bluuebunny/crossref_metadata_2025 huggingface dataset:
(034) EDI QUALITY IMPROVEMENT IN REPRODUCTIVE MEDICAL EDUCATION: A WORKED MODEL
Authors: Bailey K , Kostov S
Published: June 2024

Introduction

Countless patients face challenges obtaining holistic generalist care and experience health disparities related to race/ethnicity and social structural determinants of health (SSDOH). Revisions to medical curriculum are necessary to ensure that graduates can competently provide care that is socially accountable and aligns with the needs of patients. Evidence supports the inclusion of generalist and equity, diversity and inclusion (EDI) content in curriculum to foster such competency. However, a 2022 study conducted at our medical school revealed a lack of generalism and EDI content in the case based learning (CBL) curriculum. An evidence-based process for assessing existing CBL curriculum for generalist content exists, but no process for revision has been described. While a process to revise EDI content in CBL curriculum exists, no studies to date have focused on reproductive medicine and urology content and the unique challenges associated with this area of medicine, such as the additional impact of stigma, trauma and discrimination related to pregnancy-related choice, sexual orientation or gender diversity.

Objective

To enhance generalist and EDI content within the Reproductive Medicine and Urology Course (RMUC) CBL curriculum. Further, to develop a worked model for enhancing generalist and EDI content in an existing CBL reproductive medicine and urology curriculum. Lastly, to provide medical graduates with the tools to provide care that is socially accountable and aligns with the current needs of patients.

Methods

We evaluated and revised five CBL cases in our medical school’s RMUC curriculum. We employed the Toronto Generalism Assessment Tool (T-GAT) to assess generalism, and adapted guidelines from Krishnan et al. to assess and implement the necessary changes related to EDI. Upon completion, we re-evaluated the RMUC CBL curriculum to ensure the incorporation of generalism and EDI content. We also used existing revision processes described by Bruner et al. to guide our overall approach.

Results

RMUC CBL cases were modified and our methods documented. Through this process, several challenges were identified and include difficulties with: (1) obtaining images due to lack of commercially available content that includes members of equity-deserving groups, (2) the time needed to appropriately incorporate SDOH already present in the cases, and (3) detecting content that was subtly paternalistic or missing a trauma-informed approach.

Conclusions

Generalism and EDI were lacking within the RMUC curriculum. Development of a worked model, accompanied by reflections on navigating encounters challenges, is underway. This will serve as a guide to others wishing to incorporate generalism and EDI into their reproductive medicine education programs.

Disclosure

No.
(049) HOW MUCH OF THE GENITAL AREA CAN WOMEN ACTUALLY SEE DIRECTLY WITH THEIR OWN EYES? AN ASSESSMENT OF GENITAL VISUAL FIELDS IMPORTANT FOR CIS-GENDER AND TRANS-GENDER WOMEN
Authors: Sandhu S , Smith S , Mallavarapu S , Stelmar J , Yuan N , Garcia M
Published: June 2024

Introduction

Many urologic surgeries and urologic conditions that urologists manage (e.g. STD’s, genital pain and injury, wound care) involve the genital area. Throughout the process of urologic care, urologists depend on patients to be able to assess the appearance of their genital area so that they can alert their urologist of worrisome changes. Urologists assume that patients can see their genital areas clearly. However, there is no literature to date that assesses how reliable this assumption is. That is, to date, we do not know how much of the genital area is commonly visible to people with female genital anatomy.

Objective

In the present work, we ask adult women to indicate how far posteriorly in their genital area they can see. We also query whether patient age and BMI predict visibility in genital sub-fields.

Methods

A total of 82 cis-gender and 12 transgender women participated in our study. No subjects had visual or ambulation deficits. Each was shown an anatomic illustration with genital anatomy subdivided into various subfields (anterior to posterior). Subjects were asked to circle each field that they are able to see with their own eyes, on their body, without the aid of a camera or mirror. Age, height, and weight were recorded. Logistic regression was performed for visibility by age and BMI.

Results

Average visibility decreased the more posteriorly the visual field was located. Visibility decreased precipitously for all fields posterior to the clitoris. For cis-gender women, 44-91% could not see their vulva below their clitoris (i.e. peri-urethral area, vaginal introitus, majority of their Labia, and anus. These results were more extreme for transgender women who have undergone vaginoplasty surgery. Interestingly, BMI was not a significant predictor of field-visibility.

Conclusions

Visibility of the genital areas posterior to the clitoris is limited among cis and transgender women. Visibility decreases the more posterior a visual field is, and elevated BMI significantly reduces genital visibility. Providers should bear in mind that many women cannot directly see a significant portion of their genital area. This is especially important during monitoring after genital area surgery, and may other urologic, primary, and gynecologic care conditions. This is the first study to describe how much of the genital area is directly visible to patients.

Disclosure

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(058) HAVING SEX OUT OF A SENSE OF DUTY: THE INFLUENCE OF NONCONSENSUAL SEXUAL EXPERIENCES AND SEXUAL FUNCTIONING
Authors: Metcalfe K , Kilimnik C , Meston C
Published: June 2024

Introduction

Pleasure and emotional bonding are two motives for why women have sex that are commonly discussed in the literature. Less commonly reported, but frequently endorsed by women, is the motive “duty sex,” in which an individual engages in sex out of a sense of obligation to maintain a relationship or their partner’s feelings towards them, to ensure their partner will not leave them, or to avoid conflict. Engaging in duty sex can yield negative outcomes such as emotional discomfort and lower relationship satisfaction, although there have been some reports of positive outcomes, including feelings of closeness (O’Sullivan & Allgeier, 1998). Women with a history of nonconsensual sexual experiences (NSEs) show high rates of sexual dysfunction (Pulverman et al., 2018), and sexual dysfunction in women has been linked to a higher tendency to engage in duty sex (Meston & Stanton, 2017).

