Survivors of infant atypical teratoid/rhabdoid tumors present with severely impaired cognitive functions especially for fluid intelligence and visual processing: data from the German brain tumor studies.

BACKGROUND: The contribution of tumor type, multimodal treatment, and other patient-related factors upon long-term cognitive sequelae in infant brain tumor survivors remains undefined. We add our retrospective analysis of neuropsychological and quality of survival (QoS) outcome data of survivors of atypical teratoid/rhabdoid tumors (ATRT) and extracranial malignant rhabdoid tumors of the soft tissues (eMRT) and kidneys (RTK) treated within the same framework. Neuropsychological data from children with ATRT were compared to data from children with non-irradiated low-grade glioma (LGG). PATIENTS AND METHODS: Following surgery, patients (0-36 months at diagnosis) had received radio-chemotherapy (up to 54 Gy; ATRT: n = 13; eMRT/RTK: n = 7), chemotherapy only (LGG: n = 4; eMRT/RTK: n = 1) or had been observed (LGG: n = 11). Neuropsychological evaluation employing comparable tests was performed at median 6.8 years (ATRT), 6.6 years (eMRT/RTK), and 5.2 years (LGG) post diagnosis. RESULTS: We detected sequelae in various domains for all tumor types. Group comparison showed impairments, specifically in fluid intelligence (p = .041; d = 1.11) and visual processing (p = .001; d = 2.09) in ATRT patients when compared to LGG patients. Results for psychomotor speed and attention abilities were significantly below the norm for both groups (p < .001-.019; d = 0.79-1.90). Diagnosis predicted impairments of cognitive outcome, while sex- and age-related variables did not. QoS outcome for all rhabdoid patients displayed impairments mainly in social (p = .008; d = 0.74) and school functioning (p = .048; d = 0.67), as well as lower overall scores in psychosocial functioning (p = .023; d = 0.78) and quality of life (p = .006; d = 0.79) compared to healthy controls. CONCLUSION: Survivors of infant ATRT experience various late effects in cognition and QoS following multimodal treatment, while infant LGG patients without radiotherapy demonstrated comparable impairments in psychomotor and attention abilities. Early onset and multimodal treatment of rhabdoid tumors require close monitoring of neuropsychological and QoS sequelae.

Neurosurgical morbidity in pediatric supratentorial midline low-grade glioma: Results from the German LGG studies.

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. Records were retrospectively analyzed from 318 patients with SML-LGG from successive German multicenter LGG studies, undergoing surgery between May 1998 and June 2020. Exactly 537 operations (230 resections, 167 biopsies, 140 nontumor 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 following 254/537 (47.3%) and medical morbidity following 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 ≥80 cm3 , presence of hydrocephalus, complete resection, surgery in centers with less than median reported tumor-related procedures and during the earlier study period between 1998 and 2006, while the neurosurgical approach, tumor location, NF1 status or previous nonsurgical treatment were not. 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.

Parent-reported health-related quality of life in pediatric childhood cancer survivors and factors associated with poor health-related quality of life in aftercare.

PURPOSE: Despite advances in cancer treatment, there is a prevalence of pediatric childhood cancer survivors still at risk of developing adverse disease and treatment outcomes, even after the end of treatment. The present study aimed to (1) explore how mothers and fathers assess the health-related quality of life (HRQoL) of their surviving child and (2) evaluate risk factors for poor parent-reported HRQoL in childhood cancer survivors about 2.5 years after diagnosis. METHODS: We assessed parent-reported HRQoL of 305 child and adolescent survivors < 18 years diagnosed with leukemia or tumors of central nervous system (CNS) with the KINDL-R questionnaire in a prospective observational study with a longitudinal mixed-methods design. RESULTS: In agreement with our hypotheses, our results show that fathers rate their children's HRQoL total score as well as the condition-specific domains family (p = .013, d = 0.3), friends (p = .027, d = 0.27), and disease (p = .035, d = 0.26) higher than mothers about 2.5 years after diagnosis. Taking variance of inter-individual differences due to family affiliation into account, the mixed model regression revealed significant associations between the diagnosis of CNS tumors (p = .018, 95% CI [- 7.78, - 0.75]), an older age at diagnosis, (p = .011, 95% CI [- 0.96, - 0.12]), and non-participation in rehabilitation (p = .013, 95% CI [- 10.85, - 1.28]) with poor HRQoL in children more than 2 years after being diagnosed with cancer. CONCLUSION: Based on the results, it is necessary for health care professionals to consider the differences in parental perceptions regarding children's aftercare after surviving childhood cancer. High risk patients for poor HRQoL should be detected early, and families should be offered support post-cancer diagnosis to protect survivors' HRQoL during aftercare. Further research should focus on characteristics of pediatric childhood cancer survivors and families with low participation in rehabilitation programs.

