Craniopharyngiomas (CP) are rare malformational tumors. Clinical presentation and outcome of pediatric patients with CP with specific regard to age at diagnosis is not clear. The aim of this cohort ...study was to determine clinical presentation and outcome in these patients diagnosed at different ages at diagnosis.
Seven hundred and nine patients diagnosed with CP were recruited from 1999 to 2021 in HIT-Endo and KRANIOPHARYNGEOM 2000/2007/Registry 2019 and prospectively observed.
Age at diagnosis was categorized as infants and toddlers (<2 years), early childhood (2-6 years), middle childhood (6-12 years), and early adolescence (12-18 years). Overall and event-free survival (EFS), functional capacity (FMH), and quality of life (QoL) (PEDQOL) were assessed.
Severe obesity (body mass index BMI >3 standard deviation score SDS) was prevalent in 45.4% at last visit. A lower EFS but better QoL was observed in children with age at diagnosis <6 years compared with ≥6 years. Reduced functional capacity percentiles were associated with increased BMI-SDS at last visit (rho = -0.125, 95% confidence interval CI; -0.21; -0.04) and age at diagnosis <2 years. Posterior hypothalamic involvement and hypothalamic lesion (HL) were independent risk factors for reduced EFS (hazard ratio = 1.59, 95% CI 1.12-2.26) and obesity at last visit (odds ratio = 2.94, 95% CI 1.73-5.08). Age at diagnosis did not contribute to severe obesity and reduced QoL.
Diagnosis of CP at age <6 years may help patients to adapt early to disabilities but may lead to a higher probability of CP relapse. Not age at diagnosis but posterior HL may be the contributing factor to severe obesity and a reduced QoL.
NCT00258453; NCT01272622; NCT04158284.
The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). ...Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis.
Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection.
We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival.
These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis.
Abstract
BACKGROUND: Magnetic resonance imaging (MRI) of patients with medulloblastoma (MB) often shows persistent residual findings after primary treatment. Criteria for characterizing these lesions ...and consensus on further therapeutic approaches are not established. MATERIAL AND METHODS: Eighty-four patients ≥4 years with centrally reviewed residual lesions on MRI at the end of primary therapy with initial surgery between 2000 and 2018 were identified. Data were extracted from the German HIT-MED database. RESULTS: Median age at initial diagnosis was 9.3 (4.0-20.8) years. 91.7% were histologically classified as CMB, 7.1% as LC/AMB and 1.2% as DMB. The majority (65.5%) of the evaluated cohort was assigned to molecular subgroup 4, 24.1% to group 3, 6.8% to WNT, 3.4% to SHH. Median follow-up for survivors was 5.96 (1.41-16.67) years. Univariate analysis revealed that patients showing an overall partial response (PR) to primary therapy have a significantly lower risk of progression of residual lesions compared to patients with stable disease (SD) (5-year PFS PR: 62.5±7,0; 5-year PFS SD: 35.9±12.8; 5-year OS PR: 85.6±5.1; 5-year OS SD: 54.1±13.7; p=0.02 PFS, p=0.04 OS). Additionally, patients with multiple residual lesions (M+ and R+) were at higher risk of progression (5-year PFS R+ only: 72.4±12.0, 5-year PFS R+/M+: 22.9±17.9; p=0.02 PFS). Further procedures after the end of primary therapy (additional resections, chemotherapy, radiotherapy) did not impact on PFS and OS. These results were confirmed by multivariate Cox regression. For molecular or histological type no significant effect was found, presumably due to small cohort. CONCLUSION: PFS in patients with residual lesions at the end of primary treatment depends on the overall response to primary therapy. Additional procedures do not seem to be superior compared to watch-and-wait strategies. Decisions regarding further therapies should be scrutinized on a case-by-case basis. Further identification of biomarkers is warranted.
