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Aims:Herein we report successful eye salvage following combined intravitreal and intracameral administration of melphalan for anterior chamber recurrence of retinoblastoma. Methods:A 12-month-old boy was referred with a sporadic bilateral retinoblastoma staged as group D and V in the right eye and group E and V in the left eye. Treatment initially involved 6 cycles of 3 drugs followed by focal treatments. The left eye was enucleated. Three months after the end of systemic chemotherapy, multiple recurrent lesions were noted in the ciliary body and the anterior chamber. A series of intravitreal (IVT) and intracameral (IC) injections of melphalan combined with a 7th cycle of systemic chemotherapy was performed. The therapeutic schedule alternated: week A an IVT of melphalan (30 μg/0.1 mL) for a total of 4 versus week B IC injections of melphalan (15 μg/0.05 mL) 4 IC in total. Each injection was preceded by an anterior chamber. Cryotherapy to the injection punctures was systematically performed. Results:Rapidly, iris and ciliary body nodules regressed completely based on clinical and ultrasound biomicroscopic examinations. After 3 years of follow-up, the patient has shown no evidence of recurrence. Conclusion:In our patient, combined IVT and IC administration of melphalan proved highly efficacious in eradicating the ciliary body and anterior chamber disease and salvage of his one remaining functional eye.

Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewing sarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneity in genetically homogeneous cancers. We performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels: between cancers, between tumors, and within tumors. We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma. DNA methylation differences between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures. There was substantial epigenetic heterogeneity within tumors, particularly in patients with metastatic disease. In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma and thereby highlights the importance of considering nongenetic aspects of tumor heterogeneity in the context of cancer biology and personalized medicine.

Synovial sarcoma (SS) is a high-grade soft tissue sarcoma characterized by local invasiveness and a propensity to metastasize, affecting pediatric, adolescent, and adult populations. The peak incidence is observed in the third decade of life and SS is the most common nonrhabdomyosarcoma soft tissue sarcoma in childhood and adolescence. Although pediatric and adult SS appear clinically and radiologically identical, treatment modalities may differ according to the patient’s age. For many years, pediatric oncologists have treated SS as a chemosensitive tumor according to the “rhabdomyosarcoma philosophy.” In contrast, adult oncologists generally treat this tumor as a poorly chemosensitive tumor and focus on local control. The authors propose an update of SS in the pediatric population and analyze their results to those obtained in adults.

Le rétinoblastome est la tumeur maligne intra-oculaire la plus fréquente de l’enfant avec une incidence de 1/15 000 à 1/20 000 naissances. Soixante pour cent de ces tumeurs sont unilatérales avec un âge médian au diagnostic de deux ans, la plupart étant des formes non héréditaires. Le rétinoblastome est bilatéral dans 40 % des cas, avec un âge médian de survenue au diagnostic plus précoce, autour de un an. Toutes les formes bilatérales et unilatérales multifocales sont héréditaires et constituent un syndrome de prédisposition génétique au cancer. L’ensemble des enfants atteints d’une forme bilatérale ou familiale ainsi que 10 à 15 % des enfants ayant une atteinte unilatérale sont porteurs d’une altération constitutionnelle du gène RB1. Les deux symptômes révélateurs les plus fréquents sont la leucocorie et le strabisme. L’examen du fond d’œil va permettre le diagnostic, aidé de l’échographie et l’IRM réalisant le bilan d’extension. La prise en charge des patients doit tenir compte du type de rétinoblastome (unilatéral/bilatéral, taille, localisation…), du risque visuel et de la possible nature héréditaire de la tumeur. Les aspects pronostiques essentiels restent la détection précoce et la prise en charge adaptée par une équipe spécialisée multidisciplinaire. Une énucléation est souvent encore nécessaire en cas de forme unilatérale, un traitement adjuvant étant indiqué en fonction des facteurs de risques histologiques. Les plus grandes avancées thérapeutiques concernent les traitements conservateurs maintenant proposés pour au moins un œil dans la plupart des formes bilatérales : chimiothérapie, thermo-chimiothérapie, cryothérapie, disque d’iode. Récemment, le développement de nouvelles techniques de traitement à visée conservatrice comme la perfusion sélective intra-artérielle de chimiothérapie a pour but de tenter de préserver la vision de ces enfants et de diminuer le recours à l’énucléation et l’irradiation externe. Le pronostic est actuellement excellent dans les pays industrialisés mais la survie à long terme des patients atteints de forme héréditaire de rétinoblastome reste menacée par le risque de survenue de tumeurs secondaires, principalement des sarcomes. Le rétinoblastome nécessite une prise en charge multidisciplinaire ainsi qu’un suivi spécialisé à long terme. L’information précoce des patients et de leur famille concernant les risques de transmission de la maladie et le risque de développement de tumeurs secondaires est nécessaire.

