0000000000175095
AUTHOR
Torsten Pietsch
Strategies to improve the quality of survival for childhood brain tumour survivors
Abstract Background Tumours of the central nervous system (CNS) are the most frequent solid tumours and the second most frequent type of cancer in children and adolescents. Overall survival has continuously improved in Germany, since an increasing number of patients have been treated according to standardised, multicentre, multimodal treatment recommendations, trials of the German Paediatric Brain Tumour Consortium (HIT-Network) or the International Society of Paediatric Oncology-Europe (SIOP-E) during the last decades. Today, two out of three patients survive. At least 8000 long-term childhood brain tumour survivors (CBTS) are currently living in Germany. They face lifelong disease- and tr…
Frequency, Risk-Factors and Survival of Children With Atypical Teratoid Rhabdoid Tumors (AT/RT) of the CNS Diagnosed between 1988 and 2004, and Registered to the German HIT Database
Purpose To analyze the frequency, prognostic factors, and outcome of children with atypical teratoid/rhabdoid tumors (AT/RT), a rare and highly malignant embryonal brain tumor. Materials and Methods Clinical data of patients diagnosed between 1988 and 2004 with AT/RT who were registered to the German HIT trial center, were correlated with outcome. Patient numbers for AT/RT were compared to numbers for primitive neuroectodermal tumors and medulloblastomas (PNET/MB) registered to the population-based HIT trials. Results We identified 56 patients with the centrally confirmed histopathological diagnosis of AT/RT with a median age of 1.2 years (range, 0.1–14.0 years). The AT/RT:PNET/MB ratio was…
Embryonic neural cell adhesion molecules on human natural killer cells
The neural cell adhesion molecules (NCAM) are surface glycoproteins that were first described in brain tissue. NCAM mediate adhesion in a variety of cell-cell interactions. In the present study we show that the so-called "embryonic" NCAM, i.e., the highly polysialylated forms of these proteins, are expressed on natural killer cells and some CD3+ cells in man. Homotypic binding of NCAM, believed to be of importance for cell-cell adhesion in neural tissues, appears not to be essential for NK cell-mediated killing. Yet, NCAM might be involved in NK cell migration, homing or related functions.
Abstract 3463: Treatment of young children with localized medulloblastoma by chemotherapy alone: Final results of the prospective multicenter trial HIT 2000 confirming the prognostic impact of histology
Abstract Background: This study was designed to confirm the previously observed favorable survival rates and prognostic factors in young children with non-metastatic medulloblastoma (MB) treated by postoperative chemotherapy alone. Methods: Patients diagnosed between January 2001 and December 2005 and younger than 4 years received three cycles of postoperative systemic multiagent chemotherapy and intraventricular methotrexate. In case of complete remission, treatment was terminated after two additional cycles of chemotherapy. Otherwise secondary surgery, radiotherapy and consolidation chemotherapy were recommended. Results: The 5-year event-free survival (EFS) and overall survival (OS) (±SE…
Impact of chemotherapy on disseminated low-grade glioma in children and adolescents: Report from the HIT-LGG 1996 trial
Background We describe demographic data of disseminated childhood low-grade glioma (DLGG) prospectively recruited in the HIT-LGG 1996 study and evaluate the impact of primary chemotherapy (CT) on the outcome of these tumors, which have previously only been described in small and retrospective series. Patients and Methods The multicenter study HIT-LGG 1996 accrued 1181 children and adolescents with low-grade glioma. 61 patients (5.2%) had tumor dissemination, with 2.8% being present at diagnosis. Frequencies of dissemination for different subgroups were calculated. Efficiency of first-line CT with vincristine/carboplatin was defined in 24 children with dissemination prior to first-line non-s…
