Imaging Delay Following Liver-Directed Therapy Increases Progression Risk in Early- to Intermediate-Stage Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths in the world. Patients with early-stage HCC are treated with liver-directed therapies to bridge or downstage for liver transplantation (LT). In this study, the impact of HCC care delay on HCC progression among early-stage patients was investigated. Early-stage HCC patients undergoing their first cycle of liver-directed therapy (LDT) for bridge/downstaging to LT between 04/2016 and 04/2022 were retrospectively analyzed. Baseline variables were analyzed for risk of disease progression and time to progression (TTP). HCC care delay was determined by the number of rescheduled appointments related to HCC care. The study cohort consisted of 316 patients who received first-cycle LDT. The HCC care no-show rate was associated with TTP (p = 0.004), while the overall no-show rate was not (p = 0.242). The HCC care no-show rate and HCC care delay were further expanded as no-show rates and rescheduled appointments for imaging, laboratory, and office visits, respectively. More than 60% of patients experienced HCC care delay for imaging and laboratory appointments compared to just 8% for office visits. Multivariate analysis revealed that HCC-specific no-show rates and HCC care delay for imaging (p < 0.001) were both independently associated with TTP, highlighting the importance of minimizing delays in early-stage HCC imaging surveillance to reduce disease progression risk.

Plasma Concentration of 36 (Poly)phenols and Prospective Body Weight Change in Participants from the EPIC Cohort.

INTRODUCTION: Dietary intake of (poly)phenols has been linked to reduced adiposity and body weight (BW) in several epidemiological studies. However, epidemiological evidence on (poly)phenol biomarkers, particularly plasma concentrations, is scarce. We aimed to investigate the associations between plasma (poly)phenols and prospective BW change in participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: This study included 761 participants with data on BW at baseline and after 5 years of follow-up. Plasma concentrations of 36 (poly)phenols were measured at baseline using liquid chromatography-tandem mass spectrometry. Associations were assessed through general linear mixed models and multinomial logistic regression models, using change in BW as a continuous or as a categorical variable (BW loss, maintenance, gain), respectively. Plasma (poly)phenols were assessed as log2-transformed continuous variables. The false discovery rate (FDR) was used to control for multiple comparisons. RESULTS: Doubling plasma (poly)phenol concentrations showed a borderline trend towards a positive association with BW loss. Plasma vanillic acid showed the strongest association (-0.53 kg/5 years; 95% confidence interval [CI]: -0.99, -0.07). Similar results were observed for plasma naringenin comparing BW loss versus BW maintenance (odds ratio: 1.1; 95% CI: 1.0, 1.2). These results did not remain significant after FDR correction. CONCLUSION: Higher concentrations of plasma (poly)phenols suggested a tendency towards 5-year BW maintenance or loss. While certain associations seemed promising, they did not withstand FDR correction, indicating the need for caution in interpreting these results. Further studies using (poly)phenol biomarkers are needed to confirm these suggestive protective trends.

Lineage-specific regulation of PD-1 expression in early-stage hepatocellular carcinoma following 90yttrium transarterial radioembolization - Implications in treatment outcomes.

BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths in the world. Liver-directed therapies, including 90Yttrium (90Y) radioembolization, play an integral role in the management of HCC with excellent response rates. This has led to clinical trials of immunotherapy in combination with 90Y. Elevated PD-1 expression and lymphopenia were recently shown as risk factors for disease progression in early-stage HCC treated with liver-directed therapies. The aim of this study was to investigate PD-1 expression dynamics in bridge/downstage to transplant in HCC patients receiving first-cycle 90Y and evaluate the impact of these changes on response rates and time-to-progression (TTP). METHODS: Patients with HCC receiving first-cycle 90Y as a bridge to liver transplantation (n = 99) were prospectively enrolled. Blood specimens were collected before 90Y and again during routine imagining follow-up to analyze PD-1 expression via flow cytometry. Complete and objective response rates (CR and ORR) were determined using mRECIST. RESULTS: In 84/88 patients with available follow-up imaging, 83% had a localized ORR with 63% having localized CR. For overall response, 71% and 54% experienced ORR and CR, respectively. Post-90Y PD-1 upregulation in CD8 + associated with HCC progression and decreased TTP. Treatment with 90Y was associated with an anticipated significant post-treatment drop in lymphocytes (P < 0.001) that was independent of PD-1 expression for either CD4+ or CD8+ T cells (P = 0.751 and P = 0.375) and not associated with TTP risk. The change in lymphocytes was not correlated with PD-1 expression following treatment nor TTP. CONCLUSIONS: Elevated PD-1 expression on peripheral T cells is associated with increased risk of HCC progression and shorter time to progression in bridging/downstaging to transplant HCC patients undergoing first-cycle 90Y. Treatment-induced lymphopenia was not associated with treatment response, or increased progression risk, suggesting this anticipated adverse event does not impact short-term HCC outcomes.

