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BACKGROUND: Medulloblastoma is the most common malignant paediatric brain tumour, and cerebrospinal fluid (CSF) dissemination (M1 stage) is a high-risk prognostic factor. Criteria for CSF evaluation and for differentiating M0 from M1 stage are not clearly defined, and the prognostic significance of M1 stage in this context is unknown.PATIENTS AND METHODS: CSF investigations from 405 patients with medulloblastoma of the prospective multicenter trial HIT-2000 (HIirnTumor-2000) were reviewed. Data from 213 patients aged ≥4 years were related to 5-year progression-free (5y-PFS) and overall survival.RESULTS: Patients with cytological tumour dissemination only (M1 stage only) aged ≥4 years (n = 18) and patients with radiologically detected metastases (M2/3, n = 85) showed a worse 5y-PFS than M0 patients (n = 110) without signs of metastatic disease (5y-PFS 61.1% and 59.6% vs 80.7%; p < 0.02 and p < 0.01, log rank). Patients with positive samples drawn early after surgery who turned negative within 14 days postoperatively (n = 9) and patients with atypical cells (n = 6) showed a 5y-PFS similar to M0 patients. No tumour cells were detected in samples containing CONCLUSION: Based on our results, we suggest that CSF medulloblastoma staging should be performed 14 days postoperatively by lumbar puncture, and specimens should contain at least 10 nucleated cells. Cytological tumour dissemination alone (M1 stage only) appears a high-risk prognostic factor associated with an outcome comparable to M2/M3 stage. Tumour cell clusters seem to have a greater impact on prognosis than single tumour cells. This should be validated further.

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 (2012-2014; n = 12), and earlier HIT trials (n = 4) were selected for analysis. Results Age-adjusted incidence rate was 1.35 per 1 million children (aged 1-4 years) in the years 2012-2014. Median age at diagnosis for 35 patients was 2.9 years. Metastases at diagnosis were detected in 9 patients. One patient died due to postoperative complications. For 30 patients with non-brainstem tumor location, 5-year progression-free survival (PFS) and overall survival (OS) were 35% and 47% after treatment with CARBO/ETO + HDCT (n = 17), compared to 0% and 8% with other treatments (n = 13, P[OS] = .011). All 4 patients with brainstem tumor died within 10 months after diagnosis. By multivariable analysis, supratentorial location: (HR [PFS]: 0.07 [95%CI: 0.01-0.38], P = .003), localized disease (M0): (HR [OS] M0, no residual tumor: 0.30 [95%CI: 0.009-1.09], P = .068; M0, residual tumor: 0.18 [95%CI: 0.04-0.76], P = .020), and CARBO/ETO + HDCT treatment (HR [OS]: 0.16 [95%CI: 0.05-054], P = .003) were identified as independent prognostic factors. Of 9 survivors, 6 were treated with radiotherapy (craniospinal 4; local 2). Conclusions Our data indicate improved survival with intensified chemotherapy (CARBO/ETO + HDCT). However, despite intensive treatment, the outcome was poor. Thus, innovative therapies need to be evaluated urgently in an upfront setting.

BACKGROUND Pediatric ependymoma is a heterogenous disease. Subgroup-specific clinical information on prospectively treated patients will help to improve treatment stratification. METHODS Within the population based, prospective, multicenter E-HIT-trial (2001–2011) patients with localized ependymoma confirmed by neuropathological central-review, received hyperfractionated local radiotherapy (68Gy, 2x1Gy/day) followed by chemotherapy (stratum-A), or chemotherapy followed by local radiotherapy (54Gy, 1.8Gy/day) (children < 4years, stratum-B), or age-adapted radiotherapy with pre-/post-irradiation chemotherapy (residual tumor, diagnosis after 2005, stratum-C). Retrospective classification of DNA-methylation was available for n=164 E-HIT-trial participants, and n=80 patients with comparable treatment and prospective registration in the subsequent HIT-interim-registry (2012–2014). FINDINGS: For 291 E-HIT-trial patients, 5-year progression-free (PFS) and overall survival (OS) were 61±3%, and 81±2%. Five-year PFS/OS after complete resection were 71±4% and 87±3% in stratum-A (n=127), and 64±5% and 86±4% in stratum-B (n=86). Outcome was poor after incomplete resection, irrespective of treatment-stratum (n=78, 5-year PFS/OS: 43±6%, 68±5%). In the pooled trial- and registry-cohort, there were 152 patients with PF-EPN-A (5-year PFS/OS: 44±4%, 77±4%), 40 of them with 1q-gain (5-year PFS/OS: 28±7%, 66±8%), 21 with PF-EPN-B (5-year PFS/OS: 90±7%, 100%), 59 with ST-EPN-RELA (5-year PFS/OS: 63±7%, 87±5%), and 4 with ST-EPN-YAP1 (2 progression/relapse, no death). CONCLUSION Outcome differed between molecular subgroups and insufficient survival rates were achieved for patients with PF-EPN-A with 1q-gain, despite combined radio- and chemotherapy treatment. Treatment reduction in the context of a clinical trial may be considered for PF-EPN-B.

