bluuebunny/crossref_metadata_2025_split huggingface dataset:
SPCR-10 CANCER CO-ROUNDS: A NOVEL INPATIENT MULTIDISCIPLINARY ONCOLOGY ROUNDING MODEL
Authors: Ni Lisa , Viner Jennifer , Phuong Christina , Liu S John , Yee Emily , Petrofsky Mary , Kwon Daniel H , Brondfield Sam , Boreta Lauren C , Daras Mariza 
Published: August 2023

Abstract

BACKGROUND
Although tumor boards are well-established for coordinating care of patients with cancer in the outpatient setting, few studies have evaluated interventions for improving consultative care coordination for hospitalized patients. This study evaluated the hypothesis that implementation of an inpatient co-rounding model of care including medical-, neuro-, and radiation-oncology consult teams would improve the alignment of recommendations from these oncologic services, as perceived by primary teams.

METHODS
A co-rounding model was implemented in September 2021 for hospitalized patients with cancer at a tertiary medical center. The oncologic consulting services met virtually twice weekly to discuss patient care. Providers from the most common primary services for patients with cancer, internal medicine (IM) and neurosurgery, were surveyed via institutional email listservs. The survey included Likert-type questions about the alignment of recommendations across services and open-ended questions for feedback on collaboration among these services. Pre-intervention surveys were distributed, and post-intervention surveys were distributed 9 months later. Wilcoxon rank-sum tests were used to compare responses pre- and post-intervention.

RESULTS
At each session, a median of 6 providers attended (range, 4-8 providers), and a median of 6 patients were discussed (range, 4-8 patients). Of the 331 providers surveyed, there were 119 (36%) respondents pre-intervention and 34 (10%) respondents post-intervention. The 132 unique respondents comprised 68 (52%) IM attending physicians, 48 (36%) IM resident physicians, 6 (5%) neurosurgery advanced practice providers, 6 (5%) neurosurgery attendings, and 4 (3%) neurosurgery residents. Post-intervention, respondents were significantly more likely to perceive alignment in oncologic consultant recommendations (67% strongly agree) compared to pre-intervention (23% strongly agree, p&lt;0.01).

CONCLUSIONS
A novel inpatient co-rounding model was successfully implemented between medical-, neuro-, and radiation-oncology. Primary teams perceived greater alignment in recommendations among these consulting services after implementation. Future directions include evaluation of the impact of this model on patient outcomes.
SPCR-12 A PROCESS IMPROVEMENT FOR INCREASING DEPRESSION AND ANXIETY SCREENING IN PATIENTS WITH BRAIN TUMORS
Authors: O’Sullivan Mary 
Published: August 2023

Abstract
Anxiety and depression are highly prevalent in patients with brain tumors. These conditions significantly affect quality of life and are associated with worsened survival. The Alvord Brain Tumor Center at UW did not have a process to screen patients for anxiety and depression. In response to this, a quality improvement project was developed to identify barriers and facilitators to mood screening and to introduce a new standard process for screening. We formed an interdisciplinary mood screening committee in the clinic to ensure a collaborative process with each profession’s voice accounted. The new process for mood screening consisted of the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) being automatically sent to all return patients’ MyChart accounts 24 hours before their scheduled appointment, repeating up to every six months. Upon completion of the questionnaires, the results would immediately file into the patient’s electronic medical record. The new process was implemented and we collected data from clinic visits over two weeks to determine its impact. Of all patients eligible for screening, 18% completed the screenings as a result of the new screening process, compared to the baseline 15% who had already completed the screenings in the last six months at other clinics within the health system, effectively doubling the number of patients in the clinic with mood screening in the last 6 months. Among those with MyChart accounts, the total response rate to the screenings was 24%. The automaticity of the process will help ensure an ongoing baseline standard for patients to be screened. In the future, an additional process will be developed to ensure that those without access to MyChart have equal opportunity for screening and treatment of mood disorders.
SYST-03 PHASE 1B STUDY OF AVELUMAB AND WHOLE BRAIN RADIOTHERAPY (WBRT) IN PATIENTS WITH LEPTOMENINGEAL DISEASE (LMD) FROM EPITHELIAL CARCINOMAS: FINAL RESULTS AND MOLECULAR ANALYSES WITH SINGLE CELL RNA SEQUENCING
Authors: Pina Yolanda , Chen Ann , Arrington John , Macaulay Robert , Tran Nam , Liu James , Mokhtari Sepideh , Li Jiannong , Law Vincent , Sahebjam Solmaz , Ahmed Kamran , Creelan Ben , Gray Jhanelle , Evernden Brittany , Khushalani Nikhil , Czerniecki Brian , Smalley Inna , Vogelbaum Michael , Yu Michael , Smalley Keiran , Forsyth Peter 
Published: August 2023

