United States

Background
Neuroblastoma is the most common extracranial childhood tumor. Despite intensive multi-modality therapies, approximately 50% of high-risk patients die from progressive disease. Although retinoic acid-based therapies provide clinical benefit, patients eventually relapse due to resistance, underscoring the critical need for novel treatments. Amplification of MYCN, an oncogene present in 40-50% of high-risk neuroblastoma cases, is associated with poor patient prognosis and poor response to retinoid therapies. However, MycN is “undruggable,” prompting efforts to indirectly impair its expression or function. The aryl hydrocarbon receptor (AhR) is a transcription factor whose role in neuroblastoma remains incompletely characterized. Here, we investigate AhR as a novel tumor promoter that regulates MycN and retinoic acid pathways in neuroblastoma. 

Methods
Human neuroblastoma cells were modified to over- or under-express AhR, or were treated pharmacologically with the AhR antagonist, clofazimine (CLF). To assess tumorigenicity, invasion, clonogenicity, and tumor growth were measured. For MycN regulation studies, AhR and MycN protein expression were detected by immunoblotting. Cells were treated with retinoic acid after AhR depletion or inhibition and examined by microscopy. 

Results
We found AhR depletion decreases clonogenicity and tumor growth in vivo. Notably, treatment with clofazimine (CLF), an FDA-approved anti-leprosy drug we previously identified to be a novel AhR antagonist, has the same effect. CLF is orally bioavailable, safe, cost-effective, and approved for use in children, representing a promising new therapy for neuroblastoma patients. Our work further reveals that AhR depletion and inhibition reduces MycN expression and induces differentiation. Finally, we found AhR depletion and inhibition potentiates retinoid-induced neuroblastoma differentiation. 

Conclusion
Our work uncovers a novel role for AhR as a tumor promoter in neuroblastoma and could lead to an already FDA-approved drug, CLF, as a promising new therapy for neuroblastoma patients that improves efficacy of retinoic acid-based treatments. 


AMA Research Challenge 2022

The Aryl Hydrocarbon Receptor (AhR) as a Novel Therapeutic Target in Neuroblastoma

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Ricardo Correa, MD, EdD
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Stephanie Strohbeen, MD
 
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Jessica Li, MD/PhD Candidate
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Charles Lopresto, DO

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Welcome to the largest national, multi-specialty research event featuring research from 750 medical students, residents and fellows, and international medical graduates.


technical paper

Immigrant Haitian women in New York City (NYC) have the highest rate of Severe Maternal Morbidity of 494.0 per 10,000 deliveries, compared to 229.8 for U.S.-born women. There is little study into the needs and barriers of the Haitian immigrant community, which is one of the largest growing immigrant populations in the United States today. We sought to understand pregnant and postpartum Haitian women’s barriers to healthcare services in NYC and explore ways to improve their overall health outcomes.

The Barriers to Healthcare Pregnant and Postpartum Haitian Women Experience in New York City

Background 
Patients with severe aplastic anemia (SAA) develop high-risk infections. Prior data suggest efficacy and safety of granulocyte transfusion (GT) as an infection management tool in this population. A multicenter randomized control trial of GT in patients with severe neutropenia of varying etiologies did not reveal a significant difference in overall survival (OS) or microbial response but was limited by low enrollment and variable granulocyte dose. In this study of SAA patients who received GTs at our institution, we characterize patients’ clinical and survival outcomes and the role of GTs as a bridge to curative therapy. 

Methods 
SAA patients treated with immunosuppressive therapy who received GTs between 2011 and 2020 are included in our analysis. The primary outcomes are survival from first GT, including OS, and number of patients surviving to discharge and HSCT in patients awaiting HSCT. Secondary outcomes include evaluation of response at 30 days after initiation of GTs based on clinical, microbiological, and radiographical criteria. Cox proportional-hazards model was utilized to determine impact of neutrophil response and infection type on survival. Kaplan-Meier was used to assess OS. 

