Molecular characterization of disseminated pilocytic astrocytomas.

AIM: Pilocytic astrocytomas represent the most common paediatric tumours of the central nervous system. Dissemination through the ventricular system occurs rarely in patients with pilocytic astrocytomas; however, it is more common in infants with diencephalic tumours, and is associated with a poor outcome. Despite histological similarities with classic pilocytic astrocytomas, it is still unclear whether disseminated pilocytic astrocytomas may have specific molecular features. METHODS: Seventeen disseminated pilocytic astrocytomas were investigated using the molecular inversion probe array and screened for the presence of gene fusions (KIAA1549-BRAF) and mutations (BRAF, RAS and FGFR1). RESULTS: Along with evidence of a constitutive MAPK activation in all cases, the molecular inversion probe array, fluorescence in situ hybridization analysis and mutational study revealed KIAA1549-BRAF fusions in 66% and BRAF(V600E) mutations in 5% of cases. No KRAS, HRAS, NRAS or FGFR1 mutations were found. CONCLUSIONS: disseminated pilocytic astrocytomas showed genetic features similar to classic pilocytic astrocytoma, including a similar incidence of KIAA1549-BRAF fusions, BRAF mutations and a stable genetic profile. Given common activation of the MAPK pathway, the use of specific inhibitors can be hypothesized for the treatment of disseminated pilocytic astrocytomas, along with standard chemo- and/or radiotherapy.

Cerebellar location may predict an unfavourable prognosis in paediatric high-grade glioma.

BACKGROUND: High-grade glioma (HGG) of the cerebellum accounts for only 5% of paediatric HGG. Since little is known about these tumours, the present study aimed at their further characterisation. METHODS: Twenty-nine paediatric patients with centrally reviewed cerebellar HGG were identified from the HIT-GBM/HIT-HGG database. Clinical and epidemiological data were compared with those of 180 paediatric patients with cortical HGG. RESULTS: Patients with cerebellar tumours were younger (median age of 7.6 vs 11.7 years, P=0.028), but both groups did not differ significantly with regard to gender, tumour predisposing syndromes, secondary HGG, primary metastasis, tumour grading, extent of tumour resection, chemotherapy regimen, or radiotherapy. Except for an increased incidence of anaplastic pilocytic astrocytoma (APA) in the cerebellar subset (20.7% vs 3.3%; P<0.001), histological entities were similarly distributed in both groups. As expected, tumour grading had a prognostic relevance on survival. Compared with cortical HGG, overall survival in the cerebellar location was significantly worse (median overall survival: 0.92 ± 0.02 vs 2.03 ± 0.32 years; P=0.0064), and tumour location in the cerebellum had an independent poor prognostic significance as shown by Cox-regression analysis (P=0.019). CONCLUSION: High-grade glioma represents a group of tumours with an obviously site-specific heterogeneity associated with a worse survival in cerebellar location.

Radiotherapy in pediatric pilocytic astrocytomas. A subgroup analysis within the prospective multicenter study HIT-LGG 1996 by the German Society of Pediatric Oncology and Hematology (GPOH).