Extracranial metastasizing solitary fibrous tumors (SFT) of meninges: Histopathological features of a case with long-term follow-up
Extrapleural solitary fibrous tumors are uncommon mesenchymal neoplasms frequently observed in middle-aged adults and are classified, according to the WHO classification of soft tissue tumors, as part of the hemangiopericytoma tumor group. However, these two entities remain separated in the WHO classification of tumors of the central nervous system. In fact, meningeal solitary fibrous tumors are believed to be benign lesion and only in a minority of cases local relapses have been described, although detailed survival clinical studies on solitary fibrous tumors of meninges are rare. In contrast to hemangiopericytoma, which frequently shows distant extracranial metastases, such an event is ex…
Postponed Is Not Canceled: Role of Craniospinal Radiation Therapy in the Management of Recurrent Infant Medulloblastoma—An Experience From the HIT-REZ 1997 & 2005 Studies
Purpose To evaluate the efficacy of craniospinal irradiation (CSI) in the management of recurrent infant medulloblastoma after surgery and chemotherapy alone. Methods and Materials Seventeen pediatric medulloblastoma patients registered in the HIT-REZ 1997 and 2005 studies underwent CSI as salvage treatment at first recurrence. All patients had achieved complete remission after first-line treatment consisting of surgery and chemotherapy. Eleven patients showed metastatic disease at relapse. Five patients underwent surgery prior to radiation therapy, which resulted in complete resection in 1 case. In 1 patient, complete resection of the residual tumor was performed after CSI. Eleven patients…
Treatment of Children and Adolescents With Metastatic Medulloblastoma and Prognostic Relevance of Clinical and Biologic Parameters
Purpose To assess an intensified treatment in the context of clinical and biologic risk factors in metastatic medulloblastoma. Patients and Methods Patients (4 to 21 years old, diagnosed between 2001 and 2007) received induction chemotherapy, dose-escalated hyperfractionated craniospinal radiotherapy, and maintenance chemotherapy. Subgroup status and other biologic parameters were assessed. Results In 123 eligible patients (median age, 8.2 years old; median follow-up, 5.38 years), 5-year event-free survival (EFS) and overall survival (OS) were 62% (95% CI, 52 to 72) and 74% (95% CI, 66 to 82), respectively. OS was superior compared with the precedent HIT ’91 trial. The 5-year EFS and OS wer…
Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort
PURPOSE The HIT-2000-BIS4 trial aimed to avoid highly detrimental craniospinal irradiation (CSI) in children < 4 years of age with nonmetastatic medulloblastoma by systemic chemotherapy, intraventricular methotrexate, and risk-adapted local radiotherapy. PATIENTS AND METHODS From 2001-2011, 87 patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for nonresponse or progression. After 2006, local radiotherapy was introduced for nonresponders or patients with classic medulloblastoma (CMB) or large-cell/anaplastic medulloblastoma (LCA). DNA methylation profiles of infantile sonic hedgehog-activated medulloblastoma (SHH-INF) were subdivided i…
Children <1 year show an inferior outcome when treated according to the traditional LGG treatment strategy: A report from the german multicenter trial HIT-LGG 1996 for children with low grade glioma (LGG)