Results 
Twenty-eight SAA patients of median age 20 years (range 6-65 years) underwent 30 GT courses of median 8 products per course (range 1-39 products), over median 23.5 days (range 3-103 days), with a per-dose median 1.28 x 10^9 granulocyte cells/kg (range 0.45-4.52 x 10^9). Infection type included bacterial (n=15), fungal (n=12), and mixed (n=3). OS from initial GT was 50% with a median length of follow up at 550.5 days (range 2-4213 days). 18 of 28 (64.3%) patients survived to hospital discharge. Of the 21 patients awaiting HSCT during granulocyte therapy, 18 (85.7%) received HSCT. Patients achieving complete, partial or stable response at 30 days had significantly improved OS compared to non-responders (p=0.00004). Sex, type of infection, or % of days with ANC >200 cells/mcL during the granulocyte course, were not predictive of survival (p=0.52, p=0.7, p=0.28 respectively). 

Conclusion 
GTs of adequate dose and course duration are a valuable adjunctive therapy to manage severe infections in SAA patients and may be particularly valuable as a bridge to undergoing curative treatment with HSCT.

The Clinical Role of Granulocyte Transfusions in Severe Aplastic Anemia

Strabismus is a visible disability that impacts one's ability to make eye contact. In this study, we evaluate the impact that strabismus has on quality of life in adults and explore how strabismus surgery can be effective in improving quality of life.

The impact of strabismus on quality of life in adults

Introduction: The Rotterdam CT (RCT) score is a prognostic metric used to predict mortality in patients with traumatic brain injury (TBI) using injury characteristics observed on initial CT. Withdrawal of life-sustaining therapies (WLST) following trauma may be related to certain patient factors such as age and injury severity, but its relationship to RCT remains unknown. 

Objectives: The present study aims to determine whether the RCT score can be used as a reliable predictor of WLST in patients with TBI and to validate previous studies demonstrating that the RCT score can reliably predict mortality in patients with TBI. 

Methods: All patients ≥ 18 years old with TBI were identified from the MetroHealth TBI Database, a registry of patients admitted to MetroHealth Medical Center (Cleveland, OH) with TBI between 2018-2021. We collected factors related to RCT score, baseline demographic data, clinical presentation, neurosurgical intervention, and do not attempt resuscitation (DNAR) orders. The primary outcome measure was WLST, and the secondary outcome measure was mortality. Binary logistic regression models were created to determine factors independently associated with WLST and mortality. 

Results: A total of 1110 patients were identified. The median age was 61 years old and 69.3% (770/1110) were male. In this cohort, 11.3% (n = 125) of patients underwent WLST. A bivariate logistic regression model revealed that RCT score (continuous) (odds-ratio (OR) 1.6 [95% confidence-interval (95%-CI) 1.2-2.2]), Glasgow Coma Scale (continuous; GCS) (OR 0.84 [95%-CI 0.78-0.91]), Injury Severity Scale score (continuous; ISS) (OR 1.04 [95%-CI 1.01-1.07]), ventricular drain (OR 4.7 [95%-CI 1.1-19.6]), and DNAR (OR 47.8 [23.8-95.6]) were all independently associated with WLST. An additional bivariate logistic regression model revealed that RCT score (OR 2.08 [95%-CI 1.49-2.91]), ISS (OR 1.06 [95%-CI 1.03-1.10]), GCS (OR 0.81 [95%-CI 0.74-0.88]), undergoing a craniectomy (OR 0.28 [95%-CI 0.09-0.83]), and DNAR (OR 73.3 [95%-CI 34.8-145.7]) were all independently associated with mortality. These models demonstrated excellent accuracy and discrimination ability for both WLST and mortality as endpoints, as demonstrated by concordance statistics of 0.97.

Conclusion: In adult TBI patients, the RCT score can be accurately used to independently predict both WLST and mortality with high predictive validity.