Objective

This study aimed to investigate the potential connections between sexual dysfunction and the frequency of duty sex in women with NSE histories.

Methods

Women (N = 820; mean age = 35.36, SD = 11.32) completed the Nonconsensual Sexual Experiences Inventory (NSEI; Kilimnik & Meston, 2017), the Female Sexual Function Index (FSFI; Rosen et al., 2000), items indicative of duty sex from the Sexual Motivations Scale (Cooper et al., 1998), as well as other measures not reported here.

Results

Women were categorized as either having NSE history (n = 465) or not (n = 355) based on the NSEI. FSFI total scores predicted duty sex such that women with lower sexual functioning reported engaging in more duty sex, R2 = .18, F(1, 654) = 147.30, p < .01, and higher levels of duty sex predicted lower sexual satisfaction, R2 = .057, F(1, 807) = 50.13, p < .01. Results from a multiple linear regression revealed that NSE history significantly predicted engagement in duty sex after controlling for sexual function, R2 = .19, F(2, 653) = 77.06, p < .01.

Conclusions

The results suggest that women with NSE histories endorse a higher frequency of duty sex motives compared to women without NSE histories that cannot be explained by variability in sexual functioning. That is, women with NSE histories were more likely to engage in sex out of fear that their partner would love them less, be angry with them, or leave them if they refused to engage in sex, and this effect was over and above the relationship of these motives with sexual dysfunction. As engaging in these duty sex motives was linked to overall sexual dissatisfaction, future research that examines the cognitive mechanisms by which having a history of NSE leads women to feel obligated to have sex out of a sense of duty would help enhance the sex lives of women with NSE histories.

Disclosure

No.
(064) DIFFERENCES IN EROGENOUS SENSATION AND SEXUAL SATISFACTION BETWEEN PRE- VERSUS POSTMENOPAUSAL CISGENDER WOMEN
Authors: Stelmar J , Zaliznyak M , Isaacson D , Duralde E , Gaither T , Topp K , Garcia M
Published: June 2024

Introduction

Menopause has been associated with a myriad of genitourinary and sexual function symptoms that revolve around changes to the vulva and vagina. The medical literature at present primarily assesses genitourinary syndromes of menopause, with limited focus on how these physiological changes to the vulva and vagina may impact sexual function and satisfaction.

Objective

To describe differences that exist between pre- versus postmenopausal women in erogenous sensation zone (ESZ) maps of the vulva and measured satisfaction with partnered sex.

Methods

Sexually active cisgender women were recruited via Qualtrics and completed an anonymous, online questionnaire. Respondents viewed anatomic illustrations of the vulva with nine predefined areas and were instructed to select structures that bring them pleasure when touched during sex with a partner. A map of erogenous sensation of the vulva was then created based on the number of respondents selecting each structure. Respondents also completed the New Sexual Satisfaction Scale (NSSS), a 20-item psychometric survey that assesses sexual satisfaction with partnered sex on a 5-point Likert scale, with potential scores ranging from 20 (minimal sexual satisfaction) to 100 (maximum sexual satisfaction).

Results

Pre- and postmenopausal women were equally as likely to select at least one ESZ of the vulva (77% premenopausal women vs 81% postmenopausal women, p=0.4). The vaginal introitus, peri urethra, and clitoris were the three most frequently selected structures out of the nine ESZs of the vulva out of all respondents (Figure 1). Assessment for differences in selection between pre- and postmenopausal women for each structure revealed that significantly more premenopausal women selected the clitoris as erogenous (43% vs 32%, p<0.03). There was no statistically significant difference in the other vulvar ESZs. With respect to partnered sexual satisfaction (as measured by the NSSS), there was no statistically significant difference between groups. Premenopausal women reported an average NSSS score of 69 out of 100 and postmenopausal women 67 out of 100 (p=0.3).

Conclusions

While premenopausal women were significantly more likely to report the clitoris as erogenous as compared to postmenopausal women, there was no significant difference between groups in erogenous mapping of the eight other vulvar structures. This finding of reduced clitoral erogeneity is supported by the phenomenon of vulvovaginal atrophy, which is associated with the reduction in estrogen and other sex steroids that occurs during menopause. While menopause has been associated with sexual dysfunction, we found no statistically significant difference in self-reported satisfaction with partnered sexual activities.

Disclosure

No.
(068) VAGINAL ESTROGEN PRESCRIPTION COVERAGE IN THE MID-ATLANTIC: A CROSS-SECTIONAL STUDY
Authors: Clarke B , Vallabhaneni S , Gaddam N , Davenport A
Published: June 2024

Introduction

Vaginal estrogen is an essential medication for many post-menopausal women. However, cost can be prohibitive for patients and insurance coverage can be difficult to predict.

Objective

The objective of this study was to describe the insurance coverage of vaginal estrogen formulations in terms of overall coverage score and cost across the Mid-Atlantic for 2024 insurance plans.

Methods

This is a cross-sectional study examining coverage scores, tiers, and cost of vaginal estrogen formulations (generic estradiol cream and tablets, Premarin, Imvexxy, Femring, Estring, Estrace cream and tablets, Vagifem, Yuvafem) in the mid-Atlantic states (Delaware, District of Columbia, Maryland, New York, New Jersey, Pennsylvania, Virginia, and West Virginia). Census data was used to identify the most populous three districts in each state. All insurance plans for the top ten insurers in each district were then reviewed for the tier and cost of vaginal estrogen formulations. A weighted coverage score ranging from 0.2 to 1.0 was then adopted based on the proportion of tier coverage for each formulation, with lower tiers (and thus better prescription coverage) conferring a greater weight in the calculation of the score. Analyses were performed using STATA. Fisher’s exact test and chi-squared tests were used where appropriate. Medians were used as the distribution of cost was non-parametric. Multivariate regression including formulation, location, and insurer was also performed.

Results

Three-hundred and forty-two insurance plans were ultimately included in the analysis. The median cost of tier 1 formulations was $0 (IQR $0 to $0) while the median cost of tier 4 formulations was $100 (IQR $36 to $226). Non-formulary medications were much more expensive with a median cost of $413 (IQR $204 to $413). Estradiol tablets overall had the best coverage score of 0.75 compared to Estrace tablets and Vagifem which had coverage scores of 0.2. On initial analysis by high ($150 or greater) or low (<$150) cost formulations, prescriptions from Delaware made up a greater percentage of higher compared to lower cost (14% vs 9%, p<0.001), while formulations from Virginia made up a greater percentage of lower compared higher cost (24% vs 18%, p=0.02). Insurer impacted cost and this persisted on regression analysis when controlling for location and tier, with Aetna (aOR 1.18, p=0.048) and Kaiser (aOR 2.9, p<0.001) remaining predictive for higher cost.

Conclusions

High costs of vaginal estrogen may be prohibitive to patients using these medications. Living in Delaware or having Aetna or Kaiser insurance may result in higher costs.

Disclosure

No.
(071) IMPROVING TRAINEE COMFORT IN ASSESSMENT AND MANAGEMENT OF FEMALE SEXUAL HEALTH AND MENOPAUSE THROUGH AN INTERACTIVE WORKSHOP
Authors: Mannion S , Cyriac J , Nordhues H
Published: June 2024

Introduction

Concerns related to female sexual health and menopause are common in clinical practice, but these topics are often inadequately covered during training. Many medical schools and residency programs lack a formal curriculum, and trainees in internal medicine, family medicine, and obstetrics and gynecology often graduate feeling uncertain in their management of these conditions.

Objective

Improve resident comfort with assessment and management of female sexual health and menopause through an interactive workshop.

Methods

We created a 90-minute, interactive workshop focused on female sexual health and menopause. Residents in internal medicine at a large academic medical center were invited to participate. A multidisciplinary group including physicians, advanced practice providers, registered nurses and a certified sex therapist were recruited to lead the workshop.

Results

Participants rotate through three 30-minute sessions targeted to learning objectives. One session focuses on conducting a symptom-based pelvic exam. A 3-dimensional model is used to review the anatomy of the female pelvic floor and demonstrate physical exam techniques to evaluate vaginal and vulvar symptoms, pelvic pain, and dyspareunia. Diagnostic skills include vulvar inspection to assess for skin and mucosal changes, cotton swab test of the vestibule, and assessment of pelvic floor musculature. A second session focuses on the genitourinary syndrome of menopause (GSM). The pathophysiology, presentation and treatment of GSM is introduced. Next, registered nurses with expertise in female sexual health and menopause lead an interactive demonstration of vaginal moisturizers and lubricants. Advice for counseling patients on the proper use and application of vaginal estrogens is also reviewed. The final session focuses on sexual health counseling, including sexual history-taking skills. Participants are taught about the domains of sexual function, female sexual response cycle, types of desire, patient resources, and sexual aids. Feedback following the initial iteration of this workshop was very positive. All participants felt that the experience was an effective use of time, would recommend it to others, and were confident in their ability to apply skills to their clinical practice.

Conclusions

This interactive workshop led by a multidisciplinary group of providers aims to improve trainee comfort in evaluation and management of female sexual health and menopause. Given the commonplace nature of these topics in primary care and paucity of existing curricula, consideration could be given to the inclusion of a similar educational experience into internal medicine, family medicine and/or obstetrics and gynecology residency programs.

Disclosure

No.
(087) SMALL FIBER NEUROPATHY AND FEMALE SEXUAL FUNCTION
Authors: Pollard J , De E , Walia J , Feustel P , Patel S
Published: June 2024

Introduction

Small fiber neuropathy (SFN) can result in a variety of pain and autonomic symptoms due to its impact on small-diameter somatic and autonomic unmyelinated C-fibers and/or thinly myelinated A-delta (Aδ) fibers. It has been identified in 66% of patients with complex (refractory or multisystem) pelvic pain.

Objective

The objective of this study was to characterize the differences between sexual symptoms in patients with and without SFN.

Methods

This was a retrospective case control study involving patients seen at a subspecialty Urogynecology and Reconstructive Surgery clinic between January 2023 and October 2023. All patients presenting for evaluation were offered an electronic pre-visit intake form inclusive of the PISQ-IR (evaluation tool validated by the IUGA for sexual dysfunction symptoms). The primary outcome measured was self-reported quality of sexual function, represented by PISQ-IR score. Secondary outcomes included comparisons of survey scores for arousal, orgasm, and dyspareunia between SFN and non-SFN patients.

Results

A total of 89 patients were analyzed, 11 with definitive SFN and 78 without SFN. Results were compared between these two groups using chi-square tests and Mann-Whitney U tests. PISQ-IR scores were significantly different between SFN and non-SFN patients. Mean scores of 2.9 (SD 0.6) and 3.5 (SD 0.6) were calculated, respectively, indicating worse overall sexual function in SFN patients (p = 0.01). Secondary outcomes analyzed were significant for lower orgasm intensity scores in SFN patients (median of 2 vs 3 in non-SFN patients, p = 0.02 Mann-Whitney test). Arousal scores and pain scores were not significantly different between the two patient populations.

Conclusions

SFN is associated with worse sexual function and decreased orgasm intensity in the subspecialty Urogynecology and Reconstructive Surgery population.

Disclosure

No.
(128) ABORTION AND THE MYTH OF THE HARM-FREE PREGNANCY
Authors: Creatura C
Published: June 2024

Introduction

A comprehensive description of the impact of pregnancy and childbirth on the human body has never been published. All pregnancies pose an unquantifiable threat to one's health and childbirth has permanent, irreversible effects that are cumulative and often late-manifesting. This reality refutes the anti-abortion, pro-natalist claim that there is any such thing as an elective abortion.

Objective

Abortion access supports the fundamental human right to bodily autonomy and sexual self-determination, hence every abortion is performed in the service of the pregnant person's health. The neglect of these principles has allowed politically-motivated legislatures to introduce imprecise health exception language that does not acknowledge the actual impact of pregnancy and childbirth. Affirming that abortion is life-saving healthcare refutes the health exception fallacy.

Methods

Maternal mortality and morbidity statistics are flawed and incomplete. None of the standard measures adequately captures the effects of pregnancy, whether voluntary or forced, upon the health of the parturient or her community. This report elucidates the unpredictable and often unattributed morbidity associated with pregnancy and childbirth, and argues for a human rights approach to abortion policy.

Results

Abortion bans have downstream effects that negatively impact the care of all pregnancy-capable people and their communities. Allowing non-experts to legislate against evidence-based care creates confusion and leads to mistrust of the healthcare system. Gendered disinformation, gag rules, and criminalization of pregnancy all result in stigma and harm.

Conclusions

The cultural reluctance to seriously study the effects of pregnancy on health is linked to gender inequality and is correlated with restrictive abortion laws that violate ethical principles of beneficence and patient autonomy. Involuntary pregnancy is a major and preventable cause of human suffering that can be relieved with permissive abortion policies based on ethical and scientific standards of care.

Disclosure

No.
Phytic acid-based nanomedicine against mTOR represses lipogenesis and immune response for metabolic dysfunction-associated steatohepatitis therapy
Authors: Xu Fenghua , Zhao Shoujie , Zhu Yejing , Zhu Jun , Kong Lingyang , Li Huichen , Ma Shouzheng , Wang Bo , Qu Yongquan , Tian Zhimin , Zhao Junlong , Liu Lei
Published: June 2024

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common chronic liver diseases and is mainly caused by metabolic disorders and systemic inflammatory responses. Recent studies have indicated that the activation of the mammalian (or mechanistic) target of rapamycin (mTOR) signaling participates in MASH progression by facilitating lipogenesis and regulating the immune microenvironment. Although several molecular medicines have been demonstrated to inhibit the phosphorylation or activation of mTOR, their poor specificity and side effects limit their clinical application in MASH treatment. Phytic acid (PA), as an endogenous and natural antioxidant in the liver, presents significant anti-inflammatory and lipid metabolism-inhibiting functions to alleviate MASH. In this study, considering the unique phosphate-rich structure of PA, we developed a cerium-PA (CePA) nanocomplex by combining PA with cerium ions possessing phosphodiesterase activity. CePA intervened in the S2448 phosphorylation of mTOR through the occupation effect of phosphate groups, thereby inhibiting the inflammatory response and mTOR-sterol regulatory element-binding protein 1 (SREBP1) regulation axis. The in vivo experiments suggested that CePA alleviated MASH progression and fat accumulation in high-fat diet-fed mice. Mechanistic studies validated that CePA exerts a liver-targeted mTOR repressive function, making it a promising candidate for MASH and other mTOR-related disease treatments.
A Relational Theory of Dignity and Human Rights: An Alternative to Autonomy
Authors: Metz Thaddeus
Published: June 2024

In this article I draw on resources from the Global South, and particularly the African philosophical tradition, to construct a theory of human rights grounded on dignity that presents a challenge to globally dominant, autonomy-based approaches. Whereas the latter conceive of human rights violations as degradations of our rational nature, the former does so in terms of degradations of our capacity to be party to harmonious or friendly relationships. Although I have in the past presented the basics of this relational approach, in this article I present new argumentation in support of it. I defend it from criticism and also go on the offensive by arguing that understanding the human rights violations of torture and rape to be (roughly) behavior that treats innocent parties in an extremely discordant or unfriendly way is, if not more plausible than standard Kantian understandings, at least a promising alternative to them.
A Plasmodium apicoplast-targeted unique exonuclease/FEN exhibits interspecies functional differences attributable to an insertion that alters DNA-binding
Authors: Chatterjee Tribeni , Tiwari Anupama , Gupta Ritika , Shukla Himadri , Varshney Aastha , Mishra Satish , Habib Saman
Published: June 2024

