Citations

Abstract Background and Aims Immunotherapy has emerged as an effective treatment for patients with advanced‐stage HCC. We aimed to investigate the efficacy of immunotherapy for advanced HCC in a nationwide cohort and racial and ethnic disparities in access to immunotherapy. Approach and Results We used the US National Cancer Database to identify patients with tumor‐node‐metastasis stage 3 or 4 HCC between 2017 and 2018. We performed multivariable Cox regression to identify factors associated with overall survival (OS) and logistic regression to identify factors associated with receipt of immunotherapy. Of the 3,990 patients treated for advanced HCC, 3,248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first‐line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR: 0.76, 95% CI: 0.65–0.88) after adjusting for covariates. There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted OR [aOR]: 0.63, 95% CI: 0.46–0.83) and Black patients (aOR: 0.71, 95% CI: 0.54–0.89) less likely to receive immunotherapy compared with White patients. There was a significant interaction between race‐ethnicity and facility type, with higher disparity observed in nonacademic centers (interaction p = 0.004). Conclusions Immunotherapy was associated with improved OS compared with chemotherapy in advanced HCC. There are significant disparities in early access to immunotherapy, likely due to differential access to clinical trials and experimental therapies. A comprehensive approach to monitoring and eliminating racial‐ethnic disparities in the management of advanced HCC is urgently needed.

Abstract Background : Studies have proposed an inverse association between allergic diseases and cancer risk, but few studies to date have specifically investigated the risk of primary liver cancer (hepatocellular carcinoma, HCC; intrahepatic cholangiocarcinoma, ICC) in patients with or without allergic diseases. Objective : The aim of this study was to evaluate the association between allergic diseases and risk of developing liver cancer.Methods: A retrospective cohort study of the Korean National Health Insurance Service database was performed to study 405,512 South Korean adults ages 40 and above who underwent routine health screening after January 1st, 2005. All participants were followed for liver cancer diagnosis or death until December 31st, 2013. Those who died before the index date, had pre-diagnosed cancer, or did not undergo health screening were excluded. Cox proportional hazards regression was performed to determine the adjusted hazard ratios(aHRs) and 95% confidence intervals (CIs) for risk of developing liver cancer according presence or absence of atopic dermatitis, asthma and allergic rhinitis.Results: The aHR (95% CI) for overall liver cancer among allergic patients was 0.72 (0.64-0.81). Allergic patients had significantly reduced risk of HCC (aHR: 0.70, 95% CI: 0.61-0.81) but not ICC (aHR: 0.99, 95% CI: 0.71-1.08). Presence of allergic diseases was associated with significantly lower risk of liver cancer in both patients with (aHR: 0.61, 95% CI: 0.47-0.8) or without (aHR: 0.74, 95% CI: 0.65-0.85) chronic Hepatitis B/C infections. Presence of allergic diseases was associated with significantly lower risk of liver cancer in patients without cirrhosis (aHR: 0.72, 95% CI 0.63-0.82), but not in those with cirrhosis (aHR: 0.98, 95% CI 0.68-1.41). Patients with multiple allergies had even lower risk of liver cancer compared to patients with single allergy. Conclusion: Patients with allergic diseases have significantly lower risk of developing liver cancer compared to those without allergic diseases, which supports the rationale for immunotherapy as an effective treatment of liver cancer.

