United States

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies globally, largely due to its profoundly immunosuppressive tumor microenvironment (TME), which can foster tumor progression and impede effective therapies. While tumor genotype is recognized to influence the immune cell composition of tumors, which specific oncogenic KRAS alleles shape the tumor microenvironment remain poorly understood. Although over 90% of PDACs contain KRAS mutations, there is significant variation in clinical outcomes among KRAS genotypes. KRASG12D (representing about 40% of human PDAC cases) has been shown to modify the
immune landscape of tumors, while the effects of other oncogenic KRAS alleles such as KRASG12R (representing about 18% of human PDAC cases) has not yet been explored. This study investigates KRAS allele-specific immune cell differences in pancreatic cancer. Murine pancreatic organoids carrying KrasG12D or KrasG12R mutations were orthotopically implanted into syngeneic C57/BL6 mice. These tumors recapitulated human PDAC histopathology and survival patterns. Tumors were harvested at 4 weeks for immune profiling by immunofluorescence. The KrasG12D tumors exhibited poor differentiated, high-grade histological features, with significantly larger tumor weights at 4 weeks. In contrast, KrasG12R tumors demonstrated more differentiated, predominantly tubular architecture with small tumors. KrasG12R tumors also showed increased infiltration of CD3+, CD4+ and Foxp3+ cells at 4 weeks, suggesting a more immunoreactive TME. These findings reveal KRAS allele-specific differences in the immune microenvironment of PDAC. Enhanced T cell infiltration in KrasG12R tumors aligns with their less aggressive phenotype, pointing to a potentially less immunosuppressive milieu. This underscores the promise of exploring KrasG12R tumor-targeted immunotherapeutic strategies. Ongoing work aims to confirm these findings using human resection specimens and examination of the biochemical mechanisms underlying these immune differences.

2025 AMA Research Challenge – Member Premier Access

Diverse Immune Landscapes in Distinct KRAS-Mutant Alleles of Pancreatic Cancer

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Background
Highly pathogenic avian influenza (HPAI) poses a tremendous threat to human health and possesses considerable pandemic potential due to
the ongoing H5N1 panzootic. HPAI, which includes the influenza A virus (IAV) H5N1 and H7N9 subtypes, has a case fatality rate of 40-50% in
humans historically, and an HPAI pandemic could have devastating consequences. The development of effective prophylactic and therapeutic
countermeasures for containment of HPAI infections in humans is therefore of paramount importance for pandemic preparedness efforts.
Methods
To facilitate the development of efficacious HPAI vaccination regimens and the isolation of HPAI-neutralizing monoclonal antibodies (nmAbs)
for prophylactic and therapeutic use, we developed an array of novel mRNA-lipid nanoparticles (mRNA-LNPs) and recombinant adenovirus
type 5 (rAd5) vectors encoding various HPAI hemagglutinins (HAs), then assessed their immunogenicity in three distinct vaccination regimens
in six IAV-naïve Indian rhesus macaques (RMs; Macaca mulatta).
Results
Binding Abs recognizing the H5N1 and H7N9 HAs were detectable in all six RMs following vaccination. HPAI-neutralizing Abs were detected in
RMs vaccinated with full-length HAs, but not in RMs vaccinated with HA stems alone. A heterologous prime-boost-boost regimen comprising
mRNA-LNPs and a rAd5 vector encoding the full-length HAs of one H7N9 strain and two different H5N1 strains elicited potent HPAIneutralizing
Abs in both animals receiving this regimen, with peak half-maximal inhibitory serum dilution (ID50) values of ~ 1:100,000 against
H5N1 and ~ 1:50,000 against H7N9. Our vaccination regimens also elicited cross-reactive Abs recognizing the HAs of seasonal IAV subtypes
H1N1 and H3N2, although H1N1 reactivity was superior to H3N2 reactivity in most vaccinees. HA-specific B cells were readily detectable
within vaccinee PBMCs using our fluorophore-conjugated HA probes.
Conclusion
In this study, we demonstrate the immunogenicity of our HA-encoding vaccines and the efficacy of our novel HPAI vaccination regimens in
eliciting both HPAI-binding and neutralizing Abs in nonhuman primates. Exceptionally high serum HPAI neutralization activity was observed in
two of our animals—the most potent HPAI serum neutralization activity ever recorded in a primate. These data suggest that our vaccination
regimen could elicit similar responses in humans. Furthermore, we demonstrate the efficacy of our fluorophore-conjugated HA probes in
identifying HA-specific B cells in circulation, which could be used to isolate potent and broadly-reactive HPAI-nmAbs in the future. Collectively,
our findings provide insight into vaccine-induced humoral immune responses against HPAI and could facilitate the development of both
prophylactic and therapeutic agents for HPAI infections of humans to enhance pandemic preparedness.

