bluuebunny/crossref_metadata_2025 huggingface dataset:
SDPS-38 A BRAIN METASTASES PREDICTION MODEL IN BREASTCANCER WOMEN
Authors: Cacho-Díaz Bernardo , Reynoso-Noveron Nancy
Published: August 2023

BACKGROUND

Breast cancer (BC) is a leading cause of mortality and the most frequent malignancy in women; most deaths are due to metastatic disease, expressly brain metastases (BM). Currently, there is no biomarker or a prediction model to accurately predict BM.

OBJECTIVE

To generate a BM prediction model from variables acquired at BC diagnosis.

METHODS

A retrospective cohort of BC women diagnosed from 2009 to 2020 at a single center was divided into training (TD) and validation datasets (VD). The TD was used to generate a multivariable prediction model. The modeĹs performance was measured applying the area under the curve (AUC), C-statistic, and the Akaike information criteria (AIC).

RESULTS

5,009 patients were divided into a TD (n 3339) and a VD (n 1670). In the TD, the model with the best performance (lowest AIC) was built with the following variables: Age, estrogen receptor status, tumor size, axillar adenopathy, AJCC anatomic clinical stage, Ki-67, and the Scarf-Bloom-Richardson score. This model had an AIC of 1241 and an AUC of 0.793 (95%CI 0.761 – 0.825) p <0.0001 in the TD. A 10-fold cross-validation showed good stability of the model. In the VD, the model had an AUC = 0.812 (IC95% 0.774 – 0.850) P < 0.0001 and an AIC = 644. Finally, we present with an online APP and an online calculator for its clinical use.

CONCLUSION

In a retrospective cohort of women with breast cancer, a prediction model built with clinical and pathological variables at diagnosis displayed a robust performance to measure the individual odds of BM. The model is currently considered for external validation in other institutions and countries.
SDPS-40 MEDULLOBLASTOMA MOLECULAR SUBTYPE PREDICTION USING PATHOMIC FEATURE ANALYSIS
Authors: Mahtabfar Aria , Familiar Ariana , Kazerooni Anahita Fathi , Kiani Mahsa , Khanna Omaditya , Viswanathan Karthik , Resnick Adam , Storm Phillip , Viaene Angela , Nabavizadeh Ali
Published: August 2023

The clinical course of pediatric medulloblastoma patients exhibits wide variability based on molecular subtype. The ability to predict medulloblastoma molecular subtypes (Group 3/4, WNT, SHH) based on histopathologic features alone has immense utility by providing clinicians insight into the molecular and biological underpinnings of the tumor. Although the use of computational pathology (“pathomics”) is expanding in multiple disciplines, its application in pediatric neuro-oncology has been limited. Our preliminary analysis highlights the potential for application in medulloblastoma and pediatric brain tumor research. Using the Children’s Brain Tumor Network database, pediatric patients with available clinical data, whole-slide images (WSI) and molecular subtyping were evaluated for inclusion. Regions-of-interest (ROI) on each H&E-stained WSI were selected for pathomic analysis, and features were extracted using a digital pathology software package (Qupath). 25 pathomic features capturing cellular and nuclear-level intensity and morphology properties were included. Subsequently, a histogram gradient boosting classifier was used to perform binary classification of Group 3/4 vs. SHH/WNT with leave-one-subject-out cross validation. A total of 68 subjects, with median age at diagnosis of 8.19 years (range 0.29-18.69), and median overall survival (OS) of 56 months (range 0.76-258.37) were identified. Our cohort included 44 and 24 subjects in Group 3/4 and SHH/WNT, respectively. Pathomic features classified subjects into Group 3/4 or SHH/WNT with a classification accuracy of 71% (SEM=0.06). A t-test against stratified chance accuracy (57%) showed significantly above-chance testing performance (p=.019). Inspection of the confusion matrix indicated better discrimination of Group 3/4 compared to SHH/WNT subjects, likely due to the larger number of these subjects in the dataset. Our preliminary analysis shows acceptable testing accuracy in distinguishing Group 3/4 from SHH/WNT medulloblastoma, and highlights the possibility of gaining molecular insight purely from histopathologic images. The potential of pathomic features should be considered an untapped resource.
SDPS-42 METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) AND BRAIN EDEMA: A TOPOGRAPHICAL AND CLINICOPATHOLOGIC INVESTIGATION
Authors: Yun Jonathan , Kurker Kristina , Maragkos Georgios , Sutherland Grant , Farzad Faraz , Sukumar Rohit , Feng Xue , Yener Ulas , Patel Sohil , Schiff David , Lopes Beatriz , Askun Melike Mut
Published: August 2023

Tumor-associated vasogenic brain edema is a well-known contributor of morbidity and mortality in patients with metastatic disease to the brain. It is widely accepted that metastatic disease to the brain is associated with extensive edema and can cause increased symptomatology such as pain, neurologic deficit, and elevated intracranial pressure depending on extent and location. We present a retrospective artificial intelligence (AI) mediated analysis of radiological and clinicopathologic data including specific molecular markers, presenting symptoms, and tumor location of 86 patients with non-small cell carcinoma of the lung (NSCLC) and brain metastases who underwent surgical resection and were not previously on steroids. We found that overall, tumors in all locations demonstrated a mean 10:1 edema to tumor ratio (ETR) and an occipital tumor location was associated with a significantly elevated ETR. Within our cohort there were no other factors that were significantly associated with ETR. This study demonstrates a proof of concept that NSCLC is associated with significant peritumoral edema and that topographical factors may be associated with increased extent of edema.
SDPS-44 RAPID DETECTION OF MUTATIONS IN CSF-CFTNA WITH THE GENEXUS INTEGRATED SEQUENCER
Authors: Arjuna Srividya , Shah Mauli , Dono Antonio , Pichardo Pavel , Nunez-Rubiano Luis , Zhu Jay-Jiguang , Riascos-Castaneda Roy F , Luthra Rajyalakshmi , Roy-Chowdhuri Sinchita , Duose Dzifa , Lang Frederick F , Esquenazi Yoshua , Ballester Leomar Y
Published: August 2023

