Depression, anxiety and health-related quality of life in paediatric intracranial germ cell tumor survivors

Background Little is known about depression and anxiety among paediatric intracranial germ cell tumour (iGCT) survivors. We aimed to evaluate the risk factors associated with depression, anxiety and health-related quality of life (HRQoL) in paediatric iGCT survivors. Methods We recruited 200 iGCT patients (and their parents) from Beijing Tiantan Hospital and assessed their HRQoL using the Paediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales. The Children’s Depression Inventory, Screen for Child Anxiety Related Emotional Disorders, and Symptom Checklist 90 were used to evaluate depression and anxiety. The results were analysed based on disease recurrence, tumour location and treatment strategies. Results Survivors with recurrent tumours had worse HRQoL scores than those with non-recurrent tumours. Patients with tumours involving both the suprasellar and basal ganglia regions had the worst HRQoL scores. A large proportion of survivors had depression or anxiety. Both depression and anxiety scores were highly correlated with the HRQoL emotional functioning scores. The parent proxy-reports (PPR) and child self-reports were highly correlated in all domains. Conclusions This study demonstrated the clinical factors affecting paediatric iGCT survivors’ depression, anxiety, and HRQoL. Therefore, psychological interventions should be implemented. It also suggests that the PedsQL PPR would be helpful for routine screening.

A pragmatic diagnostic approach to primary intracranial germ cell tumors and their treatment outcomes

Background: Primary intracranial germ cell tumors (ICGCT) are often diagnosed with tumor markers and imaging, which may avoid the need for a biopsy. An intracranial germ cell tumor with mild elevation of markers is seldom stratified as a distinct entity. Methods: Fifty-nine patients were stratified into three groups: pure germinoma (PG), secreting germinoma (SG) and non-germinomatous germ cell tumors (NGGCTs). Results: At 5 years, progression-free survival and overall survival of the three groups (PG vs SG vs NGGCT) were 91% versus 81% versus 59%, and 100% versus 82% versus 68%, respectively. There was no statistically significant difference in outcome among histologically and clinically diagnosed germinomas. Conclusion: A criterion for clinical diagnosis when a biopsy is not feasible is elucidated, and comparable outcomes were demonstrated with histologically diagnosed germinomas.

Reduced radiotherapy by combining chemotherapy with intrathecal administration of methotrexate for pediatric patients with intracranial germ cell tumor

Background: Treatment of intracranial germ cell tumors (GCTs) involves radiation therapy to the whole ventricle or the whole neuroaxis, but late sequelae are a concern. Therefore, an alternative modality is needed to reduce the overreliance on radiation therapy. Intrathecal methotrexate (IT-MTX) was examined as a partial alternative to radiotherapy. Procedure: Low-risk (LR) patients (germinoma) were treated with four cycles of cisplatin, etoposide, and IT-MTX, while intermediate-risk (IR) (human chorionic gonadotropin [HCG]-producing germinoma) and high-risk (HR) (non-germinomatous GCT) patients were treated with five cycles of cisplatin, etoposide, cyclophosphamide, and IT-MTX. Local irradiation of 24 Gy was performed for the LR and IR patients, while irradiation with 51.2 Gy was performed for the HR cases. For patients with multifocal diseases and/or tumors extending to the 3rd ventricle, whole ventricle irradiation was performed. Results: A total of 57 patients were enrolled, of which three withdrew consent. Thus, 54 patients were included in the outcome analysis. The 5-year progression-free survival and overall survival were 92.0% (standard error 4.4%) and 100%, respectively, for 28 LR and 10 IR patients (median follow-up: 63 months), and 86.7% (8.8%) and 93.3% (6.4%) (median follow-up: 67 months), respectively, for 16 HR patients. The major toxicity was hematological, and most patients experienced grade 4. Conclusion: The toxicity of chemotherapy containing IT-MTX was limited, and the results suggested that this regimen could reduce the need for radiotherapy.