Abstract

BACKGROUND
LMD has a dismal prognosis with median overall survival (mOS) of 3-4 months (mo). Preclinical studies showed PD-1 axis blocking therapy promotes antigen presentation within the CSF compartment, and increases BBB permeability and ingress of activated T cells into the meninges/CSF space. In an open-label phase IB trial, we tested the safety and efficacy of Avelumab with WBRT in LMD (NCT0371768).

METHODS
Patients received Avelumab 800mg IV q2 weeks, up to 5 cycles (until PD or unacceptable toxicity) with WBRT 3000 cGy, 10 daily fractions. Primary endpoints were safety/DLTs and 3-mo OS. Secondary endpoints i.e., CSF T-cell transcriptome trajectory i.e., single cell RNA sequencing (scRNAseq). Patients with prior PD-1/PD-L1/CTLA-4/CD137 targeting therapy within 6mo were excluded.

RESULTS
15 patients were enrolled i.e., breast (8), lung (4), nasopharyngeal (1), ovary (1), and pancreas (1). 87% female, median age 59 range 32-82. 1 patient did not complete WBRT. 2 out of 15 patients had gr. 3/4 immune-related AEs (i.e., hypoadrenalism, hypothyroidism, lymphopenia); 5 patients had treatment-related &lt;gr. 3 AEs, i.e., hypoadrenalism, anemia, diarrhea, hypothyroidism, lymphopenia, thrombocytopenia, leukopenia). Median follow-up was 3.7mo (range, 0.9-36.8mo; 95% CI 1.3-14.7mo). Median follow-up time for survival analyses was 19.8mo. 10 out of 15 patients (66.7%) were alive at 3mo. mOS was 10.5 (95% CI 1.2 - 19.8mo). 1-year OS was 44% (95% CI: 19-68%). Median PFS was 4.3mo (95% CI, 0.9-15.2mo). 2 patients remain alive and well. ScRNAseq analyses are underway; signatures correlated with outcomes in short vs. long term survivors.

CONCLUSIONS
Combination of Avelumab and WBRT is safe, well tolerated, and shows encouraging activity in LMD with an OS longer than other published series. Multiple platform interrogation of CSF will be used to explore mechanisms of LMD response and resistance. Functional studies of scRNAseq and short vs. long term survivors should be further explored.
SYST-07 PLASMA MEMBRANE PROFILING REVEALS A TARGETABLE CELL-SURFACE PHENOTYPE OF WNT-MEDULLOBLASTOMA
Authors: Taylor Jessica , Williamson James , Masih Katherine , Bonner Sigourney , Lehner Paul , Gilbertson Richard 
Published: August 2023

