bluuebunny/crossref_metadata_2025_split huggingface dataset:
(113) PRACTICAL DISTRESS AT DIAGNOSIS PORTENDS WORSE SEXUAL WELL-BEING DURING BREAST CANCER TREATMENT
Authors: Higgins M , Ludwigson A , Helmkamp L , Adams M , Baurle E , Vemuru S , Huynh V , Colborn K , Coons H , Rojas K E , Tevis S 
Published: June 2024

Abstract

Introduction
A breast cancer diagnosis and subsequent treatment can have profound impacts on patients' body image and sexual health. Sexual health and well-being are an unmet concern for many and declines in sexual function have been associated with higher distress and anxiety.

Objective
Our study aims to evaluate how distress at diagnosis is related to sexual well-being and referral to ancillary resources during breast cancer treatment at a comprehensive cancer center.

Methods
All patients with newly diagnosed breast cancer were offered a distress screening tool which measures distress in the emotional (I.e. worry, nervousness), physical (I.e. nausea, sexual intimacy, fatigue), social (I.e. relating with others), and practical domains (I.e. bills, housing, transportation). High distress in a domain was defined as a score greater than 5. Patients were then invited to complete the Breast-Q module, a validated patient reported outcome (PRO) scale that quantifies outcomes related to sexual well-being (SW). Participants who had at least one distress measure at baseline and at least one PRO at either baseline or 6-months post-operatively were eligible for inclusion. Chart review was conducted for referral to and utilization of ancillary services including sexual health consultation. Multivariable linear mixed models were used to compare high and low distress with an interaction between distress and time.

Results
227 patients were included in the study population. The median baseline SW score was 55.4 (standard deviation = 22.9). High practical distress was found in 18.4% of patients, however, those with high practical distress at baseline were more likely to have greater decline in their SW scores between the pre-operative and 6-month post-operative time points (p = 0.03) (Figure 1). After adjusting for age, stage, and treatment received, this relationship remained significant. Of the available ancillary resources, social work and care management services were the most common referrals with 135 patients seen. Only 4 patients attended a sexual health consultation based on clinician discretion. Change in pre-operative and 6-month post operative SW was not related to emotional, physical, or social distress.

Conclusions
Sexual well-being trajectories are related to practical distress at diagnosis. This suggests that patients who are already struggling with the logistics of a new breast cancer diagnosis may suffer the most when it comes to their sexual health. Most patients here received some ancillary support however it is clear something is still missing given the observed declines in sexual well-being. Further study is necessary to understand the drivers of this relationship and how these patients can receive early intervention to prevent worsening of their sexual well-being during breast cancer treatment.

Disclosure
No.
(119) COPING WITH BREAST CANCER: A LOOK AT EXPRESSIVE WRITING INTERVENTIONS
Authors: Patel P , Bachmann G 
Published: June 2024

Abstract

Introduction
Introduction: Coping with a breast cancer diagnosis is individualized and patient strategies vary throughout their dealing with this cancer. Coping methods include, but are not limited to: support groups, counseling, practicing mindfulness, spending time with family and friends, etc. One such technique is expressive writing (EW); writing that is focused on intrusive thoughts and emotional aspects related to their cancer.

Objective
Objectives: This meta-analysis reviewed published data regarding EW and its effects on the quality of life (QOL), including the sexual life, of breast cancer patients and survivors. Writing is a form of self-expression, which not only allows patients control of their emotions and treatment but also serves to improve the quality of care given to breast cancer patients and survivors. Thus, the ability to better implement personalized medicine remains at the center of holistic care. Additionally, we aimed to emphasize the existing clinical gap between minority groups, specifically Asian Americans, and ethnically prevalent groups.

Methods
Methods: A literature search was performed using PubMed to identify Randomized Controlled Trials (RCT) conducted within the United States between the years 2008 and 2023. Only RCTs with quantitative results from pre- and post-writing intervention were considered. While the structure of RCTs varied, all included interventions incorporated one or more EW group(s) and/or one or more NW (neutral writing) group(s). Measures of interest included: self-reflections from participants, linguistics, sleep quality, and Post-traumatic Stress (PTSD) symptoms.

Results
Results: The writing interventions studied included both NW and EW groups. These interventions resulted in various reductions of physical symptoms (ex: pain, nausea, headaches, etc.) and psychological changes (in mood, sleep, depression, and anxiety), after patients in EW groups self-reflected. Writing interventions with ethnic minorities are limited; however, writing interventions with Asian American participants improved PTSD-related symptoms and quality of life. Chinese-American women face cultural stigmatism, which may cause patients to fear sharing their deepest emotions, a possible explanation for the observed positive influence of EW for these participants. Unfortunately, no RCTs that associated EW with sexual well-being were analyzed.