Intake of the Total, Classes, and Subclasses of (Poly)Phenols and Risk of Prostate Cancer: A Prospective Analysis of the EPIC Study.

Existing epidemiological evidence regarding the potential role of (poly)phenol intake in prostate cancer (PCa) risk is scarce and, in the case of flavonoids, it has been suggested that their intake may increase PCa risk. We investigated the associations between the intake of the total and individual classes and subclasses of (poly)phenols and the risk of PCa, including clinically relevant subtypes. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort included 131,425 adult men from seven European countries. (Poly)phenol intake at baseline was assessed by combining validated center/country-specific dietary questionnaires and the Phenol-Explorer database. Multivariable-adjusted Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). In total, 6939 incident PCa cases (including 3501 low-grade and 710 high-grade, 2446 localized and 1268 advanced, and 914 fatal Pca cases) were identified during a mean follow-up of 14 years. No associations were observed between the total intake of (poly)phenols and the risk of PCa, either overall (HRlog2 = 0.99, 95% CI 0.94-1.04) or according to PCa subtype. Null associations were also found between all classes (phenolic acids, flavonoids, lignans, and stilbenes) and subclasses of (poly)phenol intake and the risk of PCa, overall and according to PCa subtype. The results of the current large prospective cohort study do not support any association between (poly)phenol intake and PCa incidence.

Impact of presenting stroke severity and thrombolysis on outcomes following urgent carotid interventions.

BACKGROUND: Carotid interventions are increasingly performed in select patients following acute stroke. We aimed to determine the effects of presenting stroke severity (National Institutes of Health Stroke Scale [NIHSS]) and use of systemic thrombolysis (tissue plasminogen activator [tPA]) on discharge neurological outcomes (modified Rankin scale [mRS]) after urgent carotid endarterectomy (uCEA) and urgent carotid artery stenting (uCAS). METHODS: Patients undergoing uCEA/uCAS at a tertiary Comprehensive Stroke Center (January 2015 to May 2022) were divided into two cohorts: (1) no thrombolysis (uCEA/uCAS only) and (2) use of thrombolysis before the carotid intervention (tPA + uCEA/uCAS). Outcomes were discharge mRS and 30-day complications. Regression models were used to determine an association between tPA use and presenting stroke severity (NIHSS) and discharge neurological outcomes (mRS). RESULTS: Two hundred thirty-eight patients underwent uCEA/uCAS (uCEA/uCAS only, n = 186; tPA + uCEA/uCAS, n = 52) over 7 years. In the thrombolysis cohort compared with the uCEA/uCAS only cohort, the mean presenting stroke severity was higher (NIHSS = 7.6 vs 3.8; P = .001), and more patients presented with moderate to severe strokes (57.7% vs 30.2% with NIHSS >4). The 30-day stroke, death, and myocardial infarction rates in the uCEA/uCAS only vs tPA + uCEA/uCAS were 8.1% vs 11.5% (P = .416), 0% vs 9.6% (P < .001), and 0.5% vs 1.9% (P = .39), respectively. The 30-day stroke/hemorrhagic conversion and myocardial infarction rates did not differ with tPA use; however, the difference in deaths was significantly higher in the tPA + uCEA/uCAS cohort (P < .001). There was no difference in neurological functional outcome with or without thrombolysis use (mean mRS, 2.1 vs 1.7; P = .061). For both minor strokes (NIHSS ≤4 vs NIHSS >4: relative risk, 1.58 vs 1.58, tPA vs no tPA, respectively, P = .997) and moderate strokes (NIHSS ≤10 vs NIHSS >10: relative risk, 1.94 vs 2.08, tPA vs no tPA, respectively; P = .891), the likelihood of discharge functional independence (mRS score of ≤2) was not influenced by tPA. CONCLUSIONS: Patients with a higher presenting stroke severity (NIHSS) had worse neurological functional outcomes (mRS). Patients presenting with minor and moderate strokes were more likely to have discharge neurological functional independence (mRS of ≤2), regardless of whether they received tPA or not. Overall, presenting NIHSS is predictive of discharge neurological functional autonomy and is not influenced by the use of thrombolysis.

Ochsner Emergency Department Overcrowding Scale (OEDOCS): predicting Emergency Department crowding among diverse academic hospital settings.