INTRODUCTION: Cirrhosis is associated with cardiac dysfunction and distinct electrocardiogram (ECG) abnormalities. This study aimed to develop a proof-of-concept deep learning-based artificial intelligence (AI) model that could detect cirrhosis-related signals on ECG and generate an AI-Cirrhosis-ECG (ACE) score that would correlate with disease severity. METHODS: A review of Mayo Clinic's electronic health records identified 5,212 patients with advanced cirrhosis ≥18 years who underwent liver transplantation at the 3 Mayo Clinic transplant centers between 1988 and 2019. The patients were matched by age and sex in a 1:4 ratio to controls without liver disease and then divided into training, validation, and test sets using a 70%-10%-20% split. The primary outcome was the performance of the model in distinguishing patients with cirrhosis from controls using their ECGs. In addition, the association between the ACE score and the severity of patients' liver disease was assessed. RESULTS: The model's area under the curve in the test set was 0.908 with 84.9% sensitivity and 83.2% specificity, and this performance remained consistent after additional matching for medical comorbidities. Significant elevations in the ACE scores were seen with increasing model for end-stage liver disease-sodium score. Longitudinal trends in the ACE scores before and after liver transplantation mirrored the progression and resolution of liver disease. DISCUSSION: The ACE score, a deep learning model, can accurately discriminate ECGs from patients with and without cirrhosis. This novel relationship between AI-enabled ECG analysis and cirrhosis holds promise as the basis for future low-cost tools and applications in the care of patients with liver disease.

Physiologic aging leads to attrition of telomeres and replicative senescence. An acceleration of this process has been hypothesized in the progression of chronic liver disease. We sought to examine the association of telomere length (TL) with liver disease and its impact on mortality risk. A cohort of 7,072 adults with leukocyte TL measurements from the National Health and Nutrition Examination Survey 1999‐2002 with mortality follow‐up through 2015 was analyzed. Liver disease was defined by aminotransferase levels and classified into etiology‐based and advanced fibrosis categories. Multivariable‐adjusted linear regression models estimated effect sizes, with 95% confidence intervals (CIs), of the presence of liver disease on TL. Cox regression models evaluated associations between TL and all‐cause mortality risk using adjusted hazard ratios (HRs). The cohort was representative of the US population with mean age 46.1 years and mean TL 5.79 kilobase pairs. No overall association between TL and liver disease was found; however, there was a significant negative association of TL and advanced liver fibrosis in individuals aged 65 and above. The liver disease cohort (HR 1.22, 95% CI 0.99‐1.51) and those with metabolic syndrome (HR 1.26, 95% CI 0.96‐1.67) had increased mortality risk with shorter TL. The relationship between TL and all‐cause mortality was stronger in women (HR 1.51, 95% CI 1.02‐2.23) and in non‐Hispanic Whites (HR 1.37, 95% CI 1.02‐1.84). Conclusion: Shortened leukocyte TL is independently associated with advanced liver disease at older ages, and with a higher risk of all‐cause mortality in those with liver disease. These associations reaffirm the need to better understand the role of telomeres in the progression of liver disease.

Prognosis of hepatocellular carcinoma (HCC) could be affected by lack of or delayed therapy. We aimed to characterize the prevalence, correlates, and clinical impact of therapeutic underuse and delay in patients with HCC. Patients with HCC diagnosed between 2010 and 2017 were analyzed from the United States National Cancer Database. Logistic regression analysis identified factors associated with no and delayed (>90 days after diagnosis) HCC treatment. Cox proportional hazards regression with landmark analysis assessed the association between therapeutic delay and overall survival (OS), accounting for immortal time bias. Of 116,299 patients with HCC, 24.2% received no treatment and 18.4% of treated patients had delayed treatment. Older age, Black, Hispanic, lower socioeconomic status, earlier year of diagnosis, treatment at nonacademic centers, Northeast region, increased medical comorbidity, worse liver dysfunction, and higher tumor burden were associated with no treatment. Among treated patients, younger age, Hispanic, Black, treatment at academic centers, West region, earlier tumor stage, and receipt of noncurative treatment were associated with treatment delays. In multivariable Cox regression with a landmark of 150 days, patients with and without treatment delays had similar OS (adjusted hazard ratio [aHR], 1.01; 95% confidence interval [CI], 0.98‐1.04) with a median survival of 33.7 vs. 32.1 months, respectively. However, therapeutic delay was associated with worse OS in patients who had tumor, nodes, and metastases (TNM) stage 1 (aHR, 1.06; 95% CI, 1.01‐1.11) or received curative treatment (aHR, 1.12; 95% CI, 1.05‐1.18). Conclusion: One‐fourth of patients with HCC receive no therapy and one‐fifth of treated patients experience treatment delays. Both were associated with demographic, socioeconomic, and clinical characteristics of patients as well as facility type and region. The association between therapeutic delay and survival was stage and treatment dependent.

