Distinct relapse pattern across molecular ependymoma types.

BACKGROUND: Ependymoma (EPN) is not a uniform disease but represents different disease types with biological and clinical heterogeneity. However, the pattern of when and where different types of EPN relapse is not yet comprehensively described. METHODS: We assembled 269 relapsed intracranial EPN from pediatric (n=233) and adult (n=36) patients from European and Northern American cohorts and correlated DNA methylation patterns and copy-number alterations with clinical information. RESULTS: The cohort comprised the following molecular EPN types: PF-EPN-A (n=177), ST-EPN-ZFTA (n=45), PF-EPN-B (n=31), PF-EPN-SE (n=12), and ST-EPN-YAP (n=4). First relapses of PF-EPN-B (PF: posterior-fossa) and PF-EPN-SE (SE: subependymoma) occurred later than of PF-EPN-A, ST-EPN-YAP (ST: supratentorial), or ST-EPN-ZFTA (median time to relapse: 4.3 and 6.0 years vs. 1.9/1.0/2.4 years; p<0.01). Metastatic or combined recurrences in PF-EPN-B and -A more often involved the spinal cord than in ST-EPN-ZFTA (72.7% and 40.0 vs. 12.5%; p<0.01). No distant relapses were observed in ST-EPN-YAP (n=4) or PF-EPN-SE (n=12). Post-relapse survival (PRS) was poor for PF-EPN-A and ST-EPN-ZFTA (5-year PRS: 44.5±4.4/47.8±9.1%), whereas PF-EPN-B and PF-EPN-SE displayed a 5-year PRS of 89.5±7.1/90.0±9.5% (p=0.03). However, 10-year PRS for PF-EPN-B dropped to 45.8±17.3%. Neither between radiation field and relapse pattern nor between radiation field and spinal involvement at relapse an impact was identified. Notably, all patients with relapsed ST-EPN-YAP did not receive upfront radiotherapy, but were successfully salvaged using irradiation at relapse. CONCLUSIONS: Relapse patterns of specific EPN types are different. Future clinical trials, treatment adaptions, duration of surveillance and diagnostics should be planned incorporating entity-specific relapse information.

High parathyroid hormone rather than low vitamin D is associated with reduced event-free survival in childhood cancer.

BACKGROUND: Vitamin D deficiency is linked to poor cancer outcomes, but the impact of its consequence, elevated parathyroid hormone (PTH) remains understudied. PTH receptor activation influences cancer progression in vitro, yet the effect of elevated PTH on pediatric cancer survival is unexamined. METHODS: This retrospective study examines associations between PTH, 25-OH vitamin D (25OHD), and event-free survival (EFS) and overall survival (OS) in pediatric cancer patients. Laboratory data from 4,349 patients (0-18 years) at a tertiary pediatric cancer unit were analyzed for the highest PTH and lowest 25OHD levels at diagnosis and the following five years. Data on relapse, secondary malignancies, and mortality were stratified by PTH levels above/below the cohort median (47 pg/ml) and 25OHD levels ≤ 30 nmol/L. EFS and OS were analyzed, and hazard ratios (HR) were calculated for the entire cohort and six cancer subgroups. RESULTS: PTH and 25OHD values were available for 1,286 patients (731 male). Higher PTH associated with inferior EFS in primary malignant brain tumors (HR 1.80 [1.19-2.72]), embryonal (HR 2.20 [1.1-4.43]), and lymphatic malignancies (HR 1.98 [1.05-3.72]). Vitamin D deficiency associated with inferior EFS in embryonal malignancies (HR 2.41 [1.24-4.68]). In a multivariate Cox model, only higher PTH remained significant for inferior EFS. CONCLUSIONS: Elevated PTH may indicate adverse outcomes in certain pediatric cancers. IMPACT: This study identifies elevated parathyroid hormone (PTH) as a potential marker for poor outcomes in pediatric cancer patients, emphasizing the need for adequate vitamin D and calcium management.

Radiotherapy for Recurrent Medulloblastoma in Children and Adolescents: Survival after Re-Irradiation and First-Time Irradiation.