Conclusions
Conclusions: The findings of this meta-analysis note that RCTs suggest that there is a link between EW and better coping with breast cancer. However, results may differ based on population, demographics, and cancer stage/treatment. The narrow scope of RCTs with ethnic minorities highlights that EW as a coping method for such populations remains understudied. As well, there are no data on its impact on sexual well-being-an area of research that requires more attention as women of all walks of life navigate their respective breast cancer diagnoses.

Disclosure
No.
(133) SELF-REPORTED EFFICACY OF PELVIC FLOOR PHYSICAL THERAPY AS A TREATMENT FOR PUDENDAL NEURALGIA: A CROSS-SECTIONAL STUDY
Authors: Niedenfuehr J , Stevens D , King L 
Published: June 2024

Abstract

Introduction
Pudendal neuralgia (PN) is a devastating sexual pain disorder characterized as pain of the genital and/or perineal regions and is often due to injury, irritation, or entrapment of the pudendal nerve. Pelvic floor physical therapy (PFPT) is a recommended treatment for PN despite the lack of clinical evidence supporting its use.

Objective
We aimed to understand the efficacy of PFPT for treating PN by evaluating self-reported efficacy from PN patients.

Methods
An online survey was conducted on PN patients who had participated in PFPT as a treatment for PN. Participants were asked to evaluate the efficacy of PFPT specifically regarding its effects on PN symptoms using a seven-point Patient Global Impression of Change (PGIC) scale: 1=very much worse, 2=much worse, 3=minimally worse, 4=no change, 5=minimally improved, 6=much improved, 7=very much improved. If lasting symptom improvement was achieved, participants were asked how many sessions before they first noticed an improvement in symptoms.

Results
The average PGIC score among participants was 4.6 ± 1.3 (n=144), indicating no to minimal improvement in symptoms. Twelve percent of participants scored 3 or lower, indicating worsening of symptoms, and only 22% scored 6 or 7, indicating much or very much improvement of symptoms. For those who had symptom improvement, 14.6% of participants reported improvement after only one PFPT session, and five was the median number of sessions before first noticing improvement.

Conclusions
PFPT is a minimally effective, and sometimes harmful, treatment for pudendal neuralgia. Better transparency should be provided to patients regarding PFPT’s lack of efficacy and potential harm for treating PN symptoms.

Disclosure
No.
BIOM-02. DISSECTING CDK4/6 INHIBITOR RESISTANCE MECHANISMS IN RECURRENT PEDIATRIC BRAIN TUMORS WITH LONGITUDINAL CSF LIQUID BIOPSIES FROM THE SJDAWN CLINICAL TRIAL
Authors: Han Katie , Kostecka Anna , Smith Kyle S , Dhanda Sandeep , Lin Hong , Mikkelsen Margit , Robinson Giles W , Northcott Paul A 
Published: June 2024

Abstract

BACKGROUND
SJDAWN (NCT03434262) is a St. Jude Children’s Research Hospital phase 1 trial that assessed the safety and benefit of CDK4/6 inhibitor-based therapy in patients with relapsed CNS tumors. To capture tumor evolution dynamics and arising resistance mechanisms in response to treatment, 143 longitudinal CSF samples were collected from 34/68 (50%) patients for cell-free DNA (cfDNA) analysis.

METHODS
cfDNA was extracted from CSF liquid biopsies and analyzed using a novel methylation-based platform that integrates copy number, tumor classification, and deconvolution of methylation signatures into normal vs. disease fractions. Samples with measurable residual disease (MRD) were further characterized by deep whole-genome sequencing to discover mutation-driven resistance mechanisms. When available, pre- and post-SJDAWN tumor tissues were processed for single-nucleus multi-omics to track tumor evolution at single-cell resolution.

RESULTS
In the context of CDK4/6 inhibitor-based therapy, longitudinal cfDNA assessment revealed treatment-induced selection for subclones with focal amplification of positive cell cycle regulators CDK6, CCND2, and MYCN. Emergence of these resistance mechanisms notably preceded disease progression on MRI and CSF cytology by up to 6 months. Of the 68 patients enrolled on SJDAWN, 4 patients (3 Group 3/4, subtype III medulloblastomas and 1 anaplastic ependymoma) achieved &gt;2-year progression-free survival. Interestingly, serial cfDNA profiling of 1 long-term survivor (Group 3/4, subtype III medulloblastoma) exhibited undetectable MRD status for &gt;1.5 years prior to reemergence, suggesting tumor senescence by CDK4/6 inhibition may impede circulating tumor DNA (ctDNA) release kinetics. CSF liquid biopsies were further evaluated in comparison to matched tumor tissues, and changes in CSF-specific subclones were observed in response to treatment.

