Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone: results of Study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster 93.

PURPOSE: To improve outcome in high-risk patients, high-dose cytarabine and mitoxantrone (HAM) was introduced into the treatment of children with acute myelogenous leukemia (AML) in study AML-BFM 93. Patients were randomized to HAM as either the second or third therapy block, for the purpose of evaluation of efficacy and toxicity. PATIENTS AND METHODS: A total of 471 children with de novo AML were entered onto the trial; 161 were at standard risk and 310 were at high risk. After the randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical in the two risk groups and also comparable to that in study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster (AML-BFM) 87. RESULTS: Overall, 387 (82%) of 471 patients achieved complete remission, and 5-year survival, event-free survival (EFS), and disease-free survival rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell reduction in the bone marrow on day 15. Estimated survival and probability of EFS were superior in study AML-BFM 93 compared with study AML-BFM 87 (P =.01, log-rank test). This improvement, however, was restricted to the 310 high-risk patients (remission rate and probability of 5-year EFS in study AML-BFM 93 v study AML-BFM 87: 78% v 68%, P =.007; and 44% v 31%, P =.01, log-rank test). Probability of 5-year EFS among standard-risk patients in study AML-BFM 93 was similar to that in study AML-BFM 87 (65% v 63%, P = not significant). Whether HAM was placed as the second or third therapy block was of minor importance. However, patients who received the less intensive daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Improved treatment results in children with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.

Arginine deiminase inhibits proliferation of human leukemia cells more potently than asparaginase by inducing cell cycle arrest and apoptosis.

L-Asparaginase is used for the treatment of acute leukemias, but is sometimes ineffective or associated with severe side-effects. We report here that the enzyme arginine deiminase is approximately 100-fold more potent than L-asparaginase in inhibiting the proliferation of cultured human lymphatic leukemia cell lines while it appears to be less effective in leukemia cells of myeloid origin. The inhibition of cell proliferation involves cell growth arrest in the G1- and/or S-phase and eventually apoptotic cell death. Our results suggest the possibility of a future use of arginine deiminase for the therapy of leukemia.

Postoperative radiotherapy of spinal and intracranial ependymomas: analysis of prognostic factors.

PURPOSE: Postoperative radiation therapy adds significantly to disease control and survival of patients with ependymoma. However, much controversy exists about the radiation treatment policy. We report the long-term results of a cohort of 56 patients with primary intracranial and spinal ependymomas. Special effort has been taken to define prognostic indicators as a basis for future treatment strategies. PATIENTS AND METHODS: Between November 1963 and May 1995, 56 patients with histological proven ependymoma were referred to our clinic for further treatment following surgery. Thirty patients had a high grading tumor and 26 had low grade tumors. Seventeen patients had supratentorial tumors and 24 had infratentorial tumors. Fifteen patients suffered from localized spinal tumors. RESULTS: The mean survival time for all patients was 77 months. Five- and 10-year survival probabilities were 60 and 51%, respectively. The mean progression free survival (PFS) probability for all patients was 67 months with corresponding 5- and 10-year PFS probabilities of 53 and 39%, respectively. On univariate analysis initial performance status, age and tumor grade were significant for survival probability. Concerning PFS radiation dose was significant with improved survival with doses > 45 Gy. On multivariate analysis, tumor grade and initial performance status proved to be the only independent prognostic factors. CONCLUSIONS: Tumor grade, age, initial performance status and radiation dose are significant factors for the clinical course of patients and have to be taken into account for the urgently needed prospective trials.

Transplantation of CD34-enriched peripheral stem cells from an HLA-haplotype mismatched donor to a patient with severe aplastic anemia.

A 14-year-old girl developed very severe aplastic anemia unresponsive to steroids, cyclosporine, ATG and filgrastim. She experienced repeated bacterial infections, hypermenorrhagia and epistaxis and received numerous transfusions. Lacking a matched family or unrelated donor, she was transplanted 6 months after diagnosis with CD34+ cell-enriched peripheral stem cells from her HLA-haploidentical uncle. Conditioning included fludarabine, cyclophosphamide, 800 cGy TLI and OKT3. Prompt and sustained trilineage engraftment occurred. Acute GVHD grade 1 and herpes esophagitis were successfully treated. Eight months after grafting she was well with stable hematopoiesis. She then succumbed to fulminant hepatic failure due to adenovirus infection.