Brain metastases commonly arise in patients with lung and breast carcinomas and pose distinctive clinical challenges. Genomic alterations are fundamental for diagnosis and therapy selection in cancer patients. However, the turn-around-time (TAT) of standard next generation sequencing (NGS) assays is a limiting factor in the timely delivery of genomic information for clinical decision making. The GenexusTM Sequencer automates the NGS workflow delivering results in less than 24hrs. The Oncomine Precision Assay (OPA) evaluates somatic mutations, copy number variations and fusions in hot-spot regions of 50 cancer-related genes. In this study, we evaluated genomic alterations in 46 cerebrospinal fluid (CSF) samples from 33 patients with metastatic lung cancer (mLC) (N=32) and metastatic breast cancer (mBC) (N=14) to the brain. Cell-free total nucleic acids, (cfTNA) were extracted using QIAamp Circulating Nucleic Acid kit with cfDNA concentrations ranging from 0.1-11.2(ng/ul) and 0.5-6.6 (ng/ul) for mLC and mBC samples, respectively. Median base coverage was 37,913X and 33,576.5X for mLC and mBC samples, respectively, with cfDNA input ranging from 2-20ng. Mutations were detected in 15/32 (46.8%) mLC and 8/14 (57.1%) mBC CSF samples. Among the samples with no mutations detected, 18/23 (78.2%) had suboptimal DNA input (<20ng). The EGFR exon 19 deletion was detected in 4 samples from one patient, with increasing mutant allele fraction in CSF over time, highlighting the potential of CSF-cfTNA analysis for monitoring patients. Moreover, the EGFR T790M mutation was detected in a patient with prior EGFR inhibitor treatment. In addition, ESR1 D538G and ESR1::CCDC170 alterations, associated with endocrine therapy resistance, were detected in 2 mBC patients. The average TAT from cfTNA-to-results was ~16hrs. In summary, our results indicate that CSF-cfTNA analysis with the OPA in the Genexus instrument can provide clinically relevant information in patients with brain metastases with a short TAT.
SPCR-07 REDEFINING BOUNDARIES: STEREOTACTIC RADIOSURGERY FOR ENHANCED QUALITY OF LIFE AND SURVIVAL IN PATIENTS WITH 5-20 BRAIN METASTASES
Authors: Cialdella Fia , van Grinsven Eva , van der Boog Arthur , Nagtegaal Steven , Smid Ernst , Claes An , Kleynen Karin , Seravalli Enrica , Philippens Marielle , van Zandvoort Martine , Verhoeff Joost
Published: August 2023

INTRODUCTION

Brain metastases (BMs) occur in 10-30% of adult patients with cancer. The therapeutic approach for BMs depends on several factors including lesion number, location and size, primary cancer type, and the patient’s overall health. ASCO-SNO-ASTRO guidelines conditionally recommend stereotactic radiosurgery (SRS) for 1-10 BMs. The aim of this study was to investigate the outcomes of radiotherapy in patients with 5 or more BMs using SRS.

METHODS

We implemented the prospective Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) to examine all patients with BM(s) who underwent radiotherapy. In this sub-study we investigated overall survival (OS) and health related quality of life (HRQoL) for 47 patients with 5 to 20 BMs. We evaluated patients’ HRQoL using the EQ5D-VAS, at baseline and at 3 monthly intervals after radiotherapy.

RESULTS

Median OS was 21.3 months for patients with 5-10 BMs (n=38) and 12.5 months for patients with >10 BMs (n=9). Questionnaires at both baseline and 6 months after radiotherapy showed stability or improvement on the EQ5D-VAS after radiotherapy in 58.1%. Additionally, independence in self-care was not limited before or after SRS. Also, the proportion of patients (66.7%) reporting no limitation on their ability to do daily activities remained stable after radiotherapy. Fewer patients reported pain or other discomfort after SRS compared to before (25% vs 40%).

CONCLUSION

Our findings suggest that radiotherapy may improve QoL in patients with 5-20 BMs. Furthermore, compared to the literature, we observed a prolonged OS in this prospective cohort, suggesting that SRS should be considered as the treatment option for these patients. These results highlight the need for further investigation of the role of SRS instead of Whole Brain Radiotherapy (WBRT) in the management of patients with multiple BMs.
SPCR-08 ACADEMIC READINESS AMONG CHILDREN TREATED FOR BRAIN TUMORS IN INFANCY
Authors: Silverman Melanie , Ashford Jason , Swain Michelle , Harder Lana , Carlson-Green Bonnie , Wallace Joanna , Kaner Ryan , Billups Catherine , Onar-Thomas Arzu , Merchant Thomas , Gajjar Amar , Conklin Heather
Published: August 2023

BACKGROUND

Children treated for brain tumors are more likely to have academic difficulties, receive special education services, and experience lower educational attainment than peers. Infants receiving treatment are at highest risk due to increased vulnerability of the developing brain and missed early developmental opportunities. The current study is the first to examine the emergence of academic readiness in children treated for brain tumors in infancy.