Integrated molecular and clinical analysis of low-grade gliomas in children with neurofibromatosis type 1 (NF1).

Low-grade gliomas (LGGs) are the most common childhood brain tumor in the general population and in individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Surgical biopsy is rarely performed prior to treatment in the setting of NF1, resulting in a paucity of tumor genomic information. To define the molecular landscape of NF1-associated LGGs (NF1-LGG), we integrated clinical data, histological diagnoses, and multi-level genetic/genomic analyses on 70 individuals from 25 centers worldwide. Whereas, most tumors harbored bi-allelic NF1 inactivation as the only genetic abnormality, 11% had additional mutations. Moreover, tumors classified as non-pilocytic astrocytoma based on DNA methylation analysis were significantly more likely to harbor these additional mutations. The most common secondary alteration was FGFR1 mutation, which conferred an additional growth advantage in multiple complementary experimental murine Nf1 models. Taken together, this comprehensive characterization has important implications for the management of children with NF1-LGG, distinct from their sporadic counterparts.

Doubling Recruitment of Pediatric Low-grade Glioma within Two Decades does not change Outcome - Report from the German LGG Studies.

BACKGROUND: 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. METHODS AND RESULTS: 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/adolescents<15 years). The consecutive LGG studies recruited 899 (HIT-LGG 1996), 1592 (SIOP-LGG 2004), and 1836 (LGG-registry) patients with similar distribution of tumor-sites, histology, and dissemination. 5-year overall survival was 96%-98% at median observation time of 8.1 years. Acknowledging unequal follow-up periods, 589/899 (66%), 1089/1582 (69%), and 1387/1836 (76%) patients remained under observation, while 1252/4317 received adjuvant treatment with decreasing frequency of front-line radiotherapy from 16% to 5%. CONCLUSION: Pediatric LGG incidence rates in Germany are now comparable to other European countries. The rise in patient numbers followed implementation of standard-of-care treatment protocols, but did not result in relevant changes of epidemiologic or clinical parameters or survival. Shifts in patient distribution between treatment arms reflect growing acceptance of the LGG therapy algorithm. HINTERGRUND: In den vergangenen 20 Jahren hat sich die jährliche Patientenrekrutierung in den aufeinanderfolgenden multizentrischen Studien für pädiatrische niedrig-gradige Gliome (LGG) in Deutschland verdoppelt. Wir haben untersucht, ob sich mit dieser Zunahme auch epidemiologische Merkmale oder das Überleben verändert haben. METHODIK UND ERGEBNISSE: Zwischen 1996 und 2018 meldeten die teilnehmenden Zentren insgesamt 4634 Patienten mit der radiologischen/histologischen Diagnose eines LGG. Die Zahl stieg von anfangs 109 bis 278 Patienten pro Jahr. Gleichzeitig stieg der Anteil der LGGs an allen am Deutschen Kinderkrebsregister gemeldeten pädiatrischen Hirntumoren von 32 auf 51%, die jährliche Inzidenz erhöhte sich von 0,94 auf 2,12/100 000 Kinder/Jugendliche<15 Jahre. Die aufeinanderfolgenden LGG-Studien rekrutierten 899 (HIT-LGG 1996), 1592 (SIOP-LGG 2004) und 1836 (LGG-Register) Patienten mit vergleichbarer Verteilung von Tumorsitz, Histologie und Disseminierung. Das 5-Jahres-Überleben lag bei einer medianen Nachbeobachtungszeit von 8,1 Jahren zwischen 96 und 98%. Unter Berücksichtigung der ungleich langen Follow-up-Zeit wurden 589/899 (65,5%), 1089/1582 (68,8%) und 1387/1836 (75,5%) Patienten bislang beobachtet, während 1252/4317 eine adjuvante Therapie erhielten. Dabei sank der Anteil der primären Radiotherapie von 16 auf 5%. SCHLUSSFOLGERUNG: Die Rekrutierung pädiatrischer LGG ist dank Implementierung verbindlicher Therapiestandards in Deutschland gestiegen, ohne zu relevanten Veränderungen epidemiologischer oder klinischer Merkmale oder des Überlebens zu führen. Die Inzidenz ist mit anderen europäischen Ländern vergleichbar. Verschiebungen der Patientenzuteilung zwischen den Therapiearmen spiegeln die zunehmende Akzeptanz des LGG-Therapie-Algorithmus wider.