Abstract
BACKGROUND: Proton beam therapy (PBT) compared to photon-based radiotherapy (XRT) offers the benefit to administer lower radiation doses to critical organs thereby possibly minimizing the ...risk of sequelae in patients with residual craniopharyngiomas (CP) after hypothalamus-sparing surgery. The validation in large CP patient cohorts is still pending. PATIENTS AND METHODS: Of 290 childhood-onset CP patients included 2007-2019 in the prospective multicenter trial KRANIOPHARYNGEOM 2007, 99 (34%) received external RT (65% PBT, 35% XRT). Outcome was compared between the different groups in terms of overall (OS) and event-free survival (EFS), quality of life (QoL using PEDQOL), functional capacity (FMH), and auxological data (BMI and height SDS) one, three and five years after irradiation/CP diagnosis. RESULTS: PBT became the predominant irradiation technique during the study period (used in 23% and 77% of all irradiated patients registered within the first and second half of the enrollment period, respectively). PBT as well as XRT were associated with high (p<0.001) EFS (PBT: 0.917 ± 0.040; XRT: 0.940 ± 0.041) compared to non-RT (EFS: 0.669 ± 0.044). OS was similar in all groups. No differences between PBT, XRT and non-RT CP patients concerning functional capacity and anthropometric parameters (height SDS, BMI SDS) have been obtained. Only in the PEDQOL domain “physical function”, proxy-assessed QoL was lower one year after PBT when compared to XRT treated and non-irradiated CP patients. CONCLUSION: PBT is similar efficient in preventing relapses and recurrences in childhood-onset CP patients. During follow-up, no clinically relevant differences between PBT and XRT in terms of QoL, functional capacity and degree of obesity as a marker of hypothalamic syndrome were detectable. While PBT is increasingly applied, studies on larger CP cohorts with longer follow-up after RT are warranted to analyze, whether it can prevent sequelae such as hypothalamic syndrome and severe obesity compared to XRT.
Abstract
BACKGROUND: Cerebral infarction (CI) is a known vascular complication following treatment of suprasellar tumors. Risk factors for CI, incidence rate, and long-term prognosis are unknown for ...patients with childhood-onset craniopharyngioma (CP). METHODS: MRI of 244 CP patients, recruited between 2007 and 2019 in KRANIOPHA-RYNGEOM 2007, were reviewed for CI. Risk factors for CI and outcome after CI were analyzed. RESULTS: Twenty-eight of 244 patients (11%) presented with CI based on reference assessment of MRI. One CI occurred before initial surgery and one case of CI occurred after release of intracystic pressure by a cyst catheter. 26 of 28 CI were detected after surgical tumor resection at a median postoperative interval of one day (range: 0.5 - 53 days). Vascular lesions during surgical procedures were documented in 7 cases with CI. No relevant differences with regard to surgical approaches were found. In all 12 irradiated patients, CI occurred before irradiation. Multivariable analyses showed that hydrocephalus and gross-total resection at the time of primary diagnosis / surgery both were risk factors for CI. After CI, quality of life (PEDQOL) and functional capacity (FMH) were impaired. CONCLUSIONS: CI occurs in 11% of surgically-treated CP cases. Degree of resection and increased intracranial pressure are risk factors, which should be considered in the planning of surgical procedures for prevention of CI.
Abstract
PURPOSE: Childhood-onset craniopharyngiomas (CP) are diagnosed due to clinical symptoms (symCP) or incidentally (incCP). We investigated clinical manifestations and outcome in incCPs and ...symCPs. METHODS: IncCP were discovered in 4 (3m / 1f) and symCP in 214 (101m / 113f) CP recruited 2007–2014 in KRANIOPHARYNGEOM 2007. Age, sex, height, body mass index (BMI), tumor volume, degree of resection, pre- and postsurgical hypothalamic involvement/lesions, pituitary function and outcome were compared between both subgroups. RESULTS: Reasons for imaging in incCP were cerebral palsy, head trauma, nasal obstruction, and tethered-cord syndrome, whereas headache (44%), visual impairment (25%), and growth retardation (17%) lead to imaging in symCP. Tumor volume at diagnosis was smaller in incCP (median 2.39 cm3; range: 0.14 – 4.10 cm3) when compared with symCP (15.86 cm3; 0.002 – 286.34 cm3). Age, gender, BMI, height, hydrocephalus, tumor location, and hypothalamic involvement at diagnosis of incCP were within the range of these parameters in symCP. Complete resections were achieved more frequently (3/4 patients) in incCP when compared with symCP (20%). Surgical hypothalamic lesions were distributed similar in incCP and symCP. Irradiation was performed only in symCP (33%). No noticeable differences were observed concerning survival rates, endocrine deficiencies, BMI, height, functional capacity and quality of life of the 4 incCP cases when compared with the symCP cohort. CONCLUSIONS: IncCP are rare (1.8%) and characterized by lack of endocrine deficiencies, resulting in normal height and BMI, no hydrocephalus, and smaller tumor volume at diagnosis when compared with symCPs. Outcome of the observed incCP is similar with symCP.
