Grace L Su | University of Michigan (original) (raw)

Papers by Grace L Su

Journal of Surgical Research, Dec 1, 2000

Background. The first step in bacterial clearance by leukocytes is attachment and phagocytosis. A... more Background. The first step in bacterial clearance by leukocytes is attachment and phagocytosis. Although lipopolysaccharide-binding protein (LBP) is best known for potentiating LPS-induced cytokine production through a CD14-dependent pathway, recent studies suggest that LBP plays a critical role in clearance of gram-negative bacteria and is essential for survival after bacterial challenge. We therefore sought to examine LBP's effect on Escherichia coli phagocytosis by alveolar macrophages (AMs) and to determine if this effect is mediated through CD14. Materials and methods. Phosphatidylinositolspecific phospholipase C (PIPLC)-treated and untreated rat AMs were incubated in the presence of increasing doses of recombinant LBP or negative control protein (choramphenicol acetyltransferase) prior to E. coli-FITC (Ec-F) BioParticle challenge. Phagocytosed bacteria were assayed by fluorescence measurement. A time course study was also performed. Results. LBP potentiated phagocytosis of Ec-F Bio-Particles by AMs in a dose-dependent fashion. Kinetic studies showed that LBP augmented Ec-F phagocytosis by 76% at 30 min. Treatment of AMs with PIPLC to remove CD14 resulted in only a partial decrease in LBP-mediated enhancement of phagocytosis. Conclusion. These results clearly demonstrate that LBP plays an important role in enhancing Ec-F binding and phagocytosis in a time-and dose-dependent manner. This observed increase may not require the presence of CD14 as significant potentiation of phagocytosis still occurred after PIPLC treatment. We postulate that the LBP-mediated increase in Ec-F phagocytosis can occur in the absence of CD14 through the presence of another receptor.

Gastroenterology

BACKGROUND & AIMS Hepatocellular carcinoma (HCC), the most common primary liver cancer, remai... more BACKGROUND & AIMS Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a deadly cancer, with an incidence that has tripled in the United States since 1980. In recent years, new systemic therapies for HCC have been approved and a critical assessment of the existing data is necessary to balance benefits and harms and inform the development of evidence-based guidelines. METHODS The American Gastroenterological Association formed a multidisciplinary group consisting of a Technical Review Panel and a Guideline Panel. The Technical Review Panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of systemic therapies in patients with advanced-stage HCC. The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence. The Guideline Panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations. RESULTS The Panel reviewed the evidence, summarized in the Technical Review, for the following medications approved by the US Food and Drug Administration for HCC: first-line therapies: bevacizumab+atezolizumab, sorafenib, and lenvatinib; second-line therapies: cabozantinib, pembrolizumab, ramucirumab, and regorafenib; and other agents: bevacizumab, nivolumab, and nivolumab+ipilimumab. CONCLUSIONS The Panel agreed on 11 recommendations focused on systemic therapy for HCC in patients who are not eligible for locoregional therapy or resection, those with metastatic disease and preserved liver function, those with poor liver function, and those on systemic therapy as adjuvant therapy.

Additional file 6. Facilitator Discussion Packet. Given to the small group facilitators to help t... more Additional file 6. Facilitator Discussion Packet. Given to the small group facilitators to help them guide the discussions.

Annals of Allergy, Asthma & Immunology, 2020

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new stu... more Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new studies have been reported recently that describe EoE management. An expert panel was convened by the American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a technical review to be used as the basis for an updated clinical guideline. This technical review was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Eighteen focused EoE management questions were considered, with 15 answered using the GRADE framework and 3 with a narrative summary. There is moderate certainty in the evidence that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to <15 per high-power field over a short-term treatment period of 4e12 weeks, but very low certainty about the effects of using topical glucocorticosteroids as maintenance therapy. Multiple dietary strategies may be effective in reducing esophageal eosinophil counts to <15 per high-power field over a short-term treatment period, with moderate certainty for elemental diets, low certainty for empiric 2-, 4-, and 6-food elimination diets, and very low certainty that allergy-based testing dietary eliminations have a higher failure rate compared to empiric diet elimination. There is very low certainty for the effect of proton pump inhibitors in patients with esophageal eosinophilia. Although esophageal dilation appears to be relatively safe, there is no evidence that it reduces esophageal eosinophil counts. There is very low certainty in the effects of multiple other medical treatments for EoE: antieinterleukin-5 therapy, antieinterleukin-13 therapy, anti-IgE therapy, montelukast, cromolyn, and anti-TNF therapy.

American Journal of Physiology-Gastrointestinal and Liver Physiology, 2000

The cause of the cycle of urinary alcohol levels (UALs) in rats fed ethanol continually at a fixe... more The cause of the cycle of urinary alcohol levels (UALs) in rats fed ethanol continually at a fixed rate is unknown. Rats were fed ethanol intragastrically at a constant dose for 2 mo, and daily body temperatures and UALs were recorded. Body temperature cycled inversely to UAL, suggesting that the rate of metabolism could be mechanistically involved in the rate of ethanol elimination during the cycle. To document this, whole body O2consumption rate was monitored daily during the cycle. The rate of O2consumption correlated positively with the change in body temperature and negatively with the change in UAL. Since the metabolic rate responds to changes in body temperature, thyroid hormone levels were measured during the UAL cycle. T4levels correlated positively with the O2consumption rate and negatively with the UALs. In a second experiment using propylthiouracil treatment, UALs did not cycle and a fall in body temperature failed to stimulate an increase in the rate of ethanol eliminat...

