Citations

Abstract BACKGROUND NF1-OPGs are amorphous tumors involving either single or multiple locations (optic nerve, chiasm, tract) along the anterior visual pathway (AVP). In this prospective study, we investigated how volumetric MRI measures of the AVP as well as other clinical variables are associated with treatment decisions in children with newly diagnosed NF1-OPGs. METHODS Children with newly diagnosed NF1-OPG whose MRI included a T1-weighted volumetric sequence without significant artifact at their enrollment visit were eligible for inclusion. All subjects underwent a quantitative ophthalmic exam to determine if visual acuity (VA) was normal. The neuro-oncologist/NF1 expert determined whether the subject would be observed or undergo treatment at that baseline visit. Volumetric MRI analysis was automatically performed using a deep learning network that measured AVP volume (mm3). Non-parametric group comparisons and multivariable logistic regression models evaluated the impact of age at enrollment, sex, NF1 inheritance type, AVP volume, and VA on the decision for immediate treatment with chemotherapy versus observation. RESULTS One-hundred twenty-three subjects met inclusion criteria. Subjects assigned to observation (N=112, 44% female) and subjects immediately treated with chemotherapy (N=11, 80% female) at enrollment were of similar age (2.7 and 2.8 years, respectively) and inheritance (p > 0.05). Abnormal VA was present more often in the treatment group (46%) compared to the observation group (17%, p <0.001). AVP volume was significantly greater in the treatment group (4,181.1mm3) compared to the observation group (1,819.8mm3, p <0.001). AVP volume, sex, and VA reached significance in univariable regression, however, in the multivariable regression model only the AVP volume (p < 0.001) was significantly associated with treatment initiation. DISCUSSION Children with greater NF1-OPG AVP volumes are treated more often compared with those with lower volumes. Volumetric measures of NF1-OPGs are a valuable metric in understanding treatment patterns and are positioned to help inform clinical decision making.

Abstract BACKGROUND Atypical teratoid/rhabdoid tumor (ATRT) is a malignant, highly aggressive embryonal tumor of the central nervous system. Long-term survival remains dismal despite aggressive multimodal therapy, including a maximal safe surgical resection and intensive systemic chemotherapy +/- radiation therapy. While these tumors typically present in infancy or early childhood, there are scattered case reports of adult-onset ATRT. Making prognostic conclusions or therapeutic decisions for this older patient population remains challenging due to the paucity of these reports. CASE REPORT A 25-year-old female with Down syndrome presented with nausea, vomiting, dysphagia, and facial droop and was found to have an avidly enhancing, left cerebellopontine angle mass. There was initial clinical suspicion for leukemic chloroma given the patient’s Down syndrome status and known association with higher rates of hematologic malignancy concurrent with a dramatic scarcity of solid tumors in the Down syndrome population. However, histology demonstrated sheets of high-grade rhabdoid cells with loss of INI1 expression, pathognomonic for ATRT. Further sequencing defined a frameshift mutation in SMARCB1 (p.C298), and methylation profiling matched with high confidence to the MYC subclass of ATRT. The patient was treated with subtotal surgical resection and focal proton radiation, followed by chemotherapy on a modified regimen based on the Children’s Oncology Group protocol, ACNS0333. Systemic methotrexate and all consolidative high-dose chemotherapy with stem cell rescue were omitted due to concern for heightened risk of treatment-related toxicity. The patient remains alive and clinically asymptomatic 19 months from diagnosis. CONCLUSION This report represents the first known case of ATRT in an adult patient with Down syndrome, offering unique mechanistic insight into the tumorigenesis of ATRT. Adult ATRT is a rare entity without standardized treatment or established prognostic understanding. Further studies are needed to define an appropriate risk-adapted therapeutic approach for this patient population.