The human malaria parasite Plasmodium falciparum genome is among the most A + T rich, with low complexity regions (LCRs) inserted in coding sequences including those for proteins targeted to its essential relict plastid (apicoplast). Replication of the apicoplast genome (plDNA), mediated by the atypical multifunctional DNA polymerase PfPrex, would require additional enzymatic functions for lagging strand processing. We identified an apicoplast-targeted, [4Fe–4S]-containing, FEN/Exo (PfExo) with a long LCR insertion and detected its interaction with PfPrex. Distinct from other known exonucleases across organisms, PfExo recognized a wide substrate range; it hydrolyzed 5′-flaps, processed dsDNA as a 5′-3′ exonuclease, and was a bipolar nuclease on ssDNA and RNA–DNA hybrids. Comparison with the rodent P. berghei ortholog PbExo, which lacked the insertion and [4Fe–4S], revealed interspecies functional differences. The insertion-deleted PfExoΔins behaved like PbExo with a limited substrate repertoire because of compromised DNA binding. Introduction of the PfExo insertion into PbExo led to gain of activities that the latter initially lacked. Knockout of PbExo indicated essentiality of the enzyme for survival. Our results demonstrate the presence of a novel apicoplast exonuclease with a functional LCR that diversifies substrate recognition, and identify it as the candidate flap-endonuclease and RNaseH required for plDNA replication and maintenance.
ATRT-01. MODELLING ATYPICAL TERATOID/ RHABDOID TUMOUR AND HEALTHY BRAIN CROSSTALK
Authors: Porter Harry Dean , McCrorie Phoebe , Diksin Mohammed , Moloney Cara , Grundy Richard , Rahman Ruman
Published: June 2024

BACKGROUND

Atypical Teratoid/Rhabdoid Tumours (ATRT) are aggressive paediatric brain tumours which mostly occur in the first three years of life and which rapidly recur after surgical resection. There has been debate over the use of cytotoxic consolidation therapy due to the severity of off target effects associated with chemo/radiotherapy use in young patients. Astrocytes have previously been shown to support progression and therapy resistance of other brain tumours; however, their role in ATRT pathophysiology is yet to be elucidated.

METHODS

To better understand how adjacent “healthy” brain tissue may be complicit in ATRT recurrence, we have developed a 3D in vitro model in which ATRT cells are co-cultured with astrocytes within a bespoke decellularized human cerebellum extracellular matrix (ECM) hydrogel.

RESULTS

Immunofluorescence confirmed that human cerebellar ECM hydrogels retain human brain ECM components (hyaluronic acid, laminin, and fibronectin). ATRT-astrocyte co-culture spheroids were formed within the ECM hydrogel and observed to display a distinctive morphology relative to monoculture controls, with no difference in overall viability. Co-cultured tumour cells were successfully harvested from the model and isolated from astrocyte populations using fluorescence activated cell sorting. In both 2D and 3D culture, we have shown that astrocytes labelled with CM-DiI transfer this cell tracker dye to ATRT-MYC (BT12, BT16) and ATRT-TYR (BT37) cells, potentially indicating intercellular trafficking. Furthermore, in 2D culture ATRT-MYC (BT12 and BT16) cells form actin rich cell-cell processes with astrocytes when co-cultured in vitro.

CONCLUSIONS

This work represents a comprehensively characterised model of ATRT interaction with the healthy brain. Future work will analyse changes in ATRT cell transcriptomes when astrocytes are present in the model. By understanding how the presence of astrocytes in the tumour microenvironment may promote tumour survival and progression, we aim to use this data to identify candidate therapeutics to inhibit crosstalk and improve patient outcomes.
ATRT-03. PRIMARY DIFFUSE LEPTOMENINGEAL ATYPICAL TERATOID/RHABDOID TUMOR (ATRT) OF CHILDHOOD DEMONSTRATING UNEXPECTED IMPROVEMENT UPON CESSATION OF CONVENTIONAL THERAPY FOR PRESUMED PROGRESSION; A MOLECULARLY CHARACTERIZED CASE REPORT
Authors: Stivaros Stavros , Parkes Laura , Bedir Rania , Cheesman Edmund , Ram Dipak , Leung Lydia , Huang Annie , Kilday John-Paul
Published: June 2024

BACKGROUND

Atypical teratoid/rhabdoid tumors (ATRTs) are malignant tumors of the central nervous system, typically presenting in the posterior fossa of very young children. Prognosis remains poor despite current therapy, while tumorigenesis implicates both genomic and epigenetic dysregulation. Primary diffuse leptomeningeal disease (PDL ATRT), without a defined intraparenchymal lesion, is an extremely rare ATRT variant with only seven cases reported. None of these preceding cases had undergone molecular characterization. We compared our case, who demonstrated an atypical clinical and radiological trajectory, against these seven cases.

CASE PRESENTATION

We describe a PDL ATRT, with hitherto novel molecular and imaging characteristics, in a pediatric patient who subsequently demonstrated radiological and clinical recovery from radiologically diagnosed metastatic relapse in the absence of conventional ATRT salvage treatment. Our case is the first to utilize Magnetic Resonance Imaging Arterial Spin Labelling perfusion imaging to suggest an underlying malignancy as the responsible etiology for this patient’s complex presentation, and the first to use methylation profiling to establish a tumor molecular subgroup for a PDL ATRT patient (identifying a MYC-subgroup in this case).

