bluuebunny/crossref_metadata_2025 huggingface dataset:
RARE-52. RB1 GENE DELETIONS ARE THE NOVEL MECHANISM OF CHOROID PLEXUS TUMORS (CPT) ONCOGENESIS
Authors: Druy Alexander , Yasko Liudmila , Valiakhmetova Andge , Novichkova Galina , Papusha Liudmila
Published: December 2020

BACKGROUND

CPTs are known to be rare TP53-dependent neoplasms, while major molecular alterations underlying tumor progression, especially in TP53-wild type cases, are still unclear.

METHODS

18 primary CPT, including 16 choroid plexus carcinomas (CPC) and two atypical choroid plexus papillomas (CPP), were evaluated for copy number status of 87 major oncogenes and tumor suppressor genes by nCounter Cancer CNV assay by Nanostring and TP53 and RB1 by MLPA. Germline TP53 nucleotide substitutions were analyzed by Sanger sequencing.

RESULTS

Pathogenic germline TP53 variants were present in 4 cases confirming Li-Fraumeni syndrome (LFS). Two patients have somatic TP53 substitutions. Only one patient with LFS harbored somatic TP53 deletion. In 7 patients, heterozygous deletions of RB1 involving from 3 exons to the whole coding sequence detected by MLPA were discovered. All these findings were validated by nCounter CNV assay. Additionally, four patients have WT1 deletions, two patients – BRCA2, and in 1 case - NF1, concomitant with RB1 deletions in 3 cases. Interestingly, in one patient who faced a progression of CPP to CPC germline, RB1 deletion was detected, and in both subsequent tumors, the length of the deleted region progressively increased. Notably, that RB1 deletions are mostly mutually exclusive to TP53 substitutions. 3 of 4 patients with RB1 deletions having follow-up period >1 year faced with tumor-related adverse events.

CONCLUSIONS

Somatic or uncommon germline RB1 heterozygous deletions have been unraveled as a novel mechanism of aggressive CPT and could be implemented in prognosis definition schemes.
RARE-56. PERITONEAL SEEDING OF A DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR IN A CHILD
Authors: Messiaen Julie , Uyttebroeck Anne , Depreitere Bart , Bempt Isabelle Vanden , Sciot Raf , Jacobs Sandra A
Published: December 2020

Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare neoplasms of the central nervous system and have been included in the 2016 update of the WHO classification. This is the first description of a DLGNT disseminating to the peritoneal cavity via a ventriculoperitoneal shunt (VPS) in a child. We describe an 11-year old girl who received a VPS for a Dandy-Walker malformation at the age of seven, and was diagnosed with a spinal pilocytic astrocytoma with leptomeningeal metastases six months later. She received chemotherapy (SIOP-LGG protocol) with partial response, and had progressive disease eight months after therapy cessation. Following a novel biopsy, the diagnosis was revised to a DLGNT, with a KIAA1549-BRAF fusion and loss of 1p. She received vinblastine, but was clinically progressive and craniospinal radiotherapy was initiated. 13 months later, she suddenly presented with ascites. The inferior vena cava was compressed due to the ascites, and an abdominal drain was placed, with massive fluid release. Abdominal MRI indicated an omental cake and peritoneal contrast enhancement. Bone metastases were suspected in the iliac and femoral bones. Anatomopathological examination of the ascites showed an atypical cell population, with irregular, hyperchromatic and enlarged nuclei resembling the primary tumor. The cells were positive for synaptophysin, MAP2 and weakly positive for S100. Pan-NTRK staining was negative. The diagnosis of a metastatic localization of the DLGNT was made, due to seeding of tumoral cells via the VPS. Treatment with a MEK-inhibitor was initiated, but was stopped due to progressive disease and she died 3 weeks later.
RARE-60. PREGNANCIES AFTER CHILDHOOD CRANIOPHARYNGIOMA – RESULTS OF KRANIOPHARYNGEOM 2000/2007
Authors: Sowithayasakul Panjarat , Boekhoff Svenja , Bison Brigitte , Müller Hermann L
Published: December 2020

BACKGROUND

Data on female fertility, pregnancy, and outcome of offspring after childhood-onset craniopharyngioma (CP) are rare.

STUDY DESIGN

Observational study on pregnancy rate and offspring outcome in female CP patients recruited in KRANIOPHARYNGEOM 2000/2007.

RESULTS

A total of 451 CP patients (223 female) have been recruited, and 269 (133 female) were postpubertal at study. Six of 133 female CP patients (4.5%) with median age of 14.9 years at CP diagnosis had 9 pregnancies, giving birth to 10 newborns. Three patients achieved complete surgical resections. No patient underwent postoperative irradiation. Five natural pregnancies occurred in 3 CP patients without pituitary deficiencies. Four pregnancies in 3 CP patients with hypopituitarism were achieved under assisted reproductive techniques (ART) (median 4.5 cycles, range: 3–6 cycles). Median maternal age at pregnancy was 30 years (range: 22–41 years). Six babies (60%) were delivered by caesarean section. Median gestational age at delivery was 38 weeks (range: 34–43 weeks); median birth weight was 2,920 g (range: 2,270– 3,520 g), the rate of preterm delivery was 33%. Enlargements of CP cysts occurred in 2 women during pregnancy. Other complications during pregnancy, delivery, and postnatal period were not observed.

CONCLUSIONS

Pregnancies after CP are rare and were only achieved after ART in patients with hypopituitarism. Close monitoring by an experienced reproductive physician is necessary. Due to a potentially increased risk for cystic enlargement, clinical, ophthalmological, and MRI monitoring are recommended in patients at risk. Perinatal complications, birth defects, and morbidity of mothers and offspring were not observed.
RARE-61. BODY COMPOSITION AND NUCHAL SKINFOLD THICKNESS IN PEDIATRIC BRAIN TUMOR PATIENTS
Authors: Peng Junxiang , Boekhoff Svenja , Eveslage Maria , Bison Brigitte , Sowithayasakul Panjarat , Müller Hermann L
Published: December 2020

BACKGROUND

Obesity, cardiovascular disease (CVD), and relapse/progression have major impact on prognosis in pediatric brain tumor (BT) patients. Cranial MRI is part of routine follow-up.

