bluuebunny/crossref_metadata_2025_split huggingface dataset:
MDB-44. A TRANSFER LEARNING APPROACH FOR AUTOMATIC SEGMENTATION OF TUMOR SUB-COMPARTMENTS AND TUMOR HABITAT IN PEDIATRIC MEDULLOBLASTOMA
Authors: Bareja Rohan , Ismail Marwa , Martin Doug , Nayate Ameya , Yadav Ipsa , Labbad Murad , Tamrazi Benita , Salloum Ralph , Margol Ashley , Judkins Alexander , Iyer Sukanya , de Blank Peter , Tiwari Pallavi 
Published: June 2023

Abstract

PURPOSE
Accurate delineation of pediatric medulloblastoma (MB) tumors is required for accurate surgical resection and efficient treatment planning. However, manual delineation is time consuming and prone to errors and inter-reader variability. We present the first attempt at automatic segmentation of MB tumors via a transfer learning approach that utilizes adult brain tumor segmentations to optimize segmentation of 1) the pediatric tumor habitat, comprising enhancing tumor (ET), necrosis/non-enhancing tumor (NET), and edema sub-compartments, and 2) the individual tumor sub-compartments.

METHODS
Our cohort consisted of 300 adult tumor MRI scans (BRATS) and 78 pediatric MB scans (46 training, 32 testing) with Gd-T1w, T2w, and FLAIR protocols. Training set subjects were collected from Children’s Hospital of Los Angeles (N=18) and Cincinnati Children’s Hospital Medical Center (N=28), whereas test set subjects were collected from Children’s Hospital of Philadelphia. Preprocessing included age-specific atlas registration, skull stripping, and bias correction. Then, using nnUnet framework, we trained 3D- deep learning U-net models on BRATS dataset for the tumor sub-compartments: ET, edema, and NET + necrosis, as well as the tumor habitat. Our initial learning rate was 0.01, with stochastic gradient descent as optimizer, and an average of dice loss and cross-entropy loss as the loss function. We then performed transfer learning using Models Genesis on the pediatric subjects.

RESULTS
Our segmentation model yielded mean dice scores of 0.87± .02 for tumor habitat, .83± .04 for ET, .742±.05 for edema, and .54±.11 for NET + necrosis, across fivefold cross-validation runs. For test set, our model yielded mean dice scores of 0.80 for the tumor habitat, 0.67 for ET, 0.54 for edema, and 0.28 for NET + necrosis.

CONCLUSION
Our transfer learning model shows promise in accurate automatic delineation of the MB tumor habitat and its individual sub-compartments, towards efficient surgical and treatment planning in MB tumors.
SURG-04. INFLUENCE OF LOW-INTENSITY FOCUSED ULTRASOUND ON LOCOREGIONAL DRUG DELIVERY TO THE BRAIN
Authors: Martin Brice , Uribe Rafael , Larabee Madeline , Stavarache Mihaela , Dahmane Nadia , Kaplitt Michael , Souweidane Mark 
Published: June 2023

Abstract

INTRODUCTION
Efficient delivery of therapeutic drugs across the blood-brain barrier (BBB) for the treatment of central nervous system (CNS) tumors is a major challenge to the development of safe and efficacious therapies. Among the different approaches developed to circumvent these limitations to improve drug delivery to a target tissue, low-intensity focused-ultrasound (LIFU) is a particularly appealing strategy as it will transiently disrupt the blood-brain barrier. Locoregional (intrathecal [IT] and convection-enhanced delivery [CED]) are clinically relevant routes of drug delivery that bypass the BBB and avoid systemic exposure. These routes of administration are known to achieve otherwise unobtainable drug concentration in specified target tissue. However, it remains unknown how locoregional routes of delivery coupled with FUS could change the drug targeting and pharmacokinetics.

METHODS
In the present study, we quantitatively assessed how FUS coupled with IT, IV, or CED altered fluorescent dye (Dextran 2000kD) distribution and concentration in a predetermined neurotomical region in a naïve murine model. We then analyzed the pharmacokinetic effects of using FUS mediated BBB disruption coupled with CED by measuring the volume of distribution and time-dependent concentration of the dye.

RESULTS
Our results indicate that IV administration coupled with LIFU will successfully cause diffusion of dye into the pre-defined sonication targets. Alternatively, measurable dye in the sonication target was hardly detected when administered IT in comparison to IV delivery (VIT = 1.25mm3; VIV = 36.20mm3). In addition, our preliminary qualitative analysis suggests that LIFU coupled with CED shows shorter time of residence of the dye in the parenchyma when compared to CED alone. This suggests that increased BBB permeability from FUS leads to faster drug clearance.