Loss of efficacy of subsequent nonsurgical therapy after primary treatment failure in pediatric low-grade glioma patients-Report from the German SIOP-LGG 2004 cohort.

First-line treatment of pediatric low-grade glioma using surgery, radio- or chemotherapy fails in a relevant proportion of patients. We analyzed efficacy of subsequent surgical and nonsurgical therapies of the German cohort of the SIOP-LGG 2004 study (2004-2012, 1558 registered patients; median age at diagnosis 7.6 years, median observation time 9.2 years, overall survival 98%/96% at 5/10 years, 15% neurofibromatosis type 1 [NF1]). During follow-up, 1078/1558 patients remained observed without (n = 217), with 1 (n = 707), 2 (n = 124) or 3 to 6 (n = 30) tumor volume reductions; 480/1558 had 1 (n = 332), 2 (n = 80), 3 or more (n = 68) nonsurgical treatment-lines, accompanied by up to 4 tumor-reductive surgeries in 215/480; 265/480 patients never underwent any neurosurgical tumor volume reduction (163/265 optic pathway glioma). Patients with progressing tumors after first-line adjuvant treatment were at increased risk of suffering further progressions. Risk factors were young age (<1 year) at start of treatment, tumor dissemination or progression within 18 months after start of chemotherapy. Progression-free survival rates declined with subsequent treatment-lines, yet remaining higher for patients with NF1. In non-NF1-associated tumors, vinblastine monotherapy vs platinum-based chemotherapy was noticeably less effective when used as second-line treatment. Yet, for the entire cohort, results did not favor a certain sequence of specific treatment options. Rather, all can be aligned as a portfolio of choices which need careful balancing of risks and benefits. Future molecular data may predict long-term tumor biology.

Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II-Report from the German/Swiss SIOP-LGG 2004 cohort.

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.

Favorable prognosis in pediatric brainstem low-grade glioma: Report from the German SIOP-LGG 2004 cohort.

Reports on pediatric low-grade glioma (LGG) of the caudal brainstem are retrospective with heterogeneous cohorts, variable treatments and inconsistent outcome data. We analyzed their natural history and asked whether brainstem location proved unfavorable for survival within the framework of the comprehensive SIOP-LGG 2004 management strategy. Within the prospectively registered, population-based German SIOP-LGG 2004 cohort 116 patients (age 0.2-16.5 years, 10% Neurofibromatosis NF1) were diagnosed with LGG of the pons (27%) and medulla oblongata (73%). After biopsy (23%), variable resection (63%) or radiologic diagnosis only (14%), 59 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemo- (n = 39) or radiotherapy (n = 18). After further progression (28/57), salvage treatments included multiple treatment lines for 12/28 patients. Five-years event-free survival dropped to 0.40, while 5-years overall survival was 0.95 (median observation time 6.8 years). Higher extent of resection yielded lower progression rate (p = 0.001), but at a cost of 21/100 patients suffering from new postsurgical complications including respiratory insufficiency. Central review confirmed pilocytic astrocytoma (56%), diffuse astrocytoma (8%) or glioneuronal histology (16%) (others 4%, no histology 17%). Malignant evolution was documented in five patients associated with Histone3 mutation in 2/5. Our treatment algorithm conveyed high overall survival for pediatric brainstem LGG. Extensive neurosurgical resection did increase additional postoperative neurologic deficits but not overall survival in this often-chronic disease. More than half of all patients can be safely followed by observation, while multimodal adjuvant treatment can control progressive tumors. Molecular assessment should confirm low-grade diagnosis and may detect patterns prognostic for malignant evolution.

Fear of progression in parents of childhood cancer survivors: A dyadic data analysis.