Les tumeurs malignes du nasopharynx sont surtout représentées, en pédiatrie, par le carcinome indifférencié du nasopharynx (UCNT). Ces tumeurs sont communément révélées par une obstruction nasale, des céphalées ou la découverte d’adénopathies cervicales. L’imagerie puis la biopsie de la masse du nasopharynx ou d’un ganglion cervical confirmera le diagnostic. En pédiatrie, il s’agit d’une tumeur très chimio- et radiosensible. L’irradiation du nasopharynx et des aires ganglionnaires cervicales reste le traitement de référence de cette maladie. La majorité des protocoles pédiatriques y associe de la chimiothérapie. L’intérêt d’une chimiothérapie concomitante ou suivant la radiothérapie est toujours débattue en pédiatrie. Le stade T et N au diagnostic déterminé par la classification TNM semble être un facteur pronostique important. L’importance des séquelles locorégionales et le bon pronostic global font proposer une diminution des doses totales d’irradiation délivrées au niveau cervical et nasopharyngien, particulièrement en cas de bonne réponse à la chimiothérapie première. Cet article fait le point sur les particularités évolutives et thérapeutiques des UCNT en pédiatrie.

AbstractSpectral-broadening of the APOLLON PW-class laser pulses using a thin-film compression technique within the long-focal-area interaction chamber of the APOLLON laser facility is reported, demonstrating the delivery of the full energy pulse to the target interaction area. The laser pulse at 7 J passing through large aperture, thin glass wafers is spectrally broadened to a bandwidth that is compatible with a 15-fs pulse, indicating also the possibility to achieve sub-10-fs pulses using 14 J. Placing the post-compressor near the interaction makes for an economical method to produce the shortest pulses by limiting the need for high damage, broadband optics close to the final target rather than throughout the entire laser transport system.

The survival of patients with rhabdomyosarcoma has been progressively improved with successive protocols due to the development of multidisciplinary management and the data accumulated by international groups. Orbital rhabdomyosarcoma represents 10% of all cases and affects young children (median age: 6.8 years). It is a chemosensitive and radiosensitive tumour. Chemotherapy is designed to decrease the indications for local therapy (mainly radiotherapy) responsible for a high rate of sequelae (cosmetic, functional or secondary cancer). According to the International Society of Paediatric Oncology guidelines, local therapy is not indicated as first-line treatment in case of complete remission after chemotherapy. The 10-year survival of children with non-parameningeal orbital rhabdomyosarcoma is currently 87% and identical survivals are reported by the various collaborative groups despite the use of different treatments. Despite clinical trials demonstrating the efficacy of many types of chemotherapy (cisplatin, etoposide, doxorubicin, dacarbazine), the value of adding these drugs to combination chemotherapy comprising of an alkylating agent (cyclophosphamide or ifosfamide), vincristine and dactinomycin has not been formally demonstrated in terms of survival benefit for children with rhabdomyosarcoma. The authors review these various results and compare the current guidelines for the management of orbital rhabdomyosarcoma recommended by North American and European groups.

The purpose of this study was to evaluate retrospectively the value of leukocyte-labeled scintigraphy, ultrasonography, and contrast radiography compared with endoscopy in children suspected of having inflammatory bowel disease (IBD).