CONCLUSIONS
In addition to early MRD detection, liquid biopsies capture tumor evolution dynamics and can inform developing resistance mechanisms. Focal amplification of CDK6, CCND2, and MYCN facilitates CDK4/6 inhibitor resistance. In responders, treatment-induced senescence may inhibit ctDNA release kinetics.
BIOM-13. THE MIR-17/92 CO-EXPRESSED NETWORK IS ENRICHED IN AGGRESSIVE PEDIATRIC BRAIN TUMORS
Authors: Arif Shehbeel , Rathi Komal S , Naqvi Ammar S , Coyle Anne M , Hollawell Madison L , Storm Phillip B , Resnick Adam C , Madsen Peter J , Koptyra Mateusz P 
Published: June 2024

Abstract

BACKGROUND
Over the past two decades, the understanding of miRNA biology has drastically increased as miRNAs have been found to pervade most aspects of molecular biology–from cellular growth to apoptosis. Nevertheless, there has been little understanding of the role of miRNAs in pediatric brain tumors. In this study, we sought to correlate miRNA expression with pediatric brain tumor histologies.

METHODS
Weighted gene co-expression network analysis (WGCNA) was performed to determine co-expressed miRNA networks that correlated with distinct brain tumor histologies. Our study cohort consisted of miRNA-sequencing of 262 pediatric brain tumor histologies consisting of Atypical Teratoid/Rhabdoid tumors, Craniopharyngioma, Ependymomas, Ganglioglioma, Low-grade astrocytic tumors, High-grade astrocytic tumors, and Medulloblastoma. We utilized associated multi-omics data from the Open Pediatric Brain Tumor Atlas to validate the results.

RESULTS
WGCNA analysis revealed a distinct miRNA network consisting of 32 miRNAs with miR-17-5p as the hub miRNA that was markedly upregulated in the aggressive brain tumor group (p&lt;0.001). Interestingly, the majority of the miRNA network consisted of the miR-17/92 family of miRNAs, which are known for their oncogenic role in various cancers. To determine the transcriptional regulatory mechanism of miR-17/92 miRNAs, we first looked at sample-matched RNA-sequencing data. The gene encoding for the miR-17/92 miRNAs, MIR17HG, was significantly overexpressed (p&lt;0.001). Further upstream, we observed that E2F1/2/3, known transcriptional regulators of MIR17HG, gene and protein expressions were significantly overexpressed (p&lt;0.01). Sample-matched phospho-proteomics data indicated the E2F regulator, RB1, being hyperphosphorylated–additionally supporting the E2F activity in these samples.

CONCLUSION
These findings reveal a network of oncogenic miRNAs consisting of the miR-17/92 family that are distinctly overexpressed in aggressive pediatric brain tumors. Moreover, we suggest that the E2F-RB1 axis is the upstream regulator of the miR-17/92 family of miRNAs.
CNSC-02. PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC)-056: A PHASE 1 STUDY OF THE ADAM-10 INHIBITOR, INCB007839, IN CHILDREN WITH RECURRENT/PROGRESSIVE HIGH-GRADE GLIOMAS TO TARGET MICROENVIRONMENTAL NEUROLOGIN-3
Authors: Lenzen Alicia , Partap Sonia , Billups Catherine , Poussaint Tina Young , Sait Sameer Farouk , Robison Nathan , Castellino Craig C , Felker James , Stewart Clinton , Fangusaro Jason , Onar-Thomas Arzu , Dunkel Ira J , Warren Katherine E , Monje Michelle 
Published: June 2024

Abstract

BACKGROUND
Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine glioma (DIPG), are a leading cause of central nervous system tumor-related morbidity and mortality in children. Neuronal activity promotes growth of HGGs; one key mechanism is neuronal activity-regulated shedding of neuroligin-3 into the glioma microenvironment, mediated by the protease (A Disintegrin and Metalloprotease) ADAM10. ADAM10 inhibition slows tumor growth in preclinical pHGG models. Here, we report results of the clinical trial PBTC-056 (NCT04295759) evaluating safety and tolerability of INCB007839, an inhibitor of the ADAM 10 and 17 proteases.

