Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening.

BACKGROUND: A next-generation multitarget stool DNA test, including assessments of DNA molecular markers and hemoglobin level, was developed to improve the performance of colorectal cancer screening, primarily with regard to specificity. METHODS: In a prospective study, we evaluated a next-generation multitarget stool DNA test in asymptomatic adults 40 years of age or older who were undergoing screening colonoscopy. The primary outcomes were sensitivity of the test for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions). Advanced precancerous lesions included one or more adenomas or sessile serrated lesions measuring at least 1 cm in the longest dimension, lesions with villous histologic features, and high-grade dysplasia. Secondary objectives included the quantification of sensitivity for advanced precancerous lesions and specificity for nonneoplastic findings or negative colonoscopy and comparison of sensitivities for colorectal cancer and advanced precancerous lesions between the multitarget stool DNA test and a commercially available fecal immunochemical test (FIT). RESULTS: Of 20,176 participants, 98 had colorectal cancer, 2144 had advanced precancerous lesions, 6973 had nonadvanced adenomas, and 10,961 had nonneoplastic findings or negative colonoscopy. With the next-generation test, sensitivity for colorectal cancer was 93.9% (95% confidence interval [CI], 87.1 to 97.7), and specificity for advanced neoplasia was 90.6% (95% CI, 90.1 to 91.0). Sensitivity for advanced precancerous lesions was 43.4% (95% CI, 41.3 to 45.6), and specificity for nonneoplastic findings or negative colonoscopy was 92.7% (95% CI, 92.2 to 93.1). With the FIT, sensitivity was 67.3% (95% CI, 57.1 to 76.5) for colorectal cancer and 23.3% (95% CI, 21.5 to 25.2) for advanced precancerous lesions; specificity was 94.8% (95% CI, 94.4 to 95.1) for advanced neoplasia and 95.7% (95% CI, 95.3 to 96.1) for nonneoplastic findings or negative colonoscopy. As compared with FIT, the next-generation test had superior sensitivity for colorectal cancer (P<0.001) and for advanced precancerous lesions (P<0.001) but had lower specificity for advanced neoplasia (P<0.001). No adverse events occurred. CONCLUSIONS: The next-generation multitarget stool DNA test showed higher sensitivity for colorectal cancer and advanced precancerous lesions than FIT but also showed lower specificity. (Funded by Exact Sciences; BLUE-C ClinicalTrials.gov number, NCT04144738.).

Stool-Based Colorectal Cancer Screening Test Performance Characteristics in Those With and Without Hemorrhoids.

Objective: To evaluate the effect of hemorrhoids on noninvasive stool test performance for colorectal cancer (CRC) screening. Patients and Methods: We conducted a retrospective cohort study of test characteristics for the fecal immunochemical test (FIT) and the multitarget stool DNA (mt-sDNA) test, on the basis of hemorrhoid status, recorded at the time of colonoscopy, among patients enrolled in the pivotal prospective study for mt-sDNA that was conducted from June 2011, to May 2013. Test characteristics (sensitivity, specificity, positive, and negative predictive values) for FIT and mt-sDNA (performed < 90 days before colonoscopy) were stratified by the presence of hemorrhoids and compared. Results: Hemorrhoids were found in 51.7% (5163 of 9989) of the study cohort. Across all test characteristics, there were no statistically significant differences for FIT or mt-sDNA when stratified by hemorrhoid status. Analysis revealed mt-sDNA sensitivity of 44% and 41% for advanced precancerous lesions in nonhemorrhoidal and hemorrhoid patients, respectively (P=.41). The FIT sensitivity among the same lesion category was 24.9% in patients without hemorrhoids and 22.8% in those with hemorrhoids (P=.48). The mt-sDNA specificity was 86.4% in patients without hemorrhoids vs 87.7% in those with hemorrhoids (P=.67), although FIT specificity was 95.0% among patients without hemorrhoids vs 94.7% in those with hemorrhoids (P=.44). Conclusion: The presence of asymptomatic hemorrhoids did not adversely affect test performance in this large clinical study. These findings suggest that in the absence of overt gastrointestinal bleeding, FIT and mt-sDNA are options for CRC screening, irrespective of hemorrhoid status. Trial Registration: clinicaltrials.gov Identifier: NCT01397747.

Adaptive servo-ventilation and mortality in patients with systolic heart failure and central sleep apnea: a single-center experience.