Background Children diagnosed with LGG at an age <1 year are reported to have an impaired prognosis in comparison to older patients. Analysis of this subgroup could reveal the necessity to develop risk-adapted treatment approaches. Procedure Children <1 year at diagnosis (n = 66, median age 7.3 months, 33 female, none NFI) from the HIT-LGG 1996 cohort were analyzed for risk factors for EFS, PFS and OS. Several children suffered from diencephalic syndrome (DS, n = 22) and primary dissemination (DLGG, n = 9), 50 had a supratentorial midline (SML) location. Extent of resection was complete/subtotal in 12, partial in 15, biopsy in 27. Tumors were pilocytic astrocytoma WHO grade I (n = 33), othe…
A long duration of the prediagnostic symptomatic interval is not associated with an unfavourable prognosis in childhood medulloblastoma
Due to the lacking specificity of symptoms making a correct diagnosis can be a challenge in children with medulloblastoma. This can lead to prediagnostic symptomatic intervals (PSIs) of several weeks to months. It is unknown whether the length of the PSI is associated with an inferior survival outcome in this population.To study the association of PSI with disease stage at diagnosis, tumour control and survival in children with medulloblastoma, prospectively collected data on PSI, clinical, and biological features were analysed in 224 patients diagnosed at the age of 3-18 years and treated within the prospective randomised multicentre trial HIT'91.Patients with lower-stage disease tended to…
MBCL-07. NON-METASTATIC MEDULLOBLASTOMA OF EARLY CHILDHOOD: RESULTS FROM THE PROSPECTIVE CLINICAL TRIAL HIT-2000 AND AN EXTENDED VALIDATION COHORT
Abstract OBJECTIVE To avoid craniospinal irradiation (CSI) in children younger than four years with non-metastatic medulloblastoma by chemotherapy, intraventricular methotrexate and risk-adapted local radiotherapy. PATIENTS AND METHODS Eighty-seven patients received systemic chemotherapy and intraventricular methotrexate. Until 2006, CSI was reserved for non-response or progression. After 2006, local radiotherapy was introduced for non-responders or classic (CMB), anaplastic or large-cell medulloblastoma (LCA). Infantile SHH-activated medulloblastomas (SHH_INF) were subdivided by DNA-methylation profiling. Survival in SHH_INF subtypes were also assessed in a validation cohort (n=71). RESULT…
Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma – A Report From the HIT 2000 Trial
Purpose: We aimed to compare treatment results in and outside of a randomized trial and to confirm factors influencing outcome in a large retrospective cohort of nonmetastatic medulloblastoma treated in Austria, Switzerland and Germany. Methods and Materials: Patients with nonmetastatic medulloblastoma (n = 382) aged 4 to 21 years and primary neurosurgical resection between 2001 and 2011 were assessed. Between 2001 and 2006, 176 of these patients (46.1%) were included in the randomized HIT SIOP PNET 4 trial. From 2001 to 2011 an additional 206 patients were registered to the HIT 2000 study center and underwent the identical central review program. Three different radiation therapy protocols…
BIOM-08. DNA METHYLATION-BASED SUBGROUPING PREDICTS SURVIVAL BENEFIT FROM LOMUSTINE/TEMOZOLOMID COMBINATION THERAPY IN MGMT PROMOTOR-METHYLATED GLIOBLASTOMA
Abstract BACKGROUND The CeTeG/NOA-09 trial showed that lomustine/temozolomide chemotherapy prolongs survival for newly diagnosed MGMT-methylated glioblastoma patients. Previous reports on temozolomide monotherapy suggested, that the survival benefit of temozolomide in MGMT-methylated tumors may be restricted to the RTK II methylation subgroup and absent in RTK I and MES subgroups. To identify patients with a particularly strong benefit from CCNU/TMZ, we explored the association of methylation subgroups with outcome after lomustine/temozolomide therapy. METHODS All patients from the CeTeG/NOA-09 trial with sufficiently available tumor tissue (n = 98) underwent 850K methylation array analysis…
Treatment of embryonal tumors with multilayered rosettes with carboplatin/etoposide induction and high-dose chemotherapy within the prospective P-HIT trial