METHODS

Children were treated on a prospective, longitudinal multisite study with chemotherapy, with or without focal proton or photon radiation therapy (SJYC07). Academic readiness was monitored with the Bracken School Readiness Composite (SRC), and once age-appropriate, academic skills were assessed with the Woodcock Johnson III (WJII) word reading and applied math subtests. A subset of patients (n=70; median age at treatment 1.7 years; 67% male; 79% White) who completed the SRC during at least 2 timepoints were included.

RESULTS

Linear mixed models revealed SRC scores decreased significantly over time (p=0.033). There was a main effect of socioeconomic status (SES) such that lower SES predicted lower SRC scores, irrespective of time since treatment (p<0.0001). Other demographic and clinical factors were not predictive (i.e., age at diagnosis, disease risk, resection extent, number of surgeries, chemotherapy vs photon irradiation vs proton irradiation, shunt status, tumor location; ps>0.05). At the most distal assessment timepoint (median time since treatment 5.96 years), 28.8% and 20.3% scored below average (less than one standard deviation) on WJIII word reading and applied math, respectively; the former was significantly greater than normative expectations (16%, p=0.007).

CONCLUSIONS

Treatment for brain tumors in infancy appears to slow development of academic readiness skills, with SES predictive of risk and a disproportionate number of long-term survivors performing below age expectations in reading. These findings suggest the need for monitoring and interventions targeting early academic skills in this population.
SYST-18 BELZUTIFAN TREATMENT FOR PATIENTS WITH VON HIPPEL-LINDAU DISEASE–ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMAS ENROLLED IN THE PHASE 2 LITESPARK-004 STUDY
Authors: Narayan Vivek , Iliopoulos Othon , Iversen Ane B , Maughan Benjamin L , Beckermann Kathryn E , Oudard Stephane , Else Tobias , Maranchie Jodi K , Fu Wei , Perini Rodolfo F , Liu Yanfang , Linehan W Marston , Srinivasan Ramaprasad , Jonasch Eric
Published: August 2023

Previous results of the ongoing single-arm, phase 2 LITESPARK-004 (NCT03401788) study showed clinically meaningful antitumor activity with the HIF-2α inhibitor belzutifan for von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), CNS hemangioblastomas, and other neoplasms. Adults with VHL disease diagnosis based on germline VHL alteration, ≥1 measurable RCC tumor, and no prior systemic anticancer treatment received belzutifan 120 mg orally once daily. End points included ORR, DOR, and PFS per RECIST v1.1; linear growth rate (LGR); and safety. CNS hemangioblastomas were assessed with measurable (≥1 cm) and/or nonmeasurable disease at baseline, which included associated cysts if present, or with measurable disease at baseline excluding associated cysts. Of enrolled patients, 50/61 (82%) had ≥1 CNS hemangioblastoma evaluable at baseline; 22/50 patients (44%) underwent ≥1 CNS-related surgery within 4 years before starting belzutifan treatment. Median follow-up for patients with CNS hemangioblastomas was 38.0 months (range, 36.1-46.1). ORR was 44% and DCR was 90%. Median DOR was not reached (NR; range, 3.7+ to 38.7+ months). Median PFS was NR (95% CI, 38 months-NR). After initiating belzutifan, median LGR for all evaluable patients was –1.6 mm/year (range, –7.0 to 3.1). A total of 25/50 patients (50%) had ≥1 measurable CNS hemangioblastomas, excluding any associated cysts. For these patients, ORR was 76% and DCR was 96%. Median DOR was NR (range, 3.7+ to 38.7+ months). Median PFS was NR (95% CI, 36 months-NR). After initiating belzutifan, median LGR was –1.1 mm/year (range, –3.9 to –0.1). Of all patients, 1/50 (2%) underwent a CNS-related surgery after starting belzutifan. Two patients (3%) discontinued treatment due to treatment-related adverse events. In summary, consistent and durable antitumor activity was observed in patients with CNS hemangioblastomas. Our data demonstrated that belzutifan induced the shrinkage of VHL disease-related CNS hemangioblastomas with or without the presence of associated cysts.
SYST-32 A NOVEL APPROACH TO TARGET TREG-MEDIATED IMMUNOSUPPRESSION IN GBM
Authors: Pant Ayush , Jain Aanchal , Jackson Christopher , Lim Michael
Published: August 2023

Macrophage inflammatory protein-3, or MIP-3α, is a chemokine that is highly expressed in gliomas, with expression progressively increasing with tumor grade. It is one of the top expressed genes in pseudopalisading and perinecrotic zones of glioblastoma (GBM) and as a chemokine, can greatly influence tumor-immune interactions. The receptor for MIP-3α, CCR6, is found on a variety of GBM-infiltrating immune subsets such as γδ T cells, conventional CD4 T cells and most notably, Tregs, which is disproportionately increased in GBM patients. Patients with lower CCR6-MIP3α gene signatures in tumors have improved overall survival and disease-free progression. We have found that circulating MIP-3α is also increased in the presence of intracranial glioma in mice, and can be normalized with immunotherapy. We note that ablation of CCR6 remarkably improves response of glioma-bearing mice to anti-PD-1 therapy. Mechanistically, we observed a reduction in regulatory T cell immunosuppressive phenotype with CCR6 ablation, which improves CD8 T cell effector function against tumor cells. Specifically, we found that CCR6 expression marks highly glycolytic Tregs, which is a known mechanism of immunosuppression of CD8 T cells, and that ablation of CCR6 from Tregs reduces their glycolytic capacity and immunosuppressivity. Targeting the CCR6:MIP-3α axis can therefore be a promising approach to alleviate CD8 T cell immunosuppression in GBM and to improve anti-tumor response.
TIPS-04 A RANDOMIZED, MULTI-INSTITUTIONAL PILOT STUDY TO EVALUATE THE MOLECULAR AND CELLULAR RESPONSE TO TREATMENT WITH NIVOLUMAB WITH EITHER ADJUVANT IPILIMUMAB OR RELATLIMAB IN ADULT PATIENTS WITH SURGICALLY RESECTABLE MELANOMA BRAIN METASTASES: ONGOING TRIAL
Authors: Pina Yolanda , Chen Ann , Tran Nam , Etame Arnold , Liu James , Furlan Andre Beer , Mokhtari Sepideh , Peguero Edwin , Li Jiannong , Law Vincent , Khushalani Nikhil , Smalley Inna , Vogelbaum Michael , Yu Michael , Arrington John , Macaulay Robert , Tawbi Hussein , Smalley Keiran , Forsyth Peter
Published: August 2023