BACKGROUND: Central sleep apnea (CSA) is associated with increased mortality and morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Treatment of CSA with a certain type of adaptive servo-ventilation (ASV) device that targets minute ventilation (ASVmv) was found to be harmful in these patients. A newer generation of ASV devices that target peak flow (ASVpf) is presumed to have different effects on ventilation and airway patency. We analyzed our registry of patients with HFrEF-CSA to examine the effect of exposure to ASV and role of each type of ASV device on mortality. METHODS: This is a retrospective cohort study in patients with HFrEF and CSA who were treated with ASV devices between 2008 and 2015 at a single institution. Mortality data were collected through the institutional data honest broker. Usage data were obtained from vendors' and manufacturers' servers. Median follow-up was 64 months. RESULTS: The registry included 90 patients with HFrEF-CSA who were prescribed ASV devices. Applying a 3-h-per-night usage cutoff, we found a survival advantage at 64 months for those who used the ASV device above the cutoff (n = 59; survival 76%) compared to those who did not (n = 31; survival 49%; hazard ratio 0.44; CI 95%, 0.20 to 0.97; P = 0.04). The majority (n = 77) of patients received ASVpf devices with automatically adjusting end-expiratory pressure (EPAP) and the remainder (n = 13) received ASVmv devices mostly with fixed EPAP (n = 12). There was a trend towards a negative correlation between ASVmv with fixed EPAP and survival. CONCLUSION: In this population of patients with HFrEF and CSA, there was no evidence that usage of ASV devices was associated with increased mortality. However, there was evidence of differential effects of type of ASV technology on mortality.

Clinical and financial impact of sleep disordered breathing on heart failure admissions.

BACKGROUND: The impact of sleep disordered breathing (SDB) on heart failure (HF) is increasingly recognized. However, limited data exist in support of quantification of the clinical and financial impact of SDB on HF hospitalizations. METHODS: A sleep-heart registry included all patients who underwent inpatient sleep testing during hospitalization for HF at a single cardiac center. Readmission data and actual costs of readmissions were obtained from the institutional honest broker. Patients were classified based on the inpatient sleep study as having no SDB, obstructive sleep apnea (OSA), or central sleep apnea (CSA). Cumulative cardiac readmission rates and costs through 3 and 6 months post-discharge were calculated. Unadjusted and adjusted (age, sex, body mass index, and left ventricular ejection fraction) modeling of cost was performed. RESULTS: The cohort consisted of 1547 patients, 393 (25%) had no SDB, 438 (28%) had CSA, and 716 (46%) had OSA. Within 6 months of discharge, 195 CSA patients (45%), 264 OSA patients (37%), and 109 no SDB patients (28%) required cardiovascular readmissions. Similarly, 3- and 6-month mortality rates were higher in both SDB groups than those with no SDB. Both unadjusted and adjusted readmission costs were higher in the OSA and CSA groups compared to no SDB group at 3 and 6 months post-discharge with the CSA and OSA group costs nearly double (~ $16,000) the no SDB group (~ $9000) through 6 months. INTERPRETATION: Previously undiagnosed OSA and CSA are common in patients hospitalized with HF and are associated with increased readmissions rate and mortality.

Outcomes of Nonvariceal Upper Gastrointestinal Bleeding in Patients With Cirrhosis: A National Analysis.

GOALS: We sought to evaluate hospital outcomes of cirrhosis patients with nonvariceal upper gastrointestinal bleeding (NVUGIB). BACKGROUND: NVUGIB is common in patients with cirrhosis. However, national outcome studies of these patients are lacking. STUDY: We utilized the 2014 Nationwide Readmission Database to evaluate NVUGIB in patients with cirrhosis, further stratified as no cirrhosis (NC), compensated cirrhosis (CC), or decompensated cirrhosis (DC). Validated International Classification of Diseases, Ninth Revision, Clinical Modification codes captured diagnoses and interventions. Outcomes included 30-day readmission rates, index admission mortality rates, health care utilization, and predictors of readmission and mortality using multivariable regression analysis. RESULTS: Overall, 13,701 patients with cirrhosis were admitted with NVUGIB. The 30-day readmission rate was 20.8%. Patients with CC were more likely to undergo an esophagogastroduodenoscopy (EGD) within 1 calendar day of admission (74.1%) than patients with DC (67.9%) or NC (69.4%). Patients with DC had longer hospitalizations (4.1 d) and higher costs of care ($11,834). The index admission mortality rate was higher in patients with DC (6.2%) than in patients with CC (1.7%, P <0.001) or NC (1.4%, P <0.001). Predictors of 30-day readmission included performing an EGD >1 calendar day from admission (OR: 1.21; 95% CI, 1.00 to 1.46) and DC (OR: 1.78; 95% CI, 1.54 to 2.06). DC was a predictor of index admission mortality (OR: 3.68; 95% CI, 2.67 to 5.05). CONCLUSIONS: NVUGIB among patients with DC is associated with higher readmission rates, mortality rates, and health care utilization compared with patients with CC and NC. Early EGD is a modifiable variable associated with reduced readmission rates. Early identification of high-risk patients and adherence to guidelines may improve clinical outcomes.