Abstract
WNT-medulloblastoma has an excellent prognosis, with an overall survival rate of 90% among children receiving standard-of-care surgical resection, radiotherapy, and chemotherapy. While curative, this treatment is associated with major, long-term, debilitating side effects. Therefore, it is crucial we develop effective, less toxic therapies for these children. The Gilbertson lab has previously shown that WNT-medulloblastomas are devoid of a Blood-Brain-Barrier (BBB). This disruption allows large molecules such as monoclonal antibodies (mAbs) to penetrate WNT-medulloblastomas. To discover WNT-medulloblastoma specific antigens for mAb targeting, we have first generated bulk and single-cell RNA sequencing profiles of the wild-type and WNT-medulloblastoma-prone mossy-fibre progenitor lineages in the lower rhombic lip, as well as human medulloblastoma patient derived orthotopic xenograft (PDOX) tumours. We next generated plasma membrane proteome profiles of hindbrain germinal zones and WNT-medulloblastomas. Plasma Membrane Profiling (PMP) deploys an isobaric chemical labelling approach -Tandem Mass Tags (TMT) - that allows multiplexing of up to sixteen variables per mass spectrometry experiment and ex vivo TMT-labelling of primary cells. Using this approach, we have mapped the cell surface proteome of our medulloblastoma models. Interrogation of these developmental and tumour data has unmasked WNT-medulloblastoma associated antigens that are specific for prenatal brain and WNT-medulloblastoma, but that are not expressed on critical postnatal tissues. Our workflow integrates multi-omic data sets to uncover a targetable landscape on the surface of WNT-medulloblastoma cells that we have cross-validated with a large cohort of patient RNA sequencing profiles and histological samples of both mouse and human tumours. To translate this dataset to real patient benefit, we are generating high affinity antibodies of these validated cell-surface proteins for assessment in our pre-clinical mouse models. Through our comparative analyses we have additionally identified non-WNT-specific targets and thus aim to expand this approach to identifying targets in other more agressive CNS tumours and brain metastases.
SYST-13 AAV VECTOR ENCODING FC MODIFIED HER2 ANTIBODIES REDUCES TUMOR BURDEN WITH MINIMIZED PERIPHERAL EXPOSURE IN MODELS OF BREAST CANCER BRAIN METASTASIS
Authors: Laks Dan , Ren Xiaoqin , Shah Ishan , Thompson Jeffrey , Clement Joe , Moyer Tyler , Nonnenmacher Mathieu , Carter Todd 
Published: August 2023

Abstract
We engineered a HER2 Ab that inhibited HER2+ breast cancer cell growth in vitro and led to a profound increase in Ab-dependent CD16A receptor stimulation relative to trastuzumab, the standard of care. Blood-brain barrier penetrant AAV vectors were administered intravenously to mice orthotopically engrafted with HER2+ cancer cells. In both prophylactic AAV administration and a treatment model where AAV was dosed post-engraftment, the vectorized Ab significantly reduced tumor burden and prolonged survival. We employed single-cell RNA-Seq to characterize immune responses to these vectorized Abs. Upon dissociation of brains from tumor engrafted mice that underwent intravenous AAV treatment, we performed transcriptomic profiling of CD45+ immune cells. Our results indicate a pronounced innate immune response to the HER2 Ab that increased tumor-proximal natural killer cells and proliferating microglia. Response to gene therapy also included dendritic cells that are mediators of adaptive immune activation. Therefore, the adaptive immune system could augment the efficacy of the therapy when non-exhausted, tumor-associated T lymphocytes are present. To minimize potential neuronal toxicity, we evaluated the use of a GFAP promoter for astrocyte specific expression. Furthermore, to reduce patient risk of cardiac toxicity induced by antibody exposure, we engineered the Fc domain of the antibody so that it would not bind to FcRN, a receptor which promotes antibody recycling and subsequent increased antibody levels in the periphery. In mouse studies, treatment with a BBB-penetrant capsid with a GFAP driven construct and with binding to FcRN eliminated resulted in a 96% reduction in serum antibody levels, to 84% below an estimated cardiac toxicity threshold. Additionally, there was a 78% reduction in antibody levels in the heart, to 98% below an estimated cardiac toxicity threshold. Remarkably, brain levels were maintained. Our animal data indicate that vectorized HER2 antibody gene transfer may address unmet medical needs of patients.
SYST-14 D2C7 CAR EFFECTIVELY AND SAFELY TREATS EGFRWT AND EGFRVIII-EXPRESSING TUMORS FOLLOWING INTRACRANIAL ADMINISTRATION
Authors: Wilkinson Daniel , Wilson Joseph , Lerner Emily , Ryan Katherine , Chandramohan Vidyalakshmi , Landi Daniel , Bigner Darell , Fecci Peter 
Published: August 2023