Inflammatory Bowel Diseases

Background Although imaging, endoscopy, and inflammatory biomarkers are associated with future Cr... more Background Although imaging, endoscopy, and inflammatory biomarkers are associated with future Crohn disease (CD) outcomes, common laboratory studies may also provide prognostic opportunities. We evaluated machine learning models incorporating routinely collected laboratory studies to predict surgical outcomes in U.S. Veterans with CD. Methods Adults with CD from a Veterans Health Administration, Veterans Integrated Service Networks (VISN) 10 cohort examined between 2001 and 2015 were used for analysis. Patient demographics, medication use, and longitudinal laboratory values were used to model future surgical outcomes within 1 year. Specifically, data at the time of prediction combined with historical laboratory data characteristics, described as slope, distribution statistics, fluctuation, and linear trend of laboratory values, were considered and principal component analysis transformations were performed to reduce the dimensionality. Lasso regularized logistic regression was used...

BMC Medical Informatics and Decision Making, Dec 1, 2021

Background: Patients with hepatitis C virus (HCV) frequently remain at risk for cirrhosis after s... more Background: Patients with hepatitis C virus (HCV) frequently remain at risk for cirrhosis after sustained virologic response (SVR). Existing cirrhosis predictive models for HCV do not account for dynamic antiviral treatment status and are limited by fixed laboratory covariates and short follow up time. Advanced fibrosis assessment modalities, such as transient elastography, remain inaccessible in many settings. Improved cirrhosis predictive models are needed. Methods: We developed a laboratory-based model to predict progression of liver disease after SVR. This prediction model used a time-varying covariates Cox model adapted to utilize longitudinal laboratory data and to account for antiretroviral treatment. Individuals were included if they had a history of detectable HCV RNA and at least 2 AST-toplatelet ratio index (APRI) scores available in the national Veterans Health Administration from 2000 to 2015, Observation time extended through January 2019. We excluded individuals with preexisting cirrhosis. Covariates included baseline patient characteristics and 16 time-varying laboratory predictors. SVR, defined as permanently undetectable HCV RNA after antiviral treatment, was modeled as a step function of time. Cirrhosis development was defined as two consecutive APRI scores > 2. We predicted cirrhosis development at 1-, 3-, and 5-years follow-up. Results: In a national sample of HCV patients (n = 182,772) with a mean follow-up of 6.32 years, 42% (n = 76,854) achieved SVR before 2016 and 16.2% (n = 29,566) subsequently developed cirrhosis. The model demonstrated good discrimination for predicting cirrhosis across all combinations of laboratory data windows and cirrhosis prediction intervals. AUROCs ranged from 0.781 to 0.815, with moderate sensitivity 0.703-0.749 and specificity 0.723-0.767. Conclusion: A novel adaptation of time-varying covariates Cox modeling technique using longitudinal laboratory values and dynamic antiviral treatment status accurately predicts cirrhosis development at 1-, 3-, and 5-years among patients with HCV, with and without SVR. It improves upon earlier cirrhosis predictive models and has many potential population-based applications, especially in settings without transient elastography available.

Hepatology, 2005

We thank Dr. Sentilhes and coworkers for their interest in the results from the observational par... more We thank Dr. Sentilhes and coworkers for their interest in the results from the observational part of the Swedish ICP study, in which we demonstrated that fetal risk correlated with maternal bile acid levels. We stratified a large patient material (n 690) of pregnant women with pruritus into three groups: no ICP (serum bile acids 10 mol/ L), mild ICP (10-39 mol/L) and severe ICP ( 40 mol/L). Spontaneous preterm delivery; asphyxial events (operative delivery due to asphyxia, arterial umbilical pH 7.05, or Apgar score 7 at 5 minutes); and meconium staining of amniotic fluid, placenta, and membranes were found to be significantly increased in the group with severe ICP compared with the groups with no ICP and mild ICP. No differences in these variables were detected between the group with no ICP and the group with mild ICP. Furthermore, a higher frequency of intrauterine fetal death (IUFD) in prior pregnancies was reported by women in the group with severe ICP (4.1%) compared with the groups with no ICP (0.6%) and mild ICP (0.8%) (P .001). The rates of IUFD in the group with no ICP and the group with mild ICP did not differ significantly from the overall IUFD rate in Sweden (0.4%). In their comments, our French colleagues referred to the fact that one of our IUFD cases had bile acid levels below 40 mol/L (27 mol/L). This case was a twin pregnancy, in which one fetus died and the other survived. At delivery, a tight knot on the umbilical cord of the dead twin was found. Fetuses in twin pregnancies are indeed exposed to a higher risk, and all cases of IUFD in ICP pregnancies are not necessarily related to the disease. A recent study by Williamson et al.1 investigated fetal outcome in women with ICP, and they reported high fetal complication rates. However, in this study several confounding factors were present. Their patient material was based on a questionnaire survey in women with ICP that were identified by a patient support group. As the authors themselves stated in the article, this fact may indicate that the material was enriched by pregnancies in which complications had occurred. It should be pointed out that induction of labor, especially before term, is associated with an increase of fetal and maternal risk in terms of prolonged labor, higher frequencies of emergency cesarean section, and fetal asphyxia. We agree that the slight increase in risk of respiratory distress syndrome in the neonate is not an important issue when deciding to induce labor. Nevertheless, it should be underlined that inductions of labor should be conducted only in cases in which benefits outweigh risks. Our study proved that fetuses in pregnant women with bile acid levels exceeding 40 mol/L were exposed to an increased risk, and in this group it seems reasonable to propose active management (pharmacological treatment or induction of labor). Because we could not find any increase of fetal risk in our large study population of women with ICP and bile acid levels 10 to 39 mol/L, we cannot find any evidence to support that these women would benefit from routine induction before term. To further address this issue, a randomized study between active and expectant management should be conducted in this specific group.

