bluuebunny/crossref_metadata_2025 huggingface dataset:
Policy Analysis and Investment Appraisal in the Water Sector
Authors: Borgomeo Edoardo
Published: June 2024

Since the earliest forms of human settlement, water resources have shaped societies and have been integral to their proper functioning. In developing—and maintaining—their relationship with water, societies have relied on myriad approaches to appraise options to manage water, that is, identifying expectations and objectives related to water and choosing the course of action to achieve them. This article describes some methodological issues of conventional approaches for policy analysis and investment appraisal in the water sector and then charts a way forward to further strengthen them to achieve water security in the Anthropocene.

Despite their clear benefits to society, demonstrated by extensive application to address water-related challenges around the world, conventional approaches to appraising policy options and investments suffer from some limitations. First, appraisal typically focuses on inputs and outputs, not paying enough attention to the outcomes and services that societies expect to obtain from water-related development. Second, appraisal methods still largely consider water as a plentiful resource, paying little attention to its opportunity cost and its multiple values to different users, including ecosystems. Third, most appraisals still ignore behavioural responses and societal dynamics arising from water-related policies and investments. A fourth limitation relates to the deterministic nature of appraisal that fails to properly account for uncertainties and interdependencies. Finally, appraisal still largely focuses on individual projects rather than portfolios of options, largely privileging technological fixes to respond to narrowly defined water-related challenges.

Methodological advances in the appraisal of policy options and investments provide a significant opportunity to overcome these limitations and build a more robust and inclusive platform to plan for water security. While further refinements are required, particularly to achieve deeper and more formal integration across disciplines, attention needs to focus on application and uptake of these methodological advances to address urgent water security challenges.
Fighting the next pandemic? Civil–military collaboration in health emergencies after COVID–19
Authors: McInnes Colin
Published: June 2024

Over the past decade, militaries have been highly visible elements in the response to health emergencies and in particular disease outbreaks. Although there has been a long tradition of civil–military collaboration in health, COVID–19 saw an unprecedented worldwide use of militaries which occurred within a permissive environment established by narratives of global health, humanitarian intervention and multi-sectorality. This creates a dilemma: militaries will likely be an important element in responding to a major health emergency and this risks not only militarizing health emergencies, but affects the balance between society and the military more generally. Moreover, the response to the COVID pandemic suggested that current emergency planning is often poorly prepared for the use of militaries in health crises, thereby reducing the effectiveness of a response. This article engages with how concerns over the securitization of health have evolved into concerns over militarization, and the question of how militaries might be used effectively in future health emergencies without risking the militarization of health or damaging civil–military relations more widely.
Breath Biomarkers of Pediatric Malaria: Reproducibility and Response to Antimalarial Therapy
Authors: Berna Amalia Z , Wang X Rosalind , Bollinger Lucy B , Banda Josephine , Mawindo Patricia , Evanoff Tasha , Culbertson Diana L , Seydel Karl , Odom John Audrey R
Published: June 2024

Background

Many insect-borne pathogens appear to manipulate the odors of their hosts in ways that influence vector behaviors. In our prior work, we identified characteristic changes in volatile emissions of cultured Plasmodium falciparum parasites in vitro and during natural human falciparum malaria. In the current study, we prospectively evaluate the reproducibility of these findings in an independent cohort of children in Blantyre, Malawi.

Methods

We enrolled febrile children under evaluation for malaria and collected breath from children with and without malaria, as well as healthy controls. Using gas chromatography/mass spectrometry, we characterized breath volatiles associated with malaria. By repeated sampling of children with malaria before and after antimalarial use, we determined how breath profiles respond to treatment. In addition, we investigated the stage-specificity of biomarkers through correlation with asexual and sexual-stage parasitemia.

Results

Our data provide robust evidence that P. falciparum infection leads to specific, reproducible changes in breath compounds. While no individual compound served as an adequate classifier in isolation, selected volatiles together yielded high sensitivity for diagnosis of malaria. Overall, the results of our predictive models suggest the presence of volatile signatures that reproducibly predict malaria infection status and determine response to therapy, even in cases of low parasitemia.
The Impact of Commercial Military Actors on Armed Conflict Termination, 1990–2010
Authors: Petersohn Ulrich
Published: June 2024

