A machine learning clinic scoring system for hepatocellular carcinoma based on the Surveillance, Epidemiology, and End Results database.

Background: Hepatocellular carcinoma (HCC) poses a global threat to life; however, numerical tools to predict the clinical prognosis of these patients remain scarce. The primary objective of this study is to establish a clinical scoring system for evaluating the overall survival (OS) rate and cancer-specific survival (CSS) rate in HCC patients. Methods: From the Surveillance, Epidemiology, and End Results (SEER) Program, we identified 45,827 primary HCC patients. These cases were randomly allocated to a training cohort (22,914 patients) and a validation cohort (22,913 patients). Univariate and multivariate Cox regression analyses, coupled with Kaplan-Meier methods, were employed to evaluate prognosis-related clinical and demographic features. Factors demonstrating prognostic significance were used to construct the model. The model's stability and accuracy were assessed through C-index, receiver operating characteristic (ROC) curves, calibration curves, and clinical decision curve analysis (DCA), while comparisons were made with the American Joint Committee on Cancer (AJCC) staging. Ultimately, machine learning (ML) quantified the variables in the model to establish a clinical scoring system. Results: Univariate and multivariate Cox regression analyses identified 11 demographic and clinical-pathological features as independent prognostic indicators for both CSS and OS using. Two models, each incorporating the 11 features, were developed, both of which demonstrated significant prognostic relevance. The C-index for predicting CSS and OS surpassed that of the AJCC staging system. The area under the curve (AUC) in time-dependent ROC consistently exceeded 0.74 in both the training and validation sets. Furthermore, internal and external calibration plots indicated that the model predictions aligned closely with observed outcomes. Additionally, DCA demonstrated the superiority of the model over the AJCC staging system, yielding greater clinical net benefit. Ultimately, the quantified clinical scoring system could efficiently discriminate between high and low-risk patients. Conclusions: A ML clinical scoring system trained on a large-scale dataset exhibits good predictive and risk stratification performance in the cohorts. Such a clinical scoring system is readily integrable into clinical practice and will be valuable in enhancing the accuracy and efficiency of HCC management.

Esophagogastroduodenoscopy findings that do no not explain dysphagia are associated with underutilization of high-resolution manometry.

In patients with dysphagia that is not explained by upper endoscopy, high-resolution esophageal manometry (HRM) is the next logical step in diagnostic testing. This study investigated predictors of failure to refer for HRM after an upper endoscopy that was performed for but did not explain dysphagia. This was a retrospective cohort study of patients >18 years of age who underwent esophagogastroduodenoscopy (EGD) for dysphagia from 2015 to 2021. Patients with EGD findings that explained dysphagia (e.g. esophageal mass, eosinophilic esophagitis, Schatzki ring, etc.) were excluded from the main analyses. The primary outcome was failure to refer for HRM within 1 year of the index non-diagnostic EGD. We also investigated delayed referral for HRM, defined as HRM performed after the median. Multivariable logistic regression modeling was used to identify risk factors that independently predicted failure to refer for HRM, conditioned on the providing endoscopist. Among 2132 patients who underwent EGD for dysphagia, 1240 (58.2%) did not have findings to explain dysphagia on the index EGD. Of these 1240 patients, 148 (11.9%) underwent HRM within 1 year of index EGD. Endoscopic findings (e.g. hiatal hernia, tortuous esophagus, Barrett's esophagus, surgically altered anatomy not involving the gastroesophageal junction, and esophageal varices) perceived to explain dysphagia were independently associated with failure to refer for HRM (adjusted odds ratio 0.45, 95% confidence interval 0.25-0.80). Of the 148 patients who underwent HRM within 1 year of index EGD, 29.7% were diagnosed with a disorder of esophagogastric junction outflow, 17.6% with a disorder of peristalsis, and 2.0% with both disorders of esophagogastric outflow and peristalsis. The diagnosis made by HRM was similar among those who had incidental EGD findings that were non-diagnostic for dysphagia compared with those who had completely normal EGD findings. Demographic factors including race/ethnicity, insurance type, and income were not associated with failure to refer for HRM or delayed HRM. Patients with dysphagia and endoscopic findings unrelated to dysphagia have a similar prevalence of esophageal motility disorders to those with normal endoscopic examinations, yet these patients are less likely to undergo HRM. Provider education is indicated to increase HRM referral in these patients.

Narrative review of management of cirrhosis during the treatment of hepatocellular carcinoma.