Objective.To study the concordance between abdominal scintigraphy using technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO)-labelled leucocytes (ASTLL) and ileocolonoscopy in patients with spondyloarthropathies (SpA) and without clinical evidence of inflammatory bowel disease (IBD).Patients and methods.Fifteen patients with SpA (European Spondylarthropathy Study Group 1991) criteria) without clinical evidence of IBD were studied prospectively with ASTLL and ileocolonoscopy.Results.This cohort consisted of seven men and eight women aged 31.8 ± 10.5 yr (18-47) [mean age ± S.D. (range)] and with a disease duration of 6.0 ± 4.4 yr (0.4-15). ASTLL showed abnormal uptake in four patients. Ileocolonoscopy was abnormal in five patients, showing acute inflammatory lesions in one patient with reactive arthritis, undifferentiated chronic inflammatory lesions in two cases, and features indistinguishable from those of Crohn's disease in two cases. ASTLL was negative in two cases in which ileocolonoscopy showed inflammatory lesions and was positive (terminal ileum) in one case with normal ileocolonoscopy. The concordance between the two examinations was statistically significant (k=0.53; P=0.008).Conclusion.ASTLL may be an interesting tool to detect subclinical gut inflammation in patients with SpA.Keywords:Scintigraphy, Ileocolonoscopy, Spondyloarthropathy, Inflammatory bowel disease.

A patient presenting in the first year of life with feeding difficulties and failure to grow had variable but persistent lactic acidemia noted at age 20 months. Nonspecific nutritional and biochemical therapy was accompanied by improvement in general clinical status, growth, gait, and development. However, she died in a catastrophic illness at the end of the third year of life. Studies in intact fibroblast mitochondria were consistent with an isolated but partial defect in cytochrome c oxidase. On direct assay of this enzyme complex in fibroblast homogenates and mitochondria, activity was much more severely depressed (±8 of control). Her fibroblasts normally synthesized the three cytochrome c oxidase subunits encoded on the mitochondrial genome. These data confirm that this patient had cytochrome c oxidase deficiency and demonstrate significant biochemical heterogeneity, since the results of the intact mitochondrial studies correlate better with her clinical course than do those of the direct enzymatic assays.

BALB/cByJ (J) mice have short-chain acyl-CoA dehydrogenase (SCAD) deficiency and an organic aciduria similar to that of human SCAD deficiency. [9,10(n)-JH)- and [15,16(n)-3H)paimitale oxidations in J mouse fibroblasts were 96 and 35 of control, respectively, consistent with an isolated SCAD defect. Acyl-CoA deby-drogenase activities were assayed in muscle and fibroblast mitochondria from BALB/cBy controls (Y) and SCAD-deficient J mice. Medium-chain acyl-CoA dehydrogenase (MCAD) activities were comparable in both J and Y mice from all tissues. In the presence of MCAD antiserum, SCAD activities in J mice were undetectable in both tissues. Apparent Km and Vmaxvalues in liver mitochondria suggested a somewhat increased affinity of MCAD for butyryl-CoA in J mice, as compared with MCAD from other species. Immunoblot studies using mitochondria revealed identical apparent SCAD molecular weight in liver, muscle, and fibroblasts from Y and mice and no detectable SCAD antigen in J mice; MCAD antigen was detected in comparable amounts from both Y and J mice. Radiolabeling and immunoprecipitation studies in J mouse fibroblasts revealed no SCAD synthesis, but normal MCAD synthesis. These data argue against the existence of tissue-specific SCAD isoforms in the mouse and confirm that this mouse strain is a model for the human organic aciduria resulting from this β-oxidation defect. (Pediatr Res31: 552–556, 1992)

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The effects of the R-(-) and S-(+)ibuprofen enantiomers were first studied in vitro with mouse liver mitochondria incubated in the presence of various concentrations of exogenous coenzyme A. In the presence of a low concentration of coenzyme A (2.5 microM), the R-(-)enantiomer (which forms an acylcoenzyme A) inhibited stereoselectively the beta oxidation of [1-14C]palmitic acid but not that of [1-14C]palmitoyl-L-carnitine (which can directly enter the mitochondria). In the presence, however, of a concentration of coenzyme A (50 microM) reproducing that present in liver cell cytosol, both enantiomers (2 mM) slightly inhibited the beta oxidation of [1-14C]palmitic acid and markedly inhibited the beta oxidation of [1-14C]octanoic acid and [1-14C]butyric acid. In vivo, both enantiomers (1 mmol.kg-1) similarly inhibited the formation of [14C]CO2 from [1-14C]fatty acids. Both enantiomers similarly decreased plasma ketone bodies. Both similarly increased hepatic triglycerides, and both produced mild microvesicular steatosis of the liver. We conclude that both ibuprofen enantiomers inhibit beta oxidation of fatty acids in vitro and in vivo. In addition, the R-(-)enantiomer may stereoselectively sequester coenzyme A; at low concentrations of coenzyme A in vitro, this may stereoselectively inhibit the mitochondrial uptake and beta oxidation of long chain fatty acids.