Journal of Clinical Gastroenterology, Sep 1, 2011

Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but ea... more Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but earlier studies suggest that it is used less than one-third of the time. Patient factors associated with surveillance rates are incompletely understood. The aims of our study were to determine HCC surveillance rates in a tertiary-care center and to identify patient predictors of receiving surveillance. Patients with Child A or B cirrhosis seen in the University of Michigan liver clinics between October 2008 and March 2009 were enrolled to complete a self-administered survey. Surveillance rates and clinical data were extracted from the patient electronic medical record. Of the 160 patients enrolled, 74.4% had HCC surveillance performed in the past year. On multivariate analysis, predictors of receiving surveillance included male sex (odds ratio 7.1, 95% confidence interval, 1.2-43.2) and patient involvement in their care (odds ratio 3.4, 95% confidence interval, 1.5-7.9). Patients expressed high levels of concern regarding HCC, desired more information from their physicians, and wanted to be more involved in their care. HCC surveillance rates in a tertiary-care center were significantly higher than earlier reported rates. Direct patient involvement in decisions regarding HCC surveillance may help to improve surveillance rates.

Cancer Research and Treatment, Apr 15, 2018

The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembol... more The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is often uncertain. We aimed to utilize analytic morphomics, a high-throughput imaging analysis, to assess if body composition is predictive of post-TACE survival. Materials and Methods We included patients from a single center (Ann Arbor VA) who had TACE as the primary treatment for HCC and had a pre-treatment CT scans. Univariate analysis and multivariate conditional inference tree analysis were utilized to identify the morphomic characteristics predictive of one-year survival. Results were validated in an external cohort (University of Michigan Health System) of HCC patients who underwent TACE as their primary treatment. Results In the 75 patients in the derivation cohort, median survival was 439 (IQR: 377-685) days from receipt of TACE, with 1-year survival of 61%. Visceral fat density (VFD) was the only morphomic factor predictive of overall and 1-year survival (p<0.001). Patients with VFD above the 56th percentile had a 1-year survival of 39% vs. 78% for those below the 56th percentile. VFD also correlated with 1-year survival in the external validation cohort (44% vs. 72%, p<0.001). In a secondary analysis, patients with higher VFD were significantly more likely to experience hepatic decompensation after TACE (p<0.001). Conclusions VFD served as an objective predictor of mortality in patients undergoing TACE, possibly through its ability to predict hepatic decompensation. VFD may serve as a radiographic biomarker in predicting TACE outcomes.

JAMA network open, Sep 1, 2020

IMPORTANCE Deep learning, a family of machine learning models that use artificial neural networks... more IMPORTANCE Deep learning, a family of machine learning models that use artificial neural networks, has achieved great success at predicting outcomes in nonmedical domains. OBJECTIVE To examine whether deep learning recurrent neural network (RNN) models that use raw longitudinal data extracted directly from electronic health records outperform conventional regression models in predicting the risk of developing hepatocellular carcinoma (HCC). DESIGN, SETTING, AND PARTICIPANTS This prognostic study included 48 151 patients with hepatitis C virus (HCV)-related cirrhosis in the national Veterans Health Administration who had at least 3 years of follow-up after the diagnosis of cirrhosis. Patients were identified by having at least 1

Hepatology, 2005

Currently there is no consensus which staging system is best in predicting the survival of patien... more Currently there is no consensus which staging system is best in predicting the survival of patients with hepatocellular carcinoma (HCC). The aims of this study were to identify independent predictors of survival and to compare 7 available prognostic staging systems in patients with HCC. A total of 239 consecutive patients with cirrhosis and HCC seen between January 1, 2000, and December 31, 2003, were included. Demographic, laboratory, and tumor characteristics and performance status were determined at diagnosis and before therapy. Predictors of survival were identified using the Kaplan-Meir test and the Cox model. Sixty-two percent of patients had hepatitis C, 56% had more than 1 tumor nodule, 24% had portal vein thrombosis, and 29% did not receive any cancer treatment. At the time of censorship, 153 (63%) patients had died. The 1-and 3-year survival of the entire cohort was 58% and 29%, respectively. The independent predictors of survival were performance status (P < .0001), MELD score greater than 10 (P ‫؍‬ .001), portal vein thrombosis (P ‫؍‬ .0001), and tumor diameter greater than 4 cm (P ‫؍‬ .001). Treatment of HCC was related to overall survival. The Barcelona Clinic Liver Cancer (BCLC) staging system had the best independent predictive power for survival when compared with the other 6 prognostic systems. In conclusion, performance status, tumor extent, liver function, and treatment were independent predictors of survival mostly in patients with cirrhosis and HCC. The BCLC staging system includes aspects of all of these elements and provided the best prognostic stratification for our cohort of patients with HCC. (HEPATOLOGY 2005;41:707-716.

Digestive Diseases and Sciences, Jun 28, 2014

Background/Aim-Transarterial chemoembolization (TACE) is the recommended treatment for patients w... more Background/Aim-Transarterial chemoembolization (TACE) is the recommended treatment for patients with Barcelona stage B hepatocellular carcinoma; however, community practice varies from these American Association for the Study of Liver Diseases guidelines. In this study, we sought to assess factors determining outcome after TACE and examine adherence to guidelines. Methods-From January 2006 to December 2012, 308 patients with newly diagnosed HCC were treated at the Veterans Affairs (VA) Ann Arbor Healthcare System. Of these, 109 patients underwent TACE. The primary outcome measured mortality. Kaplan-Meier analysis was used to determine the cumulative probability of death. Cox regression was used to assess the predictors of mortality.