Abstract
Glioblastoma (GBM) is the most aggressive primary brain cancer with a median survival of less than 16 months. Therefore, significant treatment advances are of critical need. Immunotherapies, such as chimeric antigen receptor (CAR) T cells, have achieved remarkable success in eliminating hematological cancers. Unfortunately, CARs have overall failed to control solid tumors. One major reason for this failure is tumor heterogeneity, a characteristic especially true of GBM. In GBM, EGFRvIII is a commonly targeted tumor antigen; however, only a subset of tumor cells will express EGFRvIII. Thus, EGFRvIII-negative cells easily escape EGFRvIII-targeting CAR therapies. A better approach would be to target multiple antigens or an antigen that is more homogeneously expressed throughout the tumor. More commonly than EGFRvIII expression, glioma cells overexpress the wildtype isoform of EGFR (EGFRwt). Simultaneously targeting EGFRvIII and EGFRwt, instead of targeting each independently, with a CAR will theoretically expand the amount of tumor that will be eliminated by the CAR. Here, we adapted the D2C7scFv that binds both EGFRwt and EGFRvIII into a third generation CAR. D2C7 CAR potently and specifically killed EGFRwt and EGFRvIII-expressing U87 glioma, but not U87 with EGFR knocked out. In xenograft models, intracranially administered D2C7 CAR significantly prolonged survival of mice bearing orthotopic U87vIII, U87 (EGFRwt), and heterogeneous U87/U87vIII tumors compared tocontrols. Additionally, D2C7 CAR was an effective treatment in an orthotopic EGFR-expressing medulloblastoma model. Furthermore, D2C7 CAR treatment led to a significant survival benefit in mice bearing intrancranial A431, an aggressive, EGFR-expressing carcinoma line, a model of metastasis to the brain. Importantly, D2C7 CAR did not show reactivity towards normal tissue with EGFR expression, suggesting a tumor-specific epitope of EGFR is being targeted. Together, these data provide evidence that D2C7 CAR can treat EGFR/EGFRvIII heterogeneous or homogeneous primary or metastatic brain tumors with potentially little-to-no off-tumor toxicity.
SYST-15 GENERATION AND MULTI-DIMENSIONAL PROFILING OF A CHILDHOOD CANCER CELL LINE ATLAS DEFINES NEW THERAPEUTIC OPPORTUNITIES
Authors: Daniel Paul , Sun Claire Xin , Bradshaw Gabrielle , Shi Hui , Loi Melissa , Chew Nicole , Parackal Sarah , Tsui Vanessa , Liang Yuqing , Koptyra Mateusz , Adjumain Shazia , Sun Christie , Chong Wai Chin , Fernando Dasun , Drinkwater Caroline , Tourchi Motahhareh , Habarakada Dilru , Carvalho Diana , Storm Phillip B , Baubet Valerie , Sayles Leanne C , Fernandez Elisabet , Zhukova Nataliya , Dun Matthew D , Ludlow Louise E , Day Bryan , Stringer Brett W , Neeman Naama , Rubens Jeffrey A , Raabe Eric H , Vinci Maria , Tyrrell Vanessa , Fletcher Jamie I , Ekert Paul G , Dumevska Biljana , Ziegler David S , Tsoli Maria , Sulaiman Nur Farhana Syed , Loh Amos Hong Pheng , Low Sharon Yin Yee , Sweet-Cordero E Alejandro , Monje Michelle , Resnick Adam , Jones Chris , Downie Peter , Williams Bryan , Rosenbluh Joseph , Gough Daniel , Cain Jason E , Firestein Ron 
Published: August 2023