METHODS

In a cross-sectional study, we analyzed nuchal skinfold thickness (NST) on MRI performed for BT follow-up monitoring as a novel parameter for body composition (BC) and CVD in 177 BT patients (40 WHO grade 1–2 BT; 31 grade 3–4 BT; 106 craniopharyngioma (CP)), and 53 healthy controls (HC). Associations of NST with body mass index (BMI), waist-to-height ratio (WHtR), caliper-measured skinfold thickness (cSFT), and blood pressure (BP) were analysed in BT and HC.

RESULTS

CP patients showed higher BMI, WHtR, NST and cSFT when compared with BT and HC, whereas these differences were not detectable between BT and HC. However, WHO grade 1–2 BT patients were observed with higher BMI, waist circumference and triceps cSFT when compared to WHO grade 3–4 BT patients. NST showed high correlations with BMI, WHtR, and cSFT. NST, BMI and WHtR had predictive value for CVD in terms of increased BP, and in multivariate analysis, only BMI was selected for the final model resulting in an odds ratio of 1.25 (1.14–1.379). In CP patients with hypothalamic involvement/lesion or gross-total resection, rate and degree of obesity were increased.

CONCLUSIONS

As monitoring of MRI and BC play an important role in follow-up after BT, NST could serve as a novel useful parameter for assessment of BC and CVD risk in BT patients.
RONC-06. VOLUMETRIC-MODULATED ARC WHOLE-BRAIN RADIOTHERAPY FOR THE PREVENTION OF PERMANENT ALOPECIA IN PEDIATRIC PATIENTS
Authors: Uto Megumi , Umeda Katsutsugu , Arakawa Yoshiki , Takehana Keiichi , Kamitori Tatsuya , Iwai Atsushi , Kato Itaru , Saida Satoshi , Hiramatsu Hidefumi , Mineharu Yohei , Tanji Masahiro , Takita Junko , Mizowaki Takashi
Published: December 2020

Permanent alopecia is a grave late complication of multi-drug chemotherapy (CTx) plus cranial irradiation, reducing both patient self-esteem and quality of life in pediatric patients. We started to use craniospinal irradiation (CSI) using the volumetric-modulated arc whole-brain radiotherapy (VMAT-WBRT) in order to prevent permanent alopecia. We treated 5 pediatric patients with CSI using VMAT-WBRT, and report the initial clinical outcome. Five consecutive patients (4–11 years old) who received CSI using VMAT-WBRT from June 2015 to November 2018 were included into this study. One patient with embryonic carcinoma received radiotherapy (RT) with concurrent CTx; four patients with medulloblastoma (two patients with standard risk, and two patients with high risk) received RT followed by CTx. The prescribed doses of CSI were 23.4–35.2 Gy in 13–22 fractions, respectively. Optimization for VMAT-WBRT was performed to reduce doses to the hair follicles with keeping the dose coverage to the planning target volume. Although all patients experienced temporary alopecia, their hair fully recovered over the whole scalp within 8 months after finishing RT. One patient had disease progression after 6 months after completing CTx; this patient who was diagnosed as Group 3 subtype had diffuse meningeal dissemination confirmed with contrast enhanced spinal MRI before RT. The other four patients had no evidence of recurrence. Although CSI with VMAT-WBRT might be one of considerable options, more cases are needed to verify the efficacy to prevent permanent alopecia for pediatric patients who receive multi-drug CTx and cranial irradiation.
RONC-15. OUTCOMES OF BRAIN AND SKULL-BASE TUMOURS IN ADOLESCENTS AND YOUNG ADULTS TREATED WITH PENCIL BEAM SCANNING PROTON THERAPY
Authors: Lim Pei Shuen , Tran Sébastien , Kroeze Stephanie G C , Pica Alessia , Hrbacek Jan , Bachtiary Barbara , Walser Marc , Lomax Anthony J , Weber Damien C
Published: December 2020

BACKGROUND

The use of highly conformal proton therapy in adolescents and young adults (AYAs) for management of brain/skull-base tumours is becoming increasingly common. This study aims to assess the long-term clinical outcomes, prognostic factors and employment status of AYAs (15–39 years) treated with pencil-beam-scanning proton-therapy (PT).

METHODS

Between 1997–2018, 176 AYAs were treated with PT at the Paul Scherrer Institute. Median age was 30 years (range, 15–39) and the male/female ratio was 0.8.

RESULTS

After a median follow-up of 66 months (range, 12–236), 24 (13.6%) local failures and 1 (0.6%) distant failure were observed between 6 and 152 months after PT. The most common histologies treated were chordomas/chondrosarcomas (61.4%), followed by meningiomas (14.2%) and gliomas (15.3%). The 6-year local-control (LC), distant-progression-free survival and overall-survival (OS) rate was 83.2%, 97.4% and 90.2% respectively. On univariate analysis, age ≥24 years was a negative prognostic factor for LC. Recurrent disease, infratentorial tumours and low-grade-glioma histology were poor prognostic factors for both LC and OS. The 6-year ≥G3 PT-related late toxicity-free survival was 88.5%. The moderate-high grade late toxicity crude rates were 37.8% G2, 12.2% G3, 0.6% G4 and 0.6% G5. No secondary malignancies were observed. The unemployment rate was 7.3% at PT, rising to 25.3% at survivorship. High-grade(≥G3) toxicity rate in the unemployed vs employed group was 21% vs 8.5%.

