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.

[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.

Myelofibrosis: an unusual presentation of vitamin D-deficient rickets.

UNLABELLED: We present the case of a breast-fed 5-month-old infant who presented with pancytopenia, secondary to intense myelofibrosis during the winter months because of undiagnosed rickets. The patient responded to oral vitamin D with rapid resolution of symptoms. Secondary hyperparathyroidism was the probable cause of the myelofibrosis. CONCLUSION: Although nutritional rickets remains a problem in developing countries, children in northern climates in industrialized countries may also be at risk. Rickets must be considered when assessing myelofibrosis in a very young child.

Is there IgA from gut mucosal origin in the serum of children with Henoch-Schönlein purpura?

Thirty-two children with Henoch-Schönlein purpura with or without renal symptoms were studied to characterize the IgA hyperglobulinemia observed in the serum of most patients. It was shown that only the IgA1 subclass concentration was increased. Secretory IgA and IgA to gliadin levels were frequently increased in serum, with a good correlation between them. Circulating IgA immune complexes were detected often and contained high activity to gliadin. In contrast, IgA activity to tetanus toxoid did not change. We failed to show any differences in renal involvement. These data suggest that elevation of serum IgA in Henoch-Schönlein purpura is due in part to a disturbance of the gut mucosal immune system, and the presence of circulating IgA immune complexes with dietary antigens can be postulated but cannot explain the occurrence of urinary symptoms.

[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.

Fulminant liver failure in a 12-year-old girl with sickle cell anaemia: favourable outcome after exchange transfusions.

UNLABELLED: Acute liver failure is unusual in sickle cell anaemia. We describe a child with homozygous sickle cell anaemia who developed acute liver disease of abrupt onset during an episode of limb pain. She presented with sudden onset of persistent vomiting, headache, lethargy, epistaxis, and painful liver enlargement. Laboratory investigations were indicative of cholestasis and severe liver failure with profound prolonged clotting times, hypofibrinogenaemia, elevated serum ammonia and lactic acidosis. The symptoms were promptly and completely reversed by two partial exchange transfusions. No evidence of viral infection was found. Cholelithiasis was ruled out by ultrasonography. The child recovered from what appeared to be massive hepatic sickling with no apparent sequelae. CONCLUSION: Massive hepatic sickling should be considered in the differential diagnosis of a child with homozygous sickle cell disease who suddenly develops acute liver failure. Exchange transfusion should be promptly carried out so as to reverse ischaemic hepatic injury.

[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.

A mutation located at the 5' splice junction sequence of intron 3 in the p67phox gene causes the lack of p67phox mRNA in a patient with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is due to a functional defect of the O2(-)-generating NADPH oxidase of neutrophils. Mutations resulting in CGD have been shown to occur in only four genes, thus identifying the main components of the oxidase complex, namely the two subunits of a membrane-bound cytochrome b and two cytosolic factors of activation of 67 kD (p67phox) and 47 kD (p47phox). The present study deals with the biochemical and genetic analysis of the defect in a patient suffering from a p67phox-deficient form of CGD. The p67phox deficiency was ascertained by immunochemistry and the ability of recombinant p67phox to restore NADPH oxidase activity using a cell-free system of oxidase activation. The cellular extracts from the proband contained no p67phox protein and no p67phox mRNA when assayed by Western and Northern blot analysis. However, reverse transcription of mRNA and subsequent cDNA amplification by polymerase chain reaction using specific p67phox primers showed that trace amounts of a p67phox mRNA deleted for exon 3 were synthesized in the patient immortalized B lymphocytes. Sequence analysis of the genomic DNA showed a T-to-C transition at position +2 of intron 3. This point mutation in the consensus 5' splice site of the intron 3 was probably responsible for lack of accumulation of mRNA and also for the skipping of exon 3 detected in the few mRNA molecules that escaped cellular degradation.

[Klinefelter syndrome in 1993. Results of a multicenter study on 58 cases and review of the literature]. / Le syndrome de Klinefelter en 1993. Résultats d'une enquête multicentrique sur cinquante-huit cas et revue de la littérature.