Allogeneic CD34+ -selected peripheral stem cell transplantation from parental donors in children with non-malignant diseases.

Allogeneic peripheral stem cell transplantation in six children with non-malignant hematologic or metabolic diseases which are eventually fatal was carried out with parental donors. Given three to five HLA mismatches, all grafts underwent CD34+ cell selection as graft-versus-host prophylaxis. The patients received median doses of 16.7 x 10(6) CD34+ cells/kg and 1.2 x 10(4) CD3+ cells/kg. All transplants engrafted. Neutrophils >0.5/nl were reached on day 11 (9-19) and platelets >50/nl on day 13 (10-25). Acute GVHD responding to steriods occured in three of six patients; it was restricted to the skin and overall did not exceed grade I. Two patients died of viral infections and four are alive with stable blood counts for 13, 15, 25 and 26 months. For children with non-malignant diseases which will eventually be fatal and which can be cured or ameliorated by allogeneic BMT, CD34+-selected stem cell transplants from mismatched or even haploidentical parents can be used if no other suitable donor is available. With high CD34+ cell doses and low CD3+ cell numbers, engraftment and avoidance of acute GVHD can be expected. Infections after transplantation remain the primary threat to survival.

High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma.

Children with metastatic retinoblastoma are considered to have a poor prognosis after conventional chemotherapy. We used high-dose chemotherapy (HDC) with peripheral hematopoietic stem cell transplantation in such patients in an attempt to improve their survival. Four patients with bone marrow metastases and one child with extraorbital disease were treated with HDC after achieving complete remission by enucleation and conventional chemotherapy. The child with extraorbital tumor was the only one to receive local irradiation. The conditioning regimen included thiotepa (900 mg/m(2)), etoposide (40 mg/kg) and carboplatin (1.5 g/m(2)) in four patients, and BCNU (300 mg/m(2)), cyclophosphamide (6.8 g/m(2)) and etoposide (1.6 g/m(2)) in one child. Hematologic recovery occurred without delay in all patients. The main toxicities were diarrhea, mucositis and infectious complications. No toxic deaths or any major late toxicities were observed. The child treated with the BCNU regimen developed a meningeal relapse 10 months after HDC, which was partially resected and treated with conventional chemotherapy, but not with radiotherapy. He is in complete remission (CR) 105 months off treatment. The other patients are in CCR for 107, 57, 9 and 8 months after HDC. HDC with thiotepa, etoposide and carboplatin may represent a curative option for children with extrabulbar or disseminated retinoblastoma responsive to chemotherapy. It may control occult CNS disease. The necessity to irradiate these children and the curative potential of this strategy for patients with bulky CNS disease remain to be determined.

Adjuvant chemotherapy in osteosarcoma - effects of cisplatinum, BCD, and fibroblast interferon in sequential combination with HD-MTX and adriamycin. Preliminary results of the COSS 80 study.

In a cooperative adjuvant chemotherapy study of osteosarcoma (COSS-80), 192 patients were registered from December 1979 to March 1982. Forty-one patients have been excluded from study because of their nonadjuvant situation, therapy-limiting clinical conditions, or inadequate diagnosis. One hundred and fifty-one patients have been randomized to receive either the drug combination bleomycin + cyclophosphamide + dactinomycin (BCD) or cisplatinum (CPL) within a course of sequential multidrug chemotherapy including adriamycin (ADR) and high dose methotrexate (HDMTX). After exclusion of 51 patients with some deviation in history and/or management 100 selected patients were randomized once more to receive in addition or not fibroblast interferon after preoperative chemotherapy and surgical removal of the primary tumor. Patients were stratified for age and sex and for site and extension of tumor as well in both randomizations. Median follow up is now 12 (1-16) months. The expected 2-year disease free survival (DFS) rate of the total doubly randomized group is 78% and of the single randomized group 76%. No difference could be discerned between recombined groups receiving BCD vs CPL or interferon vs no interferon. The effect of preoperative chemotherapy on the tumor was evaluated clinically and by histopathologic grading; 66/85 (78%) patients were judged clinically as responders with pathohistologic verification of this finding in 71% of these cases. No adverse effect arose from delaying definite surgery for preoperative chemotherapy, but initial application of chemotherapy as well as planning, preparing, and performing of the surgical procedure have been facilitated. The majority of patients received some kind of limb-salvage treatment without local recurrences so far. A statistically insignificant but intriguing tendency for a slightly higher incidence of pulmonary metastases after resection as opposed to amputation could be detected. Similar to observations in the previous study COSS-77.

