Postoperative speech impairment and cranial nerve deficits after secondary surgery of posterior fossa tumours in childhood: a prospective European multicentre study.

PURPOSE: Brain tumours constitute 25% of childhood neoplasms, and half of them are in the posterior fossa. Surgery is a fundamental component of therapy, because gross total resection is associated with a higher progression-free survival. Patients with residual tumour, progression of residual tumour or disease recurrence commonly require secondary surgery. We prospectively investigated the risk of postoperative speech impairment (POSI) and cranial nerve dysfunction (CND) following primary and secondary resection for posterior cranial fossa tumours. METHODS: In the Nordic-European study of the cerebellar mutism syndrome, we prospectively included children undergoing posterior fossa tumour resection or open biopsy in one of the 26 participating European centres. Neurological status was assessed preoperatively, and surgical details were noted post-operatively. Patients were followed up 2 weeks, 2 months and 1 year postoperatively. Here, we analyse the risk of postoperative speech impairment (POSI), defined as either mutism or reduced speech, and cranial nerve dysfunction (CND) following secondary, as compared to primary, surgery. RESULTS: We analysed 426 children undergoing primary and 78 undergoing secondary surgery between 2014 and 2020. The incidence of POSI was significantly lower after secondary (12%) compared with primary (28%, p = 0.0084) surgery. In a multivariate analysis adjusting for tumour histology, the odds ratio for developing POSI after secondary surgery was 0.23, compared with primary surgery (95% confidence interval: 0.08-0.65, p = 0.006). The frequency of postoperative CND did not differ significantly after primary vs. secondary surgery (p = 0.21). CONCLUSION: Children have a lower risk of POSI after secondary than after primary surgery for posterior fossa tumours but remain at significant risk of both POSI and CND. The present findings should be taken in account when weighing risks and benefits of secondary surgery for posterior fossa tumours.

Access to essential anticancer medicines for children and adolescents in Europe.

BACKGROUND: Essential anticancer medicines are an indispensable component of multidisciplinary treatment of paediatric malignancies. A European Society for Medical Oncology (ESMO) study reported inequalities in the availability of anticancer medicines for adult solid tumours and provided a model for the present survey. The aim of this survey was to assess the accessibility of essential medicines used in paediatric cancer patients aged 0 to 18 years across Europe from 2016 to 2018. METHODS: A list of medicines was drawn with input from the European Society for Paediatric Oncology (SIOP Europe) Clinical Research Council referring to the World Health Organization Model List of Essential Medicines for Children (WHO EMLc) 2017. A survey was sent to nominated national clinician and pharmacist rapporteurs and parent associations in up to 37 countries; answers were obtained from 34 countries. RESULTS: The full survey list contained 68 medicines, including 24 on the WHO EMLc 2017. Health professionals reported that 35% of all medicines were prescribed off-label in at least one country and that 44% were always available in >90% of countries. Only 63% of the EMLc 2017 medicines were reported as always available. The main determinant of unavailability was shortages, reported for 72% of medicines in at least one country. Out-of-pocket costs were reported in eight countries. Twenty-seven percent of orally administered medicines were never available in child-friendly formulations. Parents detailed individual efforts and challenges of facilitating ingestion of oral medicines as prescribed. Inequalities in access to pain control during procedures were reported by parents across Europe. CONCLUSIONS: Children and adolescents with cancer in Europe experience lack of access to essential medicines. Urgent actions are needed to address shortages, financial accessibility, availability of safe age-appropriate oral formulations, and pain management across Europe.

Impact of cumulative anthracycline dose, preparative regimen and chronic graft-versus-host disease on pulmonary and cardiac function in children 5 years after allogeneic hematopoietic stem cell transplantation: a prospective evaluation on behalf of the EBMT Pediatric Diseases and Late Effects Working Parties.