Abstract
Paediatric solid tumours are the leading cause of cancer related death amongst children. Identification of paediatric-specific targeted therapies necessitates the use of paediatric cancer models that faithfully recapitulate the patient’s disease. In adult cancers, comprehensive cell line repositories and data atlases have enabled both hypothesis-driven research and scalable screens for new therapies. The generation and characterisation of paediatric cancer cell lines has significantly lagged behind that of their adult counterparts, underscoring the urgent need to develop a paediatric-focussed cell line resource. Herein, we establish a single-site collection of 261 cell lines, including 224 paediatric cancer cell lines representing 18 distinct extracranial and brain childhood tumour types. We subjected 182 paediatric cancer cell lines to multi-omic analyses across three dimensions (DNA-sequencing, RNA-sequencing, DNA methylation) to classify them based on clinically relevant molecular subtypes. In parallel, pharmacological and genetic CRISPR-Cas9 loss of function screens were performed to identify paediatric-specific drug sensitivities and genetic dependencies. Machine-learning approaches were employed to delineate predictive features of therapeutic vulnerabilities in different subtypes of paediatric cancers. By integrating molecular features with functional genomic and pharmacological profiles, we demonstrate how therapeutic target-biomarkers pairs may be rapidly prioritised and advanced. Lastly, we provide cell line data and resources in an open access portal (vicpcc.org.au/dashboard) to support drug development efforts, clinical trial design, and personalised medicine approaches for paediatric cancers of greatest unmet medical need.
SYST-24 PROPOFOL EXERTS ANTI-TUMOR EFFECTS IN GLIOMA AND THE TUMOR MICROENVIRONMENT VIA NON-CODING RNAS AND SECRETED EXOSOMES
Authors: Penning Donald , Cazacu Simona , Nizar Raphael , Xiang Cunli , Goldstein Hodaya , Krasner Matan , Barbiro-Michaely Efrat , Gerber Doron , Kazimirsky Gila , Rogers Lisa , Brown Stephan , Brodie Chaya 
Published: August 2023

Abstract

BACKGROUND
Glioblastoma (GBM), is the most common primary brain tumor. GBM contains a small subpopulation of glioma stem cells (GSCs) that are implicated in tumor recurrence and treatment resistance and therefore represent important therapeutic targets. Recent clinical studies suggest propofol impacts subsequent tumor response to treatments and patient prognosis. The effects of propofol on patient derived GSCs alone and in combination with radiation and temozolomide, (TMZ) have not been reported. Objectives: The molecular mechanisms underlying propofol’s anti-tumor effects on GSCs and its effect on cellular communication with microglia was studied. Using GSC spheroids, differentiated glioma and tumor cells on a microfluid chip, effects of propofol alone and together with radiation and TMZ on the self-renewal and stemness of GSCs, their mesenchymal transit and the proliferation and apoptosis of differentiated glioma cells was analyzed. Using transwell plates, the effects of propofol on the cross-talk of GSCs with human microglia cells was examined.

RESULTS
Propofol exerted a dose-dependent inhibitory effect on the self-renewal, expression of mesenchymal markers and migration of GSCs and sensitized them to both temozolomide (TMZ) and radiation. At higher concentrations propofol induced a large degree of cell death as demonstrated using microfluid chip. Propofol increased the expression of the lncRNA BDNF-AS, which acts as a tumor suppressor in GBM and silencing of this lncRNA partially abrogated propofol’s anti-tumor effects. Propofol also inhibited the pro-tumorigenic GSC-microglia cross talk via extracellular vesicles (EVs) and delivery of BDNF-AS.

CONCLUSIONS
Propofol exerted anti-tumor effects on GSCs and differentiated glioma cells by inhibiting cell renewal, proliferation, and mesenchymal transition and by inducing cell death at higher concentration. Propofol also sensitized GSCs to radiation and TMZ. Propofol, which is widely used in GBM surgeries, should be further explored as a potential repurposed drug during resection and an effective adjunct to radiation and TMZ.
SYST-27 INTERROGATION OF THE TUMOR IMMUNE MICROENVIRONMENT REVEALS DISTINCT IMMUNOSUPPRESSIVE LANDSCAPES IN GLIOBLASTOMA
Authors: Weng Linqian , Guyot Mélanie , Garg Abhishek , Lambrechts Diether , Bergers Gabriele 
Published: August 2023

