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.

Comprehensive neurological evaluation of a cohort of patients with neurofibromatosis type 1 from a single institution.

Neurofibromatosis type 1 (NF1) is a phenotypically heterogenous multisystem cancer predisposition syndrome manifesting in childhood and adolescents. Central nervous system (CNS) manifestations include structural, neurodevelopmental, and neoplastic disease. We aimed to (1) characterize the spectrum of CNS manifestations of NF1 in a paediatric population, (2) explore radiological features in the CNS by image analyses, and (3) correlate genotype with phenotypic expression for those with a genetic diagnosis. We performed a database search in the hospital information system covering the period between January 2017 and December 2020. We evaluated the phenotype by retrospective chart review and imaging analysis. 59 patients were diagnosed with NF1 [median age 10.6 years (range, 1.1-22.6); 31 female] at last follow-up, pathogenic NF1 variants were identified in 26/29. 49/59 patients presented with neurological manifestations including 28 with structural and neurodevelopmental findings, 16 with neurodevelopmental, and 5 with structural findings only. Focal areas of signal intensity (FASI) were identified in 29/39, cerebrovascular anomalies in 4/39. Neurodevelopmental delay was reported in 27/59 patients, learning difficulties in 19/59. Optic pathway gliomas (OPG) were diagnosed in 18/59 patients, 13/59 had low-grade gliomas outside the visual pathways. 12 patients received chemotherapy. Beside the established NF1 microdeletion, neither genotype nor FASI were associated with the neurological phenotype. NF1 was associated with a spectrum of CNS manifestations in at least 83.0% of patients. Regular neuropsychological assessment complementing frequent clinical and ophthalmologic testing for OPG is necessary in the care of each child with NF1.

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.

Neurofibromatosis type 1: A comparison of the 1997 NIH and the 2021 revised diagnostic criteria in 75 children and adolescents.

PURPOSE: Examining a cohort of patients suspicious of neurofibromatosis type 1 (NF1) we compared the revised diagnostic criteria with the previous National Institutes of Health (NIH) diagnostic criteria. We asked whether the refinement improved distinguishing between NF1, Legius syndrome, and constitutional mismatch repair deficiency (CMMRD). METHODS: A database search in the hospital information system of the University Children's Hospital Augsburg between 2017 and 2020 ascertained patients with International Classification of Diseases-10 code Q85.0; their clinical phenotype was evaluated by retrospective chart review. RESULTS: A total of 75 patients were identified (median age 11.0 years [range 1.1-22.6 years]; 35 female). At first suspicion of NF1, 44 patients met the NIH criteria and 56 met the revised diagnostic criteria. In total, 12 patients were diagnosed with NF1 after performing molecular genetic testing. In 31 patients, only pigmentary findings were present, whereas nonpigmentary NF1 manifestations presented with time in 9 patients. In 1 patient a heterozygous variant of uncertain significance was identified in SPRED1. Requirements for CMMRD testing were fulfilled in another patient. A total of 3 patients presented with segmental clinical findings. Three additional patients did not meet the NIH criteria, 1 of them presented with 1 additional feature of CMMRD without fulfilling requirements for testing. CONCLUSION: In our pediatric cohort, the revised diagnostic criteria discovered more patients with proven NF1 than the NIH criteria.

Hepatic sinusoidal obstruction syndrome and short-term application of 6-thioguanine in pediatric acute lymphoblastic leukemia.

Long-term treatment with 6-thioguanine (6-TG) for pediatric acute lymphoblastic leukemia (ALL) is associated with high rates of hepatic sinusoidal obstruction syndrome (SOS). Nevertheless, current treatment continues to use short-term applications of 6-TG with only sparse information on toxicity. 6-TG is metabolized by thiopurine methyltransferase (TPMT) which underlies clinically relevant genetic polymorphism. We analyzed the association between hepatic SOS reported as a serious adverse event (SAE) and short-term 6-TG application in 3983 pediatric ALL patients treated on trial AIEOP-BFM ALL 2000 (derivation cohort) and defined the role of TPMT genotype in this relationship. We identified 17 patients (0.43%) with hepatic SOS, 13 of which with short-term exposure to 6-TG (P < 0.0001). Eight of the 13 patients were heterozygous for low-activity TPMT variants, resulting in a 22.4-fold (95% confidence interval 7.1-70.7; P ≤ 0.0001) increased risk of hepatic SOS for heterozygotes in comparison to TPMT wild-type patients. Results were supported by independent replication analysis. All patients with hepatic SOS after short-term 6-TG recovered and did not demonstrate residual symptoms. Thus, hepatic SOS is associated with short-term exposure to 6-TG during treatment of pediatric ALL and SOS risk is increased for patients with low-activity TPMT genotypes.