CONCLUSION
Our results highlight the distributive and pharmacokinetic influence of FUS on various locoregional drug delivery routes.
SURG-06. ENHANCED DELIVERY OF ANTI-PD1 FOR TREATMENT OF DIFFUSE MIDLINE GLIOMA USING FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING
Authors: Kokossis Danae , Wei Hong-Jian , Gallitto Matthew , Yoh Nina , McQuillan Nicholas , Tazhibi Masih , Berg Xander , Zhang Xu , Szalontay Luca , Gartrell Robyn D , Pavisic Jovana , Zhang Zhiguo , Molotkov Andrei , Mintz Akiva , Konofagou Elisa E , Wu Cheng-Chia 
Published: June 2023

Abstract
Diffuse midline glioma with H3K27 mutation is a fatal central nervous system tumor, most commonly arising in the brainstem. Despite a multitude of clinical trials, prognosis remains poor with a median overall survival of 9-12 months. Immune-checkpoint inhibitors (ICIs) have transformed the treatment landscape of multiple solid tumors. Programmed cell death protein 1 (PD1) is an immune checkpoint protein expressed on the surface of activated T cells; interaction with its ligand, PDL1, is tumor-protective, dampening T cell response. Recent phase I clinical trials have shown that ICIs targeting proteins along the PD1/PDL1 axis are well tolerated in patients with DMG; however, efficacy remains low. The blood-brain barrier (BBB) poses a major challenge to the efficacious delivery of therapeutic agents with large molecular size, such as anti-PD1. Here we show that delivery of anti-PD1 can be enhanced over 3.5-fold using low intensity focused ultrasound (FUS) and concurrent microbubble administration to achieve reversible blood-brain barrier opening (BBBO) in a syngeneic mouse DMG model established with intracranial injection of cell line 4423 (PDGFB+, H3.3K27M, p53-/-). We measured this increased delivery of anti-PD1 after BBBO using Western Blot and 3D in vivo optical fluorescent imaging/CT (OI/CT) of Cy7 labeled anti-PD1. OI/CT revealed enhanced real-time antibody distribution peritumorally. Furthermore, we demonstrated that this combined treatment of FUS and anti-PD1 led to benefit in local control of tumor growth using volumetric analysis of MRI. Preliminary survival studies suggest a positive trend for overall survival. We consider these findings strong rationale for further investigation of the therapeutic effects of combinatorial treatment using FUS-mediated BBBO and ICIs for the treatment of DMG.
OTHR-04. DEVELOPMENT OF A FUNCTIONAL PLATFORM FOR REAL-TIME PERSONALIZED DRUG SENSITIVITY PROFILING OF PATIENT-DERIVED 3D FRESH TUMOR TISSUE CULTURES IN THE PEDIATRIC PRECISION ONCOLOGY PROGRAM INFORM
Authors: Peterziel Heike , Jamaladdin Nora , ElHarouni Dina , Gerloff Xenia F , Herter Sonja , Fiesel Petra , Berker Yannick , Blattner-Johnson Mirjam , Schramm Kathrin , Jones Barbara C , Reuss David , Turunen Laura , Friedenauer Aileen , Holland-Letz Tim , Sill Martin , Weiser Lena , Previti Christopher , Balasubramanian Gnanaprakash , Gerber Nicolas U , Gojo Johannes , Hutter Caroline , Øra Ingrid , Lohi Olli , Kattamis Antonis , de Wilde Bram , Westermann Frank , Tippelt Stephan , Graf Norbert , Nathrath Michaela , Sparber-Sauer Monika , Sehested Astrid , Kramm Christof M , Dirksen Uta , Kallioniemi Olli , Pfister Stefan M , van Tilburg Cornelis M , Jones David T W , Saarela Jani , Pietiäinen Vilja , Jäger Natalie , Schlesner Matthias , Kopp-Schneider Annette , Oppermann Sina , Milde Till , Witt Olaf , Oehme Ina 
Published: June 2023