Thermochemotherapy in hereditary retinoblastoma.

BACKGROUND/AIM: The combination of chemotherapy and transpupillary thermotherapy, thermochemotherapy (TCT) has become an established part of the treatment plan in advanced retinoblastoma. The aim of this study was to identify safe indications, the complications as well as the limitations of this new treatment for retinoblastoma. METHODS: Tumour response and side effects of TCT with an indirect laser ophthalmoscope (spot size about 400 micro m) in 55 tumours of 26 children with bilateral retinoblastoma were analysed. Using the Reese-Ellsworth classification system, nine of 35 eyes were classified as type I, 13 eyes as type II, 10 eyes as type III, and three eyes as type V. The mean age of the children was 0.74 (SD 0.61) years. The mean tumour height was 3.5 (2.3) mm with a mean diameter of 6.1 (4.1) mm. Treatment parameters were 4.3 (1.6) (median 5) thermochemotherapy sessions with a mean energy of 539 (211) mW and a mean duration of 13.5 (5.6) minutes. Chemotherapy courses (vincristine, etoposide, and carboplatin) were repeated every 3 weeks. The mean follow up period was 1.25 (0.6) years. RESULTS: Local recurrence occurred in 21 tumours (38%), with a mean onset of 3.2 (2.9) months after TCT. The risk of tumour recurrence was correlated with tumour height. The recurrence rate was 17% for tumours with a height less than 2 mm, 37% for tumours with a height between 2 and 4 mm, and 63% for larger retinoblastomas. Multivariate analysis identified fish flesh regression after TCT (p = 0.0007) as the most important risk factor for tumour recurrence besides tumour height (p = 0.001) and the necessity of increased laser power during TCT sessions (p = 0.018). Complications during therapy included transient corneal opacification in two eyes (6%), focal iris atrophy (three eyes, 8.5%), peripheral lens opacity (two eyes, 6%), circumscribed transient retinal detachment (one eye, 3%) and diffuse choroidal atrophy (one eye, 3%). CONCLUSION: TCT using an indirect laser ophthalmoscope with a spot size of about 400 micro m was efficient for retinoblastoma with a tumour height less than 4 mm. In larger tumours, the recurrence rate was unacceptably high. Fish flesh regression after TCT correlates with a higher rate of local tumour recurrence. Treatment related complications occurred in less than 9% of the treated eyes.

Benign cystic nephroblastoma.

A benign cystic nephroblastoma in a 6-month-old boy is presented. Erroneous interpretation as malignant nephroblastoma led to unnecessarily aggressive therapy. There is no evidence of recurrence or metastatic disease 12 years after the initial resection. As shown in our case and in the others previously reported in the literature, benign cystic nephroblastoma represents a distinct clinicopathological entity which does not show malignant behavior.

[Diagnosis and genetics of congenital dyserythropoietic anemias (CDA)]. / Diagnostik und Genetik der kongenitalen dyserythropoetischen Anämien (CDA).

The congenital dyserythropoietic anemias (CDA) are hereditary diseases characterized by a lifelong, mostly moderate anemia. CDA can be diagnosed already in early childhood. However, diagnosis is complicated due to poor knowledge of morphological criteria and the large number of differential diagnoses that have to be excluded. CDA type I is characterized by macrocytic anemia with megaloblastic changes in erythropoiesis and chromatin bridges between isolated erythroblasts. Type II shows a normocytic anemia with a positive acidified serum test and increased agglutination with anti-i. Erythroblasts can present with 2 or more nuclei. CDA type III presents with a macrocytic anemia and erythroblasts with up to 12 nuclei, the so called gigantoblasts. Some patients lack the typical morphological abnormalities of type I-III (variants or type IV). Besides light microscopic abnormalities, CDA type-specific changes in electron microscopy are described. The clinical picture of the patients vary between the different forms: signs of hemolysis and ineffective erythropoiesis such as icterus, splenomegaly and gall stones can be present. Most important is the tendency of a part of patients to have an increased iron absorption and iron storage. Patients with and without transfusion dependency are described. Supportive care such as iron chelation can be necessary in some patients. The CDA are inherited in an autosomal recessive manner; in type III an additional autosomal dominant variant exists. Recently, the determination of gene loci for type I, II and III was enabled by linkage analysis on different regions of chromosome 15 and 22. It is considered that CDA I and II are genetically heterogenic. Until now no gene has been identified in either type of CDA. In CDA type II, a glycosylation defect of erythrocyte membrane proteins is present. An international group plans to do further research. Therefore, identification and registration of patients in a registry is necessary. Patients' data and material would enable gene characterization. The results would allow an extended classification according to genotype and prediction of the course of the disease. Additionally, information on the regulation and control of normal and abnormal erythropoiesis could be obtained.