We developed the Ochsner Emergency Department Overcrowding Scale (OEDOCS) to help us measure and respond to crowding among diverse-sized Emergency Departments (ED) within our network. Not satisfied with our current Emergency Department (ED) crowding score, we first surveyed our ED staff to report perceived crowding and then developed models to predict perceived crowding from our Electronic Health Record (EHR) data. Staff at two ED locations, one large and one small, were asked to report a perceived crowding level between 0-200 every four hours for over 3 months. In addition, we collected Electronic Health Record (EHR) data during the same period. Next, we investigated models for predicting perceived crowding. Linear regression performed the best with an RMSE of 41.77 and 41.98% RMSE improvement over our previous crowding score. We have made OEDOCS publicly available.

Correlation Analysis between Dietary Intake of Tyrosols and Their Food Sources and Urinary Excretion of Tyrosol and Hydroxytyrosol in a European Population.

This study analyzed the correlations between the acute and habitual intake of dietary tyrosols, their main food sources, and 24 h urine excretions of tyrosol (Tyr) and hydroxytyrosol (OHTyr) in participants from the European Prospective Investigation into Cancer and Nutrition study (EPIC). Participants (n = 419) were healthy men and women aged from 34 to 73 years from 8 EPIC centers belonging to France, Italy, and Germany. Acute and habitual dietary data were collected using a standardized 24 h dietary recall software and validated country-specific dietary questionnaires, respectively. The intake of 13 dietary tyrosols was estimated using the Phenol-Explorer database. Excretions of Tyr and OHTyr in a single 24 h urine sample were analyzed using tandem mass spectrometry. Urinary excretions of Tyr, OHTyr, and their sum (Tyr + OHTyr) correlated more strongly with their corresponding acute (rhopartial~0.63) rather than habitual intakes (rhopartial~0.47). In addition, individual and combined urinary excretions of Tyr and OHTyr were weakly to moderately correlated with the acute and habitual intake of other individual tyrosol precursors (rhopartial = 0.10-0.44) and especially with major food sources, such as wine (rhopartial = 0.41-0.58), olive oil (rhopartial = 0.25-0.44), and beer (rhopartial = 0.14-0.23). Urinary Tyr + OHTyr excretions were similarly correlated with the acute intake of total tyrosols but differently correlated with food sources among countries. Based on these results, we conclude that 24 h urinary excretions of Tyr + OHTyr could be proposed as biomarkers of total tyrosol intake, preferably for acute intakes.

Telehealth and Medicare Type 2 Diabetes Care Outcomes: Evidence From Louisiana.

BACKGROUND: At the onset of the COVID-19 pandemic, the Centers for Medicare and Medicaid Services broadened access to telehealth. This provided an opportunity to test whether diabetes, a risk factor for COVID-19 severity, can be managed with telehealth services. OBJECTIVE: The objective of this study was to examine the impacts of telehealth on diabetes control. RESEARCH DESIGN: A doubly robust estimator combined a propensity score-weighting strategy with regression controls for baseline characteristics using electronic medical records data to compare outcomes in patients with and without telehealth care. Matching on preperiod trajectories in outpatient visits and weighting by odds were used to ensure comparability between comparators. SUBJECTS: Medicare patients with type 2 diabetes in Louisiana between March 2018 and February 2021 (9530 patients with a COVID-19 era telehealth visit and 20,666 patients without one). MEASURES: Primary outcomes were glycemic levels and control [ie, hemoglobin A1c (HbA1c) under 7%]. Secondary outcomes included alternative HbA1c measures, emergency department visits, and inpatient admissions. RESULTS: Telehealth was associated with lower pandemic era mean A1c values [estimate=-0.080%, 95% confidence interval (CI): -0.111% to -0.048%], which translated to an increased likelihood of having HbA1c in control (estimate=0.013; 95% CI: 0.002-0.024; P<0.023). Hispanic telehealth users had relatively higher COVID-19 era HbA1c levels (estimate=0.125; 95% CI: 0.044-0.205; P<0.003). Telehealth was not associated with differences in the likelihood of having an emergency department visits (estimate=-0.003; 95% CI: -0.011 to 0.004; P<0.351) but was associated with more the likelihood of having an inpatient admission (estimate=0.024; 95% CI: 0.018-0.031; P<0.001). CONCLUSION: Telehealth use among Medicare patients with type 2 diabetes in Louisiana stemming from the COVID-19 pandemic was associated with relatively improved glycemic control.

The Impact of Reimbursement for Non-Face-to-Face Chronic Care Management on Comprehensive Metabolic Biomarkers Among Multimorbid Patients With Type 2 Diabetes.

