Second malignant neoplasm following childhood cancer: A nested case-control study of a recent cohort (1987-2004) from the Childhood Cancer Registry of the Rhône-Alpes region in France.

From a population-based cohort of cases of first cancers diagnosed between 1987 and 2004, before the patient's age of 15 years, the authors conducted a nested case-control study, matching 64 patients who experienced a second malignant neoplasm (SMN) with 190 controls. SMNs comprised 10 leukemia or myelodysplastic syndromes, 5 lymphomas induced by Epstein-Barr virus after allograft, and 49 solid tumors, including mainly 25 carcinomas (17 of the thyroid), 9 bone sarcomas, and 7 central nervous system (CNS) tumors. The median latency occurrence was 6.5 years, and that of thyroid carcinomas induced by 12 Gy fractioned total body irradiation (TBI) was 7.6 years. The relative risk (RR) of an SMN was increased by genetic and family factors and increased 17 to 69 times according to the dose of radiotherapy administered in the region for the first cancer. Age younger than 4 years at the time of radiotherapy increased the risk of SMN. Chemotherapy adjusted according to the dose of radiotherapy administered in the field yielded a greater RR of an SMN only for cumulative doses exceeding 2 g/m2 of epipodophyllotoxin but not for alkylating agents or platinum compounds. The RR of secondary leukemia increased 10-fold following high doses of epipodophyllotoxin >2 g/m2 but was not affected by alkylating agents or anthracyclines. The crude RR of a solid SMN developing after radiotherapy was very high at 18 and reached 90.7 for thyroid carcinoma after TBI, whereas the authors observed no increased risk associated with chemotherapy. These results confirm the risk of secondary leukemia after epipodophyllotoxin and of solid tumor after radiotherapy.

[Long term mortality of five-year survivors of childhood cancer in Rhône-Alpes region]. / Mortalité tardive après cancer des enfants survivants à cinq ans dans la région Rhône-Alpes.

BACKGROUND: The population of survivors of childhood cancer is currently growing. Studies from other countries have shown an increased risk of late mortality. In order to measure this risk within a French cohort, the mortality of children who had survived five years from a cancer diagnosis were compared to the mortality of the general population, according to follow-up interval and cancer and treatment characteristics. METHODS: The study population consisted of 635 children diagnosed with cancer before the age of 15 who had survived at least five years, and were registered in the Rhone-Alpes region cancer registry from 1987 to 1992. Mortality was compared with general population rates of the Rhone-Alpes region to assess age and sex standardized mortality ratio (SMR) and absolute excess risk of death. RESULTS: The median follow-up of children was 14.0 years. Among the 42 observed deaths, 71.4% were attributed to a recurrence of the original cancer, 9.5% to a second cancer. The 15-year cumulative risk of death, all causes, was 7.1%. The overall mortality of the cohort was 20.7 fold greater than the general population (95% CI: 14.9-27.9), and the absolute excess risk of 6.9 per 1000 persons-years. The long term excess-mortality was higher in case of recurrence of original cancer (SMR=99.9, 95% CI: 67.9-141.9, absolute excess risk 35.4 per 1000 persons-years); it was raised during the five to nine years follow-up interval after diagnosis (SMR=33.8, 95% CI: 23.2-47.3) mainly due to the primary malignancy, and decreased after (10-14 years follow-up interval SMR=6.5, 95% IC 2.4-14.2). CONCLUSION: The late mortality of childhood cancer is significantly increased during the five to nine years following diagnosis and decreases after, but the cohort follow-up has to be extended in order to assess outcome beyond 15 years after diagnosis.

[Childhood cancer incidence and survival rates in the Rhône-Alpes regional paediatric registry 1987-1999]. / Les cancers de l'enfant de la région Rhône-Alpes: incidence et survie 1987-1999.

UNLABELLED: Cancer is rare in children, and pediatric malignancies represent only 1% of all cancers. OBJECTIVES: The cure rate is high and increasing, and ongoing data collection is therefore warranted. MATERIALS AND METHODS: Here we report the incidence and survival rates of childhood cancers between 1987 and 1999 in the Rhône-Alpes region of France. RESULTS: A total of 1945 cases were recorded during the study period, with an average of 149.6 new cases per year. The approximate incidence rate was 134.1/10(6) per year and the age-standardized incidence rate was 139.2/10(6) per year. The histological distribution and 5-year survival rates were respectively 30.2 and 73% for leukemia, 12.3 and 91.6% for lymphoma, 24.7 and 60.1% for CNS tumors, 9.1 and 71.1% for neuroblastoma, 2.5 and 94.1% for retinoblastoma, 5.8% and 89.9% for renal tumors, 1 and 75% for liver tumors, 6.1 and 60.9% for bone tumors, 4.1 and 58.6% for soft-tissue tumors, 1.1 and 71% for germ cell tumors, and 2.4 and 85.1% for carcinomas. CONCLUSION: The overall survival rate was 75%. Long-term treatment complications warrant further studies of children who survive into adulthood.