Abstract BACKGROUND H3K27-altered diffuse midline glioma (DMG) is a devastating pediatric brainstem tumor that affects 200-300 individuals in the US per year. Median survival is 9-11 months, and there are virtually no long-term survivors. Despite decades of clinical trials, radiation therapy remains standard of care, extending survival by 2-3 months. Elucidating the mechanisms that drive H3K27-altered DMG pathogenesis in order to uncover therapeutic vulnerabilities is of critical importance. Recent studies implicate MALT1 as a potential therapeutic target in gliomas. MALT1 is the effector molecule of the CARMA-BCL10-MALT1 (CBM) signalosome, a cytoplasmic protein complex that drives downstream pro-survival transcriptional activity. MALT1, which possesses scaffolding and protease functions, promotes cell viability, proliferation, and migration/invasion in multiple cancer types. We aim to evaluate the hypotheses that MALT1 promotes DMG cancer cell proliferation and migration and that MALT1 inhibition will abrogate tumor progression. METHODS/RESULTS We screened a panel of cells including astrocytes, neural stem cells, and DMG cell lines by Western blot and found that CBM complex members BCL10 and MALT1 are present in all cells tested. We next demonstrated that MALT1 is proteolytically active in DMG cell lines SF8628 and HSJD-DIPG-007. Specifically, we showed cleavage of the MALT1 protease substrate HOIL, which was abrogated by treatment with the MALT1 protease inhibitor MLT-748. We next generated multiple dox-inducible MALT1 shRNA DMG cell lines to assess the impact of MALT1 deficiency on DMG biology. Thus far, we find that shRNA knockdown of MALT1 does not impact SF8628 cell proliferation. CONCLUSIONS MALT1 is expressed and proteolytically active in DMG cells. Initial studies show that MALT1 knockdown does not affect proliferation of SF8628 cells. We will next evaluate the effect of MALT1 knockdown on proliferation of additional DMG cell lines, as well as the impact on other malignant features of DMG cells including migration/invasion.

In September 2022, in Banff, Alberta, Canada, the XVIth Banff meeting, corresponding to the 30th anniversary of the Banff classification, was held, leading to 2 recent publications. Discussions at the Banff meeting focused on proposing improvements to the Banff process as a whole. In line with this, a unique opportunity was offered to a selected group of 16 representatives from the pathology and transplant nephrology community, experts in the field of kidney transplantation, to review these 2 Banff manuscripts. The aim was to provide an insightful commentary, to gauge any prospective influence the proposed changes may have, and to identify any potential areas for future enhancement within the Banff classification. The group expressed its satisfaction with the incorporation of 2 new entities, namely “microvascular inflammation/injury donor-specific antibodies–negative and C4d negative” and “probable antibody-mediated rejection,” into category 2. These changes expand the classification, facilitating the capture of more biopsies and providing an opportunity to explore the clinical implications of these lesions further. However, we found that the Banff classification remains complex, potentially hindering its widespread utilization, even if a degree of complexity may be unavoidable given the intricate pathophysiology of kidney allograft pathology. Addressing the histomorphologic diagnosis of chronic active T cell–mediated rejection (CA TCMR), potentially reconsidering a diagnostic-agnostic approach, as for category 2, to inflammation in interstitial fibrosis and tubular atrophy and chronic active T cell–mediated rejection was also an important objective. Furthermore, we felt a need for more evidence before molecular diagnostics could be routinely integrated and emphasized the need for clinical and histologic context determination and the substantiation of its clinical impact through rigorous clinical trials. Finally, our discussions stressed the ongoing necessity for multidisciplinary decision-making regarding patient care.

Living kidney donors make a significant contribution to alleviating the organ shortage. The aim of this article is to provide an overview of mid- and long-term (≥12 mo) living donor psychosocial outcomes and highlight areas that have been understudied and should be immediately addressed in both research and clinical practice. We conducted a narrative review by searching 3 databases. A total of 206 articles were included. Living donors can be divided into those who donate to an emotionally or genetically related person, the so-called directed donors, or to an emotionally or genetically unrelated recipient, the so-called nondirected donors. The most commonly investigated (bio)psychosocial outcome after living donation was health-related quality of life. Other generic (bio)psychological outcomes include specific aspects of mental health such as depression, and fatigue and pain. Social outcomes include financial and employment burdens and problems with insurance. Donation-specific psychosocial outcomes include regret, satisfaction, feelings of abandonment and unmet needs, and benefits of living kidney donation. The experience of living donation is complex and multifaceted, reflected in the co-occurrence of both benefits and burden after donation. Noticeably, no interventions have been developed to improve mid- or long-term psychosocial outcomes among living donors. We highlight areas for methodological improvement and identified 3 areas requiring immediate attention from the transplant community in both research and clinical care: (1) recognizing and providing care for the minority of donors who have poorer long-term psychosocial outcomes after donation, (2) minimizing donation-related financial burden, and (3) studying interventions to minimize long-term psychosocial problems.

Small cell bladder cancer (SCBC) is a rare and aggressive disease, often treated with platinum/etoposide-based chemotherapy. Key molecular drivers include the inactivation of onco-suppressor genes (TP53, RB1) and amplifications in proto-oncogenes (MYC). We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A genomic analysis of a metastatic biopsy prior to lurbinectedin initiation revealed a TP53 mutation and amplification of the cell cycle regulators E2F3 and MYCL. A repeat biopsy following the development of lurbinectedin resistance showed a new actionable ERBB2 alteration without significant change in the tumor mutation burden (six mutations/Mb). The present report suggests that lurbinectedin may be active and should be further explored in SCBC harboring TP53 mutations and amplifications in E2F3 and MYC family complexes.