AIMS: We evaluated the impact of reimbursement for non-face-to-face chronic care management (NFFCCM) on comprehensive metabolic risk factors among multimorbid Medicare beneficiaries with type 2 diabetes in Louisiana. MATERIALS AND METHODS: We implemented a propensity score method to obtain comparable treatment (n=1501 with NFFCCM) and control (n=17,524 without NFFCCM) groups. Patients with type 2 diabetes were extracted from the electronic health records stored in REACHnet. The study period was from 2013 to February 2020. The comprehensive metabolic risk factors included the primary outcome of glycated hemoglobin (HbA1c) (as the primary outcome) and the secondary outcomes of body mass index (BMI), systolic blood pressure (BP), and low-density lipoprotein cholesterol. RESULTS: Receiving any NFFCCM was associated with improvement in all outcomes measures: a reduction in HbA1c of 0.063% (95% CI: 0.031%-0.094%; P <0.001), a reduction in BMI of 0.155 kg/m 2 (95% CI: 0.029-0.282 kg/m 2 ; P =0.016), a reduction in systolic BP of 0.816 mm Hg (95% CI: 0.469-1.163 mm Hg; P <0.001), and a reduction in low-density lipoprotein cholesterol of 1.779 mg/dL (95% CI: 0.988 2.570 mg/dL; P <0.001). Compared with the control group, the treatment group had 1.6% more patients with HbA1c <7% (95% CI: 0.3%-2.9%; P =0.013). CONCLUSIONS: Patients with diabetes in Louisiana receiving NFFCCM experienced better control of HbA1c, BMI, BP, and low-density lipoprotein outcomes.

COVID-19 bacteremic co-infection is a major risk factor for mortality, ICU admission, and mechanical ventilation.

BACKGROUND: Recent single-center reports have suggested that community-acquired bacteremic co-infection in the context of Coronavirus disease 2019 (COVID-19) may be an important driver of mortality; however, these reports have not been validated with a multicenter, demographically diverse, cohort study with data spanning the pandemic. METHODS: In this multicenter, retrospective cohort study, inpatient encounters were assessed for COVID-19 with community-acquired bacteremic co-infection using 48-h post-admission blood cultures and grouped by: (1) confirmed co-infection [recovery of bacterial pathogen], (2) suspected co-infection [negative culture with ≥ 2 antimicrobials administered], and (3) no evidence of co-infection [no culture]. The primary outcomes were in-hospital mortality, ICU admission, and mechanical ventilation. COVID-19 bacterial co-infection risk factors and impact on primary outcomes were determined using multivariate logistic regressions and expressed as adjusted odds ratios with 95% confidence intervals (Cohort, OR 95% CI, Wald test p value). RESULTS: The studied cohorts included 13,781 COVID-19 inpatient encounters from 2020 to 2022 in the University of Alabama at Birmingham (UAB, n = 4075) and Ochsner Louisiana State University Health-Shreveport (OLHS, n = 9706) cohorts with confirmed (2.5%), suspected (46%), or no community-acquired bacterial co-infection (51.5%) and a comparison cohort consisting of 99,170 inpatient encounters from 2010 to 2019 (UAB pre-COVID-19 pandemic cohort). Significantly increased likelihood of COVID-19 bacterial co-infection was observed in patients with elevated ≥ 15 neutrophil-to-lymphocyte ratio (UAB: 1.95 [1.21-3.07]; OLHS: 3.65 [2.66-5.05], p < 0.001 for both) within 48-h of hospital admission. Bacterial co-infection was found to confer the greatest increased risk for in-hospital mortality (UAB: 3.07 [2.42-5.46]; OLHS: 4.05 [2.29-6.97], p < 0.001 for both), ICU admission (UAB: 4.47 [2.87-7.09], OLHS: 2.65 [2.00-3.48], p < 0.001 for both), and mechanical ventilation (UAB: 3.84 [2.21-6.12]; OLHS: 2.75 [1.87-3.92], p < 0.001 for both) across both cohorts, as compared to other risk factors for severe disease. Observed mortality in COVID-19 bacterial co-infection (24%) dramatically exceeds the mortality rate associated with community-acquired bacteremia in pre-COVID-19 pandemic inpatients (5.9%) and was consistent across alpha, delta, and omicron SARS-CoV-2 variants. CONCLUSIONS: Elevated neutrophil-to-lymphocyte ratio is a prognostic indicator of COVID-19 bacterial co-infection within 48-h of admission. Community-acquired bacterial co-infection, as defined by blood culture-positive results, confers greater increased risk of in-hospital mortality, ICU admission, and mechanical ventilation than previously described risk factors (advanced age, select comorbidities, male sex) for COVID-19 mortality, and is independent of SARS-CoV-2 variant.

Assessing the impact of privacy-preserving record linkage on record overlap and patient demographic and clinical characteristics in PCORnet®, the National Patient-Centered Clinical Research Network.