The Predictive Validity of the Rotterdam Computed Tomography Score on Withdrawal of Life-Sustaining Therapies in Patients with Traumatic Brain Injury

Objective: 
The primary purpose of this study was to determine if treating endometriosis with optimal excision surgery leads to lower rates of repeat surgery as compared to historical rates of repeat surgery by ablation. A secondary outcome was to examine whether the use of hormonal suppression differed before surgery, depending on the stage of endometriosis found at surgery.
Study design: 
We performed a prospective cohort study (Canadian Task Force class II-3).
Materials and methods: 
Preoperative data, operative data, and follow-up postoperative data were collected prospectively (IRB 20900) at the Saint Louis University Center for Endometriosis, a referral center for the surgical management of endometriosis specializing in the optimal excision of endometriosis, from time frame 2012-2019. Optimal excision was defined as completely excising all areas of abnormal peritoneum, wherever found in the pelvis, having looked systematically with near contact laparoscopy. All surgeries were performed by a single surgeon specializing in optimal excision. Follow-up data was collected from annual questionnaires sent postoperatively to patients.
Results: 
Of the 756 patients in the database who underwent surgery for endometriosis, 620 patients had histological confirmation of endometriosis in any location excised, yielding a rate of finding tissue-proven endometriosis to be 82%. The mean follow-up time period in months was 32 months (range 5-136 months). Of the 620 patients with tissue-proven endometriosis, 570 women had optimal excision (OE) surgery for endometriosis (91.9%) of which 14 patients underwent repeat surgery (2.5%). Of the 620 patients, 366 women (60%) were on hormonal suppression specifically: 96.4% of the 366 women on hormonal contraceptives, 29.5% on GnRH agonists/antagonists/chemical menopause, and 14.6% on progesterone-secreting IUDs with a median length of suppression of 36 months. At surgery, 62.9% of patients were categorized as endometriosis stage 1 or 2, 11.8% for stage 3, and 25.3% for stage 4. There was also no significant association between hormonal suppression before endometriosis excision surgery with the stage of endometriosis found at surgery. 
Conclusion: 
The rate of repeat surgery is an important clinical factor when looking at surgical outcomes. The rate of repeat surgery after optimal excision surgery for endometriosis was remarkably low (2.5%) as compared to historical rates of repeat surgery by ablation (40-60% in 1-2 years following initial procedure ). Additionally, the lack of significant evidence between hormonal suppression use and progression of stage of endometriosis provides implicit evidence that hormonal suppression does not prevent progression of the disease. Further controlled studies are needed to verify these findings.


The Rate of Repeat Surgery After Optimal Excision Surgery of Endometriosis at a Single Tertiary Referral Center

BACKGROUND: Otitis Media (OM) is one of the most prevalent pediatric infectious diseases often comprising two common diagnoses: acute otitis media (AOM) and otitis media with effusion (OME). The current guidelines on managing OM have emphasized the need to accurately diagnose fluid presence in the ear, and the latest methods for OM diagnosis are often inaccurate or under-utilized. This frequently results in over-usage of antibiotics for AOM or misdiagnosis of middle ear effusion in OME. Emerging technologies including leveraging artificial intelligence (AI) and automation to improve OM diagnosis are likely to play a significant role for clinicians into the future. As a specific example, optical coherence tomography (OCT), capable of imaging body cavities and tissue, has recently been introduced as a promising technology for the accurate diagnosis of OM. This study was conducted to capture the current state of advances in automation and technological innovations in OM diagnosis.
METHODS: A qualitative systematic review of PubMed, Scopus, and Google Scholar was conducted to analyze the role of AI and automation in the diagnosis and management of OM. Articles were reviewed for eligibility and 41 studies met inclusion criteria.
RESULTS: Across studies, use of AI has shown promising progress toward more accurate diagnosis of AOM. Clinicians can use AI and obtain reliable imaging focused on AOM and OME, aiding in both management and diagnosis. Applications of OCT have provided for high- quality detection, diagnostics, and monitoring prognosis of OM. Smartphone attachments employing acoustic reflectance have recently demonstrated great potential for cost-effective and remote OM diagnosis. Although smartphone otoscopes are available for remote use by parents, there remains risk for discrepancies when compared to data acquired by physicians.
CONCLUSION: Through the development of an automated diagnostic algorithm for OM, AI and automation technologies would provide several benefits to OM patients worldwide. This cost-effective approach can account for early detection of OM in pediatric patients, assist parents in deciding whether their children need professional help, and aid clinicians in managing OM with potentially more reliability than current technologies.

The Role of Artificial Intelligence and Automation in the Diagnosis and Management of Otitis Media

Abstract Title: Time to Hemorrhage Response After Implementation of an Obstetric
Hemorrhage Bundle
Background: Obstetric hemorrhage (OBH) is a leading cause of maternal mortality on day of birth. Alarmingly, but not surprisingly, maternal mortality tracks closely with racial disparities, with patients from underserved backgrounds at a greater risk for death during pregnancy and childbirth. Despite several effective uterotonic interventions available for postpartum bleeding, the rate of OBH per 10,000 births has seen a sharp increase, from 4.3 in 1993 to 21.1 in 2014. OBH “bundles” that standardize hemorrhage recognition and response have been shown to reduce OBH rates, however the mechanisms for reduction in morbidity are unclear. Imprecise estimate of blood loss leading to delayed provider response to hemorrhage has been theorized as a contributing factor for the rise in hemorrhage rates. This is the first study to compare the time delay of uterotonic interventions for OBH before and after the implementation of an OBH bundle.
Methods: We performed a retrospective study of 7276 deliveries before and after
implementation of an OBH bundle which includes risk assessment tools and quantitative blood loss measurement. A random sample of deliveries from January to December 2016 was selected for the pre-intervention group. All deliveries from January 2018 to December 2019 were included in the post-intervention group. The primary outcome was time from delivery to first dose of oxytocin; secondary outcome was the number of uterotonic interventions utilized. Groups were compared using Student’s t-tests and chisquared tests.
Results: Of the 7276 deliveries, 1944 (27%) occurred pre-intervention and 5332 (73%) occurred post-intervention. After bundle implementation, average oxytocin time delay decreased from 8.3 minutes to 5.9 minutes (p <0.01). The frequency of second line uterotonic interventions increased from 16% to 18% post-intervention (p <0.05).
Conclusion: This is the first study to investigate how implementation of standard OBH treatment drives clinical decision making such as medication administration. Implementation of this OBH bundle was associated with more prompt delivery of uterotonic interventions. Future studies should explore the effect of OBH bundle protocols on hemorrhage-related outcomes.

Time to Hemorrhage Response After Implementation of a Obstetric Hemorrhage Bundle

Abstract Title: Tissue Anchoring Nanomedicine Alleviates Osteoarthritis Knee Model in Mice

Background 
Osteoarthritis (OA) is the most common joint disorder in the United States. The CDC estimates more than 32.5 million US adults suffer from clinical OA. According to the AAOS evidence-based guidelines, intraarticular anti-inflammatory therapy is the first line treatment for knee OA. Currently available therapies have critical shortcomings, primarily the inability to modify pathophysiological disease progression limiting treatment solely to palliative care. Further, rapid clearance of these drugs from the joint space limits therapeutic potential and results in systemic side effects. Given the established anti-inflammatory potential and readily modifiable structure of nanoparticle fullerene (C60), we attempt to develop a more precise treatment for knee OA.
Methods
We have previously developed a targeted C60 nanoparticle composed of a C60 cage with a conjugated cFLFLF peptide (cFLFLF-C60) that binds specifically to formyl peptide receptor-1, a receptor abundantly expressed on activated macrophages. Using Raw 264.7 macrophages, Lipopolysaccharide, and the Cy5 fluorophore integrated in the cFLFLF peptide, the nanoparticle’s preferential binding was evaluated, and anti-inflammatory efficacy analyzed by PCR. Ten to 12-week-old Balb/c mice underwent destabilization of middle meniscus (DMM) surgery to induce OA, with seven mice receiving a cFLFLF-C60 injection and six serving as control (injected with saline). IVIS imaging was then used to evaluate the functionalized-C60’s distribution 2 weeks post-injection. After 6 weeks, the mice were sacrificed, and the knee joints scanned and analyzed by microCT as well as sectioned and stained for histological analysis.
Results
The cFLFLF-C60 demonstrated preferential binding to LPS-stimulated macrophages versus non-inflammed macrophages. IVIS imaging revealed significant retention within the injured knee joint compared to fluorophore-labeled saline. MicroCT analysis revealed that compared to control mice joints, cFLFLF-C60 effectively attenuated OA morphological changes (subchondral sclerosis, osteophyte formation) and restored trabeculae morphological parameters back to those of sham group (trabeculae number, spacing, and connectivity density). Histologic analysis revealed improved OARSI grading and tidemark measurements in the cFLFLF-C60 cohort.
Conclusion
cFLFLF-C60 preferentially anchors to activated macrophages, leading to significantly increased joint space retention. The pathophysiological changes that define OA were attenuated by intra-articular injection of cFLFLF-C60 as confirmed by microCT and histological analysis.