This prospective study focused on risk factors and clinical outcome of pulmonary and cardiac late effects after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We prospectively evaluated 162 children by pulmonary function tests (PFTs) and cardiac shortening fraction (SF) before allo-HSCT and yearly up to the 5th year of follow-up. The 5-year cumulative incidence of lung and cardiac impairment was 35 (hazard rate=0.03) and 26% (hazard rate=0.06), respectively. Patients presenting abnormal PFTs and SF at last follow-up were 19 and 13%, respectively, with a median Lansky performance status of 90% (70-100). Chronic graft-versus-host disease (c-GVHD) was the major risk factor for reduced lung function in univariate (P=0.02) and multivariate analysis (P=0.02). Total body irradiation (TBI) alone and TBI together with pre-transplant anthracycline administration were significant risk factors for reduced cardiac function in univariate analysis, only (P=0.04 and 0.004, respectively). In conclusion, our prospective study demonstrates an asymptomatic post-allo-HSCT deterioration of pulmonary and cardiac function in some long-term survivors, who had been transplanted in childhood, and thus emphasizes the need for lifelong cardiopulmonary monitoring and the development of new strategies both to reduce pre-transplant cardiotoxic regimens and to treat more efficiently c-GVHD.

Bone mass after treatment for acute lymphoblastic leukemia in childhood.

PURPOSE: To study bone mass after childhood acute lymphoblastic leukemia (ALL) and determine if reduced bone mass is related to previous therapy or endocrine status at follow-up. PATIENTS AND METHODS: We studied 95 survivors of childhood ALL who were in first remission a median of 11 years (range, 3 to 23 years) after diagnosis and who had never been irradiated outside a cranial field. The bone mass was measured by dual-energy x-ray absorptiometry. The results were compared with data on 396 local controls. RESULTS: Adjusted for sex and age, the mean whole-body bone mineral content (BMC) and bone mineral areal density (BMDA) were both significantly reduced (0.4 SDs less than the predicted mean value). This was mainly caused by reduced bone mass in the 33 participants who were aged 19 years or older at follow-up. In these young adults, the mean height for age, bone area for height, and BMC for bone area were all significantly reduced. This indicated that the reduced whole-body bone mass was caused by both reduced bone size and reduced size-adjusted bone mass. Reduced bone size was related to previous cranial irradiation. Reduced size-adjusted bone mass was not significantly related to age at diagnosis or at follow-up, length of follow-up, cranial irradiation, cumulative dose of methotrexate or corticosteroids, or endocrine status at follow-up. CONCLUSION: The whole-body bone mass was reduced 11 years after diagnosis of childhood ALL. If these abnormalities remain, survivors of childhood ALL will have an increased risk for osteoporotic fractures later in life.

Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia.

PURPOSE: Late anthrocycline cardiotoxicity after treatment for childhood cancer is common and often progressive. A safe anthracycline dose that will not result in late cardiac abnormalities has not been established due to the limited dose ranges used in existing studies. PATIENTS AND METHODS: To determine the relationship between cumulative anthracycline dose and late cardiotoxicity, we performed echocardiograms on 189 survivors of childhood acute lymphoblastic leukemia a median of 8.1 years (range, 2.0 to 23.4) after completion of anthracycline therapy. Patients were treated according to protocols that used widely varying cumulative anthracycline doses, but comparable nonanthracycline chemotherapy. Patients were divided into four groups based on the city of treatment and cumulative anthracycline dose: Copenhagen, 0 to 23 mg/m2 (n = 32); Boston, 45 mg/m2 (n = 17); Copenhagen, 73 to 301 mg/m2 (n = 53); and Boston, 244 to 550 mg/m2 (n = 87). Left ventricular dimension and fractional shortening were adjusted for sex and age or body-surface area through use of a control population (n = 296), and then compared among the four groups. RESULTS: Mean left ventricular dimension was significantly increased in the high-dose Boston group (observed:predicted value, 4.57 cm:4.45 cm; P = .002) and significantly higher than in the two Copenhagen groups. In the three lower-dose groups, there was no significant increase in mean left ventricular dimension, and the groups were not significantly different from each other. Similarly, the mean left ventricular fractional shortening was significantly depressed in the high-dose Boston group (observed:predicted value, 29.0%:33.8%; P = .0001) and significantly lower than in the three lower-dose groups. CONCLUSION: Depressed left ventricular fractional shortening and left ventricular dilatation were uncommon years after treatment of childhood leukemia when cumulative anthracycline doses were < or = 300 mg/m2.