OBJECTIVE: Fear of progression (FoP), also referred to as fear of cancer recurrence, is gaining increasing interest in survivorship research as it constitutes a great burden for patients and relatives. However, only little is known about FoP in parents of childhood cancer survivors. The objective of this study was to investigate the impact of FoP on quality of life (QoL) in parental couples. METHODS: We analyzed dyadic data of 197 couples parenting childhood cancer survivors (aged 0-17 years at diagnosis of leukemia or central nervous system tumor) after the end of intensive cancer treatment. The actor-partner interdependence model calculated by structural equation modelling was used to examine actor effects (effect of one's own FoP on one's own QoL) and partner effects (effect of one's own FoP on the partner's QoL). RESULTS: Eighty-one percentage of the parents reported moderate or high FoP levels. Mothers reported higher FoP levels (p < .01) and lower overall QoL levels than fathers (p < .01). The results revealed a significantly positive intra-dyadic correlation between FoP of mothers and fathers of the same dyad (r = .431, p < .001). We found significantly negative actor effects for both mothers and fathers for the overall QoL (p < .001) as well as for several QoL subscales. No significant partner effects were found. CONCLUSIONS: Most parents reported elevated levels of FoP. Our results show that FoP in parents of childhood cancer survivors is strongly negatively associated with QoL. Parental FoP should therefore be explored in future research and needs to be targeted by health care providers.

[Registries and studies in the Society for Pediatric Oncology and Hematology (GPOH) - What contribution do they make to progress?] / Register und Studien in der Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) ­ Welchen Beitrag leisten sie zum Fortschritt?

Cancer in children and adolescents under the age of 18 is rare; in 2017, approximately 2220 new cases in Germany were reported to the German Childhood Cancer Registry. The aim of the GPOH has always been to treat as many affected patients as possible in a standardized way, preferably in prospective, controlled studies. The Joint Federal Committee has also laid down this requirement in the paediatric oncology guideline. In a survey among the study chairs of the GPOH, it was determined how the number of clinical trials has changed following the amended drug legislation. In 2002, 33 therapy optimization studies (TOS) of the GPOH were open. Overall, TOS decreased from 33 in 2002 to 2 in 2017. The number of drug trials has increased to 16 by 2017 (almost 1100 patients registered). At the time, the number of clinical registries has increased to 28 with a total of more than 1800 registered patents. This observation shows that the clinical registers have taken on a new significance in paediatric oncology. Three examples are used to examine what contributions registries can make in relation to studies on the treatment of patients and to scientific progress. In summary, the experience gained so far from the examples discussed illustrates that studies and registries mutually represent a meaningful and necessary addition to the study group structure in paediatric oncology.

SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma.

Low grade gliomas (LGGs) constitute the largest, yet clinically and (molecular-) histologically heterogeneous group of pediatric brain tumors of WHO grades I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest. Around 40% of all LGG patients can be cured by complete neurosurgical resection and are followed by close observation. In case of relapse, second resection often is possible. Following incomplete resection observation is recommended, as long as there is no radiologic tumor growth and the patient does not suffer from significant, tumor-related symptoms. This also applies to patients with a diagnosis of LGG on the basis of radiological criteria. By contrast, clinical worsening and / or radiologic progression are an indication to treatment with either chemo- or radiotherapy. Overall survival is around 90%, and many patients survive with residual tumor, i. e. they suffer from chronic disease. All patients need comprehensive neuro-oncological care, the principles and details of which are summarized in the current guidelines. These represent standard of care for diagnostic work-up (including neuroimaging and neuropathology), and for therapeutic decisions (including the indications to non-surgical treatment) as well as concepts for neurosurgical intervention, chemotherapy and radiotherapy as well as surveillance and rehabilitation. The current treatment algorithm was compiled by members of the LGG working group of the SIOP-E brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports.

Management of Primary Tectal Plate Low-Grade Glioma in Pediatric Patients: Results of the Multicenter Treatment Study SIOP-LGG 2004.