Abstract Background Embryonal tumors with multilayered rosettes (ETMR) are highly aggressive tumors occurring in early childhood. Published clinical data refer to retrospective, heterogeneously treated cohorts. Here, we describe the outcome of patients treated according to the prospective P-HIT trial and subsequent HIT2000-interim-registry. Patients and methods Age-stratified treatment included carboplatin/etoposide induction, tandem high-dose chemotherapy (“CARBO/ETO + HDCT”), and response-stratified radiotherapy. Patients with centrally reviewed neuropathological and molecularly confirmed diagnosis of ETMR recruited within the P-HIT trial (2001-2011; n = 19), the HIT2000-interim-registry …
Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features
Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity…
Neural antigens in oligodendrogliomas and dysembryoplastic neuroepithelial tumors
Oligodendrogliomas and dysembryoplastic neuroepithelial tumors (DNT) are frequently associated with epilepsies and share the presence of oligodendroglia-like cells with small round nuclei and optically empty perinuclear halos. The two entities may be difficult to discriminate in small surgical specimens and the origin and differentiation of the oligodendroglia-like cells has been controversial. To better characterize and distinguish the two entities we examined 25 oligodendrogliomas and 16 DNT immunohistochemically for the presence of the proliferation-associated Ki-67 antigen and the following neural antigens: the alpha 1 subunit of the GABAA receptor (GABAR), N-methyl-D-aspartate receptor…
Allelic loss but absence of mutations in the polyspecific transporter geneBWR1Aon 11p15.5 in hepatoblastoma
Chromosomal region 11p15.5 shows frequent maternal allelic loss in embryonal tumors, including rhabdomyosarcoma (RMS), Wilms' tumor (WT) and hepatoblastoma (HB), consistent with the presence of at least one tumor suppressor gene in this region, which should be paternally imprinted, i.e., expressed from the maternal allele only. The BWR1A gene encodes a polyspecific transmembrane transporter and is located on 11p15.5. It is highly expressed in liver, paternally imprinted and was found to be mutated in an RMS cell line, making it a plausible tumor suppressor gene for HB. We therefore screened 62 HBs, 3 HB cell lines and 1 pediatric hepatocellular carcinoma for BWR1A mutations using single-str…
Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT‘91
PURPOSE: To analyse long-term outcome and clinical prognostic factors in medulloblastoma. METHODS: We analysed 280 patients with medulloblastoma (3-18 years) included from 1991 to 1997 in the randomised multicentre trial HIT'91 comparing pre-('sandwich') and postradiation ('maintenance') chemotherapy (median follow-up of survivors for 10 years). RESULTS: In 187 patients with complete staging, overall survival (OS) was higher after maintenance compared to sandwich treatment for M0 (10-year OS 91% and 62%, p=0.001) and M1 patients (10-year OS 70% and 34%, p=0.020). In M2/3 disease, 10-year OS was 42% and 45%. Incomplete staging, metastases, younger age and sandwich chemotherapy were independe…
Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma
Objective: This is the final report of a phase III randomized study to evaluate whole-brain radiotherapy (WBRT) in primary therapy of primary CNS lymphoma (PCNSL) after a median follow-up of 81.2 months. Methods: Patients with newly diagnosed PCNSL were randomized to high-dose methotrexate (HDMTX)–based chemotherapy alone or followed by WBRT. We hypothesized that the omission of WBRT would not compromise overall survival (OS; primary endpoint), using a noninferiority design with a margin of 0.9. Results: In the per-protocol population (n = 320), WBRT nonsignificantly prolonged progression-free survival (PFS) (median 18.2 vs 11.9 months, hazard ratio [HR] 0.83 [95% confidence interval (CI) 0…
The CD34 epitope is expressed in neoplastic and malformative lesions associated with chronic, focal epilepsies.
