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1.
Pediatr Blood Cancer ; 66(2): e27495, 2019 02.
Article in English | MEDLINE | ID: mdl-30345604

ABSTRACT

BACKGROUND: Very few previous studies have addressed the question of colorectal cancer (CRC) after childhood cancer treatment. We aimed to quantify the roles of radiation therapy and chemotherapy agents in the occurrence of subsequent CRC. METHODS: A nested case-control study was conducted using 36 CRC cases and 140 controls selected from 7032 five-year survivors of the French Childhood Cancer Survivor Study (FCCSS) cohort, treated from 1945 to 2000 in France. The radiation dose-distribution metrics at the site of CRC and doses of individual chemotherapeutic agents were calculated. Conditional logistic regressions were performed to calculate odds ratios (ORs). RESULTS: Overall, patients who received radiotherapy with estimated dose to colon had a 4.3-fold (95% CI, 1.3-17.6) increased risk for CRC compared with patients who did not receive radiotherapy, after adjustment for chemotherapy. This risk increased to 8.9-fold and 19.3-fold among patients who received radiation doses ranging from 20 to 29.99 Gy and ≥30 Gy, respectively. Our data reported a significantly elevated OR for anthracyclines, after controlling for radiotherapy and MOPP regimen. But, restricted analyses excluding patients who had received ≥30 Gy showed that only radiation doses ranging from 20 to 29.99 Gy produced a significant increase in subsequent CRC risk (OR = 7.8; 95% CI, 1.3-56.0), after controlling for anthracyclines and MOPP regimen. CONCLUSIONS: The risk of subsequent CRC was significantly increased after radiation dose (even < 30 Gy). This novel finding supports the need to update monitoring guidelines for CRC to optimize the long-term follow-up for subsequent CRC in survivors of childhood cancer.


Subject(s)
Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/etiology , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/etiology , Radiotherapy/adverse effects , Adolescent , Antineoplastic Agents/adverse effects , Case-Control Studies , Child , Child, Preschool , Female , History, Ancient , Humans , Infant, Newborn , Male , Risk Factors
2.
Eur J Heart Fail ; 21(4): 509-518, 2019 04.
Article in English | MEDLINE | ID: mdl-30592114

ABSTRACT

BACKGROUND: Paediatric cancer survivors have a high risk of developing cardiac diseases, and the most frequent cardiac disease is heart failure (HF). The radiation dose-volume effects in the heart and cardiac substructures have not been explored in childhood cancer survivors (CCS). Therefore, the role of irradiated heart volume in the occurrence of HF among this population remains unclear. The aims of this study were to determine the doses and irradiated volumes of the heart and left ventricle (LV) related to the risk of HF in CCS and to investigate the impact of anthracycline exposure on this risk. METHODS AND RESULTS: A case-control study nested in the French Childhood Cancer Survivors Study cohort. The mean heart and left ventricular doses and volumes indicators were estimated by reconstruction of individual treatments. A total of 239 HF cases and 1042 matched controls were included. The median age of HF diagnosis was 25.1 years. The median volume of the heart that received ≥ 30 Gy was 61.1% for cases and 16.9% for controls. In patients who did not receive anthracycline, the risk of HF was increased 3.6-fold when less than 10% of the LV received ≥ 30 Gy when compared to patients who were not exposed to any cardiac radiation and anthracycline. CONCLUSIONS: Small irradiated volumes of the heart or LV were significantly associated with HF risk. To the author's knowledge, this is the first study to report a dose-response relationship based on dose-volume indicators in CCS, which can be translated efficiently into current clinical practice.


Subject(s)
Cardiac Volume/radiation effects , Cardiotoxicity/physiopathology , Heart Failure/physiopathology , Heart/radiation effects , Neoplasms/radiotherapy , Radiotherapy/adverse effects , Adult , Anthracyclines/adverse effects , Anthracyclines/therapeutic use , Cardiac Volume/drug effects , Cardiotoxicity/etiology , Case-Control Studies , Child , Child, Preschool , Dose-Response Relationship, Radiation , Female , Heart/drug effects , Heart Failure/chemically induced , Heart Failure/etiology , Heart Ventricles/drug effects , Heart Ventricles/radiation effects , Humans , Male , Radiation Dosage
3.
Haematologica ; 102(10): 1727-1738, 2017 10.
Article in English | MEDLINE | ID: mdl-28751566

ABSTRACT

Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of non-very high-risk patients by comparing prolonged (long-asparaginase) versus standard (short-asparaginase) native E. coli asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children's Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native E. coli asparaginase were switched to equivalent doses of Erwinia or pegylated E. coli asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87; P=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89; P=0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70; P=0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3-4 infection during consolidation (25.2% versus 14.4%) and late intensification (22.6% versus 15.9%) and the incidence of grade 2-4 allergy were higher in the long-asparaginase arm (30% versus 21%). Prolonged native E. coli asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy. This trial was registered at www.clinicaltrials.gov as #NCT00003728.


Subject(s)
Asparaginase/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Asparaginase/administration & dosage , Asparaginase/adverse effects , Child , Child, Preschool , Consolidation Chemotherapy , Escherichia coli Proteins/administration & dosage , Escherichia coli Proteins/adverse effects , Escherichia coli Proteins/therapeutic use , Female , Humans , Induction Chemotherapy , Infant , Lymphoma, Non-Hodgkin/diagnosis , Lymphoma, Non-Hodgkin/mortality , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Survival Analysis , Time Factors , Treatment Outcome
4.
Circulation ; 133(1): 31-8, 2016 Jan 05.
Article in English | MEDLINE | ID: mdl-26487757

ABSTRACT

BACKGROUND: Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between the heart radiation dose (HRD) received during childhood and the risk of CD. METHODS AND RESULTS: The cohort comprised 3162 5-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them were rated grade ≥3. Cox and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11.0% (95% confidence interval [CI], 9.5-12.7) and 7·4% (95% CI, 6.2-8.9) when only the CDs of grade ≥3 were considered. In comparison with patients who received no anthracycline and either no radiotherapy or an HRD<0·1Gy, the risk was multiplied by 18·4 (95% CI, 7.1-48.0) in patients who had received anthracycline and no radiotherapy or a HRD <0.1Gy, by 60.4 (95% CI, 22.4-163.0) in those who had received no anthracycline and an HRD≥30Gy, and 61.5 (95% CI, 19.6-192.8) in those who had received both anthracycline and an HRD≥30Gy. CONCLUSIONS: Survivors of childhood cancers treated with radiotherapy and anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it.


Subject(s)
Antineoplastic Agents/adverse effects , Heart Diseases/etiology , Neoplasms/drug therapy , Neoplasms/radiotherapy , Adult , Anthracyclines/adverse effects , Antineoplastic Protocols , Child , Child, Preschool , Cohort Studies , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Female , Heart Diseases/chemically induced , Heart Diseases/epidemiology , Humans , Male , Neoplasms/epidemiology , Risk Factors
5.
J Clin Endocrinol Metab ; 100(11): 4282-90, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26327481

ABSTRACT

CONTEXT: Thyroid carcinoma is a frequent complication of childhood cancer radiotherapy. The dose response to thyroid radiation dose is now well established, but the potential modifier effect of other factors requires additional investigation. OBJECTIVE: This study aimed to investigate the role of potential modifiers of the dose response. DESIGN: We followed a cohort of 4338 5-year survivors of solid childhood cancer treated before 1986 over an average of 27 years. The dose received by the thyroid gland and some other anatomical sites during radiotherapy was estimated after reconstruction of the actual conditions in which irradiation was delivered. RESULTS: Fifty-five patients developed thyroid carcinoma. The risk of thyroid carcinoma increased with a radiation dose to the thyroid of up to two tenths of Gy, then leveled off for higher doses. When taking into account the thyroid radiation dose, a surgical or radiological splenectomy (>20 Gy to the spleen) increased thyroid cancer risk (relative risk [RR] = 2.3; 95% confidence interval [CI], 1.3-4.0), high radiation doses (>5 Gy) to pituitary gland lowered this risk (RR = 0.2; 95% CI, 0.1-0.6). Patients who received nitrosourea chemotherapy had a 6.6-fold (95% CI, 2.5-15.7) higher risk than those who did not. The excess RR per Gy of radiation to the thyroid was 4.7 (95% CI, 1.7-22.6). It was 7.6 (95% CI, 1.6-33.3) if body mass index at time of interview was equal or higher than 25 kg/m(2), and 4.1 (95% CI, 0.9-17.7) if not (P for interaction = .1). CONCLUSION: Predicting thyroid cancer risk following childhood cancer radiation therapy probably requires the assessment of more than just the radiation dose to the thyroid. Chemotherapy, splenectomy, radiation dose to pituitary gland, and obesity also play a role.