CONCLUSION

PT is an effective treatment for AYAs with brain/skull-base tumours with good tumour control and acceptable long-term toxicity. Despite having satisfactory clinical outcomes, around 1 in 4 AYAs surviving brain/skull base tumours are unemployed.
RONC-22. SECOND TUMORS IN PEDIATRIC PATIENTS TREATED WITH PROTON THERAPY TO THE CENTRAL NERVOUS SYSTEM
Authors: Indelicato Daniel J , Bates James , Mailhot-Vega Raymond , Morris Christopher , Sandler Eric , Aldana Phillip , Bradley Julie
Published: December 2020

BACKGROUND

Previous institutional data suggests the 10-year cumulative incidence of second tumors is 3% in children treated with photon radiation for central nervous system (CNS) malignancy, with 90% of these tumors occurring in areas receiving ≤36 Gy. Comparative figures for children treated with proton therapy (PT) does not exist.

METHODS

1056 consecutive pediatric patients with a median follow-up of 5.0 years were treated between 2006–2019 with double-scattered PT to a site within the craniospinal axis. 230 patients were ≤3 years old and 14 had neurofibromatosis. A second tumor was defined as any solid neoplasm with histologic features different from the original tumor that had arisen within the irradiated volume.

RESULTS

Five patients developed second tumors resulting in a 5- and 10-year cumulative incidence of 0.2% (95% CI: 0–1.2%) and 1.6% (95% CI: 0.6%-3.9%), respectively. Of those who developed second tumors, median age at radiation was 4.3 years old (range, 2.1 to 5.1 years old) and diagnoses consisted of medulloblastoma (n=2), ependymoma (n=2), and craniopharyngioma (n=1). The second tumors included high grade gliomas (n=3) and high grade sarcoma (n=1) that occurred in regions receiving at least 54 Gy. One patient with neurofibromatosis developed both a low-grade glioma and choroidal melanoma in craniospinal irradiation regions receiving 36 Gy. Four of five patients with second tumors are alive.

CONCLUSION

The reduction in moderate-to-low dose radiation exposure from proton therapy may be associated with a decreased incidence of second tumors in children treated for CNS neoplasms. More follow-up is needed to confirm these findings.
RONC-24. PROTON THERAPY FOR PEDIATRIC EPENDYMOMA: MATURE OUTCOMES FROM THE UNIVERSITY OF FLORIDA AND MASSACHUSETTS GENERAL HOSPITAL
Authors: Indelicato Daniel J , Ioakeim-Ioannidou Myrsini , Bradley Julie , Mailhot-Vega Raymond , Morris Christopher , Tarbell Nancy , Yock Torunn , MacDonald Shannon
Published: December 2020

OBJECTIVE

Report long-term efficacy and toxicity of proton therapy for pediatric ependymoma.

MATERIALS AND METHODS

Between 2000–2017, 318 children with nonmetastatic grade II/III intracranial ependymoma received proton therapy at Massachusetts General Hospital and the University of Florida. Median age was 3.5 years (range, 0.7–21.3 years); 56% were male. Most (69%) tumors were in the posterior fossa and classified as WHO grade III (64%). Eighty-four percent had a gross total or near total tumor resection before radiotherapy and 30% received chemotherapy. Median radiation dose was 55.8 CGE (range, 50.4–59.4 CGE).

RESULTS

Median follow-up was 6 years (range, 0.6–19.2 years). Seven-year local control, progression-free survival, and overall survival rates were 77.1% (95% CI 71.7–81.7%), 64.4% (95% CI 58.6–69.8%), and 82% (76.9–86.2%), respectively. Subtotal resection was associated with inferior local control (60% vs 80%; p<0.01), progression-free survival (49% vs 67%; p<0.01), and overall survival (69% vs 84%; p<0.05). Male gender was associated with inferior progression-free (59% vs 71%; p<0.01) and overall survival (77% vs 89%; p<0.05). Twenty patients (6.2%) require hearing aids; of these, 12/20 received cisplatin. Grade 3+ brainstem toxicity rate was 1.6% and more common in patients who received >54 CGE. The rate of second malignancy was 0.9%.

CONCLUSION

Proton therapy offers commensurate disease control to modern photon therapy without unexpected toxicity. The high rate of long-term survival justifies efforts to reduce radiation exposure in this young population with brain tumors. Independent of modality, this large series confirms extent of resection as the most important modifiable factor for survival.
RONC-25. A CASE OF PEDIATRIC PONTINE GLIOMA TREATED WITH GAMMA KNIFE SURGERY
Authors: Kaneko Satoshi , Kiyokawa Juri , Hirota Shin , Murota Yasuhiro , Ishikawa Mariko , Yamaoka Hiroto , Yoshimura Masataka , Yamamoto Masaaki , Yamamoto Shinji
Published: December 2020

BACKGROUND

Pediatric brainstem gliomas rarely occur and are a heterogeneous group of diseases, which increases the difficulty of treatment strategy. Here, we present a case of pediatric pontine glioma treated with Gamma Knife surgery (GKS) after open biopsy. CASE DESCRIPTION: An 11-year-old boy presented with diplopia due to the left MLF syndrome. MRI showed a well-circumscribed, protruding tumor with partial gadolinium enhancement in the dorsal pons. An open biopsy was performed via the suprafacial triangle following midline suboccipital approach. Histological examinations revealed high cellularity and mild atypia. Immunohistochemistry demonstrated positive stain for GFAP and Olig2 antibodies, and negative for p53 protein. The Ki67-labeling index was 6.8%. Pyrosequence analysis indicated IDH1/2 wild type (wt), BRAF V600 wt, H3F3A K27 wt, FGFR1 wt, and TERT wt. The final diagnosis was pediatric diffuse astrocytoma, WHO grade II, pons. GKS was performed one month after the biopsy. After transient worsening of the symptom, it disappeared gradually. The tumor is stable for three years with mild shrinkage of the size. DISCUSSION: Gross total resection (GTR) of pediatric low-grade, brainstem gliomas may result in a good prognosis. However, unlike pilocytic astrocytoma, diffuse astrocytoma is not easy to perform GTR without any complications. There are some reports regarding GKS for brainstem gliomas, which prove an increase in progression free survival rate. No marked tumor regression is achieved in our case, but tumor growth is well-controlled so far.