Bone marrow transplantation for acute myeloid leukemia: the EBMT experience. A prospective analysis from HLA-typing. The EMBT Leukemia Working Party.

In 1990, 4,234 BMT were performed in Europe; 2,097 autologous BMT (388 AML) and 2,137 allogeneic BMT (494 AML). Although an established therapy with leukemia free survival (LFS) at five years of 41% +/- 5% (EBMT results) its value compared to alternative therapies remains controversial. During the year 1985, the EBMT conducted a prospective evaluation study. In 12 centres 168 patients with AML were registered at the time of HLA-typing. Basic patient data and treatment intention were recorded. 79 patients were HLA-typed at diagnosis. 68 patients in 1st CR and 21 at other stages. Follow-up of these patients was obtained as of January 1, 1991. Three-year LFS is 44% for patients with an HLA-identical donor and 21% for those without (p = 0.02). Of the 68 patients HLA-typed in first CR, 40 had an HLA-identical donor and 28 no donor. Three-year LFS is 42% and 35%. resp. (n.s.). The difference in results between patients typed at diagnosis and first CR patients illustrates the problem of selection. We conclude that patient registration early in the disease can give insight into the process of selection. Allogeneic BMT incorporated prospectively at diagnosis into therapy offers a survival advantage for patients in this age category compared to alternative therapies.

New developments in stem cell transplantation with special reference to the first in utero transplants in humans.

Based on the experience acquired in post-natal liver transplantation since 1974, we recently initiated pre-natal, in utero stem cell transplantation from the human fetal liver. The first two fetuses that we treated had immunodeficiencies, the third one had thalassemia major. Donors and recipients were not matched. The fetal cells were infused in the umbilical vein of the first two patients and injected intraperitoneally into the third one, under ultrasonic visualization. The first patient, born in 1988, has both engraftment of donor cells and reconstitution of cell-mediated immunity. This child, who had bare lymphocyte syndrome, has no clinical manifestation of the disease and he lives normally at home. The second child, born in 1989, has not yet developed a significant reconstitution of immunity although donor cell engraftment has been proven (Y chromosome in this female patient). The third patient has also evidence of donor cell take (Y chromosome in a female patient) but the effect on thalassemia has not yet been fully analyzed (donor hemoglobin present in small quantity). In all 3 cases, no side-effect of any kind developed in the mother nor in the fetus. Several advantages appear to be associated with in utero FLT: increased probability of graft take, ideal isolation of patient (in the uterus), optimal environment for fetal cell development (in the fetal host).

In utero transplantation of stem cells in humans: immunological aspects and clinical follow-up of patients.

Four human fetuses were treated by transplantation of human fetal liver stem cells. Two of them had severe immunodeficiency disease and the two other ones had thalassemia major. Three of these in utero transplants were followed by engraftment. The three patients are now born: the first one is now very healthy thanks to the reconstitution of cell-mediated immunity associated with this transplant, and he lives normally at home; the two other ones, who have been more recently treated, have a significant improvement of their condition and they also live normally at home. This procedure, for the first time used in humans, has therefore demonstrated its feasibility and its efficacy: during early fetal development, foreign cells engraft readily and may result in cure or significant correction of a large variety of inherited diseases.

Persistence of t(4;11) in cytologically normal bone marrow treated ex vivo with Asta-Z.

The chromosomal anomaly t(4;11) is closely related to a specific type of acute leukemia: occurrence in young children, hyperleukocytosis with a particular immunologic phenotype, and poor response to therapy. Allogeneic bone marrow (BM) transplantation has been done in a few cases. We report a case in which a complete remission was obtained after intensive therapy. Because no donor was available, an autologous BM transplantation was performed after purge ex vivo of the BM collection by Asta-Z. Relapse occurred at day 45.

[Heterogeneity of glycogenosis with alpha-1,4-glucosidase deficiency: enzymatic studies in three families (author's transl)]. / Hétérogénéité de la glycogénose par déficit en alpha-1,4-glucosidase: etude enzymatique dans trois familles.

The authors describe four cases of atypical forms of glycogenosis with alpha-1,4-glucosidase (acid maltase) deficiency. The results of clinical, microscopic, histochemical, enzymological and immunological studies are described. Acid maltase activity has been studied in muscle, leukocytes and fibroblasts. The authors show no difference in the properties of acid maltase; the authors study the purified enzyme from various tissues.

