United States

Background: Intervertebral disc (IVD) degeneration (IDD) is the leading cause of low back pain, affecting 25% of U.S. adults in any 3-month period and nearly 40 million workers. 40% of individuals over age 40 and 80-90% by age 80 exhibit IDD. Low back and neck pain lead U.S. healthcare spending among 154 conditions, totaling $134.5 billion annually. Although early nucleus pulposus (NP) degeneration is critical for diagnosis and treatment, it is often missed on standard Magnetic Resonance Imaging (MRI). Micro-computed tomography (micro-CT) offers excellent three-dimensional (3D) bone visualization but lacks soft tissue contrast to visualize the IVD. While contrast-enhanced micro-CT has been investigated, an effective contrast agent for IVD has not been identified. This study investigates potassium iodide (KI) as an effective contrast agent for micro-CT-based IVD visualization across multiple animal models to study IDD. 

Methods: We harvested spines and tails from skeletally matured mice, rats, rabbits, and sheep, incubated in 25% aqueous KI solution, and scanned using micro-CT (Sky Scan 1273) with a resolution of 10 μm. To evaluate KI in IDD, we performed caudal IVD annular puncture on 12-week-old mice (n=10) using a 30-gauge needle, with adjacent IVDs as sham control. Tails were collected two weeks post-surgery. For the aging model, we compared IVDs from 18–21-month mice (n=5) to 3-month controls (n=5) and validated our method on rabbit and sheep (n=5) IVDs. Micro-CT results were compared with histological data from the same sample. 

Results: Compared to unstained IVDs, KI-stained IVDs exhibited strong x-ray attenuation comparable to surrounding bone, enabling high-resolution 3D visualization of IVDs in all animal models. Quantitative measures such as IVD height and volume showed high reproducibility. KI staining of punctured IVDs showed significant reduction in IVD height, NP area, and volume versus sham controls (p=0.014), mirroring histological findings from the same samples. In aging spines, KI staining revealed varying degrees of degeneration in lumbar IVDs. After scanning, KI was removed by PBS wash for histology and immunostaining, with no additional antigen retrieval step required. 

Conclusion: This preclinical study presents KI as a rapid, reversible, non-destructive, histologically-compatible, and accessible contrast agent for detailed micro-CT IVD imaging. It clearly identifies degenerative changes across species and models, is significantly faster (&lt;1 hr) than previously published methods (&gt;24 hr to 2 months), uses FDA-approved KI, and standard micro-CT scanners. Clinical development of this method could substantially reduce delays in MRI access and diagnostic imaging.

AMA Research Challenge 2025 

A Rapid, Non-Destructive, Specific Method for Intervertebral Disc Imaging With KI-Enhanced Micro-CT

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AAAI 2026

We are pleased to announce the Fortieth AAAI Conference on Artificial Intelligence (AAAI-26), which will be held in Singapore EXPO from January 20 to January 27, 2026.

Background: Intervertebral disc (IVD) degeneration (IDD) is the leading cause of low back pain, affecting 25% of U.S. adults in any 3-month period and nearly 40 million workers. 40% of individuals over age 40 and 80-90% by age 80 exhibit IDD. Low back and neck pain lead U.S. healthcare spending among 154 conditions, totaling $134.5 billion annually. Although early nucleus pulposus (NP) degeneration is critical for diagnosis and treatment, it is often missed on standard Magnetic Resonance Imaging (MRI). Micro-computed tomography (micro-CT) offers excellent three-dimensional (3D) bone visualization but lacks soft tissue contrast to visualize the IVD. While contrast-enhanced micro-CT has been investigated, an effective contrast agent for IVD has not been identified. This study investigates potassium iodide (KI) as an effective contrast agent for micro-CT-based IVD visualization across multiple animal models to study IDD. 

Methods: We harvested spines and tails from skeletally matured mice, rats, rabbits, and sheep, incubated in 25% aqueous KI solution, and scanned using micro-CT (Sky Scan 1273) with a resolution of 10 μm. To evaluate KI in IDD, we performed caudal IVD annular puncture on 12-week-old mice (n=10) using a 30-gauge needle, with adjacent IVDs as sham control. Tails were collected two weeks post-surgery. For the aging model, we compared IVDs from 18–21-month mice (n=5) to 3-month controls (n=5) and validated our method on rabbit and sheep (n=5) IVDs. Micro-CT results were compared with histological data from the same sample. 