CONCLUSION

GKS after biopsy can be a useful treatment option for pediatric low-grade brainstem gliomas.
RONC-27. PROTON THERAPY REDUCES DOSE TO CRITICAL CENTRAL NERVOUS SYSTEM STRUCTURES IN MEDULLOBLASTOMA: A DOSIMETRIC ANALYSIS OF CHILDREN’S ONCOLOGY GROUP (COG) ACNS0331
Authors: Deek Matthew , Ladra Matthew , Lin Lan , Li Yimei , Han Yuanyuan , Hardy Kristina , Michalski Jeff
Published: December 2020

BACKGROUND

Recently published data demonstrated proton therapy (PRT) significantly reduced cognitive decline relative to photons for pediatric medulloblastoma. These findings imply that reductions in dose to critical CNS structures during the boost phase may account for better outcomes over time. Here, we examine differences in dosimetric data for medulloblastoma patients treated on ACNS0331 with photon (Intensity Modulated Radiation Therapy, 3D-Conformal Radiation Therapy) vs PRT to identify potential structures responsible for cognitive benefit.

METHODS

COG ACNS0331 was a randomized trial examining the impact of reduced craniospinal irradiation (CSI) dose (standard vs low dose, in patients aged 3–7) and volume (whole posterior fossa vs involved field) in pediatric medulloblastoma patients. We identified 136 patients (IMRT=95, 3DCRT=28, Proton=13) enrolled on ACNS0331 with complete radiation and imaging data and re-contoured 10 critical brain structures to calculate dose.

RESULTS

Proton therapy significantly reduced the dose to critical structures. For example, temporal lobe mean dose and V30 were 30Gy/38% (PRT), 40Gy/89% (IMRT), 41Gy/84% (3DCRT)), hippocampi mean dose were 51 Gy (IMRT), 52 Gy (3DCRT), and 44Gy (PRT) and cochlear mean dose were 43 Gy (IMRT), 49 Gy (3DCRT), and 31Gy (PRT). Dose to several other critical structures were also significantly reduced including the whole brain, supratentorium, cerebellum, and pituitary.

CONCLUSIONS

Proton therapy greatly reduces dose to critical CNS structures when compared to IMRT or 3DCRT. Further studies are needed to correlate dose reductions in these structures with improved cognitive outcomes.
SURG-02. INITIAL MANAGEMENT OF HYDROCEPHALUS IN THE PEDIATRIC AND YOUNG-ADULT PATIENTS WITH BRAIN TUMORS; THE EFFICACY OF LONG-TERM INDWELLING EXTERNAL VENTRICULAR DRAINAGE
Authors: Yamaguchi Shigeru , Motegi Hiroaki , Ishi Yukitomo , Okamoto Michinari , Iguchi Akihiro , Cho Yuko , Sugiyama Minako , Manabe Atushi , Houkin Kiyohiro
Published: December 2020

BACKGROUND

Pediatric and Young-Adult (AYA) brain tumors often present with hydrocephalus. As temporary cerebrospinal fluid (CSF) diversion procedure, we perform long-term indwelling external ventricular drainage (EVD) in the case of the management of CSF diversion more than two weeks presumably. The aim of this study is to investigate the initial management for hydrocephalus in pediatric /AYA patients with brain tumor, especially about long-term EVD.

MATERIALS AND METHODS

The patients less than 30 years of age diagnosed with brain tumor between 2005 and 2019 were retrospectively analyzed. Procedures of long-term EVD were similar to that of ventriculoperitoneal shunt (VPS) operation. Using flow-control VPS system, peritoneal catheter passed out of the body at the anterior chest, and distal end of the catheter was connected to standard EVD system.

RESULTS

In total of 345 patients with brain tumor, 109 had hydrocephalus at presentation. Among them, 25 patients (23%) underwent long-term EVD. The main reasons for selecting long-term EVD were to avoid intraperitoneal dissemination (n=13), and to maintain longer period of CSF diversion for the treatment of tumor (n=12). The median of long-term EVD was 38 days (range: 12 – 222 days). Although one case suffered from drainage tube occlusion at 59 days, there were no other complications such as infection or accidental evulsion. Eventually, 3 cases required permanent VPS for persistent hydrocephalus.

CONCLUSION

Long-term EVD is safe and effective option for CSF diversion. This procedure should be taken into consideration if patients have a risk of dissemination and may elude permanent VPS.
SURG-07. CEREBELLAR PEDUNCLE TUMORS IN PEDIATRIC NEUROSURGERY: FEW CITATIONS FOR BEING RARE OR FOR LACK OF AWARENESS
Authors: Sanders Felipe Hada , Matushita Hamilton
Published: December 2020

We present a case-series of 6 pediatric patients, with a follow-up for a minimum of 1 year, with a diagnostic, therapeutic and prognostic description. This type of disease was first mentioned by Professor Tomita in 1986, in a case-series with 4 patients, with few citations in literature, no other case series cited at the literatures. and in our oncology center of excellence it is an entity that draws attention for diverging from intrinsic tumors of the cerebellum, fourth ventricle and trunk. In this way, we created an algorithm approaching these patients and would like to present this associated to honouring the esteemed professor in neurosurgery.
SURG-08. SUPRASELLAR DERMOID CYST IN A PEDIATRIC PATIENT
Authors: Almeida Carlos , Mançano Bruna Minniti , Almeida Gisele Caravina , Eugui Gilda D’Agostino , Cavalcante Carlos Bezerra
Published: December 2020

BACKGROUND

Intracranial dermoid cysts (DC) are rare congenital non-neoplastic lesions that account for 0.04 – 0.6% of all intracranial tumors. They are formed by a fibrous capsule composed of epidermal and dermal derivatives (hair follicles, sebaceous and sweat glands), enclosing a viscous fluid. Intradural DC often arise in the midline and are more common in infratentorial locations. CASE REPORT: A 14-year-old male patient presented with headache, partial motor seizures and behavioral changes. Neurological examination and endocrine workup revealed no abnormalities. Brain magnetic resonance imaging showed a lesion that was 4.4cm x 2.2cm x 4.4cm in size, located at supraselar region, and extended superiorly to the left lateral ventricle and anterolaterally to the left orbitofrontal lobe, associated with hyperintense fat droplets in the right lateral ventricle. We performed a left transventricular microsurgical approach. The tumor capsule was coagulated and opened and a subtotal resection with peacemeal removal of the the lesion was obtained: it had gelatinous consistency, composed of droplets of fat and hair and keratinized scamous epihelium content. A total removal of the DC capsule was not possible due to its firm adherence to optic chiasm and to hypothalamus. Histological examination revealed dermoid cyst.