A retrospective multicenter study found 58 cases of Klinefelter syndrome of which 23 (39%) were diagnosed before puberty. Although as common as Down syndrome, Klinefelter syndrome is underdiagnosed and often recognized only in adulthood. Suggestive manifestations in infants, children, and teenagers include facial dysmorphism, micropenis, and delayed speech and should lead to examination of the karyotype. Early recognition of Klinefelter syndrome could be achieved by routinely measuring the size of the testes in school-boys aged 11 to 15 years and performing a karyotype in boys with a volume of less than 2 ml. Early psychological and educational support and testosterone replacement therapy initiated at onset of puberty may lead to improved social and academic outcomes.

Bone marrow transplantation for acute myeloblastic leukaemia: an EBMT Leukaemia Working Party prospective analysis from HLA-typing.

The optimal post-remission therapy for patients with acute myeloblastic leukaemia remains controversial. Allogeneic bone marrow transplantation, autologous bone marrow transplantation, and consolidation chemotherapy are the major options. In order to evaluate their respective value the European Group for Bone Marrow Transplantation conducted a prospective registration study. Patients with newly diagnosed acute myeloblastic leukaemia were registered at the time of HLA-typing and intention to treat in case of presence or absence of an HLA-identical donor was recorded. 27/79 (34%) patients HLA-typed at diagnosis had an identical donor identified. The estimated survivals at 3 years from HLA-typing were 44% and 21% among patients with or without HLA-identical donor, respectively (P = 0.02). 22/26 (85%) patients for whom allogeneic bone marrow transplantation was intended were transplanted but only 15/47 (32%) patients for whom autologous bone marrow transplantation was intended were indeed transplanted (P < 0.001). The survival was 50%, 29% and 17% (P = 0.004) for patients treated with allogeneic bone marrow transplantation, autologous bone marrow transplantation, or chemotherapy, respectively. 40/68 patients HLA-typed in first complete remission had an HLA-identical donor. The estimated 3-year survival among patients typed in first remission with and without HLA-identical donors was 42% and 35% (n.s.), respectively. This technique of early patient registration illustrates the problems of patient selection during the course of the disease and might be used as a complement to randomized trials when comparing bone marrow transplantation and other treatment options.

Transient erythroblastopenia of childhood presenting with echovirus 11 infection.

We report a case of transient erythroblastopenia in a three-year-old girl presenting with echovirus 11 infection. Viral infection was demonstrated by isolation of echovirus 11 in stool cultures and the presence of echovirus 11-specific IgM antibody in serum. We suggest that echovirus may have played a role in the pathogenesis of transient erythroblastopenia of childhood in this patient.

[Citrullinemia: management and clinical course. Apropos of a familial case]. / La citrullinémie: prise en charge et évolution. A propos d'une observation familiale.

The authors report two cases of citrullinemia in siblings which add to 68 observations from the literature. They overview the clinical presentation, diagnosis and therapeutic management of the disease. The prognosis of severe neonatal form remains poor but an early adequate management may contribute to an acceptable outcome.

[Study of serum kinetics of vancomycin during the "antibiotic-lock" technique]. / Etude de la cinétique sérique de la vancomycine au décours de la technique de "blocage in situ".

The serum kinetics of vancomycin was studied in two patients aged 3 and 15 years during antibiotic therapy for catheter related sepsis associated with Staphylococcus epidermidis. Vancomycin was administered, simultaneously, by parenteral conventional doses (30 mg/kg/day div q 8 h) and using the antibiotic-lock technique in the infected catheter at a high concentration (150 mg/ml) during one hour, 3 hours after each infusion. Pharmacokinetics data did not show any significant change in the serum kinetics of the antibiotic. The results suggest that delivering a high concentration of vancomycin in the infected catheter using the lock technique may be useful to sterilize infected catheter without toxic effect.

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.

[Intracranial venous sinus thrombosis in nephrotic syndrome]. / Thrombose des sinus veineux intracrâniens au cours d'un syndrome néphrotique.

A 3-year old child was admitted for a third relapse of nephrotic syndrome associated with intracranial hypertension related to dural sinus thrombosis (tomodensitometry). The treatment consisted in the association of low dose heparin and fresh frozen plasma. After a 3 year-follow-up, there was no neurologic sequelae, and the nephrotic syndrome was on complete remission. The radiologic features and the management of sinus thrombosis are discussed.