CONCLUSIONS

For this reported case of pediatric MYC-subgroup PDL ATRT, MR perfusional imaging aided in establishing the diagnosis and predicting potential relapse as part of a multi-parametric imaging assessment. We administered upfront intensive multimodal therapy, including high-dose CSRT to the patient, resulting in the longest overall survival for any patient reported with this extremely challenging ATRT variant. His unanticipated clinical and radiological improvement following a subsequent radiological diagnosis of tumor relapse highlights the importance of confirming recurrence by tissue extraction where feasible, but suggests that further evaluation of histone deacetylase inhibition as a potential future therapy in ATRT is warranted.
ATRT-07. PRC1/BMI1 ACTIVITY ALTERS CHROMATIN ACCESSIBILITY TO REGULATE DIFFERENTIATION IN ATYPICAL TERATOID RHABDOID TUMORS
Authors: Alimova Irina , Murdock Gillian , Pierce Angela M , Danis Etienne , Wang Dong , Serkova Natalie , Foreman Nicholas , Dahl Nathan , Venkataranman Sujatha , Vibhakar Rajeev
Published: June 2024

BACKGROUND

SMARCB1 is a member of the SWI/SNF chromatin remodeling complex that is responsible for determining cellular pluripotency and lineage commitment. Atypical Teratoid Rhabdoid Tumor (ATRT) is a highly aggressive pediatric brain tumor and characterized by SMARCB1 deletion.

METHODS

Genome wide RNAi screen, RNA-seq and ChIP-Seq analysis, colony formation assay, cell cycle, western blotting, immunoprecipitation, mass spectrometry analysis, mouse xenograft model, IVIS and MRI imaging.

RESULTS

We performed an RNAi-based functional genomic screen to identify key epigenetic regulators that co-operate with SMARCB1 loss and contribute to tumorigenesis in ATRT. 406 genes associated with epigenetic regulation in patient-derived ATRT cell lines were targeted. This screen identified BMI1, a component of the Polycomb Repressive Complex 1 (PRC1), as one of the top targets essential for ATRT cell growth. Using RNA-seq and ChIP-Seq analysis we demonstrated that BMI1 co-operates with SMARCB1 deletion to suppress transcription of pro-differentiation pathways and promote self-renewal of tumor stem cells. In SMARCB1 deficient cells BMI1 forms a partial PRC1 complex devoid of DNA binding components. We found that genetic inactivation of BMI1 suppresses ATRT cell clonogenicity and neurosphere formation, leads to S-phase arrest and induces ATRT cell differentiation in vitro. In vivo BMI1 inhibition induces apoptosis, leading to significantly increasing survival of treated mice. By Doxycycline-inducible SMARCB1 re-expression system we revealed activation of proapoptotic proteins p16 and p21. With immunoprecipitation for BMI1, followed by mass spectrometry analysis we demonstrated that re-expression of SMARCB1 activates two PRC1 chromatin localizing components CBX4 and CBX8. Moreover, SMARCB1 re-expression significantly prolongs mice survival and decreases tumor size as evaluated by IVIS imaging system and T2-MRI.

CONCLUSION

Thus, we demonstrated that SMARCB1 deletion results in reprograming of BMI1 chromatin occupancy away from lineage specification by altering the components of the PRC1 complex and that PRC1/BMI1 inhibition is a novel therapeutic approach in ATRT.
ATRT-20. ATYPICAL TERATOID RHABDOID TUMOR: ASSOCIATION OF CLINICAL, HISTOLOGICAL, RADIOLOGICAL, MOLECULAR, AND THERAPEUTIC DATA WITH THE SURVIVAL OF PATIENTS ATTENDED AT IOP/GRAACC/UNIFESP
Authors: Rodrigues Jéssica Benigno , Cappellano Andrea Maria , da Silva Frederico Adolfo Benevides , Cavalheiro Sergio , Dastoli Patricia , da Costa Marcos Devanir Silva , de Alves Maria Teresa Seixas , de Toledo Silvia Regina Caminada , Tesser-Gamba Francine , da da Silva Nasjla Saba Silva Saba
Published: June 2024

BACKGROUND

In childhood, Atypical Rhabdoid Teratoid Tumor accounts for 2% of cases of brain tumors. There is no consensus for the treatment, resulting in multiple protocols.

METHODS

Retrospective study at the Institute of Pediatric Oncology-IOP/GRAACC/UNIFESP, from January 2000 to December 2022. There were 31 patients admitted during this period. The classification of the histological type into rhabdoid/classic, small round and blue cells, epithelial, and mesenchymal was carried out by the same pathologist, and a 50% cutoff characterized the predominant pattern. A neuro-radiologist reviewed the radiological data. Molecular analysis was performed using NGS.

RESULTS

In patients <3yo, 74.9% of patients died. Overall survival (OS) at 3 years was 24.5%, and progression-free survival (PFS) at 3 years was 13.8%. In patients <3yo, the absence of metastases was associated with a higher OS and PFS (3y-OS 35.6% and 3y-PFS 23.7%, vs 3y-OS 10% and 3y-PFS 0% in patients with M+). The OS was higher in patients who received radiotherapy at the first treatment (3y-OS of 66.6% vs 7.8% in the non-irradiated group). The classic histological pattern had a lower PFS than the epithelial and small cell groups (p=0.021). In patients>3 yo, 57.1% of patients died. The 3y-OS was 38.1% and the 3y-PFS was 53.5%. In this age group, there was no difference in OS and PFS considering metastases, location, histological pattern, and tumor volume. For post-surgical status, only PFS was significantly higher in patients with complete resection (3y-PFS of 75%, p=0.008). The mean survival time in patients <3 yo was 1.9 years, and the mean survival time in patients >3 yo was 2.5 years. The genetic alterations found were SMARCB1, NOTCH1, and KMT2D.