CONCLUSION

Surgery is the only effective treatment, and its goal should be the radical resection of the lesion to avoid recurrence. Whenever radical resection is not possible, because of the adhesions of the cyst capsule to surrounding tissues, a subtotal resection with piecemeal removal may be a satisfactory option in such cases to avoid high morbidity.
SURG-12. PAEDIATRIC BRAIN TUMOUR SURGERY: HOW CAN WE REPORT OUR SURGICAL OUTCOMES AND OPERATIVE MORBIDITY?
Authors: Foster Mitchell , Hennigan Dawn , Greystone Rebecca , van Baarsen Kirsten , Sunderland Geraint , Millward Christopher , Srinivasan Harishchandra , Ferguson Deborah , Totimeh Teddy , Pizer Barry , Mallucci Conor
Published: December 2020

OBJECTIVE

Our objective was to quantify resection outcomes and operative morbidity in paediatric brain tumour surgery using existing scales, assessing their applicability.

METHODS

We investigated morbidity using the Clavien-Dindo (CD) scale and the Drake classification. All paediatric patients receiving a biopsy or craniotomy for an intracranial tumour in a single tertiary paediatric neurosurgery centre between January 2008 and December 2018 were studied. Complications up to day 30 post op were graded.

RESULTS

There were 459 operations: 92 biopsies and 367 craniotomies comprising 166 infratentorial and 292 supratentorial tumours. Median age was 9 years (56% male). The surgical goal was achieved or exceeded in 94% of cases. Thirty-day mortality was 1.31% with all deaths related to disease and none to surgical complications. The overall CD score was 1 in 10.9% of cases, 2 in 18.9%, 3A in 1.7%, 3B in 11.8%, and 4 in 1.1%. There was no operative morbidity in 54% of cases. Using the Drake classification, meningitis was seen in 3.92% of cases, seizures in 3.92%, neurological deficit (that persisted at 30 days) in 8.5%, CSF leak in 5.01%, wound infection in 1.96%, haemorrhage 1.75 %, shunt infection in 1.53%, shunt block in 0.65%, medical complications in 2.4%, and others in 3.05%.

CONCLUSIONS

This is the largest series presenting morbidity from paediatric brain tumour surgery, and the first to validate the CD scale. Our morbidity on the Drake scale was comparable with other series. There is a need to develop improved tools to quantify morbidity in this high-risk specialty.
SURG-20. DIENCEPHALIC SYNDROME IN PEDIATRIC NEUROSURGERY
Authors: Sanders Felipe Hada , Matushita Hamilton , Azambuja Alessandra , Frasseto Fernando
Published: December 2020

This report details the histories of twelve patients with clinical diencephalic syndrome who collectively demonstrate the variability found in the syndrome with respect to: (1) clinical course, (2) site of the tumor, and (3) ease of obtaining radiologic confirmation of the presence of a tumor. Timely diagnosis of diencephalic syndrome is not often the case for patients presenting with failure to thrive (FTT) because of its rarity and lack of specific symptoms. These cases illustrate the importance of cranial imaging and consideration of diencephalic syndrome for children presenting with FTT despite normal or increased caloric intake.
SURG-21. ENDO- AND EXOSCOPIC SURGERY FOR PEDIATRIC NEUROSURGICAL OPERATION
Authors: Kurozumi Kazuhiko , Kameda Masahiro , Fujii Kentarou , Shimazu Yosuke , Yasuhara Takao , Date Isao
Published: December 2020

INTRODUCTION

Recently endo- and exoscopic surgeries have been gradually performed in neurosurgery. To improve the accuracy and safety of our endoscopic procedures, we are currently trialing 4K or 8K systems. Here we report our experience of endo- and exoscopic procedures for pediatric neurosurgery.

METHODS

We retrospectively identified 22 patients (15 males, 7 females; mean age, 9.2 years) who underwent surgery for sellar lesions and intraventricular or intraparenchymal lesions with an endo- or exoscopic procedure at our institute between 2010 and 2020. We used a full HD endoscope system (Storz) and an organic electroluminescence (EL) monitor (Sony), and a 4K system (Sony and Olympus). VITOM 3D (Storz) was used as the exoscope. Videoscope (Olympus) was used as a flexible scope for intraventricular tumors.

RESULTS

We performed surgical procedures as 11 biopsies, 6 third ventriculostomies, 5 resections, and 3 fenestrations. The full HD system with organic EL monitor presented high color contrast. We could easily distinguish between tumor microstructure and the normal structure with the 4K system comparing to full HD. Moreover, electronic zoom function enabled us to discriminate tumor boundaries without having to move the endoscope closer. As a result, we could delineate the surgical working space. VITOM 3D was simple to sharpen the focus on the wider surgical field, similar to the application of an operating microscope.