BACKGROUND: Tectal plate low-grade gliomas (LGGs) most often present with increased intracranial pressure and sometimes as incidental findings from brain imaging. Prognostic factors predicting outcome are largely unknown. METHODS: From 2004 until 2012, 71 patients with tectal plate LGG from Germany and Switzerland were followed within the SIOP-LGG 2004 study. Median age at diagnosis was 9.7 (range: 0.1-17.5) years, and median follow-up time of surviving patients was 6.3 (interquartile range: 4.9-8.3) years. RESULTS: A total of 41 out of 71 patients received no tumor treatment (12 with and 29 without biopsy). The 10-year event-free survival (EFS) rate (± standard error ) for patients with an initial tumor volume of ≤3 cm3 was 56% (±7%), as opposed to 12% (±8%) for those with tumors >3 cm3 (p < 0.001). The 10-year EFS for patients without contrast enhancement on initial magnetic resonance imaging (MRI) was 52% (±9%), and for those with enhancement, it was 23% (±9%) (p = 0.003). The 10-year overall survival rate was 96% (±3%) (death due to disease, 1; ventriculoperitoneal shunt infection, 1). Sixty-three (89%) patients had at least one cerebrospinal fluid diversion procedure. CONCLUSIONS: More than half of patients were managed without tumor treatment. Favorable prognostic factors for EFS were small initial tumor volume (≤3cm3) and the absence of initial contrast enhancement on MRI. Overall survival was excellent.

Reintegration into school, kindergarten and work in families of childhood cancer survivors after a family-oriented rehabilitation program.

Objective: To describe the situation of childhood cancer survivors and their parents before and one year after a family-oriented rehabilitation program (FOR) and to identify factors influencing reintegration. Methods: We included parents of children diagnosed with leukemia or central nervous system tumor. We assessed parental functioning using the functioning subscale of the Ulm Quality of Life Inventory for Parents (ULQIE) and children's school/kindergarten related quality of life (parental assessment, subscale KINDL-R). Descriptive analyses, group comparisons and multiple regression analyses on data of 285 parents of 174 children diagnosed with leukemia or central nervous system tumor. Results: Parents reported changes in their work situation (e.g., reduction of working hours) due to their child's diagnosis. Parental functioning increased significantly over time. Children's leukemia diagnosis and shorter time since the end of treatment were associated with higher functioning in parents one year after FOR. Parents reported difficulties in the child's work pace, concentration, stress resilience and empathy. The school/kindergarten-related quality of life (QoL) of the children was lower than in the general population. One year after FOR, most children reintegrated fully in school/kindergarten, partly with support (e.g., integration assistant). No significant predictors for children's reintegration were identified. Discussion: Parents and children experience major changes in their work/school/kindergarten life. One year after FOR most parents reported a reintegration of their children, however the children's school/kindergarten-related QoL remained below average compared to norm values. Even after rehabilitation families of childhood cancer survivors might benefit from psychosocial and practical support offers to support families with the reintegration into work/school/kindergarten.

Adaption of neurosurgical resection patterns for pediatric low-grade glioma spanning two decades-Report from the German LGG-studies 1996-2018.

INTRODUCTION: Neurosurgery is considered the mainstay of treatment for pediatric low-grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long-term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. PATIENTS AND METHODS: Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1-5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1-status, sex, and age. RESULTS: The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres. CONCLUSIONS: The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1-status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals.

Fear of progression in parents of childhood cancer survivors: prevalence and associated factors.

PURPOSE: Recent research demonstrated that fear of progression (FoP) is a major burden for adult cancer survivors. However, knowledge on FoP in parents of childhood cancer survivors is scarce. This study aimed to determine the proportion of parents who show dysfunctional levels of FoP, to investigate gender differences, and to examine factors associated with FoP in mothers and fathers. METHODS: Five hundred sixteen parents of pediatric cancer survivors (aged 0-17 years at diagnosis of leukemia or central nervous system (CNS) tumor) were consecutively recruited after the end of intensive cancer treatment. We conducted hierarchical multiple regression analyses for mothers and fathers and integrated parent-, patient-, and family-related factors in the models. RESULTS: Significantly more mothers (54%) than fathers (41%) suffered from dysfunctional levels of FoP. Maternal FoP was significantly associated with depression, a medical coping style, a child diagnosed with a CNS tumor in comparison to leukemia, and lower family functioning (adjusted R2 = .30, p < .001). Paternal FoP was significantly associated with a lower level of education, depression, a family coping style, a child diagnosed with a CNS tumor in comparison to leukemia, and fewer siblings (adjusted R2 = .48, p < .001). CONCLUSIONS: FoP represents a great burden for parents of pediatric cancer survivors. We identified associated factors of parental FoP. Some of these factors can be targeted by health care professionals within psychosocial interventions and others can provide an indication for an increased risk for higher levels of FoP. IMPLICATIONS FOR CANCER SURVIVORS: Psychosocial support targeting FoP in parents of childhood cancer survivors is highly indicated.