Elicitation of potent H5N1- and H7N9-neutralizing antibodies by vaccination of rhesus macaques

Background: Obesity is a major risk factor for HFpEF. While glucagon-like peptide 1 (GLP-1) receptor agonists have demonstrated benefit in obesity-related HFpEF, access remains limited. Phentermine/topiramate is a cost-effective alternative, producing up to 13% body weight loss, but concerns about cardiovascular safety have limited its use.

Methods: We retrospectively studied patients with obesity-related HFpEF treated with phentermine/topiramate. Outcomes included mean weight loss, proportion achieving >10% weight loss, changes in cardiometabolic parameters, and safety events. Data were collected at baseline, 6 ± 1 months, and 12 ± 1 months of treatment.

Results: Thirty-four patients (mean age 62.9 ± 12.4 years; 64.7% female; body mass index (BMI) 41.84 ± 7 kg/m²) were included. At 12 months, weight decreased by 11.04 ± 11.51 kg (11.1%), and BMI by 4.11 ± 4.21 kg/m²; 38% lost >10% of body weight. Mean heart rate increased by 3.3 ± 13.67 bpm; systolic blood pressure decreased by 6.6 ± 14.9 mmHg. Lipid profiles and glycemic parameters showed modest improvement or minimal change. No major adverse cardiac events occurred, and side effects were minor.

Conclusion: In patients with obesity-related HFpEF, phentermine/topiramate was associated with meaningful weight loss and no major adverse cardiovascular events. The small increase in heart rate appears clinically insignificant and is similar to that reported with GLP-1 agonists. Given its safety and affordability, phentermine/topiramate may be a viable first-line or adjunctive therapy in this population.

Safety and Efficacy of Phentermine and Topiramate for Weight Loss in Obesity-Related HFpEF

Background
Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting up to 20% of children worldwide, with increasing incidence in industrialized nations. Disruption of the early-life microbiome has been proposed as a contributor to allergic disease pathogenesis. Antibiotics, commonly prescribed in infancy, may alter gut and skin microbial communities during critical immune development windows, potentially increasing susceptibility to AD. Previous studies have yielded inconsistent findings, necessitating an updated quantitative synthesis of the evidence.
Methods
We performed a systematic review and meta-analysis of observational studies published from 2000 to 2024 assessing the association between early-life systemic antibiotic exposure (within the first 1–2 years of life) and the subsequent development of atopic dermatitis. MEDLINE, Embase, and Web of Science were searched, and eligible studies included cohort, case-control, and cross-sectional designs that reported adjusted effect estimates. Data extraction followed PRISMA guidelines. A random-effects meta-analysis was used to compute pooled odds ratios (ORs), with subgroup analyses based on exposure timing (≤12 months vs. ≤24 months) and frequency of antibiotic courses (1 vs. ≥2). Sensitivity analyses assessed heterogeneity and study quality impact.
Results
Twenty-eight studies comprising over 1.1 million children were included. The pooled relative effect estimate (REE) for AD in children with early antibiotic exposure versus no exposure was 1.30 (95% CI: 1.17–1.44), indicating a 30% increased risk. A dose-response relationship was observed: one antibiotic course was associated with a REE of 1.12 (95% CI: 1.04–1.20), while two or more courses yielded a REE of 1.22 (95% CI: 1.03–1.46). Findings were robust across study designs and persisted in sensitivity analyses excluding lower-quality studies and studies reporting non-OR measures.
Conclusion
This meta-analysis provides evidence that systemic antibiotic exposure in early life is associated with a modest but statistically significant increase in the risk of developing atopic dermatitis, with a clear dose-response pattern. These findings support antibiotic stewardship initiatives in pediatric populations and highlight the potential long-term immunologic implications of early microbiome disruption. Judicious antibiotic use in infancy may represent a modifiable risk factor in the prevention of allergic skin disease.