Cancer Epidemiology, Biomarkers & Prevention, May 1, 2012

Background: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrh... more Background: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but the effectiveness of a surveillance program in clinical practice has yet to be established. Aims: To evaluate the effectiveness of a surveillance program with ultrasound and alpha-fetoprotein (AFP) to detect early HCCs. Methods: Four hundred and forty-six patients with Child A/B cirrhosis were prospectively enrolled between January 2004 and September 2006 and followed until July 2010. HCC surveillance using ultrasound and AFP was conducted per the treating hepatologist, although the standard was every 6 to 12 months. HCC was diagnosed using American Association for the Study of Liver Disease (AASLD) guidelines and early HCC defined by Barcelona Clinic Liver Cancer (BCLC) staging. Performance characteristics were determined for surveillance using AFP, ultrasound, or the combination. Results: After a median follow-up of 3.5 years, 41 patients developed HCCs, of whom 30 (73.2%) had early HCCs. The annual incidence of HCC was 2.8%, with cumulative 3-and 5-year incidence rates of 5.7% and 9.1%, respectively. Surveillance ultrasound and AFP had sensitivities of 44% and 66% and specificities of 92% and 91%, respectively, for the detection of HCCs. Sensitivity significantly improved to 90%, with minimal loss in specificity (83%) when these tests were used in combination. Conclusions: When used as a surveillance program in a real-world clinical setting, combination of ultrasound and AFP is the most effective strategy to detect HCC at an early stage. Impact: Our results differ from the guidelines of the AASLD. Cancer Epidemiol Biomarkers Prev; 21(5); 793-9. Ó2012 AACR.

Clinical and translational gastroenterology, May 1, 2016

OBJECTIVES: Existing prognostic models for patients with hepatocellular carcinoma (HCC) have limi... more OBJECTIVES: Existing prognostic models for patients with hepatocellular carcinoma (HCC) have limitations. Analytic morphomics, a novel process to measure body composition using computational image-processing algorithms, may offer further prognostic information. The aim of this study was to develop and validate a prognostic model for HCC patients using body composition features and objective clinical information. METHODS: Using computed tomography scans from a cohort of HCC patients at the VA Ann Arbor Healthcare System between January 2006 and December 2013, we developed a prognostic model using analytic morphomics and routine clinical data based on multivariate Cox regression and regularization methods. We assessed model performance using C-statistics and validated predicted survival probabilities. We validated model performance in an external cohort of HCC patients from Parkland Hospital, a safety-net health system in Dallas County. RESULTS: The derivation cohort consisted of 204 HCC patients (20.1% Barcelona Clinic Liver Cancer classification (BCLC) 0/A), and the validation cohort had 225 patients (22.2% BCLC 0/A). The analytic morphomics model had good prognostic accuracy in the derivation cohort (C-statistic 0.80, 95% confidence interval (CI) 0.71-0.89) and external validation cohort (C-statistic 0.75, 95% CI 0.68-0.82). The accuracy of the analytic morphomics model was significantly higher than that of TNM and BCLC staging systems in derivation (Po0.001 for both) and validation (Po0.001 for both) cohorts. For calibration, mean absolute errors in predicted 1-year survival probabilities were 5.3% (90% quantile of 7.5%) and 7.6% (90% quantile of 12.5%) in the derivation and validation cohorts, respectively. CONCLUSION: Body composition features, combined with readily available clinical data, can provide valuable prognostic information for patients with newly diagnosed HCC.

Gastroenterology, May 1, 2023

recurrence during follow-up, while 5 patients in normal fibrinogen group (39 cases) developed tum... more recurrence during follow-up, while 5 patients in normal fibrinogen group (39 cases) developed tumor recurrence. Univariate analysis of factors revealed that age<50 years old, tumor size>5cm, tumor number>3, vascular invasion, serum alpha-fetoprotein (AFP) level≥400μg/ L, beyond Milan criteria, and fibrinogen level ≥2.71g/L were preoperative predictors of DFS and OS. Cox regression analysis showed that vascular invasion, tumor number>3, AFP≥400μg/L, and fibrinogen level≥2.71g/L were independent prognostic factors of poorer DFS, and vascular invasion, AFP≥400μg/L, and fibrinogen level≥2.71g/L were independent prognostic factors of poorer OS. Conclusion: Pretransplant elevated plasma fibrinogen level is associated with tumor recurrence and poor prognosis in patients after liver transplantation for HCC. Pretransplant plasma fibrinogen level may aid in the selection of patients that would most benefit from transplantation for HCC.

Currently there is no consensus which staging system is best in predicting the survival of patien... more Currently there is no consensus which staging system is best in predicting the survival of patients with hepatocellular carcinoma (HCC). The aims of this study were to identify independent predictors of survival and to compare 7 available prognostic staging systems in patients with HCC. A total of 239 consecutive patients with cirrhosis and HCC seen between January 1, 2000, and December 31, 2003, were included. Demographic, laboratory, and tumor characteristics and performance status were determined at diagnosis and before therapy. Predictors of survival were identified using the Kaplan-Meir test and the Cox model. Sixty-two percent of patients had hepatitis C, 56% had more than 1 tumor nodule, 24% had portal vein thrombosis, and 29% did not receive any cancer treatment. At the time of censorship, 153 (63%) patients had died. The 1-and 3-year survival of the entire cohort was 58% and 29%, respectively. The independent predictors of survival were performance status (P < .0001), MELD score greater than 10 (P ‫؍‬ .001), portal vein thrombosis (P ‫؍‬ .0001), and tumor diameter greater than 4 cm (P ‫؍‬ .001). Treatment of HCC was related to overall survival. The Barcelona Clinic Liver Cancer (BCLC) staging system had the best independent predictive power for survival when compared with the other 6 prognostic systems. In conclusion, performance status, tumor extent, liver function, and treatment were independent predictors of survival mostly in patients with cirrhosis and HCC. The BCLC staging system includes aspects of all of these elements and provided the best prognostic stratification for our cohort of patients with HCC. (HEPATOLOGY 2005;41:707-716.