Subject(s)
Neoplasms, Radiation-Induced/epidemiology , Radiotherapy/adverse effects , Thyroid Neoplasms/epidemiology , Adolescent , Antineoplastic Agents/adverse effects , Child , Child, Preschool , Cohort Studies , Dose-Response Relationship, Radiation , Humans , Incidence , Infant , Infant, Newborn , Nitrosourea Compounds/adverse effects , Obesity/complications , Obesity/epidemiology , Pituitary Gland/radiation effects , Radiation Dosage , Retrospective Studies , Risk Factors , Splenectomy , Thyroid Gland/radiation effects
6.
Pediatr Blood Cancer ; 62(10): 1733-8, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25893277

ABSTRACT

BACKGROUND: Rhabdomyosarcoma (RMS) occasionally occurs in a context of a predisposition syndrome. The most common predisposition syndromes include germline TP53 mutations and constitutive alterations in RAS pathway activation, such as Costello syndrome, Noonan syndrome and neurofibromatosis type 1. We report a national retrospective series of 16 RMS occurring in neurofibromatosis type 1 (NF1) patients during childhood, within a 20-year period. RESULTS: The mean age at diagnosis of the cancer was 2.5 years. All were embryonal subtype. Most tumours developed in the pelvis. One was metastatic. Chemotherapy and radiotherapy were normally scheduled without any specific toxicity. The 5-year event-free survival and overall survival were 67% and 87%, respectively. Long-term sequel related to chemotherapy consisted in two chronic tubulopathies, hence not obviously different from non-NF1 patients. No second cancer was reported so far with a median follow-up of 9.7 years. The genomic analysis performed on six samples revealed the abnormalities commonly observed in sporadic RMS: gain of chromosome 2 (5/6), 8 (6/6) and chromosome 11p loss of heterozygosity (5/6). Interestingly, we identified small deletions in tumour suppressor genes that may synergize with NF1 inactivation. CONCLUSIONS: Patients with neurofibromatosis are prone to develop embryonal-type RMS that require the same treatment as sporadic cases.


Subject(s)
Neurofibromatosis 1/complications , Rhabdomyosarcoma/complications , Child, Preschool , Cohort Studies , Disease-Free Survival , Female , Humans , Infant , Kaplan-Meier Estimate , Male , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Rhabdomyosarcoma/genetics , Rhabdomyosarcoma/mortality
7.
Strahlenther Onkol ; 191(7): 604-12, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25896312

ABSTRACT

INTRODUCTION: Neuroblastoma (NB) is the most frequent indication for extracranial pediatric radiotherapy. As long-term survival of high-risk localized NB has greatly improved, we reviewed treatment-related late toxicities in pediatric patients who received postoperative radiotherapy (RT) for localized NB within two French prospective clinical trials: NB90 and NB94. PATIENTS AND METHODS: From 1990-2000, 610 children were enrolled. Among these, 35 were treated with induction chemotherapy, surgery, and RT. The recommended RT dose was 24 Gy at ≤ 2 years, 34 Gy at > 2 years, ± a 5 Gy boost in both age groups. RESULTS: The 22 patients still alive after 5 years were analyzed. The median follow-up time was 14 years (range 5-21 years). Late effects after therapy occurred in 73 % of patients (16/22), within the RT field for 50 % (11/22). The most frequent in-field effects were musculoskeletal abnormalities (n = 7) that occurred only with doses > 31 Gy/1.5 Gy fraction (p = 0.037). Other effects were endocrine in 3 patients and second malignancies in 2 patients. Four patients presented with multiple in-field late effects only with doses > 31 Gy. CONCLUSION: After a median follow-up of 14 years, late effects with multimodality treatment were frequent. The most frequent effects were musculoskeletal abnormalities and the threshold for their occurrence was 31 Gy.


Subject(s)
Neuroblastoma/radiotherapy , Radiation Injuries/etiology , Radiotherapy, Adjuvant , Adolescent , Child , Child, Preschool , Dose Fractionation, Radiation , Female , France , Gene Amplification , Humans , Infant , Male , N-Myc Proto-Oncogene Protein , Neoplasm, Residual/mortality , Neoplasm, Residual/radiotherapy , Neoplasms, Radiation-Induced/etiology , Neuroblastoma/genetics , Neuroblastoma/mortality , Nuclear Proteins/genetics , Oncogene Proteins/genetics , Prospective Studies , Radiotherapy Dosage , Survival Analysis
8.
J Pediatr Hematol Oncol ; 37(1): 68-71, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25411866

ABSTRACT

Transient remissions (TRs) of acute leukemia without any antileukemic treatment are extremely rare events. We report 2 TRs of acute lymphoblastic leukemia and acute myeloid leukemia in a 2-year-old boy and a 12-year-old girl, respectively, both associated with red blood cells and platelets transfusions and infection. These 2 factors are frequently present in previously reported cases and could induce a stimulation of the immune system although the underlying mechanisms of TRs are still unknown.