For several decades, the rate of civil war onset has outpaced the rate of conflict termination leading to a “relentless accumulation of ongoing civil wars” (Brandt). The deployment of commercial military actors (CMAs), i.e., private military and security companies and mercenaries, has been considered by some observers as an opportunity to put a halt to this trend, and end a war by writing a cheque. Others are more skeptical and consider CMAs to rather aggravate crises. The argument put forward in this investigation is that a cheque issued early in the conflict facilitates termination, while a later one does not. In the initial state of the conflict, contestants are unprepared to fight, lack capability, and are vulnerable to defeat. However, due to their own weakness, contestants are frequently unable to exploit the opportunity. A CMA intervention early in the conflict can remedy a client's weakness and enable exploitation of the opponent's weakness, and, in turn, conflict termination becomes more likely. The overall results show that CMA intervention within the first year of the conflict is associated with an increased risk of termination as opposed to later or no intervention. The investigation employs Cox proportional hazard models to test the influence of CMAs on conflict termination, and draws on our newly developed Commercial Military Actor Database, which includes PMSC and mercenary deployments in all civil wars between 1980 and 2016.
(047) ORGASM ABILITY AND MAPPED EROGENOUS SENSATION DURING RECEPTIVE VAGINAL AND ANAL INTERCOURSE
Authors: Stelmar J , Zaliznyak M , Isaacson D , Duralde E , Gaither T , Topp K , Sandhu S , Garcia M
Published: June 2024

Introduction

Erogenous sensation zones (ESZs) elicit feelings of sexual arousal in response to touch. Prior research has generated whole-body erogenous sensation maps, but they do not differentiate between individual anatomical structures or assess for erogenous sensation of internal surfaces of the body, such as the vagina and anal canal. There is an even greater paucity of literature on the ability to orgasm from vaginal and anal receptive intercourse.

Objective

To describe detailed maps of erogenous sensation of the vagina and anal canal amongst cisgender women, and assess for ability to orgasm from receptive intercourse.

Methods

Respondents were recruited via Qualtrics and completed an anonymous, online questionnaire. They were instructed to indicate ESZs by selecting from predefined areas that bring them pleasure when touched during sex with a partner from anatomic illustrations of the vagina and anal canal. Respondents were also queried on their ability to orgasm from receptive vaginal and anal intercourse. All statistical analyses were completed using Qualtrics Stats iQ software, with p<0.05 indicating statistical significance. ESZ maps were generated based on the proportion of respondents selecting each anatomical structure as erogenous.

Results

A sample of 441 sexually active cisgender women completed the study survey (mean age 48.9±15.6y). Of the five ESZs of the vagina (Figure 1), the superficial anterior (selected by 48% respondents) and superficial posterior (33%) regions were the most frequently selected areas. The four ESZs of the anal canal further revealed greater erogeneity at the superficial anterior (18%) and superficial posterior (11%) walls (Figure 2). With respect to ability to orgasm from receptive intercourse, 35% of cisgender women reported being able to orgasm from vaginal penetration alone while 45% required simultaneous costimulation of another body part and 10% reported an inability to orgasm during receptive vaginal intercourse, regardless of costimulation (Figure 3a). Additionally, 19% of cisgender women reported an ability to orgasm from receptive anal intercourse alone, while 50% required costimulation and 31% reported an inability to orgasm during receptive anal intercourse, regardless of costimulation (Figure 3b).

Conclusions

Erogenous sensation of the vagina and anal canal is primarily localized to the superficial walls of both structures, with a greater preference for the superficial anterior zones. These findings support the proposed location of the “G-spot” existing proximal to Skene’s glands in the anterior portion of the vaginal canal. Results from this study further highlight the importance of costimulation in achieving orgasm during receptive vaginal and anal intercourse, with only a minority of respondents reporting an ability to orgasm from vaginal or anal penetration alone.

Disclosure

No.
(050) RESULTS FROM A PATIENT SURVEY EXPLORING THE EFFECTS OF FLIBANSERIN IN WOMEN WITH HYPOACTIVE SEXUAL DESIRE DISORDER (HSDD) BASED ON TREATMENT DURATION
Authors: Kingsberg S , Quaile H
Published: June 2024

Introduction

Flibanserin is approved in the US to treat premenopausal women and in Canada for pre- and naturally postmenopausal women ≤60 years with acquired, generalized HSDD. Improvement in symptoms can emerge as early as 4 weeks after starting flibanserin but may take up to 8 weeks of daily use. There is limited real-world data exploring patient response to flibanserin based on treatment duration.

Objective

Analyze results from a patient survey to explore the effects of flibanserin based on treatment duration

Methods

Women aged ≥18 years with HSDD prescribed flibanserin via a telehealth platform were invited to participate. Invitational emails containing a secure study link, generated via the platform, were sent 60 days after an initial or renewed flibanserin prescription during the study period (August 1, 2022, to September 30, 2023). The first question screened for current flibanserin use. Women who had discontinued treatment exited the survey. Questions captured changes in HSDD symptoms, partner relationships, weight, sleep, and mood since starting flibanserin. Five multiple-choice response options accompanied each question. A response of “improved a lot” or “improved a little” was categorized as “Benefit”, and a response of “no change,” “worsened a little,” or “worsened a lot” was categorized as “No Benefit”. Results were analyzed descriptively based on treatment duration.