Abstract
The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.
OTHR-05. A LIVING EX VIVO PLATFORM FOR FUNCTIONAL, PERSONALIZED PEDIATRIC BRAIN CANCER DIAGNOSIS
Authors: Mann Breanna , Zhang Xiaopei , Bell Noah , Adefolaju Adebimpe , Thang Morrent , Dasari Rajaneekar , Kanchi Krishna , Valdivia Alain , Yang Yang , Quinsey Carolyn , Rauf Yasmeen , Kram David , Cassidy Noah , Viziri Cyrus , Corcoran David L , Rego Stephan , Jiang Yuchao , Graves Lee M , Dunn Denise , Floyd Scott , Baldwin Albert , Hingtgen Shawn , Satterlee Andrew 
Published: June 2023

Abstract
Functional precision medicine platforms are emerging as promising strategies to improve pre-clinical drug testing and guide clinical decisions. We have developed an organotypic brain slice culture (OBSC)-based platform and multi-parametric algorithm which enable rapid engraftment, treatment, and analysis of fresh patient brain tumor tissue and patient-derived cell lines. The platform has supported engraftment of every patient tumor tested to this point: high- and low-grade adult and pediatric tumor tissue rapidly establish on OBSCs among endogenous astrocytes and microglia while maintaining the tumor’s original DNA profile. Our algorithm calculates dose-response relationships of both tumor kill and healthy tissue toxicity, generating summarized drug sensitivity scores based on therapeutic window and allowing us to normalize response profiles for a panel of FDA-approved and exploratory agents. Summarized patient tumor scores after OBSC treatment revealed positive associations to clinical outcomes, suggesting the OBSC platform can provide rapid, accurate, functional testing to ultimately guide patient care.
OTHR-06. NARRATIVE MEDICINE AND THE PRACTICE OF PEDIATRIC NEURO-ONCOLOGY: GRAPPLING WITH THE UNTHINKABLE
Authors: Riley Kathy , Toback Alison 
Published: June 2023

Abstract
As pediatric neuro-oncology team members work with patients, they engage in life and death struggles on behalf of children. Among patients who survive, many are left with intellectual decline, psychological difficulties, inability to take on daily life skills, and an overall decrease in health-related quality of life (Castellino et al., 2014). Absorbing the weight of these stories of illness and complex survival leads to risk of burnout and moral distress. This research sought to understand how pediatric neuro-oncology team members at a U.S. hospital interact with, interpret, and make meaning of the illnesses, complex recoveries, and deaths of patients as a result of participating in a series of narrative medicine workshops. In the workshops, team members encountered fictional stories of loss and longing for restoration as they engaged in close reading and discussion of a text. Writing about the text after participating in discussion helped members connect more deeply to their own formative stories. Further, it enlarged their capacity to connect to the stories of fellow team members and the narratives of patients and their families. Those who practice narrative medicine seek “to recognize, absorb, interpret, and be moved to action by the stories of others” (Charon et al., 2017, p. 1). Its methods harness creativity and insight to equip those in healthcare not only to diagnose and treat their patients but to bear witness to what patients undergo (Charon et al., 2017). If team members train themselves to see the beauty, pain, complexity, and ambiguity in a work of art, they may in turn see their patients and one another as works of art. The act of engaging in narrative medicine practice as a healthcare team in and of itself alleviates distress and fosters collaborative relationships among team members as they grapple with unthinkable loss in their work.
OTHR-11. THE IMPORTANCE AND INFLUENCE OF PATIENT FAMILY INVOLVEMENT IN PEDIATRIC NEURO-ONCOLOGY RESEARCH
Authors: Lyons Nicole , Resnick Adam , Waanders Angela , Nazarian Javad , Bornhorst Miriam , Minturn Jane E , Koptyra Mateusz , Monje-Deisseroth Michelle , Souweidane Mark , Greenfield Jeffery P , Smith Amy , Hegert Julia , McLean Ginny , Gustafson Patti , Gustafson Allen , Ward Lisa 
Published: June 2023