Early-Life Antibiotic Exposure and Risk of Atopic Dermatitis: A Systematic Review and Meta-Analysis

Purpose: In this study, the performance of a suite of rapid smartphone vision tests was evaluated for monitoring visual function in patients with multiple sclerosis (MS) with prior optic neuritis (ON), without prior optic neuritis, and normal subjects. We demonstrate how smartphone tests can differentiate MS without ON, MS with prior ON history and normal subjects in a clinic setting that can provide accessible standardized testing to neurology and ophthalmology clinics.
Methods: In this pilot study, 117 patients with MS (relapse remitting MS and secondary progressive MS) with prior optic neuritis (MS+ON; n=43) or without prior optic neuritis (MS-ON; n=74) and 104 age-matched controls were tested in the Aalborg, Denmark University Hospital Multiple Sclerosis Clinic using a battery of smartphone visual function tests (Landolt C acuity, Landolt C contrast sensitivity, critical flicker fusion contrast threshold at 7.5, 15, and 30 Hz, related to visual conduction speed). Testing was performed with the patient wearing their glasses (if applicable). One eye was used for statistical comparisons between groups (ANOVA rank test with pairwise multiple comparisons using Dunn’s method).
Results: Each smartphone test took approximately 15 seconds to complete and was intuitive enough that patients were able to immediately perform the visual task. Contrast at which 15 and 30 Hz critical flicker fusion occurred provided the greatest separation between MS patients and normal subjects, with or without prior optic neuritis. 
Conclusions: Portable and rapid smartphone tests of visual function, specifically visual acuity, contrast sensitivity, and flicker sensitivity, can give valuable information about the function of the afferent visual system, which could help in the triage and monitoring of patients with MS and patients with other vision threatening disorders. Interestingly, smartphone flicker sensitivity, a test of visual speed of conduction, provided the greatest discrimination between eyes of MS patients with or without a previous diagnosis of optic neuritis compared to normal eyes. This finding motivates the importance of using a behavioral visual test of visual conduction speed, such as critical flicker fusion or flicker sensitivity, which is resistant to optical blur, to monitor various causes of visual dysfunction.

eyeApps: Smartphone-Based, Objective Quantification of Visual Function Tests in Multiple Sclerosis

Background
Periprosthetic infection (PI) remains a feared complication of implant-based reconstruction (IBR), with reported rates of 10-20% despite multiple prevention techniques​​. PI leads to patient morbidity and healthcare costs, requiring systemic antibiotics and potentially implant removal. Antibiotic-impregnated bone discs (ABC) have been utilized to prevent infection in orthopedic procedures, but evidence for ABC in IBR is scarce and limited primarily to implant salvage​. 

Methods
Patients underwent two stage IBR with tissue expander (TE) and ABC disc placement after mastectomy. ABC was prepared by adding antibiotics to polymethacrylate bone cement to a total concentration of 2.4 g tobramycin and 3 g vancomycin and forming the compound into discs. These discs were implanted underneath the TE and inserted in the prepectoral plane with complete acellular dermal matrix coverage. Discs were removed at exchange of TE to implant. We evaluated wound complications and need for explantation postoperatively. 

Results
Sixty-six patients (one hundred and thirteen breasts) were included in the study. Twenty-one (30.3%) patients had unilateral reconstruction, and forty-six (69.7%) had bilateral. Complications included seromas, which were aspirated in 3 patients (2.7%), hematoma in one breast (0.9%), superficial skin or partial flap necrosis treated conservatively in five patients (4.4%), and mastectomy flap necrosis requiring debridement and replacement of TE in three patients (2.7%). Two (1.8%) TE explants of seven (6.2%) were due to infection of the TE.

Conclusion
We found a low postoperative complication rate and only two periprosthetic infections with the use of ABC discs in IBR. This technique is a promising modality for reducing morbidity associated with implant-associated infection.