Journal of Surgical Research, Dec 1, 2000

Background. The first step in bacterial clearance by leukocytes is attachment and phagocytosis. A... more Background. The first step in bacterial clearance by leukocytes is attachment and phagocytosis. Although lipopolysaccharide-binding protein (LBP) is best known for potentiating LPS-induced cytokine production through a CD14-dependent pathway, recent studies suggest that LBP plays a critical role in clearance of gram-negative bacteria and is essential for survival after bacterial challenge. We therefore sought to examine LBP's effect on Escherichia coli phagocytosis by alveolar macrophages (AMs) and to determine if this effect is mediated through CD14. Materials and methods. Phosphatidylinositolspecific phospholipase C (PIPLC)-treated and untreated rat AMs were incubated in the presence of increasing doses of recombinant LBP or negative control protein (choramphenicol acetyltransferase) prior to E. coli-FITC (Ec-F) BioParticle challenge. Phagocytosed bacteria were assayed by fluorescence measurement. A time course study was also performed. Results. LBP potentiated phagocytosis of Ec-F Bio-Particles by AMs in a dose-dependent fashion. Kinetic studies showed that LBP augmented Ec-F phagocytosis by 76% at 30 min. Treatment of AMs with PIPLC to remove CD14 resulted in only a partial decrease in LBP-mediated enhancement of phagocytosis. Conclusion. These results clearly demonstrate that LBP plays an important role in enhancing Ec-F binding and phagocytosis in a time-and dose-dependent manner. This observed increase may not require the presence of CD14 as significant potentiation of phagocytosis still occurred after PIPLC treatment. We postulate that the LBP-mediated increase in Ec-F phagocytosis can occur in the absence of CD14 through the presence of another receptor.

Gastroenterology

BACKGROUND & AIMS Hepatocellular carcinoma (HCC), the most common primary liver cancer, remai... more BACKGROUND & AIMS Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a deadly cancer, with an incidence that has tripled in the United States since 1980. In recent years, new systemic therapies for HCC have been approved and a critical assessment of the existing data is necessary to balance benefits and harms and inform the development of evidence-based guidelines. METHODS The American Gastroenterological Association formed a multidisciplinary group consisting of a Technical Review Panel and a Guideline Panel. The Technical Review Panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of systemic therapies in patients with advanced-stage HCC. The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence. The Guideline Panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations. RESULTS The Panel reviewed the evidence, summarized in the Technical Review, for the following medications approved by the US Food and Drug Administration for HCC: first-line therapies: bevacizumab+atezolizumab, sorafenib, and lenvatinib; second-line therapies: cabozantinib, pembrolizumab, ramucirumab, and regorafenib; and other agents: bevacizumab, nivolumab, and nivolumab+ipilimumab. CONCLUSIONS The Panel agreed on 11 recommendations focused on systemic therapy for HCC in patients who are not eligible for locoregional therapy or resection, those with metastatic disease and preserved liver function, those with poor liver function, and those on systemic therapy as adjuvant therapy.

Additional file 6. Facilitator Discussion Packet. Given to the small group facilitators to help t... more Additional file 6. Facilitator Discussion Packet. Given to the small group facilitators to help them guide the discussions.

Annals of Allergy, Asthma & Immunology, 2020

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new stu... more Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new studies have been reported recently that describe EoE management. An expert panel was convened by the American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a technical review to be used as the basis for an updated clinical guideline. This technical review was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Eighteen focused EoE management questions were considered, with 15 answered using the GRADE framework and 3 with a narrative summary. There is moderate certainty in the evidence that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to <15 per high-power field over a short-term treatment period of 4e12 weeks, but very low certainty about the effects of using topical glucocorticosteroids as maintenance therapy. Multiple dietary strategies may be effective in reducing esophageal eosinophil counts to <15 per high-power field over a short-term treatment period, with moderate certainty for elemental diets, low certainty for empiric 2-, 4-, and 6-food elimination diets, and very low certainty that allergy-based testing dietary eliminations have a higher failure rate compared to empiric diet elimination. There is very low certainty for the effect of proton pump inhibitors in patients with esophageal eosinophilia. Although esophageal dilation appears to be relatively safe, there is no evidence that it reduces esophageal eosinophil counts. There is very low certainty in the effects of multiple other medical treatments for EoE: antieinterleukin-5 therapy, antieinterleukin-13 therapy, anti-IgE therapy, montelukast, cromolyn, and anti-TNF therapy.

American Journal of Physiology-Gastrointestinal and Liver Physiology, 2000

The cause of the cycle of urinary alcohol levels (UALs) in rats fed ethanol continually at a fixe... more The cause of the cycle of urinary alcohol levels (UALs) in rats fed ethanol continually at a fixed rate is unknown. Rats were fed ethanol intragastrically at a constant dose for 2 mo, and daily body temperatures and UALs were recorded. Body temperature cycled inversely to UAL, suggesting that the rate of metabolism could be mechanistically involved in the rate of ethanol elimination during the cycle. To document this, whole body O2consumption rate was monitored daily during the cycle. The rate of O2consumption correlated positively with the change in body temperature and negatively with the change in UAL. Since the metabolic rate responds to changes in body temperature, thyroid hormone levels were measured during the UAL cycle. T4levels correlated positively with the O2consumption rate and negatively with the UALs. In a second experiment using propylthiouracil treatment, UALs did not cycle and a fall in body temperature failed to stimulate an increase in the rate of ethanol eliminat...