PURPOSE: We evaluated clinical outcomes in the subset of patients who underwent radiotherapy (RT) due to progressive pilocytic astrocytoma within the Multicenter Treatment Study for Children and Adolescents with a Low Grade Glioma HIT-LGG 1996. PATIENTS AND METHODS: Eligibility criteria were fulfilled by 117 patients. Most tumors (65 %) were located in the supratentorial midline, followed by the posterior fossa (26.5 %) and the cerebral hemispheres (8.5 %). Median age at the start of RT was 9.2 years (range 0.7-17.4 years). In 75 cases, external fractionated radiotherapy (EFRT) was administered either as first-line nonsurgical treatment (n = 58) or after progression following primary chemotherapy (n = 17). The median normalized total dose was 54 Gy. Stereotactic brachytherapy (SBT) was used in 42 selected cases. RESULTS: During a median follow-up period of 8.4 years, 4 patients (3.4 %) died and 33 (27.4 %) experienced disease progression. The 10-year overall (OS) and progression-free survival (PFS) rates were 97 and 70 %, respectively. No impact of the RT technique applied (EFRT versus SBT) on progression was observed. The 5-year PFS was 76 ± 5 % after EFRT and 65 ± 8 % after SBT. Disease progression after EFRT was not influenced by gender, neurofibromatosis type 1 (NF1) status, tumor location (hemispheres versus supratentorial midline versus posterior fossa), age or prior chemotherapy. Normalized total EFRT doses of more than 50.4 Gy did not improve PFS rates. CONCLUSION: EFRT plays an integral role in the treatment of pediatric pilocytic astrocytoma and is characterized by excellent tumor control. A reduction of the normalized total dose from 54 to 50.4 Gy appears to be feasible without jeopardizing tumor control. SBT is an effective treatment alternative.

Disseminated choriocarcinoma in infancy is curable by chemotherapy and delayed tumour resection.

Infantile choriocarcinoma has a poor prognosis with only 2 surviving children reported in the literature. 2 additional successfully treated children are presented. 2 infants (age 3 and 4 months at diagnosis) suffering from rapidly progressive choriocarcinoma with widespread haematogenous metastases involving the liver were treated according to the cooperative germ cell tumour treatment protocol (MAKEI 96) of the German Society of Pediatric Oncology and Hematology (GPOH). PEI-chemotherapy (cisplatin, etoposide, ifosfamide; no ifosfamide before the age of 4 months) was combined with delayed tumour resection. Treatment resulted in sustained remission in both children (event-free survival 42 and 40 months). Interphase fluorescent in situ hybridisation (FISH) analysis of the paraffin-embedded tumour sample from case one revealed four to eight copies of chromosomes X, 1 and 17 and two Y chromosomes. Hybridisation with sub-telomere and centromere specific probes for chromosome 1 displayed an imbalance between the short and long arms of chromosome 1. In the tumour cells from case 2, only a polysomy of chromosome X could be proven, other aberrations were not analysed in this case for technical reasons.

12q13, a new recurrent breakpoint in acute non-lymphoblastic leukemia.

The karyotypes of 312 successfully analyzed samples of children with acute non-lymphoblastic leukemia (ANLL), which were sent to us by 72 German hospitals, were examined in order to find new recurrent chromosome abnormalities of possible clinical relevance. Whereas most of the patients had one of the specific aberrations of ANLL or a normal karyotype, random numerical or structural changes were found in 61 children (20%). Four of them showed an abnormality involving band 12q13: t(12;17)(q13;q21), t(12;21)(q13;q21), t(2;12)(p13;q13), and t(5;12)(p11;q13). Despite the fact that FAB subtypes were different (M0, M1 M6, AHL), the blasts of all patients were characterized by immaturity and were difficult to classify. The breakpoint 12q13 might be of clinical importance in ANLL, because the four patients in our study, as well as the 21 patients with this aberration found in the literature, had a very poor prognosis.

Secondary dissemination in children with high-grade malignant gliomas and diffuse intrinsic pontine gliomas.

In children, treatment regimen for high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG) are generally not stratified according to disease stage. The hypothesis was that secondary disseminating disease (SDD) in children with HGG is related to an even worse outcome. Description of SDD pattern was performed. In total, 270 children with newly diagnosed HGG or DIPG were eligible for retrospective analysis of SDD. Medical and computer records of these patients were reviewed for demographic characteristics, sites of dissemination, prognostic variables. Forty-six (17%) of the 270 patients had developed SDD. The median time to SDD was 8.2 months. The median overall survival (OS) after dissemination was 3.2 months. The SDD was located parenchymal in the supratentorial (34.8%), infratentorial (6.5%), supratentorial and infratentorial (19.6%), spinal (10.9%), spinal and cerebral (6.5%) regions of the CNS, or leptomeningeal (21.7%). For HGG patients, the median OS was shorter among patients with SDD than among patients without SDD (1.02 vs 1.41 years, P=0.0495). In the group of patients with SDD, patients with cerebrospinal fluid dissemination had a worse outcome compared with patients with parenchymal metastases. Summarising, SDD is a negative prognostic factor for patients with HGG outside the pons. Treatment stratification should be considered.