Subject(s)
Leukemia, Myeloid, Acute/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Remission, Spontaneous , Child , Child, Preschool , Diagnosis, Differential , Erythrocyte Transfusion , Female , Humans , Male , Platelet Transfusion
9.
Haematologica ; 99(7): 1220-7, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24727815

ABSTRACT

Dexamethasone could be more effective than prednisolone at similar anti-inflammatory doses in the treatment of childhood acute lymphoblastic leukemia. In order to check if this "superiority" of dexamethasone might be dose-dependent, we conducted a randomized phase III trial comparing dexamethasone (6 mg/m(2)/day) to prednisolone (60 mg/m(2)/day) in induction therapy. All newly diagnosed children and adolescents with acute lymphoblastic leukemia in the 58951 EORTC trial were randomized on prephase day 1 or day 8. The main endpoint was event-free survival; secondary endpoints were overall survival and toxicity. A total of 1947 patients with acute lymphoblastic leukemia were randomized. At a median follow-up of 6.9 years, the 8-year event-free survival rate was 81.5% in the dexamethasone arm and 81.2% in the prednisolone arm; the 8-year overall survival rates were 87.2% and 89.0% respectively. The 8-year incidences of isolated or combined central nervous system relapse were 2.9% and 4.5% in the dexamethasone and prednisolone arms, respectively. The incidence of grade 3-4 toxicities during induction and the frequency of osteonecrosis were similar in the two arms. In conclusion, dexamethasone and prednisolone, used respectively at the doses of 6 and 60 mg/m(2)/day during induction, were equally effective and had a similar toxicity profile. Dexamethasone decreased the 8-year central nervous system relapse incidence by 1.6%. This trial was registered at www.clinicaltrials.gov as #NCT00003728.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Child , Child, Preschool , Dexamethasone/administration & dosage , Female , Humans , Immunophenotyping , Induction Chemotherapy , Infant , Infant, Newborn , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prednisolone/administration & dosage , Risk Factors , Treatment Outcome
10.
Pediatr Blood Cancer ; 61(6): 1041-8, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24482108

ABSTRACT

OBJECTIVES: To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so-called Kostmann syndrome, in France. STUDY DESIGN: Two pedigrees were identified from the French registry. RESULTS: The study included five subjects (three males), which represent 0.7% of the 759 SCN cases registered in France. The age at diagnosis was 0.3 years (range: 0.1-1.2 years) and the median age at the last follow-up was 7.3 years (range: 1.2-17.8 years). A novel large homozygous deletion of the HAX1 gene (exons 2-5) was found in one pedigree; while, a homozygous frameshift mutation was identified in exon 3 (c.430dupG, p.Val144fs) in the second pedigree. Severe bacterial infections were observed in four patients, including two cases of sepsis, one case of pancolitis, a lung abscess, and recurrent cellulitis and stomatitis. During routine follow-up, the median neutrophil value was 0.16 × 10(9)/L, associated with monocytosis (2 × 10(9)/L). Bone marrow (BM) smears revealed a decrease of the granulocytic lineage with no mature myeloid cells above the myelocytes. One patient died at age 2 from neurological complications, while two other patients, including one who underwent a hematopoietic stem cell transplantation (HSCT) at age 5, are living with very severe neurological retardation. CONCLUSIONS: SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Neutropenia/congenital , Adaptor Proteins, Signal Transducing/chemistry , Adaptor Proteins, Signal Transducing/physiology , Atrophy , Bacterial Infections/etiology , Brain/pathology , Child , Child, Preschool , Congenital Bone Marrow Failure Syndromes , Consanguinity , Developmental Disabilities/genetics , Developmental Disabilities/pathology , Ethnicity/genetics , Exons/genetics , Female , France , Genes, Recessive , Granulocyte Colony-Stimulating Factor/therapeutic use , Hematopoietic Stem Cell Transplantation , Humans , Immunocompromised Host , Infant , Intellectual Disability/genetics , Male , Mutation, Missense , Myelopoiesis/genetics , Myelopoiesis/physiology , Neutropenia/blood , Neutropenia/genetics , Neutropenia/pathology , Neutropenia/surgery , Pakistan/ethnology , Pedigree , Polymorphism, Single Nucleotide , Protein Isoforms/chemistry , Protein Isoforms/genetics , Protein Isoforms/physiology , Sequence Deletion
11.
Radiat Environ Biophys ; 53(2): 381-90, 2014 May.
Article in English | MEDLINE | ID: mdl-24419490