Introduction Despite extensive studies on the relationship between diabetes mellitus (DM) and depression, the associations of depressive symptom severity with prevalence, awareness, treatment, and control of diabetes remain unclear. We aimed to investigate changes in these outcomes of diabetes as depressive symptoms aggravate. Research design and methods We conducted a cross-sectional analysis of 14 328 participants in the 2011–2016 National Health and Nutrition Examination Survey. Participants were classified into depressive symptom groups of none, mild, moderate, moderately severe, and severe depending on their Patient Health Questionnaire-9 scores. Multivariate logistic regression analyses were conducted in three models adjusted for expanding confounders to evaluate the associations between severity of depressive symptoms and prevalence, awareness, treatment, and control of DM. Results As depressive symptom severity worsened, both prevalence and awareness of DM increased regardless of models (p value for trend <0.01 in all models for prevalence and awareness; adjusted OR (aOR) 2.14, 95% CI 1.29 to 3.56 for prevalence in the severe group, model 1; aOR 2.43, 95% CI 1.27 to 4.64 for awareness in the moderately severe group, model 1). Notwithstanding higher awareness of diabetes in the moderately severe and severe groups (84.5% and 86.2%, respectively, vs 71.3% in the none group), these groups were treated less (aOR 0.25, 95% CI 0.11 to 0.55 in the severe group, model 3) or inadequately controlled (aOR 0.51, 95% CI 0.27 to 0.98 in the moderately severe group, model 3). Conclusions The gap between patients’ higher awareness and lower treatment rate or control of diabetes among individuals with severe depressive symptoms highlights the unmet needs for postdiagnostic multidisciplinary care for patients with comorbid depression and DM.

Background and Aims Patients with cirrhosis on the liver transplant (LT) waiting list may die or be removed because of complications of portal hypertension (PH) or infections. von Willebrand factor antigen (vWF‐Ag) and C‐reactive protein (CRP) are simple, broadly available markers of these processes. Approach and Results We determined whether addition of vWF‐Ag and CRP to the Model for End‐Stage Liver Disease‐Sodium (MELD‐Na) score improves risk stratification of patients awaiting LT. CRP and vWF‐Ag at LT listing were assessed in two independent cohorts (Medical University of Vienna [exploration cohort] and Mayo Clinic Rochester [validation cohort]). Clinical characteristics, MELD‐Na, and mortality on the waiting list were recorded. Prediction of 3‐month waiting list mortality was assessed by receiver operating characteristics curve (ROC‐AUC). In order to explore potential mechanisms underlying the prognostic utility of vWF‐Ag and CRP in this setting, we evaluated their association with PH, bacterial translocation, systemic inflammation, and circulatory dysfunction. In the exploration cohort (n = 269) vWF‐Ag and CRP both improved the predictive value of MELD‐Na for 3‐month waitlist mortality and showed the highest predictive value when combined (AUC: MELD‐Na, 0.764; MELD‐Na + CRP, 0.790; MELD‐Na + vWF, 0.803; MELD‐Na + CRP + vWF‐Ag, 0.824). Results were confirmed in an independent validation cohort (n = 129; AUC: MELD‐Na, 0.677; MELD‐Na + CRP + vWF‐Ag, 0.882). vWF‐Ag was independently associated with PH and inflammatory biomarkers, whereas CRP closely, and MELD independently, correlated with biomarkers of bacterial translocation/inflammation. Conclusions The addition of vWF‐Ag and CRP—reflecting central pathophysiological mechanisms of PH, bacterial translocation, and inflammation, that are all drivers of mortality on the waiting list for LT—to the MELD‐Na score improves prediction of waitlist mortality. Using the vWFAg‐CRP‐MELD‐Na model for prioritizing organ allocation may improve prediction of waitlist mortality and decrease waitlist mortality.