CONCLUSION

Patients >3yo seem to have a higher OS and PFS than those <3 yo. Early diagnosis of ATRT may corroborate to a better outcome. The radiotherapy in the first treatment can improve the outcome of patients under 3 years of age. The classic histological pattern was associated with worse PFS.
BIOM-11. TUMOUR SUPPRESSIVE ROLES OF MIR-206 AND MIR-383 VIACORO1C ANDSV2B IN AGGRESSIVE PAEDIATRIC AND ADULT BRAIN MALIGNANCIES
Authors: Mustafov Denis , Lambrou George I , Siddiqui Shoib S , Braoudaki Maria
Published: June 2024

Medulloblastoma (MB), the most prevalent brain malignancy in children, poses challenges in paediatric oncology due to its aggressiveness and potential for metastasis. Tailored treatment strategies are essential due to the impact of treatment-related toxicities and long-term side effects on children’s developing brains. This study aimed to identify therapeutic targets for paediatric MB and explore common biosignatures with glioblastoma multiforme (GBM), the most aggressive adult brain tumour. Total RNA and microRNAs (miRNAs) were extracted from eleven paediatric brain tissues (normal brain tissues, n=2; MB tumour tissue, n=8; pilocytic astrocytoma, n=1). High-throughput small-RNA sequencing (sRNA-seq) and transcriptomics were performed to identify the most deregulated miRNAs in paediatric MB tissue samples. Selected miRNAs, gene targets and encoded proteins were evaluated in vitro and ex vivo via real-time polymerase chain reaction (RT-qPCR), western blotting and immunohistochemistry (IHC). The sRNA-seq demonstrated that miR-383 and miR-206 were highly down regulated in MB samples suggesting their tumour suppressor properties. Bioinformatics analysis using miRSystem and TargetScan identified SV2B and CORO1C as their direct targets, respectively. Transcriptomics showed significant upregulation of SV2B and CORO1C in MB tissue samples. RT-qPCR analysis confirmed overexpression of SV2B and CORO1C within GBM cell lines and IHC depicted significant overexpression of SV2B and CORO1C proteins in paediatric MB and GBM patient cohorts (n=28) compared to their normal brain counterparts (n=32). Elevated CORO1C expression was also detected in adult MB (n=23) and GBM (n=73) tissue samples, when compared to normal brain tissue. Western blotting further verified the significant overexpression of CORO1C and SV2B within GBM cells, suggesting their role as potential oncoproteins. Collectively, our preliminary study proposes the clinical significance of miR-206 and miR-383 when overexpressed in the therapy of aggressive paediatric and adult brain malignancies.
CP-01. FATIGUE IN PATIENTS WITH HYPOTHALAMIC SYNDROME – A CROSS-SECTIONAL ANALYSIS IN THE GERMAN CHILDHOOD-ONSET CRANIOPHARYNGIOMA COHORT
Authors: Beckhaus Julia , Özyurt Jale , Mehren Aylin , Friedrich Carsten , Müller Hermann L
Published: June 2024

BACKGROUND

Patients with tumors of the sellar region are at risk of developing hypothalamic syndrome. Survivors experience fatigue and excessive daytime sleepiness even years after tumor treatment. The aim of this cross-sectional study was to determine the severity of fatigue in patients with and without hypothalamic syndrome.

METHODS

Patients diagnosed with CP or pilocytic astrocytoma were recruited from the KRANIOPHARYNGEOM 2000/2007/Registry 2019 studies and included in this analysis. Eligibility criteria were regular participation in outpatient after-care, one completed Multidimensional Fatigue Inventory-20 (MFI-20) questionnaire and complete medical records on criteria for hypothalamic syndrome. With univariable and multivariable linear regression, the relation of hypothalamic syndrome and levels of fatigue symptoms (MFI-20 sum score) were assessed. MFI-20 scores were compared to sex- and age-matched reference values from a German normative population using paired t-test.

RESULTS

Data on 46 patients, with a median age of 20 years, was available for this analysis of which 28 (61%) patients presented with hypothalamic syndrome. After adjustment for age and sex, patients with hypothalamic syndrome reported higher scores in the physical (= 3.61 [95% CI: 1.38–5.85]), mental (= 2.80 [95% CI: 0.28–5.32]) and sum MFI-20 (= 12.02 [95% CI: 2.93–21.10]) domain than patients without hypothalamic syndrome. Compared to reference values from a general German population, all patients reported higher mean scores in each fatigue domain. Regardless of the level of daytime sleepiness in patients with hypothalamic syndrome, the reported fatigue scores were high. Daytime sleepiness did not correlate with fatigue.