ABSTRACT

Bone sarcoma as a second malignancy is rare but highly fatal. The present knowledge about radiation-absorbed organ dose-response is insufficient to predict the risks induced by radiation therapy techniques. The objective of the present study was to assess the treatment-induced risk for bone sarcoma following a childhood cancer and particularly the related risk of radiotherapy. Therefore, a retrospective cohort of 4,171 survivors of a solid childhood cancer treated between 1942 and 1986 in France and Britain has been followed prospectively. We collected detailed information on treatments received during childhood cancer. Additionally, an innovative methodology has been developed to evaluate the dose-response relationship between bone sarcoma and radiation dose throughout this cohort. The median follow-up was 26 years, and 39 patients had developed bone sarcoma. It was found that the overall incidence was 45-fold higher [standardized incidence ratio 44.8, 95 % confidence interval (CI) 31.0-59.8] than expected from the general population, and the absolute excess risk was 35.1 per 100,000 person-years (95 % CI 24.0-47.1). The risk of bone sarcoma increased slowly up to a cumulative radiation organ absorbed dose of 15 Gy [hazard ratio (HR) = 8.2, 95 % CI 1.6-42.9] and then strongly increased for higher radiation doses (HR for 30 Gy or more 117.9, 95 % CI 36.5-380.6), compared with patients not treated with radiotherapy. A linear model with an excess relative risk per Gy of 1.77 (95 % CI 0.6213-5.935) provided a close fit to the data. These findings have important therapeutic implications: Lowering the radiation dose to the bones should reduce the incidence of secondary bone sarcomas. Other therapeutic solutions should be preferred to radiotherapy in bone sarcoma-sensitive areas.


Subject(s)
Bone Neoplasms/etiology , Neoplasms, Radiation-Induced/etiology , Neoplasms, Second Primary/etiology , Radiotherapy/adverse effects , Sarcoma/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Bone Neoplasms/chemically induced , Bone Neoplasms/epidemiology , Child , Child, Preschool , Cohort Studies , Dose-Response Relationship, Radiation , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Models, Statistical , Neoplasms, Radiation-Induced/chemically induced , Neoplasms, Radiation-Induced/epidemiology , Neoplasms, Second Primary/chemically induced , Neoplasms, Second Primary/epidemiology , Radiotherapy Dosage , Risk , Sarcoma/chemically induced , Sarcoma/epidemiology , Survivors , Young Adult
12.
Br J Haematol ; 164(2): 266-71, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24152194

ABSTRACT

A minority of children with chronic immune thrombocytopenia (ITP) require therapeutic intervention to prevent haemorrhagic risk. This retrospective national study evaluated romiplostim in childhood non-responsive or refractory chronic ITP. Between 2009 and 2012, 10 patients whose Buchanan score was 3-4 were treated with romiplostim. The median duration of thrombocytopenia was 1·9 years (0·8-15). The median duration of romiplostim treatment was 9 months (3-36). A response was observed in 5/10 patients (one complete, four partial). No serious adverse effect was noticed. The long-term benefit/risk balance of this innovative treatment is currently recorded by Centre de Référence National des Cytopénies Auto-immunes de l'Enfant.


Subject(s)
Purpura, Thrombocytopenic, Idiopathic/drug therapy , Receptors, Fc/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Thrombopoietin/therapeutic use , Adolescent , Child , Child, Preschool , Female , Follow-Up Studies , France , Humans , Infant , Male , Receptors, Fc/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Retrospective Studies , Thrombopoietin/administration & dosage , Thrombopoietin/adverse effects , Treatment Outcome
13.
Pediatr Blood Cancer ; 61(3): 473-8, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23970385

ABSTRACT

PURPOSE: Describe the epidemiology, clinical profiles and outcomes associated with head and neck (H&N) involvement in children/adolescents with B-cell non-Hodgkin lymphoma (B-NHL). METHODS: Analysis of children/adolescents with H&N B-NHL prospectively enrolled in the SFOP LMB-89 trial (July 1989-June 1996). RESULTS: One hundred and twelve of 561 patients (20%) had H&N involvement. The mean age of the patients was 8.4 years. Murphy staging differed between the H&N patients and the others (P < 0.0001): 9% versus 5% of the patients presented with stage I disease, 36% versus 11% presented with stage II disease, 12% versus 59% presented with stage III disease, 17% versus 10% with stage IV disease and 27% versus 16% with B-AL. Twenty-nine H&N patients (26%) had CNS involvement at diagnosis versus 8.5% in the group without H&N involvement (P < 0.0001). Patients were treated according to the LMB89 protocol: 3 H&N patients were allocated to group A, 70 to group B and 39 to group C. Ninety-seven percent of H&N patients achieved CR and event-free and overall survival at 4 years was 95.5% (5 deaths in patients with CNS disease). On multivariate analysis, EFS was significantly better in H&N patients than in non-H&N patients (P = 0.021), but not OS (P = 0.11). CONCLUSION: The H&N site is the second most common location for B-NHL at diagnosis and is more frequently associated with disseminated disease and CNS involvement than other sites. However, outcomes are no worse for these patients than for the rest of the population.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, B-Cell/drug therapy , Lymphoma, B-Cell/drug therapy , Acute Disease , Adolescent , Child , Child, Preschool , Cyclophosphamide/therapeutic use , Cytarabine/therapeutic use , Doxorubicin/therapeutic use , Etoposide/therapeutic use , Female , Follow-Up Studies , Humans , Hydrocortisone/therapeutic use , Infant , L-Lactate Dehydrogenase/blood , Leucovorin/therapeutic use , Leukemia, B-Cell/mortality , Leukemia, B-Cell/pathology , Lymphoma, B-Cell/mortality , Lymphoma, B-Cell/pathology , Male , Methotrexate/therapeutic use , Neoplasm Staging , Prednisone/therapeutic use , Vincristine/therapeutic use
14.
Blood ; 121(13): 2415-23, 2013 Mar 28.
Article in English | MEDLINE | ID: mdl-23321258