Abstract
High-resolution sequencing technologies have revealed significant inter-and intra-tumoral molecular heterogeneity in glioblastoma (GBM), leading to an urgent need for novel targeted therapies. Our research using representative murine GBM models and various experimental techniques has shown that classical GBMs (e.g., EGFRvIII+, TIMElow) and mesenchymal GBMs (e.g., NF1ko/PTENko/p53ko, TIMEhigh) are both immunosuppressive but in distinct ways. TIMElow GBMs have a more impaired and less functional tumor vasculature, resulting in low infiltration of T cells with anergic features. TIMEhigh GBMs have a more intact BBB revealing overall more adaptive and innate immune cell infiltrates, but with highly dysfunctional T cells and immunosuppressive TME. Congruently, GSEA analysis of both human and murine GBM scRNA-seq data demonstrated enriched immunosuppressive signatures in the myeloid cell populations of TIMEhigh GBM compared to TIMElow GBM. Our findings have also revealed potential adaptive and intrinsic resistant mechanisms to antiangiogenic immunotherapy in TIMElow and TIMEhigh GBMs, respectively, with TIMElow GBMs exhibiting a transitory response to the treatment, while TIMEhigh GBMs being intrinsically resistant due to their intact tumor vasculature and reliance on dysfunctional T cells. We then tested the efficacy of different immunotherapies, including dendritic cell vaccination, a CD40 agonist, and a myeloid cell PI3K activity inhibitor in TIMElow and TIMEhigh tumors. Surprisingly, our results revealed that the response to these treatments can be either beneficial or detrimental and may depend on factors such as tumor antigenicity and TIME subtype. Overall, our study provides new insights into the intricate immune landscape of GBMs, emphasizes the importance of considering tumor subtypes as they may lead to potential unintended consequences of immunotherapies.
TIPS-09 FIRST-IN-HUMAN PHASE 1 TRIAL OF THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PRELIMINARY ANTI-TUMOR ACTIVITY OF WSD0922-FU (NCT04197934): TRIAL IN PROGRESS
Authors: Kizilbash Sani , Jaeckle Kurt , Mrugala Maciej , Allred Jacob , Reid Joel , Zhong Wei , Burns Terry , Giannini Caterina , Sarkaria Jann , Adjei Alex 
Published: August 2023

Abstract
WSD0922-Fu is an oral, central nervous system (CNS)-penetrant, small molecule, ATP non-competitive, reversible EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). MC1914 (NCT04197934, sponsored by Wayshine Biopharma and FDA OOPD) is a first-in-human phase 1 dose-escalation trial investigating the safety and tolerability of WSD0922-Fu in patients with EGFR aberrant recurrent HGA and NSCLC. Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR mutant and/or EGFR amplified HGA were initially treated with oral WSD0922-FU, with doses escalated in cohorts based on a standard 3 + 3 design to determine the maximum tolerated dose (MTD). After establishing the MTD, this trial has now activated three dose expansion cohorts. Two of these cohorts evaluate different dose/schedule strategies in independent populations. The NSCLC cohort includes patients with EGFR mutant NSCLC and CNS metastases, and examines the safety, tolerability, plasma pharmacokinetics and preliminary efficacy of continuous WSD0922-Fu dosing (twice daily, seven days per week). The HGA cohort includes patients with EGFRvIII mutant HGA at first recurrence after prior radiation/temozolomide and examines the impact of higher doses of WSD0922-Fu administered intermittently (twice daily, five days per week). The HGA cohort also includes a food-effect study which evaluates the effect of the fed and fasted states on plasma PK. The third cohort (Brain tumor penetration cohort) includes patients with HGA (any EGFR mutation and/or EGFR amplification) who need a surgical resection for recurrent disease. Patients enrolled will be treated pre-operatively with WSD0922-Fu for five days, and tumor PK/PD will be examined in samples obtained from image-registered brain tumor biopsies. WSD0922-Fu therapy will be resumed after post-operative recovery. Patient enrollment to all three dose expansion cohorts is ongoing.