Using Antibiotic-Impregnated Discs for Infection Control in Implant-Based Breast Reconstruction

Background
Accurate detection and classification of intracranial hemorrhages (ICH) from computed tomography (CT) images are critical for timely clinical intervention. Large language models (LLMs) like GPT have shown potential in medical imaging tasks, yet their effectiveness in complex classification scenarios remains unclear. This study assesses GPT-4o's capability to identify hemorrhage presence and categorize hemorrhage subtypes using publicly available CT imaging data.

Methods
CT scans from the PhysioNet Intracranial Hemorrhage CT Dataset were preprocessed into axial slices, normalized to 8-bit grayscale, and combined into composite images to comply with GPT-4o’s token constraints. The evaluation consisted of two tasks:
Binary classification (hemorrhage presence vs. absence) involving 75 scans (36 positive, 39 negative).
Multi-class classification of hemorrhage subtypes (intraventricular, intraparenchymal, subarachnoid, epidural, subdural) among the 36 positive cases.
Model outputs were assessed using accuracy, precision, recall, F1-score, exact match accuracy, and Hamming scores.

Results
In the binary classification task, GPT-4o achieved an overall accuracy of 0.52, with precision of 0.50, recall of 0.14, and F1-score of 0.22 for detecting hemorrhages. Non-hemorrhagic cases were identified with higher recall (0.87) but similar precision (0.52), yielding an F1-score of 0.65.

For subtype classification, precision was highest for epidural hemorrhages (1.0) but accompanied by low recall (0.14) and an F1-score of 0.25. Intraparenchymal hemorrhage showed balanced precision (0.46) and recall (0.75), achieving an F1-score of 0.57. Exact match accuracy was low (0.06), indicating GPT-4o rarely identified all subtypes correctly in a single prediction. The average Hamming score was moderate at 0.54, highlighting partial accuracy across subtypes.

Conclusion
GPT-4o demonstrated modest performance in hemorrhage detection, particularly limited by low recall in positive cases. While specificity was comparatively better, the overall diagnostic capability remained suboptimal. Subtype classification posed additional challenges, reflected by poor exact match accuracy despite acceptable partial label accuracy. These findings suggest the necessity of refined training approaches, targeted model tuning, and potential integration with hybrid analytical methods to improve clinical reliability.


Evaluating GPT-4o Performance for Hemorrhage Detection and Subtype Classification in Head CT Scans


Background:
Male breast cancer is a rare malignancy, accounting for less than 1% of all breast cancer cases, typically affecting men around age 65, though younger cases occur. In 2025, about 2,800 new cases and 510 deaths are expected in the U.S. African American men experience worse outcomes despite a lower incidence. The lifetime risk is roughly 1 in 726, influenced by genetic and environmental factors including BRCA2 mutations, radiation exposure, hormonal imbalances, liver disease, and obesity. Germline mutations, especially BRCA2, contribute significantly, with up to 10% of cases linked to this gene. BRCA1 mutations are less common but relevant. Other hereditary genes implicated include CHEK2 (notably the 1100delC variant), PALB2, and ATM. PALB2 mutations occur in about 1–2% of cases and confer a 4- to 6.6-fold increased risk. Invasive ductal carcinoma is the predominant histologic subtype, accounting for 65–95% of male cases, while lobular carcinoma is rare. Identifying hereditary syndromes is crucial for risk stratification and screening.

Case presentation:
We report a 59-year-old African American man with a history of Hodgkin’s lymphoma treated with radiation. In September 2024, he presented with a right subareolar lump without itching, tenderness, or skin changes. Given a strong family history of breast cancer (sister, uncle, mother) and stomach cancer (father), germline testing revealed a PALB2 mutation; BRCA1/2 mutations were negative. Ultrasound showed a right retroareolar solid mass; biopsy confirmed a well-differentiated invasive ductal carcinoma (IDC) measuring 1.2 cm. PET-CT excluded metastasis. On October 24, 2024, he underwent a right mastectomy with sentinel lymph node biopsy. Pathology revealed a 2.2 x 1.5 x 1.5 cm Grade 2 IDC (T2N0M0, Stage IIA) with rare vascular invasion, deep dermal extension, and in situ ductal carcinoma with comedo necrosis. Immunohistochemistry was ER/PR positive and HER2 negative, supporting hormonal therapy. Oncotype DX score was 18, indicating low recurrence risk, so chemotherapy was not recommended. Given prior radiation and surgery, no further radiation was advised, and Tamoxifen 20 mg daily was started.