[Fatal outcome of retinoblastoma. Retrospective study of 22 patients]. / Letale Verläufe bei Retinoblastom. Retrospektive Studie über 22 Patienten.

18 patients of 22 lethal cases of retinoblastoma died of recurrence or metastases of the primary tumor, which were mostly located in the head. Two clinical groups can be distinguished. In the patients with recurrence from the side of the enucleated eye, the mean survival time was 26 months, whereas the four children with a relaps originating in the conservatively treated eye survived 23 to 65 months. Two other children died of secondary tumors, and two of unrelated disease.

Persistent Epstein-Barr virus infection associated with monosomy 7 or chromosome 3 abnormality in childhood myeloproliferative disorders.

This report deals with myeloproliferative disorders associated with chronic, persistent Epstein-Barr virus (EBV) infection and with monosomy 7 and aberrations concerning chromosomes 3 and 5. Altogether five children were affected, their age ranging from 1 to 4 years at time of clinical diagnosis. Principal symptoms were: hepatomegaly, splenomegaly, recurring upper respiratory tract infection and anaemia. The serum IgG level remained persistently increased. Anti EBV antibody concentrations were measured over a period of 9 months to 6 years, demonstrating persistently increased concentrations of IgG antibodies to viral capsid antigen (VCA) and against early antigen (EA). In three patients IgA antibodies were also studied and were found to be elevated. Within 2-5 years two children developed chronic myelomonocytic leukaemia from the chronic myeloproliferative syndrome. A third patient who initially was diagnosed as chronic myelomonocytic leukaemia developed acute leukaemia within a period of 12 months. A fourth patient with myeloproliferative syndrome went into spontaneous remission after an observation period of 2 years. A fifth patient, the only one with translocation t(3;5)(q27;q33), displayed symptoms and a clinical course that can best be characterized as juvenile chronic myelocytic leukaemia. The clinical, haematological, serological and cytogenetic findings may be related.

Multiple angiogenesis stimulators in a single malignancy: implications for anti-angiogenic tumour therapy.

Anti-angiogenesis is likely to develop into a novel therapeutic approach for patients with solid malignancies. Most current clinical trials evaluate anti-angiogenic drugs aimed primarily against single angiogenesis stimulators. Here, we show that a single solid malignancy, i.e., a human embryonal rhabdomyosarcoma, produces in vivo at least three biologically active angiogenesis stimulators (vascular endothelial growth factor, basic fibroblast growth factor and interleukin-8). This suggests that tumour angiogenesis results from the activity of multiple, rather than a single angiogenesis stimulator(s). We, furthermore, show that a combination of anti-angiogenic drugs is more effective in inhibiting tumour-induced endothelial cell growth than a single agent. Our results imply that clinical anti-angiogenic strategies for the treatment of solid malignancies may be most effective when multiple rather than single antiangiogenic drugs are used.

Differential cytology of bronchoalveolar lavage fluid in immunosuppressed children with pulmonary infiltrates.

OBJECTIVE: Bronchoalveolar lavage (BAL) is a well established technique for the detection of pathogens in immunosuppressed children, but its diagnostic yield is variable. The aim of this study was to investigate whether BAL differential cell counts are helpful in the evaluation of pulmonary infiltrates in immunocompromised children. STUDY DESIGN: BAL was performed 28 times in 27 febrile immunocompromised children with pulmonary infiltrates. All patients were pretreated with broad spectrum antibiotics; 11 children also received amphotericin B. BAL was conducted with a flexible bronchoscope wedged in the area of maximal pathology as suggested by the chest radiograph or in the middle lobe in patients with diffuse interstitial radiographic changes. Differential cell counts were performed from cell smears obtained after centrifugation of BAL fluid. RESULTS: Bacterial or fungal organisms were detected in BAL fluid of 12 patients. Patients with bacterial or fungal infections (group 1) had a significantly higher percentage of granulocytes in BAL fluid both compared with patients with sterile BAL cultures (group 2) and with a control group of children without pulmonary disease (p < 0.001, Wilcoxon test). The proportion of lymphocytes was not different from the control group in group 1 but significantly increased in group 2 (p < 0.001, Wilcoxon test). Blood differential cell counts were not different in the two patient groups. Lymphocyte subsets of BAL fluid obtained in a subgroup of patients were not significantly different from controls. CONCLUSION: These data suggest that BAL differential cell counts may be a useful adjunct in the differential diagnosis of pulmonary infection in immunocompromised children.