Inflammatory Bowel Diseases

Background Although imaging, endoscopy, and inflammatory biomarkers are associated with future Cr... more Background Although imaging, endoscopy, and inflammatory biomarkers are associated with future Crohn disease (CD) outcomes, common laboratory studies may also provide prognostic opportunities. We evaluated machine learning models incorporating routinely collected laboratory studies to predict surgical outcomes in U.S. Veterans with CD. Methods Adults with CD from a Veterans Health Administration, Veterans Integrated Service Networks (VISN) 10 cohort examined between 2001 and 2015 were used for analysis. Patient demographics, medication use, and longitudinal laboratory values were used to model future surgical outcomes within 1 year. Specifically, data at the time of prediction combined with historical laboratory data characteristics, described as slope, distribution statistics, fluctuation, and linear trend of laboratory values, were considered and principal component analysis transformations were performed to reduce the dimensionality. Lasso regularized logistic regression was used...

BMC Medical Informatics and Decision Making, Dec 1, 2021

Background: Patients with hepatitis C virus (HCV) frequently remain at risk for cirrhosis after s... more Background: Patients with hepatitis C virus (HCV) frequently remain at risk for cirrhosis after sustained virologic response (SVR). Existing cirrhosis predictive models for HCV do not account for dynamic antiviral treatment status and are limited by fixed laboratory covariates and short follow up time. Advanced fibrosis assessment modalities, such as transient elastography, remain inaccessible in many settings. Improved cirrhosis predictive models are needed. Methods: We developed a laboratory-based model to predict progression of liver disease after SVR. This prediction model used a time-varying covariates Cox model adapted to utilize longitudinal laboratory data and to account for antiretroviral treatment. Individuals were included if they had a history of detectable HCV RNA and at least 2 AST-toplatelet ratio index (APRI) scores available in the national Veterans Health Administration from 2000 to 2015, Observation time extended through January 2019. We excluded individuals with preexisting cirrhosis. Covariates included baseline patient characteristics and 16 time-varying laboratory predictors. SVR, defined as permanently undetectable HCV RNA after antiviral treatment, was modeled as a step function of time. Cirrhosis development was defined as two consecutive APRI scores > 2. We predicted cirrhosis development at 1-, 3-, and 5-years follow-up. Results: In a national sample of HCV patients (n = 182,772) with a mean follow-up of 6.32 years, 42% (n = 76,854) achieved SVR before 2016 and 16.2% (n = 29,566) subsequently developed cirrhosis. The model demonstrated good discrimination for predicting cirrhosis across all combinations of laboratory data windows and cirrhosis prediction intervals. AUROCs ranged from 0.781 to 0.815, with moderate sensitivity 0.703-0.749 and specificity 0.723-0.767. Conclusion: A novel adaptation of time-varying covariates Cox modeling technique using longitudinal laboratory values and dynamic antiviral treatment status accurately predicts cirrhosis development at 1-, 3-, and 5-years among patients with HCV, with and without SVR. It improves upon earlier cirrhosis predictive models and has many potential population-based applications, especially in settings without transient elastography available.

Hepatology, 2005

We thank Dr. Sentilhes and coworkers for their interest in the results from the observational par... more We thank Dr. Sentilhes and coworkers for their interest in the results from the observational part of the Swedish ICP study, in which we demonstrated that fetal risk correlated with maternal bile acid levels. We stratified a large patient material (n 690) of pregnant women with pruritus into three groups: no ICP (serum bile acids 10 mol/ L), mild ICP (10-39 mol/L) and severe ICP ( 40 mol/L). Spontaneous preterm delivery; asphyxial events (operative delivery due to asphyxia, arterial umbilical pH 7.05, or Apgar score 7 at 5 minutes); and meconium staining of amniotic fluid, placenta, and membranes were found to be significantly increased in the group with severe ICP compared with the groups with no ICP and mild ICP. No differences in these variables were detected between the group with no ICP and the group with mild ICP. Furthermore, a higher frequency of intrauterine fetal death (IUFD) in prior pregnancies was reported by women in the group with severe ICP (4.1%) compared with the groups with no ICP (0.6%) and mild ICP (0.8%) (P .001). The rates of IUFD in the group with no ICP and the group with mild ICP did not differ significantly from the overall IUFD rate in Sweden (0.4%). In their comments, our French colleagues referred to the fact that one of our IUFD cases had bile acid levels below 40 mol/L (27 mol/L). This case was a twin pregnancy, in which one fetus died and the other survived. At delivery, a tight knot on the umbilical cord of the dead twin was found. Fetuses in twin pregnancies are indeed exposed to a higher risk, and all cases of IUFD in ICP pregnancies are not necessarily related to the disease. A recent study by Williamson et al.1 investigated fetal outcome in women with ICP, and they reported high fetal complication rates. However, in this study several confounding factors were present. Their patient material was based on a questionnaire survey in women with ICP that were identified by a patient support group. As the authors themselves stated in the article, this fact may indicate that the material was enriched by pregnancies in which complications had occurred. It should be pointed out that induction of labor, especially before term, is associated with an increase of fetal and maternal risk in terms of prolonged labor, higher frequencies of emergency cesarean section, and fetal asphyxia. We agree that the slight increase in risk of respiratory distress syndrome in the neonate is not an important issue when deciding to induce labor. Nevertheless, it should be underlined that inductions of labor should be conducted only in cases in which benefits outweigh risks. Our study proved that fetuses in pregnant women with bile acid levels exceeding 40 mol/L were exposed to an increased risk, and in this group it seems reasonable to propose active management (pharmacological treatment or induction of labor). Because we could not find any increase of fetal risk in our large study population of women with ICP and bile acid levels 10 to 39 mol/L, we cannot find any evidence to support that these women would benefit from routine induction before term. To further address this issue, a randomized study between active and expectant management should be conducted in this specific group.