Results: Compared to unstained IVDs, KI-stained IVDs exhibited strong x-ray attenuation comparable to surrounding bone, enabling high-resolution 3D visualization of IVDs in all animal models. Quantitative measures such as IVD height and volume showed high reproducibility. KI staining of punctured IVDs showed significant reduction in IVD height, NP area, and volume versus sham controls (p=0.014), mirroring histological findings from the same samples. In aging spines, KI staining revealed varying degrees of degeneration in lumbar IVDs. After scanning, KI was removed by PBS wash for histology and immunostaining, with no additional antigen retrieval step required. 

Conclusion: This preclinical study presents KI as a rapid, reversible, non-destructive, histologically-compatible, and accessible contrast agent for detailed micro-CT IVD imaging. It clearly identifies degenerative changes across species and models, is significantly faster (<1 hr) than previously published methods (>24 hr to 2 months), uses FDA-approved KI, and standard micro-CT scanners. Clinical development of this method could substantially reduce delays in MRI access and diagnostic imaging.

poster

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Background
Acute kidney injury (AKI) is a common and life-threatening complication of sepsis, yet early, non-invasive detection of tubular dysfunction remains challenging. Resazurin, a redox-sensitive dye traditionally used in cell viability assays, has emerged as a novel in vivo biosensor of renal tubular function. Following systemic administration, resazurin is taken up by proximal tubular epithelial cells, where it is enzymatically reduced to the fluorescent compound resorufin. Urinary resorufin levels reflect mitochondrial metabolic activity and serve as a functional readout of tubular health. In prior murine models of AKI such as cisplatin and ischemic reperfusion injury, diminished resorufin signal correlated with worse histologic injury and elevations in conventional biomarkers such as blood urea nitrogen (BUN) and creatinine.
Methods
We are evaluating resazurin in two murine models of sepsis-induced AKI: (1) cecal ligation and perforation (CLP), a surgical model inducing polymicrobial sepsis, and (2) lipopolysaccharide (LPS) injection, which triggers endotoxemia via systemic inflammation. Mice received intravenous resazurin, and urinary fluorescence of resorufin was measured at defined intervals. Renal function was concurrently assessed using BUN, creatinine, and histopathology.
Results
Preliminary findings show that both CLP and LPS models produce consistent and comparable patterns of renal tubular dysfunction. In both models, a marked decline in urinary resorufin levels was observed early, preceding significant elevations in BUN and creatinine. Histological analysis confirmed tubular injury in parallel with reduced metabolic activity detected via resazurin imaging. These results validate resazurin as a sensitive and non-invasive reporter of early tubular dysfunction in inflammatory kidney injury.
Conclusion
Resazurin offers a rapid, non-invasive, and translationally promising approach for real-time monitoring of renal tubular function. Its application in sepsis models highlights its potential as a functional biomarker for early AKI detection, with broad utility for preclinical and future clinical research.