Results

Invitational emails were sent to 17,113 women. Of 638 women who accessed the link, 199 had discontinued flibanserin and exited the survey, and 439 completed the survey (mean age 40 [range 21-66] years). Duration of therapy was <1 month, 1-2 months, and >2 months in 44, 231, and 164 women, respectively. The percentage of women reporting benefits in HSDD symptoms and partner relationships consistently increased with longer treatment. For weight loss and mood, there was a trend of more women experiencing benefit with continued use. For those who experienced improved sleep quality, the improvement began early (<1 month); the percentage of respondents experiencing benefit or lack of benefit in sleep did not change over prolonged use.

Conclusions

Daily flibanserin use may increase interest in sexual activity and improve partner relationships in certain women. These improvements may emerge as early as one month following treatment initiation. However, consistent with previous findings, some women may need longer treatment durations. As expected, effects on weight and mood may take longer to emerge. The impact on sleep quality may be apparent early in treatment and remain consistent with continued use.

Disclosure

Yes, this is sponsored by industry/sponsor: Sprout Pharmaceuticals, Inc

Clarification: Industry initiated, executed and funded study

Any of the authors act as a consultant, employee or shareholder of an industry for: Sprout Pharmaceuticals, Inc.
(067) ASSESSING THE IMPACT OF SEX EDUCATION ON SEXUAL SCHEMAS, SEXUAL SELF-ESTEEM, AND SEXUAL SATISFACTION IN MENOPAUSAL WOMEN
Authors: Behzadipour S , Alibakhshi Z , Azartash F
Published: June 2024

Introduction

Menopause represents a crucial life phase for women, characterized by significant physical and psychological changes.

Objective

This study aims to explore the influence of sex education on women's sexual schemas, sexual self-esteem, and sexual satisfaction among menopausal women.

Methods

This research employed a quasi-experimental pre-test/post-test study with a control group. Participants were selected from women who had sought counseling at counseling center. They were randomly assigned to either the experimental group (15 pairs) or the control group (15 pairs). Data were collected using the Questionnaire of Cognitive Schemas Activation in Sexual Context (QCSASC), Women's Sexual Self-esteem Questionnaire (SSFIW), and Women's Sexual Satisfaction (ISS). The independent variable, sex education, was implemented for the experimental group over 15 hours across a six-week period, with one session per week. Subsequently, the three aforementioned questionnaires were administered to both the experimental and control groups

Results

ANCOVA analysis indicated that the sex education intervention had an impact on women's sexual self-esteem and sexual satisfaction but did not affect women's sexual schemas.

Conclusions

Training in sex skills can enhance and elevate women's sexual satisfaction, even during a period where a decline in sexual self-esteem might be anticipated

Disclosure

No.
(110) THE SURGICAL ANATOMY OF CLITORAL INNERVATION: A REVIEW OF THE CURRENT MEDICAL LITERATURE
Authors: Burr E , Bains K , Bottorff E , Amukamara A , Rubin R
Published: June 2024

Introduction

The clitoris is a crucial structure for sexual arousal and orgasm in people with gynecological anatomy. Despite its functional importance, the innervation of the clitoris has historically been understudied. The innervation of the clitoris includes somatic afferents of the dorsal nerve of the clitoris, a branch of the pudendal nerve and sacral plexus, and autonomic afferents of the cavernous nerve, a branch of the inferior hypogastric plexus. Although we have identified these structures, there remains a paucity of research on surgical techniques to avoid clitoral innervation during pelvic surgery, despite the importance of these nerves in gynecological sexual function.

Objective

This paper aims to summarize the current literature on clitoral innervation with special attention paid to the anatomical locations of nervous structures within the pelvis to inform future pelvic surgeons and reduce sexual side effects related to clitoral nerve damage.

Methods

We performed a PubMed search from inception through June 14, 2023 utilizing the Medical Subject Headings (MeSH) search terms “(clitor*)) AND (innerv* OR nerv*) AND (surg*)” and imported this search into Covidence software. Included in the literature search were observational studies, clinical trials, review articles, correspondence, and communications, and only articles in English were included.