BACKGROUND Cerebrospinal fluid (CSF) dissemination of medulloblastoma (M1 stage) is a high-risk prognostic factor. However, because diagnostic criteria for M1 staging are missing we specified process-related and cytomorphological parameters influencing the predictive value of the CSF status. PATIENTS AND METHODS CSF samples and cytology reports from 405 medulloblastoma patients of the prospective multicenter trial HIT-2000 were reviewed and related to 5-year progression free survival (5y-PFS). RESULTS Tumor cells were detected in 237/1073 CSF cytospins. M1-patients and M2/3 patients with radiologically detected metastases showed a worse 5y-PFS than M0 patients (54% and 52% vs. 76%; p=0.01 and p50% lytic cells and/or less than 10 nucleated cells showed a decreased 5y-PFS (61%). Further investigation of cytological parameters revealed a poor outcome for cases harboring > 3 tumor cell clusters and individual tumor cells (5y-PFS 33%) vs. cases with ≥ 2 individual tumor cells but no clusters (5y-PFS 61%). In bi-variable Cox-regression, ≥ 2 vs. 0 or 1 tumor cells were associated with a Hazard Ratio (HR) of 0.52 (95%-Confidence Interval (CI): 0.12, 2.30; p=0.39), whereas > 3 vs. no tumor cell clusters were associated with a HR of 8.94 (95%-CI: 1.66, 48.22; p=0.01). CONCLUSIONS CSF staging in medulloblastoma should comprise lumbar specimens with

In den letzten Jahren wurden in vielen Disziplinen der padiatrischen Neuroonkologie neue Erkenntnisse generiert. Dazu zahlen wichtige Fortschritte zum Verstandnis der Biologie von Medulloblastom, Ponsgliom, niedrig- und hochgradigem Gliom, Ependymom, embryonalem Tumor mit mehrschichtigen Rosetten (ETMR) und atypischen teratoiden/rhabdoiden Tumoren (AT/RT), die eine neue Ara klinischer und molekularer Diagnostik sowie Therapie eingelautet haben. Forschungsergebnisse des deutschen Behandlungsnetzwerks HIT sowie eine selektive Literaturubersicht publizierter Studien aus den letzten 40 Jahren sind die Grundlage dieser Arbeit. Moderne Therapiekonzepte werden, basierend auf dem erweiterten Verstandnis der Tumorbiologie, schrittweise in klinische Behandlungsempfehlungen integriert. Aktuelle Therapieansatze werden nach klinischem und biologischem Risiko modifiziert, um so die Langzeittoxizitat bei Patienten mit guter Prognose zu reduzieren und ungunstige Heilungsraten in Hochrisikogruppen zu verbessern. Neue bildgebende Verfahren wie die Verfugbarkeit von intraoperativem MRT haben neurochirurgische Operationen begunstigt. Verbesserungen in der Radiotherapieplanung und zunehmende Verfugbarkeit der Protonentherapie schuren Hoffnung auf langfristig verminderte Morbiditat nach Bestrahlung. Ein besseres Verstandnis der Pathophysiologie der Schaden fur die Entwicklung des Gehirns und andere therapieassoziierte Spatfolgen rucken zunehmend in den Fokus der Forschung − mit dem Ziel, Schaden zu mildern und den Kindern Bewaltigungsmechanismen bieten. Fur die Validierung und Weiterentwicklung der aufgezeigten biologischen und klinischen Aspekte sind auch kunftig prospektive Studien im Behandlungsnetzwerk HIT erforderlich.