CONCLUSIONS

Fatigue symptoms are present in patients with CP. However, patients with hypothalamic syndrome are more affected in mental, physical and overall fatigue. It is crucial in clinical practice, to distinguish between sleep disorders and fatigue and to target patients with hypothalamic syndrome.
CP-05. MAPK PATHWAY ACTIVATION, CLONAL EVOLUTION, INCLUDING RARE TP53 LOSS, AND THE IMMUNE ENVIRONMENT OF RECURRENT CRANIOPHARYNGIOMA
Authors: Apps John R , Gonzalez-Meljem Mario , Guiho Romain , Pickles Jessica C , Prince Eric , Schwalbe Edward , Joshi Nikhil , Stone Thomas J , Ogunbiyi Olumide , Chalker Jane , Bassey Akang , Otto Georg , Davies Rosalind , Hughes Debbie , Tan Enrica , Brandner Sebastian , Lee Victoria , Hayhurst Caroline , Kline Cassie , Castellano Sergi , Hankinson Todd C , Deutschbein Timo , Jacques Thomas S , Martinez-Barbera Juan Pedro
Published: June 2024

BACKGROUND

Craniopharyngiomas are rare challenging tumours, with around 25% of cases recurring despite surgery and/or radiotherapy. Relatively little is known about the biology of recurrence and there is an urgent need to develop new therapies. Our previous studies have suggested preclinical efficacy of MEKinhition with trametinib in human and murine adamantinomatous craniopharyngoioma (ACP) tissue. At ISPNO2022 we reported methylation and expression profiling results from a cohort of relapsed craniopharyngioma, identifying acquisition of chromosomal abnormalities across recurrence, the persistent activation of MAPK pathway at recurrence, the presence of myeloid cells and a rare case of malignant transformation associated with TP53 loss.

METHODS

Here we present an update from this study through exploring additional datasets, preclinical drug testing, and genetic manipulation of genetic engineered mouse models of ACP

RESULTS

Exploration of whole genome sequencing data from 67 cases of ACP from Children’s Brain Tumour Network has confirmed the presence of chromosomal arm changes in 7 (10%) of cases, including at diagnosis, confirming that the genomic landscape of ACP is more complex than previously thought. To further explore the potential of MAPK pathway inhibiton we have demonstrated efficacy of a further two clinically available MEK inbhiibtors, Selumetinib and Binimetinib, in reducing proliferation and inducing cell death in ex vivo explants of murine ACP. To explore the role of TP53 loss in aggressive craniopharyngioma, we show that Trp53 loss in a murine ACP model results in very aggressive tumours and reduced mouse survival. Finally, we have further characterised the tumour immune infiltrate showing differences in the cellular composition between ACP and Papillary CP, and revealing a diverse phenotype of macrophages in ACP.

CONCLUSIONS

Together, this research provides further preclinical support for the ongoing evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in patients with craniopharyngioma.
DIPG-02. LIN28B EXPRESSION IN DIFFUSE MIDLINE GLIOMA
Authors: Knowles Truman , An Shejuan , Huang Tina , Qi Jin , Saratsis Amanda
Published: June 2024

BACKGROUND

Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is a RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. Therefore, we sought to determine the pattern of expression and potential function of LIN28B in DMG using rare DMG cell lines.

METHODS

All studies were performed on DMG cell lines (n=6) and controls (normal human astrocytes n=1, human neural stem cells n=1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen).

RESULTS

Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC>2 or <-2, p<0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71.

CONCLUSIONS

Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
DIPG-29. PHENOTYPIC SCREENS IDENTIFY GENETIC REGULATORS OF NANOPARTICLE DELIVERY IN DIFFUSE MIDLINE GLIOMAS
Authors: Tsai Jessica W , Coppola Marissa , Kenny-Serrano Julianna , Doench John G , Hammond Paula T , Bandopadhayay Pratiti , Straehla Joelle P
Published: June 2024

BACKGROUND

Diffuse midline gliomas (DMGs) are a universally fatal pediatric brain tumor with a median survival of 12 months. There is a dire need to develop novel treatment strategies for these patients. Nanomedicine harbors great potential to encapsulate cargoes across tissue barriers and selectively target cells of interest. To effectively utilize existing nanomedicines and develop design criteria for novel formulations, an improved understanding of nano-bio interactions within the context of disease and development is required.

METHODS

We harnessed a lentiviral all-in-one CRISPR/Cas9 knock-out library paired with fluorescence-activated cell sorting to probe the functional impact of 700 genes on the delivery of lipid-based nanoparticles to DMGs. Layer-by-layer electrostatic assembly was utilized to synthesize a library of liposomal nanoparticles with polymer surface coatings.

RESULTS

Two patient-derived neurosphere models of DMG were transduced with the pooled, barcoded all-in-one CRISPR/Cas9 library. Following selection, cells were incubated with nanoparticles for 1, 4, or 24 hours and dynamically sorted into populations based on nanoparticle affinity. Genomic DNA was isolated from sorted cells and subjected to next generation sequencing for barcode identification. The relative enrichment of each single guide RNA in each population was determined relative to matched controls. We found strong agreement between biologic replicates and both cell lines, and our phenotypic screens revealed strong genetic regulators of nanoparticle uptake. We identified formulation-dependent and independent regulators, as well as regulators that were time-dependent. The top target genes are currently being validated in DMG and human neural stem cell models.

CONCLUSIONS

In ongoing work, we are leveraging genetic and chemical inhibition to sensitize DMG cells to nanoparticle therapeutics. We plan to leverage our screening technique to develop novel combination therapy approaches that could be implemented across multiple administration routes to enhance the use of nanomedicine for DMG and other pediatric brain tumors.