Results

An initial abstract screen of 200 articles resulted in 87 articles that were fully screened and 53 articles that were utilized as within the scope of this paper. 45 papers discussed the dorsal nerve of the clitoris, while 15 papers explored autonomic afferents via the cavernous nerve. The anatomical location of the dorsal nerve of the clitoris has been tracked in 29 papers, most of which utilize cadaver dissection, with at least six anatomic variations identified. The cavernous nerve’s exact location, however, has not been traced as extensively as has the location of the dorsal nerve of the clitoris, perhaps due to its smaller diameter and shorter length. Additional innervation to the clitoris was proposed in 12 studies as well. Many studies suggested that commonly performed procedures, including midurethral sling placement for stress urinary incontinence, labiaplasty, clitoral hood reduction, clitoroplasty, and urogenital sinus repair may interfere with clitoral innervation if not otherwise modified. Two studies discussed sensory mapping techniques prior to pelvic surgery to account for anatomic variation in clitoral innervation.

Conclusions

The clitoris is a vastly innervated structure with both somatic and autonomic afferents whose locations and anatomic variations should be considered when performing pelvic surgery. Failure to consider not only the dorsal nerve of the clitoris but the cavernous nerve as well may have consequences that negatively impact clitoral sensitivity, engorgement and erection, orgasmic ability, and overall sexual function.

Disclosure

No.
(112) SEXUAL HEALTH AFTER RISK REDUCING SALPINGO-OOPHERECTOMY FOR BRCA PATIENTS
Authors: Rowen T , Chen L M , Goldman M , Boscardin J , Jacoby V
Published: June 2024

Introduction

There is no study assessing the changes in sexual health after risk reducing oopherectomy in premenopausal women.

Objective

Objective: To evaluate the effect of risk-reducing salpingo-oophorectomy (RRSO) on change in sexual function in women aged 34-50 years with pathogenic variants in BRCA1 or BRCA2 (BRCA1/2).

Methods

Methods: The PROSper (Prospective Research of Outcomes after Salpingo-oophorectomy) study is a prospective cohort of women aged 34-50 years with BRCA1 or two germline pathogenic variants that compares health outcomes after RRSO to a non-RRSO control group with ovarian conservation. Women aged 34-50 years, who were planning either RRSO or ovarian conservation, were enrolled for 3 years of follow-up. Sexual Function was measured using the Sexual Health Outcomes in Women (SHOW-Q) a validated survey tool that measures sexual desire, frequency, satisfaction, orgasm, and discomfort specifically in patients with a history of a pelvic condition, including oophorectomy. Differences in sexual function between the RRSO and non-RRSO groups, were determined by using mixed effects multivariable linear regression models.

Results

Results: Of 100 PROSper participants, all completed SHOW Q. At baseline patients who had undergone RRSO before enrollment had lower SHOW-Q scores (71 vs 64). Across all 60 months of the study the SHOW-Q scores remained persistently lower in those undergoing RRSO raging from 6-13 points across the time studied (p <0.05) controlling for age, depression, partner, menopausal symptoms and hormone therapy

Conclusions

Conclusion: Women with pathogenic variants in BRCA1/2 who undergo RRSO before the age of 50 years have greater effects on sexual function than those that do not. The detrimental effect of rRRSO is not otherwise explained by hormone therapy, depression or menopausal symptoms. This information should be incorporated into counseling and post op management to consider options to improve sexual health post surgery

Disclosure

Any of the authors act as a consultant, employee or shareholder of an industry for: sprout pharma.
(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

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

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

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

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 >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 >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

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<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<0.001). Further upstream, we observed that E2F1/2/3, known transcriptional regulators of MIR17HG, gene and protein expressions were significantly overexpressed (p<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

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

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 <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

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<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<0.001) and reduced activation of inflammatory pathways, including the complement, inflammatory response, and IL6-JAK-STAT3 pathways (NES<-1.6, adj. p<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

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 >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
DIPG-36. DRD2 ANTAGONISM RESCUES IMMUNE-TUMOR SURVEILLANCE, WARMING THE TUMOR IMMUNE MICROENVIRONMENT OF DIFFUSE MIDLINE GLIOMA MODELS
Authors: Persson Mika L , Jackson Evangeline R , Duchatel Ryan J , de la Nava Daniel , Thomas Bryce C , Savary Clara , McEwen Holly P , Beitaki Tyrone S , Kearney Padraic S , Findlay Izac J , Douglas Alicia M , Larsen Martin R , Faridi Pouya , Holst Jeff , Mayall Jemma , Hondermarck Hubert , Horvat Jay , Nixon Brett , Cartaxo Rodrigo T , Nazarian Javad , Hulleman Esther , Mueller Sabine , Vitanza Nicholas A , Koshmann Carl , Alonso Marta M , Carvalheiro Tiago , van der Lugt Jasper , Dun Matthew D
Published: June 2024