BACKGROUND Impact of isolated spread into the cerebrospinal fluid (CSF) is still not investigated comprehensively for childhood medulloblastoma and the best therapeutic strategy is currently unclear. MATERIAL AND METHODS Sixty-six patients with isolated M1-MB registered to the HIT-MED-database from 2000–2018 were identified. CSF and MRI were centrally reviewed for all patients. Patients were stratified by age and either treated with upfront craniospinal irradiation (CSI) followed by maintenance chemotherapy (CT) or with postoperative CT and delayed CSI. RESULTS Forty-nine patients were non-infants ≥4 years and seventeen were infants CONCLUSION Isolated M1-MB is rare. Patients without contraindication for CSI appear to benefit from treatment by upfront CSI followed by maintenance CT, while cumulative CT-doses would be reduced compared to sandwich strategies.

BACKGROUND For infant ependymoma (EP), decision for radiotherapy during first-line therapy is a dilemma. We analyzed therapy outcomes of EP patients younger than 12 months at diagnosis according to molecular subgroup. PATIENTS AND METHODS Between 2001 and 2017, 30 patients with histological diagnosis of intracranial EP RESULTS In 3/30, DNA methylation-based CNS tumor classification suggested a diagnosis other than EP or could not be assigned to a reference class. Of the remaining 27 tumors, 16 were classified as PF-A, 8 as RELA-fusion positive and 3 as YAP-fusion positive. Median age at diagnosis was 0.73 (0.30–0.99) years. After a median follow-up time of 5.36 (0.20–12.90) years, 59.3% experienced progressive disease (PD). 5y-PFS and -OS for the whole cohort were 38.2% and 73.1%. RELA- and YAP-fusion positive EP had significantly better OS than PF-A (5y-OS for PF-A: 55.9%; RELA 100%; YAP 100%; p=0.023). PFS was not significantly different. All but one patient with relapsed PF-A died despite multimodal salvage strategies. In contrast, patients with relapsing RELA- and YAP-fusion positive EP (n=5), survived with a combination of re-surgery and first or second local radiotherapy. CONCLUSION In this cohort of infants

OBJECTIVE Molecular subtypes of Group 3/4 medulloblastoma have been identified by unsupervised clustering methods in different studies. We hypothesized that risk stratification using these subtypes I-VIII improves outcome prediction. PATIENTS AND METHODS n=340 patients with Group 3 or Group 4 medulloblastoma defined by DNA methylation array profiling enrolled into the HIT2000 study and HIT-MED registries were subtyped by the Heidelberg Medulloblastoma Classifier. The discovery cohort consisted of n=162 previously published samples, the validation cohort of n=178 newly analyzed samples. RESULTS AND DISCUSSION: n=300/340 (88%) MBs could be assigned to one of the subtypes with confidence (score >0.8; Heidelberg Medulloblastoma classifier). Subtype II,III and V showed a poor PFS and OS and were classified as HR (discovery:5y-PFS 45%[95%-CI:33–62], 5y-OS 50%[37–67]; validation:5y-PFS 32%[20–50], 5y-OS 40%[27–61]). Subtypes I, IV, VI-VIII fared better (discovery:5y-PFS 67%[58–77], 5y_OS 84%[77–91]; Validation:5y-PFS 70%[58–83], 5y-OS 89%[81–99]). Survival prediction by subtype-based risk assessment was improved compared to Group 3 versus 4 differentiation in both cohorts in univariate and multivariable Cox regression models (PFS:Hazard ratio HR versus LR 2.474, p CONCLUSION We showed that molecular subtypes I-VIII improved risk stratification of Group 3/4 medulloblastomas. Group 3 subtype IV MB treated with RT had very high cure rates.

Gorlin syndrome is an autosomal dominant inherited cancer predisposition syndrome characterized by basal cell carcinomas, odontogenic keratocysts, skeletal and multiple other anomalies, and medulloblastoma (MB). Most patients harbor a heterozygous germline mutation in PTCH1 or SUFU, genes that play a pivotal role in sonic hedgehog (SHH) signaling. We describe 17 patients with Gorlin syndrome diagnosed with MB between 1992 and 2017 who were treated according to HIT studies (HIT’91, SKK’92, HIT2000, and I-HIT-MED registry) and had available data on initial staging and treatment. Diagnosis of Gorlin syndrome was made clinically by fulfilling the syndrome criteria (N=9) or by proven PTCH1 (N=7) or SUFU (N=3) germline mutation. Median age at diagnosis of MB was 0.96 years. MB with extensive nodularity (N=5) and desmoplastic medulloblastoma (N=11) were the predominant histologic diagnoses, both typically associated with sonic hedgehog pathway activation (classical MB N=1). 12 of 17 patients had localized disease, 5 patients had metastases at initial diagnosis. 16 patients received HIT-SKK chemotherapy alone, 1 had primary craniospinal radiotherapy. HIT-SKK therapy was reduced in 3 patients with increased toxicities. Median follow up was 10.3 years. All patients are alive, two suffered from relapse 1.5 and 1.7 years after initial diagnosis. 10 year progression free survival was 82%±12%. Basal cell carcinoma was diagnosed in 2 patients, who were treated with radiotherapy. Gorlin syndrome and genetic counselling should be considered in all young children with SHH activated MB. Radiotherapy can be successfully avoided in most patients by HIT-SKK chemotherapy and is contraindicated within first-line therapy strategies.