CONCLUSION

In pediatric neurosurgery, an endo- or exoscope enables clear visual recognition of a boundary between tumor and normal area.
TBIO-03. THE GIFT FROM A CHILD PROGRAM IS EMPOWERING POST-MORTEM TISSUE DONATION ACROSS THE UNITED STATES
Authors: Waanders Angela , Williams Melissa , Wadwhani Nitin , Li Xiao-Nan , Goldman Stewart , Tran-Du Kella , Minturn Jane , Mason Jennifer , Santi Mariarita , Viaene Angela , Koptyra Mateusz , Monje-Deisseroth Michelle , Nazarian Javad , Kambhampati Madhuri , Eze Augustine , Souweidane Mark , Lyons Nicole , McLean Ginny , Gustafson Patti , Gustafson Allen
Published: December 2020

The Gift from a Child (GFAC) program was inspired by the dream of one child to donate his brain for research, recognizing the need to study tumor tissue collected at diagnosis, recurrence, and at the time of death. Founded by the Swifty Foundation in 2016, GFAC currently is comprised of five “Centers of Excellence” at institutions with expertise in pediatric neuro-oncology. Partnering with the Children’s Brain Tumor Network, the program’s mandate is twofold: make it possible for families to donate no matter where they live in the United States and make tissue available to scientists globally to empower discovery. In order to overcome barriers that have stifled postmortem collection in the past, GFAC has invested in Tissue Navigators - individuals at each center who coordinate all aspects of donation and communicate with families, medical providers, and laboratory scientists. In 2019 alone, GFAC coordinated 55 autopsy collections from multiple diagnosis. A key metric of the program is also capturing the global sharing and usage of each tissue sample, ensuring that tissue isn’t simply “banked” but is actively being actively used to help unravel tumor biology. To date, tissue has been used for genomic and molecular data generation, preclinical model development including cell lines and PDX models, and for novel drug screening. Together with Children’s Brain Tumor Network, the Gift from a Child program is helping to ensure the most precious gift that a family can make is used to accelerate the path to cures.
TBIO-05. GENOME-SCALE NUCLEOTIDE-SPECIFIC CHARACTERIZATION OF 5-HYDROXYMETHYLCYTOSINE IN PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Azizgolshani Nasim , Petersen Curtis L , Salas Lucas , Chen Youdinghuan , Perreard Laurent , Nguyen Lananh N , Christensen Brock C
Published: December 2020

Though aberrant cytosine modifications are prevalent in cancer, nucleotide-specific 5-hydroxymethylcytosine (5hmC) modifications remain understudied, including in pediatric CNS tumors. Brain 5-hydroxymethylation is linked with development and differentiation. We measured genome-scale nucleotide-specific 5hmC in patients with diagnoses of glioma, ependymoma, and embryonal tumors under age 18 (n=36), and in non-tumor pediatric brain tissues (n=3). DNA was processed with tandem oxidative (OxBS) and bisulfite (BS) treatments followed by hybridization to the Illumina Methylation EPIC Array that interrogates over 860,000 CpG sites. We used the OxyBS R package to determine levels of 5hmC and 5mC. Mean 5hmC levels were lower in tumors (gliomas 4.1%, ependymomas 3.9%, and embryonal tumors 3.4%) compared to nontumor tissues (5.3%). We subset to the CpGs with the 5% highest 5hmC content for downstream analyses (37,173 CpGs). These sites were enriched among regulatory elements, including TFBS (Odds Ratio 1.14 p-value 3.57E-20) and super-enhancers (OR 1.93, p-value 1.14E-126). Linear mixed-effects models adjusted for age, sex, and cell type proportions tested the CpG-specific differences in 5hmC between tumor and nontumor samples, as well as between tumor subtypes. 5hmC levels were depleted across tumors compared with nontumor brain tissues, including at CpG islands. Model-based clustering (RPMM) results indicated that patients with low 5hmC patterns have poorer overall survival and increased risk of recurrence. Our results indicate that 5hmC localizes to sites in the DNA critical to gene regulation and is associated with patient outcomes. This study offers an opportunity to potentially contribute to classification markers for childhood brain tumors.
TBIO-12. THE SPECTRUM OF MITOCHONDRIAl DNA (mtDNA) MUTATIONS IN PEDIATRIC CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Kaneva Kristiyana , Triska Petr , Merkurjev Daria , Bootwalla Moiz , Cotter Jennifer , Ostrow Dejerianne , O’Halloran Katrina , Biegel Jaclyn , Gai Xiaowu
Published: December 2020

To explore the role of mitochondrial DNA mutations in pediatric CNS tumors, we analyzed 749 tumor-normal paired whole genome sequencing data sets from the Children’s Brain Tumor Tissue Consortium (CBTTC). We detected 307 somatic mtDNA mutations in 222 CNS tumors (29.6%). Most frequently observed were missense mutations (38.1%). We also detected 34 loss-of-function mutations. Different pediatric CNS tumor subtypes have distinct mtDNA mutation profiles. For categorical comparisons, we analyzed subtypes with at least 15 samples. The highest number of mtDNA mutations per tumor sample was in meningiomas (0.85), while atypical teratoid rhabdoid tumors (ATRTs) had the lowest number per sample (0.18). High-grade gliomas had a higher number of mtDNA mutations per sample than low-grade gliomas (0.56 vs. 0.31) (p = 0.0011), with almost twice as many missense mtDNA mutations per sample (0.22 vs. 0.13) (p < 0.001), and higher average heteroplasmy levels (11% vs. 9%). The average heteroplasmy was 10.1%, ranging from 15.6% in medulloblastoma to 6.36% in schwannoma suggesting that these are clonal alterations and not artifacts. Intriguingly, the two chordoma patients in the CBTTC database had an identical heteroplasmic m.10971G>A MT-ND4 nonsense mutation. Similarly, our patient with recurrent gliofibroma harbored the same somatic MT-ND4 synonymous variant (m.10700A>G) detected at 53% heteroplasmy in the initial tumor, 79% in the first recurrence, and 97% in the second recurrence. Although the functional consequences of these alterations are not yet understood, our findings suggest that sequencing the mtDNA genome may be used to characterize CNS tumors at diagnosis and monitor disease progression.
TBIO-13. USE OF NEXT GENERATION SEQUENCING TO IDENTIFY MOVE DRIVERS OF CRYPTIC, CLINICALLY AGGRESSIVE BRAIN TUMORS
Authors: Younes Subhi Talal , Boudreaux Amanda , Weaver Kristin , Karlson Cynthia , Herrington Betty
Published: December 2020

INTRODUCTION

Next generation sequencing (NGS) is an emerging technology which allows for in-depth analysis of pediatric brain tumors. NGS has particular use in the context of ambiguous or aggressive neoplasms, where it can be leveraged to discover novel drivers, inform pathologic classification, and direct targeted therapies.