Discussion:
This case highlights the multifactorial nature of male breast cancer, showing the interplay between environmental exposure and genetic predisposition. Prior chest irradiation was the principal carcinogenic factor, while the PALB2 mutation likely increased susceptibility. Though BRCA mutations are most common, this case underscores the importance of other predisposition genes like PALB2 and the need for long-term surveillance in male cancer survivors with genetic risk and radiation history.

Radiation-Induced Male Breast Cancer in the Setting of a PALB2 Germline Mutation

Background:

Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis, is a rare necrotizing vasculitis affecting small to medium-sized vessels, commonly involving the respiratory tract and kidneys. The disease has a strong association with anti-neutrophil cytoplasmic antibodies (ANCA), particularly c-ANCA directed against proteinase-3. Early diagnosis is challenging due to overlapping symptoms with infections and other inflammatory conditions.

Case Presentation:

A 52-year-old non-diabetic, non-hypertensive female presented with a one-month history of fever with chills, a single episode of haemoptysis, and a recent onset of weight loss, anorexia, and productive cough. On examination, she was pale, tachycardic, and required supplemental oxygen. Auscultation revealed bilateral basal crepitations. Laboratory findings included leukocytosis, elevated CRP (239), and a positive c-ANCA test. Chest X-ray and HRCT thorax revealed multiple cavitary lesions with surrounding consolidation and ground-glass opacities. Despite empirical anti-tubercular and antibiotic therapy, the patient worsened with persistent fever and desaturation. A CT-guided lung biopsy showed granulomatous inflammation with Langhans giant cells and dense lymphoplasmacytic infiltrates, confirming the diagnosis of GPA. She was treated with pulse steroids (IV methylprednisolone 1 g for 3 days), followed by oral corticosteroids, co-trimoxazole, and cyclophosphamide infusions per standard protocol.

Discussion:

The diagnosis was initially confounded by a presumptive diagnosis of pulmonary tuberculosis. However, the absence of microbiological evidence, c-ANCA positivity, constitutional symptoms, and progressive respiratory involvement shifted the suspicion towards GPA with diffuse alveolar hemorrhage. The case highlights the importance of high clinical suspicion, ANCA testing, and timely histopathological confirmation in atypical pulmonary presentations.

Conclusion:

GPA is a life-threatening, multi-system autoimmune vasculitis. Prompt diagnosis and early immunosuppressive therapy with corticosteroids and cyclophosphamide are critical for improving outcomes, especially in cases presenting with diffuse alveolar
hemorrhage. Clinicians must maintain a differential diagnosis of GPA in patients with cavitating lung lesions and systemic symptoms unresponsive to standard antimicrobial therapy.

Granulomatosis with Polyangiitis Presenting as Diffuse Alveolar Hemorrhage: A Case Report

Background 
Pituitary adenomas (PA) are common, typically benign tumors with a prevalence of approximately 22%. Endoscopic transsphenoidal (TSS) resection of PAs is the standard of care for large or symptomatic tumors presenting with visual disturbances or endocrinopathies. Postoperative complications include cerebrospinal fluid (CSF) leak, hormonal and visual disturbances, and hematomas leading to acute visual decline. Delayed cyst formation is well-documented and consists largely of arachnoid cysts. Rapid postoperative suprasellar cyst development leading to acute visual deterioration is exceedingly rare, with only 1 case reported in the literature. A cyst composed of normal pituitary gland has not been previously reported. We present the rapid formation of a nonneoplastic pituitary cyst following TSS resection of a large PA. The management and functional outcome are reviewed and the underlying pathogenesis is explored.