Journal of Clinical Gastroenterology, Sep 1, 2011

Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but ea... more Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but earlier studies suggest that it is used less than one-third of the time. Patient factors associated with surveillance rates are incompletely understood. The aims of our study were to determine HCC surveillance rates in a tertiary-care center and to identify patient predictors of receiving surveillance. Patients with Child A or B cirrhosis seen in the University of Michigan liver clinics between October 2008 and March 2009 were enrolled to complete a self-administered survey. Surveillance rates and clinical data were extracted from the patient electronic medical record. Of the 160 patients enrolled, 74.4% had HCC surveillance performed in the past year. On multivariate analysis, predictors of receiving surveillance included male sex (odds ratio 7.1, 95% confidence interval, 1.2-43.2) and patient involvement in their care (odds ratio 3.4, 95% confidence interval, 1.5-7.9). Patients expressed high levels of concern regarding HCC, desired more information from their physicians, and wanted to be more involved in their care. HCC surveillance rates in a tertiary-care center were significantly higher than earlier reported rates. Direct patient involvement in decisions regarding HCC surveillance may help to improve surveillance rates.

Cancer Research and Treatment, Apr 15, 2018

The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembol... more The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is often uncertain. We aimed to utilize analytic morphomics, a high-throughput imaging analysis, to assess if body composition is predictive of post-TACE survival. Materials and Methods We included patients from a single center (Ann Arbor VA) who had TACE as the primary treatment for HCC and had a pre-treatment CT scans. Univariate analysis and multivariate conditional inference tree analysis were utilized to identify the morphomic characteristics predictive of one-year survival. Results were validated in an external cohort (University of Michigan Health System) of HCC patients who underwent TACE as their primary treatment. Results In the 75 patients in the derivation cohort, median survival was 439 (IQR: 377-685) days from receipt of TACE, with 1-year survival of 61%. Visceral fat density (VFD) was the only morphomic factor predictive of overall and 1-year survival (p<0.001). Patients with VFD above the 56th percentile had a 1-year survival of 39% vs. 78% for those below the 56th percentile. VFD also correlated with 1-year survival in the external validation cohort (44% vs. 72%, p<0.001). In a secondary analysis, patients with higher VFD were significantly more likely to experience hepatic decompensation after TACE (p<0.001). Conclusions VFD served as an objective predictor of mortality in patients undergoing TACE, possibly through its ability to predict hepatic decompensation. VFD may serve as a radiographic biomarker in predicting TACE outcomes.

JAMA network open, Sep 1, 2020

IMPORTANCE Deep learning, a family of machine learning models that use artificial neural networks... more IMPORTANCE Deep learning, a family of machine learning models that use artificial neural networks, has achieved great success at predicting outcomes in nonmedical domains. OBJECTIVE To examine whether deep learning recurrent neural network (RNN) models that use raw longitudinal data extracted directly from electronic health records outperform conventional regression models in predicting the risk of developing hepatocellular carcinoma (HCC). DESIGN, SETTING, AND PARTICIPANTS This prognostic study included 48 151 patients with hepatitis C virus (HCV)-related cirrhosis in the national Veterans Health Administration who had at least 3 years of follow-up after the diagnosis of cirrhosis. Patients were identified by having at least 1

Hepatology, 2005

Currently there is no consensus which staging system is best in predicting the survival of patien... more Currently there is no consensus which staging system is best in predicting the survival of patients with hepatocellular carcinoma (HCC). The aims of this study were to identify independent predictors of survival and to compare 7 available prognostic staging systems in patients with HCC. A total of 239 consecutive patients with cirrhosis and HCC seen between January 1, 2000, and December 31, 2003, were included. Demographic, laboratory, and tumor characteristics and performance status were determined at diagnosis and before therapy. Predictors of survival were identified using the Kaplan-Meir test and the Cox model. Sixty-two percent of patients had hepatitis C, 56% had more than 1 tumor nodule, 24% had portal vein thrombosis, and 29% did not receive any cancer treatment. At the time of censorship, 153 (63%) patients had died. The 1-and 3-year survival of the entire cohort was 58% and 29%, respectively. The independent predictors of survival were performance status (P < .0001), MELD score greater than 10 (P ‫؍‬ .001), portal vein thrombosis (P ‫؍‬ .0001), and tumor diameter greater than 4 cm (P ‫؍‬ .001). Treatment of HCC was related to overall survival. The Barcelona Clinic Liver Cancer (BCLC) staging system had the best independent predictive power for survival when compared with the other 6 prognostic systems. In conclusion, performance status, tumor extent, liver function, and treatment were independent predictors of survival mostly in patients with cirrhosis and HCC. The BCLC staging system includes aspects of all of these elements and provided the best prognostic stratification for our cohort of patients with HCC. (HEPATOLOGY 2005;41:707-716.

Digestive Diseases and Sciences, Jun 28, 2014

Background/Aim-Transarterial chemoembolization (TACE) is the recommended treatment for patients w... more Background/Aim-Transarterial chemoembolization (TACE) is the recommended treatment for patients with Barcelona stage B hepatocellular carcinoma; however, community practice varies from these American Association for the Study of Liver Diseases guidelines. In this study, we sought to assess factors determining outcome after TACE and examine adherence to guidelines. Methods-From January 2006 to December 2012, 308 patients with newly diagnosed HCC were treated at the Veterans Affairs (VA) Ann Arbor Healthcare System. Of these, 109 patients underwent TACE. The primary outcome measured mortality. Kaplan-Meier analysis was used to determine the cumulative probability of death. Cox regression was used to assess the predictors of mortality.