Pseudoprogression Is Frequent After Front-Line Radiation Therapy in Pediatric Low-Grade Glioma: Results From the German Low-Grade Glioma Cohort.

PURPOSE: Expansion of magnetic resonance imaging T2- or T1-tumor lesion volume after radiation therapy (RT) may indicate pseudoprogression (PsPD). The differentiation between true progression and PsPD is a clinical challenge and underinvestigated in pediatric low-grade glioma (LGG). We evaluated radiologic criteria for PsPD after front-line RT and investigated the frequency and duration of PsPD after 3 RT-modalities within the framework of the German pediatric multicenter LGG-studies. METHODS AND MATERIALS: Baseline and follow-up magnetic resonance imaging scans of 136 patients (72 male [52.9%], median age at start of RT of 11.3 years [range, 0.8-25.9]) of the Society for Pediatric Oncology-LGG 2004 study and LGG-registry cohorts (125iodine-interstitial [IS] RT [n = 51], photon-beam [XRT; n = 60], or proton-beam RT [PBT; n = 25]) were centrally evaluated for increasing: (1) total tumor-associated T2 lesion, (2) focal tumor-associated T2 lesion, and (3) contrast-enhancing tumor during a period of 24 months after RT. The pattern of these criteria initiated "suspicion" of PsPD; their evolution determined "definite" PsPD. RESULTS: Definite PsPD was radiologically determined in 54 of 136 (39.7%) without differences in frequency between RT-modalities: IS 22 of 48 versus XRT 24 of 54 versus PBT 11 of 20; P = .780. Definite PsPD occurred at median 6.3 months (IS 7.2 months; XRT 4.4 months; PBT 6.5 months) after RT-initiation and persisted for median 7.2 months (IS 8.5 months; XRT 7 months; PBT 7.4 months). Appearance of necrosis within the focal tumor-associated T2 lesion proved to be a relevant associated predictor of definite PsPD (P < .001). CONCLUSIONS: PsPD is frequent after irradiation of pediatric LGG and independent of the RT modality (IS vs XRT vs PBT). Adequate identification of PsPD versus true progression is imperative to prevent unneeded salvage treatment.

Long-term follow-up of surgical intervention pattern in pediatric low-grade gliomas: report from the German SIOP-LGG 2004 cohort.

OBJECTIVE: Neurosurgical treatment is an integral part of the treatment algorithms for pediatric low-grade glioma (LGG), yet patterns of surgical procedures are rarely challenged. The objective of this study was to evaluate surgical treatment patterns in pediatric LGG. METHODS: The German Societé Internationale d'Oncologie Pédiatrique (SIOP)-LGG 2004 cohort was analyzed to identify relevant patient and tumor characteristics associated with time to death, next surgery, number of resections, and radiological outcome. RESULTS: A total of 1271 patients underwent 1713 neurosurgical interventions (1 intervention in 947, 2 in 230, 3 in 70, and 4-6 in 24). The median age of the study population was 8.57 years at first surgery, and 46.1% were female. Neurofibromatosis type 1 (NF1) was found in 4.4%, and 5.4% had tumor dissemination. Three hundred fifty-four patients (27.9%) had chemotherapy and/or radiotherapy. The cumulative incidence of second surgery at 10 years was 26%, and was higher for infants, those with spinal and supratentorial midline (SML) tumors, and those with pilomyxoid astrocytomas. The hazard ratio for subsequent surgery was higher given dissemination and noncomplete initial resection, and lower for caudal brainstem and SML tumors. Among 1225 patients with fully documented surgical records and radiological outcome, 613 reached complete remission during the observation period, and 50 patients died. Patients with pilocytic astrocytoma had higher chances for a final complete remission, whereas patients with initial partial or subtotal tumor resection, dissemination, NF1, or primary tumor sites in the spinal cord and SML had lower chances. CONCLUSIONS: Neurosurgery is a key element of pediatric LGG treatment. In almost 50% of the patients, however, at least some tumor burden will remain during long-term follow-up. This study found that most of these patients reached a stable disease status without further surgeries. Multidisciplinary team decisions must balance the goal of complete resection, risk factors, repeated surgeries, and possible treatment alternatives in a wide range of heterogeneous entities. Procedural details and neurological outcome should be recorded to better assess their impact on long-term outcome.