Brain Microstructural Changes Associated With Neurocognitive Outcome in Intracranial Germ Cell Tumor Survivors

BackgroundChildhood intracranial germ cell tumor (GCT) survivors are prone to radiotherapy-related neurotoxicity, which can lead to neurocognitive dysfunctions. Diffusion kurtosis imaging (DKI) is a diffusion MRI technique that is sensitive to brain microstructural changes. This study aimed to investigate the association between DKI metrics versus cognitive and functional outcomes of childhood intracranial GCT survivors.MethodsDKI was performed on childhood intracranial GCT survivors (n = 20) who had received cranial radiotherapy, and age and gender-matched healthy control subjects (n = 14). Neurocognitive assessment was performed using the Hong Kong Wechsler Intelligence Scales, and functional assessment was performed using the Lansky/Karnofsky performance scales (KPS). Survivors and healthy controls were compared using mixed effects model. Multiple regression analyses were performed to determine the effects of microstructural brain changes of the whole brain as well as the association between IQ and Karnofsky scores and the thereof.ResultsThe mean Intelligence Quotient (IQ) of GCT survivors was 91.7 (95% CI 84.5 – 98.8), which was below the age-specific normative expected mean IQ (P = 0.013). The mean KPS score of GCT survivors was 85.5, which was significantly lower than that of controls (P < 0.001). Cognitive impairments were significantly associated with the presence of microstructural changes in white and grey matter, whereas functional impairments were mostly associated with microstructural changes in white matter. There were significant correlations between IQ versus the mean diffusivity (MD) and mean kurtosis (MK) of specific white matter regions. The IQ scores were negatively correlated with the MD of extensive grey matter regions.ConclusionOur study identified vulnerable brain regions whose microstructural changes in white and grey matter were significantly associated with impaired cognitive and physical functioning in survivors of pediatric intracranial GCT.

Intracranial Germ Cells Tumour: a single institution experience in Argentina

Background: Intracranial germ cell tumor (iGCT) represents a rare and heterogeneous group, with variable incidence and diverse treatment strategies. Although multiagent chemotherapy with reduced radiotherapy strategy has been applied by several cooperative groups in North America and Western Europe, there is a paucity of data to understand if this combined regimen issuitable in low-middle income countries (LMIC).Methods: We evaluate the outcome in a cohort of iGCT treated by SIOP-CNS-GCT-96 strategy at Hospital J.P Garrahan in Argentinaover the last 20 years. Radiation field and dose included focal radiotherapy (FRT) before 2009 or focal radiotherapy plus whole ventricular radiotherapy (WVRT) after 2009 for localized germinoma and FRT or FRT plus WVRT or CSI for non germinomatous germ cell tumors (NGGCT)Results: Sixty iGCT were identified; 39 germinoma and 21 NGGCT. Median follow-up was 6.57 years (range 0.13-20.5). Five-year PFS and OS were 83.5% (95% CI [165.53 - 223.2]) and 88.7% (95% CI [169.84 - 223.2]) for the germinoma group, while for the NGGCT group were 75% (95% CI [133.27 – 219.96]) and 64.2% (95% CI [107.38 – 201.81]) respectively. The localized germinoma group showed poor results between 2000-2009 with 5-year PFS and OS of 69% and 75% respectively, and an excellent outcome between 2010-2019 with a 5-years PFS and OS of 92.8% and 100%. A univariable analysis identified this difference in survival as related to the field of radiotherapy, specifically whole ventricular radiotherapy. FRT increased the risk of recurrence in localized germinoma, involving not only ventricular relapses; but spinal cord and disseminated disease as well. There were no relapses of localized NGGCT after FRT and FRT plus WVRT.Conclusion: Herein we demonstrate that intensive chemotherapy followed by FRT plus WVRT for germinoma is a feasible and effective strategy, warranting further study in the developing world.

GCT-08. PROTON BEAM RADIOTHERAPY FOR PEDIATRIC AND YOUNG-ADULT PATIENTS WITH INTRACRANIAL GERM CELL TUMOR

BACKGROUND To reduce treatment-related adverse events in pediatric and young-adult patients with brain tumors, proton beam radiotherapy (PBT) has recently been performed instead of conventional X-ray radiotherapy. However, whether PBT is as effective as X-ray radiotherapy has not been sufficiently investigated, especially in patients receiving whole-ventricular irradiation. METHODS We report a retrospective observation of 15 patients with intracranial germ cell tumors (GCT), who received PBT at our institution from April 2014 to September 2019. We evaluated their clinical course, short-term adverse events, and prognosis. RESULTS/ CONCLUSION Fifteen patients (9 males and 6 females; median age 13 years) who received PBT following induction chemotherapy were analyzed. Nine patients received 23.4–27.0 GyE of whole-ventricular irradiation due to GCT in the pituitary gland, pineal body, or hypothalamic area. Three patients received 23.4 GyE of whole-brain irradiation: one of them had boost irradiation for basal ganglia. Three patients received 30.6 GyE of craniospinal irradiation (CSI). Six of the 15 patients experienced nausea (grade 2, according to the CTCAE version 4.0). Four patients, including two who received CSI, showed myelosuppression: decrease in white blood cell count, lymphocyte cell count, and neutrophil count (grade 3). No other severe short-term adverse events of >grade 2 was observed in any of the patients. At a median follow-up of 21 months (2-62 months) after irradiation. all patients are alive without recurrence. Our results may be encouraging and further investigations with a larger scale is warranted.

