bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of plasma-activated water forEscherichia colidecontamination and shelf-life extension of kale
Authors: Wang Hexiang , Li Yingxia , Xi Qian , Han Rongwei , Cullen Patrick J , Du Qijing , Yang Yongxin , Forghani Fereidoun , Zhang Jiacheng , Wang Jun
Published: June 2022

The aim of this study was to examine the effectiveness of plasma-activated water (PAW) for inactivating Escherichia coli (E. coli) and retention of key quality factors for kale. Different plasma discharge times (1, 2, 3, 4, 5, and 10 min) and different exposure times (2, 4, 6, 8, 10, and 15 min) were used to investigate the inactivation effect of E. coli spot-inoculated on kale. The influence of different exposure times on the pH, hardness and color of kale was studied post-treatment. In addition, the effects of PAW on the shelf-life of kale over 12 d of storage at 4 °C were investigated. The results showed that after the treatment of 5-PAW-8 (8 min treatment by PAW generated by 5 min plasma discharge), the population of E. coli on kale was reduced by approximately 1.55 log colony-forming units (CFU)/g and the changes in pH, hardness and color of kale were not significant (P>0.05). During the storage period after 5-PAW-8 treatment, the hardness, weight loss, color, surface morphology and ascorbic acid were found to be better than those of the two control groups (P<0.05). Furthermore, no significant changes were observed in pH values, the content of total phenols, or 1,1-dipheny1-2-picrylhydrazyl radical scavenging capacity (P>0.05). It is indicated that PAW treatment is a promising method for improving microbiological safety and extending the shelf-life of kale.
The Evolution of Offspring Size: A Metabolic Scaling Perspective
Authors: Pettersen Amanda K , Schuster Lukas , Metcalfe Neil B
Published: June 2022

Size at the start of life reflects the initial per offspring parental investment—including both the embryo and the nutrients supplied to it. Initial offspring size can vary substantially, both within and among species. Within species, increasing offspring size can enhance growth, reproduction, competitive ability, and reduce susceptibility to predation and starvation later in life, that can ultimately increase fitness. Previous work has suggested that the fitness benefits of larger offspring size may be driven by energy expenditure during development—or how offspring metabolic rate scales with offspring size. Despite the importance of early-life energy expenditure in shaping later life fitness trajectories, consideration of among-species scaling of metabolic rate at the time of birth as a potential source of general metabolic scaling patterns has been overlooked by theory. Here, we review the patterns and processes of energy expenditure at the start of life when mortality is often greatest. We compile existing data on metabolic rate and offspring size for 191 ectotherm species spanning eight phyla and use phylogenetically controlled methods to quantify among-species scaling patterns. Across a 109-fold mass range, we find that offspring metabolic rate scales hypometrically with size, with an overall scaling exponent of 0.66. This exponent varies across ontogenetic stage and feeding activity, but is consistently hypometric, including across environmental temperatures. Despite differences in parental investment, life history and habitat, large-offspring species use relatively less energy as a proportion of size, compared with small-offspring species. Greater residual energy can be used to fuel the next stages of life, particularly in low-resource environments. Based on available evidence, we conclude that, while large knowledge gaps remain, the evolution of offspring size is likely shaped by context-dependent selection acting on correlated traits, including metabolic rates maintaining hypometric scaling, which operates within broader physical constraints.
Neuropathologic Findings in Elderly HIV-Positive Individuals
Authors: Magaki Shino D , Vinters Harry V , Williams Christopher K , Mareninov Sergey , Khanlou Negar , Said Jonathan , Nemanim Natasha , Gonzalez Jessica , Morales Jose G , Singer Elyse J , Yong William H
Published: June 2022

The elderly HIV-positive population is growing due to the widespread use of combination antiretroviral therapy (cART), but the effects of longstanding HIV infection on brain aging are unknown. A significant proportion of HIV-positive individuals develop HIV-associated neurocognitive disorder (HAND) even on cART, but the pathogenesis of HAND is unknown. Although neuroinflammation is postulated to play an important role in aging and neurodegenerative diseases such as Alzheimer disease (AD), it is unclear whether HIV accelerates aging or increases the risk for AD. We examined the brains of 9 elderly HIV-positive subjects on cART without co-infection by hepatitis C virus compared to 7 elderly HIV-negative subjects. Microglial and astrocyte activation and AD pathologic change in association with systemic comorbidities and neurocognitive assessment were evaluated. There was no difference in microglial or astrocyte activation between our HIV-positive and HIV-negative cohorts. One HIV-positive subject and 2 HIV-negative subjects demonstrated significant amyloid deposition, predominantly in the form of diffuse senile plaques, but these individuals were cognitively normal. Neurofibrillary tangles were sparse in the HIV-positive cohort. There was a high prevalence of cardiovascular comorbidities in all subjects. These findings suggest that multiple factors likely contribute to aging and cognitive impairment in elderly HIV-positive individuals on cART.
A low appendiceal mucinous neoplasm lesion in an inflamed appendix within an inguinal hernia
Authors: Arenas Daniel J , Hernandez Paul T , Hwang Jasmine , Agarwal Divyansh , Warshauer Alexander K , Holena Daniel N
Published: June 2022

Amyand’s hernia, an incarcerated appendix inside an inguinal hernia, accounts for <1% of hernias in children and even less in adults. Similarly, low-grade appendiceal mucinous (LAMN) lesions are only found in <1% of removed appendices. We present the case of a 72-year-old man with a 15-year history of a large right inguinoscrotal hernia that presented with right lower quadrant pain, was found by computed tomography imaging to have an incarcerated appendix with a large fluid collection, and was post-operatively diagnosed with an LAMN lesion. Although our case is rare due to the simultaneity of the Amyand’s hernia and LAMN conditions, each separate condition is prevalent enough for most surgical providers to encounter at least one of these. For our case, we discuss the decisions made in the pre-operative and post-operative management and relevant literature.
Gastrointestinal tract Candida spp colonization shows mostly a monoclonal pattern: an intra-patient pilot study
Authors: Mesquida Aina , Álvarez-Uría Ana , Vicente Teresa , Muñoz Patricia , Guinea Jesús , Escribano Pilar
Published: June 2022