Degree of fatness after treatment for acute lymphoblastic leukemia in childhood.

Excessive fatness is considered a frequent late complication of treatment for childhood acute lymphoblastic leukemia. Most previous studies, however, were based on body mass index (BMI) rather than more direct fat mass measurements. We studied 95 survivors of childhood acute lymphoblastic leukemia a median of 11 yr (range, 3-23 yr) after diagnosis. BMI values at diagnosis, at cessation of therapy, yearly thereafter for up to 10 yr, and at follow-up were compared with French reference values. Whole body percent fat was measured at follow-up by dual energy x-ray absorptiometry and compared with data from 463 local controls. Adjusted for sex and age, the mean BMI increased significantly during therapy and remained largely unchanged thereafter. At follow-up, BMI did not differ significantly between patients and local controls. On the other hand, the whole body percent fat was significantly increased (mean observed/predicted value, 21.8/19.0%; P < 0.0002). Twenty-five patients (26%) had a percent fat above the 90th percentile of the reference values, which indicates excessive fatness. Adjusted for sex and age, a higher percent fat was related to cranial irradiation or GH insufficiency, but not to sex, the cumulative doses of anthracyclines or corticosteroids, or the type of corticosteroid used. BMI was a poor measure of body fatness.

Degree of fatness after allogeneic BMT for childhood leukaemia or lymphoma.

Excess fatness is frequent after childhood ALL treated without BMT. We measured the whole-body percent fat by dual-energy X-ray absorptiometry and the body-mass index (weight/height(2) (kg/m(2)), BMI) in 25 survivors of childhood leukaemia or lymphoma (21 with ALL) who had received TBI and allogeneic BMT a median of 8 years ago (range 4-13). Adjusted for sex and age, the mean BMI was slightly but significantly reduced (0.4 s.d. below predicted) and the whole-body percent fat was significantly increased compared with healthy controls (1.1 s.d. above predicted). Eleven of 25 patients had a percent fat above the 90 percentile of the reference values, which indicates excess fatness. Adjusted for sex and age, a higher percent fat was related to additional cranial irradiation. Controlled for this, the whole-body percent fat seemed to be unrelated to age at BMT, length of follow-up, and previous chemotherapy. Compared with untransplanted ALL survivors treated with cranial irradiation, BMT survivors had significantly reduced BMI but similar whole body percent fat. BMI was a poor measure of body fatness in these patients. In conclusion, survivors of BMT for childhood leukaemia or lymphoma are adipose and slightly underweight and consequently have a substantially reduced lean body mass.

Allogeneic bone marrow transplantation in first remission for children with very high-risk acute lymphoblastic leukemia: a retrospective case-control study in the Nordic countries. Nordic Society for Pediatric Hematology and Oncology (NOPHO).

Among children with high-risk (HR) ALL there are subgroups with very-high-risk (VHR) features and poor prognosis despite developments in conventional chemotherapy for childhood ALL. We evaluated the outcome of VHR-ALL in children receiving allogeneic BMT (allo-BMT) in first remission (1CR) in a retrospective case-control study. In the population-based ALL material of the five Nordic countries, 22 children with VHR-ALL have undergone allo-BMT in 1CR between 1981-1991. We compared the outcome in these 22 children with 44 closely matched control patients who received conventional chemotherapy on HR-ALL protocols, as well as with a group of 405 children representing the remaining HR-ALL patients in the Nordic ALL database. The disease-free survival at 10 years was 73% in children receiving allo-BMT in 1CR, 50% in the matched controls (P = 0.02), and 59% in the remaining HR-ALL patients. The good prognosis of the allo-BMT group was due to a low relapse rate of 9%, as opposed to 41% in the group of matched controls. The superiority of allo-BMT as therapy in 1CR was mainly apparent in those with a very high WBC of > or = 100 x 10(9)/I at diagnosis; in the allo-BMT group 9/10 survived, as opposed to 8/20 of the matched controls (P = 0.03). We conclude that allo-BMT in 1CR should be seriously considered for children with a matched sibling donor and a VHR-ALL with WBC of > or = 100 and other established VHR criteria.