BACKGROUND

Less than 10% of patients with diffuse midline glioma (DMG) survive 2-years post-diagnosis, with no approved treatments other than palliative radiotherapy. Immune-checkpoint inhibition has failed in the clinic, likely due to a lack of tumor infiltrating lymphocytes (TILs) and limited/no expression of immune checkpoint proteins or proinflammatory cytokines in the tumor immune microenvironment (TIME). Similarly, glioblastoma patients suffer from a ‘cold’ TIME, linked to the sequestration of T cells in the bone marrow (BM) through β-arrestin-induced internalization of S1PR1. β-arrestin is activated by Dopamine receptors (DRD2); therefore, we hypothesized that systemic DRD2 antagonism using the antagonist ONC201, might reverse lymphopenia, increasing TIL populations.

METHODS

Flow cytometry analysis was performed on bloods from DMG patients at diagnosis. Circulating immune cells and BM from the immunocompetent PPK model +/-ONC201 and tumor-naïve mice were analyzed by a hematology analyzer and flow cytometry. Immunocompromised SU-DIPG-VI and HSJD-DIPG-007 and immunocompetent XFM murine models were treated +/-ONC201 and tumors analyzed by immunoblotting, immunohistochemistry, and flow cytometry. scRNAseq and scATACseq analysis was performed on tumors from immunocompetent PPK models +/-ONC201.

RESULTS

DMG patients displayed low levels of total lymphocytes, including CD4+, CD8+ and NK subsets (n=9). Similarly, DMG-bearing mice displayed lower levels of lymphocytes (CD45+, CD4+, CD8+ subsets, n=3) compared to sham-engrafted mice. ONC201 treated mice showed lymphocyte levels comparative to sham-engrafted mice, reversing tumor-induced lymphopenia. A significant increase of T cells expressing S1PR1+ was seen in the BM following ONC201. Tumor immune cell infiltration following ONC201 was confirmed in both immunocompromised and immunocompetent models. Multiomics analysis identified ONC201 to promote pro-inflammatory polarization of microglia/macrophages (MHC II and CD86) and increase expression of immune checkpoints (VISTA and PD-L1).

CONCLUSIONS

DMG patients suffer from low peripheral lymphocytes, likely contributing to cold TIME. ONC201 reversed tumor-induced lymphopenia, promoting TIL recruitment within the tumor, warming the TIME.
DIPG-41. CONVECTION ENHANCED DELIVERY-MEDIATED RADIOSENSITIZATION FOR DIFFUSE MIDLINE GLIOMA
Authors: Gallitto Matthew , De Santos Genesis Los , Wei Hong-Jian , Zhang Xu , Zhang Zhiguo , Wu Cheng-Chia
Published: June 2024

BACKGROUND

Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. The only approved standard of care is radiation therapy (RT). Studies examining the role of other systemic agents have failed to demonstrate a survival benefit, partially due to tumor extension to areas of the brain where the blood-brain barrier (BBB) remains intact. As our laboratory has recently determined active NAD(P)H Quinone Dehydrogenase 1 (NQO1) expression in patient-derived DMG tumor samples, we sought to investigate NQO1 bioactivatable agent Napabucasin to augment reactive oxygen species (ROS) production and overcome radioresistance in DMG. Furthermore, we explore the safety and feasibility of convection-enhanced deliver (CED) to overcome limitations of the BBB.

METHODS

Using two DMG cell lines, we performed clonogenic survival assays with increasing doses of RT with and without Napabucasin. We then created subcutaneous xenograft mouse models, treating with (1) vehicle control, (2) Napabucasin, (3) 2 Gy of RT daily, or (4) combination treatment with RT and Napabucasin. Using a syngeneic orthotopic DMG mouse model, we implanted 7-day osmotic infusion pumps containing either vehicle control or 80uM Napabucasin. Mice then underwent a second randomization with or without daily RT for 5 days.

RESULTS

We identified a robust radiosensitizing effect with Napabucasin using in vitro clonogenic survival assays. In subcutaneous flank models, combination treatment led to a statistically significant smaller tumor volume post-treatment completion when compared to any monotherapy. In our syngeneic orthotopic DMG mouse model, RT after CED pump implantation in the brainstem did not lead to significant morbidity or mortality. Combination RT and CED of Napabucasin led to a significant survival benefit when compared to monotherapy.

CONCLUSIONS

In this study, we show Napabucasin as a promising radiosensitizer in DMG. Furthermore, this is the first preclinical study showing safety/efficacy of CED with concurrent RT in DMG.