OBJECTIVE: This article describes the implementation of a privacy-preserving record linkage (PPRL) solution across PCORnet®, the National Patient-Centered Clinical Research Network. MATERIAL AND METHODS: Using a PPRL solution from Datavant, we quantified the degree of patient overlap across the network and report a de-duplicated analysis of the demographic and clinical characteristics of the PCORnet population. RESULTS: There were ∼170M patient records across the responding Network Partners, with ∼138M (81%) of those corresponding to a unique patient. 82.1% of patients were found in a single partner and 14.7% were in 2. The percentage overlap between Partners ranged between 0% and 80% with a median of 0%. Linking patients' electronic health records with claims increased disease prevalence in every clinical characteristic, ranging between 63% and 173%. DISCUSSION: The overlap between Partners was variable and depended on timeframe. However, patient data linkage changed the prevalence profile of the PCORnet patient population. CONCLUSIONS: This project was one of the largest linkage efforts of its kind and demonstrates the potential value of record linkage. Linkage between Partners may be most useful in cases where there is geographic proximity between Partners, an expectation that potential linkage Partners will be able to fill gaps in data, or a longer study timeframe.

Unexpected Term Neonatal Intensive Care Unit Admissions and a Potential Role for Centralized Remote Fetal Monitoring.

OBJECTIVE: Centralized remote fetal monitoring (CRFM) has been proposed as a method to improve the performance of intrapartum fetal heart rate (FHR) monitoring and perinatal outcomes. The purpose of this study is to determine whether CRFM was associated with a reduction in unexpected term neonatal intensive care unit (NICU) admissions. STUDY DESIGN: A pre-post design was used to examine the effectiveness of CRFM which was implemented in stages across five hospitals. The exposure group was all women who underwent intrapartum monitoring via CRFM. The unexposed group was of women who delivered at the same hospitals prior to implementation of CRFM. Pregnancies with expected NICU admissions, gestational age <37 weeks, birth weight <2,500 g, or major fetal anomalies detected prenatally were excluded. The primary outcome was unexpected term NICU admission; secondary outcomes were cesarean and operative vaginal delivery (OVD), and 5-minute Apgar's score of <7 rates. Maternal and delivery characteristics were examined with Student's t, Wilcoxon's, Chi-square, and Fisher's exact tests. Multivariable logistic regression was performed to control for potential confounders. RESULTS: There were 19,392 live births included in this analysis. In the univariable analysis, the odds of unexpected term NICU admission was lower among the CRFM exposed group compared with the unexposed group (odds ratio [OR] = 0.86, 95% confidence interval [CI]: 0.75-0.99; p = 0.038). In multivariable analysis, this did not reach statistical significance (OR = 0.92, 95% CI: 0.79-1.06; p = 0.24). Cesarean and OVD were less likely in the exposed group (OR = 0.91, 95% CI: 0.85-0.97; p = 0.008) and (OR = 0.70, 95% CI: 0.59-0.83, p < 0.001), respectively, in univariable analysis. When adjusted for potential confounders, the effect remained statistically significant for cesarean delivery (OR = 0.92, 95% CI: 0.85-0.98; p = 0.012). When adjusted for hospital, OVD rate was lower at the highest volume and highest acuity site (OR = 0.48, 95% CI: 0.36-0.65, p < 0.001). CONCLUSION: In some practice settings, utilization of a CRFM system may decrease the risk of unexpected term NICU admission, cesarean, and OVD rate. KEY POINTS: · CRFM may decrease unexpected term NICU admissions in some clinical settings.. · CRFM may decrease cesarean delivery rates in some clinical settings.. · CRFM may decrease OVD rates in some clinical settings..

Clopidogrel resistance is common in patients undergoing vascular and coronary interventions.

OBJECTIVES: "Clopidogrel resistance," also defined as heightened platelet reactivity (HPR) while on clopidogrel therapy, may lead to a sub-optimal antiplatelet effect and a potential thrombotic event. There is limited literature addressing the prevalence of HPR in a large cohort of patients receiving either coronary or endovascular interventions. METHODS: In a large integrated healthcare system, patients with a P2Y12 reaction units (PRU) test were identified. HPR was defined as a PRU ≥ 200 during clopidogrel therapy. Vascular and coronary interventions were identified utilizing CPT codes, HPR prevalence was calculated, and Fischer's exact test was used to determine significance. RESULTS: From an initial cohort of 2,405,957 patients (October 2014 to January 2020), we identified 3301 patients with PRU tests administered. Of these, 1789 tests had a PRU ≥ 200 (HPR overall prevalence, 54%). We then identified 1195 patients who underwent either an endovascular or coronary procedure and had a PRU measurement. This corresponded to 935 coronary and 260 endovascular interventions. In the coronary cohort, the HPR prevalence was 54% (503/935). In the vascular cohort, the HPR prevalence was 53% (137/260); there was no difference between cohorts in HPR prevalence (p = 0.78). CONCLUSION: "Clopidogrel resistance" or HPR was found to be present in nearly half of patients with cardiovascular disease undergoing intervention. Our data suggest HPR is more common in the cardiovascular patient population than previously appreciated. Evaluating patients for HPR is both inexpensive ($25) and rapid (< 10 min). Future randomized studies are warranted to determine whether HPR has a clinically detectable effect on revascularization outcomes.