Case Presentation
A 63-year-old female presented with a large PA causing significant compression of the optic apparatus. Preoperative evaluation demonstrated normal visual acuity and fields. Gross total resection was achieved via the endoscopic approach and cytological analysis revealed a pituitary gonadotroph, subtype positive for follicle-stimulating hormone. The patient remained neurologically intact and immediate postoperative computed tomography (CT) confirmed complete resection and decompression of the optic apparatus. On postoperative day 6, the patient developed a sudden bitemporal hemianopsia. CT revealed a new suprasellar cystic lesion compressing the optic chiasm. The patient underwent emergent craniotomy and a cyst clearly emanating from the pituitary stalk was identified and resected. The attachment was sharply transected and the stalk was left both anatomically and functionally intact. Pathology demonstrated non-neoplastic anterior pituitary gland. Visual acuity and fields returned to the preoperative baseline. Six months post-resection the patient has normal pituitary function and vision and magnetic resonance imaging demonstrates no evidence of residual or recurrent disease.

Discussion
We present a rare case of a rapidly growing cyst of pituitary origin after TSS resection of a PA. A literature review into postoperative cyst formation after TSS for sellar masses yielded 469 articles, with 6 describing cyst growth within a year of TSS. The fastest developing lesion was a suprasellar arachnoid cyst that presented with acute visual impairment 1 day after surgery. There are no reports of postoperative cysts of pituitary origin. Emergent cyst resection resulted in preservation of vision and pituitary function, supporting surgical management. The pathogenesis of this lesion remains unknown. Future surgical and pathology reports will help identify variables contributing to postoperative cyst formation after PA resection.


Rapid Pituitary Cyst Development After Endoscopic Transsphenoidal Resection of Pituitary Adenoma

Background:
Spinal dural arteriovenous fistulas (SDAVFs) are rare vascular malformations involving an abnormal connection between a dural artery and a medullary vein, leading to venous hypertension and progressive myelopathy. Literature estimates an annual incidence of 5 cases per million, with a strong male predominance between 50-70 years old (~80%), with women accounting for only 20% of cases. This case presents a patient with a proposed novel mechanism for acquired SDAVF through equestrian activity.
Case Presentation:
An 81-year-old woman with hypertension and hypothyroidism presented with bilateral leg paresthesias progressing over three weeks to flaccid lower extremity paralysis, urinary retention, and constipation. She denied back or neuropathic pain. At baseline, she was fully independent and had recently taken up horseback riding.
Lumbar spine MRI revealed multilevel degenerative disc disease and foraminal narrowing. She was discharged to a skilled nursing facility with presumed lumbar radiculopathy. Two weeks later, she re-presented with worsening symptoms: 0/5 strength in the lower extremities, areflexia, T12-L1 sensory level, mute plantar responses, and sphincter dysfunction.
Thoracic spine MRI showed long-segment T2 hyperintensity, cord expansion, and serpentine flow voids. Digital subtraction angiography confirmed an SDAVF at the right T12 intercostal artery. She underwent Onyx-18 embolization with minimal improvement, followed by T11–L1 laminoplasty and direct ligation with nBCA embolization of a residual extradural component.
Postoperatively, she regained movement in hips, knees, and feet but remained Foley- dependent. She is undergoing rehabilitation with gradual improvement.
Discussion:
SDAVFs are acquired lesions often associated with dural sinus thrombosis, trauma, or prior surgery. This patient had none of these risk factors and her only recent change was picking up horseback riding as a new hobby in the last year, which introduced repetitive axial spinal stress. However, with her history of hypertension weakening the arterial walls and the introduction of horseback riding, this could have contributed to the formation of the abnormal connection between arteries and veins that characterizes a SDAVF. This may have triggered angiogenic pathways, particularly vascular endothelial growth factor (VEGF), leading to abnormal arteriovenous shunt formation. Additional mediators such as FGF and IL-6 could have contributed to endothelial injury and neovascularization. No prior literature has linked equestrian activity with SDAVF, making this a novel etiologic consideration. The delay in diagnosis reflects the overlap of symptoms with more common conditions like lumbar stenosis. Clinicians should consider SDAVF in elderly patients with progressive myelopathy and sphincter dysfunction even if the etiology does not follow medical norms for SDAVF’s.

Next from 2025 AMA Research Challenge – Member Premier Access

Elicitation of potent H5N1- and H7N9-neutralizing antibodies by vaccination of rhesus macaques