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Background Integrated multimodal care is needed for patients with Ewing sarcoma, which is the second most common primary bone malignancy in children and adolescence. Chemotherapy increases survival from less than 5% to 65–70% for patients with localized tumors and to 25–30% for those with metastases at diagnosis. Surgery is a major tool, whereas advances in imaging techniques have improved the indications for and the optimization of treatment. Radiotherapy remains useful, either alone or in addition to surgery, and new techniques (conformational RT and IMRT) will reduce short-term toxic effects. Pediatric oncologists do not outweigh surgeons or radiation therapists, but they are the ones who coordinate the medical team, which also includes pathologists and imaging specialists. Methods The point of view of the pediatric oncologist was assessed as follows: the place of chemotherapy in Ewing tumor treatment, the place of radiotherapy in Ewing tumor treatment (including why avoid radiotherapy when technically possible in children), and how to proceed into the future? The place of surgery as local treatment for Ewing tumors was also evaluated. Results These reviews show a dynamic and kaleidoscopic panorama of intense activity at the laboratory and clinical levels. Conclusions Though good survival rates have been achieved, improvements using entirely new approaches are needed. © 2003 Wiley-Liss, Inc.

N-myc amplification is a major prognostic factor in neuroblastomas and is systematically investigated by Southern blot or polymerase chain reaction (PCR). A retrospective study of N -myc amplification has been carried out using fluorescence in situ hybridization (FISH) in 97 fixed neuroblastomas. For each tumour, FISH was performed on the area that contained the most immature neuroblasts. Among these 97 neuroblastomas, 16 were amplified and 12 were not interpretable. FISH was not interpretable in six cases. All neuroblastomas with N-myc amplification detected by Southern blot/PCR were amplified with FISH, except three that were not interpretable. Four tumours that were not interpretable in Southern blot/PCR contained more than five copies of N-myc by FISH: one was aneuploid and three were truly amplified, containing more than ten copies of N-myc. Among these three patients, two died in a short time of their tumours. Ten cases were not amplified by Southern blot/PCR and showed more than five copies by FISH: four were aneuploid and two showed heterogeneous amplification, with a few cells clearly amplified whereas most were not. Four cases were amplified, of which two patients died of their tumours. This study confirms that when applied to the most immature areas of fixed neuroblastomas, FISH displayed a higher sensitivity than molecular techniques (p < 0.001) and could detect heterogeneous amplification. FISH could therefore become an important complementary procedure in assessing prognosis in neuroblastomas.

Objective To review the epidemiological evidence on neuroblastoma and to use it in the framework of a statistical model to assess the value of screening children for this disease at different ages. Procedure A simple two-stage model of the disease is used to estimate the prevalence at screening from incidence and from the distribution of the length of the preclinical phase. Results It is shown that screening at 6 months would anticipate the diagnosis for a maximum of 25 cases per million. Given the detection rate of the existing programs, it would imply a 50% overdiagnosis. Furthermore, if the case with an anticipated diagnosis had a survival rate of 85%, the reduction in mortality would be at most 20%, whatever the age at screening. To detect such a reduction would need several millions of children to be enrolled in a trial. Conclusions Considering these results and the likely persistence of overdiagnosis when screening at 12 months, the epidemiological and statistical evidence plead against further research on neuroblastoma screening. Its efficacy can be evaluated with sufficient reliability from the present evidence: the likely small benefit on mortality does not compensate for the cost of overdiagnosis. Med. Pediatr. Oncol. 31:401–407, 1998. © 1998 Wiley-Liss, Inc.

We investigated the possible causative role of interleukin 6 (IL-6) in the paraneoplastic inflammatory syndrome and in paraneoplastic cholestasis (Stauffer syndrome) associated with renal-cell carcinoma in a series of 119 patients with metastases. IL-6 levels were found significantly higher in patients with paraneoplastic fever and weight loss. Patients with detectable serum IL-6 (n = 90, 76%) had significantly higher serum CRP, haptoglobin, and serum alkaline-phosphatase and gammaglutamyl-transferase levels. Platelets, polymorphonuclear neutrophil (PMN) and monocyte counts were also significantly higher in patients with detectable serum IL-6; in contrast, hemoglobin levels were significantly lower in patients with serum IL-6 over 80 pg/ml. Three of these patients were included in a phase-II trial of an anti-IL-6 monoclonal antibody given daily during 21 days. Reductions of CRP, haptoglobin and serum alkalin phosphatases were observed in all 3 patients during anti-IL-6 administration, with a subsequent increase up to or above pre-treatment levels after the end of anti-IL-6. Decrease of platelets, PMN and monocyte counts were also observed in the 3 patients during anti-IL-6 administration, with a normalization of cell counts in a patient with increased platelets, PMN and monocyte counts. Hemoglobin concentration, serum albumin concentration and lymphocyte counts remained stable in the 3 patients during and after anti-IL-6 administration. Serum IL-6, as evaluated by IRMA, decreased in the 3 patients during anti-IL-6 administration, but increased above pre-treatment levels after the end of anti-IL-6 administration. These results demonstrate that IL-6 is involved in the physiopathology of paraneoplastic syndromes observed in patients with metastatic renal-cell carcinoma, in particular CRP and haptoglobin increase, paraneoplastic cholestasis, also paraneoplastic thrombocytosis, neutrophilia and monocytosis.

Chromosome I abnormalities are indicators of prognosis in neuroblastoma (NB) but are not yet routinely exploited because conventional methods are technically demanding. We evaluated the pertinence of interphase cytogenetics fluorescence in situ hybridization (FISH) for the analysis of chromosome I in NB, compared with conventional methods. Deletion of Ip was detected in 8 of 9 cell lines analyzed by both FISH and restriction fragment length polymorphism (RFLP), but was evidenced in only 2 cases by conventional cytogenetics, painting analysis being required to reveal the other cases. The chromosome I number evaluated by FISH reflected the total chromosome modal number obtained by cytogenetics. Twenty-eight specimens obtained from ultrasound-guided punctures, surgical biopsies of the primary tumor and bone-marrow aspirates were studied by FISH on frozen cytocentrifuged smears; 12 had a chromosome I trisomy and 16 a disomy. Requirements for a reliable control analysis of Ip deletion by RFLP were met in only 23 cases. The retention of 2 alleles was observed in 15 cases and Ip deletion in 7, by both techniques. In one case, an interstitial deletion of Ip was evidenced only by RFLP, and one of 5 cases analyzed only by FISH had a Ip deletion. Although FISH might be improved by using additional probes, it presents major advantages for routine exploitation. Determining Ip deletion in individual cells makes it possible to analyze small and heterogeneous tumoral specimens; the technique requires only a few hours and can easily be standardized in non-specialized laboratories. The number of chromosome I homologues per cell might serve as a rapid screening for ploidy.

Background. Desmoplastic small round cell tumors (DSRCT) have been only recently identified. Methods. The authors report DSRCT in two pediatric patients (an 8-year-old boy and 12-year-old boy). In both patients, the initial diagnosis was rhabdomyosarcoma. The resistance to standard chemotherapy and radiation therapy prompted the authors to review the initial biopsy specimens and perform complementary immunophenotypic characterization. Results. These analyses revealed that the tumor cells were strongly positive for keratin epithelial marker antigen, desmin, vimentin, neurospecific enolase, and S100 protein, corresponding to pleomorphic differentiation, characteristic of DSRCT. Conclusions. The authors suggest that extensive immunohistologic characterization be performed in all cases of small round cell tumors of the abdomen so that the diagnosis of DSRCT is not overlooked. These rare tumors are refractory to chemotherapy, and initial aggressive surgery is warranted.

LFA-3, ICAM-1, HLA.ABC and HLA.DR expression was analyzed on 66 neuroblastoma specimens. HLA.ABC was expressed on 26 specimens, HLA.DR on 2, LFA-3 on 20 and ICAM-1 on 10. HLA.ABC and LFA-3 were positive on ganglioneuroblastoma or ganglioneuroma, but they were negative on neuroblastoma, independently of the clinical staging; HLA.ABC and LFA-3 were induced in vivo by chemotherapy in parallel with tumoral cell differentiation, in both the primary and the metastases. The expression of ICAM-1 was restricted to 5 of the 10 low-grade stage-1 or stage-2 specimens, 1 stage-3 specimen, and the primary tumors of 2 patients with stage-4 disease, analyzed hence at diagnosis and after chemotherapy (4 specimens); metastatic cells obtained in 1 of these patients were negative. HLA.ABC and LFA-3 expressed on both mycN-negative and -positive specimens, whereas ICAM-1 was restricted to MYCN-negative specimens. LFA-3 diffusely stained partially differentiated neuroblasts, Schwann cells and ganglion cells. The expression of HLA.ABC on differentiated neuroblasts varied from one sample to another and within the same tumor; Schwann cells were strongly positive, but ganglion cells were negative. In positive samples, ICAM-1 was expressed on differentiated neuroblasts and Schwann cells, but negative on ganglion cells; however, most of the differentiated tumors were ICAM-1-negative, suggesting ICAM-1 induction by unknown local signal. The 4 markers were negative on undifferentiated neuroblasts. The distribution of these 4 markers on clinical specimens was in agreement with their reactivity on fetal tissues, as well as with results obtained on neuroblastoma cell lines before and after in vitro treatment with IFN-gamma.