Gastrointestinal tract Candida genotypes may associate with isolates later causing infections. We genotyped Candida spp isolates (n = 200 individual colonies) from rectal swabs to assess whether gastrointestinal gut colonization is caused by a single genotype (monoclonal pattern) or a combination of them (polyclonal pattern). C. glabrata showed a sheer monoclonal pattern. C. parapsilosis and C. tropicalis showed a monoclonal pattern involving the presence of either exclusively identical genotypes or a combination of clonally-related genotypes; in the latter case, a dominant genotype was always found. C. albicans showed mostly a polyclonal pattern involving a combination of dominant clonally-related genotypes and unrelated genotypes.

Lay Summary

We genotyped C. albicans, C. parapsilosis, C. tropicalis, and C. glabrata isolates prospectively from rectal swabs to study the gastrointestinal colonization pattern in the patients. Gastrointestinal tract colonization is mostly monoclonal and commonly dominated by one genotype.
The Dark Energy Survey supernova program: cosmological biases from supernova photometric classification
Authors: Vincenzi M , Sullivan M , Möller A , Armstrong P , Bassett B A , Brout D , Carollo D , Carr A , Davis T M , Frohmaier C , Galbany L , Glazebrook K , Graur O , Kelsey L , Kessler R , Kovacs E , Lewis G F , Lidman C , Malik U , Nichol R C , Popovic B , Sako M , Scolnic D , Smith M , Taylor G , Tucker B E , Wiseman P , Aguena M , Allam S , Annis J , Asorey J , Bacon D , Bertin E , Brooks D , Burke D L , Rosell A Carnero , Carretero J , Castander F J , Costanzi M , da Costa L N , Pereira M E S , De Vicente J , Desai S , Diehl H T , Doel P , Everett S , Ferrero I , Flaugher B , Fosalba P , Frieman J , García-Bellido J , Gerdes D W , Gruen D , Gutierrez G , Hinton S R , Hollowood D L , Honscheid K , James D J , Kuehn K , Kuropatkin N , Lahav O , Li T S , Lima M , Maia M A G , Marshall J L , Miquel R , Morgan R , Ogando R L C , Palmese A , Paz-Chinchón F , Pieres A , Malagón A A Plazas , Reil K , Roodman A , Sanchez E , Schubnell M , Serrano S , Sevilla-Noarbe I , Suchyta E , Tarle G , To C , Varga T N , Weller J , Wilkinson R D ,   (DES Collaboration)
Published: June 2022

Cosmological analyses of samples of photometrically identified type Ia supernovae (SNe Ia) depend on understanding the effects of ‘contamination’ from core-collapse and peculiar SN Ia events. We employ a rigorous analysis using the photometric classifier SuperNNova on state-of-the-art simulations of SN samples to determine cosmological biases due to such ‘non-Ia’ contamination in the Dark Energy Survey (DES) 5-yr SN sample. Depending on the non-Ia SN models used in the SuperNNova training and testing samples, contamination ranges from 0.8 to 3.5 per cent, with a classification efficiency of 97.7–99.5 per cent. Using the Bayesian Estimation Applied to Multiple Species (BEAMS) framework and its extension BBC (‘BEAMS with Bias Correction’), we produce a redshift-binned Hubble diagram marginalized over contamination and corrected for selection effects, and use it to constrain the dark energy equation-of-state, w. Assuming a flat universe with Gaussian ΩM prior of 0.311 ± 0.010, we show that biases on w are <0.008 when using SuperNNova, with systematic uncertainties associated with contamination around 10 per cent of the statistical uncertainty on w for the DES-SN sample. An alternative approach of discarding contaminants using outlier rejection techniques (e.g. Chauvenet’s criterion) in place of SuperNNova leads to biases on w that are larger but still modest (0.015–0.03). Finally, we measure biases due to contamination on w0 and wa (assuming a flat universe), and find these to be <0.009 in w0 and <0.108 in wa, 5 to 10 times smaller than the statistical uncertainties for the DES-SN sample.
Nanomolar affinity of EF-hands in neuronal calcium sensor 1 for bivalent cations Pb2+, Mn2+, and Hg2+
Authors: Alam Md Shofiul , Azam Samiol , Pham Khoa , Leyva Dennys , Fouque Kevin Jeanne Dit , Fernandez-Lima Francisco , Miksovska Jaroslava
Published: June 2022