Recommendations of the Brain Tumor Subcommittee for the reporting of trials. SIOP Brain Tumor Subcommittee. International Society of Pediatric Oncology.

Since its constitution during the 22nd annual meeting of the International Society of Pediatric Oncology in Rome in 1990, the Brain Tumor Subcommittee has worked to arrive at a consensus for reporting criteria that should be adopted when brain tumor trials are presented. This consensus is presented here concerning minimum requirements for diagnostic procedures and a systematic approach to define the extent of surgically achieved resection by a radiodiagnostic classification aided by the surgical report as well as response and remission criteria.

Terminal differentiation in vitro of patient-derived post-TMD megakaryoblastic AML cells.

Differentiation induction is a therapeutic principle in acute promyelocytic leukemia (AML) using all- trans retinoic acid. In cell lines with properties of AML M6/M7 (K562 and CMK), differentiation towards megakaryopoietic and erythropoietic phenotypes can be induced in vitro. Transitory myeloproliferative disorder (TMD) is a self-limited disorder of newborn infants with Down syndrome, phenotypically resembling acute myeloid leukemia of megakaryoblastic lineage. Despite spontaneous disappearance of blasts from blood and bone marrow, in about 10% of the patients, overt acute megakaryoblastic leukemia (AML M7) develops up to 4 years later. Recently, mutations of the GATA1 transcription factor have been identified in the megakaryoblastic leukemia of Down syndrome. Here, we studied cells from a patient suffering from megakaryoblastic AML at the age of 2.5 years after spontaneous remission of neonatal TMD. In vitro, terminal differentiation towards a megakaryocyte-like phenotype could be induced by phorbol myristate acetate (PMA), with typical morphological features, upregulation of platelet-specific and downregulation of erythroid antigens, going along with downregulation of c-myc. Whether spontaneous resolution of TMD is a process due to terminal differentiation is still open; however, here we give evidence that in vitro differentiation can be induced even in blasts deriving from an overt AML French-American-British (FAB) M7 after TMD.

[HIT-LGG: effectiveness of carboplatin-vincristine in progressive low-grade gliomas of childhood--an interim report]. / HIT-LGG: Effektivität von Carboplatin-Vincristin bei progredienten Gliomen niedrigen Malignitätsgrades im Kindesalter--Zwischenbericht.

BACKGROUND: The rationale of the HIT-LGG protocol is to delay standard radiotherapy through administration of chemotherapy for children with progressive low grade glioma at an age under 5 years and in older children upon individual decision. PATIENTS AND METHOD: Until October 10th., 1999, 402 patients from 69 hospitals were registered. 130 children with progressive tumors were treated after a median observation time of 5 months: 46 patients received primary radiotherapy and 84 primary chemotherapy. A ten week induction period with weekly Vincristine and pulses of Carboplatin at weeks 1, 4, 7 and 10 is followed by consolidation with simultaneous application of both drugs every 4 weeks until week 53. RESULTS: Of 84 patients in the chemotherapy arm of the study (49 male, 35 female, 23 NF I, median age 2.99 years) 36 received treatment at diagnosis and 43 after a median observation time of 19.7 months. 94.3% achieved a clinical and neuroradiological response according to protocol criteria (5 CR, 30 PR/OR, 31 SD) after a median of 5.1 months. 4 tumors showed primary progression (9 too early, 5 not known). Only 6 of 84 children received radiation therapy for progressive disease during (2) or after termination (4) of chemotherapy, after a median delay of 25.6 months at a median age of 6.0 years. At a median observation time of 21.0 months, 6 children are in CR, 11 in PR, 48 have SD, 4 tumors are progressive and 3 children died of their tumor. (9 too early, 3 not known). PFS is at 72% after 36 months. 24 of 27 children experiencing allergic reactions to Carboplatin had to interrupt chemotherapy prematurely. CONCLUSIONS: Combination therapy with Carboplatin and Vincristine can effectively delay the start of radiotherapy in children with progressive low-grade glioma. The high rate of hypersensitivity reactions has to prompt future modifications of treatment.