SUMMARY Using experimental models with normal allogeneic bone marrow (BM) contaminated with Burkitt or neuroblastoma cell lines, and a liquid culture assay, we demonstrated that, when used in optimal conditions, the immunomagnetic depletion technique permitted a reproducible elimination of 3–4 log malignant cells. Results were very similar to those obtained with the complement lysis procedure in Burkitt lymphoma. This immunomagnetic procedure was used in 123 cases of autologous bone marrow transplantation (ABMT) in children with neuroblastoma. The analysis of the cases demonstrated, first, that the procedure induced a significant loss of mononuclear cells but was not toxic for BM precursors. Delays to engraftment observed in a few patients were probably due to the combination of pejorative factors, especially the damage caused to the micro-environment by previous heavy and prolonged chemotherapy or the double ABMT programme. Second, patients presented with profound T-cell defect with undetectable IL2 secretion up to 1 year post-graft but they all had normal NK functions from the first month post-graft, these functions exceeding normal values on the second and third months post-graft. Finally, in 20 cases, dual-immunofluorescence staining permitted the demonstration that the autograft contained malignant cells before purging that were eliminated by the immunomagnetic depletion.

The expression of receptors for proliferation and differentiation factors was analyzed by indirect immunofluorescence on 29 Burkitt lymphoma (BL) cell lines previously classified into 3 groups on the basis of their reactivity with 8 monoclonal antibodies (MAbs), including anti-CALLA, BL13 and TU1. BL13 and HB5 antibodies recognize different epitopes of the EBV/CR2 receptors. The determinant recognized by BL13 has been previously shown to be expressed only on cell lines of the first two groups, supposed to derive from the germinal center and to be negative on a third group of lines of putative BM origin and established from sporadic cases of BL. In contrast, and as expected from its reactivity on normal B cells in the BM or in the lymph nodes, HB5 antibody reacts with all BL lines except one. The receptor for transferrin is expressed on the 29 lines. Two new MAbs, Bac-1 and B1H5, could recognize respectively receptors for BCGF1 and BCGF2. Bac-1 reacts with 15 of 17 BL lines belonging to the first two groups and 7 of 12 BL lines of the third group; 14 of 15 EBV + lines express Bac-1. No BL line expresses B1H5. The IL2 receptor is weakly expressed on 5 EBV + cell lines and one EBV (-) line. All delta are BCGF1-positive. The almost constant expression of BCGF1 receptor on EBV + cell lines is the only strict relation between the expression of receptors for growth factors and their characteristics (i.e. EBV association, translocation, ethnic origin and clinical presentation). The maturation stage or the origin of BL cell lines in relation to the expression of growth factor receptors and the functional significance of these receptors will be discussed.

Burkitt's lymphoma was diagnosed in a male Algerian child presenting with abdominal and jaw tumours. Viral studies revealed that this non-endemic case was associated with the Epstein-Barr virus. Cytogenetic examination of tumour cells showed a complex three-way rearrangement involving chromosomes 2, 8 and 9. Our report indicates that, in Burkitt's lymphoma, not only simple but also complex translocations involving chromosome 8 may arise. This finding in a North African case emphasizes the need for more detailed study of the clinical, virological and cytogenetic features of Burkitt's lymphoma throughout the world.

The histogenesis of Ewing sarcoma, the second most frequent bone tumor in humans, remains controversial. Four Ewing cell lines were analyzed by immunological methods. A panel of antibodies directed to T, B, and myelomonocytic markers gave negative results. Surface antigens recognized on Ewing cells were found to be related to the neuroectoderm lineage. Ganglioside GD2, a marker of neuroectodermal tissues and tumors, was present on all lines. These were also stained by the mouse monoclonal antibody HNK-1, which detects a carbohydrate epitope present on several glycoconjugates of the nervous system, including two glycoproteins, the myelin-associated glycoprotein and the neural cell-adhesion molecule (N-CAM), and an acidic glycolipid of the peripheral nervous system. The P61 monoclonal antibody, which reacts with a peptide moiety of N-CAM, and a rabbit antiserum, raised to purified mouse N-CAM and not recognizing the HNK-1-defined epitope, were also reactive. By contrast, all antibodies specific for hematopoietic cell surface antigens were totally negative. Besides these antigenic features, Ewing sarcoma cells are characterized by a specific t(11;22)(q24;q12) translocation also observed in neuroepithelioma, a neuroectodermal tumor, suggesting a possible evolutionary related origin. The recent finding that the human N-CAM gene is located at the vicinity of the breakpoint on chromosome 11 indicates that it might be involved in genetic rearrangements occurring in this region.

Two cases of fatal interstitial pneumonitis developing after an autologous bone marrow transplantation are described. In both cases the autopsy revealed diffuse malignant pulmonary involvement. The first case involved a 4-year-old boy who had a Burkitt's lymphoma; the second case involved a 4-year-old girl with a neuroblastoma. The authors postulate that in these cases, the clinical picture may have been related to reinfusion of malignant cells.