Establishing a framework for privacy-preserving record linkage among electronic health record and administrative claims databases within PCORnet®, the National Patient-Centered Clinical Research Network.

OBJECTIVE: The aim of this study was to determine whether a secure, privacy-preserving record linkage (PPRL) methodology can be implemented in a scalable manner for use in a large national clinical research network. RESULTS: We established the governance and technical capacity to support the use of PPRL across the National Patient-Centered Clinical Research Network (PCORnet®). As a pilot, four sites used the Datavant software to transform patient personally identifiable information (PII) into de-identified tokens. We queried the sites for patients with a clinical encounter in 2018 or 2019 and matched their tokens to determine whether overlap existed. We described patient overlap among the sites and generated a "deduplicated" table of patient demographic characteristics. Overlapping patients were found in 3 of the 6 site-pairs. Following deduplication, the total patient count was 3,108,515 (0.11% reduction), with the largest reduction in count for patients with an "Other/Missing" value for Sex; from 198 to 163 (17.6% reduction). The PPRL solution successfully links patients across data sources using distributed queries without directly accessing patient PII. The overlap queries and analysis performed in this pilot is being replicated across the full network to provide additional insight into patient linkages among a distributed research network.

Distinct Gene Expression Profiles in Viable Hepatocellular Carcinoma Treated With Liver-Directed Therapy.

Background: Hepatocellular carcinoma is a heterogeneous tumor that accumulates a mutational burden and dysregulated signaling pathways that differ from early to advanced stages. Liver transplant candidates with early-stage hepatocellular carcinoma (HCC) undergo liver-directed therapy (LDT) to delay disease progression and serve as a bridge to liver transplantation (LT). Unfortunately, >80% of LDT-treated patients have viable HCC in the explant liver, dramatically increasing recurrence risk. Understanding the effect of LDT on early-stage HCC could help identify therapeutic targets to promote complete pathologic necrosis and improve recurrence-free survival. In this study, transcriptomic data from viable HCC in LDT-treated bridged to transplant patients were investigated to understand how treatment may affect tumor signaling pathways. Methods: Multiplex transcriptomic gene analysis was performed with mRNA extracted from viable tumors of HCC patients bridged to transplant using LDT. The NanoString nCounter® Tumor Signaling 360 panel was used that contained 780 genes from 48 pathways involved in tumor biology within the microenvironment as well as antitumoral immune responses. Results: Hierarchical clustering separated tumors into three subtypes (HCC-1, HCC-2, and HCC-3) each with distinct differences in anti-tumoral signaling and immune infiltration within the tumor microenvironment. Immune infiltration (neutrophils, T cells, and macrophages) were all lowest in subtype HCC-3. The tumor inflammatory signature consisting of 18 genes associated with PD-1/PD-L1 inhibition, antigen presentation, chemokine secretion, and adaptive immune responses was highest in subtype HCC-1 and lowest in HCC-3. History of decompensation and etiology were associated with HCC subtype favoring downregulations in inflammation and immune infiltration with upregulation of lipid metabolism. Gene expression among intrahepatic lesions was remarkably similar with >85% of genes expressed in both lesions. Genes differentially expressed (<8 genes per patient) in multifocal disease were all upregulated in LDT-treated tumors from pathways involving epithelial mesenchymal transition, extracellular matrix remodeling, and/or inflammation potentially implicating intrahepatic metastases. Conclusion: Incomplete response to LDT may drive expression patterns that inhibit an effective anti-tumoral response through immune exclusion and induce intrahepatic spread.

Neurologic outcomes of carotid and other emergent interventions for ischemic stroke over 6 years with dataset enhanced by machine learning.