Abiogenic metals Pb and Hg are highly toxic since chronic and/or acute exposure often leads to severe neuropathologies. Mn2+ is an essential metal ion but in excess can impair neuronal function. In this study, we address in vitro the interactions between neuronal calcium sensor 1 (NCS1) and divalent cations. Results showed that non-physiological ions (Pb2+ and Mn2+) bind to EF-hands in NCS1 with nanomolar affinity and lower equilibrium dissociation constant than the physiological Ca2+ ion. (Kd, Pb2+ = 7.0 ± 1.0 nM; Kd, Mn2+ = 34.0 ± 6.0 nM; K). Native ultra-high resolution mass spectrometry (FT-ICR MS) and trapped ion mobility spectrometry—mass spectrometry (nESI-TIMS-MS) studies provided the NCS1-metal complex compositions—up to four Ca2+ or Mn2+ ions and three Pb2+ ions (M⋅Pb1-3Ca1-3, M⋅Mn1-4Ca1-2, and M⋅Ca1-4) were observed in complex—and similarity across the mobility profiles suggests that the overall native structure is preserved regardless of the number and type of cations. However, the non-physiological metal ions (Pb2+, Mn2+, and Hg2+) binding to NCS1 leads to more efficient quenching of Trp emission and a decrease in W30 and W103 solvent exposure compared to the apo and Ca2+ bound form, although the secondary structural rearrangement and exposure of hydrophobic sites are analogous to those for Ca2+ bound protein. Only Pb2+ and Hg2+ binding to EF-hands leads to the NCS1 dimerization whereas Mn2+ bound NCS1 remains in the monomeric form, suggesting that other factors in addition to metal ion coordination, are required for protein dimerization.
CircadiOmics: circadian omic web portal
Authors: Samad Muntaha , Agostinelli Forest , Sato Tomoki , Shimaji Kohei , Baldi Pierre
Published: June 2022

Circadian rhythms are a foundational aspect of biology. These rhythms are found at the molecular level in every cell of every living organism and they play a fundamental role in homeostasis and a variety of physiological processes. As a result, biomedical research of circadian rhythms continues to expand at a rapid pace. To support this research, CircadiOmics (http://circadiomics.igb.uci.edu/) is the largest annotated repository and analytic web server for high-throughput omic (e.g. transcriptomic, metabolomic, proteomic) circadian time series experimental data. CircadiOmics contains over 290 experiments and over 100 million individual measurements, across >20 unique tissues/organs, and 11 different species. Users are able to visualize and mine these datasets by deriving and comparing periodicity statistics for oscillating molecular species including: period, amplitude, phase, P-value and q-value. These statistics are obtained from BIO_CYCLE and JTK_CYCLE and are intuitively aggregated and displayed for comparison. CircadiOmics is the most up-to-date and cutting-edge web portal for searching and analyzing circadian omic data and is used by researchers around the world.
Noncanonical amino acid mutagenesis in response to recoding signal-enhanced quadruplet codons
Authors: Chen Yan , He Xinyuan , Ma Bin , Liu Kun , Gao Tianyu , Niu Wei , Guo Jiantao
Published: June 2022

While amber suppression is the most common approach to introduce noncanonical amino acids into proteins in live cells, quadruplet codon decoding has potential to enable a greatly expanded genetic code with up to 256 new codons for protein biosynthesis. Since triplet codons are the predominant form of genetic code in nature, quadruplet codon decoding often displays limited efficiency. In this work, we exploited a new approach to significantly improve quadruplet UAGN and AGGN (N = A, U, G, C) codon decoding efficiency by using recoding signals imbedded in mRNA. With representative recoding signals, the expression level of mutant proteins containing UAGN and AGGN codons reached 48% and 98% of that of the wild-type protein, respectively. Furthermore, this strategy mitigates a common concern of reading-through endogenous stop codons with amber suppression-based system. Since synthetic recoding signals are rarely found near the endogenous UAGN and AGGN sequences, a low level of undesirable suppression is expected. Our strategy will greatly enhance the utility of noncanonical amino acid mutagenesis in live-cell studies.
ATRT-09. Outcome and therapeutic interventions in relapsed and refractory ATRT – The EU-RHAB perspective
Authors: Steinbügl Mona , Nemes Karolina , Gruhle Miriam , Johann Pascal , Gil-da-Costa Maria Joao , Ebinger Martin , Sehested Astrid , Hauser Peter , Reinhard Harald , Hettmer Simone , Jakob Marcus , Rutkowski Stefan , Driever Pablo Hernáiz , Fleischhack Gudrun , Kerl Kornelius , Witt Olaf , Gerss Joachim , Siebert Reiner , Schüller Ulrich , Hasselblatt Martin , Frühwald Michael C
Published: June 2022

Currently an internationally accepted consensus treatment for relapsed/refractory ATRT is missing. Little is known about relapse patterns, prognostic factors and outcome. In a recently published cohort of 143 ATRTs from the EU-RHAB registry, progression on therapy or relapse occurred in 64% (n=91). Previously published strategies for treatment failure have been restricted to individual, mostly clinically guided, attempts or early phase trials with limited sample sizes. We present a cohort of 55 patients with relapsed/refractory ATRT identified between 2015 and 2021 (total ATRT recruited n=147). Median age was 19 months; in 27.3% (n=15) a germline mutation was identified. A total of 43/55 tumors were subgrouped [60.5% SHH (n=26), 14.0% MYC (n=6), 23.3% TYR (n=10), one patient with SHH+TYR]. Salvage therapy was applied to 83.6% (46/55). Sixty therapy attempts with 17 different regimens subclassified into conventional chemotherapy, epigenetic, targeted or metronomic therapy were applied to 40/55 patients. Median overall survival (OS) was 20±1.8 weeks following the first event, median time to progression was 11±1.8 weeks. 12 months OS was 23.1%. No significant differences in survival were noted between different molecular subgroups; neither was germline mutation in SMARCB1 prognostic. Patients <12 months (n=9;16.4%) had a significantly reduced OS compared to older patients. (9±6.0wks vs. 22±3.2wks, p<0.05) Those who received therapy according to metronomic approaches such as MEMMAT (8/55;14.5%) survived longer than patients treated with other regimens, including epigenetic and targeted therapy. (72±36.8wks vs. 25±6.2wks, p<0.05) Our data provide valuable insights into a vulnerable group of patients deserving evidence based clinical management and access to clinical trials of all phases. Prospectively we aim to merge the results with data from other, international cohorts to generate more robust and valuable results.
ATRT-18. Atypical Teratoid/Rhabdoid Tumor in Children: Case Reports from Indonesia
Authors: Ramadhan Diko Anugrah , Gautami Wanda , Rahmartani Ludi Dhyani , Rafli Ahmad , Gunawan Kevin , Amal Mohamad Yanuar , Susanto Eka , Handoko Handoko
Published: June 2022

Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system is a sporadic and highly malignant tumor that usually affects very young children and is typically deadly despite very aggressive treatment. The optimal treatment for AT/RT remains unclear, including surgery, radiotherapy, and chemotherapy. Here we report cases of AT/RT in Indonesia. Case 1: A three-year-old girl came with worsening intermittent headaches with projectile vomiting, progressive and insidious right spastic hemiparesis, and slowly progressive weight loss three months before admission. She had septate multiloculated hydrocephalus. Head MRI demonstrates a solid lobulated mass with heterogeneous enhancement and MRS shows an aggressive metabolite pattern, arising from posterior fossa extending into the cerebellum and cerebellopontine angle, causing severe obstructive hydrocephalus. She underwent tumor resection with a midline suboccipital approach, then continued with craniospinal irradiation with dose of 36 Gy in 20 fractions then followed by 18 Gy in 10 fractions booster to posterior fossa, making the total dose to posterior fossa (the tumor) to be 54 Gy. Case 2: A twenty-month-old baby with a history of recurrent seizures, tremors, and less activity in the last two months. She had spasticity with hyperreflexia. She has been referred to our center for further evaluation and management after biopsy and VP shunt surgery at the previous hospital. Head CT scan demonstrates a large solid heterogeneous mass in the right hemisphere cerebral, causing midline shift and hydrocephalus. After the VP shunt was repaired, she underwent Head Start III chemotherapy protocol cycle 1. Both pathology examinations of the patients revealed a hypercellular tumor with prominent hyperchromatic nucleoli and loss of INI-1 staining on immunohistochemistry consistent with an ATRT diagnosis. Unfortunately, both patients died due to severe sepsis after treatment. Although AT/RT has become increasingly recognized, prognosis of ATRT is generally unfavorable, especially in developing countries.
ATRT-19. Functional genomics reveal distinct modulators of response to CDK4/6 inhibitors in ATRTs
Authors: Merk Daniel , Hirsch Sohpie , Tsiami Foteini , Walter Bianca , Haeusser Lara , Babaei Sepideh , Admard Jakob , Casadei Nicolas , Roggia Cristiana , Spohn Michael , Schittenhelm Jens , Singer Stephan , Schüller Ulrich , Piccioni Federica , Persky Nicole , Root David , Claassen Manfred , Tatagiba Marcos , Tabatabai Ghazaleh
Published: June 2022

Brain tumors are the leading cause of cancer-related deaths in children, and atypical teratoid rhabdoid tumors (ATRTs) are among the most common aggressive brain tumors in infants. With no standard-of-care treatment so far, ATRTs continue to have relatively low survival estimates, illustrating the urgent need for more efficacious treatment options. We have previously used genome-wide CRISPR/Cas9 knockout screens in combination with small-molecule drug assays to identify targetable vulnerabilities in ATRTs. CDK4/6 inhibitors, among the most promising drugs in our study with direct translational potential, are capable of inhibiting tumor growth due to mutual exclusive dependency of ATRTs on either CDK4 or CDK6. We here used genome-wide loss-of-function and gain-of-function strategies to identify modulators of response to CDK4/6 inhibition in ATRTs. Of note, while some well-known resistance mechanisms such as loss of RB1 or FBXW7 are shared by ATRT cell lines, we have also identified modulators of response to CDK4/6 inhibition with opposing effects across ATRT cell lines. As such, loss of AMBRA1, a recently described master regulator of D type cyclins, can either oppose the effects of or synergize with CDK4/6 inhibitors based on the cellular background. We are currently using a proteomics approach to further delineate the mechanism driving this functional heterogeneity of AMBRA1 in ATRTs. Our study will therefore provide deeper insights into the response of ATRTs to CDK4/6 inhibitors, which represent one of the most promising class of targeted agents for the treatment of ATRTs.
ATRT-25. CERVICAL ATYPICAL TERATOID RHABDOID TUMOR IN PEDIATRIC PATIENTS: A STUDY OF THE LAST DECADE
Authors: Fonseca Rodrigues Amanda Cyntia Lima , Louro Letícia dos Santos , Kostakis Maria Eduarda Geddo , Fialho Milena Henriques , Ruiz Kananda Oliveira Garcia , Costa Beatriz Patriota Saraiva , Gomes Monique Benemérita Vilela
Published: June 2022

BACKGROUND: Atypical rhabdoid teratoid tumor (AT/RT) is an extremely rare primary tumor of the central nervous system (CNS) with a high incidence in children under 3 years of age. The existing literature involving this tumor is scarce, even though AT/RT is considered one of the most malignant brain tumors due to its aggressive course and short survival time, which generally does not exceed 1 year. METHODS: The “PubMed” database was used for this study using the MeSH Terms “Child” and “Atypical Teratoid Rhabdoid Tumor” and the filter “Case Reports” in order to carry out a study with the clinical cases of the last decade and the involvement of this tumor in the cervical region of pediatric patients. 96 articles were found, however, only 10 articles were selected for this review. RESULTS: It is possible to affirm that the cases of AT/RT are found in greater numbers in children under 3 years of age and are predominantly located in the cervical region when they affect the spinal cord. In addition, MRI usually shows a solid heterogeneous mass that results in the appearance of symptoms, since the mass compresses the conus medullaris and consequently generates pain in the spine. The prognosis is reported to be a difficult one and the median patient survival time is less than one year. CONCLUSION: Therefore, AT/RT is rare, fatal, primary and malignant in the CNS that have a high degree of recurrence and dissemination. The diagnosis is made through anatomopathological examination and the loss of INI-1 expression constitutes an important finding for its conclusion. Treatment is multimodal and may combine surgery, chemotherapy and radiotherapy.
RARE-04. Hypothalamic syndrome – severe sequelae due to different sellar and parasellar masses
Authors: Müller Hermann L
Published: June 2022