Cancer Epidemiology, Biomarkers & Prevention, May 1, 2012

Background: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrh... more Background: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but the effectiveness of a surveillance program in clinical practice has yet to be established. Aims: To evaluate the effectiveness of a surveillance program with ultrasound and alpha-fetoprotein (AFP) to detect early HCCs. Methods: Four hundred and forty-six patients with Child A/B cirrhosis were prospectively enrolled between January 2004 and September 2006 and followed until July 2010. HCC surveillance using ultrasound and AFP was conducted per the treating hepatologist, although the standard was every 6 to 12 months. HCC was diagnosed using American Association for the Study of Liver Disease (AASLD) guidelines and early HCC defined by Barcelona Clinic Liver Cancer (BCLC) staging. Performance characteristics were determined for surveillance using AFP, ultrasound, or the combination. Results: After a median follow-up of 3.5 years, 41 patients developed HCCs, of whom 30 (73.2%) had early HCCs. The annual incidence of HCC was 2.8%, with cumulative 3-and 5-year incidence rates of 5.7% and 9.1%, respectively. Surveillance ultrasound and AFP had sensitivities of 44% and 66% and specificities of 92% and 91%, respectively, for the detection of HCCs. Sensitivity significantly improved to 90%, with minimal loss in specificity (83%) when these tests were used in combination. Conclusions: When used as a surveillance program in a real-world clinical setting, combination of ultrasound and AFP is the most effective strategy to detect HCC at an early stage. Impact: Our results differ from the guidelines of the AASLD. Cancer Epidemiol Biomarkers Prev; 21(5); 793-9. Ó2012 AACR.

Clinical and translational gastroenterology, May 1, 2016

OBJECTIVES: Existing prognostic models for patients with hepatocellular carcinoma (HCC) have limi... more OBJECTIVES: Existing prognostic models for patients with hepatocellular carcinoma (HCC) have limitations. Analytic morphomics, a novel process to measure body composition using computational image-processing algorithms, may offer further prognostic information. The aim of this study was to develop and validate a prognostic model for HCC patients using body composition features and objective clinical information. METHODS: Using computed tomography scans from a cohort of HCC patients at the VA Ann Arbor Healthcare System between January 2006 and December 2013, we developed a prognostic model using analytic morphomics and routine clinical data based on multivariate Cox regression and regularization methods. We assessed model performance using C-statistics and validated predicted survival probabilities. We validated model performance in an external cohort of HCC patients from Parkland Hospital, a safety-net health system in Dallas County. RESULTS: The derivation cohort consisted of 204 HCC patients (20.1% Barcelona Clinic Liver Cancer classification (BCLC) 0/A), and the validation cohort had 225 patients (22.2% BCLC 0/A). The analytic morphomics model had good prognostic accuracy in the derivation cohort (C-statistic 0.80, 95% confidence interval (CI) 0.71-0.89) and external validation cohort (C-statistic 0.75, 95% CI 0.68-0.82). The accuracy of the analytic morphomics model was significantly higher than that of TNM and BCLC staging systems in derivation (Po0.001 for both) and validation (Po0.001 for both) cohorts. For calibration, mean absolute errors in predicted 1-year survival probabilities were 5.3% (90% quantile of 7.5%) and 7.6% (90% quantile of 12.5%) in the derivation and validation cohorts, respectively. CONCLUSION: Body composition features, combined with readily available clinical data, can provide valuable prognostic information for patients with newly diagnosed HCC.

Gastroenterology, May 1, 2023

recurrence during follow-up, while 5 patients in normal fibrinogen group (39 cases) developed tum... more recurrence during follow-up, while 5 patients in normal fibrinogen group (39 cases) developed tumor recurrence. Univariate analysis of factors revealed that age<50 years old, tumor size>5cm, tumor number>3, vascular invasion, serum alpha-fetoprotein (AFP) level≥400μg/ L, beyond Milan criteria, and fibrinogen level ≥2.71g/L were preoperative predictors of DFS and OS. Cox regression analysis showed that vascular invasion, tumor number>3, AFP≥400μg/L, and fibrinogen level≥2.71g/L were independent prognostic factors of poorer DFS, and vascular invasion, AFP≥400μg/L, and fibrinogen level≥2.71g/L were independent prognostic factors of poorer OS. Conclusion: Pretransplant elevated plasma fibrinogen level is associated with tumor recurrence and poor prognosis in patients after liver transplantation for HCC. Pretransplant plasma fibrinogen level may aid in the selection of patients that would most benefit from transplantation for HCC.

Currently there is no consensus which staging system is best in predicting the survival of patien... more Currently there is no consensus which staging system is best in predicting the survival of patients with hepatocellular carcinoma (HCC). The aims of this study were to identify independent predictors of survival and to compare 7 available prognostic staging systems in patients with HCC. A total of 239 consecutive patients with cirrhosis and HCC seen between January 1, 2000, and December 31, 2003, were included. Demographic, laboratory, and tumor characteristics and performance status were determined at diagnosis and before therapy. Predictors of survival were identified using the Kaplan-Meir test and the Cox model. Sixty-two percent of patients had hepatitis C, 56% had more than 1 tumor nodule, 24% had portal vein thrombosis, and 29% did not receive any cancer treatment. At the time of censorship, 153 (63%) patients had died. The 1-and 3-year survival of the entire cohort was 58% and 29%, respectively. The independent predictors of survival were performance status (P < .0001), MELD score greater than 10 (P ‫؍‬ .001), portal vein thrombosis (P ‫؍‬ .0001), and tumor diameter greater than 4 cm (P ‫؍‬ .001). Treatment of HCC was related to overall survival. The Barcelona Clinic Liver Cancer (BCLC) staging system had the best independent predictive power for survival when compared with the other 6 prognostic systems. In conclusion, performance status, tumor extent, liver function, and treatment were independent predictors of survival mostly in patients with cirrhosis and HCC. The BCLC staging system includes aspects of all of these elements and provided the best prognostic stratification for our cohort of patients with HCC. (HEPATOLOGY 2005;41:707-716.