Utilizing Resazurin Dye to Detect Kidney Dysfunction in Sepsis

Introduction: 
An estimated 1.5 million people in the U.S. are living with, or in remission from, a hematological malignancy (HM). Many of these individuals are particularly vulnerable to infections such as COVID-19, influenza, and pneumococcal disease. Immunocompromised patients often experience more severe illness, prolonged disease, higher rates of ICU admission, and death. Vaccination remains a key strategy for reducing these adverse outcomes. The aim of this study was to assess vaccination rates and identify modifiable factors associated with COVID-19, influenza, and pneumococcal vaccinations in HM survivors.
Methods: 
We conducted a cross-sectional analysis of data from the 2022 and 2023 CDC Behavioral Risk Factor Surveillance System-Cancer Survivorship Optional Module. Population-based vaccination estimates and 95% CIs were calculated. All statistical tests were 2-sided with p < .05 was considered significant.
Results: 
Of the 1,335 HM survivors, 56.8% had lymphoma, 29.7% had leukemia, and 13.5% had other blood malignancies. The vaccination rates for COVID-19, influenza, and pneumococcal were 46.0%, 57.7%, and 57.4%, respectively. Influenza vaccination was associated with having had an annual physical exam (p = .000), having CVD (p = .003), diabetes (p = .034), not being a current smoker (p = .001), and having 3+ comorbidities (p = .001). Pneumococcal vaccination was associated with having had an annual physical exam (p = .019), receiving follow-up instructions from a doctor after completing HM treatment (p = .020), having COPD (p = .000), CVD (p = .000), diabetes (p = .001), CKD (p = .029), not being a current smoker (p = .003), and having 3+ comorbidities (p = .019). Older age (65+) is associated with higher rates of both influenza and pneumococcal vaccinations. No variable significantly predicted COVID-19 vaccination. Vaccination rates did not vary by type of HM. 18.9% of patients did not receive follow-up instructions from their doctor after completing cancer treatment, and only 10.9% reported participating in a clinical trial as part of their cancer care.
Conclusions:
We identified several modifiable factors, underreported in the literature, that are associated with non-vaccination. Improving awareness among both physicians and patients may help increase vaccination rates and enhance protection for this at-risk population.

Factors Associated with COVID-19, Influenza, and Pneumococcal Vaccination in survivors of Hematologic Malignancies

An Expert-Validated Survey to Assess Lead Tethering Following Hypoglossal Nerve Stimulation Surgery

Authors: Rishi Raghavan, Roberto Spilka, Arman Saeedi, Mihai Bentan, Aaron Tucker, Maria Suurna, MD, Ryan Nord, MD
Background: 
Hypoglossal nerve stimulation (HNS) is an increasingly utilized treatment for obstructive sleep apnea (OSA), especially for patients who are unable to tolerate CPAP therapy. However, lead tethering—a mechanical complication causing neck tightness, discomfort, restricted mobility, or psychological distress—may negatively impact long-term postoperative outcomes. Despite anecdotal reports in clinical practice, no validated patient-reported outcome (PRO) instrument currently exists to assess these specific symptoms. This study aimed to develop and validate a concise, reliable survey to measure physical, cosmetic, and psychosocial effects associated with lead tethering following HNS implantation.
Methods: 
An initial 12-item survey was constructed through literature review and expert feedback, addressing domains of discomfort, appearance, movement limitation, and emotional response. Six specialists in otolaryngology and sleep medicine rated item relevance on a 4-point scale. Items with item-level content validity index (I-CVI) scores below 0.78 or deemed redundant were revised or removed, resulting in a final 5-item instrument. Twenty-eight HNS recipients completed the survey at two intervals separated by at least 2 weeks (mean: 4 weeks). A 4-point Likert scale captured responses. Test–retest reliability was assessed using Gwet’s AC2 with ordinal weights.
Results: 
All survey items demonstrated strong reliability across timepoints: neck appearance (AC2 = 0.895), tightness (0.778), movement restriction (0.771), interference with daily activities (0.881), and distress or anxiety (0.963); all p < 0.001. Descriptive agreement analysis supported temporal consistency.
Conclusion: 
The findings support the reliability and content validity of a novel 5-item PRO instrument tailored for assessing lead tethering symptoms in HNS recipients. While additional validation in broader populations is recommended, the survey may offer a useful framework for postoperative monitoring and future research.


An Expert-Validated Survey to Assess Lead Tethering 
Following Hypoglossal Nerve Stimulation Surgery

Background
One in four children experience emotional, physical, or sexual abuse, with negative impacts on development that persist into adulthood, including emotion dysregulation and cognitive control issues. However, there is little known about the association between childhood abuse with neural networks and psychological problems in late adulthood. Given the well-known link between childhood abuse and depression, this study examined the impact of abuse on resting-state functional connectivity (FC) in adults with late-life depression (LLD), and whether FC changes mediate the relationship between abuse and anger-hostility.

Methods
98 participants aged ≥60 years with LLD were recruited from the NBOLD clinical research cohort. Childhood abuse was assessed using the Adverse Childhood Experiences (ACEs) questionnaire and coded as a binary variable (0 = no abuse, 1 = any abuse). Anger-related emotion dysregulation was measured using the NEO-PI anger-hostility subscale (N2). Resting-state fMRI data was processed in CONN toolbox. A whole-brain ROI-to-ROI ANCOVA was performed to identify FC differences between abuse and non-abuse groups, controlling for age, gender, education, and baseline depression severity (measured by the Montgomery-Åsberg Depression Rating Scale). Significant FC values (FDR-corrected p < 0.05) were extracted, and linear regression was used to test for association with anger-hostility. A mediation analysis was conducted in Jamovi with FC as the mediator between abuse and N2.

Results
Participants with a history of childhood abuse showed greater FC between the right anterior supramarginal gyrus (aSMG) and right cerebellar lobule VI (T = 3.82, p = 0.0273), and between the right inferior frontal gyrus (IFG) pars opercularis and left cerebellar lobule X (T = 3.98, p = 0.0224). Childhood abuse was associated with higher anger-hostility scores (β = 0.322, p = 0.001). Only aSMG-cerebellum FC was significantly associated with anger-hostility (β = 0.285, p = 0.006) while IFG-cerebellum FC was not (β = 0.126, p = 0.281). Mediation analysis showed that aSMG-cerebellum FC partially mediated the relationship between childhood abuse and anger-hostility (β = 0.104, p = 0.026), though the direct effect of abuse on anger remained significant (β = 0.219, p = 0.035).

Conclusion
Altered aSMG-cerebellum FC, which has been found to be associated with depression and ADHD in adolescents, may represent a neurobiological pathway linking childhood abuse to anger-related emotional dysregulation in LLD. The persistence of a direct effect in the mediation analysis indicates other mediators involved in cognitive control deficits in emotion dysregulation (e.g., rumination) warrant investigation. Understanding this relationship may inform targeted treatments for trauma-exposed individuals.

Altered right aSMG-cerebellum functional connectivity partially mediates the association of childhood abuse with anger-related emotional dysregulation in adults with late-life depression

Background:
Ventricular tachyarrhythmias precipitate sudden cardiac death (SCD) which can be averted by implantable cardioverter-defibrillators (ICD). The growing number of ICD implantations also increases prevalence of complications including right ventricular lead dislodgement (RVLD). We discuss a case of an ICD RVLD causing repeated shocks and death.

Case Presentation:
A 51-year-old male with non-ischemic cardiomyopathy (LVEF 20% that had since recovered) and an ICD for primary prevention received multiple ICD shocks in rapid succession and presented in cardiac arrest. On arrival, he was defibrillated and treated with amiodarone with return of spontaneous circulation. Persistent ICD shocks during sinus tachycardia (ST) prompted ICD deactivation.
Interrogation revealed RVL oversensing of atrial depolarizations on the far-field channel, confirmed by surface ECG, causing 64 recurrent defibrillations before ICD deactivation. Radiography showed RVLD to the tricuspid annulus causing simultaneous detection of atrial and ventricular activation. Neurologic evaluation showed no brain activity, and care was withdrawn.

Discussion:
Upon recognizing RVLD, urgent device interrogation and ICD tachytherapy deactivation should follow. The ICD misinterpreted atrial events during ST as ventricular depolarizations while simultaneously sensing the RV, triggering inappropriate anti-tachycardia pacing. The device interpreted this as VF, leading to frequent defibrillations. In cases like this, the incidence of life-threatening presentations may be mitigated by optimizing guideline-directed medical therapy for cardiomyopathy prior to ICD implantation—potentially avoiding unnecessary prophylactic devices—and by conducting routine device interrogations to detect lead dysfunction before life-threatening events occur. This case emphasizes the need for selective implantation, routine follow-up, and rapid identification of electrophysiologic emergencies like RVLD.

Right Ventricular Lead Dislodgement Causing Inappropriate ICD Shocks and Cardiac Arrest

Background
Subacute cutaneous lupus erythematosus (SCLE) is a type of cutaneous lupus erythematosus that classically presents as a non-scarring, photosensitive rash. Anti-Ro/SSA antibodies are often present. It may be associated with systemic lupus erythematosus (SLE) but also occurs without systemic involvement. It has been estimated that up to 30% of all of all subacute cutaneous lupus erythematosus cases are drug-induced, with more than more than 100 drugs implicated. Proton pump inhibitors (PPIs) are a growing cause of drug-induced SCLE (DI-SCLE) and may be underrecognized. 

Case Presentation
A 72-year-old woman presented to the dermatologist with scaly, pink, annular, thin plaques diffusely on the upper and lower back, central upper chest, and less prominent on the abdomen, right arm, and thighs. She was found to have positive anti-SSA and anti-histone antibodies. Complete blood count was notable for lymphopenia, but she had otherwise normal anti-nuclear antibody levels, complement 3, complement 4, and creatinine. Initial rheumatology evaluation indicated idiopathic SCLE and the patient was to initiate hydroxychloroquine. Further review of her medication list revealed that the rash developed six months after initiating omeprazole for gastroesophageal reflux disease. Timeline and serology raised concern for DI-SCLE. Omeprazole was promptly discontinued and triamcinolone 0.1% ointment was initiated, leading to complete resolution of the rash. 

Discussion
Drug-induced SCLE is a well-described entity that may occur in the absence or presence of SLE. PPIs are among a growing cause, with omeprazole representing a common trigger. The mechanism may involve drug-induced photosensitization and immune activation in genetically predisposed individuals. The appearance of lower limb SCLE lesions has also been noted to be characteristic of PPI-induced SCLE. Clinicians may misinterpret these eruptions as presentations of idiopathic SCLE, however, temporal relationship to drug initiation along with resolution upon withdrawal supports a diagnosis of DI-SCLE. Recognition of DI-SCLE is essential to prevent chronicity and unnecessary immunosuppression. This case highlights the need for vigilance regarding drug-induced cutaneous manifestations. Omeprazole should be considered a potential trigger for SCLE. Prompt identification and withdrawal of the offending agent may lead to significant clinical improvement.

Recognition of PPI-Induced Subacute Cutaneous Lupus Erythematosus in Clinical Practice

Background: Colorectal cancer (CRC) poses a substantial and widespread threat to cancer-related mortality in both the United States and worldwide. In recent decades, there has been a noticeable uptick in its incidence among younger adults, prompting a reassessment of CRC screening guidelines. Studies have substantiated this trend of rising incidence among younger age groups particularly in the absence of heritable risk factors.

Case Presentation: We present a case of a 28-year-old male, with no familial history of CRC, who presented with chronic diarrhea, crampy abdominal pain, blood in the stools, weight loss and anemia for 6 months. The patient was previously treated with antibiotics, which provided only transient symptom relief. Notably, he has a history of marijuana use. Colonoscopy identified a substantial, obstructive polypoid mass located in the transverse colon leading to intermittent intussusception of the bowel segment. This condition led to the above-mentioned spectrum of symptoms. Subsequent biopsy of the colon mass confirmed the diagnosis of invasive, moderately differentiated adenocarcinoma. Immunohistochemical analysis for mismatch repair (MMR) proteins demonstrated a loss of nuclear expression of MLH1 and PMS2. The tumor was classified as microsatellite instability high. The patient underwent surgical resection followed by adjuvant chemotherapy, resulting in improved condition and ongoing monitoring.

Discussion: This case, characterized by the loss of MLH1 and PMS2 expression, highlights the importance of identifying molecular markers commonly associated with sporadic CRC. Understanding these molecular alterations can aid in distinguishing between sporadic and hereditary CRC, which is crucial for developing appropriate management strategies. This case underscores the necessity for further research into the environmental and lifestyle factors contributing to the increasing incidence of CRC in the young, as well as potential factors influencing MLH1 and PMS2 mutations. This case signifies the critical importance of vigilance in prospective diagnosis, as it can easily be misattributed to less severe, benign conditions. It also emphasizes the pressing need to refine screening guidelines to include younger individuals at risk, irrespective of family history to improve prognosis and overall patient survival. 