BACKGROUND

Melanoma brain metastases (MBM) is a major cause of morbidity and mortality. The way melanoma malignant cells interact with the microenvironment in distal sites including the brain, plays a major role in tumorigenesis, metastasis, and tumor survival. Data supports the tumor microenvironment (TME) in MBM is different at the molecular/cellular level than the TME in other metastatic sites. Objectives: (1) to determine the safety and feasibility of presurgical administration of Nivolumab (Nivo) in combination with Ipilimumab (Ipi) or Opdualag (Nivo + Relatlimab [Rela]); and (2) to investigate the TME and estimate the immune cell population difference between the different treatment groups.

METHODS

We are carrying a randomized open label pilot study with adult patients (n=24) with MBM with surgically resectable brain tumors, who have not received treatment with immune-checkpoint inhibitors for six months or with BRAF/MEK inhibitors for 1 month, and on ≤3 mg/day dexamethasone or equivalent/day. Patients will be treated with either Nivo+Ipi, Opdualag, or no treatment pre-surgery (NCT05704933). Following treatment, all subjects will undergo surgical resection of their brain tumors and systemic disease biopsy, if clinically indicated. Post-surgery, all subjects will receive stereotactic radiosurgery (SRS) or fractionated SRS (fSRS), followed by Nivo+Ipi x4 dosages and adjuvant Nivo for 1 year or until disease progression and/or intolerable adverse events. All subjects will be on levetiracetam 500 mg twice a day or equivalent medication throughout the duration of the study. A lumbar puncture for CSF collection will be performed if clinically indicated and CSF and blood collected at different time points. Collected tissue will be send for sc RNA-seq, TCR/BCR seq. A one-way ANOVA will be used to compare the cellular population differences between treatment arms. CNS clinical response will be defined using RANO-BM and i-RANO. Trial is open and actively recruiting.
TIPS-11 EFFICACY AND SAFETY OF STUPP REGIMEN WITH OR WITHOUT ANLOTINIB FOR NEWLY DIAGNOSED GLIOBLASTOMA: INTERIM RESULTS OF A MULTICENTER, DOUBLEBLIND, RANDOMIZED PHASE II TRIAL
Authors: Chen Yuanyuan , Liu Guihong , Li Meihua , Wang Liang , Sun Pengfei , Chen Zhongping
Published: August 2023

BACKGROUND

Postoperative radiotherapy with concomitant temozolomide (TMZ) followed by ≤ six cycles of adjuvant TMZ chemotherapy (STUPP regimen) is the standard treatment for newly diagnosed glioblastoma (GBM) with limited effectiveness. Anlotinib inhibits both tumor angiogenesis and tumor cell proliferation by targeting multiple kinases, and showing promising results in preclinical GBM models and phase I clinical trials. We designed a phase II trial to verify the efficacy and safety of the STUPP regimen plus anlotinib (NCT 04959500).

METHODS

This is a multicenter, double-blind, randomized, placebo-controlled trial with an expected 150 patients randomly assigned 1:1 ratio to receive TMZ-based radiochemotherapy with anlotinib or placebo. Major eligibility criteria include histologically confirmed newly diagnosed GBM and an ECOG performance score ≤2. Other criteria for inclusion include age ≥18 years and lack of significant comorbidity. The primary endpoint is the median progression-free survival (PFS). Secondary endpoints include 1-year overall survival rate, PFS at 6 months, overall response rate, duration of response, disease control rate, quality of life, and toxicity.

RESULTS

From July 2021 to February 8th 2023, 147 patients were enrolled. The results in this abstract were all obtained without exposing the blind state. The median PFS was 9.9 months (95% CI, 9.5-11.9) in the overall patient population, while the predicted mPFS of placebo group was 7 months according to the results of STUPP and AVAGlio trials. Grade 1 (72.82%) and grade 2 (24.27%) adverse events (AEs) were mainly observed, while grade 3 or worse AEs accounted for 2.9% among all AEs. The most frequent TRAEs were lymphocytopenia, decreased platelet count, decreased white blood cell count, decreased neutrophil count and hypertension. Two death cases occurred due to COVID-19 and severe pneumonia.