Bone mass after allogeneic BMT for childhood leukaemia or lymphoma.

The bone mass was measured by dual energy X-ray absorptiometry in 25 survivors of childhood leukaemia or lymphoma (21 with ALL) who had received TBI and allogeneic BMT a median of 8 years ago (range 4-13). Results were compared with local data on 463 healthy controls and 95 survivors of childhood ALL treated without BMT. Adjusted for sex and age, the mean whole-body bone mineral content (BMC) and bone mineral areal density were significantly less than in healthy controls (0.8 and 0.5 s.d. less than predicted). The reduced BMC was caused by a significantly reduced height for age, whereas bone area for height and BMC for bone area were similar to controls. Less bone mass tended to be related to additional cranial irradiation and age above 20 years at follow-up. Controlled for this, the whole-body bone mass seemed to be unrelated to previous chemotherapy and endocrine status at follow-up and tended to be only marginally less in BMT patients than in ALL survivors treated without BMT. In conclusion, 8 years after allogeneic BMT for childhood leukaemia or lymphoma, the whole-body bone mass was only slightly reduced and the size-adjusted bone mass (BMC for bone area) was normal. Bone Marrow Transplantation (2000) 25, 191-196.

Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood.

Internal genitalia and uterine blood flow were assessed by ultrasound in 12 females 4.0-10.9 years after total body irradiation and allogeneic bone marrow transplantation for childhood leukaemia or lymphoma. Median age of the participants was 12.7 years (range 6.1-17.6) at bone marrow transplantation and 21.5 years (11.6-25.6) at the follow-up study. At follow-up all had entered puberty and 11/12 females had experienced the menarche. Eight females received sex steroid replacement therapy, three had spontaneous pubertal development and one woman experienced symptoms of estrogen deficiency. Median uterine and ovarian volumes were significantly reduced to -2.6 standard deviation scores (SDS) (-6.3 to -0.6), P = 0.002, and -2.6 SDS (-4.8 to -0.5), P = 0.002, respectively, compared with normal controls. Follicles were only detectable in two individuals. Uterine blood flow was impaired, as a systolic blood flow could be measured in 6/9 individuals, and a diastolic blood flow in 1/9 females. Our results indicate that the prescribed dosage of hormone replacement therapy, which was sufficient to induce bleeding and suppress other stigmata of premature menopause, was inadequate to generate normal uterine growth. In order to achieve uterine growth higher doses of hormone replacement therapy may be required. Our results confirm pelvic ultrasound as a reliable tool for investigation of internal female genitalia; however, in an infertility setting further tests are indicated.

Growth, growth hormone and final height after BMT. Possible recovery of irradiation-induced growth hormone insufficiency.

The aim of the present study was to assess growth, final height, growth hormone (GH) secretion and growth factors after BMT including TBI in childhood. The median age of the 25 participants was 11.3 years at BMT, and a median of 7.5 years had elapsed since BMT. The median height standard deviation score (SDS) declined significantly from diagnosis until 4 years after BMT (n = 25, P = 0.015), and decreased 1.08 SDS from diagnosis until final height (n = 14, P = 0.030). Sitting height to standing height ratio was impaired, -0.64 SDS, P < 0.05. GH insufficiency was found in 32% at follow-up. Repeated assessments of GH production over the years indicated improvement in GH secretion in nine individuals. Evaluation of spontaneous 24-h GH secretion indicated a secretory pattern similar to controls, although the total amount of GH secreted was lower. Neither insulin-like growth factor-1 (IGF-1) nor IGF binding protein-3 (IGFBP-3) alone could be used as a marker of GH insufficiency. IGF-1 was low: -1.18 SDS; (P < 0.001). In conclusion, our study demonstrated the impact on growth, final height, body proportions, GH secretion and growth factors after BMT including TBI. We hypothesize that children who receive BMT at a younger age are more at risk of loss of final height and abnormal body proportions. Our data indicate that some improvement in GH production may occur over the years.

Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: a population-based case control study from the Nordic countries.

This study compares allogeneic BMT with conventional chemotherapy for childhood ALL in second remission. Seventy-five children were transplanted between July 1981 and December 1995. For each patient two control patients matching the following criteria were selected from the Nordic database of ALL: (1) time of diagnosis, (2) T vs. non-T ALL, (3) site of relapse, (4) initial risk group, (5) sex and (6) relapse < or > or =6 months after cessation of therapy. The minimal time of follow-up was 24 months. Mortality rate in CR2, leukemic relapse rate and the proportion in continued second remission were 16/75 (21%), 22/75 (29%) and 37/75 (50%), respectively. P2.-EFS for the BMT group was significantly better than that for the control group (0.40 vs. 0.23, P = 0.02). Children transplanted for bone marrow relapses in particular had a higher P2.-EFS (0.35 vs. 0.15 for the control group, P<0.01). Also, children grafted for early BM relapses had a higher P2.-EFS (0.32 vs. 0.11 for the control group P = 0.01). The outcome was similar when children were transplanted after early or late relapse. Also, there was no difference in outcome between the BMT and the chemotherapy group for children with late relapses. We conclude that allogeneic BMT with an HLA-identical sibling donor or other family donor should be performed in children relapsing in bone marrow during therapy or within 6 months of discontinuing therapy.

Normal final height after treatment for acute lymphoblastic leukemia without irradiation.

In order to evaluate the influence of chemotherapy on linear growth, 28 children treated for acute lymphoblastic leukemia without irradiation were evaluated before, during and after the end of therapy. Median age at diagnosis was 4.4 years (range 2.2-12.7 years) and treatment was discontinued after a median period of 3.1 years (3.0-5.2 years). We observed a significant decrease in height SDS (p = 0.006) from diagnosis to the end of chemotherapy, followed by catch-up in height SDS from the end of chemotherapy to final observation. Catch-up growth took place mainly within the first 2 years after cessation of therapy. In 22 patients final height was reached. Final height was normal (median height SDS -0.035) and even significantly higher than mid-parental height SDS (p = 0.012). In those patients who attained adult stature, the sitting height to standing height ratio was also normal. In conclusion, in children treated for acute lymphoblastic leukemia, chemotherapy exerted a negative influence on growth, but catch-up occurred within 2 years after cessation of therapy, resulting in normal final height and body proportions.

Body mass index of 0 to 45-y-old Danes: reference values and comparison with published European reference values.

OBJECTIVES: To generate body mass index (weight/height(2) (kg/m(2)), BMI) reference values for 0 to 45-y-old Danes and compare these with published European reference values. SUBJECTS: A national sample used to generate the current Danish height and weight reference (29 106 measurements made 1965-1977; age 0-21 y; sample I), and four samples from Copenhagen (3391 measurements made 1981-1985; age 7-45 y; samples II-III and 2608 measurements made 1991-1994; age 6-45 y; samples IV-V). DATA ANALYSIS: Using the LMS method, Danish BMI reference values by age and sex were constructed from samples I and II. These were compared with BMI reference values from Sweden (age 6-16 (girls) or 6-19 y (boys)), Germany (6-19 y), UK (0-23 y), and France (0-87 y). Two recently examined but smaller Danish cohorts (samples IV and V) were compared with the reference values to assess the secular trend in BMI. RESULTS: Overall, Danish BMI reference values (samples I and II) fitted best with French reference values and were systematically below UK, Swedish and German reference values. However, the BMI centiles of young adult Danish women were above French reference values and the BMI of Danes was substantially below French and UK reference values during the first months of life. The mean BMI Z-score of the recently examined samples was 0.24 (sample IV, P=0.0001) and 0.15 (sample V, P=0.0001) based on the French reference values and 0.19 (sample IV, P=0.0007) and 0.01 (sample V, P=0.49) based on the Danish reference values. CONCLUSION: For clinical purposes, we recommend comparing the BMI of Danish children and adolescents with the present Danish reference values and the new IOTF cut-off values and comparing the BMI of Danish adults with the WHO cut-off values. For research purposes, cut-off values and national or internationally used BMI reference values may be used, depending on the research questions.