PURPOSE/METHODS: Methylation-based tumor classification results were obtained from 86 patients younger than four years with medulloblastoma treated with systemic chemotherapy and intraventricular methotrexate to avoid craniospinal radiotherapy (CSI). 70 were HIT trial participants and 16 observational patients. Subgroup specific survival was analyzed. RESULTS: Median follow-up was 8.3 years in the 61 patients alive at last follow-up. 33 patients presented with metastatic disease. Methylation profiling results were WNT (n=1), SHH_INF (n=43), Group 3 (GRP3; n=32) and Group 4 (GRP4; n=10). Of 39 patients with desmoplastic/nodular histology, 38 patients had SHH_INF, one GRP4 medulloblastoma. Survival differed significantly according to methylation subgroup (5y-PFS WNT: 0%, SHH_INF: 79%, GRP3: 31%, GRP4: 70%, p

Item does not contain fulltext Background.: Pineoblastoma is a rare pineal region brain tumor. Treatment strategies have reflected those for other malignant embryonal brain tumors. Patients and Methods.: Original prospective treatment and outcome data from international trial groups were pooled. Cox regression models were developed considering treatment elements as time-dependent covariates. Results.: Data on 135 patients with pineoblastoma aged 0.01-20.7 (median 4.9) years were analyzed. Median observation time was 7.3 years. Favorable prognostic factors were age >/=4 years (hazard ratio [HR] for progression-free survival [PFS] 0.270, P < .001) and administration of radiotherapy (HR for PFS 0.282, P < .001). Metastatic disease (HR for PFS 2.015, P = .006), but not postoperative residual tumor, was associated with unfavorable prognosis. In 57 patients /=4 years, PFS/OS were 72 +/- 7%/73 +/- 7% for patients without metastases, and 50 +/- 10%/55 +/- 10% with metastases. Seventy-three patients received radiotherapy (48 conventionally fractionated CSI, median dose 35.0 [18.0-45.0] Gy, 19 hyperfractionated CSI, 6 local radiotherapy), with (n = 68) or without (n = 6) chemotherapy. The treatment sequence had no impact; application of HDCT had weak impact on survival in older patients. Conclusion.: Survival is poor in young children treated without radiotherapy. In these patients, combination of HDCT and local radiotherapy may warrant further evaluation in the absence of more specific or targeted treatments. CSI combined with chemotherapy is effective for older non-metastatic patients.

Enhanced proliferation of human coronary artery smooth muscle cells (HCASMCs) and thereby formation of neointima is one of the factors contributing to failure of coronary stents. Even if the use of drug eluting stents (DES) and thereby the local delivery of cytotoxic compounds has significantly improved the clinical outcome, unselective cytotoxic effects are assumed to hamper clinical success. Novel pharmacological approaches are required to enhance cellular selectivity of locally delivered drugs. Cell specific overexpression of a drug transporter could be used to enhance cellular accumulation and therefore cell specificity. In the herein reported study we tested the possibility of cell specific transporter expression to enhance drug effects in HCASMCs. We generated adenoviral constructs to overexpress the organic cation transporter 1 (OCT1) under control of the promoter of SM22α, which had been previously reported as muscle cell specific gene. First the activity of the SM22α-promoter was assessed in various cell types supporting the notion of muscle cell specificity. Subsequently, the activity of the transporter was compared in infected HCAECs and HCASMCs revealing enhanced accumulation of substrate drugs in HCASMCs in presence of the SM22α-promoter. Testing the hypothesis that this kind of targeting might serve as a mechanism for cell-specific drug effects, we investigated the impact on paclitaxel treatment in HCASMC and HCAECs, showing significantly increased antiproliferative activity of this substrate drug on muscle cells. Taken together, our findings suggest that cell-specific expression of transport proteins serves as mechanism governing the uptake of cytotoxic compounds for a selective impact on targeted cells.