Comparison of a multitarget blood test to ultrasound and alpha-fetoprotein for hepatocellular carcinoma surveillance: Results of a network meta-analysis.

Ultrasound-based surveillance has suboptimal sensitivity for early detection of hepatocellular carcinoma (HCC) in patients with cirrhosis. There are several emerging alternatives, including a novel multitarget HCC blood test (Mt-HBT). We compared performance of mt-HBT against ultrasound with or without alpha-fetoprotein (AFP) for early HCC detection in patients with cirrhosis. Per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, two reviewers searched PubMed, Cochrane, Embase, and clinicaltrials.gov databases from January 1990 through December 2020 to identify studies reporting sensitivity and/or specificity of ultrasound and AFP for overall and early stage HCC detection in patients with cirrhosis. Mt-HBT diagnostic performance was derived from a clinical validation study. A network meta-analysis model was built for comparative assessment, and pooled estimates of sensitivity at a fixed specificity were estimated based on Bayesian binormal receiver operating characteristic models for each modality. Forty-one studies (comprising 62,517 patients with cirrhosis) met inclusion criteria. Ultrasound-alone sensitivity was 51.6% (95% credible interval [CrI], 43.3%-60.5%) for early stage HCC detection, which increased with the addition of AFP to 74.1% (95% CrI, 62.6%-82.4%); however, this was offset by decreased specificity (87.9% vs. 83.9%, respectively). With specificity fixed at 90%, mt-HBT sensitivity for early stage HCC detection was higher than ultrasound alone (18.2%; 95% CrI, 0.2%-37.7%) and similar to ultrasound with AFP (-3.3%; 95% CrI, -22.3%-17.4%). Pairwise posterior probabilities suggested a preference for mt-HBT over ultrasound alone in 97.4% of cases but only 36.3% of cases versus ultrasound with AFP. Conclusion: A blood-based mt-HBT has higher sensitivity than ultrasound alone for early stage HCC detection but similar sensitivity compared to ultrasound and AFP. Mt-HBT could be a comparable alternative to existing methods for HCC surveillance in patients who are at risk.

EARLY INITIATION OF VASOPRESSIN REDUCES ORGAN FAILURE AND MORTALITY IN SEPTIC SHOCK.

ABSTRACT: Purpose : The aim of the study is to determine whether initiating vasopressin earlier in septic shock reduces organ dysfunction and in-hospital all-cause mortality. Methods : This multicenter, retrospective, cohort study evaluated patients admitted to the medical intensive care unit between October 2011 and August 2018 with septic shock who received vasopressin within 48 hours of shock onset. The primary composite outcome was the proportion of patients with a change in the Sequential Organ Failure Assessment score greater than 3 from baseline to 72 hours after initiation of vasopressin and/or in-hospital all-cause mortality. Secondary outcomes included time to hemodynamic stability, acute kidney injury, and intensive care unit length of stay. Results : A total of 385 patients included in the final evaluation with a mean Acute Physiology and Chronic Health Evaluation II score of 31 and a mean baseline Sequential Organ Failure Assessment score of 13. Median time to initiation of vasopressin after norepinephrine was 7.3 hours. The primary composite outcome was significantly reduced in patients who had vasopressin initiated earlier in septic shock (odds ratio = 1.08, 95% confidence interval = 1.03-1.13, P < 0.001). After controlling for baseline data in a multivariable regression model the primary outcome remained statistically significant (odds ratio = 1.04, 95% confidence interval = 1.02-1.07, P = 0.001). Conclusions : Early initiation of vasopressin in septic shock may reduce the risk of in-hospital all-cause mortality and/or organ dysfunction.

Incidence and Risk Factors for New-Onset Diabetes Mellitus After Surgical Resection of Pancreatic Cystic Lesions: A MarketScan Study.

OBJECTIVES: There is a paucity of literature evaluating new-onset diabetes mellitus (NODM) after resection of pancreatic cystic lesions (PCLs). We sought to characterize the incidence and risk factors associated with NODM after partial pancreatectomy for PCLs. METHODS: We utilized the IBM MarketScan Database (2012-2018) to identify all nondiabetic adults who underwent partial pancreatectomy for PCLs. Patients with any other pancreatic disease were excluded. We performed Kaplan-Meier analysis and multivariable Cox proportional hazards regression to define the incidence and risk factors of postoperative NODM. RESULTS: Among 311 patients, the overall risk (95% confidence interval) of NODM was 9.1% (6.3-12.9%), 15.1% (11.3-20.2%), and 20.2% (15.3-26.4%) at 6, 12 and 24 months, respectively. Multivariable analysis (adjusted hazard ratio; 95% confidence interval) revealed that older age (1.97; 1.04-3.72; 55-64 vs 18-54 years), obesity (2.63; 1.35-5.12), hypertension (1.79; 1.01-3.17), and cardiovascular disease (2.54; 1.02-6.28) were independent predictors of NODM. Rates of NODM were similar after distal pancreatectomy versus pancreaticoduodenectomy. CONCLUSIONS: Within 2 years, 1 in 5 patients without any other pancreatic disease will develop NODM after partial pancreatectomy for PCLs. Those with advanced age, metabolic syndrome features, and/or cardiovascular disease may benefit from preoperative counseling and intensive postoperative monitoring, education, and treatment for diabetes mellitus.