Differential diagnosis of suprasellar tumors in children.

In contrary to the adult age the most common suprasellar tumors in children are with decreasing frequency craniopharyngiomas, chiasmatic/hypothalamic low-grade gliomas, germinomas and lesions attributable to a Langerhans cell histiocytosis. For differential diagnostic purposes also the rare hypothalamic hamartoma and meningeal metastases in the infundibular recess of the third ventricle are included. The typical aspects of the various tumors on computed tomography (CT) and magnetic resonance imaging (MRI) together with important clinical differences are illustrated. On the basis of imaging results and clinical symptoms differential diagnosis between the various tumor entities should be feasible in many cases. Of course, only in strictly defined cases like typical chiasmatic/hypothalamic and optic pathway gliomas or bilocular germ cell tumors a histological confirmation is dispensable.

Low grade chiasmatic-hypothalamic glioma-carboplatin and vincristin chemotherapy effectively defers radiotherapy within a comprehensive treatment strategy -- report from the multicenter treatment study for children and adolescents with a low grade glioma -- HIT-LGG 1996 -- of the Society of Pediatric Oncology and Hematology (GPOH).

BACKGROUND: Low grade gliomas arise in all CNS-locations and age groups, chiasmatic-hypothalamic tumors occur especially in young children. Early radiotherapy (RT) shall be deferred by chemotherapy (CT) within the concept of the HIT-LGG 1996 study, offering a comprehensive treatment strategy for all age groups. PATIENTS: 198 of 905 protocol patients (21.9 %) had a chiasmatic (34), chiasmatic-hypothalamic (144) or hypothalamic (20) primary tumor, median age at diagnosis 3.6 years (0.2-16.3 y.), 54 had neurofibromatosis (27.3 %), 108 female (54.5 %). 98 children had severe visual impairment as their first symptom. The initial neurosurgical intervention resulted in 5 complete, 26 subtotal, 45 partial resections, 67 biopsies; 55 children had a diagnosis on the basis of neuroradiologic findings. Histology showed 132 pilocytic astrocytoma I degrees , 6 astrocytoma II degrees /nos and 2 DIGG/DIA I degrees (3 not known). RESULTS: 82 children were treated at diagnosis, 68 upon clinical or radiological progression following observation times of 3.0 to 115.0 months. RT: 27 children received conventional (18) or interstitial (8) RT (1 not documented) at a median age of 7.3 years; 7 tumors went into further progression. At a median observation time of 50.1 months 21 tumors are stable, 3 regressive (2 not evaluable, 1 death). CT: 123 children received vincristin/carboplatin at a median age of 3.7 years. 105/123 achieved CR/PR/SD. 44/123 tumors were progressive after median 22.5 months, 37 with a chiasmatic-hypothalamic primary, 16/44 were irradiated. At a median observation time of 44.7 months 2 children are in complete remission, 92 tumors are stable, 8 regressive, 9 progressive. 4 children died, 8 are not evaluable. At 60 months overall survival of the cohort is 0.93; PFS of the CT-group is 0.61, the RT-free survival 0.83. Within the CT-group children with an age at diagnosis < 1 year and non-pilocytic histology are at increased risk for early progression. Causative factors cannot be defined, yet. CONCLUSION: Within the comprehensive treatment strategy for low grade glioma HIT-LGG 1996 chemotherapy is effective to delay the need for early radiotherapy in chiasmatic-hypothalamic glioma. More effective reduction of the risk for progression has to be sought for young children < 1 year.