OBJECTIVE

The objective of this case series was to utilize NGS technology to illuminate the biology of aggressive brain tumors with ambiguous pathologic features and clinically aggressive behavior.

METHODS

FFPE tumor tissue and matched germline DNA were subjected to whole exome sequencing (WES). Data were analyzed according to the GATK pipeline.

RESULTS

The first case is a 6-year-old male who presented with innumerable foci of leptomeningeal nodules throughout the neuroaxis. Original pathology was CNS embryonal tumor. WES identified loss of chromosome 1p and 16q with gain of 1q and amplification of MYC and OTX2 loci (cytogenetic aberrations characteristic of group 3 medulloblastoma) and a deleterious mutation in BCL7B, a known tumor suppressor gene. The second case is a 2-year-old female who presented with a parietal lobe mass diagnosed as high grade neuroepithelial tumor with C11orf95 translocation, but no RELA fusion. WES revealed loss of small region of chromosome 2p and mutations in IDH3G, TRAF2, and JMJD1C, suggesting novel targets for further study.

CONCLUSIONS

In both cases, NGS studies were able to shed light on the underlying tumor biology and/or refine the pathologic diagnosis. These data underscore the utility of applying NGS technology to study the biology of pediatric brain tumors.
TBIO-14. CHARACTERISATION OF THE ARGININE PATHWAY ENZYMES IN PAEDIATRIC BRAIN TUMOURS TO DETERMINE SUSCEPTIBILITY TO THERAPEUTIC ARGININE DEPLETION
Authors: Bishop Eleanor , Dimitrova Monika , Storer Lisa , Grundy Richard , Dandapani Madhumita
Published: December 2020

INTRODUCTION

Extracellular arginine dependency (auxotrophy) is increasingly being recognised in several tumours. This is due to the inability of cancer cells to recycle or synthesise intracellular arginine through the urea cycle pathway compared to normal cells. Whilst adult glioblastoma is known to exhibit this, the expression of the arginine pathway enzymes has not been delineated in paediatric brain tumours.

METHODS

We used immunohistochemical methods to stain for arginine pathway enzymes in Paediatric High grade glioma (pHGG), low grade glioma (pLGG) and medulloblastoma (MB) tumour tissue microarrays (TMAs). The antibodies detected protein expression of the metaboliser Arginase (Arg2), recycling enzymes ornithine transcarbamoylase (OTC), Arginosuccinate synthetase (ASS1) and arginosuccinate lyase (ASL) as well as the transporter SLC7A1.

RESULTS

Deficiency of OTC, ASS1 and ASL were seen in 92%, 98% and 93% of pHGG samples (n=156) respectively, with deficiency defined as low (<20%) or negative antibody expression. Identical results were seen in pLGG (n=98) - 83%, 97% and 95% were deficient in OTC, ASS1 and ASL. Both pHGG and pLGG highly expressed SLC7A1 and Arg2, demonstrating that they could transport and utilise arginine. In MB (n=82), this auxotrophic signature was again seen in 90% of TMAs with absent or low expression of OTC, ASS1 and ASL and high Arg2 and SLC7A1 expression.

CONCLUSIONS

These results show that pHGG, pLGG and MB are arginine auxotrophs. Pegylated arginase (BCT-100) is currently in Phase I/II trials in relapsed pHGG. Our results suggest that therapeutic arginine depletion may also be useful in MB and pLGG.
TBIO-15. MODELING DEVELOPMENTAL GENE EXPRESSION DYNAMICS AT CELLULAR RESOLUTION TO INTERPRET PEDIATRIC BRAIN TUMOR TRANSCRIPTIONAL PROGRAMS
Authors: Jessa Selin , Kabir Nisha , Vladoiu Maria , Hébert Steven , Taylor Michael D , Jabado Nada , Kleinman Claudia L
Published: December 2020

A central challenge in understanding the biology of pediatric brain tumors is defining the cellular and molecular context where oncogenesis occurs. We hypothesize that spatiotemporally restricted cell types are uniquely susceptible to specific genetic alterations, which alter normal neurodevelopmental programs and ultimately lead to oncogenesis. The resulting tumors retain some transcriptomic features of their lineage of origin. To delineate these origins, we assembled a densely sampled developmental time course of the mouse forebrain and pons, doubling our recently published single-cell atlas. This dataset comprises >100,000 cells at 9 timepoints from E10-P6. However, while single cell transcriptomics reveal rich gene dynamics during cell differentiation, interpretation of individual genes can be challenging due to data sparsity. Leveraging this time-series, we present strategies to model and visualize the expression of a given gene across differentiation of distinct lineages. We demonstrate an interactive web app to interrogate the expression of genes or gene sets during brain development, extract temporally correlated genes, and search active transcription factor regulatory modules. Finally, we profile the expression of core transcriptional programs of several pediatric brain tumor entities during development. Our analyses reveal genes with restricted expression patterns that elucidate tumor etiology. More broadly, these resources harness single cell data to enable exploration of neurodevelopmental gene programs with great relevance to pediatric brain tumor oncogenesis.
TBIO-16. NOTCH1 PATHWAY AS TARGET FOR DRUG INTERVENTION FOR HISTONE 3 G34R MUTATED pHGG
Authors: Foot Katie , Lourdusamy Anbarasu , Christou Sofia , Rahman Ruman , Layfield Robert , Grundy Richard , Haque Farhana
Published: December 2020