Café au lait spots in ataxia-telangiectasia (A.T.). Histochemical and ultrastructural study in one case.

Café au lait spots appear to represent one of the cutaneous features of Ataxia-telangiectasia (A.T.). At the cellular level, they are characterized by an epidermal hypermelanosis with a normal number of melanocytes. At the subcellular level, two basic abnormalities are observed: (1) an increase in the synthesis of melanosomes; (2) a modification of their distribution within the epidermal keratinocytes. Numerous pendulous melanocytes project into the upper dermis. Altered melanocytes are also observed. These show mitochondrial dilatation, melanosomal autophagic vacuoles, as well as lipid droplets. These abnormalities are not observed in the normal surrounding skin. The significance of these observations is discussed and stress is placed on the difficulty in establishing a differential diagnosis of café au lait spots, based on their histoenzymological and ultrastructural features.

[A familial case with generalized resistance to thyroid hormones]. / Une observation familiale de résistance généralisée aux hormones thyroïdiennes.

BACKGROUND: The syndrome of generalized resistance to thyroid hormones is more frequent than was thought. CASE REPORTS: A 13-year old girl was examined for her short stature. Evaluation of her thyroid function showed increased levels of IT3 and IT4 and normal value of TSH; she also had mosaic Turner's syndrome. Her cousin was rapidly diagnosed as suffering from the same syndrome because of moderately high thyrotropic levels found during neonatal screening; this syndrome was confirmed by molecular biology tests. Five generations of this family were identified as being affected with a pattern indicating autosomal dominant inheritance. CONCLUSION: The clinical manifestations of familial generalized resistance to thyroid hormones vary but this syndrome is easy to biologically confirm. The importance of diagnosing affected children as early as possible should be emphasized, as in such cases their development must be closely monitored particularly where their growth and neurodevelopment are concerned.

[Symptomatic rickets in adolescents]. / Le rachitisme symptomatique de l'adolescent.

Although systematic vitamin D supplementation in adolescents remains debated, rickets is nevertheless a well recognized pathology in this age group. Adolescence is an at-risk period because of rapid growth, insufficient calcium intake and/or vitamin D status. Surveys have shown that calcium intake is insufficient (< 1000 mg a day) in 45% of boys and 71% of girls and that vitamin D status is deficient (25-OH-D < 10 ng/ml). The aims of the study carried out by the Calcium Group of the Société Française de Pédiatrie, were to evaluate the frequency of rickets, and to define the criteria for the adolescent population at risk. Forty-one adolescents with rickets were hospitalized between 1985 and 2000. Most of the cases were from the Northern France: 20 from Paris and suburbs, eight from the North-West, four from the North, four from the North-East; five were from the Center of France. The mean age was 13 years and two months for the 28 girls, and 14 years and four months for the 13 boys. Eighty per cent of the adolescents were from immigrant families (33/41): 15 were from sub-Saharan Africa, ten from North Africa, six from Pakistan and two from Turkey. Two thirds of the adolescents were hospitalized in the 2nd quarter of the year. Some adolescents suffered from lower limb pain, 16 had deformations of lower limbs, particularly genu valgum, associated with pain; seven others had either muscle spasms (4), tetany (3). Serum calcium level was low (average 1.84 mmol/l: [1.1-2.5]), and serum 25-OH D level was extremely low. Radiographic characteristics observed were metaphyseal strips on the knees, with condensed edges at times, with the presence of bone demineralization. The treatment combined calcium and vitamin D, and was often administered intravenously when a hypocalcemia was detected. Rickets is not frequent in adolescents, but nonetheless this pathology is not exceptional, and the number of cases is probably under-estimated. Rickets affects immigrant adolescents in particular but nevertheless could also present a certain risk period for the general population.

[The association of polyarteritis nodosa and familial Mediterranean fever]. / Association périartérite noueuse et maladie périodique.

INTRODUCTION: Some necrotizing vasculitis may be associated with familial Mediterranean fever (FMF). We report a new case of polyarteritis nodosa (PAN) that preceded the diagnosis of FMF. OBSERVATION: A young woman of Turkish origin had a long childhood history of inflammatory arthralgia and myalgia, leading to the provisional diagnosis of chronic juvenile arthritis, then, after a confirmative muscle biopsy, to the diagnosis of PAN, whose outcome remained benign. At the age of 19, she was diagnosed as having FMF on clinical and genetic grounds, and colchicine led to the regression of most symptoms. DISCUSSION: As with Henoch-Schönlein's purpura, PAN seems significantly associated with FMF. Its characteristics are a younger age at onset, more frequent peri-renal hematoma, overlap between classical PAN and micropolyangeitis, and overall better prognosis. In its muscular form, PAN is difficult to distinguish from protracted febrile myalgia, a recently described manifestation of FMF, in which pathological findings are poorly documented.