Hypothalamic syndrome is a rare disorder caused by disease- and/or treatment-related injury to the hypothalamus, most commonly associated with rare, noncancerous parasellar masses such as craniopharyngioma, germ cell tumours, gliomas, cysts of Rathke’s pouch and Langerhans cell histiocytosis as well as genetic neurodevelopmental syndromes such as Prader-Willi syndrome and septo-optic dysplasia. Hypothalamic syndrome is characterized by intractable weight gain associated with severe morbid obesity and memory impairment, attention deficit, reduced impulse control as well as increased risk of cardiovascular and metabolic disorders. Currently, there is no cure for this condition. Treatments used for general obesity such as surgery, medication and counselling are often tried in hypothalamic syndrome, but are mostly ineffective, and there are no medications specifically approved for hypothalamic syndrome. The most important aspects of presentation and outcome of hypothalamic syndrome due to different neuro oncological diseases, its risk factors and an overview of currently available therapeutic interventions aiming to decrease and ameliorate the consequences of hypothalamic dysfunction will be presented. Furthermore, novel aspects and perspectives for future research will be discussed.
RARE-09. Treatment of childhood-onset craniopharyngioma patients using proton beam therapy versus photon-based radiation therapy in the prospective KRANIOPHARYNGEOM 2007 trial
Authors: Friedrich Carsten , Boekhoff Svenja , Sowithayasakul Panjarat , Eveslage Maria , Bison Brigitte , Timmermann Beate , Müller Hermann L
Published: June 2022

BACKGROUND: Proton beam therapy (PBT) compared to photon-based radiotherapy (XRT) offers the benefit to administer lower radiation doses to critical organs thereby possibly minimizing the risk of sequelae in patients with residual craniopharyngiomas (CP) after hypothalamus-sparing surgery. The validation in large CP patient cohorts is still pending. PATIENTS AND METHODS: Of 290 childhood-onset CP patients included 2007-2019 in the prospective multicenter trial KRANIOPHARYNGEOM 2007, 99 (34%) received external RT (65% PBT, 35% XRT). Outcome was compared between the different groups in terms of overall (OS) and event-free survival (EFS), quality of life (QoL using PEDQOL), functional capacity (FMH), and auxological data (BMI and height SDS) one, three and five years after irradiation/CP diagnosis. RESULTS: PBT became the predominant irradiation technique during the study period (used in 23% and 77% of all irradiated patients registered within the first and second half of the enrollment period, respectively). PBT as well as XRT were associated with high (p<0.001) EFS (PBT: 0.917 ± 0.040; XRT: 0.940 ± 0.041) compared to non-RT (EFS: 0.669 ± 0.044). OS was similar in all groups. No differences between PBT, XRT and non-RT CP patients concerning functional capacity and anthropometric parameters (height SDS, BMI SDS) have been obtained. Only in the PEDQOL domain “physical function”, proxy-assessed QoL was lower one year after PBT when compared to XRT treated and non-irradiated CP patients. CONCLUSION: PBT is similar efficient in preventing relapses and recurrences in childhood-onset CP patients. During follow-up, no clinically relevant differences between PBT and XRT in terms of QoL, functional capacity and degree of obesity as a marker of hypothalamic syndrome were detectable. While PBT is increasingly applied, studies on larger CP cohorts with longer follow-up after RT are warranted to analyze, whether it can prevent sequelae such as hypothalamic syndrome and severe obesity compared to XRT.
RARE-16. Differential expression of miRNAs in adamantinomatous craniopharynngioma reveals dysregulation of pathogenic pathways
Authors: Apps John
Published: June 2022

MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of target mRNAs and can control whole gene networks. ACPs are benign pituitary tumours that can result in significant morbidity and premature mortality. ACPs harbour mutations in CTNNB1 and are driven by the activation of the WNT/beta-catenin pathway. We sought to explore the expression of miRNAS in adamantinomatous craniopharyngioma (ACP) in a cohort of samples previously subjected to RNA-Seq analysis (Apps et al, Acta Neuropathologica, 2018, May;135(5):757-777). Total RNA ACP samples (n=18), non-functioning pituitary adenomas (n=3) and normal foetal pituitaries (n=3) underwent miRNA sequencing using the Qiagen miRNA library prep kit on a NextSeq 500 to a depth of 16 million reads. Differential expression was performed using DESeq2 and functional analysis with mirPath v.3. Expression of miRNAs was correlated with previously published mRNA expression We found that 210 miRNA were upregulated and 275 down regulated in ACP compared with controls (adjusted p-value <0.1). MIR-205-5p was the most upregulated miRNA (619 fold) and its expression correlated with genes expressed within the tumour epithelium (e.g. TP63). miR-375 an inhibitor of the WNT pathway was the most down regulated miRNA (361 fold). KEGG Pathway analysis identified Glycosphingolipid synthesis as the most enriched pathway targeted by upregulated miRNAs. Pathways that were enriched by down regulated miRNAs included: ECM-receptor interaction, fatty acid biosynthesis, Hippo, TGF-beta, WNT, and ErbB pathways. Down regulation of miR-132 has previously been suggested as a marker of aggressiveness in ACP, and was 16 fold down regulated (adjusted p-value<0.001) in this cohort and expression was inversely correlated with genes relating to epithelial development. This data confirms previous studies indicating that miRNA expression is altered in ACP. In silico analysis suggest that the dysregulation of miRNA affects the expression of genes involved in pathogenic pathways in ACP.
RARE-19. Molecular characterization and treatment response of metastatic DIA/DIG
Authors: Petropoulos James , Finkbeiner Melanie , Assis Zarina , Gallagher Clare , Hader Walter , Chan Jennifer , Strother Douglas , Lafay-Cousin Lucie
Published: June 2022