Long-term cognitive deficits in pediatric low-grade glioma (LGG) survivors reflect pretreatment conditions-report from the German LGG studies.

BACKGROUND: Disease and treatment contribute to cognitive late effects following pediatric low-grade glioma (LGG). We analyzed prospectively collected neuropsychological data of German pediatric LGG survivors and focused on the impact of hydrocephalus at diagnosis, neurofibromatosis type 1 (NF1) status, and extent of surgery. METHODS: We used the Neuropsychological Basic Diagnostic screening tool based on the Cattell-Horn-Carroll model for intelligence and the concept of cross-battery assessment at 2 and 5 years from diagnosis for 316 patients from the German pediatric LGG study and LGG registry (7.1 years median age; 45 NF1; cerebral hemispheres 16%, supratentorial midline 39%, infratentorial 45%). Hydrocephalus was classified radiologically in 137 non-NF1 patients with infratentorial tumors (95/137 complete/subtotal resection). RESULTS: Patients with NF1 versus non-NF1 exhibited inferior verbal short-term memory and visual processing (P < .001-.021). In non-NF1 patients, infratentorial tumor site and complete/subtotal resection were associated with sequelae in visual processing, psychomotor speed, and processing speed (P < .001-.008). Non-NF1 patients without surgical tumor reduction and/or nonsurgical treatment experienced similar deficits. Degree of hydrocephalus at diagnosis had no further impact. Psychomotor and processing speed were impaired comparably following chemo-/radiotherapy (P < .001-.021). Pretreatment factors such as NF1 or tumor site were relevant at multivariate analysis. CONCLUSIONS: All pediatric LGG survivors are at risk to experience long-term cognitive impairments in various domains. Even surgical only management of cerebellar LGG or no treatment at all, that is, biopsy only/radiological diagnosis did not protect cognitive function. Since pattern and extent of deficits are crucial to tailor rehabilitation, neuropsychological and quality of survival assessments should be mandatory in future LGG trials.

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.

Natural History of Pediatric Low-Grade Glioma Disease - First Multi-State Model Analysis.

Background: Pediatric low-grade glioma [PLGG] is often a chronic progressive disease requiring multiple treatments, i.e. surgery, chemotherapy and irradiation. The multi-state model [MSM] allows an extended analysis of disease-states, that patients may undergo, incorporating competing risks over the course of time. Purpose: We studied disease-state-probabilities of the German SIOP-LGG 2004 cohort from the initial state "diagnosis" to the final state "death". Transient "disease-states" incorporated successive surgical and non-surgical treatments. We evaluated clinical risk factors for highly progressive disease requiring multiple interventions and death. Results: We identified 22 states within 1587 patients (median follow-up 6.3 years). For robust statistical calculation, we reduced the model to 7 states and eventually to three levels of disease-progressiveness: non, low and highly progressive. Five years after diagnosis state-probabilities were: 0.11 no therapy, 0.49 one and 0.11 two or more surgeries only, 0.19 one and 0.06 two or more non-surgical interventions with or without prior surgery. At this time point higher probability for highly progressive disease was found in infants (0.30), supratentorial-midline location (0.17) and diffuse astrocytoma WHO-grade II (0.12). Neurofibromatosis type-1 patients were most likely not to be treated (0.36) or to have received only non-surgical therapy (0.45). Two years after diagnosis 3-year predictions for highly progressive disease and death increased with the number of interventions patients underwent in the first 2 years after diagnosis. Conclusion: In this first MSM analysis we delineated a refined description of PLGG disease course over time, identifying three levels of progressiveness. Growth behavior in the first two years predicted future progressiveness and death.

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.