Cystic fibrosis patients on cystic fibrosis transmembrane conductance regulator modulators have a reduced incidence of cirrhosis.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators significantly improve pulmonary function in patients with cystic fibrosis (CF) but the effect on hepatobiliary outcomes remains unknown. We hypothesized that CF patients on CFTR modulators would have a decreased incidence of cirrhosis compared to patients not on CFTR modulators or on ursodiol. AIM: To investigate the effect of CFTR modulators on the development of cirrhosis in patients with CF. METHODS: A retrospective analysis was performed using Truven MarketScan from January 2012 through December 2017 including all patients with a diagnosis of CF. Patients were excluded if they underwent a liver transplantation or if they had other etiologies of liver disease including viral hepatitis or alcohol use. Subjects were grouped by use of CFTR modulators, ursodiol, dual therapy, or no therapy. The primary outcome was development of cirrhosis. Kaplan-Meier curves estimated the incidence of cirrhosis and log-rank tests compared incidence curves between treatment groups. RESULTS: A total of 7201 patients were included, of which 955 (12.6%) used a CFTR modulator, 529 (7.0%) used ursodiol, 105 (1.4%) used combination therapy, and 5612 (74.3%) used neither therapy. The incidence of cirrhosis was 0.1% at 1 year and 0.7% at 4 years in untreated patients, 5.9% and 10.1% in the Ursodiol group, and 1.0% and 1.0% in patients who received both therapies. No patient treated with CFTR modulators alone developed cirrhosis. Patients on CFTR modulators alone had lower cirrhosis incidence than untreated patients (P = 0.05), patients on Ursodiol (P < 0.001), and patients on dual therapy (P = 0.003). The highest incidence of cirrhosis was found among patients treated with Ursodiol alone, compared to untreated patients (P < 0.001) or patients on Ursodiol and CFTR modulators (P = 0.01). CONCLUSION: CFTR modulators are associated with a reduction in the incidence of cirrhosis compared to other therapies in patients with CF.

A Comparison of Machine Learning Methods and Conventional Logistic Regression for the Prediction of In-Hospital Mortality in Acute Biliary Pancreatitis.

OBJECTIVES: For population databases, multivariable regressions are established analytical standards. The utilization of machine learning (ML) in population databases is novel. We compared conventional statistical methods and ML for predicting mortality in biliary acute pancreatitis (biliary AP). METHODS: Using the Nationwide Readmission Database (2010-2014), we identified patients (age ≥18 years) with admissions for biliary AP. These data were randomly divided into a training (70%) and test set (30%), stratified by the outcome of mortality. The accuracy of ML and logistic regression models in predicting mortality was compared using 3 different assessments. RESULTS: Among 97,027 hospitalizations for biliary AP, mortality rate was 0.97% (n = 944). Predictors of mortality included severe AP, sepsis, increasing age, and nonperformance of cholecystectomy. Assessment metrics for predicting the outcome of mortality, the scaled Brier score (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.16-0.33 vs 0.18; 95% CI, 0.09-0.27), F-measure (OR, 43.4; 95% CI, 38.3-48.6 vs 40.6; 95% CI, 35.7-45.5), and the area under the receiver operating characteristic (OR, 0.96; 95% CI, 0.94-0.97 vs 0.95; 95% CI, 0.94-0.96) were comparable between the ML and logistic regression models, respectively. CONCLUSIONS: For population databases, traditional multivariable analysis is noninferior to ML-based algorithms in predictive modeling of hospital outcomes for biliary AP.

Pathways of Microcirculatory Endothelial Dysfunction in Obstructive Sleep Apnea: A Comprehensive Ex Vivo Evaluation in Human Tissue.

