Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients?

PURPOSE: Because of the high heterogeneity of EWS gene fusions with FLI1 and ERG genes due to variable chromosomal breakpoint locations in Ewing tumors (ET) (14 different chimeric transcripts identified so far), we evaluated the clinical impact of the expression of diverse fusion transcripts in ET patients. PATIENTS AND METHODS: In a European multicenter study, 147 ET were analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR) and the molecular data statistically compared with all clinical data available. RESULTS: Most tumors expressed chimeric transcripts with fusion of EWS exon 7 to FLI1 exon 6 (75 of 147) (type I) or five (39 of 147) and EWS exon 10 to FLI1 exon 5 (eight of 147) or 6 (five of 147). In five cases, chimerism between EWS exon 9 and FLI1 exons 4 and EWS exon 7 and FLI1 exon 7 or 8 was observed. Fifteen cases of EWS-ERG rearrangement were identified. In 85 of these patients treated in the European Cooperative Ewing Sarcoma Studies, molecular results were analyzed in comparison to age, sex, tumor localization, tumor volume, and disease extension. No significant correlation between the various fusion types and these features were observed. Relapse-free survival (RFS) for the 31 patients with localized disease and fusion type I tended to be longer compared with the 24 patients with localized tumors bearing other chimeric transcripts (P = .04). CONCLUSION: Results suggest a possible advantage in PFS for patients with localized disease and fusion type I transcripts, although this will require prospective validation with a larger number of patients and longer follow-up periods.

[Long-term monitoring of therapy-induced computerized tomographic cranial changes in children with acute lymphoblastic leukemia]. / Langzeitbeobachtung der therapiebedingten cranialen computertomographischen Veränderungen bei Kindern mit akuter lymphoblastischer Leukämie.

PURPOSE: Long-term follow-up of cranial CT scans of children with acute lymphoblastic leukemia and evaluation of the influence of chemo- and radiotherapy on the CCT changes. PATIENTS AND METHODS: CCT scans of 68 children with non-B-ALL were analyzed retrospectively for signs of atrophy and changes in density. Patients were treated between 1981 and 1990 at the St. Anna Childrens Hospital Vienna according to the ALL-BFM protocols. Children were examined with CCT in defined periods from diagnosis until 3 years after cessation of treatment. As a control group served 69 patients with solid tumors who had not received corticoids or cranial irradiation. RESULTS: At the initial examination 56% of the ALL-patients showed CCT changes, 85% of these patients had already received corticoids. In the control group only 20% of the CCTs were found abnormal (p = 0.005). In both groups an age-dependence was found: 64% of the ALL-patients under five years of age and 22% of the patients above 5 years had initial CCT changes (p = 0.001). In the control group 39% of the patients under five years of age and 7% of the older patients showed CCT changes at the beginning of treatment (p = 0.003). The highest incidence of abnormal CCT scans (68%) was seen during intensive chemo- and radiotherapy. Until the end of therapy the incidence of abnormal CCTs decreased to 32%. After cessation of antileukemic therapy 35% of the patients whose CNS-prophylaxis included cranial irradiation, and 12% of the non-irradiated patients had abnormal CCT scans. CONCLUSION: Corticoids can cause reversible signs of cerebral atrophy. In the assessment of CCTs a physiological age-dependence of the volume of the CSF compartment has to be taken into consideration. The main reason for non-reversible CCT changes is the CNS- prophylaxis, above all the cranial irradiation, whereby younger children seem to be particular vulnerable.

Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study.

BACKGROUND: Single-system (SS) disease is the most common presentation in Langerhans cell histiocytosis (LCH) with a heterogenous clinical picture and course. Mostly bone and rarely skin or lymph nodes are involved. PROCEDURE: One hundred and seventy patients with SS-LCH were registered in the DAL-HX 83/90 studies. They were diagnosed according to uniform diagnostic criteria and followed by a standardised schedule. RESULTS: Single bone lesions were most common (68%), followed by multiple bone lesions (19%), isolated skin disease (11%), and isolated lymph node involvement (4 patients). In the detection of bone lesions radiographic skeletal survey proved to be superior to bone scan (97% vs. 82%). Treatment comprised surgery, irradiation and local instillation of steroids, and standardised chemotherapy for multifocal bone disease. After initial therapy 81% of the patients remained disease free. Reactivations restricted to the skeleton occurred in 18% of both unifocal and multifocal bone disease. Two skin patients had a chronic course. Fatality occurred only in one infant with skin disease who progressed to multi-system disease. Twenty-five percent of all patients developed permanent consequences, which were already present at diagnosis in about half of these patients and comprised mainly orthopedic problems related to lesional sites. Diabetes insipidus occurred in 3% and anterior pituitary dysfunction in 2% of the patients. CONCLUSIONS: The course in SS%LCH was benign. In bone disease reactivations remained restricted to the skeleton and did not influence survival. However, reactivations had an impact on morbidity, as permanent consequences were mostly related to the site of disease activity. Med Pediatr Oncol 2001;37:108-114.

Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group.

Treatment of Langerhans cell histiocytosis (LCH) remains problematic. To test the hypothesis that rapid initiation and long-term continuation of chemotherapy can improve survival and reduce recurrence and late consequences of disseminated LCH, we have completed a prospective clinical trial (DAL HX-83). One hundred six newly diagnosed patients were stratified into three risk groups (A: multifocal bone disease [n = 28]; B: soft tissue involvement without organ dysfunction [n = 57]; C: organ dysfunction [n = 21]). All patients received an identical initial 6-week treatment (etoposide [VP-16], prednisone, and vinblastine), and continuation treatment for 1 year, slightly adapted according to stratification at diagnosis. It included oral 6-mercaptopurine and eight pulses of vinblastine and prednisone for all patients, plus VP-16 in group B and VP-16 and methotrexate in group C. Eighty-nine percent and 91% of patients in groups A and B and 67% of the most severely affected group C, achieved complete resolution of disease. The speed of resolution was rapid (median 4 months) and independent of disease severity. The frequency of recurrence after initial resolution was low (12%, 23%, and 42% in groups A, B and C); overall fully 77% of patients have remained free of recurrence. Permanent consequences developed after diagnosis in 20% of the patients. Diabetes insipidus after initiation of treatment occurred in only 10% of patients. Mortality (9%) was limited to patients of groups B (two patients) and C (eight patients). Finally, among the 106 patients treated by DAL HX-83 none have developed a malignancy (median follow-up 6 years, 9 months). The shorter duration of active disease, low rate of recurrence and permanent consequences, and improved survival among patients with poor prognosis support the strategy of rapid initiation of a predefined prolonged treatment upon the diagnosis of disseminated LCH.

Influence of fractionated total body irradiation on mucosal toxicity in intensified conditioning regimens for autologous bone marrow transplantation in pediatric cancer patients.

From April 1988 to March 1991 28 children with generalized solid tumors (N = 15) or hematologic malignancies (N = 13) received intensified myelotoxic regimens followed by autologous stem cell rescue (ABMT). These intensified regimens consisted of 12 Gy fractionated total body irradiation (FTBI) and 2 (or 3) cytotoxic drugs (group A, n = 19) or a combination of 3 cytotoxic drugs (group B, n = 9). FTBI-containing regimens produced more severe mucositis > = WHO grade 3 (p = 0.01) and a longer duration of severe mucositis. The mucositis had a median duration of 8 days (range 0-28) in group A compared with median 0 days (range 0-7) in group B (p < 0.01). Acute renal and liver toxicity were not different. The probability of overall survival at day +100 was 89% in all patients. In terms of long-term survival FTBI containing regimen did not prove superior: 5 out of 19 patients in group A and 6 out of 9 patients in group B have been survivors for a minimum of 3 years. In conclusion, severe gastrointestinal toxicity of such intensive regimens is avoidable if FTBI is omitted.

Prognostic significance of myeloid-associated antigen expression on blast cells in children with acute lymphoblastic leukemia. The Austrian Pediatric Oncology Group.

The prognostic significance of expression of myeloid-associated antigens in childhood acute lymphoblastic leukemia (myA+ALL) was evaluated. From 1984 to 1990, 251 children with immunologically verified ALL were treated in two prospective consecutive Austrian studies. Complete immunophenotyping was performed in 206 cases (82%). Out of these 175 cases were classified as B-cell precursor ALL, 31 cases as T-ALL. Expression of myeloid-associated antigens was demonstrated in 23 cases (13.1%) of childhood B-cell precursor ALL, particularly in immature (CD10 negative) forms (P < .0001), and in 1 case (3.2%) of T-ALL. CDw65 was expressed most frequently (12 cases), followed by CD13 and CD15 (5 cases each), CD33 (4 cases), and blood-group H (3 cases). Compared to myA- ALL prognosis of children with myA+ B-cell precursor ALL was poor, despite intensive multiagent chemotherapy according to BFM protocols. Remission rates were not impaired, but pEFS was 74.6% for myA- ALL, and only 37.8% for myA+ ALL (P = .0001). As demonstrated by multivariate analysis the expression of myeloid-associated antigens was the most important prognostic variable for EFS in B-cell precursor ALL, whether or not CD10 was expressed.