Pediatric NUT-midline carcinoma: Therapeutic success employing a sarcoma based multimodal approach.

A subset of poorly differentiated squamous cell carcinomas, NUT midline carcinomas (NMC) are characterized by a translocation t(15;19)(q13;p13) [ 1 ]. The prognosis is generally dismal [ 2 ] and therapeutic success has been limited to exceptional cases [ 3 ]. We present two cases of pediatric NMC from two different institutions treated according to a multimodal sarcoma approach involving surgery, chemotherapy, and focal radiotherapy. One patient has remained in complete continuous remission for over 6 years, while the other is in CR in early follow-up off therapy. Our proposed multimodal strategy apparently meets the aggressive biologic nature of NMC and should be considered for further evaluation in this context potentially in the setting of a clinical trial.

A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma - A final report.

BACKGROUND: The use of chemotherapy to manage newly diagnosed low grade glioma (LGG) was first introduced in the 1980s. One randomised trial has studied two- versus four-drug regimens with a duration of 12 months of treatment after resection. METHODS: Within the European comprehensive treatment strategy for childhood LGG, the International Society of Paediatric Oncology-Low Grade Glioma (SIOP LGG) Committee launched a randomised trial involving 118 institutions and 11 countries to investigate the addition of etoposide (100 mg/m2, days 1, 2 & 3) to a four-course induction of vincristine (1.5 mg/m2 × 10 wkly) and carboplatin (550 mg/m2 q 3 weekly) as part of 18-month continuing treatment programme. Patients were recruited after imaging diagnosis, resection or biopsy with progressive disease/symptoms. Some 497 newly diagnosed patients (M/F 231/266; median age 4.26 years (interquartile range (IQR) 2.02-7.06)) were randomised to receive vincristine carboplatin (VC) (n = 249) or VC plus etoposide (VCE) during induction (n = 248), stratified by age and tumour site. FINDINGS: No differences between the two arms were found in term of survival and radiological response. Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS. 5-year OS for patients in early progression at week 24 were 46% (StDev 13.8) and 49% (StDev 16.5) in the two arms, respectively. INTERPRETATION: The addition of etoposide to VC did not improve PFS or OS. High non-progression rates at 24 weeks justify retaining VC as standard first-line therapy. Infants with diencephalic syndrome and early progression need new treatments to be tested. Future trials should use neurological/visual and toxicity outcomes and be designed to discriminate between the impact on disease outcomes of 'duration of therapy' and 'age at stopping therapy'.

Differential imaging characteristics and dissemination potential of pilomyxoid astrocytomas versus pilocytic astrocytomas.

INTRODUCTION: Pilomyxoid astrocytoma (PMA) is a rare WHO grade II tumor occurring most often in young children. PMA is associated with worse outcome as compared to the pathologically related pilocytic astrocytoma (PA). The radiological differentiation of PMAs from PAs is challenging. Furthermore, it is not completely clarified whether PMA is associated with a higher rate of cerebrospinal fluid (CSF) dissemination in the youngest pediatric population as compared to PA. The aim of our study was firstly to compare imaging features of these tumors and, secondly, to evaluate the occurrence of CSF dissemination. METHODS: The study population included 15 children with PMA and 32 children with PA. The initial MRI and CT scans from the time of the diagnosis were retrospectively analyzed according to standardized criteria and the findings compared between the two tumor types. Furthermore, we also compared the occurrence of imaging evidences of CSF dissemination. RESULTS: PMAs showed less frequently cystic components (p = 0.03) and never had large tumor cysts. Gadolinium enhancement of PMAs was more frequently homogeneous (p = 0.006). PMAs appeared to show more often intratumoral hemorrhages (p = 0.047). Within the subgroup of children <6 years of age, the PMA histology tended to have a larger effect on the occurrence of CSF dissemination than the age (p = 0.05 vs. 0.12). CONCLUSION: Some imaging features like enhancement pattern or presence of cysts or hemorrhage may help differentiating these low-grade gliomas. Our results confirm previous scarce data suggesting a higher rate of CSF dissemination in PMAs, even in the youngest patient population.