CONCLUSIONS

Under the condition of data blinding, these interim results suggest that the STUPP regimen with anlotinib demonstrate potential promising efficacy and a tolerable safety.
TIPS-15 NEUROCOGNITIVE FUNCTION AND NEUROCOGNITIVE CONCERNS IN AN ONGOING PHASE III TRIAL OF PRE-OPERATIVE SRS VERSUS POST-OPERATIVE SRS FOR BRAIN METASTASES
Authors: Wefel Jeffrey , Noll Kyle , Rao Ganesh , Ferguson Sherise , Tawbi Hussein , Huse Jason , Johnson Jason , Court Laurence , O'Brien Barbara , Lang Frederick , Ejezie Lynette , Sullaway Catherine , Thomas Ashley , Suki Dima , Yeboa D Nana
Published: August 2023

In our ongoing phase III randomized trial (NCT03741673) evaluating risk of leptomeningeal disease (LMD) in patients with brain metastasis, patients are stratified by tumor size, location, and histology, and randomized to pre-operative SRS versus post-operative SRS. The primary endpoint is 1-year LMD-free rate, and exploratory endpoints include neurocognitive function (NCF). NCF is assessed prior to treatment and longitudinally (1.5, 6, and 12 months from the start of treatment) with the HVLT-R, TMT, and COWA yielding the Clinical Trial Battery Composite score (CTB COMP). Patients also complete the MDASI-BT, which includes a Cognitive Factor measuring patient reported cognitive concerns. Currently, 41 patients completed pre-treatment NCF baseline. Characteristics of patients with pre-treatment NCF baseline include mean (SD): age 60.0+/-11.7 years, 2.6+/-2.2 metastases, 15.2+/-10.1 cc brain metastases volume, median KPS 90 (range: 70-100), 83% white, 52% male, and 50% received AEDs at time of surgery. The most common primary cancers among this cohort were: 31% NSCLC, 19% RCC, 14% melanoma, 7% breast, 2% thyroid, and 26% other. Mean (SD) NCF z-scores ranged from z= -0.09 (1.08) to -3.09 (6.13), CTB COMP z=-1.13 (1.65), and the mean (SD) MDASI-BT Cognitive Factor score was 1.1 (1.3). Using multivariable linear regression including CTB COMP, MDASI-BT Cognitive and Affective Factor, KPS, number of and intracranial volume of metastases, only intracranial volume of metastases was statistically significantly associated with CTB COMP (B=-.058, p=.034) and only the MDASI-BT Affective Factor was statistically significantly associated with the MDASI-BT Cognitive Factor (B=.305, p=<.001). At baseline, disease factors such as tumor burden appear to be the primary driver of objectively measured neurocognitive dysfunction and mood factors appear to be the primary driver of subjective patient reported neurocognitive concerns. This has important implications for interpretation of these different clinical outcome assessments in clinical trials measuring objective neurocognitive function and subjective neurocognitive concerns.
TIPS-22 A TWO-PART, PHASE 1 STUDY OF RHENIUM (186RE) OBISBEMEDA (186RNL) DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) FOR RECURRENT, REFRACTORY, OR PROGRESSIVE CHILDHOOD EPENDYMOMA AND HIGH-GRADE GLIOMA (HGG)
Authors: Plant Ashley , DeCuypere Michael , Lam Sandi , Quijano Carla , Bao Ande , Moore Melissa , LaFrance Norman , Hedrick Marc , Brenner Andrew , Michalek Joel
Published: August 2023

INTRODUCTION: Childhood ependymoma and HGG are difficult tumors to treat. Recurrent ependymoma is treated with re-resection and multiple rounds of EBRT. HGG is treated with chemoradiation followed by clinical trials, if available. While EBRT remains a central component of management, it is limited by tolerance of the surrounding normal brain tissue. 186RNL permits the selective delivery of beta-emitting radiation with excellent tumor retention. In an adult Phase 1/2 trial for recurrent glioblastoma (NCT01906385), the mean absorbed dose to the tumor was ~300-500 Gy, markedly higher than absorbed doses typically delivered by EBRT. Despite this, no dose-limiting toxicity was observed, and no treatment-related serious adverse events have occurred. Here, we describe the first pediatric trial using a two-part, Phase 1 dose-finding study followed by expansion cohorts to explore efficacy. Enrolling subjects will be 6 to 21 years of age with a diagnosis of recurrent ependymoma or HGG. Subjects will be allowed to enroll either if they have exhausted standard of care options or if they are clinically stable and surgical resection can be deferred by 4 weeks. Part 1 will enroll up to 24 subjects to determine the maximum feasible dose (MFD) of 186RNL administered by CED. Tumor size and concentration of infusate will be escalated in each cohort (A-D) to a maximum tumor diameter of 6 cm (114.1 mL) and a concentration of 2mCi/ml. Up to 4 CED catheters will be used. Part 2 will independently evaluate 186RNL in 2 different expansion cohorts: Cohort 2A: recurrent ependymoma; Cohort B: recurrent HGG. The primary endpoint for Cohort 2A is overall response rate (ORR) by Radiographic Assessment in Pediatric Neuro-Oncology (RAPNO) criteria and the primary endpoint for Cohort 2B is progression free survival. Planned enrollment will begin in early 2023.
TIPS-23 SAFETY AND FEASIBILITY RESULTS FROM A PHASE 1/2 CLINICAL TRIAL OF RHENIUM (186RE) OBISBEMEDA (186RNL) IN RECURRENT GLIOMA: THE RESPECT-GBM TRIAL
Authors: Brenner Andrew , Patel Toral , Youssef Michael , Bao Ande , Phillips William , Hedrick Marc , Moore Melissa , LaFrance Norman , Weinberg Jeffrey , Floyd John , Michalek Joel
Published: August 2023

OBJECTIVES

186RNL is BMEDA-chelated 186Re encapsulated in nanoliposomes. 186Re’s ~2 mm beta emission path length provides direct delivery of radiation therapy while sparing surrounding healthy tissue. 186RNL is delivered via convection enhanced delivery (CED) to achieve durable, localized tumor retention with high absorbed radiation doses. We present results from our ongoing ReSPECT-GBM trials (NCT01906385).