AbstractAn otherwise healthy 4‐week‐old term female of Japanese heritage presented with a 1‐week history of asymptomatic progressive, generalized skin lesions. The lesion morphology, distribution, and dermatopathology result was consistent with Sweet syndrome. The patient was found to have a congenital type H rectovestibular fistula. This case highlights the rare association of rectovestibular fistula in neonatal Sweet syndrome which has only been described in neonates of Japanese heritage.

Abstract Introduction Pelvic inflammatory disease (PID) is a common and potentially serious reproductive health condition that may require hospitalization for proper management. Accurate prediction of the length of stay (LOS) for PID hospitalizations can aid clinicians in resource allocation, patient counseling, and improving overall patient care. Prior studies have explored potential risk factors for a poor clinical course among women hospitalized with PID, but to our knowledge, no study to date has explored potential predictors of LOS in PID hospitalization. Objective This study aims to characterize the predictors for LOS in PID hospitalizations based on patient and hospital characteristics using a large national database. Methods The National Inpatient Sample (NIS) database was queried from 2019 to 2020 for all female patients 18 years and older with a primary diagnosis of acute pelvic inflammatory disease using ICD-10 codes. Data on patient demographics, clinical characteristics, comorbidities, and hospital-related variables were collected using variables as defined by NIS and summarized using descriptive statistics. Bivariate and multivariable associations between LOS and covariates were assessed using linear regression models and estimates were reported as regression coefficients. Covariates that were statistically significant in the bivariate models were included as covariates during the multivariate regression analysis. Results A total of 14,505 hospitalized female patients with a principal diagnosis code for acute PID were included. Mean LOS for PID hospitalization was 5.8 days, with a range of 0 – 88 days. The average patient age was 42.9 years (age range 18 – 90 years old), with 55.1% White, 23.4% Black, 12.5% Hispanic, and 2.3% Asian or Pacific Islander. The main primary payers included Medicaid (40.0%), private insurance (36.1%), Medicare (19.1%), and self-pay (4.7%). About 34% of patients were in the lowest quartile for median household income, 45% in the middle two quartiles, and 19% in the highest quartile. In univariable analysis, increased LOS was associated with increasing age, larger hospital bed size, urban teaching hospital status, and the presence of hypertension, diabetes, obesity, or immunodeficiency. Decreased LOS was associated with Hispanic or Native American race and having a non-Medicare primary payer. In multivariable analysis, increased LOS was associated with increasing age (+0.06 days per increasing year, p < 0.0001) and large hospital bed size (+0.6 days compared to small bed size, p = 0.03). Decreased LOS was associated with Asian or Pacific Islander race (-1.1 days compared to White race, p = 0.02), Native American race (-1.4 days compared to White race, p = 0.03), and being billed as ‘no charge’ (-2.1 days compared to Medicare, p = 0.03). Conclusions This study identifies possible predictors of LOS in PID hospitalization, providing insights that may help optimize resource allocation and better characterize factors that may impact PID management. Several factors, including age, race, expected primary payer, and bed size of hospital were found to significantly impact LOS. Additionally, this study highlights the potential role of social determinants of health in PID hospitalization and management and can help guide future research and initiatives aimed at improving population health and addressing disparities in PID. Disclosure No.

Abstract Introduction Sexual and reproductive history taking is a fundamental yet often overlooked aspect of medical education. Most medical schools in North America do not provide adequate sexual health training to students, with 44% of schools lacking a sexual and reproductive health curriculum (1). Moreover, there are currently no national standards across medical schools for training students to take a sexual health history (2). Existing programs vary widely and often consist of limited hours or electives, leaving many medical graduates feeling unprepared (3). Objective To develop a multimodal course and standardized curriculum for first-year medical students. Methods Through a combination of video presentations, live demonstration, interactive lecture, and Group Observed Structured Clinical Experience (GOSCE) sessions with standardized patients, students were guided in learning and practicing sexual history taking skills. Post-course surveys were sent to all 52 students after completion of the course, with 46 students completing the survey (response rate 88%). Students were asked to rank their knowledge of the course topic on a scale from 1 (not at all knowledgeable) to 5 (extremely knowledgeable) both before and after participating. Results On average, there was a significant change in knowledge, regarding navigating sexual health biases and effectively obtaining a sexual history from patients, by 1.2 points after students partook in the course (p < 0.0001). The majority (80%) reported that there was the right amount of lecture and patient interactive learning. Ninety-six percent of students agreed that the course met the learning objectives and indicated they would use what they learned in the course in the future. Conclusions After participating in this multimodal sexual health course, students demonstrated an improvement in knowledge and indicated that the course met the learning objectives. These results suggest that multimodal teaching methods may address the gap in sexual health education. Disclosure No.

Abstract 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.