Abstract
The involvement of patient families in clinical research in pediatric brain cancer is an underutilized tool that benefits all those involved. These families are ultimately responsible for making decisions on treatment, as well as end-of-life decisions such as post-mortem tissue donation. As demonstrated by organizations such as Gift from a Child, listening to family input on how to best have the conversation surrounding post-mortem tissue donation has led to an increase in total donations, as well as parents stating they are overwhelmingly happy with their decision to donate. Tissue donation is just one example of a large, complex hindrance in the field that had not previously been addressed successfully. Due to the rarity and devastating impact of pediatric brain tumors, the family community is tight-knit and passionate. There is incredibly impactful communication that happens between families influencing decision-making for treatment, funding, and advocacy. Partnering with families allows care teams and researchers both the ability to understand the decision-making process as well as educate and discuss with the families. Surveys of families overwhelmingly show satisfaction with the decision to donate post-mortem and dissatisfaction when they are deprived of the option. Frustration with the lack of treatment has led families to become more proactive in both their child’s treatment and future research. Increasingly, family advocates are becoming more sophisticated in their support of research opportunities. An example of this spearheading the creation of an open access, safe, anonymized data bank with clinical data paired to the patient’s tumor tissue. Family foundations are actively partnering with researchers and industry to make it happen. It is clear that this type of partnership is a strong force for change that benefits researchers, clinicians, and most importantly, patients and their families.
XRT-01. LONG-TERM HEARING LOSS IN CHILDREN WITH MEDULLOBLASTOMA AFTER PROTON IRRADIATION AND CHEMOTHERAPY
Authors: Abu-Arja Mohammad H , Brown Austin L , Su Jack M , Okcu M Fatih , Lindsay Holly B , McGovern Susan L , McAleer Mary Frances , Grosshans David R , Chintagumpala Murali M , Paulino Arnold C 
Published: June 2023

Abstract

PURPOSE
To evaluate the incidence and risk factors for hearing loss (HL) among children with medulloblastoma treated with proton irradiation and cisplatin.

METHODS
We identified children with medulloblastoma ≥3 years of age treated at Texas Children’s Hospital between 2007-2022. Audiograms were graded using the International Society of Pediatric Oncology-Boston scale (SIOP-Boston). Time to grade ≥3 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI).

RESULTS
Seventy-eight patients (65.4% male) were treated with craniospinal irradiation (CSI) at a median age of 7.6 years (range: 3-21). The mean cochlear irradiation dose was 31.5±9 Gy, and the cumulative cisplatin dose was 295±50 mg/m2. Fifty-six patients (72%) received amifostine. Patients completed a median of 9 audiograms (range: 4-22) with a median audiogram follow-up of 49 months (range: 3-177). Grade ≥3 HL was documented in 25 patients (32%). In adjusted Cox models, mean cochlear dose (HR=1.12, 95% CI: 1.06-1.18) and the age at CSI (HR=0.81, 95% CI: 0.68-0.98) were associated with grade ≥3 HL. Among children who received irradiation after or at 7 years of age, the estimated probability of grade ≥3 HL at three years post-CSI was 12.6% (95% CI: 4.1-34.6) in children exposed to &lt;36 Gy cochlear irradiation and 35.6% (95% CI: 17.4-63.6) in children exposed to &gt;36 Gy cochlear irradiation. Among children who received irradiation before 7 years of age, the estimated probability of grade ≥3 HL at three years post-CSI was 16.5% (95% CI: 5.6-43) in children exposed to &lt;36 Gy cochlear radiation and 66.7% (95% CI: 35.4-93.7) in children exposed to &gt;36 Gy cochlear irradiation.

CONCLUSION
Long-term follow-up shows that children who received a cochlear dose ≥36 Gy before 7 years of age are at higher risk for HL, regardless of the amifostine and the cisplatin dose.
XRT-03. EFFICACY OF RE-IRRADIATION FOR PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Cai Linbo , Lai Mingyao , Li Juan , Zhou Jiangfen , Li Shaoqun 
Published: June 2023

Abstract

OBJECTIVE
To analyze the efficacy and prognosticators of pediatric diffuse intrinsic pontine glioma (DPC) treated with re-irradiation.

METHODS
The clinical data and prognostic information of DIPG children younger than 18 years old who received re-irradiation in the Department of Oncology of Guangdong Sanjiu Brain Hospital from May 1, 2021, to November 1, 2022, were collected. The overall survival (OS) was calculated, and univariate analysis was performed to analyze the effect of tumor volume change and rate of change on survival.

RESULTS
Fifteen patients met the inclusion criteria. The median interval between the first and second radiotherapy was 8.8 months. The median survival after re-irradiation was 3.9 months, and the median overall survival was 16.9 months. Severe complications such as fatal radiation brain necrosis was observed after re-irradiation.