The etiology and pathogenesis of complex focal lesions associated with chronic, intractable epilepsy are largely unknown. Some data indicate that malformative changes of the central nervous system may preceed the development of gangliogliomas and other epilepsy-associated neoplasms. In the present immunhistochemical study, we have examined epilepsy-associated lesions for CD34, a stem cell marker transiently expressed during early neurulation. Surprisingly, most tissue samples from patients with chronic epilepsy (n = 262) revealed neural cells immunoreactive for CD34. Prominent immunoreactivity was detected in gangliogliomas (74%), low-grade astrocytomas (62%) and oligodendrogliomas (59%). O…
MBCL-11. TIME TO RADIOTHERAPY IMPACTS SURVIVAL IN PEDIATRIC AND ADOLESCENT NON-METASTATIC MEDULLOBLASTOMA TREATED BY UPFRONT RADIOTHERAPY – A REPORT FROM THE HIT 2000 TRIAL
Abstract PURPOSE To evaluate prognostic factors and impact of participation in a randomized trial in non-metastatic medulloblastoma. METHODS AND PATIENTS 382 patients with non-metastatic medulloblastoma aged 4–21 years with primary neurosurgical resections between 2001 and 2011 were enrolled into the HIT 2000 trial and centrally reviewed. Between 2001 and 2006, 176 of these patients participated in the randomized trial HIT-SIOP PNET 4. Three different radiotherapy protocols were applied. Molecular subgroup was available for 157 patients. RESULTS Median follow-up was 6.35 [0.09–13.86] years. The 5-year progression-free (PFS) and overall survival (OS) rates were 80.3 % ± 2.1 % and 86.5 % ± 1.…
ACTR-58. PHASE III TRIAL OF CCNU/TEMOZOLOMIDE (TMZ) COMBINATION THERAPY VS. STANDARD TMZ THERAPY FOR NEWLY DIAGNOSED MGMT-METHYLATED GLIOBLASTOMA PATIENTS: THE CeTeg/NOA-09 trial
There is an urgent need for more effective therapies in glioblastoma (GBM). Data from the single arm UKT-03 trial (Glas et al., J Clin Oncol 27, 1257, 2009) suggested that combined lomustine/temozolomide (CCNU/TMZ) therapy might have superior activity in MGMT-methylated GBM. The phase III CeTeG/NOA-09 trial was set up to test this hypothesis in a randomized setting. Patients with MGMT-methylated GBM were randomized (1:1) for standard therapy with daily TMZ (75 mg/m2) during local radiotherapy (RT, 30 x 2 Gy) followed by 6 courses of TMZ (150–200 mg/m2/day for 5 days q4w) or experimental therapy with CCNU/TMZ in addition to local RT. Six 6-week courses of CCNU/TMZ (CCNU 100 mg/m2 d1, TMZ 100…
Treatment of early childhood medulloblastoma by postoperative chemotherapy alone.
The prognosis for young children with medulloblastoma is poor, and survivors are at high risk for cognitive deficits. We conducted a trial of the treatment of this brain tumor by intensive postoperative chemotherapy alone.After surgery, children received three cycles of intravenous chemotherapy (cyclophosphamide, vincristine, methotrexate, carboplatin, and etoposide) and intraventricular methotrexate. Treatment was terminated if a complete remission was achieved. Leukoencephalopathy and cognitive deficits were evaluated.Forty-three children were treated according to protocol. In children who had complete resection (17 patients), residual tumor (14), and macroscopic metastases (12), the five…
Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy
To investigate the utility of postoperative chemotherapy in delaying radiotherapy and to identify prognostic factors in early childhood medulloblastoma, we studied children younger than 3 years of age registered to the HIT-SKK'87 (Therapieprotokoll für Säuglinge und Kleinkinder mit Hirntumoren [Brain Tumor Radiotherapy for Infants and Toddlers with Medulloblastoma] 1987) trial who received systemic interval chemotherapy until craniospinal radiotherapy was applied at 3 years of age or at relapse, from 1987 to 1993. Children with postoperative residual tumor or metastatic disease received systemic induction chemotherapy prior to interval chemotherapy. Twenty-nine children were eligible for an…
Doubling Recruitment of Pediatric Low-grade Glioma within Two Decades does not change Outcome – Report from the German LGG Studies
Successive multicenter studies for pediatric low-grade glioma (LGG) in Germany were accompanied by a doubling of annual recruitment over 2 decades. We investigated whether this increase conveyed a change of epidemiologic characteristics or survival.Participating centers reported 4634 patients with the radiologic/histologic diagnosis of LGG (1996-2018), rising from 109 to 278/year. Relating these numbers to all pediatric CNS tumors registered at the German Childhood Cancer Registry, the LGG fraction and annual crude incidence rates increased (32% to 51%; 0.94 to 2.12/100,000 children/adolescents15 years). The consecutive LGG studies recruited 899 (HIT-LGG 1996), 1592 (SIOP-LGG 2004), and 183…
Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA–09): a randomised, open-label, phase 3 trial
Summary Background There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial. Methods In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18–70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance …