United States

Background

Staging is devised to assess prognosis and direct the management of cancers. Although staging systems don&#39;t necessarily confirm chronological progression, there is near consensus that advanced stages are &#39;later&#39; versions of a given cancer. Tumor Mutational Burden (TMB) is a metric measuring proliferative state, representing a “molecular clock” (Vogelstein) of sorts and a surrogate for chronology. TMB is commonly provided to oncologists as essential clinical data, however proper interpretation is still evolving. We hypothesized that (i) advanced-stage is a qualitative rather than chronologic indicator, (ii) proliferation rates will be mirrored in TMB, and (iii) TMB will correlate with clinical virulence.


Methods

(i) We mined the TCGA database (cbioportal.org) for incremental increases in TMB relative to increasing neoplasm clinical stage from 558 samples (Breast, Colon, Renal cell, Pancreatic, Cervical). (ii) We compared the TMB in Burkitt&#39;s with follicular lymphoma representing lymphoma proliferative spectrum. (iii) We compared the TMB in cutaneous squamous carcinoma (CSC) with Acute Myelogenous Leukemia, representing indolent versus aggressive malignancies, respectively.


Results

(i) The 95% Confidence Intervals (CI) surrounding the median TMB were overlapping without statistical significance across all stages within every histology examined. (ii) To our surprise, the TMB 95% CI were overlapping between the 2 subsets of B-cell lymphoma examined. (iii) TMB was substantially higher in CSC (median of ~800) compared with 8 in AML.


Conclusion

Assuming the validity of Vogelstein’s molecular clock model, mutational probing does not support the concept that a stage IV malignancy is a chronologically delayed manifestation of a given neoplasm. Rather, we suggest that aggressive/metastatic cancers are inherently &#39;different&#39; with unique abilities. We also posit that cells that live for years (follicular lymphoma) can accumulate comparable TMB levels as Burkitt&#39;s because the limited life span in Burkitt&#39;s (days to weeks) precludes the accumulation of high TMB. Finally, a malignancy’s clinical outcome cannot be discerned from the degree or mutability— which is rationally a predictor of immune susceptibility. It&#39;s noteworthy that the observed levels of mutations in CSC, reflective of sun-induced mutagenicity, is more than 3-fold of that reported for melanoma (~274) and may explain the rarity of metastatic CSC resulting from immune clearance of metastases.

AMA Research Challenge 2022

Validity of Mutations as a Cancer Chronometer

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Ricardo Correa, MD, EdD
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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.


Background

Staging is devised to assess prognosis and direct the management of cancers. Although staging systems don't necessarily confirm chronological progression, there is near consensus that advanced stages are 'later' versions of a given cancer. Tumor Mutational Burden (TMB) is a metric measuring proliferative state, representing a “molecular clock” (Vogelstein) of sorts and a surrogate for chronology. TMB is commonly provided to oncologists as essential clinical data, however proper interpretation is still evolving. We hypothesized that (i) advanced-stage is a qualitative rather than chronologic indicator, (ii) proliferation rates will be mirrored in TMB, and (iii) TMB will correlate with clinical virulence.


Methods

(i) We mined the TCGA database (cbioportal.org) for incremental increases in TMB relative to increasing neoplasm clinical stage from 558 samples (Breast, Colon, Renal cell, Pancreatic, Cervical). (ii) We compared the TMB in Burkitt's with follicular lymphoma representing lymphoma proliferative spectrum. (iii) We compared the TMB in cutaneous squamous carcinoma (CSC) with Acute Myelogenous Leukemia, representing indolent versus aggressive malignancies, respectively.


Results

(i) The 95% Confidence Intervals (CI) surrounding the median TMB were overlapping without statistical significance across all stages within every histology examined. (ii) To our surprise, the TMB 95% CI were overlapping between the 2 subsets of B-cell lymphoma examined. (iii) TMB was substantially higher in CSC (median of ~800) compared with 8 in AML.


Conclusion

Assuming the validity of Vogelstein’s molecular clock model, mutational probing does not support the concept that a stage IV malignancy is a chronologically delayed manifestation of a given neoplasm. Rather, we suggest that aggressive/metastatic cancers are inherently 'different' with unique abilities. We also posit that cells that live for years (follicular lymphoma) can accumulate comparable TMB levels as Burkitt's because the limited life span in Burkitt's (days to weeks) precludes the accumulation of high TMB. Finally, a malignancy’s clinical outcome cannot be discerned from the degree or mutability— which is rationally a predictor of immune susceptibility. It's noteworthy that the observed levels of mutations in CSC, reflective of sun-induced mutagenicity, is more than 3-fold of that reported for melanoma (~274) and may explain the rarity of metastatic CSC resulting from immune clearance of metastases.

poster

Background
Multiple Myeloma (MM) has been associated with extensive morbidity and mortality in hospitalized patients. MM has been considered a treatable disease entity with the advent of novel therapeutics. Vitamin D deficiency (VDD) affects 1 in 7 individuals worldwide and is a key element in bone modulation. In this study, we aim to provide greater clarity on the relationship between VDD and MM and outcomes of VDD amongst multiple myeloma patients.
Methods
We performed a retrospective cross-sectional study using HCUP data from 2016 to 2018. Patients with MM and VDD were identified using ICD 10 codes. We used SAS 9.4 for univariate analyses (unpaired student’s t-test and chi-square test) and multivariate survey regression analysis to evaluate demographic characteristics, epidemiology, the association between VDD and MM, and outcomes of patients with VDD. Adjusted odds ratio and 95% confidence interval were calculated and sensitivity index (C-index) was obtained. A P-value less than 0.05 was considered significant.
Results
Analysis revealed 330,175 patients had multiple myeloma out of 11,480 (0.035%) had VDD. VDD was more common in the middle age group (50-75 years: 3.6% vs >75 years: 3.3%), female (4.1% vs male: 2.9%), Asian-Pacific Islander race (3.8% vs Black: 3.5% vs White: 3.5% vs Hispanics: 3.2%), and median household income 75-100 percentile (3.8% vs 0-25 percentile: 3.4%), Midwest or North Central region states (4.5% vs Northeast: 3.3%), patients with obese 4.6% vs non-obese: 3.4%, dyslipidemia 4.1% vs non-dyslipidemia: 3.1%, renal failure 3.5% vs non-failure: 3.4%, AIDS 4% vs non-AIDS: 3.5%, and alcohol abuse 4.1% vs no-abuse: 3.5%. Prevalence of morbidity (5.1% vs 3.9%; p<0.0001) and disability (77.2% vs 73.3%; p<0.0001) were higher amongst patients with VDD in comparison without VDD amongst MM. In regression analysis, prevalence odds of VDD were significantly higher (aOR 1.41, 95%CI: 1.35-1.47, p<.0001, c=0.636) in patients with MM in comparison without MM. We also found that VDD patients were associated with 24% higher morbidity (1.24, 1.14-1.36, p<.0001, c=0.667) and 26% higher disability (1.26, 1.20-1.33, p<.0001, c=0.725).
Conclusion
There was a significant association between VDD and MM with a significant increase in morbidity and disability in patients with concurrent VDD and MM. The vast array of actions of vitamin D in various cellular pathways yields a dramatic effect on patient outcomes in MM. It is imperative to treat VDD to improve clinical outcomes in patients with MM.

A steep fall to high morbidity and disability; Vitamin D deficiency in Multiple Myeloma Patients.

Comprehensive evaluation of acute management and blood pressure response in 1596 minority patients with very severe hypertension (>220/>120 mmHg)

Abstract Title: Higher odds of the Utilization of Thrombolysis and MACCE events in Acute Kidney Injury Associated with Pulmonary Embolism: A Nationwide study
Karnav Modi, MBBS, and Akhil Jain, MD

Background
Pulmonary thromboembolism (PTE) is an acute life-threatening condition with a mortality rate of up to 65% in high-risk patients. Clinical outcomes in these patients, including mortality, are influenced by multiple factors. One such factor is acute kidney damage (AKI), a frequent complication in hospitalized patients and also known to have poorer prognoses. However, the utilization of thrombolytic therapies and frequency of major adverse cardiovascular and cerebrovascular events (MACCE) in acute pulmonary embolism (PE) patients with AKI has been poorly investigated. Therefore, this study sought to evaluate the frequency and odds of outcomes and the utilization rates of various lines of therapies in PE patients with AKI.

Methods
We used the 2019 National Inpatient Sample (NIS) dataset to identify patients with a primary discharge diagnosis of PE without acute cor pulmonale. Next, they were grouped into two cohorts based on the presence of Acute Kidney Injury (AKI). We used descriptive statistics to compare demographics, hospital-related characteristics, and comorbidities amongst two cohorts. Lastly, we used Pearson’s chi-square to identify the differences in outcomes and developed a multivariate regression model to obtain adjusted odds ratios (aOR) and incidence rate ratios (IRR) for outcomes and utilization of therapies amongst the two cohorts.


Results
Among the 170,955 patients hospitalized with acute PE, 13.8% patients (n=23,610) had AKI. AKI cohort had older (mean age 68.2 vs. 62.6 years) and more male (54.4%) patients. AKI cohort had a significantly higher rate and odds of mortality (9.9% vs. 1.9%; aOR 3.0, 95% CI: 2.6-3.5, P<0.001), mean length of stay (LOS) (6.3 vs. 3.9 days, P<0.001), and mean total cost of hospitalization (81528.7 vs. 44324.3 USD, P<0.001). Among both cohorts, inferior vena cava (IVC) filter had the highest utilization rate (7.2% vs. 4.1%, P<0.001), followed by systemic thrombolysis (4.6% vs. 1.7%, P<0.001), catheter-directed thrombolysis (CDT) (3.7% vs. 2.4%, P<0.001), and surgical embolectomy (0.021% vs. 0.007%, P=0.327). Following adjustment, the AKI cohort had higher odds of the utilization of CDT (aOR 1.6, 95% CI: 1.3-2.0, P<0.001), systemic thrombolysis (aOR 2.0, 95% CI: 1.6-2.4, P<0.001), and IVC filter (aOR 1.4, 95% CI: 1.2-1.6, P<0.001). AKI cohort had a significantly higher incidence and odds for MACCE events (a composite of death, myocardial infarction, and stroke) (17.2% vs. 5.4%; aOR 2.3, 95% CI: 2.1- 2.6, P<0.001).


Conclusion
AKI in acute PE tends to have a poorer prognosis and higher odds of mortality, MACCE events, use of IVC filter, and thrombolytic therapies, with systemic thrombolysis being used more frequently than CDT in AKI patients. In addition, AKI accounts for significantly higher utilization of hospital resources due to longer LOS and higher total cost of hospitalization

Nationwide Analysis of the Utilization of Thrombolysis in AKI associated with Pulmonary Embolism

Abstract Title:
SLCO1B1*5 allele is associated with atorvastatin discontinuation and adverse muscle symptoms in the context of routine care

Background
SLCO1B1 genotype is known to influence patient adherence to statin therapy, in part by increasing the risk for statin-associated musculoskeletal symptoms (SAMS). For simvastatin specifically, the SLCO1B1*5 allele has previously been associated with SAMS. For atorvastatin, prior studies assessing the impact of SLCO1B1*5 on SAMS have yielded inconclusive findings, due to insufficient power.

Methods
This study quantifies the impact of SLCO1B1*5 on atorvastatin discontinuation and SAMS in a large observational cohort using electronic medical record (EMR) data from a single health care system.

Results
In the study cohort (n = 1,627 patients exposed to atorvastatin during the course of routine clinical care), 56% (n = 912 of 1,627 patients) discontinued atorvastatin, and 18% (n = 303 of 1,627 patients) developed SAMS. A univariate analysis revealed that SLCO1B1*5 increased the likelihood that patients would stop atorvastatin during routine care (Odds Ratio 1.2, 95% confidence interval [C.I.]: 1.1 - 1.5, p = 0.04). Further analyses using a multivariate Cox proportional hazards model demonstrated that this same variant was associated with time to atorvastatin discontinuation (Hazard Ratio 1.2, C.I. 1.1 - 1.4, p = 0.004). Additional time-to-event analyses also revealed that SCLO1B1*5 was associated with SAMS (Hazard Ratio 1.4, C.I. 1.1 - 1.7, p = 0.02).

Conclusion
Atorvastatin discontinuation was associated with SAMS (Odds Ratio 1.67, p = 0.0001) in this cohort. It is plausible that SLCO1B1-informed statin therapy with the aim of reducing muscle side effects may lead to improved adherence for this important class of drugs.

Genetic Variation in SLCO1B1 Increases Risk for Atorvastatin Muscle Side Effects

Background: AKI is common following adult orthotopic heart transplantation (OHT) with rates ranging from 40.3% to 72.3%. AKI worsens 12-month survival with a subset of patients requiring kidney replacement therapy (KRT), developing ESRD, worsening CKD, or death. The purpose of our study was to assess the nature of AKI occurring post-adult OHT at the Medical University of South Carolina and to serve as a metric of how to best improve renal outcomes in this cohort of patients.
Methods: We analyzed AKI rates and renal outcomes in a cohort of 120 adult patients undergoing OHT at MUSC from 04/2015 to 04/2021. We investigated AKI incidence, severity, and timing; the effect of hemodilution on AKI I criteria; and KRT indication and initiation in a sub-cohort of AKI patients who required KRT (AKI-D patients). We investigated major adverse kidney events (MAKE) outcomes at 12-months post-OHT. We identified several risk factors for AKI and AKI-D and performed a univariate logistic regression analysis of risk factors.
Results: 90% of patients met AKI criteria within 7 days post-OHT; 10% had no AKI, 48.3% had stage I AKI, 15.8% stage II, and 25.8% stage III. 31% of AKI stage I patients met criteria due to hemodilution. AKI criteria diagnosis was on median day 1 post-OHT. Median initiation of KRT was POD2 for the predominant indication of volume overload. Of AKI-D patients, MAKE criteria was assessed at 12 months post-OHT and showed 74.2% (n=23) of patients had doubling SCr, 16.2% (n=5) were ESRD, and 19.4% (n=6) died. Significant risk factors for AKI included CPB time (OR: 1.007, 95% CI: 1.001-1.013; P=0.015), VIS score (OR: 1.041, 95% CI: 1.011-1.072; P=0.007), preoperative SCr (OR: 5.61, 95% CI: 2.397-13.133; P<0.001), primary graft dysfunction (OR: 8.546, 95% CI: 2.705-26.994; P<0.001), and RV failure (OR: 5.548, 95% CI: 2.263-12.606; P<0.001).
Conclusion: AKI is a common finding post-OHT, however the majority of the AKI in this cohort of patients was AKI stage I. We identified that any AKI was associated with poor renal outcomes such as MAKE-12 months. Timing of all stages of AKI suggests etiologies such as RV failure and graft dysfunction as major risk factors for AKI.

Assessment of the Nature of Acute Kidney Injury Post Adult Orthotopic Heart Transplantation: A Single Tertiary Referral Center Experience

Factors Affecting Quality of Life in Patients on Hemodialysis: Survey from the Dominican Republic

An Analysis of Demographics and Outcomes of Transfer Patients versus Direct Admits Presenting to a Level 1 Trauma Center with a Traumatic Brain Injury

Evaluation of Risk Factors for Intracranial Hemorrhage in Patients with Left Ventricular Assist Devices using a Machine Learning Model

Background
The accumulation of amyloid proteins in the brain leads to synaptic dysfunction initiated by the binding of toxic oligomeric amyloid to the synapses and causes Alzheimer disease, a neurodegenerative disorder that results in cognitive decline. Treatments aimed at blocking this toxicity must pass through the blood-brain barrier to reach their targets. Brain-derived exosomes, nanosized vesicles released by cells that contain proteins and lipids that play significant roles in neurogenesis and synaptic plasticity, have been proposed as an ideal delivery method due to their ability to cross the blood-brain barrier. While previous studies have focused on more invasive intracranial methods, we investigate whether neuronal stem cell (NSC) exosomes delivered intra-arterially can protect against the toxicity of amyloid oligomers.

Methods
Exosomes isolated from rat hippocampal-derived NSC cultures were labeled with the PKH-26 membrane-permeant cell tracker dye prior to intra-arterial infusion of the internal carotid artery. The brains of experimental rats receiving exosomes and control rats receiving sham surgery were harvested after 4 and 24 hours and analyzed for exosome presence via PKH-26 signal detection with fluorescent microscopy. Localization of exosomes in specific cell types was determined using immunofluorescent staining and changes in gene expression were measured using qPCR.

Results
Fluorescent microscopy revealed exosomes in the cortex of rat brains at both 4 and 24 hours. Localization of both PKH-26 and NeuN, a neuron biomarker, showed exosomes were primarily found in neurons. qPCR demonstrated significant changes in gene expression in the brains of exosome treated rats compared to control rats. Exosome delivery increased gene expression of STAT3, a gene involved in neural survival and regeneration, and STX5, a presynaptic modulator. Furthermore, there was decreased expression of amyloid precursor protein and BACE, an enzyme involved in amyloid beta production and a target for Alzheimer’s disease.

Conclusion
Neuronal stem cell derived exosomes successfully crossed the blood-brain barrier after intra-arterial injection, increased gene expression of proteins involved in neurogenesis in the brain, and decreased gene expression of amyloid precursor proteins implicated in the progression of Alzheimer’s disease. Intra-arterial injection shows promise as a reliable delivery mechanism for Alzheimer’s and other neurodegenerative diseases.

Intra-Arterial Injection of Neural Stem Cell Exosomes to Modulate Gene Expression in Alzheimer’s Disease

Background:
A stroke is an interruption of the blood supply to any part of the brain. Neuroprotection is a therapeutic strategy to extend the window for brain reperfusion by reducing neurological injury. Steroid receptor coactivators (SRCs) are a family of proteins consisting of SRC-1, SRC-2, and SRC-3. Since SRCs are expressed and required in the transcription of 80% of genes, they are thought to have multifactorial neuroprotective effects including intracellular proliferation and regeneration, immune response modulation, and angiogenesis. Our study aims to test whether a novel steroid receptor coactivator, MCB-613, can act as an effective neuroprotective agent.

Methods:
Twenty Sprague Dawley rats underwent middle cerebral artery occlusion, obtained by inserting a 0.41 mm diameter filament into the internal carotid artery and advancing until occlusion. Occlusion time was set for 90 minutes and confirmed by 70% drop from baseline perfusion as measured by laser doppler. MCB-613 or saline was administered through intraperitoneal injection 120 minutes after occlusion. Every 24 hours, the animal underwent behavioral testing using a modified Bederson scale and again received either MCB-613 or saline. After a 4-day survival period, brain tissue was sliced into 2 mm segments following euthanasia and stained with 2,3,5-triphenyltetrazolium to measure infarct volume. Apoptosis was measured by TUNEL and Neuron-Specific Enolase immunostaining, whereas microglia were examined by IBA-1 Fluorescence Intensity. 

Results:
Behavioral results demonstrate that subjects treated with MCB-613 suffered significantly less neurologic impairment for the 4-day survival period (p<0.01; MCB-613=1.3, Control=2.7). Additionally, subjects treated with MCB-613 experienced a greater than 50% reduction in infarct (p<0.001; mean infarct area difference: 0.016). Histologic analysis revealed decreased neuronal apoptosis, increased microglia with an M2 (ameboid) pro-reparative phenotype, upregulated Nrf2 pathway in astrocytes mitigating oxidative damage, and decreased inflammatory reaction.

Conclusion:
Our study suggests that MCB-613 has the potential as a neuroprotectant for acute ischemic stroke, confirming previous 1-day survival studies that showed decreased neurological impairment (p<0.01; MCB-613=1.8, Control=3.8). Preliminary results show that 7-day survival subjects treated with MCB-613 also suffered significantly less neurologic impairment (p<0.01; MCB-613=2.4, Control=3.4). Further histologic analysis is needed to uncover the specific mechanism of action for MCB-613 as a steroid receptor coactivator.

Next from AMA Research Challenge 2022

A steep fall to high morbidity and disability; Vitamin D deficiency in Multiple Myeloma Patients.

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