BACKGROUND AND OBJECTIVE: The management of hepatocellular carcinoma (HCC) and cirrhosis are closely linked. HCC most often occurs in the background of cirrhosis and can also lead to decompensation of underlying liver disease. The treatment of complications of cirrhosis is important to help reduce morbidity and mortality and allow for expanded treatment options of HCC. METHODS: We searched PubMed using search terms for cirrhosis and HCC. From this search, we selected references which appeared to be primary studies preferentially within the last 5 years, although also included select landmark studies which have shaped guidelines and recommendations. KEY CONTENT AND FINDINGS: The development of HCC and treatment of HCC can both cause decompensation of liver disease and worsening of liver function. For most patients, the development of HCC or progression of disease are the drivers of morbidity and mortality. However, it is important to closely monitor patients for complications of liver disease that develop either as a result of HCC or as a complication of HCC treatment, and this can have important implications on treatment options. Multidisciplinary team involvement including hepatologists, surgeons, radiologists, interventional radiologists, medical oncologists, and palliative care is essential in the care of patients with cirrhosis and HCC to help guide management decisions and treatment. CONCLUSIONS: The management of cirrhosis and HCC are both complex and interrelated. Through a multidisciplinary team approach we can best treat the complications of cirrhosis, allow for expanded treatment options, and improve quality of life through symptom management.

Invasive fungal infections in liver diseases.

Patients with liver diseases, including decompensated cirrhosis, alcohol-associated hepatitis, and liver transplant recipients are at increased risk of acquiring invasive fungal infections (IFIs). These infections carry high morbidity and mortality. Multiple factors, including host immune dysfunction, barrier failures, malnutrition, and microbiome alterations, increase the risk of developing IFI. Candida remains the most common fungal pathogen causing IFI. However, other pathogens, including Aspergillus, Cryptococcus, Pneumocystis, and endemic mycoses, are being increasingly recognized. The diagnosis of IFIs can be ascertained by the direct observation or isolation of the pathogen (culture, histopathology, and cytopathology) or by detecting antigens, antibodies, or nucleic acid. Here, we provide an update on the epidemiology, pathogenesis, diagnosis, and management of IFI in patients with liver disease and liver transplantation.

Outcomes in liver transplant recipients with nonalcoholic fatty liver disease-related HCC: results from the US multicenter HCC transplant consortium.

NAFLD will soon be the most common indication for liver transplantation (LT). In NAFLD, HCC may occur at earlier stages of fibrosis and present with more advanced tumor stage, raising concern for aggressive disease. Thus, adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001) and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49). With NAFLD among the most common causes of HCC and poised to become the leading indication for LT, a better understanding of disease-specific models to predict recurrence is needed. In this NAFLD cohort, incidental HCCs were common, raising concerns about early detection. However, despite less locoregional therapy and high neutrophil-lymphocyte ratio, explant tumor characteristics and post-transplant recurrence-free survival were not different compared to non-NAFLD patients.

Oral Microbiome Alterations and SARS-CoV-2 Saliva Viral Load in Patients with COVID-19.

Bacterial-viral interactions in saliva have been associated with morbidity and mortality for respiratory viruses such as influenza and SARS-CoV. However, such transkingdom relationships during SARS-CoV-2 infection are currently unknown. Here, we aimed to elucidate the relationship between saliva microbiota and SARS-CoV-2 in a cohort of newly hospitalized COVID-19 patients and controls. We used 16S rRNA sequencing to compare microbiome diversity and taxonomic composition between COVID-19 patients (n = 53) and controls (n = 59) and based on saliva SARS-CoV-2 viral load as measured using reverse transcription PCR (RT-PCR). The saliva microbiome did not differ markedly between COVID-19 patients and controls. However, we identified significant differential abundance of numerous taxa based on saliva SARS-CoV-2 viral load, including multiple species within Streptococcus and Prevotella. IMPORTANCE Alterations to the saliva microbiome based on SARS-CoV-2 viral load indicate potential biologically relevant bacterial-viral relationships which may affect clinical outcomes in COVID-19 disease.

COVID-19 and Effect on Liver Transplant.

