnosis. This short intensive induction programme is highly effective at achieving cytoreduction, enabling early surgery and early megatherapy procedures. It is, however, too early to draw firm conclusions about the impact of this approach to treatment on the cure rate.

Impact of childhood cancer on return to normal schooling.

Most of the research into the psychosocial impact of treatment for cancer in children has concentrated on effects on the family rather than on the children's return to school. Thus parents and teachers were questioned about the problems experienced by 117 children who returned to school after spending time in hospital. The children comprised 51 with cancer and two groups of control children (34 with chronic diseases such as renal disease and cardiac conditions and 32 with orthopaedic conditions such as thoracic scoliosis, club foot, and injuries resulting from trauma). Children in all three groups experienced problems on returning to school, the greatest number and variety occurring in the children treated for cancer and the fewest in the children with orthopaedic conditions. The variety of physical problems was greatest and the variety of academic problems was least, with psychological and behavioural problems intermediate. Several problems seemed to be related to drug treatment. Several children missed a considerable amount of full time education. Many teachers were unsure of the academic expectations and physical capabilities of children returning to school. To facilitate a smooth return to school for a child with cancer improved liaison is needed between the hospital, school, and home during the child's absence and teachers need to be better informed.

Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I).

Two hundred and eighty-six patients with medulloblastoma from 46 centres in 15 countries were treated in a prospective randomized trial designed to assess the value of adjuvant chemotherapy. All patients were treated by craniospinal irradiation. Those randomly allocated to receive adjuvant chemotherapy were given vincristine during irradiation and maintenance CCNU and vincristine, given in 6-weekly cycles, for 1 year. The overall survival was 53% at 5 years and 45% at 10 years. At the close of the trial in 1979, the difference between the disease-free survival rate for the chemotherapy and control groups was statistically significant (P = 0.005). Since then, late relapses have occurred in the chemotherapy arm and the statistically significant difference between the two groups has been lost. Although there is now no statistical difference between the two arms of the trial, a benefit for chemotherapy persists in a number of sub-groups; partial or sub-total surgery (P = 0.007), brainstem involvement (P = 0.001), and stage T3 and T4 disease (P = 0.002). A number of prognostic factors for medulloblastoma have emerged; sub-total resection, extent of disease and being male sex carry a poor prognosis.