BACKGROUND: The current mainstays of ischemic stroke treatment include the use of thrombolysis (tissue plasminogen activator [tPA]), urgent carotid endarterectomy (uCEA) or urgent carotid artery stenting (uCAS), and mechanical endovascular reperfusion/thrombectomy (MER). Scarce data describe the presenting stroke severity and neurologic outcomes for these acute ischemic stroke interventions, alone or in combination. The authors hypothesize that patients undergoing carotid interventions experience better functional neurologic outcomes than other stroke interventions. METHODS: A comprehensive stroke center dataset was combined with data for stroke-related procedures, comorbidities, complications, and physician documentation collected from electronic medical record data. A total of 10,975 patient encounter records from January 1, 2015, through July 31, 2021, were retrieved. The presenting stroke severity was determined by vascular/stroke neurologists using the National Institutes of Health Stroke Scale (NIHSS). Functional neurologic outcomes were reported using the modified Rankin scale (mRS) score, which quantifies the degree of neurologic disability. Because mRS values were only available for 3627 encounters in the original dataset, the authors developed a machine learning algorithm to analyze physician documentation and assign an mRS value. After the exclusion and machine learning analysis, a total of 5170 patient encounters were included for statistical analysis. Statistical analyses included the χ2 test, one-way analysis of variance and logistic regression on 30-day complications, stroke severity, and neurologic outcomes. RESULTS: Patients were divided into five cohorts: (1) uCEA or uCAS (n = 189), (2) tPA alone (n = 1053), (3) MER alone (n = 418), (4) tPA + MER (n = 199), and (5) no intervention (n = 3311). Patients undergoing uCEA/uCAS were significantly more likely to be male, smokers, and have a history of peripheral arterial disease compared with other stroke cohorts. The length of stay was shortest for patients who only received tPA or no intervention (6 days), followed by uCEA/uCAS (7.2 days), MER (10.2 days), and tPA + MER (8.8 days) cohorts (P < .001). The 30-day mortality was highest in the MER cohort (12.2%) and lowest in the uCEA/uCAS cohort (2.6%). The uCEA/uCAS cohort compared with other cohorts had the lowest presenting stroke severity (NIHSS 4.9 vs NIHSS 6.9-16.0), and best neurologic outcomes (mRS 1.7 vs mRS 1.8-2.6). CONCLUSIONS: After an ischemic stroke, patients undergoing urgent carotid interventions had the lowest presenting stroke severity (NIHSS) and highest rate of independent neurologic outcomes (mRS) compared with other stroke interventions. Incoming stroke severity correlates with functional neurologic outcomes, and patients who present with an NIHSS of 10 or less who undergo uCEA/uCAS have a high likelihood of independent neurologic functional outcome (mRS of ≤2).

Hypoalbuminemia Is a Hepatocellular Carcinoma Independent Risk Factor for Tumor Progression in Low-Risk Bridge to Transplant Candidates.

Due to active hepatocellular carcinoma (HCC) surveillance, many patients are diagnosed with early-stage disease and are usually amendable to curative treatments. These patients lack poor prognostic factors associated with Milan Criteria and alpha fetoprotein (AFP) biomarker levels. There are currently limited strategies to assess prognosis in the patients who remain at risk of post-treatment HCC progression. In a cohort of liver transplant (LT) candidates with HCC, this study seeks to identify factors prior to liver-directed therapy (LDT) associated with time to progression (TTP). This is a retrospective analysis of prospectively collected data from LT candidates with recently diagnosed HCC and receiving LDT as a bridge to LT at three interventional oncology programs within a single system (n = 373). Demographics, clinical hepatology and serology, and factors related to HCC burden were extracted and analyzed for associations with TTP risk. Albumin level below the cohort median (3.4 g/dL) emerged as an independent risk factor for TTP controlling for AFP > 20 ng/mL as well as Milan, T-stage, and Barcelona Clinic Liver Cancer (BCLC) stage individually. In modality-specific subgroup survival analysis, albumin-based TTP stratification was restricted to patients receiving first cycle microwave ablation (p = 0.007). In n = 162 patients matching all low-risk criteria for Milan, T-stage, BCLC stage, and AFP, the effect of albumin < 3.4 g/dL remained significant for TTP (p = 0.004) with 2-year TTP rates of 68% (<3.4 g/dL) compared to 95% (≥3.4 g/dL). In optimal bridge to LT candidates with small HCC and low AFP biomarker levels, albumin level at treatment baseline provides an HCC-independent positive prognostic factor for risk of HCC progression prior to LT.

PD-1 expression in hepatocellular carcinoma predicts liver-directed therapy response and bridge-to-transplant survival.