METHODS

ReSPECT-GBM is a multi-center, sequential cohort, open-label, dose escalation, Phase 1/2 clinical trial in adults with recurrent glioma to evaluate the safety, tolerability, and activity of a single dose of 186RNL administered by CED. Following computer-assisted MRI guidance treatment planning for CED catheter placement, patients received a single administration of 186RNL before whole body planar and SPECT/CT imaging for dosimetry and distribution. Patients were followed for safety, progression, and survival.

RESULTS

25 patients across 8 dosing cohorts including 23 with recurrent GBM were treated with a single dose of 186RNL ranging from 1.0-41.5mCi. Average absorbed radiation dose (AARD) to the tumor was ~300 Gy over a wide range. Exposure outside the brain was negligible. A single dose of 186RNL was well-tolerated, with no dose limiting toxicities. No patient had treatment-related death or withdrawals and most AEs mild or moderate (Grade 1 or 2) and non-serious. 5 patients remain alive. mOS for all patients was >12 months, with an OS30 of 25% overall and 50% for those receiving >100Gy. Cox Proportional Hazards Ratio and Accelerated Failure Time modeling both demonstrate absorbed dose and percent tumor treated to significantly correlate with overall survival (p<0.003-0.0001). Five patients have subsequently enrolled in Phase 2 and all are alive.

CONCLUSION

A single dose of 186RNL in recurrent glioma patients achieves high absorbed doses without significant toxicity, is well tolerated, and shows favorable OS. Cohort 8 and Phase 2 continue enrolling. Development progress and data will be reported.
Nursing Education as a Key Strategy to Combat Ageism: Preparing Nurses to Proactively Dismantle Their Own Ageist Views as Well as Ageist Practices Within Health Care Settings
Authors: Tweedie Jeanine
Published: August 2023

The prevalence of ageism in health care prevents nurses from providing the best care to older adults. Nursing education can prepare nurses to proactively dismantle their own ageist views as well as ageist practices within health care settings. Active learning strategies, such as role-play and case studies, can be used to teach nurses how to become anti-ageism advocates and improve the quality of health care for older adults.
Open Educational Resources: Equitable and Affordable Nursing Education
Authors: Friday Vivienne Evet , Hunt Cynthia
Published: August 2023

This research report describes findings from a study conducted to learn students’ experiences using open educational resources (OER) in an online nursing research course. Twenty-three students participated in a pilot study in which traditional textbooks were replaced with OER as the primary course material. Data were collected by administering open-ended and closed-ended questions about students’ experiences and demographic characteristics. Findings indicated that OER were cost-effective, accessible, easy to navigate, and interesting. The resources were adequate to meet student learning outcomes. Challenges experienced were related to poor Internet access for a few students.
Laparoscopic Oblique Rectus Abdominis Myocutaneous Flap Harvest for Perineal Reconstruction After Abdominoperineal Resection
Authors: Devriendt Stefanie , Van Praet Laura , Bislenghi Gabriele , D’Hoore André J. L. , Wolthuis Albert M.
Published: August 2023

BACKGROUND:

Treatment of perineal defects after abdominoperineal resection or salvage surgery for either locally advanced rectal cancer or anal carcinoma can be challenging. Myocutaneous flap reconstruction has proven to reduce perineal morbidity and abscess formation in the pelvis; however, it is associated with significant donor-site morbidity. To our knowledge, this is the first report of a laparoscopic oblique rectus abdominis myocutaneous flap harvesting for perineal reconstruction. This technical note aimed to demonstrate the feasibility of the technique.

IMPACT OF INNOVATION:

Introduction of a laparoscopic technique in harvesting of this flap can potentially further reduce morbidity associated with this flap creation by minimizing abdominal wall trauma and obviating the need for laparotomy for tunneling of the flap intra-abdominally.

TECHNOLOGY, MATERIALS, AND METHODS:

This report describes a technique using a 6-port laparoscopy, in which the harvesting of the myocutaneous flap was performed after a standardized abdominoperineal resection. The flap itself is passed through the rectus sheath toward the pelvis with the help of a retractor.

PRELIMINARY RESULTS:

Two patients successfully underwent a laparoscopic oblique rectus abdominis flap reconstruction after abdominoperineal resection.

CONCLUSION AND FUTURE DIRECTIONS:

This report describes our initial experience with laparoscopic harvesting of an oblique rectus abdominis flap for perineal reconstruction after abdominoperineal resection. We believe the technique is easy and reproducible for laparoscopic surgeons and can reduce donor-site morbidity. However, further studies will be needed to confirm this observation.
A global action agenda for turning the tide on fatty liver disease
Authors: Lazarus Jeffrey V. , Mark Henry E. , Allen Alina M. , Arab Juan Pablo , Carrieri Patrizia , Noureddin Mazen , Alazawi William , Alkhouri Naim , Alqahtani Saleh A. , Anstee Quentin M. , Arrese Marco , Bataller Ramon , Berg Thomas , Brennan Paul N. , Burra Patrizia , Castro-Narro Graciela E. , Cortez-Pinto Helena , Cusi Kenneth , Dedes Nikos , Duseja Ajay , Francque Sven M. , Gastaldelli Amalia , Hagström Hannes , Huang Terry T.K. , Ivancovsky Wajcman Dana , Kautz Achim , Kopka Christopher J. , Krag Aleksander , Newsome Philip N. , Rinella Mary E. , Romero Diana , Sarin Shiv Kumar , Silva Marcelo , Spearman C. Wendy , Terrault Norah A. , Tsochatzis Emmanuel A. , Valenti Luca , Villota-Rivas Marcela , Zelber-Sagi Shira , Schattenberg Jörn M. , Wong Vincent Wai-Sun , Younossi Zobair M. ,   on behalf of the Healthy Livers, Healthy Lives Collaborators
Published: August 2023

Background and Aims:

Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care.