Unmasking CRC in the Young: MLH1/PMS2 Mutations and a Call for Early Screening

Background
While alcoholic cirrhosis typically develops over prolonged periods of excessive alcohol consumption, instances of rapid decompensation in young adults are uncommon and warrant investigation into alternative or compounding etiologies.
Case Presentation
A 23-year-old woman with a history of alcohol use disorder (consuming half a pint daily for four years), erosive gastropathy, alcoholic cirrhosis with varices, chronic anemia, thrombocytopenia, and major depressive disorder presented with escalating abdominal distention, bilateral lower extremity edema, dyspnea, pruritus, and somnolence. She ceased alcohol intake on April 7, 2025. On admission, vital signs indicated hypotension (95/58 mmHg), and physical examination revealed jaundice, scleral icterus, ascites, and suprapubic tenderness. Laboratory findings included WBC 17, Hgb 8.6, Na 130, total bilirubin 23.1 (up from 11), INR 2.6, AST 81, ALT 21, and peak ammonia at 75.

Imaging on April 9 demonstrated cirrhosis, portal hypertension, splenomegaly, extensive varices, and a right thigh hematoma. MRCP identified cholelithiasis or sludge, peritoneal thickening, and hepatic lesions. Elevated tumor markers (CA-125 226, CA 19-9 73.0) and a family history of ovarian and pancreatic cancer raised concerns for malignancy; however, transvaginal ultrasound and abdominal MRI on April 26 revealed no acute gynecologic pathology but noted gastric wall edema and moderate ascites. AFP and CEA levels were within normal limits.

Positive EBV and CMV IgM prompted HIV testing; the combo Ag/Ab test was reactive, though HIV NAAT was negative. A repeat test was ordered. Due to rapid fluid accumulation, paracentesis was performed on April 28, resulting in a MELD 3.0 score improvement from 33 to 29.
Discussion
This case underscores the necessity of a comprehensive diagnostic approach in young patients exhibiting severe liver decompensation disproportionate to their alcohol consumption history. The patient's rapid deterioration prompted evaluations for infectious, inflammatory, and oncologic causes, highlighting the importance of considering multifactorial etiologies. Multidisciplinary collaboration was crucial in avoiding diagnostic anchoring and ensuring a thorough investigation. This case contributes to clinical practice by emphasizing the need for vigilance in atypical presentations of common conditions. It may also prompt earlier or broader diagnostic evaluation in young patients with cirrhosis whose clinical course is inconsistent with known risk factors.


Atypical Rapid Decompensation in a Young Woman with Alcoholic Cirrhosis: A Diagnostic Challenge Beyond Alcohol Use


Background
Artificial intelligence–enabled medical devices (AIMDs) are increasingly present in US clinical practice. However, nearly all AIMDs are cleared through the US Food and Drug Administration (FDA) 510(k) pathway, which does not require prospective human testing and thereby leads to many devices entering the market with limited or absent clinical validation. To investigate the clinical risk of this development and identify actionable areas for regulatory safeguards, we analyzed the contributory variables and clinical consequences of all AIMD recalls in the US.
Methods
The FDA AI/ML medical device database was used to compile a cohort of 950 FDA-cleared AIMDs. We manually extracted device information from all device approval summaries and identified 60 devices that were subject to recall and extracted data on these events using the FDA recall database. The S&P Capital IQ NetAdvantage and PrivCo databases were used to analyze AIMD manufacturers based on company trading status, headquarters location, market capitalization, and acquisition history. Multivariable logistic regression (GraphPad Prism 10; 2-sided α = .05) modeled the odds of any recall, adjusting for validation status, manufacturer type, clearance year, and clinical specialty. 
Results
Of 950 FDA-cleared AIMDs, 60 (6.3%) were recalled across 182 total recall events. Of these 182 recalls, 11% have remained unresolved for >3 years and 43% of recalls occurred within the first year following FDA clearance, double the reported rate for non-AIMD 510(k) devices. Diagnostic errors were the most common recall cause (109 recalls; 935,063 units), followed by functionality delay (44 recalls; 755,647 units), physical hazards (14 recalls; 8,192 units), and biochemical hazards (13 recalls; 76,257 units). We found that AIMDs without clinical validation had more recalls per device (mean 3.4 [SD 5.1]) than those with retrospective (1.9 [SD 1.5]) or prospective (2.0 [SD 1.4]) clinical testing. Similarly, larger publicly-traded companies manufactured 53.2% of AIMDs, but were responsible for 92% of recalls and 99% of recalled units. Multivariable analysis, revealed that lack of clinical validation (odds ratio [OR], 2.8; 95% CI, 1.6-4.7) and public company status (OR, 5.9; 95% CI, 2.4-14.6) were independently associated with higher likelihood of device recall. 
Conclusion
Recalls of FDA-cleared AIMDs are uncommon, but are concentrated early after clearance and predominantly involves products without clinical validation and manufactured by large publicly traded companies. Issuing time-limited clearances that lapse without confirmatory data, heightening pre-market clinical testing requirements, and increasing post-market surveillance measures are needed for improved identification and reduction of device errors.