[Medulloblastoma therapy studies MBL 80 and MED 84 of the Society of Pediatric Oncology and the Société Internationale d'Oncologie Pédiatrique (SIOP)]. / Die Medulloblastom-Therapiestudien MBL 80 und MED 84 der Gesellschaft für Pädiatrische Onkologie (GPO) und der Société Internationale d'Oncologie Pédiatrique (SIOP).

In both trials the principle of "sandwich" chemotherapy (administered between surgery and postoperative irradiation) is studied in medulloblastoma. GPO-MBL 80 was essentially a one-arm trial; results after a mean observation period of 3 years show an expected event-free survival rate of 46% at 6 years. "Maintenance" chemotherapy with CCNU and vincristine did not further improve the results. Preliminary results of the joint, prospective, randomised forearm SIOP-GPO trial MED 84 are presented. It is apparently too early to answer any of the two main questions asked by this trial: a) is "sandwich" chemotherapy (as administered) of any value? b) can radiotherapy doses to the supratentorial area and to the spine be moderately reduced in so-called "low risk" patients without compromising long-term results? Thus far, we cannot observe any prognostic influence of the "classical" risk factors as established by other studies.

Impact of location on outcome in children with low-grade oligodendroglioma.

BACKGROUND: Childhood low-grade oligodendroglioma (WHO grade II) are rare. No controlled pediatric study has been published, to generate high level evidence for the best treatment. Therefore, we retrospectively analyzed data available from pediatric patients. PROCEDURE: We pooled data from two prospective German multicentre studies (HIT-DOK and HIT-LGG). Eligibility criteria were: (1) primary neoplasm, (2) histology of pure oligodendroglioma WHO grade II, (3) intracranial location, (4) age <18 years, (5) date of diagnosis: 1990-2002, (6) observation time >6 months. The outcome was analyzed by using the SPSS-software. RESULTS: Nineteen boys and 13 girls were eligible (median age 10.3 years). The tumor locations included: 26 peripheral tumors (23 cerebral hemisphere, 3 cerebellum), and 6 central tumors (4 thalamus, 1 frontal mesencephalon, 1 basal ganglia). Resections were classified as complete in 18 (14 cerebral hemispheres, 3 cerebellum, 1 thalamus) and less than complete in 14 patients (3 subtotal resections, 8 partial resections, 3 biopsy). The 5-year event-free survival (EFS) and overall survival (OS) rates of all patients were 81.3 and 84.4%, respectively (median observation time 3.8 years). All of the 26 children with peripheral tumors were alive with no tumor progression, but five of six patients with central tumors died of disease (median time to death 1.6 years). This survival difference was statistically significant for EFS (P < 0.0001) and OS (P < 0.0001). The difference between completely resected versus incompletely resected tumors was far less striking (P > 0.06). CONCLUSIONS: The outcome of children with centrally located low-grade oligodendroglioma is particularly poor, while tumors of the cerebral hemispheres and cerebellum carry an excellent prognosis, even with minor tumor resection.

Oral trofosfamide and etoposide in pediatric patients with glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme in childhood is rare, and the prognosis for patients with the disease is poor. The Pediatric Oncology Society of the Germanic language group (GPOH) enrolls patients in a series of pilot trials, the first of which is reported here (HIT-GBM-A). METHODS: Twenty-two patients with glioblastoma multiforme, World Health Organization Grade 4, between the ages of 3-15 years (45% male) were enrolled during the period 1995-1997. There were 13 supratentorial tumors, 8 brainstem tumors, and 1 cerebellar tumor. The patients underwent the following procedures: stereotactic biopsy (n = 3 patients), open biopsy (n = 1 patient), partial resection (n = 6 patients), subtotal resection (n = 4 patients), and macroscopic total resection (n = 8 patients). Adjuvant treatment consisted of oral chemotherapy with trofosfamide, 100 mg/m(2), and etoposide, 25 mg/m(2), daily or for 21-day cycles interrupted by 1-week rests. Standard fractionated radiation (54 grays) was started concurrently with the first cycle. RESULTS: The chemotherapy was well tolerated, with no treatment-related deaths and only minor side effects. The responses in 12 evaluable patients after two cycles were as follows: 1 complete response, 1 partial response, 3 patients with stable disease, and 7 patients with progressive disease. The median overall survival was 12 months. The 1-year, 2-year, and 4-year overall survival rates were 52%, 26%, and 22%, respectively, and the event free survival rates were 26%, 22%, and 4%, respectively. None of the four surviving patients (3.2 years, 3.4 years, 4.0 years, and 4.2 years after diagnosis) is event free. Two patients are alive after tumor progression: One patient was diagnosed with a medulloblastoma, and one patient was diagnosed with an osteosarcoma as second malignancies. A control group extracted from the Surveillance, Epidemiology, and End Results data had lower survival rates: the difference between the groups was not statistically significant (P = 0.26). CONCLUSIONS: This chemotherapy will not be used in a randomized trial of patients with glioblastoma; however, it may be evaluated for patients with tumors that have more chemoresponsive histologies.