ABSTRACT

The aim of our study was to analyze the factors contributing to heterogeneity of prognosis in patients with hyperdiploidy>50 chromosomes (HD>50), a group of B-cell precursor acute lymphoblastic leukemia with favorable outcome. The 541 HD>50 patients registered prospectively in the 58951 European Organisation for Research and Treatment of Cancer (EORTC) Children's Leukemia Group (CLG) trial, identified by karyotype (446 patients) and by DNA index (DI) (490 patients), had a 6-year event-free survival (EFS) of 89.0% (standard error [SE] = 1.5%) and a 6-year overall survival (OS) of 95.9% (SE = 0.9%). The strongest prognostic factor was the modal number of chromosomes (MNC): the 6-year EFS of 51-53, 54-57, and 58-66 MNC groups were 80%, 89%, and 99%, respectively (P < .0001). Ploidy assessed by DI was also a favorable factor: the higher the DI, the better the outcome. The 6-year EFS of the 3 subgroups of DI < 1.16/≥1.16-<1.24/≥1.24 were 83%, 90%, and 95%, respectively (P = .009). All usual combinations of trisomies (chromosomes 4, 10, 17, 18) were significant favorable factors but had lower EFS when MNC was lower than 58. In multivariate analysis, MNC remained the strongest factor. Consequently, the best indicator for excellent outcome was ploidy assessed by karyotype because patients with 58-66 chromosomes stood every chance of being cured (OS of 100% at 6-year follow-up) with less-intensive therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003728. Registered: http://www.eortc.org/, http://clinicaltrials.gov/show/NCT00003728.


Subject(s)
Clinical Trials as Topic , Diploidy , Polyploidy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Age of Onset , Child , Child, Preschool , Chromosome Aberrations/statistics & numerical data , Chromosomes/genetics , Clinical Trials as Topic/methods , Female , Follow-Up Studies , Genetic Heterogeneity , Humans , Infant , Infant, Newborn , Karyotyping , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Remission Induction
15.
PLoS One ; 7(8): e44010, 2012.
Article in English | MEDLINE | ID: mdl-22952854

ABSTRACT

Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare ERCC3 variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.


Subject(s)
Genetic Predisposition to Disease , Hepatocyte Growth Factor/deficiency , Hepatocyte Growth Factor/genetics , Inheritance Patterns/genetics , Papillomaviridae/physiology , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/genetics , Adolescent , Amino Acid Sequence , Antigens, Viral/immunology , Base Sequence , Cell Proliferation/drug effects , Child , Codon, Nonsense/genetics , Epidermodysplasia Verruciformis/genetics , Epidermodysplasia Verruciformis/immunology , Epidermodysplasia Verruciformis/microbiology , Epidermodysplasia Verruciformis/virology , Exome/genetics , Hepatocyte Growth Factor/chemistry , Homozygote , Humans , Immunophenotyping , Infant , Male , Mitogens/pharmacology , Molecular Sequence Data , Papillomaviridae/drug effects , Proto-Oncogene Proteins/chemistry , T-Lymphocytes/drug effects , T-Lymphocytes/pathology , Young Adult
16.
Medicine (Baltimore) ; 91(4): e1-e19, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22751495

ABSTRACT

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.


Subject(s)
Immunocompromised Host/genetics , Job Syndrome/epidemiology , Job Syndrome/genetics , STAT3 Transcription Factor/deficiency , STAT3 Transcription Factor/genetics , Adolescent , Adult , Age Distribution , Child , Child, Preschool , Cross-Sectional Studies , DNA Mutational Analysis , Databases, Factual , Eczema/epidemiology , Eczema/etiology , Female , France/epidemiology , Genetic Predisposition to Disease/epidemiology , Heterozygote , Humans , Incidence , Infant , Infant, Newborn , Job Syndrome/complications , Job Syndrome/immunology , Male , Middle Aged , Phosphorylation , Pneumonia, Bacterial/epidemiology , Pneumonia, Bacterial/etiology , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/etiology , Risk Assessment , Severity of Illness Index , Sex Distribution , Signal Transduction , Skin Diseases, Bacterial/epidemiology , Skin Diseases, Bacterial/etiology , Staphylococcal Infections/epidemiology , Staphylococcal Infections/etiology , Survival Analysis , Young Adult
17.
Br J Haematol ; 158(5): 649-56, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22757721