Microvesicular steatosis of the liver has been reported in two subjects receiving amineptine (a tricyclic antidepressant metabolized by beta-oxidation of its acyl chain). A similar disease is observed after ingestion of drugs which inhibit hepatic mitochondrial fatty acid beta-oxidation, or in subjects with various inborn defects in this metabolic pathway. We therefore determined the effects of amineptine on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of beta-oxidation products during incubation of palmitic acid with mouse liver mitochondria and the various cofactors necessary for beta-oxidation was inhibited by 27, 33, 46 and 57% respectively, in the presence of 0.25, 0.5, 1 and 2 mM of amineptine. Inhibition was reversible. Tricarboxylic acid cycle activity, assessed by the in vitro formation of [14C]CO2 from [1-14C]acetyl coenzyme A by mouse liver mitochondria, was inhibited by 22, 23, 47, 54, 60 and 62%, respectively, in the presence of 0.0625, 0.125, 0.25, 0.5, 1 and 2 mM of amineptine. In vivo, administration of amineptine, 0.5 and 0.75 mmol.kg-1, inhibited by 70 and 84%, respectively, the exhalation of [14C] CO2 during the first 3 hr after the administration of a tracer dose of [U-14C]palmitic acid. Administration of amineptine, 0.0625, 0.25, 0.5 or 1 mmol.kg-1, 6 hr before the measurement, increased hepatic triglycerides by 73, 139, 295 and 320%, respectively. After 1 mmol.kg-1, accumulation of hepatic triglycerides was maximum at 24 hr, reaching 5-fold the control value; liver histology at that time showed microvesicular steatosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration of pirprofen may produce microvesicular steatosis of the liver in humans. The effects of pirprofen on the mitochondrial beta-oxidation of fatty acids have been investigated in mice. In vitro, addition of 2 mM pirprofen decreased by 50% the formation of [14C]acid-soluble beta-oxidation products, and decreased by 70% the formation of [14C]CO2 upon incubation of hepatic mitochondria with [14C]palmitic acid, ATP, carnitine and coenzyme A. In vivo, administration of pirprofen (2 mmol . kg-1 i.p.), 1 hr before that of [U-14C]palmitic acid, decreased by 70% the exhalation of [14C]CO2 during the next 6 hr. Administration of pirprofen (2 mmol . kg-1 i.p.), 1 hr before the measurement, decreased plasma beta-hydroxybutyrate by 60%, plasma acetoacetate by 30% and blood glucose by 40%. Administration of pirprofen (2 mmol . kg-1 i.p.) 6 hr before sacrifice, doubled hepatic triglycerides content and produced microvesicular steatosis of the liver. We conclude that pirprofen inhibits the mitochondrial beta-oxidation of fatty acids in mice, thus explaining the microvesicular steatosis observed in mice and in some human subjects.

ABSTRACTS: BALB/cByJ (J) mice have short-chain acyl-CoA dehydrogenase (SCAD) deficiency and an organic aciduria similar to that of human SCAD deficiency. [9,10(n)-JH)- and [15,16(n)-3H)paimitale oxidations in J mouse fibroblasts were 96 and 35% of control, respectively, consistent with an isolated SCAD defect. Acyl-CoA deby-drogenase activities were assayed in muscle and fibroblast mitochondria from BALB/cBy controls (Y) and SCAD-deficient J mice. Medium-chain acyl-CoA dehydrogenase (MCAD) activities were comparable in both J and Y mice from all tissues. In the presence of MCAD antiserum, SCAD activities in J mice were undetectable in both tissues. Apparent Km and Vmaxvalues in liver mitochondria suggested a somewhat increased affinity of MCAD for butyryl-CoA in J mice, as compared with MCAD from other species. Immunoblot studies using mitochondria revealed identical apparent SCAD molecular weight in liver, muscle, and fibroblasts from Y and mice and no detectable SCAD antigen in J mice; MCAD antigen was detected in comparable amounts from both Y and J mice. Radiolabeling and immunoprecipitation studies in J mouse fibroblasts revealed no SCAD synthesis, but normal MCAD synthesis. These data argue against the existence of tissue-specific SCAD isoforms in the mouse and confirm that this mouse strain is a model for the human organic aciduria resulting from this ß-oxidation defect.