BACKGROUND: Hepatocellular carcinoma (HCC) patients undergo liver-directed therapy (LDT) to control tumor burden while awaiting liver transplantation with response impacting waitlist survival. In this study, we investigate the link between absolute lymphocyte count (ALC) and PD-1 expression with response to LDT and bridge-to-transplant survival. METHODS: Treatment-naïve HCC patients (n = 86) undergoing LDT were enrolled at a single center from August 2016-March 2020. Response to LDT was determined using mRECIST. Blood samples were collected on the day of LDT and at follow-up. Cells were analyzed for phenotype by flow cytometry. Outcomes were liver transplantation or tumor progression. RESULTS: Incomplete response to initial LDT was associated with tumor progression precluding liver transplantation (OR: 7.6, 1.7 - 33.3, P < 0.001). Univariate analysis of baseline T cell phenotypes revealed ALC (OR: 0.44, 0.24-0.85, P = 0.009) as well as intermediate expression of PD-1 on CD4 (OR: 3.3, 1.03-10.3, P = 0.034) and CD8 T cells (OR: 3.0, 0.99-8.8 P = 0.043) associated with incomplete response to LDT. Elevations in PD-1 expression were associated with increased risk of bridge-to-transplant tumor progression (HR: 3.2, 1.2-9.4). In patients successfully bridged to liver transplantation, pre-treatment peripheral PD-1 profile was associated with advanced tumor staging (P < 0.005) with 2/4 of patients with elevations in PD-1 having T3-T4 TNM staging compared to 0 with low PD-1 expression. CONCLUSION: Low lymphocyte count or elevated expression of the PD-1 checkpoint inhibitor is associated with incomplete response to LDT and increased risk of bridge-to-transplant tumor progression. Patients with impaired T cell homeostasis may benefit from PD-1 immunotherapy to improve response to LDT and improve bridge-to-transplant outcomes.

Synergies between centralized and federated approaches to data quality: a report from the national COVID cohort collaborative.

OBJECTIVE: In response to COVID-19, the informatics community united to aggregate as much clinical data as possible to characterize this new disease and reduce its impact through collaborative analytics. The National COVID Cohort Collaborative (N3C) is now the largest publicly available HIPAA limited dataset in US history with over 6.4 million patients and is a testament to a partnership of over 100 organizations. MATERIALS AND METHODS: We developed a pipeline for ingesting, harmonizing, and centralizing data from 56 contributing data partners using 4 federated Common Data Models. N3C data quality (DQ) review involves both automated and manual procedures. In the process, several DQ heuristics were discovered in our centralized context, both within the pipeline and during downstream project-based analysis. Feedback to the sites led to many local and centralized DQ improvements. RESULTS: Beyond well-recognized DQ findings, we discovered 15 heuristics relating to source Common Data Model conformance, demographics, COVID tests, conditions, encounters, measurements, observations, coding completeness, and fitness for use. Of 56 sites, 37 sites (66%) demonstrated issues through these heuristics. These 37 sites demonstrated improvement after receiving feedback. DISCUSSION: We encountered site-to-site differences in DQ which would have been challenging to discover using federated checks alone. We have demonstrated that centralized DQ benchmarking reveals unique opportunities for DQ improvement that will support improved research analytics locally and in aggregate. CONCLUSION: By combining rapid, continual assessment of DQ with a large volume of multisite data, it is possible to support more nuanced scientific questions with the scale and rigor that they require.

Baseline Alpha-Fetoprotein, Alpha-Fetoprotein-L3, and Des-Gamma-Carboxy Prothrombin Biomarker Status in Bridge to Liver Transplant Outcomes for Hepatocellular Carcinoma.

The biomarkers α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP fraction (AFP-L3), and des-γ-carboxy prothrombin (DCP) have emerging implications in hepatocellular carcinoma (HCC) surveillance, overall prognosis, and post-surgical recurrence risk. This retrospective study investigated treatment and bridge to liver transplant (LT) prognosis associated with AFP, AFP-L3%, and DCP biomarker profiles prior to liver-directed therapy (LDT). In a 140-patient cohort, each biomarker was associated with HCC progression risk using the established thresholds of AFP > 20 ng/mL, AFP-L3 > 15%, and DCP > 7.5 ng/mL. Over 60% of the cohort expressed at least one biomarker at baseline. Although most biomarker-positive patients expressed the clinical standard AFP (57/87), only 32% were positive for AFP alone. Biomarker accumulation increased HCC progression risk but was not associated with demographic factors or preserved liver function. Biomarker triple negative patients had smaller index HCC (p = 0.003), decreased multifocal burden (p = 0.010), and a higher objective response rate (ORR, 62% compared to 46%, p = 0.011). Expressing all three biomarkers at baseline was associated with dismal first-line ORR (12%) with a median time to progression (TTP) of only 181 days post-LDT. Patients with triple negative status for the HCC biomarkers AFP, AFP-L3%, and DCP have the highest first-line ORR with < 5% HCC progression 1-year post-LDT. Biomarker profiling can establish baseline prognosis for identifying optimal bridge to LT and downstaging to LT candidates with triple negative biomarker status and providing an ideal post-LDT target as a compliment to radiographic response.