[Multidisciplinary treatment of rhabdomyosarcoma in childhood]. / Multidisziplinäre Behandlung des Rhabdomyosarkoms im Kindesalter.

From 1974 to 1978, 21 children with rhabdomyosarcoma were treated in a combined interdisciplinary protocol. All children received a polychemotherapy for 18 months. Radiotherapy and surgery were used according to the stage and localization of the tumor. The overall two-year survival rate is 86 +/- 9%, the tumor free survival rate is 78 +/- 11%. 7 patients have no evidence of disease after the end of treatment.

Intrapulmonary protein leakage in immunocompromised children and adults with pneumonia.

BACKGROUND: Pulmonary infections are associated with an increase in capillary permeability but information regarding age related differences in the local inflammatory response is lacking. To quantify the degree of capillary leakage during inflammation, the concentrations of the plasma proteins albumin, alpha1-antitrypsin, alpha2-macroglobulin and the locally produced proteins elastase, myeloperoxidase, lactoferrin and fibronectin were studied in the bronchoalveolar lavage (BAL) fluid of immunosuppressed children and adults with pneumonia. METHODS: Sixteen children aged 2-16 years and 15 adults who developed pneumonia while receiving immunosuppressive therapy for haematological malignancies were included in the study. Bronchoalveolar lavage was performed via a flexible bronchoscope with three aliquots of 1 ml/kg body weight in children and 200 ml in adults. Protein concentrations in BAL fluid were determined using highly sensitive immunoluminometric assays. RESULTS: Despite considerable variability, the median concentrations of all proteins in BAL fluid were significantly higher in both patient populations than in previously collected age adjusted reference values. The concentrations of serum derived proteins were significantly higher in children with pneumonia than in adult patients. In contrast, no differences were observed between the two groups for locally produced proteins. CONCLUSIONS: These data suggest that the degree of protein exudation is more pronounced in immunosuppressed children with pneumonia than in adults in a similar clinical situation. This is in agreement with our studies in healthy individuals and may reflect a greater permeability of the alveolar-capillary membrane in children, regardless of disease status.

[Value of ophthalmoscopy and histology for the prognosis of patients with retinoblastoma]. / Die Wertigkeit von Ophthalmoskopie und Histologie für die Prognose der Patienten mit Retinoblastom.

The predictive value of prognostic factors is of utmost importance for the treatment of patients with retinoblastoma. Functional results, that may be expected following sight saving therapy, can be deducted from ophthalmoscopic findings. Large tumors, tumors located centrally, the presence of extensive retinal detachment or diffuse vitreous seeding are poor prognostic signs. Histopathologic findings of the enucleated eye harbouring retinoblastoma correlate well with the incidence of metastatic disease. Patients in which the tumor has invaded the choroid, optic nerve or sclera have a high risk of developing metastases.

Anomalies of the kidneys and genitourinary tract in alcoholic embryopathy.

in addition to the well known major signs of growth retardation, microcephaly, mental retardation and typical craniofacial dysmorphism, malformations of the urinary tract were found in 9 of 110 patients with alcohol embryopathy. Of the 110 patients 21 have been examined adequately. An extensive urologic investigation of children with alcohol embryopathy and symptoms suggesting kidney or genitourinary tract disease is essential for early diagnosis and correction of malformations. Awarness of alcohol embryopathy in a child referred for correction of urinary tract anomalies may help to establish the diagnosis and prevent it in further offspring.

Interdisciplinary treatment of Wilms' tumour.

The results of treating the 51 children suffering from Wilms' tumour seen in the 10 years to January 1982 are described and the need of an interdisciplinary approach is stressed.