BACKGROUND: Radiotherapy (RT) involving craniospinal irradiation (CSI) is important in the initial treatment of medulloblastoma. At recurrence, the re-irradiation options are limited and associated with severe side-effects. METHODS: For pre-irradiated patients, patients with re-irradiation (RT2) were matched by sex, histology, time to recurrence, disease status and treatment at recurrence to patients without RT2. RESULTS: A total of 42 pre-irradiated patients with RT2 were matched to 42 pre-irradiated controls without RT2. RT2 improved the median PFS [21.0 (CI: 15.7-28.7) vs. 12.0 (CI: 8.1-21.0) months] and OS [31.5 (CI: 27.6-64.8) vs. 20.0 (CI: 14.0-36.7) months]. Concerning long-term survival after ten years, RT2 only lead to small improvements in OS [8% (CI: 1.4-45.3) vs. 0%]. RT2 improved survival most without (re)-resection [PFS: 17.5 (CI: 9.7-41.5) vs. 8.0 (CI: 6.6-12.2)/OS: 31.5 (CI: 27.6-NA) vs. 13.3 (CI: 8.1-20.1) months]. In the RT-naïve patients, CSI at recurrence improved their median PFS [25.0 (CI: 16.8-60.6) vs. 6.6 (CI: 1.5-NA) months] and OS [40.2 (CI: 18.7-NA) vs. 12.4 (CI: 4.4-NA) months]. CONCLUSIONS: RT2 could improve the median survival in a matched cohort but offered little benefit regarding long-term survival. In RT-naïve patients, CSI greatly improved their median and long-term survival.

Outcome After Modern Proton Beam Therapy in Childhood Craniopharyngioma: Results of the Prospective Registry Study KiProReg.

PURPOSE: Craniopharyngiomas (CPs) are rare tumors of the sellar region often leading to significant comorbidities due to their close proximity to critical structures. The aim of this study was to analyze survival outcome and late toxicities after surgery and proton beam therapy (PBT) in childhood CPs. METHODS AND MATERIALS: Within the prospective registry study "KiProReg" (DRKS0000536), data of 74 childhood patients with CP, receiving PBT between August 2013 to June 2022 were eligible. Late toxicities were analyzed according to the grading system of the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Median follow-up since first diagnosis was 4.3 years (range, 0.8-14.7). In addition, 75.7% of patients received PBT at time of disease progression or recurrence, whereas 24.3% as part of their primary therapy (definitive or adjuvant). Predominantly (85.1%), pencil beam scanning technique was used. The median total dose and initial tumor volume were 5400 cGy relative biologic effectiveness (RBE) and 17.64 cm³ (range, 3.07-300.59), respectively. The estimated (±SE) 3-year overall survival, progression-free, and cystic failure-free survival rate after PBT were 98.2% (±1.7), 94.7% (±3.0), and 76.8% (±5.4), respectively. All local failures (n = 3) were in-field relapses necessitating intervention and occurred exclusively in patients receiving PBT at progression or recurrence. Early cystic enlargements after PBT were typically asymptomatic and self-limiting. Fatigue, headaches, vision disorders, obesity, and endocrinopathies were the predominant late toxicities. No high-grade (≥3) new-onset visual impairment or cognitive deterioration occurred compared with baseline. The presence of cognitive impairments at the end of follow-up correlated with size of the planning target volume (P = .034), Dmean dose to the temporal lobes (P = .032, P = .045) and the number of surgical interventions before PBT (P = .029). CONCLUSIONS: Our findings demonstrate favorable local control rates using modern PBT with acceptable late toxicities. Cyst growth within 12 months after radiation therapy is typically not associated with tumor progression. Longer follow-up must be awaited to confirm results.

Outcome after conservative or surgical treatment for new-onset epilepsy in children with cerebral cavernous malformation.