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), other WHO grade I (n = 14), pilomyxoid astrocytomas WHO grade II (n = 3), and neuroepithelial tumors WHO grade II (n = 4). RESULTS: One-year EFS was 34.8%. SML-localisation, minor extent of surgery, pilocytic astrocytoma, DLGG and DS were unfavorable predictive factors. No additional non-surgical therapy was applied in 24, 36 were treated with VCR/carboplatin chemotherapy, 6 with radiotherapy (5/6 brachytherapy). Ten-year-PFS-rate following non-surgical therapy was 16.7%; DS and DLGG were unfavorable factors. Ten-year-OS-rate was 72.8%, lower for children <6 months at diagnosis, with DS, or with DLGG. At last follow up in August 2011, vision in 31 living children was often severely impaired. CONCLUSIONS: Children <1 year at diagnosis have a conspicuously impaired survival with current treatment approaches. Age <6 months, diencephalic syndrome and dissemination constitute risk factors for even lower PFS and OS. Treatment adaptations are needed to improve outcome and molecular genetics may explain tumor aggressiveness.

Long-term follow-up of the multicenter, multidisciplinary treatment study HIT-LGG-1996 for low-grade glioma in children and adolescents of the German Speaking Society of Pediatric Oncology and Hematology.

The Hirntumorstudien (HIT)-LGG-1996 protocol offered a comprehensive treatment strategy for pediatric patients with low-grade glioma (LGG), ie, observation, surgery, adjuvant radiotherapy, and chemotherapy to defer the start of irradiation in young children. In this current study, we sought to determine clinical factors for progression and survival. Between October 1, 1996 and March 31, 2004, 1031 patients were prospectively recruited into an observation arm (n = 668) and a nonsurgical arm stratifying 12 months of vincristine-carboplatin chemotherapy (n = 216) and conventional radiotherapy/brachytherapy (n = 147) in an age-dependent manner. Median patient age was 6.9 years; 28 patients had diencephalic syndrome, 44 had dissemination, and 108 had neurofibromatosis type 1(NF-1). Main tumor location was the supratentorial midline (40.4%), and the main histology was pilocytic astrocytoma (67.9%). Following a median observation of 9.3 years, 10-year overall survival (OS) was 0.94 and 10-year event-free survival (EFS) was 0.47. Ten-year progression-free survival was 0.62 following radiotherapy and 0.44 following chemotherapy. Sixty-one of 216 chemotherapy patients received radiotherapy 0.3-8.7 years after initial diagnosis. By multivariate analysis, diencephalic syndrome and incomplete resection were found to be unfavorable factors for OS and EFS, age ≥11 years for OS, and supratentorial midline location for EFS. Dissemination, age <1 year, and nonpilocytic histology were unfavorable factors for progression following radiotherapy (138 patients); and diencephalic syndrome, dissemination, and age ≥11 years were unfavorable factors following chemotherapy (210 patients). NF-1 patients and boys experienced prolonged tumor stabilization with chemotherapy. A nationwide multimodal treatment strategy is feasible for pediatric LGG. Extended follow-up yielded results comparable to single-institution series for the treatment groups. Three-quarters of surviving chemotherapy patients have not yet received radiation therapy. Infants with or without diencephalic syndrome and dissemination bear the highest risk for death and progression following diagnosis or treatment.

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-surgical-treatment. RESULTS: Incidence of dissemination was high among infants (16%) with hypothalamic-chiasmatic-glioma (HCG) and diencephalic syndrome. A relevant percentage of HCG showed isolated spinal dissemination. CT achieved objective and overall response rates of 25% and 79% of the primary tumor and a similar response of disseminated lesions. Clinical stabilization or improvement could be achieved in the majority of patients during treatment. However, 20 of 24 patients experienced further progression and 5-year PFS was 6%. Dissemination prior to CT was a negative prognostic factor for PFS within the study (P = 0.005). Overall-survival of primary DLGG was inferior compared to LGG without dissemination at diagnosis (P < 0.001). CONCLUSION: Complete MRI scan should be a standard diagnostic procedure in young children with hypothalamic-chiasmatic tumors especially if presenting with diencephalic syndrome. Dissemination in childhood LGG relates to impaired PFS. CT delays progression for responders. Multicenter studies have to evaluate the efficacy of extended treatment strategies in DLGG to improve outcome.