There have been no significant improvements in the treatments for childhood High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), which continue to have a very poor prognosis. These cancers harbor mutations affecting histone 3 (H3) proteins; 80% of DIPGs with histone H3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. We have generated and validated a histone 3.3 G34R mutant-specific antibody and investigated the downstream effects of H3.3 G34R mutations in pHGG. In order to identify the genes that may be deregulated by G34R mutant histone expression, we have performed chromatin immunoprecipitation (ChIP) assays with our H3.3 G34R and wild type H3 antibodies, using pHGG H3 G34R mutant and wild-type cell lines. Initial analyses of ChIP data have implicated deregulation of cell-signaling pathways including Notch1, Hedgehog, PPAR-1, PLC-beta and Androgen, in H3 G34R mutated pHGG. We are currently determining the effects of altered expression of Notch1 pathway components on tumorigenesis of H3 G34R mutated pHGG, through gene and protein expression and inhibition assays. Specifically we find that the Notch1 pathway component HES1 shows increased expression in G34R mutant cells compared to controls, directing our evaluation of the utility of gamma-secretase inhibitors as potential therapeutics. These analyses may underpin development of novel treatment strategies for H3 mutated pHGG.
TBIO-18. ESTABLISHING A PIPELINE FOR INDIVIDUALIZED TREATMENT OPTIONS FOR PEDIATRIC BRAIN CANCER
Authors: Djirackor Luna , Halldorsson Skarphedinn , Sandberg Cecilie , Euskirchen Philipp , Skaga Erlend , Kulesskiy Evgeny , Wennerberg Krister , Langmoen Iver , Vik-Mo Einar
Published: December 2020

INTRODUCTION

Despite being able to characterize pediatric brain tumors such as medulloblastoma and high-grade gliomas using detailed molecular analysis tools, this knowledge hasn’t been translated to better treatment methods. In this project, we aim to create a biobank of pediatric brain tumors (PBTs), characterize samples using next generation molecular diagnostics and identify patient specific drug-treatment options using high-throughput drug screening (HTDS).

METHODS

To establish tumor spheres from biopsies, we mechanically dissociated the tissue and digested it in trypsin. The cells isolated were cultured in serum free DMEM medium. Immunocytochemistry analysis was done to compare the spheres and original tumor. After the second passage, DNA was extracted and subjected to low-pass whole genome nanopore sequencing. HTDS with a library of FDA/EMA-approved anticancer drugs and investigational compounds was also performed.

RESULTS

We’ve established tumor sphere cultures that grew to passage two and onwards from five juvenile pilocytic astrocytomas, two gangliogliomas and two midline gliomas. The spheres expressed markers of stem cells (Nestin), neurons (β3-tubulin) and glial (GFAP), similar to the original tumor. Copy number profiling and methylation-based classification of the spheres showed the same alterations and classification as the biopsy. HTDS revealed significant differences in drug sensitivity including patient-specific vulnerabilities to anticancer drugs.

CONCLUSION

We’ve created a protocol to generate tumor spheres from PBTs. We are also building a biobank comprising high and low grade PBTs. Our tumor spheres maintain the characteristics of the original tumor and can be used for further downstream analysis including drug screening.
Can Photons Pass through Primary Coatings Used to Treat Cutaneous Wounds?
Authors: Barbosa da Silva Stefania , Salani Renata , de Cássia Ferreira Rita , Gazote Eloy Geraldo Yhago , Pavani Christiane , Setúbal Destro Rodrigues Maria Fernanda , Motta Lara J. , Fátima Teixeira Silva Daniela
Published: December 2020

OBJECTIVE

To determine the transmittance spectrum of primary dressings commonly used in the treatment of cutaneous wounds to verify if there is a real need to remove them during photobiomodulation.

METHODS

Spectroscopic analysis was performed on 17 dressings using a spectrophotometer (USB 2000+; OceanOptics, Delray Beach, Florida). A piece of each dressing was inserted into a quartz cuvette; the reflection from the slide walls was corrected for using a 0.9% saline solution to completely fill the cuvette (baseline). The transmittance of each dressing was measured between 350 and 950 nm, and a transmittance table was created based on the main wavelengths used in photobiomodulation.

RESULTS

Six dressings (Supriderme, Membracel, Cuticell Contact, UrgoTul, Tegaderm, and Opsite Flexigrid) have a transmittance greater than 50% in most of the spectral range and therefore may remain on wounds during irradiation.

CONCLUSIONS

It may not always be necessary to remove a primary dressing when lasers or LED lights are used to treat wounds. It is the authors’ hope that the results of this article will increase the effectiveness of both photobiomodulation and primary dressings and reduce patient discomfort as well as the cost of primary dressings via a reduction in unnecessary dressing changes.
The Adjunct Use of Platelet-Rich Plasma in Split-Thickness Skin Grafts: A Systematic Review
Authors: Dunn Austin , Long Tyler , Kleinfelder Raymond E. , Zarraga Matthew Belisario
Published: December 2020

OBJECTIVE

To summarize the available literature on platelet-rich plasma (PRP) as an adjunct to split-thickness skin graft (STSG) in an organized and easy-to-read format. These data may encourage surgeons to integrate PRP into their skin graft protocol.

DATA SOURCES

The authors conducted a systematic search using the PubMed, Cochrane, and ClinicalTrials.gov databases for articles published from their respective inceptions to October 1, 2019, to identify relevant studies.

STUDY SELECTION

A total of 629 articles were reviewed, and 5 were identified for inclusion in this study. The population of all studies was patients receiving an STSG to close a skin defect.

DATA EXTRACTION

Articles were screened for the following outcome measures: graft take rates, edema or hematoma formation, instant adhesion of graft, healing time, length of hospital stay, scar hypertrophy, and frequency of dressing changes.

DATA SYNTHESIS

The data were organized into two tables describing the studies and the selected outcome measures.

CONCLUSIONS

The data suggest that PRP in STSG reduces healing time, length of hospital stay, and scarring and that it eliminates the need for sutures/staples. Further, these benefits may correlate with a decrease in overall expenditure. This systematic review suggests that further research on PRP and skin grafts is warranted.