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Background: Surgical resection is a mainstay of treatment for pediatric low-grade glioma (LGG) within all current therapy algorithms, yet associated morbidity is scarcely reported. As ...supratentorial midline (SML) interventions are particularly challenging, we investigated the frequency of neurosurgical complications/new impairments aiming to identify their risk factors. Methods: Records were retrospectively analyzed from 318 patients with SML-LGG from successive German multicenter LGG studies, undergoing surgery between May 1998 and June 2020. Results: 537 operations (230 resections, 167 biopsies, 140 non-tumor procedures) were performed in 318 patients (54% male, median age: 7.6 years at diagnosis, 9.5 years at operation, 11% NF1, 42.5% optic pathway glioma). Surgical mortality rate was 0.93%. Applying the Drake classification, postoperative surgical morbidity was observed in 254/537 (47.3%) and medical morbidity in 97/537 (18.1%) patients with a 40.1% 30-day persistence rate for newly developed neurological deficits (65/162). Neuroendocrine impairment affected 53/318 patients (16.7%), visual deterioration 34/318 (10.7%). Postsurgical morbidity was associated with patient age <3 years at operation, tumor volume ≥80cm
3
, presence of hydrocephalus, complete resection, surgery in centers with less than median reported tumor-related procedures and during the earlier study period between 1998-2006, while the neurosurgical approach, tumor location, NF1 status or previous non-surgical treatment were not. Conclusions: Neurosurgery-associated morbidity was frequent in pediatric patients with SML-LGG undergoing surgery in the German LGG-studies. We identified patient- and institution-associated factors that may increase the risk for complications. We advocate that local multidisciplinary teams consider the planned extent of resection and surgical skills. Table: see text
Abstract BACKGROUND European Reference Networks (ERN) are collaborative networks connecting healthcare professionals across Europe. A virtual tumor board for pediatric patients with central nervous ...system (CNS) tumors was established within the ERN for pediatric oncology (ERN PaedCan) in September 2022. We report the feasibility, the implementation of recommendations and satisfaction of the participants. METHODS A web-based questionnaire was distributed to physicians presenting cases between November 2022 and November 2023. Questions addressed the implementation of recommendations, satisfaction and basic information about the local institution. Basic data of the presented cases were taken from anonymized tumor board protocols. RESULTS In the first year, 19 patients from 11 institutions located in nine European countries were discussed in 21 tumor boards. Median age at diagnosis was 10 (1-17) years. Demonstration of MRI findings by the German national reference center for neuroradiology was conducted in 19/21 conferences. 18/21 questionnaires (86%) were answered by physicians from eight countries. Main reason to request the discussion were questions about therapy (78%, n=14/18). Inquiring institutions treated a median of 10 (5-150) neuro-oncological pediatric patients per year. All hospitals conducted own institutional tumor boards. National central review was available in 3/8 countries (38%). Recommendations were followed, at least partly, in all cases except for one patient experiencing unexpected clinical deterioration. Recommendations were deemed helpful in 89%. All participants would recommend the tumor board to colleagues. Technical issues regarding data provision were reported as the main obstacle in 50 %. CONCLUSIONS A European virtual tumor board for pediatric patients with CNS tumors is feasible and perceived as useful by the participating institutions. Recommendations were followed frequently. Optimization of privacy-compliant data exchange is crucial for continuance of the format. This project has been supported by ERN PaedCan, which is funded by the European Union within the EU4Health Program 2021-2027. Funded by EU-grant 101085543.
Abstract BACKGROUND Brainstem gliomas account for 10-20% of all central nervous system pediatric neoplasms. Brain stem tumors in children less than three months old at diagnosis are extremely rare. ...Our aim is to study a retrospective cohort to improve the understanding of the disease course and guide patient management. METHODS This is a multicenter retrospective analysis across the European Society for Pediatric Oncology SIOP-E HGG/DIPG Working Group linked centers and included patients with a brainstem tumor diagnosed between 2009 and 2020 and aged less than 3 months at diagnosis. Clinical data was collected, and imaging characteristics were analyzed blindly and independently by two experienced neuroradiologists. RESULTS Five cases (female; n=4) were identified of which no patient received any therapy. The epicenter of 2 tumors was in the medulla oblongata alone and in the medulla oblongata and the pons in 3 cases. For patients with tumor in equal parts in the medulla oblongata and the pons (n=3) the extension at diagnosis involved the spinal cord; for the 2 patients with the tumor epicenter in the medulla oblongata alone (n=2) the extension at diagnosis included the pons (n=2) and the spinal cord (n=1). Biopsy was performed in one patient identifying a pilocytic astrocytoma. Two patients died rapidly. In one patient autopsy revealed a high-grade glioma (case 3). Three survivors showed either spontaneous tumor regression (n=2) or stable disease (n=1). The surviving patients were followed-up for 10, 7, and 0.6 years, respectively. One case had the typical imaging characteristics of a dorsal exophytic low-grade glioma. CONCLUSIONS No patient fulfilled the radiologic criteria defining a high-grade glioma. Central neuroradiological review and biopsy (if feasible) may provide useful information with regards to the patient’s management.
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