OBJECTIVE: This study aimed to investigate and compare the outcome of conservatively or surgically treated children with cerebral cavernous malformation (CCM) and new-onset CCM-related epilepsy (CRE) during a 5-year period. METHODS: In this observational monocentric cohort study, data were collected ambispectivley. Our database was screened for CCM patients treated between 2003 and 2020. Patients ≤18 years of age with complete magnetic resonance imaging dataset, clinical baseline characteristics, and diagnosis of new-onset CRE were included. Definite seizure control was classified as International League Against Epilepsy class <2. Functional outcome was assessed using the modified Rankin Scale score. CRE patients were separated into two groups according to their treatment modality. Seizure control, intake of antiseizure medication, and functional outcomes were assessed. Systematic literature research was performed to identify other cases of new-onset CRE in children and to compare the collected data with published data. RESULTS: Thirty-nine pediatric CRE patients were analyzed. A total of 18 (46.1%) patients were conservatively treated, while 21 (53.8%) underwent surgical CCM removal. While the functional outcome was similar in both groups at the last follow-up, definite seizure control was better in the surgical group (77.8%) than in the conservative group (25.0%) both after 5-years of follow-up (p = 0.038), and at last follow-up with 85.7% versus 50% respectively (p = 0.035). We found substantially higher rates of discontinuation of antiseizure medication at the last available follow-up in patients undergoing surgical resection (p = 0.009). The systematic literature review identified 4 studies with a total of 30 additional children with early onset CRE. CONCLUSION: Surgical treatment of pediatric patients with new-onset CRE had higher rates of complete seizure control and early discontinuation of antiseizure medication than conservative treatment. Neurological outcomes of patients managed surgically or conservatively were comparable. These results encourage early surgical management of children with CRE even in the absence of pharmacoresistant epilepsy, but randomized control trials are urgently needed for further decision-making.

Surface Chemistry and Specific Surface Area Rule the Efficiency of Gold Nanoparticle Sensitizers in Proton Therapy.

Gold nanoparticles (AuNPs) are currently the most studied radiosensitizers in proton therapy (PT) applicable for the treatment of solid tumors, where they amplify production of reactive oxygen species (ROS). However, it is underexplored how this amplification is correlated with the AuNPs' surface chemistry. To clarify this issue, we fabricated ligand-free AuNPs of different mean diameters by laser ablation in liquids (LAL) and laser fragmentation in liquids (LFL) and irradiated them with clinically relevant proton fields by using water phantoms. ROS generation was monitored by the fluorescent dye 7-OH-coumarin. Our findings reveal an enhancement of ROS production driven by I) increased total particle surface area, II) utilization of ligand-free AuNPs avoiding sodium citrate as a radical quencher ligands, and III) a higher density of structural defects generated by LFL synthesis, indicated by surface charge density. Based on these findings it may be concluded that the surface chemistry is a major and underexplored contributor to ROS generation and sensitizing effects of AuNPs in PT. We further highlight the applicability of AuNPs in vitro in human medulloblastoma cells.

Giant Cavernous Malformation Mimicking an Infiltrative Intracranial Neoplasm in Children-Case Report and Systematic Review of the Literature.

BACKGROUND: Giant cavernous malformations (GCMs) are rare and poorly characterized neurovascular lesions in adults or children and often misclassified. In this study, we provide a review of pediatric GCM cases to highlight this rare entity as an important differential diagnosis in preoperative assessment. METHODS: We report a pediatric case of GCM that presented as an intracerebral, periventricular, and infiltrative mass lesion. We performed a systematic review of published literature describing cases of GCM in children using the PubMed, Embase, and Cochrane Library databases. Studies describing cerebral or spinal cavernous malformation >4 cm were included. Demographic, clinical, radiographic, and outcome data were extracted. RESULTS: Thirty-eight studies accounting for 61 patients were reviewed. most patients were 1-10 years old and 55.73% were male. Average lesion sizes ranged between 4 and 6 cm (40.98% >6 cm; 8.19% >10 cm). Supratentorial localization was most common (75.40%), with frontal and parieto-occipital regions being frequent localizations. Infratentorial lesions (24.60%) were located within the cerebellum (16.39%) and brainstem (8.19%). One case of spinal cavernoma was found. The main clinical manifestations were seizures (44.26%), focal neurologic deficit (36.06%), and headache (22.95%). Imaging showed contrast enhancement (36.06%), cystic features (27.86%), and infiltrative growth pattern (4.91%). CONCLUSIONS: GCMs show variable clinical and radiologic features, representing a diagnostic challenge for treating surgeons. Imaging may show various tumorlike features such as cystic or infiltrative patterns with contrast enhancement. The existence of GCM should be considered preoperatively. Gross total resection should be attempted whenever possible, because it correlates with a good recovery and long-term outcomes. Also, a clear definition criteria of when a cerebral cavernous malformation is termed giant should be established.