PURPOSE OF REVIEW: The Coronavirus disease-2019 (COVID-19) pandemic has significantly impacted all aspects of liver transplantation. We reviewed the literature regarding COVID-19 clinical outcomes, treatment, and vaccination of liver transplant candidates and recipients. RECENT FINDINGS: Patients with chronic liver disease, especially with cirrhosis, have higher morbidity and mortality from COVID-19 than patients without liver disease. Increased mortality has not been consistently seen in liver transplant recipients, in whom severe disease is more strongly associated advanced age and medical comorbidities, rather than with transplant-specific factors. While several targeted COVID-19 therapies have reported hepatotoxicity, these therapies may be safe and effective in patients with liver disease and liver transplant recipients. Questions remain regarding whether SARS-CoV-2 can be transmitted via the donor liver and whether transplant is safe in patients and/or donors with recent or active COVID-19. SUMMARY: COVID-19 has significantly affected the care of liver transplant candidates and recipients. Guidelines for the safe practice of liver transplantation are rapidly evolving, and current recommendations are discussed.

Coronavirus Disease 2019 and Liver Transplantation: Lessons from the First Year of the Pandemic.

Over the last year, the novel coronavirus disease 2019 (COVID-19) has continued to spread across the globe, causing significant morbidity and mortality among transplantation candidates and recipients. Patients with end-stage liver disease awaiting liver transplantation and patients with a history of liver transplantation represent vulnerable populations, especially given the high rates of associated medical comorbidities in these groups and their immunosuppressed status. In addition, concerns surrounding COVID-19 risk in this patient population have affected rates of transplantation and general transplantation practices. Here, we explore what we have learned about the impact of COVID-19 on liver transplantation candidates and recipients as well as the many key knowledge gaps that remain.

Prevalence and Risk Factors for Inappropriate Continuation of Proton Pump Inhibitors After Discharge From the Intensive Care Unit.

OBJECTIVE: To determine the prevalence and risk factors for inappropriate discharge on proton pump inhibitor (PPI) therapy started in the intensive care unit (ICU) for stress ulcer prophylaxis. PATIENTS AND METHODS: This was a retrospective cohort study of adults initiated on treatment with a PPI in any of 9 affiliated ICUs from January 1, 2014, to December 31, 2018. Patients were excluded if they had an appropriate long-term PPI indication. Logistic regression modeling was used to identify characteristics associated with discharge on treatment with an inappropriate PPI. RESULTS: Of 24,751 patients admitted to an ICU, 4127 were initiated on treatment with a new PPI, with 2467 (60%) lacking a long-term PPI indication. Of these 2467, a total of 1122 (45%) were continued on PPI therapy after transfer to the floor and 668 (27%) were discharged on PPI therapy. On multivariable analysis, risk factors for inappropriate discharge on PPI therapy included having an upper endoscopy (adjusted odds ratio [aOR], 1.70; 95% CI, 1.08-2.66), admission to the surgical compared with medical ICU (aOR, 2.03; 95% CI, 1.32-3.10), and discharge to a nursing home or rehabilitation facility (aOR, 1.43; 95% CI, 1.04-1.96; and aOR, 2.29; 95% CI, 1.62-3.24, respectively). CONCLUSION: Among patients started on treatment with a PPI in the ICU without an indication for outpatient PPI use, 27% (668 of 2467) were nonetheless discharged on PPI therapy. Medically complex and surgical ICU patients are at increased risk for receiving PPIs without appropriate documented indications, and careful review of medication lists at discharge should occur in these high-risk groups.

Hepatocellular Carcinoma in Hispanic Patients: Trends and Outcomes in a Large United States Cohort.

Hepatocellular carcinoma (HCC) has a strong racial and ethnic association, with Hispanic patients having a higher incidence and mortality. However, there are limited data regarding clinical features and outcomes. This study includes Hispanic and non-Hispanic White patients with HCC diagnosed between January 2000 and June 2014 from five United States academic medical centers. The chi-square test for categorical variables and analysis of variance for continuous variables were used for statistical analysis, with two-tailed P < 0.05 considered statistically significant. Of 5,327 patients, 4,217 met inclusion criteria, of whom 12.3% were Hispanic patients. Compared to their non-Hispanic White counterparts, Hispanic patients were older at age of diagnosis (mean ± SD, 64.2 ± 10.9 vs. 61.9 ± 10.5 years; P < 0.0001), with higher body mass index (29.6 ± 6.5 vs. 28.8 ± 5.9 kg/m2; P = 0.01), and were more likely to have diabetes and hypertension. Hispanic patients had significantly more nonalcoholic fatty liver disease and alcohol-related liver disease (both P < 0.0001). Hispanic patients presented with larger tumors, more advanced stage disease, and increased rates of macrovascular invasion and extrahepatic spread. HCCs in Hispanic patients were less likely to be within Milan criteria (26% vs. 38%; P < 0.0001) and were less likely to be treated with resection (9% vs. 13%; P = 0.03) or transplantation (8% vs. 19%; P < 0.0001). Hispanic patients had a median overall survival of 1.4 years (95% confidence interval [CI], 1.22-1.56), which was similar to that of non-Hispanic White patients (1.3 years; 95% CI, 1.26-1.41; P = 0.07). Conclusion: Hispanic patients with HCC were more likely to have metabolic risk factors for chronic liver disease, including obesity. Despite diagnosis at more advanced stages with less curative intervention than non-Hispanic White patients, median overall survival was similar between groups.