INTRODUCTION: Desmoplastic infantile astrocytoma (DIA) and desmoplastic infantile ganglioglioma (DIG) are glioneuronal tumors of early childhood. Surgical resection is usually sufficient to cure these benign tumors. The presence of metastatic seeding is rare and has been reported as an adverse prognostic factor. We present 2 cases of young children with recurrent metastatic DIA/DIG to describe their presentation, therapeutic management and outcome and to highlight the importance of molecular characterization of these rare tumors to guide adjuvant therapy. CASES DESCRIPTION: The first patient developed metastatic recurrence after initial gross total resection (GTR) of a localized DIG. The disseminated relapse was treated with monthly carboplatin and vincristine (CB/VCR). Complete response was achieved after 15 cycles and the patient has remained in continuous complete remission for 5 years. Post hoc molecular analysis of the tumor revealed a BRAF-RDX fusion. The second patient presented with a disseminated intraventricular relapse following an incomplete resection of a DIA associated with a SPECC1L-NTRK2 fusion. The patient received 2 cycles of CB/VCR with minimal response and was then switched to Larotrectinib leading to a very good partial response (VGPR) 3 months into therapy and has remained on treatment since then with significant clinical improvement. DISCUSSION/ CONCLUSION: In our 2 cases, metastatic recurrence was responsive to adjuvant therapy leading to complete response with conventional chemotherapy in the first one and to VGPR with NTRK inhibitor in the second patient. Early molecular characterization of these benign tumors is critical in case of incomplete resection or metastatic seeding to widen therapeutic options and maximize chance of cure. Response with NTRK inhibitor appears rapid and significant but the total duration of treatment and sustainability of response after discontinuation remain unknown.
RARE-23. Preservation of endocrine function after Ommaya reservoir insertion in children with cystic craniopharyngioma
Authors: Lohkamp Laura-Nanna , Kulkarni Abhaya V , Drake James , Rutka James T , Hamilton Jill , Bartels Ute K
Published: June 2022

INTRODUCTION: Children with craniopharyngiomas (CP) can be subjected to significant morbidities caused by radical surgery and/or radiation with deleterious long-term consequences. Ommaya reservoir insertion (ORI) into cystic CP represents a minimally invasive procedure allowing immediate decompression and aims to avoid additional injuries. The purpose of this study was to determine the relevance of upfront ORI (+/- intracystic treatment) for preservation of endocrine function. METHODS: We performed a retrospective chart review of children with CP treated at the Hospital for Sick Children between 01/01/2000 and 15/01/2020 for review of endocrinological outcome after ORI. Endocrine function was reviewed at the time of initial surgery and throughout the course of follow-up. Event-free survival (EFS) was defined as the time to further surgical resection or irradiation. RESULTS: Seventy-nine patients were identified with a median age of 8.3 (range 2.1-18.0) years, 31 were males. Sixty-six patients underwent surgical treatment, including 41 ORI. ORI was performed as upfront treatment in 32 patients; 33 patients underwent gross total or partial resection and 1 patient radiotherapy as first treatment. Fifty-five of 79 patients had sufficient endocrine follow-up data. Endocrine function remained stable after ORI with a mean EFS of 27.64 (± 5.22) months. Surgical resection was associated with worsened endocrine function postoperatively with an EFS of 5.48 (± 1.74) months (p< 0.001). CONCLUSIONS: Upfront ORI (+/- intracystic treatment) resulted in endocrine preservation of all patients and a significantly longer EFS when compared to upfront surgical resection in this single institutional retrospective review. Further analyses will elucidate the implications of ORI with respect to ophthalmological, vascular and neurocognitive outcome.
DIPG-25. Patterns of cerebrospinal fluid diversion and survival in children with diffuse intrinsic pontine glioma: a report from the International Diffuse Intrinsic Pontine Glioma Registry
Authors: Cooney Tabitha , DeWire-Schottmiller Mariko , Lane Adam , Saab Raya , Bandopadhayay Pratiti , Dorris Kathleen , Packer Roger , Kilburn Lindsay , Minturn Jane , Dodgshun Andrew , Parkin Sara , Goldman Stewart , Sandler Eric , Greiner Robert , Gottardo Nicholas , Dholaria Hetal , Coven Scott , Hassall Tim , Hansford Jordan , Samson Yvan , Leary Sarah , Bartels Ute , Fonseca Adriana , Bouffet Eric , Tinkle Christopher , Monje Michelle , Fisher Paul , Ziegler David , Chintagumpala Murali , Wagner Lars , Koschmann Carl , Leach James , Jones Blaise , Benito Elisa Carrasquedo , Bond Hailey , Chaney Brooklyn , Black Katie , Asher Anthony , Fouladi Maryam , Hoffman Lindsey , Warren Katherine
Published: June 2022