Tissue Anchoring Nanomedicine Alleviates Osteoarthritis Knee Model in Mice

Background: There have been a few recent studies that attempt to describe the insertional anatomy of the triceps brachii muscle onto the tip of the olecranon process of the ulna. Despite the findings from these studies, the detailed complexity of this insertional footprint continues to challenge surgeons as evidenced by continued reports of triceps-associated complications following elbow procedures including tendon rupture and triceps insufficiency. The purpose of this study is to provide a more detailed understanding of the three-dimensional footprint of the triceps brachii at its olecranon insertion at the elbow.
Methods: To perform this basic science study, 22 cadaveric elbows were dissected leaving only the distal insertion of the triceps intact. The insertion was defined and probed with a three-dimensional digitizer to create a digital three-dimensional footprint allowing width, height, and surface area of the footprint to be recorded relative to the bare area. Additionally, the insertional soft tissues of tendon versus muscle along with the shape of the footprints were qualitatively described. An alpha of 0.05 was used for all statistical analysis.
Results: We found the mean width and surface area of the lateral segment to be greater in males than in females (30.07 mm vs. 24.37 mm, p=0.0339 and 282.1 mm vs. 211. 56 mm, p= 0.0181, respectively). No other statistically significant differences between the sexes were noted. In all specimens, the triceps insertional footprint was “crescent-shaped” and consisted of three regions: central tendon, medial muscular extension, and lateral muscular extension.
Conclusion: The distinction between muscles and tendons is particularly important for surgical decision making. These findings better detailing the complexity of the insertional anatomy of the triceps brachii muscle help explain the importance of avoiding these muscular structures during triceps-off approaches and provides the framework for future clinical studies.


Triceps Brachii Insertional Footprint: Under-estimated Complexity

*Purpose: The rate of living donor kidney transplants (LDKTs) performed has declined overall regardless of race. Studies show that web-based tools increase access to living organ donation (LOD). Kidney transplant candidates (KTCs) may be reluctant to ask potential donors directly. Donor app was designed to help KTCs identify potential living donors by creating social media postings about their need for transplant. The purpose of this study is to evaluate the feasibility of using Donor app in improving awareness about LOD and rates of LDKT.
*Methods: Single-center prospective pilot study of 53 adult KTCs without potential donors was conducted using Donor app. KTCs were required to have access to social media account(s) including Facebook, Messenger, Email and/or Twitter. Based on KTC preference, postings were shared on as many platforms as desired. KTCs were allowed to have donor Champion(s) that will post their own story on social media about their relationship with KTC to advocate for donation. Demographics, clinical characteristics, donor referrals and transplant outcomes were compared between KTCs who used the Donor app with 1:1 matched historic controls from our waitlist.
*Results: 47 KTCs posted their stories using the Donor app. Median age 48 yrs (Interquartile range [IQR]: 41.5-58.5 yrs); median time on waitlist 511 days (IQR: 107-777 days), with 54% AA (n=25). Total views on all platforms and patients were 8501. 67 donor referrals came on behalf of 21/47 KTCs (44%) with a median of 6 days (IQR: 1-23 days) from posting to 1st donor inquiry; 6/21 (28%) had at least 1 donor Champion. KTCs with at least 1 donor referral were also likely to have at least 1 donor Champion (p=0.009), use of multiple social media outlets for posting their story (p=0.02), and had significantly higher views vs. ones with no referrals (487 vs. 71 views/KTC respectively; p=0.003). To date, 2 underwent transplants (1 LDKT; 1 deceased direct donation) and 4 have approved living donors pending the scheduling of transplant. Another 4 KTC’s have living donors still in evaluation. None of the matched controls had any living donor referrals (p=0.01).
*Conclusions: The Donor app can significantly increase awareness & rate of LOD, including in AA. Transplant programs should consider this technology as adjunct support for KTCs who otherwise have no prospects for potential living kidney donation.

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The Aryl Hydrocarbon Receptor (AhR) as a Novel Therapeutic Target in Neuroblastoma

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