Approach and Results:

We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of “agree” responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% “agree”). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance.

Conclusions:

This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.
Host genetic variation guides hepacivirus clearance, chronicity, and liver fibrosis in mice
Authors: Brown Ariane J. , Won John J. , Wolfisberg Raphael , Fahnøe Ulrik , Catanzaro Nicholas , West Ande , Moreira Fernando R. , Nogueira Batista Mariana , Ferris Martin T. , Linnertz Colton L. , Leist Sarah R. , Nguyen Cameron , De la Cruz Gabriela , Midkiff Bentley R. , Xia Yongjuan , Evangelista Mia D. , Montgomery Stephanie A. , Billerbeck Eva , Bukh Jens , Scheel Troels K.H. , Rice Charles M. , Sheahan Timothy P.
Published: August 2023

Background & Aims:

Human genetic variation is thought to guide the outcome of HCV infection, but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus, closely related to HCV, causes chronic liver infection in rats but causes acute self-limiting hepatitis in typical strains of laboratory mice, which resolves in 2 weeks. The Collaborative Cross (CC) is a robust mouse genetics resource comprised of a panel of recombinant inbred strains, which model the complexity of the human genome and provide a system within which to understand diseases driven by complex allelic variation.

Approach & Results:

We infected a panel of CC strains with Norway rat hepacivirus and identified several that failed to clear the virus after 4 weeks. Strains displayed an array of virologic phenotypes ranging from delayed clearance (CC046) to chronicity (CC071, CC080) with viremia for at least 10 months. Body weight loss, hepatocyte infection frequency, viral evolution, T-cell recruitment to the liver, liver inflammation, and the capacity to develop liver fibrosis varied among infected CC strains.

Conclusions:

These models recapitulate many aspects of HCV infection in humans and demonstrate that host genetic variation affects a multitude of viruses and host phenotypes. These models can be used to better understand the molecular mechanisms that drive hepacivirus clearance and chronicity, the virus and host interactions that promote chronic disease manifestations like liver fibrosis, therapeutic and vaccine performance, and how these factors are affected by host genetic variation.
Legislative Advocacy on Capitol Hill
Authors: Jagger Kaeser Jennifer G. , Farley Cindy L. , Bradford Heather M. , Heitzler Ella T. , McDevitt Katie , Gutterman Zoe
Published: August 2023

Background:

Policies, regulations, and laws influence all aspects of health care, including the education of health care professionals, independent practice, and patient access to care. Health equity and social justice are mediated through policy.

Problem:

While health policy knowledge and skills are recognized as essential competencies within nursing and midwifery curricula, most students graduate with limited or no experience engaging in advocacy efforts to advance legislation that would improve health systems and the delivery of care.

Approach:

An experiential learning activity is described that gives students authentic experience in federal legislative advocacy.

Outcomes:

Students report powerful, positive learning from interacting with their legislators.

Conclusion:

Support of a legislative advocacy experiential learning activity requires ongoing faculty initiative and can promote advancement of health policy bills into law. Opportunities to participate in legislative advocacy need to be expanded within nursing and midwifery education to cultivate leaders who can effect policy change.
Nocardia australiensis sp. nov. and Nocardia spumae sp. nov., isolated from sea foam in Queensland, Australia
Authors: Wright Luke , Nouioui Imen , Mast Yvonne , Bunk Boyke , Spröer Cathrin , Neumann-Schaal Meina , Wolf Jacqueline , Katouli Mohammad , Kurtböke D. İpek
Published: August 2023

Strains USC-21046T and USC-21048T were isolated from foaming coastal marine waters on the Sunshine Coast, Queensland, Australia. Both strains displayed growth and morphological characteristics typical for members belonging to the genus

Nocardia

. The major polar lipids were diphosphatidylglycerol and phosphatidylethanolamine, and the major fatty acids were C16 : 0, C18 : 1 ω9c, C18 : 0 and C18 : 0 10-methyl. The mycolic acids of strains USC-21046T and USC-21048T consisted of chain lengths between 50–64 and 56–68, respectively. Moreover, both of those strains contained meso-diaminopimelic acid and ribose, arabinose, glucose and galactose as whole cell sugars. Based on the phylogenomic results, both strains belonged to the genus

Nocardia

with strain USC-21046T showing an 80.4 % genome similarity to

N. vinacea

NBRC 16497T and

N. pseudovaccinii

NBRC 100343T, whereas USC-21048T strain showed an 83.6 % genome similarity to

N. aobensis

NBRC 100429T. Both strains were delineated from their closely related relatives based on physiological (e.g. growth on sole carbon source) and chemotaxonomic (e.g. cellular fatty composition) differences. The digital DNA–DNA hybridization (dDDH) values between USC-21046T and USC-21048T and their closely related relatives were below the dDDH threshold value of ≤70 % used for the taxonomic classification of novel species status. The genome length of strains USC-21046T and USC-21048T were 6 878 863 and 7 066 978 bp, with G+C contents of 65.2 and 67.8 mol%, respectively. For the novel isolates, we propose the names Nocardia australiensis sp. nov. with the type strain USC-21046T (=DSM 111727T=NCCB 100867T) and Nocardia spumae sp. nov. with the type strain USC-21048T (=DSM 111726T=NCCB 100868T).
PharaohFUN: PHylogenomic Analysis foR plAnt prOtein History and FUNction elucidation
Authors: Ramos-González Marcos , Ramos-González Víctor , Arvanitidou Christina , Hernández-García Jorge , García-González Mercedes , Romero-Campero Francisco José
Published: August 2023

Motivation

Since DNA sequencing has turned commonplace, the development of efficient methods and tools to explore gene sequences has become indispensable. In particular, despite photosynthetic eukaryotes constituting the largest percentage of terrestrial biomass, computational functional characterization of gene sequences in these organisms still predominantly relies on comparisons withArabidopsis thalianaand other angiosperms. This paper introduces PharaohFUN, a web application designed for the evolutionary and functional analysis of protein sequences in photosynthetic eukaryotes, leveraging orthology relationships between them.