Functional outcome after pediatric cerebral cavernous malformation surgery.

The purpose of this study was to investigate the functional outcome following surgical resection of cerebral cavernous malformations (CCM) in pediatric patients. We screened our institutional database of CCM patients treated between 2003 and 2021. Inclusion regarded individuals younger or equal than 18 years of age with complete clinical baseline characteristics, magnetic resonance imaging dataset, and postoperative follow-up time of at least three months. Functional outcome was quantified using the modified Rankin Scale (mRS) score and assessed at admission, discharge, and last follow-up examination. The primary endpoint was the postoperative functional outcome. As a secondary endpoint, predictors of postoperative functional deterioration were assessed. A total of 49 pediatric patients with a mean age of 11.3 ± 5.7 years were included for subsequent analyses. Twenty individuals (40.8%) were female. Complete resection of the lesion was achieved in 44 patients (89.8%), and two patients with incomplete resection were referred for successive remnant removal. The mean follow-up time after surgery was 44 months (IQR: 13 - 131). The mean mRS score was 1.6 on admission, 1.7 at discharge, and 0.9 at the latest follow-up. Logistic regression analysis adjusted to age and sex identified brainstem localization (aOR = 53.45 [95%CI = 2.26 - 1261.81], p = .014) as a predictor of postoperative deterioration. This study indicates that CCM removal in children can be regarded as safe and favorable for the majority of patients, depending on lesion localization. Brainstem localization implies a high risk of postoperative morbidity and indication for surgery should be balanced carefully. Minor evidence indicates that second-look surgery for CCM remnants might be safe and favorable.

Functional outcome after initial and multiple intracerebral hemorrhages in children with cerebral cavernous malformations.

BACKGROUND AND PURPOSE: We aimed to assess the course and predictors of functional outcome after single and multiple intracerebral hemorrhage (ICH) in pediatric patients with cerebral cavernous malformations (CCMs) and to conduct a risk assessment of a third bleed during the first follow-up year after second ICH. METHODS: We included patients aged ≤18 years with complete baseline characteristics, a magnetic resonance imaging dataset, ≥1 CCM-related ICH and ≥1 follow-up examination, who were treated between 2003 and 2021. Neurological functional status was obtained using modified Rankin Scale scores at diagnosis, before and after each ICH, and at last follow-up. Kaplan-Meier analysis was performed to determine the cumulative 1-year risk of third ICH. RESULTS: A total of 55 pediatric patients (median [interquartile range] age 12 [11] years) were analyzed. Univariate analysis identified brainstem cavernous malformation (BSCM; p = 0.019) as a statistically significant predictor for unfavorable outcome after second ICH. Outcome after second ICH was significantly worse in 12 patients (42.9%; p = 0.030) than after first ICH and in five patients (55.6%; p = 0.038) after a third ICH compared to a second ICH. Cumulative 12-month risk of rebleeding during the first year after a second ICH was 10.7% (95% confidence interval 2.8%-29.37%). CONCLUSIONS: Pediatric patients with a BSCM have a higher risk of worse outcome after second ICH. Functional outcome improves over time after an ICH but worsens following each ICH compared to baseline or previous ICH. Second bleed was associated with neurological deterioration compared to initial ICH, and this deteriorated further after a third ICH.

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM.

The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.