BACKGROUND: The mechanism and markers of cardiovascular disease (CVD) in obstructive sleep apnea (OSA) remain unknown. The microcirculation is the site of early changes in OSA patients who are free of CVD risk. METHODS: Patients with newly diagnosed moderate to severe OSA (n = 7) were studied before and 12 weeks after intensive treatment with continuous positive airway pressure (CPAP), along with weight and age matched controls (n = 7). Microcirculatory vessels were isolated from gluteal biopsies and changes in critical functional genes were measured. RESULTS: The following genes changed after 12 weeks of intensive CPAP therapy in the microcirculatory vessels: angiotensin receptor type 1 (AGTR-1) (11.6 (3.4) to 6 (0.8); P = 0.019); NADPH oxidase (NOX4) (0.85 (0.02) to 0.79 (0.11); P = 0.016); and dimethylarginine dimethylaminohydrolase (DDAH 1) (1 (0.31) to 0.55 (0.1); P = 0.028). Despite decreased nitric oxide (NO) availability as measured indirectly through brachial artery flow-mediated dilation, endothelial NO synthase (NOS3) did not change with CPAP. Other disease markers of OSA that changed with treatment in the microcirculation were endothelin, hypoxia inducible factor 1a, nuclear factor kappa B, interleukin-8, and interleukin-6. CONCLUSIONS: In this ex vivo evaluation of the microcirculation of patients with OSA and no CVD risk, several pathways of CVD were activated supporting that OSA independently induces microcirculatory endothelial dysfunction and serving as disease-specific markers for future pharmacological targeting of OSA-related CVD risk. The findings support the role of renin-angiotensin activation and endothelial oxidative stress in the decreased microcirculatory NO availability in OSA.

The Impact of Bariatric Surgery on Diverticulitis Outcomes and Risk of Recurrent Hospitalizations in Adults with Clinically Severe Obesity.

PURPOSE: Clinically severe obesity (SO) is a known risk factor for worsened outcomes and recurrence of acute diverticulitis. Paucity of data exist on outcomes of diverticulitis after bariatric surgery. METHODS: The Nationwide Readmissions Database was queried for diverticulitis hospitalizations between the years 2010 and 2014. We restricted analysis to patients with SO and those who had bariatric surgery (BRS). Outcomes of mortality, surgical events, and recurrent diverticulitis admissions were compared using multivariable analysis and one-to-one propensity score matching. RESULTS: Among 52,274 diverticulitis admissions, 91.2% (47,694) patients had SO and 8.8% (4580) had prior BRS. Patients with SO had higher odds of suffering mortality on index diverticulitis admission when compared to those with prior BRS [adjusted odds ratio (aOR): 10.55; 95%CI 1.45,76.75]. Patients with SO were also more likely to undergo emergency surgery (aOR: 1.71; 95%CI 1.25,2.34) and colectomy (aOR: 1.45; 95%CI 1.26,1.68). Rates of recurrent diverticulitis readmissions within 30 days and 6 months were also higher in patients with SO compared to BRS patients (aOR: 7.94; 95%CI 1.09,57.83 and aOR: 1.98; 95%CI 1.14,3.43, respectively). Propensity score matching confirmed our findings of increased rates of mortality (OR: 17.28; 95%CI 2.02,147.6), recurrent diverticulitis, and worsened surgical outcomes within 30 days in patients with SO compared to BRS. CONCLUSION: This study is first to show improved outcomes and less recurrent hospitalizations for diverticulitis after bariatric surgery compared to patients with clinically severe obesity. Further studies are needed to understand mechanisms leading to this improvement and the role of weight loss in prevention of severe diverticulitis.

Call for action: Increased healthcare utilization with growing use of percutaneous cholecystectomy tube over initial cholecystectomy in cirrhotics.

BACKGROUND: Acute calculous cholecystitis (ACC) is frequently seen in cirrhotics, with some being poor candidates for initial cholecystectomy. Instead, these patients may undergo percutaneous cholecystostomy tube (PCT) placement. We studied the healthcare utilization and predictors of cholecystectomy and PCT in patients with ACC. METHODS: The National Database was queried to study all cirrhotics and non-cirrhotics with ACC between 2010-2014 who underwent initial PCT (with or without follow-up cholecystectomy) or cholecystectomy. Cirrhotic patients were divided into compensated and decompensated cirrhosis. Independent predictors and outcomes of initial PCT and failure to undergo subsequent cholecystectomy were studied. RESULTS: Out of 919 189 patients with ACC, 13 283 (1.4%) had cirrhosis. Among cirrhotics, cholecystectomy was performed in 12 790 (96.3%) and PCT in the remaining 493 (3.7%). PCT was more frequent in cirrhotics (3.7%) than in non-cirrhotics (1.4%). Multivariate analyses showed increased early readmissions [odds ratio (OR) = 2.12, 95% confidence interval (CI): 1.43-3.13, P < 0.001], length of stay (effect ratio = 1.39, 95% CI: 1.20-1.61, P < 0.001), calendar-year hospital cost (effect ratio = 1.34, 95% CI: 1.28-1.39, P < 0.001) and calendar-year mortality (hazard ratio = 1.89, 95% CI: 1.07-3.29, P = 0.030) in cirrhotics undergoing initial PCT compared to cholecystectomy. Decompensated cirrhosis (OR = 2.25, 95% CI: 1.67-3.03, P < 0.001) had the highest odds of getting initial PCT. Cirrhosis, regardless of compensated (OR = 0.56, 95% CI: 0.34-0.90, P = 0.020) or decompensated (OR = 0.28, 95% CI: 0.14-0.59, P < 0.001), reduced the chances of getting a subsequent cholecystectomy. CONCLUSIONS: Cirrhotic patients undergo fewer cholecystectomy incurring initial PCT instead. Moreover, the rates of follow-up cholecystectomy are lower in cirrhotics. Increased healthcare utilization is seen with initial PCT amongst cirrhotic patients. This situation reflects suboptimal management of ACC in cirrhotics and a call for action.