[Post-anesthetic hepatitis. The role of halothane and antimitotic combinations]. / Hépatite postanesthésique. Responsabilité de l'association halothane-antimitotiques.

A 12 year old boy with Burkitt's lymphoma developed severe hepatitis with hepatomegaly, subclinical jaundice, and a small rise in body temperature, associated with an important rise in SGPT and fall in prothrombin titres, 6 days after anticancer chemotherapy and 24 hours after halothane anaesthesia. Hepatitis A and B serology remained negative. This hepatic failure explained perhaps the unusually severe vincristine toxicity which gave rise to a polyneuritis with important sequelae. The association of halothane hepatitis with antimitotic drugs appeared particularly dangerous, and halothane should probably be avoided in all patients been given or about to be given anticancer chemotherapy.

[Cancer of the thyroid in children. 14 cases]. / Le cancer du corps thyroïde chez l'enfant. Quatorze observations.

Fourteen cases of thyroid gland carcinoma in children (mean age: 10 years) were reviewed. Scintigraphy showed a cold nodule in 10 and diffuse heterogeneous uptake indicating undifferentiated carcinoma in 3. The clinical risk of these tumours resides in alterations of the thyroid gland and in lymph node involvement. The favourable long-term prognosis in children justifies a conservative surgical treatment. Pulmonary metastases respond well to radioactive iodine. TSH secretion must be completely suppressed by continuous hormonal treatment. Anticancerous irradiation is fraught with potential dangers.

[Follow-up of allogenic bone marrow graft with DNA polymorphisms. Use of two minisatellite MS31 and MS43 probes. Comparison with data of chromosomal polymorphisms]. / Suivi de greffe allogénique de moelle osseuse par les polymorphismes de l'ADN. Utilisation de deux sondes minisatellites MS 31 et MS 43. Comparaison avec les données des polymorphismes chromosomiques.

OBJECTIVES: Allogenic bone marrow transplantation is widely used to treat many diseases of the haemopoietic system as well as metabolic disorders. Follow-up is essential to assess acceptance, rejection or post-graft relapse. This study was undertaken to evaluate the usefulness of the minisatellite probes MS31 and MS43 used as a routine follow-up test after bone marrow transplantation. METHODS: Twenty receivers of allogenic bone marrow transplants were followed-up. Two monoclonal minisatellite probes, MS31 and MS43, were used for comparison with the classical polymorphism methods. RESULTS: Fourteen cases of total chimeras, 3 cases of rejections and 3 cases of mixed chimeras were observed with the molecular probe techniques. In 19 of the 20 cases, this technique gave results compatible with classical polymorphism results. CONCLUSIONS: The minisatellite probes MS31 and MS43 were found to be sensitive, effective tests for bone marrow transplants which can be used in routine follow-up.

[Rare nutritional deficiency anemia: deficiency of copper and vitamin E]. / Anémies carentielles nutritionnelles de cause rare: déficit en cuivre, en vitamine E.

Copper deficiency anemia occurs in some specific situations if supplemental copper is not given: low birth-weight premature infants fed milk only, protracted total parenteral nutrition, chronic diarrhea with severe malnutrition. Severe neutropenia precedes the onset of sideroblastic anemia. Iron therapy is ineffective. Diagnosis is established by the low serum copper concentrations, the delayed osseous anomalies, and the dramatic response to copper therapy. Low serum vitamin E concentrations may be found in low birth-weight premature infants aged six to ten weeks with hemolytic anemia. In such cases, vitamin E therapy is effective. This condition occurs more often in infants fed milk formulas without supplemental copper and in infants given high doses of iron. Whether vitamin E deficiency causes anemia is still an open question. Preventive vitamin E supplementation is only partly effective.

[Growth factors and oncogenes in brain tumors: the model of glioblastoma and medulloblastoma]. / Facteurs de croissance et oncogènes dans les tumeurs cérébrales: le modèle du glioblastome et du médulloblastome.

Glioblastomas and medulloblastomas are models for studying the implication of growth factors and oncogenes in tumor development. Amplification and/or hyperexpression of oncogenes result in products that may mimic growth factors and/or their receptors; cells may demonstrate autocrine and/or paracrine activity. Prognostic implications of such findings are suggested.