[Results of the treatment of non-rhabdomyosarcomatous soft tissue neoplasms within the scope of the CWS 81 study]. / Behandlungsergebnisse der nichtrhabdomyosarkomatösen Weichteilmalignome im Rahmen der CWS-81-Studie.

347 children with all types of soft tissue sarcoma (STS) have been entered between 1981 and April 1986 into the CWS-81 study. Excluding 229 patients with rhabdomyosarcoma, 118 patients with other STS were analysed in the histological subgroups, separately. 33 synovial sarcomas (SyS), 15 undifferentiated sarcomas (US) and 13 extrasceletal Ewing's sarcoma (EES) were treated with a multimodale trial including chemotherapy and radiotherapy after initial not-mutilating resection or biopsy only, Relapse-free survival rate by Kaplan-Meier was 66% in SyS, 48% in EES and 38% in US, respectively. Patients treated according to the guidelines of the CWS-protocol showed better prognosis than patients with major protocol violations or patients with recurrence when entered into the trial. In SyS only 2 of the 7 patients with recurrence developed metastases. The tumor response rate within 7-9 weeks chemotherapy exclusively given was 71% in patients with stage III and IV. Non-responding tumors to chemotherapy had bad prognosis, irrespective of histological subtype or further treatment. EES and US developed earlier recurrence and more often metastases than SyS or rhabdomyosarcomas. The administered VACA-chemotherapy seems not to be very effective in EES and US. In all other varieties of STS recurrence at the primary site assumed relatively greater importance. Chemotherapy and radiation were not administered in all patients. Fibrosarcoma (FS) was diagnosed in 13 patients. Six of these were entered in the trial at the time of local recurrence and 4 of these 6 relapsed again locally, one with metastasis concurrently.(ABSTRACT TRUNCATED AT 250 WORDS)

[Adrenal cortex carcinoma. A rare cause of a Conn syndrome in childhood]. / Nebennierenrinden-karzinom. Eine seltene Ursache eines Conn-Syndroms im Kindesalter.

A 2 1/3 year old girl presented classical Conn-Syndrome as diagnostic feature of an adrenocortical carcinoma. Sonographic diagnosis was confirmed by CT-scan, typical hormonal pattern and subsequent surgical procedure. Without further therapy there has been no relapse with a follow-up of 3 years.

Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II.

In a multicentre randomised clinical trial 364 children with biopsy proven medulloblastoma were randomly assigned to receive or not pre-radiotherapy chemotherapy. Children with total or subtotal removal of the tumour, no evidence of invasive brain stem involvement, and no evidence of metastatic disease either within or without the cranium were designated "low risk", those with gross residual tumour, evidence of invasive brain stem involvement or metastases in the central nervous system were designated "high risk". All children were prescribed 55 Gy to the tumour bearing area. "Low risk" children could be randomised to "standard" radiotherapy 35 Gy to the craniospinal axis or "reduced" dose 25 Gy to the craniospinal axis. Chemotherapy consisted of vincristine, procarbazine, and methotrexate given in a 6-week module before radio-therapy, and for "high risk" children, vincristine and CCNU given after radiotherapy. No benefit for the receipt of pre-radiotherapy chemotherapy could be demonstrated for any group. In addition, a negative interaction was observed between the receipt of the chemotherapy and reduced dose radio-therapy with a particularly poor outcome being observed in this group of children.