GCT-15. INTEGRATED CLINICAL, HISTOPATHOLOGICAL, AND MOLECULAR DATA ANALYSIS OF 190 CENTRAL NERVOUS SYSTEM GERM CELL TUMORS FROM THE IGCT CONSORTIUM

BACKGROUND We integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management. METHODS Data from the Intracranial Germ Cell Tumor Genome Analysis Consortium were reviewed. A total of 190 cases were classified as primary GCTs based on central pathological reviews. RESULTS All but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker-positive and 6.1% of non-germinomatous GCTs were marker-negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better PFS than those at atypical sites (p=0.03). A molecular-clinical association study revealed frequent MAPK pathway mutations in males (51.4 vs 14.3 %, p=0.007), and PI3K/mTOR pathway mutations in basal ganglia cases (p=0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance. CONCLUSIONS These in-depth findings of this study regarding the clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.

GCT-17. WHAT IS THE CLINICAL OUTCOME OF PROTON BEAM THERAPY FOR PATIENTS WITH INTRACRANIAL GERM CELL TUMOR IN KOREA?

PURPOSE To evaluate the clinical outcome of patients with intracranial germ cell tumor treated with proton beam therapy (PBT). MATERIALS AND METHODS Fifty-seven patients with intracranial germ cell tumor treated with PBT between 2009 and 2016 were retrospectively analyzed. RESULTS Median follow-up duration was 63.7 months (range, 5.6–204.5). Thirty-seven patients (64.9%) were pure germinoma and 20 patients (35.1%) were non-germinomatous germ cell tumor (NGGCT). All patients except 2 patients received chemotherapy before PBT. Twenty-one patients (36.8%) of localized germinoma were treated with whole ventricle irradiation (WVI), while 36 (63.2%) patients who were diagnosed as disseminated germinoma or NGGCT received cranio-spinal irradiation (CSI). Two patients with pure germinoma in basal ganglia showed disease relapse at 3.0 and 6.9 years after PBT at the primary site and pituitary gland, respectively. There was one patient with NGGCT who died of chemotherapy-related mortality at 4.7 years after PBT while her disease was complete remission. The 7-year progression-free survival and overall survival were 70.8% and 100% for focal germinoma, 100% and 100% for disseminated germinoma, 100% and 100% for focal NGGCTs, and 100% and 80.0% for disseminated NGGCTs, respectively. CONCLUSIONS PBT of pure germinoma resulted in comparable clinical outcomes to that with photon radiotherapy. Our result for NGGCT is also excellent compared to other reports. Failure patterns of germ cell tumors originating in basal ganglia needs to be assessed in large pooled data.

GCT-34. ELUCIDATION OF THE MECHANISMS OF TUMORIGENESIS IN INTRACRANIAL GERM CELL TUMOR BY WHOLE GENOME SEQUENCE

Intracranial germ cell tumors (iGCT) are heterogenous group of primary brain tumors that consist of various subtype, and driver genetic alterations in iGCTs remain largely unknown. We have previously reported in a study of whole exome sequence that iGCTs frequently harbored mutations in the KIT gene and its downstream MAPK/PI3K pathway, regardless of tumor subtype. However, no mutations were detected in about one-quarter of germinomas and half of non-germinomatous germ cell tumors. A genome-wide methylation profiling revealed that only germinomas exhibited extreme DNA hypomethylation among iGCTs. Moreover, in mixed iGCT tumors which contained more than one tumor subtypes, each component exhibited distinct methylation status depending on the subtype, while they shared the same mutations. These data suggested that not only mutations in the coding region as previously reported, but also genetic alterations in regulatory regions including promoters and enhancers as well as non-coding RNA genes may be involved in the tumorigenesis of iGCTs. In order to comprehensively search for driver gene alterations, we performed whole genome sequence in 18 paired tumor blood samples from iGCT tumors (16germinomas and two yolk sac tumors (YST)) registered in the Intracranial Germ Cell Tumor Genome Analysis Consortium. In a preliminary analysis of four cases, YSTs harbored a significantly higher number of structural abnormalities, compared with germinomas. Of note, 62 structural abnormalities were clustered within the small genomic region of 95Mb at 1q21-44 in one YST case, suggesting a possibility of chromothripsis. A full analysis of somatic alterations is underway and will be reported.