Validation of a Novel Multitarget Blood Test Shows High Sensitivity to Detect Early Stage Hepatocellular Carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although biannual ultrasound surveillance with or without α-fetoprotein (AFP) testing is recommended for at-risk patients, sensitivity for early stage HCC, for which potentially curative treatments exist, is suboptimal. We conducted studies to establish the multitarget HCC blood test (mt-HBT) algorithm and cut-off values and to validate test performance in patients with chronic liver disease. METHODS: Algorithm development and clinical validation studies were conducted with participants in an international, multicenter, case-control study. Study subjects had underlying cirrhosis or chronic hepatitis B virus; HCC cases were diagnosed per the American Association for the Study of Liver Diseases criteria and controls were matched for age and liver disease etiology. Whole blood and serum were shipped to a central laboratory and processed while blinded to case/control status. An algorithm was developed for the mt-HBT, which incorporates methylation biomarkers (HOXA1, TSPYL5, and B3GALT6), AFP, and sex. RESULTS: In algorithm development, with 136 HCC cases (60% early stage) and 404 controls, the mt-HBT showed 72% sensitivity for early stage HCC at 88% specificity. Test performance was validated in an independent cohort of 156 HCC cases (50% early stage) and 245 controls, showing 88% overall sensitivity, 82% early stage sensitivity, and 87% specificity. Early stage sensitivity in clinical validation was significantly higher than AFP at 20 ng/mL or greater (40%; P < .0001) and GALAD (gender, age, Lens culinaris agglutinin-reactive AFP, AFP, and des-γ-carboxy-prothrombin score) of -0.63 or greater (71%; P = .03), although AFP and GALAD at these cut-off values had higher specificities (100% and 93%, respectively). CONCLUSIONS: The mt-HBT may significantly improve early stage HCC detection for patients undergoing HCC surveillance, a critical step to increasing curative treatment opportunities and reducing mortality. ClinicalTrials.gov number NCT03628651.

Weekly vs. 3-weekly paclitaxel, carboplatin, and cetuximab (PCC) in recurrent/metastatic head and neck cancer.

The combination of paclitaxel, carboplatin and cetuximab (PCC) is efficacious in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). The current study assessed the incidence of grade 3/4 (G3/4) toxicity for patients receiving weekly or 3-weekly PCC for R/M SCCHN. The present single-institution, retrospective analysis included 74 patients who received weekly [paclitaxel 45 mg/m2 and carboplatin area under the curve (AUC), 1.5] or 3-weekly (paclitaxel 175 mg/m2 and carboplatin AUC, 5) PCC. For each regimen, cetuximab was administered at 400 mg/m2 for the first week, after which the dosage was reduced to 250 mg/m2 weekly until disease progression occurred. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v4.03, and response to therapy was determined using computed tomography every 12 weeks. The results revealed that 26 patients (35%) received weekly PCC and 48 patients (65%) received PCC every 3 weeks. A total of 6 (25%) patients receiving weekly PCC experienced G3/4 toxicity compared with 30 (66%) patients that received PCC every 3 weeks (odds ratio, 0.18; 95% confidence interval, 0.05-0.64; P=0.01). The most common G3/4 side effects were neutropenia (8 vs. 53%), anemia (15 vs. 32%) and fatigue (3 vs. 10%). The incidence of G3/4 toxicity or any grade toxicity requiring dose modification or discontinuation was 74 vs. 77%, respectively. The overall response rate was 39% with weekly PCC compared with 27% in those receiving PCC every 3 weeks. The 1-year progression-free and overall survival rates were 27 and 46% for patients receiving weekly PCC, and 13 and 44% for patients receiving PCC every 3 weeks. Weekly PCC had a reduced risk of G3/4 toxicity when compared with PCC administered every 3 weeks. Considering the improved tolerance of weekly PCC, this regimen should be considered for older patients and patients being treated with second-line chemotherapy.

Cystic Fibrosis Transmembrane Conductance Regulator Modulator Use Is Associated With Reduced Pancreatitis Hospitalizations in Patients With Cystic Fibrosis.