METHODS
Patients aged 3-21 years old with recurrent/progressive pHGGs, including DIPG, were eligible. Additional eligibility criteria included measurable disease and failure of at least 1 standard treatment. One dose level (120mg/m2/dose twice daily [BID]) was tested, and the trial was subsequently amended to require prophylactic anticoagulation with enoxaparin due to an unanticipated toxicity. The primary objective was to assess the safety and tolerability of INCB007839 for children with pHGGs.

RESULTS
12 of 13 eligible subjects were evaluable. Median age was 13.5 years (4.9-20.7 years). Diagnoses included: DIPG (54%), glioblastoma multiforme (31%), anaplastic astrocytoma (8%) and CNS primary tumor NOS (8%). All patients were treated at DL1 and remained on study for 1-4 courses. The most common toxicities were lymphopenia, elevated transaminases, and fatigue. There were 3 dose-limiting toxicities: Grade 5 cerebral venous thrombosis (n=1), Grade 3 alanine aminotransferase increase (n=1) and Grade 2 thrombocytopenia (n=1). Ten patients progressed/relapsed during active treatment, 1 patient died on treatment, and 2 patients withdrew (1 prior to starting therapy).

CONCLUSIONS
INCB007839 was generally well tolerated with a recommended phase 2 dose of 120mg/m2/dose BID and concurrent prophylactic anti-coagulation. These data, combined with foundational preclinical studies targeting neuron-cancer interactions, open the door to possible cancer neuroscience strategies, including combination therapy, for pediatric high-grade gliomas.
CP-07. FEASIBILITY, TOLERABILITY AND FIRST EXPERIENCE OF INTRACYSTIC TREATMENT WITH PEGINTERFERON ALFA-2A IN PATIENTS WITH CYSTIC CRANIOPHARYNGIOMA
Authors: Hedrich Cora , Patel Priya , Haider Lukas , Taylor Tracey , Lau Elaine , Hook Roxanne , Dorfer Christian , Roessler Karl , Stepien Natalia , Lippolis Maria Aliotti , Schned Hannah , Koeller Clara , Mayr Lisa , Azizi Amedeo A , Peyrl Andreas , Lopez Bienvenido Ros , Lassaletta Alvaro , Bennett Julie , Gojo Johannes , Bartels Ute 
Published: June 2024

Abstract

BACKGROUND
Craniopharyngiomas (CP) is a life-long chronic disease predominantly affecting young children. Consequently, the developing brain is particularly sensitive to therapies such as surgery or radiotherapy. Hence, therapies allowing to avoid or delay intensive therapies provide substantial benefit. Intracystic injection of interferon alfa-2a or -2 has emerged as frequently applied treatment based on advantageous risk-benefit ratio with good effects leading to cyst shrinkage. Unfortunately, the original drug is worldwide no longer available. To overcome this shortage we performed an elaborate pharmacological review, identifying peginterferon alfa-2a (Pegasys®) as best currently available alternative drug for intracystic treatment of CP patients.

METHODS
Within an international collaboration we set up a novel protocol for intracystic peginterferon treatment. Based on the protocol five patients were treated with intracystic peginterferon alfa-2a for cystic CP. After initial CP cyst-aspiration peginterferon alfa-2a was injected once per week via an Ommaya reservoir. One treatment course was six weeks accompanied by regular response assessment with MRI (3-6 weeks). Side effect, safety and therapeutic effects were analyzed.

RESULTS
Age of patients ranged from 4 to 54 years (4 pediatric patients &lt;12 years, 1 adult patient). Intracystic therapy with peginterferon alfa-2a was generally well tolerated throughout the treatment course and resulted in cyst shrinkage in all cases. Cyst leakage was observed in one case highlighting the importance of testing cyst permeability before starting intracystic treatment courses.

CONCLUSIONS
Taken together, intracystic treatment with peginterferon alfa-2a was feasible and effective being comparable to prior intracystic interferon protocols for cystic CP being of potential clinical benefit for this severely affected patient cohort. Our experience in this small cohort indicated the potential of this treatment modality, which should be further investigated within a larger trial cohort.
CP-17. NKX3.1 AS A PROGNOSTIC MARKER IN PEDIATRIC CRANIOPHARYNGIOMA
Authors: Arif Shehbeel , Naqvi Ammar S , Coyle Anne M , Hollawell Madison L , Storm Phillip B , Resnick Adam C , Koptyra Mateusz P , Madsen Peter J 
Published: June 2024

Abstract

BACKGROUND
Craniopharyngiomas are rare, low histologic grade neoplasms of the suprasellar region. Despite their benign histology, these tumors can be challenging to manage due to the morbidities associated with surgery or radiation and their tendency to recur after treatment. In this study, we set out to identify transcriptional factors that may influence or predict recurrence.