High frequency of disease progression in pediatric spinal cord low-grade glioma (LGG): management strategies and results from the German LGG study group.

BACKGROUND: Knowledge on management of pediatric spinal cord low-grade glioma (LGG) is scarce. METHODS: We analyzed clinical datasets of 128 pediatric patients with spinal LGG followed within the prospective multicenter trials HIT-LGG 1996 (n = 36), SIOP-LGG 2004 (n = 56), and the subsequent LGG-Interim registry (n = 36). RESULTS: Spinal LGG, predominantly pilocytic astrocytomas (76%), harbored KIAA1549-BRAF fusion in 14/35 patients (40%) and FGFR1-TACC1 fusion in 3/26 patients (12%), as well as BRAFV600E mutation in 2/66 patients (3%). 10-year overall survival (OS) and event-free survival (EFS) was 93% ± 2% and 38% ± 5%, respectively. Disseminated disease (n = 16) was associated with inferior OS and EFS, while age ≥11 years and total resection were favorable factors for EFS. We observed 117 patients following total (n = 24) or subtotal/partial resection (n = 74), biopsy (n = 16), or radiologic diagnosis only (n = 3). Eleven patients were treated first with chemotherapy (n = 9) or irradiation (n = 2). Up to 20.8 years after diagnosis/initial intervention, 73/128 patients experienced one (n = 43) or up to six (n = 30) radiological/clinical disease progressions. Tumor resections were repeated in 36 patients (range, 2-6) and 47 patients required nonsurgical treatment (chemotherapy, n = 20; radiotherapy, n = 10; multiple treatment lines, n = 17). Long-term disease control for a median of 6.5 (range, 0.02-20) years was achieved in 73/77 patients following one (n = 57) or repeated (n = 16) resections, and in 35/47 patients after nonsurgical treatment. CONCLUSIONS: The majority of patients experienced disease progression, even after years. Multiple interventions were required for more than a third, yet multimodal treatment enabled long-term disease control. Molecular testing may reveal therapeutic targets.

Biology and grading of pleomorphic xanthoastrocytoma-what have we learned about it?

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma predominantly affecting children and young adults. We performed comprehensive genomic characterization on a cohort of 67 patients with histologically defined PXA (n = 53, 79%) or anaplastic PXA (A-PXA, n = 14, 21%), including copy number analysis (ThermoFisher Oncoscan, n = 67), methylation profiling (Illumina EPIC array, n = 43) and targeted next generation sequencing (n = 32). The most frequent alterations were CDKN2A/B deletion (n = 63; 94%) and BRAF p.V600E (n = 51, 76.1%). In 7 BRAF p.V600 wild-type cases, alternative driver alterations were identified involving BRAF, RAF1 and NF1. Downstream phosphorylation of ERK kinase was uniformly present. Additional pathogenic alterations were rare, with TERT, ATRX and TP53 mutations identified in a small number of tumors, predominantly A-PXA. Methylation-based classification of 46 cases utilizing a comprehensive reference tumor allowed assignment to the PXA methylation class in 40 cases. A minority grouped with the methylation classes of ganglioglioma or pilocytic astrocytoma (n = 2), anaplastic pilocytic astrocytoma (n = 2) or control tissues (n = 2). In 9 cases, tissue was available from matched primary and recurrent tumors, including 8 with anaplastic transformation. At recurrence, two tumors acquired TERT promoter mutations and the majority demonstrated additional non-recurrent copy number alterations. Methylation class was preserved at recurrence. For 62 patients (92.5%), clinical follow-up data were available (median follow-up, 5.4 years). Overall survival was significantly different between PXA and A-PXA (5-year OS 80.8% vs. 47.6%; P = 0.0009) but not progression-free survival (5-year PFS 59.9% vs. 39.8%; P = 0.05). WHO grade remained a strong predictor of overall survival when limited to 38 cases defined as PXA by methylation-based classification. Our data confirm the importance of WHO grading in histologically and epigenetically defined PXA. Methylation-based classification may be helpful in cases with ambiguous morphology, but is largely confirmatory in PXA with well-defined morphology.