BACKGROUND: There are no standard practice guidelines for cerebrospinal (CSF) diversion for diffuse intrinsic pontine glioma (DIPG), nor clear understanding of potential for palliation and life-prolongation. We evaluated CSF diversion characteristics in children with DIPG to determine incidence, indications, symptom effects, and survival. METHODS: Data were extracted from subjects registered in the International DIPG registry (IDIPGR). Univariable analyses was performed using the Fisher’s exact test or Wilcoxon rank sum test. Survival was estimated using the Kaplan-Meier method. RESULTS: Evaluable patients (n=542) met criteria for DIPG diagnosis by central radiologic review; of those, 126 (23%) had permanent CSF diversion. Median time from diagnosis to diversion was 0.5 months (IQR 0.1-4.5 months). Those with permanent diversion were significantly younger (median 5.4 years vs 7.0 years, p<0.001) and had higher incidence of hydrocephalus at diagnosis (65.3% vs 11.9%, p<0.001). Permanent CSF diversion did not significantly impact overall survival (OS) (p=0.4), even amongst the 124 patients with hydrocephalus at presentation (p=0.20). Those with permanent diversion prior to radiation therapy demonstrated longer median OS than those in whom diversion was placed after radiation (14.3 vs 9.6 months, p=0.001). Patients reported significantly less headache and vomiting at last follow up after permanent CSF diversion compared to pre-diversion (p<0.0001 and p=0.001, respectively), however steroid use was also significantly higher at last follow-up after CSF diversion (p<0.001). CONCLUSIONS: Amongst an international cohort, DIPG patients who had permanent CSF diversion were significantly younger and had higher rates of hydrocephalus at initial presentation than those without permanent diversion. Symptoms of increased intracranial pressure improved in those with CSF diversion, although a direct effect may be confounded by increased steroid use. Permanent CSF diversion did not prolong overall survival in this large cohort of patients, even amongst those who presented with hydrocephalus.
DIPG-32. Paediatric histone-mutant diffuse midline glioma: real world outcomes from a low-middle income country (LMIC) setting
Authors: Gupta Tejpal , Chatterjee Abhishek , Dasgupta Archya , Mangaj Akshay , Epari Sridhar , Sahay Ayushi , Choudhari Amit , Moiyadi Aliasgar , Shetty Prakash , Chinnaswamy Girish
Published: June 2022

BACKGROUND: Histone-mutant diffuse midline glioma (H3K27M) is a distinct high-grade central nervous system (CNS) tumor arising in the midline structures of the brain and/or spinal cord in children and young adults with dismal clinical outcomes. Real world data on this entity, particularly from the low-middle income countries (LMICs) is lacking. We report outcomes of pediatric histone-mutant diffuse midline gliomas treated between 2014-2021 at our comprehensive cancer centre in India. METHODS: Children (<16 years) with biopsy-proven diffuse midline glioma demonstrating histone mutation (H3K27M) on gene expression profiling were identified through electronic search of neuro-pathology database. Clinico-demographic characteristics, histo-molecular features, treatment details, and survival outcomes were retrieved retrospectively from institutional records. All children had undergone biopsy and occasionally debulking surgery prior to definitive radiotherapy (RT). Upfront temozolomide (TMZ) either concurrent and/or adjuvant was at the discretion of treating oncologist. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods and expressed as point estimates with 95% confidence interval (CI). RESULTS: Median age of the study cohort (N=51) was 11 years (inter-quartile range 6-14 years) with no gender predilection. Metastatic disease (leptomeningeal dissemination, sub-ependymal spread, or distant brain involvement) was seen at presentation in 7 (13.7%) patients and at first progression after definitive RT in 10 (19.6%) patients. At a median follow up of 10.3 months, 1-year Kaplan-Meier estimates of PFS and OS were 21.5% (95%CI: 12.2-37.9%) and 45.6% (33.1-62%) yielding median PFS and OS of 7.8 months (95%CI: 5.6-11 months) and 11.3 months (95%CI: 9.4-14.9 months) respectively. CONCLUSIONS: We report aggressive biological course and dismal outcomes in pediatric histone-mutant diffuse midline gliomas (H3K27M) treated in a LMIC setting. High incidence of metastatic CNS failure in our cohort suggests a potential role for testing neuraxial irradiation and aggressive systemic therapy to improve survival.
DIPG-41. Multi-omic profiling of patient-derived subclones identifies aggressive cellular subpopulations in paediatric diffuse high-grade gliomas (PDHGGs)
Authors: Kessler Ketty , Grabovska Yura , Burford Anna , Temelso Sara , Tari Haider , Molinari Valeria , Crampsie Shauna , Yu Lu , Choudhary Jyoti , Proszek Paula , Hubank Michael , Mackay Alan , Jones Chris
Published: June 2022

Paediatric-type diffuse high-grade gliomas are classified into distinct subgroups based upon their location and defining molecular alterations, with very poor clinical outcomes in patients >3yrs. This extensive inter-tumour heterogeneity is further complicated by a wide diversity of genotypically- and phenotypically-distinct subclonal populations within individual tumours, providing a substantial barrier to developing effective treatments. We have sought to understand the dynamic cellular make-up of PDHGGs such that novel strategies aimed at targeting specific subpopulations based upon their contribution to disease progression as whole may be employed. Two complementary approaches have been undertaken to address this – first by carrying out single-cell profiling of bulk specimens, and the second isolation and propagation of single-cell-derived stem cell-like cultures in vitro. To-date we have studied 10 cases and a total of 218 subclonal colonies from both DMG-H3K27 and DHG-WT. In a spinal metastatic case of DMG-H3K27, lpWGS-FISH highlighted subpopulations driven by mis-segregation of amplified oncogenic ecDNA, and mutually exclusive subpopulations defined by MYCN, PDGFRA and CCND1. Through integrated analysis of scRNA-seq and scATAC-seq, we show distinct chromatin accessibility profiles to underlie gene expression signatures defining unique subpopulations of cells. In addition to cycling populations and those associated with lineage-specificity, we identified ‘aggressive’ subpopulations defined by significant upregulation of immediate early response genes such as FOS/FOSL1/JUN, those associated with promotion of invasion-migration such as SERPINs and MMPs. These subpopulations could be mapped to isolated single-cell-derived subclones with highly proliferative or motile phenotypes, defined by comprehensive profiling of expressed and secreted proteins. Differential cis-regulation driving cell identity-tumorigenesis was found in one example to occur via a trans-histone mechanism mediated by an H4-lysine-methyltransferase, KMT5B. Application of functionally-defined interventional strategies aimed at disrupting the interactions between these subpopulations based upon evolutionary biology principles may offer a novel approach to treat these otherwise incurable tumours in children and young adults.
DIPG-53. Long-term survival from a Phase 1 dose-escalation trial using convection-enhanced delivery (CED) of radioimmunotherapeutic124I-omburtamab for treatment of diffuse intrinsic pontine glioma (DIPG).
Authors: Souweidane Mark M , Kramer Kim , Pandit-Tasker Neeta , Haque Sofia , Zanzonico Pat , Carrasquillo Jorge , Lyashchenko Serge K , Thakur Sunitha B , Khakoo Yasmin , Dunkel Ira J , Donzelli Maria , Lewis Jason S , Cheung Nai-Kong V , Larson Steve M , Reiner Anne S , Panageas Katherine S , Manino Nicole , Nielsen John Rømer
Published: June 2022