Non-alcoholic fatty liver disease (NAFLD) in non-obese individuals.

Individuals with non-alcoholic fatty liver disease (NAFLD) who lack classical risk factors also have the ability to develop nonalcoholic steatohepatitis (NASH) and progression to more advanced liver disease. The pathophysiology and risk factors for the development of NAFLD in non-obese persons are not fully understood but seem to be closely related to insulin resistance, atherogenic dyslipidaemia and alterations in body composition, with some patients harbouring predisposing genetic polymorphisms. In normal-weight individuals, also called 'lean', there is limited potential for effective lifestyle change in disease management. Additionally, biological mechanisms underlying the development of NASH in non-obese individuals may reveal novel targets for intervention. In this review, the authors discuss the clinical, histological and genetic features and risk factors for non-obese NAFLD and highlight gaps in knowledge and areas for future research.

Acute Liver Injury in COVID-19: Prevalence and Association with Clinical Outcomes in a Large U.S. Cohort.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) has been associated with acute liver injury (ALI) manifested by increased liver enzymes in reports worldwide. Prevalence of liver injury and associated clinical characteristics are not well defined. We aim to identify the prevalence of and risk factors for development of COVID-19-associated ALI in a large cohort in the United States. APPROACH AND RESULTS: In this retrospective cohort study, all patients who underwent SARS-CoV-2 testing at three hospitals in the NewYork-Presbyterian network were assessed. Of 3,381 patients, 2,273 tested positive and had higher initial and peak alanine aminotransferase (ALT) than those who tested negative. ALI was categorized as mild if ALT was greater than the upper limit of normal (ULN) but <2 times ULN, moderate if ALT was between 2 and 5 times the ULN, and severe if ALT was >5 times the ULN. Among patients who tested positive, 45% had mild, 21% moderate, and 6.4% severe liver injury (SLI). In multivariable analysis, severe ALI was significantly associated with elevated inflammatory markers, including ferritin (odds ratio [OR], 2.40; P < 0.001) and interleukin-6 (OR, 1.45; P = 0.009). Patients with SLI had a more severe clinical course, including higher rates of intensive care unit admission (69%), intubation (65%), renal replacement therapy (RRT; 33%), and mortality (42%). In multivariable analysis, peak ALT was significantly associated with death or discharge to hospice (OR, 1.14; P = 0.044), controlling for age, body mass index, diabetes, hypertension, intubation, and RRT. CONCLUSIONS: ALI is common in patients who test positive for SARS-CoV-2, but is most often mild. However, among the 6.4% of patients with SLI, a severe disease course should be anticipated.

Gender Matters: Characteristics of Hepatocellular Carcinoma in Women From a Large, Multicenter Study in the United States.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, affecting men to women at a ratio of about 4:1. Risk factors, characteristics, and outcomes for HCC in women in the United States remain poorly understood; therefore, we aim to explore gender differences further. METHODS: Patients diagnosed with HCC between January 2000 and June 2014 at 5 large centers were identified. Clinical information, tumor characteristics, and survival data were extracted manually. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS: Of 5,327 patients with HCC in our cohort, 1,203 (22.6%) were women. There were important differences in the underlying etiology of liver disease between the 2 genders (P < 0.0001): women had a significantly higher frequency of nonalcoholic fatty liver disease (23% vs 12%) and lower frequency of alcoholic liver disease (5% vs 15%). The proportion of noncirrhotic HCC was significantly higher among women (17% vs 10%, P < 0.0001). Women had less-advanced HCC at presentation by tumor, node, metastasis staging (P < 0.0001) and a higher proportion within Milan criteria (39% vs 35%, P = 0.002). Women had a greater overall survival (2.5 ± 2.9 years vs 2.2 ± 2.7 years, P = 0.0031). DISCUSSION: The frequency of underlying nonalcoholic fatty liver disease and noncirrhotic HCC were significantly higher in women than men in this large cohort. Women presented with less-advanced HCC and had a greater overall survival. Further investigation is warranted to explore potential mechanisms and implications for these gender differences, especially with noncirrhotic HCC (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B535).