METHODS
We analyzed RNA-sequencing data of 77 craniopharyngioma tissue samples from the Open Pediatric Brain Tumor Atlas cohort and corresponding clinical data. Kaplan-Meier survival analysis was performed using R. Differential expression analysis and gene set enrichment analysis (GSEA) of hallmark pathways was performed.

RESULTS
The transcription factor NKX3.1 was found to be markedly upregulated in craniopharyngioma relative to other brain tumor histologies (p&lt;0.05). NKX3.1 is a well-studied tumor suppressor in prostate cancer and its reduction or loss of expression is seen with disease progression. Patients with higher NKX3.1 expression had better event-free survival (p=0.0049) and had an average of 530 days longer event-free survival (p=0.036). There was no statistically significant difference in age, sex, tumor location, and extent of tumor resection between high and low NKX3.1 expression groups. There was no significant difference in overall survival (p=0.23). GSEA revealed that patients with high NKX3.1 expression had decreased activation of the Epithelial-Mesenchymal Transition pathway (NES=-1.84, adj. p&lt;0.001) and reduced activation of inflammatory pathways, including the complement, inflammatory response, and IL6-JAK-STAT3 pathways (NES&lt;-1.6, adj. p&lt;0.001).

CONCLUSION
These findings reveal NKX3.1 as a potential prognostic marker for craniopharyngioma recurrence. Low NKX3.1 expression also correlated with inflammatory pathway activation, a factor that has been previously associated with more aggressive behavior and worse prognosis. Future work is planned to validate NKX3.1 protein expression in patient specimens.
DIPG-28. CHEMOGENOMIC PROFILING OF HDAC ISOFORMS REVEALS A PARADIGM OF ESSENTIALITY WITH THERAPEUTICALLY RELEVANT IMPLICATIONS IN H3K27-ALTERED DIFFUSE MIDLINE GLIOMA
Authors: Groves Andrew , Poetschke Rebecca , Wang Tingjian , Chin Diana H , Asante Yaw , Kim Hyunmin , Gu Shanging , Trissal Maria , Labelle Jenna , Cruzeiro Gustavo Alencastro Veiga , Jones Kristen L , Cameron Amy , Clark Louise , De Nguyen Quang- , Gryder Berkley E , Filbin Mariella G , Qi Jun 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG), H3K27-altered, is a lethal pediatric brain tumor driven by epigenetic dysregulation. Histone deacetylase (HDAC) inhibitors have been identified as a promising drug class; however, the precise mechanism of efficacy for these agents in DMG has not been fully explored. Furthermore, their translational potential has been limited by off-target effects and poor CNS penetration of clinically available drugs.

METHODS
We investigated the genetic and chemical dependencies of HDAC isoforms in DMG cell lines using CRISPR/Cas9 screening and an HDAC inhibitor toolbox. We identified an HDAC inhibitor termed “Compound 26” with class I isoform selectivity and excellent CNS penetration (brain/plasma AUC of &gt;7). Effects of Compound 26 on DMG cells was evaluated in-vitro through assessment of cytotoxicity, proliferation and apoptosis. Mechanistic studies were undertaken using bulk RNAseq and HiChIP (H3K27ac, H3K27me3). Efficacy of Compound 26 in-vivo was determined using an aggressive orthotopic xenograft model.

RESULTS
We confirmed that HDAC class I isoforms are dependencies in DMG cell lines, with HDAC2 representing a selective dependency that is highly expressed in patient tumors. Compound 26 is cytotoxic in DMG cells, reducing proliferation through cell cycle arrest. Differential expression analysis confirmed profound effects on cycling programs with Compound 26 treatment. Furthermore, analysis of genome structure using HiChIP revealed global increases in H3K27ac contacts, with notable spreading along key cell cycle gene bodies such as p16 (CDKN2A). Interestingly, treatment with Compound 26 also significantly increased global H3K27me3 contacts, which is canonically decreased in H3K27-altered DMG. Most importantly, Compound 26 was well tolerated, effectively crossed the blood-brain barrier, and significantly extended survival in an aggressive DMG-orthotopic xenograft model.

CONCLUSIONS
This study comprehensively outlines the reliance of DMG cells on HDAC class I isoforms, elucidates novel mechanisms for this dependency, and highlights a compelling new agent to bypass prior translational pitfalls