Published models and local data can bridge the gap between reference values of lung function for children and adults.

The aim of this study was to create reference equations for pulmonary function tests (PFTs) that span the age range from childhood to young adulthood. PFT results (forced vital capacity (FVC), forced expiratory volume in one second (FEV1), ratio of FEV1 to FVC (FEV1/FVC), total lung capacity (TLC), transfer factor) of 348 healthy 13-24 yr old Caucasian never-smokers from a local population study were compared with 13 selected sets of published reference equations. Predicted and observed PFT results differed significantly for 63 of 92 reference equations tested, and most equations accounted poorly for the increase in PFT variables which takes place during adolescence. We selected the equations with the best fit and adjusted their parameters, so that the level and variance of predicted values agreed with the local data. For subjects older than 18 yrs, we selected the European Community for Steel and Coal (ECSC) equations. For subjects younger than 18 yrs, we chose European summary equations for FVC, FEV1, and FEV1/FVC, and recent British equations for TLC and transfer factor. The customized reference equations are the best available (maximum likelihood) for analysing PFTs of patients tested in our laboratory. Our approach can be used whenever generally accepted reference equations are lacking and a local sample of normal subjects is available.

Risk factors for reduced pulmonary function after malignant lymphoma in childhood.

The aim was to study pulmonary function after Hodgkin disease or non-Hodgkin Lymphoma in childhood and to evaluate if younger age at diagnosis and therapy is a risk factor for reduced pulmonary function. We studied a population-based sample of survivors of Hodgkin disease (n = 22) or non-Hodgkin lymphoma (n = 19) in childhood. Pulmonary function test results were compared with reference values for our laboratory, generated by adjusting published reference values fit 348 healthy never-smokers from a local population study. Data were analyses as standardised residuals, which are [observed minus predicted value] divided by the residual standard deviation of the reference equations. At a median of 11 years after diagnosis (range 2 to 24), the participants had significantly reduced lung volumes and transfer factor, unrelated to the few pulmonary symptoms. On average, the total lung capacity was reduced to -0.9 standardised residual and the transfer factor was reduced to -1.3 standardised residual. Young age at therapy seemed to be a risk factor for reduced lung function, especially when treatment included thoracic irradiation. No significant toxic synergism was observed between smoking and previous cancer therapy. Therapy without thoracic irradiation but with doxorubicin and cyclophosphamide was almost as toxic to lung function as therapy with thoracic irradiation but without doxorubicin and cyclophosphamide. In conclusion, lung volumes and transfer factor were reduced several years after childhood Hodgkin disease of non-Hodgkin lymphoma, with young age at therapy as a risk factor, especially when combined with thoracic irradiation.

Bone mineral density in the lumbar spine as determined by dual-energy X-ray absorptiometry. Comparison of whole-body scans and dedicated regional scans.

PURPOSE: To compare bone mineral in the lumbar spine as measured by either consecutive regional or whole-body dual-energy X-ray absorptiometry (DXA), and to develop models that predict regional results from whole-body results. MATERIAL AND METHODS: In 180 children and young adults, bone mineral in the lumbar spine was measured by a Hologic QDR-1000/W DXA scanner, using either whole-body software (which can give data for the lumbar spine subregion) or dedicated lumbar spine software. Data on 139 persons were used to compare the two methods and to develop models that predict the result of a regional scan from the result of a whole-body scan. Data on the remaining 41 persons were used to control these models. RESULTS: Bone mineral content, bone area, and bone mineral areal density (BMDA) of the lumbar spine were measured significantly lower by whole-body scans than by regional scans (p < 0.0001). The difference was larger for the lower values of bone area and BMDA. We developed models that predicted lumbar spine BMDA from whole-body results. When these models were controlled in another group, the mean error between the methods was non-significant and the error was unrelated to the BMDA value. However, the variance of the error was only minimally reduced. CONCLUSIONS: Lumbar spine bone mineral was measured significantly lower by whole-body DXA than by regional DXA. Based on local data, models were developed that removed the significant difference between the methods.

