Holger Ottensmeier

Treatment of young children with CNS-primitive neuroectodermal tumors/ pineoblastomas in the prospective multicenter trial HIT 2000 using different chemotherapy regimens and radiotherapy

BACKGROUND Especially in young children, primitive neuroectodermal tumors of the central nervous system (CNS-PNET) and pineoblastomas are associated with an unfavorable outcome, and only a few prospective trials have been conducted thus far. METHODS From January 2001 through January 2005, 17 eligible children aged <4 years with CNS-PNET not otherwise specified (n = 8), ependymoblastoma (n = 1), or pineoblastoma (n = 8) confirmed by central review were prospectively treated in the trial HIT 2000. In nonmetastatic disease (n = 11), up to 5 postoperative cycles of HIT-SKK systemic multiagent chemotherapy (8 months duration), followed by craniospinal radiotherapy (CSI), were given. In metastatic disease (M1-M3, n = 6), treatment consisted of a shorter induction chemotherapy (2-3 months) with carboplatin and etoposide, followed by tandem high-dose chemotherapy (HDCT) in case of good response to induction. During induction and HDCT, patients received intraventricular methotrexate. CSI was applied to all patients with poor response to induction or residual disease after HDCT and was optional for patients with residual disease before HDCT. RESULTS Five-year event-free survival and overall survival rates ± standard error for all eligible patients were 24% ± 10% and 40% ± 12%, respectively (median follow-up of survivors: 8.3 years). Only one patient with nonmetastatic disease remained free of relapse/progressive disease during induction. Three of 6 patients with metastatic disease responded to induction and received tandem-HDCT, followed by preventive CSI, and remain in continuous complete remission. CONCLUSIONS Short intensive induction chemotherapy followed by tandem-HDCT in young children with CNS-PNET/pineoblastomas seems to be superior to the prolonged and less intensive induction regimen.

Treatment of children with central nervous system primitive neuroectodermal tumors/pinealoblastomas in the prospective multicentric trial HIT 2000 using hyperfractionated radiation therapy followed by maintenance chemotherapy.

PURPOSE The prognosis for children with central nervous system primitive neuroectodermal tumor (CNS-PNET) or pinealoblastoma is still unsatisfactory. Here we report the results of patients between 4 and 21 years of age with nonmetastatic CNS-PNET or pinealoblastoma diagnosed from January 2001 to December 2005 and treated in the prospective GPOH-trial P-HIT 2000-AB4. METHODS AND MATERIALS After surgery, children received hyperfractionated radiation therapy (36 Gy to the craniospinal axis, 68 Gy to the tumor region, and 72 Gy to any residual tumor, fractionated at 2 × 1 Gy per day 5 days per week) accompanied by weekly intravenous administration of vincristine and followed by 8 cycles of maintenance chemotherapy (lomustine, cisplatin, and vincristine). RESULTS Twenty-six patients (15 with CNS-PNET; 11 with pinealoblastoma) were included. Median age at diagnosis was 11.5 years old (range, 4.0-20.7 years). Gross total tumor resection was achieved in 6 and partial resection in 16 patients (indistinct, 4 patients). Median follow-up of the 15 surviving patients was 7.0 years (range, 5.2-10.0 years). The combined response rate to postoperative therapy was 17 of 20 (85%). Eleven of 26 patients (42%; 7 of 15 with CNS-PNET; 4 of 11 with pinealoblastoma) showed tumor progression or relapse at a median time of 1.3 years (range, 0.5-1.9 years). Five-year progression-free and overall survival rates (± standard error [SE]) were each 58% (± 10%) for the entire cohort: CNS-PNET was 53% (± 13); pinealoblastoma was 64% (± 15%; P=.524 and P=.627, respectively). CONCLUSIONS Postoperative hyperfractionated radiation therapy with local dose escalation followed by maintenance chemotherapy was feasible without major acute toxicity. Survival rates are comparable to those of a few other recent studies but superior to those of most other series, including the previous trial, HIT 1991.

Kurzgefasste Intelligenzdiagnostik bei Hirntumoren

Zusammenfassung. Eine kurze neuropsychologisch orientierte Intelligenzdiagnostik stellt einen notwendigen Bestandteil jeder Befunderhebung bei Kindern mit zerebralen Erkrankungen dar und ist z. B. bei Hirntumoren notwendig, um Leistungsbeeintrachtigungen durch den Tumor beschreiben und eine Risikoabschatzung der Behandlungskonsequenzen durchfuhren zu konnen. Die Wurzburger Psychologische Kurz-Diagnostik (WUP-KD) ist ein Screening-Instrument, um mentale Funktionen in ca. einer Zeitstunde zu untersuchen. Diese Kurz-Intelligenzdiagnostik ist in ihren wesentlichen Teilen leicht anwendbar und wenig belastend fur das Kind. Auch schwer erkrankte Kinder sind so im Behandlungsverlauf untersuchbar. Aus diesem Grund erfasst der WUP-KD uber den IQ hinaus die sensomotorischen und feinmotorischen Funktionen, die Reaktionsfahigkeit und die Aufmerksamkeit. Erste Vergleiche des Kurztests mit der K-ABC zeigen in Regressionsanalysen gute Varianzaufklarungen wesentlicher Parameter der K-ABC. Die Auswahl der Tests erfolgte un...

Simultaneous occurrence of various mutations and polymorphisms in cis and in trans of the galactose-1-phosphate uridyltransferase gene in a Turkish family with classical galactosemia

Classical galactosemia, characterized clinically by acute hepatic dysfunction, sepsis, cataract, and failure to thrive, is caused by deficiency of galactose-1-phosphate uridyltransferase (GALT). Galactose restriction normalizes these acute symptoms; however, long-term complications such as intellectual deficits and ovarian failure are conspicuous in the majority of patients. Here we report two Turkish siblings with classical galactosemia. The clinical course of the two children differed markedly: only the older girl suffered from severe acute symptoms during the neonatal period, and she developed greater mental retardation than her younger affected brother. The functional activity of GALT was virtually absent in each affected children. The mother and two healthy siblings exhibited approximately 50% normal GALT activity and the father approximately 25%. Molecular analysis revealed that these two galactosemic siblings were homozygous for a stop codon mutation of E340X in GALT exon 10. Moreover, two additional mutations, a neutral polymorphism L218L and N314D, which are typical for the Duarte-1 variant, were found in the same GALT allele. The two healthy siblings and the parents were heterozygous for these combinations of mutations. In addition, the father’s second GALT allele revealed three intron mutations at nucleotide position 1105 (G→C), 1323 (G→A) and 1391 (G→A) and the N314D mutation, which correspond to the mutations of Duarte-2 variant. Our findings indicate that in classical galactosemia several distinct mutations can be present in one allele (in cis) of the GALT gene. Therefore it seems to be necessary to examine all introns and exons of the GALT gene in galactosemic patients who do not carry the Q188R mutation or another frequent mutation in the GALT gene.