Results

PharaohFUN incorporates a homogeneous representative sampling of key species in this group, bridging clades that have traditionally been studied separately, thus establishing a comprehensive evolutionary framework to draw conclusions about sequence evolution and function. For this purpose, it incorporates modules for exploring gene tree evolutionary history, domain identification, multiple sequence alignments, and functional annotation. The study of the CCA1 protein exemplifies how PharaohFUN unifies results for both land plants and chlorophyte microalgae, accurately tracing the evolutionary history of this protein.

Availability and Implementation

PharaohFUN web application is freely available athttps://greennetwork.us.es/AlgaeFUN/and its source code can be freely accessed athttps://github.com/fran-romero-campero/AlgaeFUN.

Contact

fran@us.es
The pace of mitochondrial molecular evolution varies with seasonal migration distance
Authors: Pegan Teresa M. , Berv Jacob S. , Gulson-Castillo Eric R. , Kimmitt Abigail A. , Winger Benjamin M.
Published: August 2023

Animals that engage in long-distance seasonal migration experience strong selective pressures on their metabolic performance and life history, with potential consequences for molecular evolution. Species with slow life histories typically show lower rates of synonymous substitution (dS) than “fast” species. Previous work has suggested that long-distance seasonal migrants have a slower life history strategy than short-distance migrants, raising the possibility that rates of molecular evolution may covary with migration distance. Additionally, long-distance migrants may face strong selection on metabolically important mitochondrial genes owing to their long-distance flights. Using over 1000 mitochondrial genomes, we assessed the relationship between migration distance and mitochondrial molecular evolution in 39 boreal-breeding migratory bird species. We show that migration distance correlates negatively with dS, suggesting that the slow life history associated with long-distance migration is reflected in rates of molecular evolution. Mitochondrial genes in every study species exhibited evidence of purifying selection, but the strength of selection was greater in short-distance migrants, contrary to our predictions. This result may indicate selection for cold tolerance on mitochondrial evolution among species overwintering at high latitudes. Our study demonstrates that the pervasive correlation between life history and molecular evolutionary rates exists in the context of differential adaptations to seasonality.
From Proteins to Ligands: Decoding Deep Learning Methods for Binding Affinity Prediction
Authors: Gorantla Rohan , Kubincová Ažbeta , Weiße Andrea Y. , Mey Antonia S. J. S.
Published: August 2023

Accuratein silicoprediction of protein-ligand binding affinity is important in the early stages of drug discovery. Deep learning-based methods exist but have yet to overtake more conventional methods such as giga-docking largely due to their lack of generalisability. To improve generalizability we need to understand what these models learn from input protein and ligand data. We systematically investigated a sequence-based deep learning framework to assess the impact of protein and ligand encodings on predicting binding affinities for commonly used kinase data sets. The role of proteins is studied using convolutional neural network-based encodings obtained from sequences and graph neural network-based encodings enriched with structural information from contact maps. Ligand-based encodings are generated from graph-neural networks. We test different ligand perturbations by randomizing node and edge properties. For proteins we make use of 3 different protein contact generation methods (AlphaFold2, Pconsc4, and ESM-1b) and compare these with a random control. Our investigation shows that protein encodings do not substantially impact the binding predictions, with no statistically significant difference in binding affinity for KIBA in the investigated metrics (concordance index, Pearson’s R Spearman’s Rank, and RMSE). Significant differences are seen for ligand encodings with random ligands and random ligand node properties, suggesting a much bigger reliance on ligand data for the learning tasks. Using different ways to combine protein and ligand encodings, did not show a significant change in performance.

TOC Graphic
XRN1deletion induces PKR-dependent cell lethality in interferon-activated cancer cells
Authors: Zou Tao , Zhou Meng , Gupta Akansha , Zhuang Patrick , Fishbein Alyssa R. , Wei Hope Y. , Zhang Zhouwei , Cherniack Andrew D. , Meyerson Matthew
Published: August 2023

Emerging data suggest that induction of viral mimicry responses through activation of double-stranded RNA (dsRNA) sensors in cancer cells is a promising therapeutic strategy. One approach to induce viral mimicry is to target molecular regulators of dsRNA sensing pathways. Here, we show that the exoribonuclease XRN1 is a negative regulator of the dsRNA sensor protein kinase R (PKR) in cancer cells with high interferon-stimulated gene (ISG) expression.XRN1deletion causes PKR activation and consequent cancer cell lethality. Disruption of interferon signaling with the JAK1/2 inhibitor ruxolitinib can decrease cellular PKR levels and rescue sensitivity toXRN1deletion. Conversely, interferon-β stimulation can increase PKR levels and induce sensitivity toXRN1inactivation. Lastly,XRN1deletion causes accumulation of endogenous complementary sense/anti-sense RNAs, which may represent candidate PKR ligands. Our data demonstrate how XRN1 regulates PKR and nominate XRN1 as a potential therapeutic target in cancer cells with an activated interferon cell state.