Treatment of paediatric pontine glioma with oral trophosphamide and etoposide.

To evaluate the overall survival of paediatric patients with pontine gliomas treated with oral trophosphamide and etoposide. Patients between 3 and 17 years of age with either typical diffuse pontine glioma on MRI or histologically proven anaplastic astrocytoma/glioblastoma multiforme located in the pons, were eligible. Treatment consisted of oral trophosphamide 100 mg x m(-2) x day(-1) combined with oral etoposide at 25 mg x m(-2) x day(-1) starting simultaneously with conventional radiation. Twenty patients were enrolled (median age 6 years, male : female=9 : 11). Surgical procedures included: no surgery: five, open biopsy: three, stereotactic biopsy: six, partial resection: three, and sub-total resection: three. Histological diagnoses included pilocytic astrocytoma: one, astrocytoma with no other specification: three, anaplastic astrocytoma: three, glioblastoma multiforme: eight, no histology: five. The most frequent side effects were haematologic and gastrointestinal. There was no toxic death. The response to combined treatment in 12 evaluable patients was: complete response: 0, partial response: three, stable disease: four, and progressive disease: five. All tumours progressed locally and all patients died. The overall median survival was 8 months. The overall survival rates at 1 and 4 years were: 0.4 and 0.05 respectively. This was not different from a control group of patients documented in the same population. Oral trophosphamide in combination with etoposide did not improve survival of pontine glioma patients. The treatment was well tolerated and should be evaluated for more chemoresponsive paediatric malignancies.

[Improved prognosis of intracranial germ cell tumors by intensified therapy: results of the MAKEI 89 therapy protocol]. / Verbesserte Prognose intracranialer Keimzelltumoren durch intensivierte Therapie: Ergebnisse des Therapieprotokolls MAKEI 89.

Germ cell tumors of the central nervous system are histological identical to the extracranial tumor sites. According to the localisation germ cell tumors of the CNS are different in symptoms, diagnostic approaches, kind and location of metastases and stratification of therapy. Since 1986 patients with intracranial germ cell tumors are registered in the ongoing study for non-testicular germ cell tumors (MAKEI) of the German Society of Pediatric Oncology and Hematology, and are treated in accordance to therapy guidelines for extracranial sites. In MAKEI 89 therapy strategy was revised with a reduction of radiotherapy and an increased cumulative cisplatinum dose from 200 mg/m2 to 400 mg/m2. Patients with germinoma receive after histologic diagnosis radiotherapy consisting of 30 Gy craniospinal irradiation and 15 Gy tumorboost. Malignant non-germinoma receive after diagnosis by tumor marker in CSF and/or serum 2 courses bleomycin 15 mg/m2 day 1-3, Etoposide 150 mg/m2 day 1 + 2 and cisplatinum 20 mg/m2 days 4-8 (BEP), continued by 2 courses Vinblastine 3 mg/m2 day 1 + 2, Ifosfamide 1500 mg/m2 days 1-5 and cisplatinum 20 mg/m2 days 1-5 (VIP), followed by 30 Gy craniospinal irradiation and 20 Gy tumor boost. In teratoma first line therapy is complete resection. In incomplete resected cases adjuvant chemotherapy according to histological grading is administered. Until 31st January, 1993 101 patients (pts) were registered, containing 69 protocol pts. Diagnosis in protocol pts was teratoma in 8 cases, 2 pts died postnatal because of extended disease, 2/8 pts relapsed, but were salvaged by chemotherapy. 40 pts offered germinomas.(ABSTRACT TRUNCATED AT 250 WORDS)