BACKGROUND: Median survival from DIPG is less than one year. In a phase 1 dose escalation study (clinicaltrials.gov NCT01502917) 124I-omburtamab targeting B7-H3 was administered intratumorally using CED. METHODS: CED was performed between 4-14 weeks post radiation therapy. Using a 3 + 3 design, 124I-omburtamab was escalated from 0.25-10.0 mCi and infusion volumes (Vi) from 250-10,000 µl with serial 124I PET/CT performed up to ~1 week post-administration. Toxicities were assessed for 30 days. Dose escalation safety was evaluated. Survival was calculated using Kaplan-Meier statistics. RESULTS: 46 children were treated and evaluable for toxicity and survival;4 patients received partial doses and were evaluable for toxicity only. Three patients experienced dose limiting toxicities. Eleven patients had transient treatment related grade 3 toxicities with no grade 4 or 5 toxicities. Grade 3 nervous system toxicities included: muscular weakness(n=8), dysarthria(n=4), ataxia(n=3), dysphagia(n=3), and gait disturbance(n=1). Lesion absorbed doses ranged from 1,000-1,500cGy/mCi, with lesion-to-whole body radiation absorbed-dose ratios of ~900. A dose of 8mCi and infusion volume of 8,000 µl is safe and may provide a distribution volume up to 20cm3. Median survival was 15.3 months (n =46, 95% CI 12.7, 17.3). Survival rate estimates (95% CI) at 1, 2, 3 and 5 years were 0.67 (0.55;0.82); 0.18 (0.09;0.35); 0.10 (0.04;0.26); and 0.05 (0.01;0.20). Four patients survived >3 years; two remain alive (61+ and 106+ months);two have died (44 and 53 month) with distant CNS disease and one with extra-CNS metastasis. CONCLUSION: Administration of escalating doses and volumes of 124I-omburtamab via CED was a viable option for this patient subgroup. The median overall survival was increased 3-4 months compared to historical controls. Anecdotal long-term survival if validated with a planned phase 2 trial would support the concept of whole neuroaxis treatment in combination with CED in a subset of DIPG patients.
DIPG-61. Preclinical efficacy of combined radiotherapy with venetoclax treatment in targeting diffuse midline gliomas
Authors: Madhavan Krishna , Balakrishnan Ilango , Lakshmanachetty Senthilnath , Pierce Angela , Sanford Bridget , Fosmire Susan , Elajaili Hanan , Walker Faye , Wang Dong , Nozik-Grayck Eva , Mitra Siddhartha , Dahl Nathan , Vibhakar Rajeev , Venkataraman Sujatha
Published: June 2022

BACKGROUND: H3K27M diffuse midline gliomas (DMGs) are highly aggressive pediatric tumors of pons, thalamus or spinal cord. The only standard-of-care for DMGs is radiation therapy (RT) since the anatomical location of such tumors does not allow surgical resection. Tumor response to RT is at best transient as tumor becomes refractory due to radioresistance. Tumor relapse after RT is a major hurdle in treating DMGs. The mechanism of development of radioresistance due to RT-induced stress has not been studied in DMGs yet. METHODS: We performed an integrated genomic analysis to determine genes responsible for radioresistance and a targeted drug screen to identify drugs synergizing with radiation in DMG. Effect of venetoclax on radiation-naïve and 6Gy radiated DMG cells was evaluated by studying cell death and apoptosis. The efficacy of combining venetoclax with radiation was evaluated in vivo using orthotopic xenograft models. RESULTS: We identified that BCL2 as a key regulator of tumor growth in DMGs after radiation. Radiation sensitizes DMGs to venetoclax treatment. While venetoclax as a monotherapy was not cytotoxic to DMG cells, post-radiation venetoclax significantly increased cell death and apoptosis. Combining venetoclax with RT significantly enhanced the survival of mice with DMG tumors in vivo. Further, we found that the mechanism of radiation-induced cytotoxic effect of venetoclax is p53-independent in DMGs. CONCLUSIONS: This study shows that venetoclax impedes the anti-apoptotic function of radiation-induced BCL2 in DMG leading to apoptosis. Our results are encouraging because, in clinical settings, majority of the DMG patients, irrespective of the tumor p53 status, will benefit from combining RT with venetoclax treatment. Since venetoclax either alone or in combination with chemotherapy drugs are currently in clinical trials for other pediatric cancers, a phase 1b trial is imminent for treating DMGs with venetoclax in combination with radiation therapy.