ABSTRACT

There is little data available regarding children and adolescents with Hodgkin lymphoma (HL) who relapse after combined-modality treatment, even though they have a substantial chance of cure. The purpose of this national retrospective study was to evaluate the outcome of patients with recurrent/refractory HL and determine adverse prognostic factors. From 1990 to 2006, 70 patients (median age 13·9 years) with refractory (n = 31) or first relapse (n = 39) HL were identified. Median time from end of treatment to relapse was 6 months (3-56). Relapses occurred in irradiated areas in 43/70 patients. Salvage therapy consisted of chemotherapy and 50 patients received high-dose chemotherapy with autologous stem cell transplantation. Radiotherapy was performed in 29 cases, tandem autologous transplantation in five and allograft in three. With a median follow-up of 40 months (2-140), significant prognostic factors were time to progression/relapse and response to therapy before autograft. Event-free survival and overall survival in patients with refractory disease, early relapse and late relapse were 35 ± 9%, 67 ± 11%, 76 ± 10% and 48 ± 11%, 89 ± 7% and 80 ± 10%, respectively. As progression <3 months was a major adverse prognostic factor, novel therapeutic approaches are needed for this group of patients. By contrast, patients have substantial chance of long term second remission in case of relapse >3 months.


Subject(s)
Hodgkin Disease/therapy , Neoplasm Recurrence, Local , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Combined Modality Therapy/mortality , Disease Progression , Disease-Free Survival , Female , France/epidemiology , Hodgkin Disease/mortality , Humans , Male , Neoplasm Recurrence, Local/mortality , Retrospective Studies , Salvage Therapy/mortality , Stem Cell Transplantation/mortality , Treatment Outcome
18.
Int J Radiat Oncol Biol Phys ; 84(2): e209-15, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22672756

ABSTRACT

PURPOSE: Very few childhood cancer survivor studies have been devoted to thyroid adenomas. We assessed the role of chemotherapy and the radiation dose to the thyroid in the risk of thyroid adenoma after childhood cancer. METHODS AND MATERIALS: A cohort of 3254 2-year survivors of a solid childhood cancer treated in 5 French centers before 1986 was established. The dose received by the isthmus and the 2 lobes of the thyroid gland during each course of radiation therapy was estimated after reconstruction of the actual radiation therapy conditions in which each child was treated as well as the dose received at other anatomical sites of interest. RESULTS: After a median follow-up of 25 years, 71 patients had developed a thyroid adenoma. The risk strongly increased with the radiation dose to the thyroid up to a few Gray, plateaued, and declined for high doses. Chemotherapy slightly increased the risk when administered alone but also lowered the slope of the dose-response curve for the radiation dose to the thyroid. Overall, for doses up to a few Gray, the excess relative risk of thyroid adenoma per Gray was 2.8 (90% CI: 1.2-6.9), but it was 5.5 (90% CI: 1.9-25.9) in patients who had not received chemotherapy or who had received only 1 drug, and 1.1 (90% CI: 0.4-3.4) in the children who had received more than 1 drug (P=.06, for the difference). The excess relative risk per Gray was also higher for younger children at the time of radiation therapy than for their older counterparts and was higher before attaining 40 years of age than subsequently. CONCLUSIONS: The overall pattern of thyroid adenoma after radiation therapy for a childhood cancer appears to be similar to that observed for thyroid carcinoma.


Subject(s)
Adenoma/epidemiology , Neoplasms, Radiation-Induced/epidemiology , Neoplasms, Second Primary/epidemiology , Survivors , Thyroid Gland/radiation effects , Thyroid Neoplasms/epidemiology , Adenoma/etiology , Adenoma/pathology , Adolescent , Adult , Antineoplastic Agents/therapeutic use , Child , Child, Preschool , Female , Follow-Up Studies , France/epidemiology , Humans , Incidence , Infant , Infant, Newborn , Male , Middle Aged , Neoplasms, Radiation-Induced/etiology , Neoplasms, Radiation-Induced/pathology , Neoplasms, Second Primary/etiology , Neoplasms, Second Primary/pathology , Radiation Dosage , Retrospective Studies , Risk Factors , Spleen/radiation effects , Splenectomy/adverse effects , Thyroid Gland/drug effects , Thyroid Neoplasms/etiology , Thyroid Neoplasms/pathology , Time Factors , Young Adult
19.
Eur J Cancer ; 48(9): 1376-85, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22516209