CONCLUSIONS
Re-irradiation is still the primary treatment for pediatric diffuse intrinsic pontine glioma, prolonging their survival.
TRLS-01. FDA ANALYSIS OF EXPANDED ACCESS USE IN PEDIATRIC PATIENTS WITH CNS TUMORS FROM 2015 TO 2020
Authors: Duke Elizabeth , Kormanik Natasha , Barone Amy , Chan Mitchell , Antony Ramya , Drezner Nicole , Kluetz Paul , Kim Tamy , Singh Harpreet , Pazdur Richard , Donoghue Martha 
Published: June 2023

Abstract
Few therapies are approved for children with central nervous system (CNS) tumors, and their prognosis is often poor. Expanded Access (EA) is a regulatory mechanism enabling patients with life-threatening or serious diseases to receive treatment with investigational drugs outside of clinical trials when no comparable or satisfactory options are available. FDA’s central database was queried for single-patient investigational new drug (spIND) applications submitted to the Office of Oncologic Diseases between January 2015-December 2020. Data collection included IND date/type/status, drug name, patient demographics. Duplicate/exempt INDs, those cancelled by physician-sponsor before initiating therapy, and those for indications occurring almost exclusively in adults or missing patient age were excluded. Of 2,901 unique spINDs granted, 534 (18%) were for patients &lt;18 years old; of those, 229 (43%) were for patients with nervous system tumors. Demographics included: 53% male, median age 5.0 years (range 0.3-17); race/ethnicity reported in &lt;1%. Patients were treated in 78 zip codes across 33 states; one-third of submissions were from 5 large academic hospitals. Tumor types included low-grade glioma (71), plexiform neurofibroma (35), high-grade glioma (32), DIPG/DMG (30), ATRT (27), medulloblastoma (11), ependymoma (11), other CNS tumors (12). Thirty-eight unique drugs were requested (1 to 56 spINDs per drug); 60% for kinase inhibitors, 30% for other small molecule inhibitors, and the remainder for immunotherapies/other drug types. Median time for FDA to review and deem safe to proceed was 1 day. While pediatric CNS tumors are rare, these patients made up almost half of spINDs granted for pediatric patients. Ongoing efforts are needed to assess the impact of EA on patient outcomes and ensure availability to patients, families, and institutions more widely. These data highlight interest within the pediatric neuro-oncology community in accessing innovative therapies, which supports early investigation of promising new drugs for these patients.
TRLS-03. IBRUTINIB DISRUPTS BLOOD-TUMOR BARRIER INTEGRITY TO ENHANCE CNS DRUG DELIVERY AND RODENT GLIOMA MODEL SURVIVAL
Authors: Lim Sanghee , Kwak Minhye , Tang Kayen , Cesaire Melissa , Robey Robert , Gottesman Michael , Jackson Sadhana 
Published: June 2023

Abstract

BACKGROUND
In the setting of malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-brain-barrier (BBB). Identifying agents that transiently increase BBB permeability would advance glioma treatment. Ibrutinib, an FDA approved lymphoma treatment, has previously impaired aortic endothelial adhesion and in combination with cytotoxic therapy, increased rodent glioma model survival. In this study, we propose ibrutinib inhibits brain endothelial cell junctional expression to disrupt BBB integrity and increase chemotherapy delivery to malignant glioma cells.

METHODS
Using rat glioma cells, S635, we evaluated treatment effects with doxil (3mg/kg), ibrutinib (25mg/kg) and combination therapy. We measured effects with serial brain MRIs, doxil plasma and brain regional concentrations, along with 3kD dextran permeability. To evaluate the effects of ibrutinib on in vitro brain endothelial cells, we measured changes in cell-cell electrical impedance and rhodamine efflux, as a surrogate of Abcb1 transporter function, over time (0 to 8h) and at varied drug concentrations (1, 5, and 10µM ibrutinib).

RESULTS
Ibrutinib in combination with doxil, prolonged median survival in rodent glioma models (18 vs. 24days, p&lt;0.05). MRI findings demonstrated a -14 or -53% vs -75% tumor volume change with doxil or ibrutinib alone vs. combination therapy, respectively (p&lt;0.05). Comparing combination therapy vs. doxil alone, ibrutinib increased CNS concentrations of doxil in the tumor injected brain regions with statistical significance (56ng/mL vs. 74.6ng/mL, p&lt;0.05). In in vitro studies, ibrutinib decreased brain endothelial cell-cell impedance maximally at 2 hours, in a dose dependently without affecting cell viability. Additionally, we observed ibrutinib dose dependently inhibit Abcb1 activity in both endothelial and glioma cells.

CONCLUSION
Our results suggest ibrutinib increases brain endothelial permeability by causing junctional disruption and inhibition of Abcb1, resulting in increased CNS drug entry and prolonged survival in glioma rat models.