INTRODUCTION: Acute pancreatitis (AP) occurs among patients with pancreas-sufficient cystic fibrosis (PS-CF) but is reportedly less common among patients with pancreas-insufficient cystic fibrosis (PI-CF). The incidence of AP may be influenced by cystic fibrosis transmembrane conductance regulator (CFTR) modulator use. We hypothesized that CFTR modulators would reduce AP hospitalizations, with the greatest benefit in PS-CF. METHODS: MarketScan (2012-2018) was queried for AP hospitalizations and CFTR modulator use among patients with CF. Multivariable Poisson models that enabled crossover between CFTR modulator treatment groups were used to analyze the rate of AP hospitalizations on and off therapy. Pancreas insufficiency was defined by the use of pancreas enzyme replacement therapy. RESULTS: A total of 10,417 patients with CF were identified, including 1,795 who received a CFTR modulator. AP was more common in PS-CF than PI-CF (2.9% vs 0.9%, P = 0.007). Overall, the observed rate ratio of AP during CFTR modulator use was 0.33 (95% confidence interval [CI] 0.10, 1.11, P = 0.07) for PS-CF and 0.38 (95% CI 0.16, 0.89, P = 0.03) for PI-CF, indicating a 67% and 62% relative reduction in AP hospitalizations, respectively. In a subset analysis of 1,795 patients who all had some CFTR modulator use, the rate ratio of AP during CFTR modulator use was 0.36 (95% CI 0.13, 1.01, P = 0.05) for PS-CF and 0.53 (95% CI 0.18, 1.58, P = 0.26) for PI-CF. DISCUSSION: CFTR modulator use is associated with a reduction in AP hospitalizations among patients with CF. These observational data support the prospective study of CFTR modulators to reduce AP hospitalizations among patients with CF.

Early toxicity and clinical outcomes after chimeric antigen receptor T-cell (CAR-T) therapy for lymphoma.

BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) infusion is associated with early toxicity. Yet, whether early toxicity development holds ramifications for long-term outcomes is unknown. METHODS: From a large cohort of consecutive adult patients treated with CAR-T therapies for relapsed or refractory lymphomas from 2016 to 2019, we assessed progression-free survival (PFS), by toxicity development (cytokine release syndrome (CRS), neurotoxicity, or cardiotoxicity]. We also assessed the relationship of toxicity development to objective disease response, and overall survival (OS). Multivariable regression was utilized to evaluate relationships between standard clinical and laboratory measures and disease outcomes. Differences in outcomes, by toxicity status, were also assessed via 30-day landmark analysis. Furthermore, we assessed the effects of early anti-CRS toxicity therapy use (at ≤grade 2 toxicity) on maximum toxicity grade observed, and long-term disease outcomes (PFS and OS). RESULTS: Overall, from 102 CAR-T-treated patients, 90 were identified as treated with single-agent therapy, of which 88.9% developed toxicity (80 CRS, 41 neurotoxicity, and 17 cardiotoxicity), including 28.9% with high-grade (≥3) events. The most common manifestations were hypotension at 96.6% and fever at 94.8%. Among patients with cardiac events, there was a non-significant trend toward a higher prevalence of concurrent or preceding high-grade (≥3) CRS. 50.0% required tocilizumab or corticosteroids. The median time to toxicity was 3 days; high grade CRS development was associated with cardiac and neurotoxicity. In multivariable regression, accounting for disease severity and traditional predictors of disease response, moderate (maximum grade 2) CRS development was associated with higher complete response at 1 year (HR: 2.34; p=0.07), and longer PFS (HR: 0.41; p=0.02, in landmark analysis), and OS (HR: 0.43; p=0.03). Among those with CRS, relative blood pressure (HR: 2.25; p=0.004), respectively, also associated with improved PFS. There was no difference in disease outcomes, or maximum toxicity grade (CRS, neurotoxicity, or cardiotoxicity) observed, based on the presence or absence of the use of early CRS-directed therapies. CONCLUSIONS: Among adult lymphoma patients, moderate toxicity manifest as grade 2 CRS after CAR-T infusion may associate with favorable clinical outcomes. Further studies are needed to confirm these findings.

Postoperative Hospital Outcomes of Elective Surgery for Nonmalignant Colorectal Polyps: Does the Burden Justify the Indication?