From Expansion to Recalls: Artificial Intelligence-Enabled Medical Devices

Background:
FLT3-ITD mutation occurs in 25–30% of acute myeloid leukemia (AML) and is associated with a poor prognosis. FLT3 inhibitors (FLT3i), such as gilteritinib and quizartinib, improve initial response rates, but relapse is common. While on-target resistance via FLT3-TKD mutations is established, emerging evidence suggests that “collateral resistance,” characterized by the outgrowth of non-FLT3 subclones, contributes significantly to therapeutic escape. This review synthesizes current data on clonal evolution under FLT3i pressure, focusing on non-FLT3 subclonal emergence.

Methods:
We conducted a comprehensive review of published studies done up to June 2025, in PubMed, Web of Science, and Scopus. Studies were included if they involved FLT3-mutated AML patients treated with FLT3 inhibitors, reported paired genomic data at diagnosis and relapse. Data on FLT3i type, resistance mechanisms, mutation spectrum, and variant allele frequency (VAF) changes were extracted from clinical trials, retrospective cohorts, and preclinical models.

Results:
In a cohort of 41 relapsed patients treated with gilteritinib, 33% developed FLT3-TKD mutations (D835, F691L), 36.6% acquired NRAS/KRAS mutations, and 5% developed BCR-ABL1 fusions. Another study found off-target RAS/MAPK pathway mutations in 30–37% of relapses, frequently co-occurring with ASXL1, RUNX1, and PTPN11 mutations. Resistance to quizartinib was driven by FLT3-TKD mutations in 33–50% of cases, yet up to 50% of relapses lacked FLT3 mutations, suggesting alternative mechanisms such as microenvironmental signaling and off-target mutations. Three reported cases of BCR-ABL1 fusion following FLT3i failure showed partial responses to combined FLT3 and ABL1 inhibition. Single-cell DNA sequencing revealed that non-FLT3 subclones, undetectable at baseline by bulk sequencing, expanded under FLT3 inhibitor pressure, demonstrating polyclonal resistance and clonal selection as key drivers of relapse. These studies consistently demonstrate that non-FLT3 resistance, particularly involving the RAS/MAPK axis, is frequent and clinically relevant following targeted therapy.

Conclusion:
Collateral resistance to FLT3 inhibitors in AML is frequently mediated by the selection of pre-existing, low-frequency non-FLT3 mutant subclones, particularly those involving the RAS/MAPK pathway. These findings emphasize the importance of comprehensive genomic profiling for diagnosis and relapse. Future therapeutic strategies should prioritize rational drug combinations targeting FLT3 and non-FLT3 pathways to overcome resistance and improve patient outcomes.


REFERENCES
1.Smith, C. C., Levis, M. J., Perl, A. E., et al. (2022). Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib. Blood Advances, 6(7), 2144–2155. https://doi.org/10.1182/bloodadvances.2021006489 (Leading Journal)
2. Smith, C. C., Lin, K., Stecula, A., Sali, A., & Shah, N. P. (2015). FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors. Leukemia, 29(12), 2390–2392. https://doi.org/10.1038/leu.2015.165 (Leading Journal)
3. Tarver, T. C., Hill, J. E., Rahmat, L., et al. (2020). Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations. Blood Advances, 4(3), 514–524. https://doi.org/10.1182/bloodadvances.2019000919 (Leading Journal)



Collateral Resistance in FLT3-Mutated AML: Unraveling Non-FLT3 Subclonal Emergence and Therapeutic Escape Under FLT3 Inhibitor Pressure - A Comprehensive Literature Review

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