ABSTRACT

AIM OF THE STUDY: To determine whether a risk factor adapted chemotherapy would improve the outcome of non-metastatic bone Ewing's sarcoma. METHODS: Standard risk tumours (SR, good histological response to chemotherapy or small unresected tumours) received the previous EW88 chemotherapy. Ifosfamide/etoposide (IE) were introduced after 3 courses of cyclophosphamide/doxorubicine when tumour regression was <50% or during consolidation therapy for the intermediate risk tumours (IR, intermediate histological response 5-30% residual cells or large unresected tumours >100ml). High risk tumours (HR, histological poor response >30% residual cells or clinical poor response <50% for unresectable tumours), received IE prior high dose busulfan/melphalan with stem cell rescue. RESULTS: From 1993 to 1999, 214 patients were enrolled. 5 y-EFS and OS were 60% (95% confidence interval (CI), 53-66) and 69% (95% CI, 63-75), respectively. 116 (54%), 46 (21%), 48 (22%) patients were considered as SR, IR and HR of relapse, respectively. No advantage to IE was observed in the IR group. As compared to previous study, tumour with poor histological response to induction chemotherapy seemed to benefit from the consolidation strategy including busulfan/melphalan: EFS were 45% (95% CI, 30-60) and 20% (95% CI, 7-43) for EW93 and EW88, respectively. Despite a risk-adapted strategy, histological response to chemotherapy remains the main prognostic factor in resected tumours, while initial tumour volume is the main prognostic factor for unresected tumours. CONCLUSION: These results showing a potential benefit of a consolidation strategy including busulfan/melphalan as compared to conventional chemotherapy needed confirmation by a randomised trial and were one of the bases of the ongoing EuroEwing99.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Neoplasms/drug therapy , Sarcoma, Ewing/drug therapy , Adolescent , Adult , Child , Child, Preschool , Drug Administration Schedule , Female , Follow-Up Studies , France , Humans , Infant , Male , Prognosis , Risk Factors , Treatment Outcome , White People , Young Adult
20.
J Clin Endocrinol Metab ; 97(1): E121-8, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22013103

ABSTRACT

CONTEXT: Among 22 independent patients from the GENHYPOPIT network who had ACTH deficiency and no identified mutation of TPIT, three of them (13.6%) displayed common variable immunodeficiency (CVID), characterized by defective Ig production. OBJECTIVE: Our objective was to describe an as yet unrecognized disease association. DESIGN: We considered the hypothesis of ACTH deficiency being associated with antipituitary autoimmunity or lymphocytic hypophysitis. In the context of a functional network between the immune and endocrine systems, we also tested the hypothesis of a common genetic cause using a candidate gene approach. SETTING: This was a multicentric study in three academic hospitals. PATIENTS: We report four patients from three unrelated families presenting with ACTH deficiency and CVID. MAIN OUTCOME MEASURES: Detection of antipituitary autoantibodies, and sequencing of candidate genes (LIF, IKAROS, EOS) were the main outcome measures. RESULTS: All patients including a pedigree with two affected siblings had ACTH deficit diagnosed from 5-15 yr, with symptomatic hypoglycemia, and CVID diagnosed from 2-8 yr revealed by recurrent infections. Three of the four patients had a hypoplastic pituitary. One patient had low IGF-I and subnormal GH response to stimulation, suggesting that secretion of other pituitary hormones may also be affected. All patients proved negative for pituitary autoantibodies and had no alteration in any of the genes tested. CONCLUSIONS: The remarkable association of two rare disorders affecting two functionally related systems in four patients from three independent pedigrees including a familial case provides strong evidence of the existence of a disease association: deficit in anterior pituitary function and variable immune deficiency, or DAVID.


Subject(s)
Adrenocorticotropic Hormone/deficiency , Autoimmune Diseases of the Nervous System/complications , Infections/complications , Pituitary Diseases/complications , Pituitary Gland, Anterior , Pituitary Hormones, Anterior/deficiency , Adrenocorticotropic Hormone/blood , Adult , Autoimmune Diseases of the Nervous System/diagnosis , Autoimmune Diseases of the Nervous System/epidemiology , Autoimmune Diseases of the Nervous System/genetics , Child , Child, Preschool , Female , Humans , Infant , Infections/epidemiology , Infections/genetics , Male , Pedigree , Phenotype , Pituitary Diseases/diagnosis , Pituitary Diseases/epidemiology , Pituitary Diseases/genetics , Pituitary Gland, Anterior/metabolism , Pituitary Gland, Anterior/pathology , Pituitary Hormones, Anterior/blood , Severity of Illness Index , Single-Chain Antibodies/genetics , Young Adult
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