INTRODUCTION: Despite the increasing availability of advanced endoscopic resections and its favorable safety profile, surgery for nonmalignant colorectal polyps has continually increased. We sought to evaluate readmission rates and outcomes of elective surgery for nonmalignant colorectal polyps on a national level in the United States. METHODS: The Nationwide Readmissions Database (2010-2014 [International Classification of Diseases, Ninth Revision] and 2016-2018 [International Classification of Diseases, 10th Revision]) was used to identify all adult subjects (age ≥18 years) who underwent elective surgical resection of nonmalignant colorectal polyps. Multivariable analyses were performed for predictors of postoperative morbidity and 30-day readmission. RESULTS: Elective surgery for nonmalignant colorectal polyps was performed in 108,468 subjects from 2010 to 2014 and in 54,956 subjects from 2016 to 2018, most of whom were laparoscopic. Postoperative morbidity and 30-day readmission rates were 20.5% and 8.5% from 2010 to 2014, and 13.0% and 7.6% from 2016 to 2018, respectively. Index admission mortality rates were 0.3-0.4%; mortality rates were higher in those with postoperative morbidity. Multivariable analyses revealed that male sex, ≥3 comorbidities, insurance status, and open surgery predicted an increased risk of both postoperative morbidity and 30-day readmission. In addition, postoperative morbidity (2010-2014 [odds ratio 1.58; 95% confidence interval 1.44-1.74] and 2016-2018 [odds ratio 1.55; 95% confidence interval 1.37-1.75]) predicted early readmission. DISCUSSION: In this investigation of national practices, elective surgery for nonmalignant colorectal polyps remains common. There is considerable risk of adverse postoperative outcomes, which highlights the importance of increasing awareness of the range of endoscopic resections and referring subjects to expert endoscopy centers.

Maternal depressive symptoms, sleep, and odds of spontaneous early birth: implications for racial inequities in birth outcomes.

STUDY OBJECTIVES: Delivery prior to full term affects 37% of US births, including ~400,000 preterm births (<37 weeks) and >1,000,000 early term births (37-38 weeks). Approximately 70% of cases of shortened gestation are spontaneous-without medically-indicated cause. Elucidation of modifiable behavioral factors would have considerable clinical impact. METHODS: This study examined the role of depressive symptoms and sleep quality in predicting the odds of spontaneous shortened gestation among 317 women (135 black, 182 white) who completed psychosocial assessment in mid-pregnancy. RESULTS: Adjusting for key covariates, black women had 1.89 times higher odds of spontaneous shortened gestation compared to White women (OR [95% CI] = 1.89 [1.01, 3.53], p = 0.046). Women who reported only poor subjective sleep quality (PSQI > 6) or only elevated depressive symptoms (CES-D ≥ 16) exhibited no statistically significant differences in odds of spontaneous shortened gestation compared to those with neither risk factor. However, women with comorbid poor sleep and depressive symptoms exhibited markedly higher odds of spontaneous shortened gestation than those with neither risk factor (39.2% versus 15.7% [OR (95% CI) = 2.69 (1.27, 5.70)], p = 0.01). A higher proportion of black women met criteria for both risk factors (23% of black women versus 11% of white women; p = 0.004), with a lower proportion experiencing neither risk factor (40.7% of black versus 64.3% of white women; p < 0.001). CONCLUSIONS: Additive effects of poor subjective sleep quality and depressive symptoms were observed with markedly higher odds of spontaneous shortened gestation among women with both risk factors. Racial inequities in rates of comorbid exposure corresponded with inequities in shortened gestation. Future empirical studies and intervention efforts should consider the interactive effects of these commonly co-morbid exposures.

Severity of COVID-19 in hospitalized patients with and without atopic disease.

BACKGROUND: Data from the 2009 influenza pandemic suggested asthma might protect from severe disease in hospitalized patients. Asthma does not appear to increase risk for hospitalization or mortality with COVID-19. OBJECTIVE: This study was undertaken to see if atopy actually protected those hospitalized with COVID-19. METHODS: Retrospective chart review on all patients testing positive for SARS-CoV-2 over 2 months at a major adult and pediatric tertiary referral center hospital. Charts were evaluated for history of atopic disease, as were the need for ICU admission, requirement for supplemental oxygen and/or intubation, and in hospital mortality. RESULTS: No significant differences in outcomes for patients (n = 275) based on atopic disease were noted: ICU admission, 43% versus 44.7% (atopic versus no atopic disease, respectively; p = 0.84); supplemental oxygen use, 79.1% versus 73.6% (p = 0.36); intubation rate, 35.8% versus 36.5% (p = 0.92); and mortality rate, 13.4% versus 20.7% (p = 0.19). More patients with atopic disease had COPD listed as a diagnosis in their chart (38.8% versus 17.3%, p < 0.001). COPD was associated with an increased rate of ICU admission (aOR = 2.22 (1.15, 4.30) p = 0.02) and intubation (aOR = 2.05 (1.07, 3.92) p = 0.03). After adjusting for COPD, patients with atopic disease had a trend for reduced mortality (aOR 0.55 (0.23, 1.28), p = 0.16), but those with asthma did not (p > 0.2). CONCLUSION: Severity of COVID-19 in hospitalized patients does not differ based on atopic status. However, adjusting for presence of COPD led to a suggestion of possible reduced severity in patients with atopy but not asthma.