Thyroid function in survivors of childhood acute lymphoblastic leukaemia: the significance of prophylactic cranial irradiation.

OBJECTIVE: Focus on long-term side-effects after cancer therapy in childhood has become of the utmost importance. The hypothalamic-pituitary thyroid (HPT) axis is exposed to irradiation when some children are treated for acute lymphoblastic leukaemia (ALL) with prophylactic cranial irradiation (CIR). Whether this treatment causes hypofunction of the HPT axis remains controversial. DESIGN: We measured plasma levels of total T3 (T3), total T4 (T4) and TSH before stimulation with TRH and plasma levels of TSH, 30 and 150 minutes after stimulation with TRH in 95 patients in first continuous remission of childhood ALL. PATIENTS: Patients diagnosed with ALL before the age of 15 years between 1970 and 1991 and who were in first continuous remission and off treatment for at least one year were studied. The children were aged between 0.5 and 14.8 years (median: 3.9) at diagnosis of ALL. Thyroid function was assessed between 1.2 and 18.3 years (median: 7.6) after completion of therapy. MEASUREMENTS: We measured T4 levels before, and compared TSH levels before and after, stimulation with TRH in patients who were treated with prophylactic CIR (15-24 Gy) (n = 38) (CIR group) with patients who were treated with chemotherapy only (n = 57) (non-CIR group). RESULTS: We found that T3 and T4 levels were normal in all individuals (excluding the women who were on oral contraceptives). The median time from end of treatment to time at follow-up was 9.1 years in the non-CIR group vs. 4.2 years in the CIR group (P < 0.001), and the effect on follow-up time was significant (P = 0.04). It was estimated that just after irradiation, the TSH levels before and 30 and 150 minutes after TRH stimulation was 49% lower in the CIR group; however, after 4.0 years, TSH levels were not significantly different between the two groups. Although within normal limits, the T4 levels were significantly higher in the CIR group compared to the non-CIR group (P = 0.003). It was estimated that, just after the end of treatment, T4 was 19.9% higher in the CIR group. However, in the CIR group, the T4 level decreased significantly over time with -1.5% per year (P = 0.025), while the difference in the non-CIR group was not significant. There was no correlation between T4 and TSH levels and sex, age at diagnosis, age at the end of treatment or age at follow-up. CONCLUSIONS: We conclude that, in our cohort of survivors of childhood ALL, prophylactic cranial irradiation of the central nervous system did not have an adverse effect on hypothalamo-pituitary-thyroid function within a median follow-up time of 8 years.

Bone mass after treatment of malignant lymphoma in childhood.

BACKGROUND: Sex hormone deficiency, growth hormone deficiency, skeletal irradiation, and treatment with corticosteroids or methotrexate may all cause reduction in bone mass after treatment for childhood malignant lymphoma. Previous studies of the bone mass of childhood cancer survivors often lacked adequate local reference data, and survivors of malignant lymphoma were never analyzed separately. PROCEDURE: The bone mass of survivors of childhood Hodgkin disease (n = 23) or non-Hodgkin lymphoma (n = 21) was measured by dual-energy X-ray absorptiometry a median of 11 years after diagnosis (range 2-25). Results were compared with local data on 463 healthy controls. RESULTS: Adjusted for gender and age, the mean whole-body bone mineral content and bone mineral areal density were slightly, but significantly, reduced (0.5 and 0.4 SD lower than predicted). The reduced bone mineral content was associated with a significantly reduced height, whereas the size-adjusted bone mass (bone mineral content for bone area) did not differ significantly from that of controls. Lower height was related to male gender and to cranial, thoracic, and lumbar spine irradiation. Whole-body bone mineral content and bone mineral density were lower in persons treated with lumbar spine irradiation and whole-body bone mineral content was higher in nine women receiving sex hormone replacement therapy or oral contraceptives. Whole-body bone mass was not related to the cumulated doses of corticosteroids or methotrexate. CONCLUSIONS: Eleven years after diagnosis of childhood Hodgkin disease or non-Hodgkin lymphoma, the whole-body bone mass of survivors was only slightly reduced and the size-adjusted bone mass was normal.