Risk projection for time-to-event outcome from population-based case-control studies leveraging summary statistics from the target population.

Risk stratification based on prediction models has become increasingly important in preventing and managing chronic diseases. However, due to cost- and time-limitations, not every population can have resources for collecting enough detailed individual-level information on a large number of people to develop risk prediction models. A more practical approach is to use prediction models developed from existing studies and calibrate them with relevant summary-level information of the target population. Many existing studies were conducted under the population-based case-control design. Gail et al. (J Natl Cancer Inst 81:1879-1886, 1989) proposed to combine the odds ratio estimates obtained from case-control data and the disease incidence rates from the target population to obtain the baseline hazard function, and thereby the pure risk for developing diseases. However, the approach requires the risk factor distribution of cases from the case-control studies be same as the target population, which, if violated, may yield biased risk estimation. In this article, we propose two novel weighted estimating equation approaches to calibrate the baseline risk by leveraging the summary information of (some) risk factors in addition to disease-free probabilities from the targeted population. We establish the consistency and asymptotic normality of the proposed estimators. Extensive simulation studies and an application to colorectal cancer studies demonstrate the proposed estimators perform well for bias reduction in finite samples.

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations.

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

A Generalized Integration Approach to Association Analysis with Multi-category Outcome: An Application to a Tumor Sequencing Study of Colorectal Cancer and Smoking.

Cancer is a heterogeneous disease, and rapid progress in sequencing and -omics technologies has enabled researchers to characterize tumors comprehensively. This has stimulated an intensive interest in studying how risk factors are associated with various tumor heterogeneous features. The Cancer Prevention Study-II (CPS-II) cohort is one of the largest prospective studies, particularly valuable for elucidating associations between cancer and risk factors. In this paper, we investigate the association of smoking with novel colorectal tumor markers obtained from targeted sequencing. However, due to cost and logistic difficulties, only a limited number of tumors can be assayed, which limits our capability for studying these associations. Meanwhile, there are extensive studies for assessing the association of smoking with overall cancer risk and established colorectal tumor markers. Importantly, such summary information is readily available from the literature. By linking this summary information to parameters of interest with proper constraints, we develop a generalized integration approach for polytomous logistic regression model with outcome characterized by tumor features. The proposed approach gains the efficiency through maximizing the joint likelihood of individual-level tumor data and external summary information under the constraints that narrow the parameter searching space. We apply the proposed method to the CPS-II data and identify the association of smoking with colorectal cancer risk differing by the mutational status of APC and RNF43 genes, neither of which is identified by the conventional analysis of CPS-II individual data only. These results help better understand the role of smoking in the etiology of colorectal cancer.

Risk-Stratified Screening for Colorectal Cancer Using Genetic and Environmental Risk Factors: A Cost-Effectiveness Analysis Based on Real-World Data.

BACKGROUND & AIMS: Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death. METHODS: Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses. RESULTS: Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test. CONCLUSIONS: Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.

Combining Asian-European Genome-Wide Association Studies of Colorectal Cancer Improves Risk Prediction Across Race and Ethnicity.

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values<0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort.

BACKGROUND: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance. METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group). RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity. CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort. IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.

Molecular and Pathology Features of Colorectal Tumors and Patient Outcomes Are Associated with Fusobacterium nucleatum and Its Subspecies animalis.

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. METHODS: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer-specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer-specific mortality, and somatic mutations. RESULTS: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer-specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07-3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer-specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. CONCLUSIONS: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer-specific mortality and specific somatic mutated genes. IMPACT: Our findings identify the F. nucleatum subspecies animalis as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.

Re-calibrating pure risk integrating individual data from two-phase studies with external summary statistics.

Accurate risk assessment is critical in clinical decision-making. It entails the projected risk based on a risk prediction model agreeing with the observed risk in the target cohort. However, the model often over- or under-estimates the risk. Building a new model for the target cohort would be ideal but costly. It is therefore of great interest to recalibrate an existing model for the target cohort. Existing methods have been proposed to recalibrate the model by leveraging the disease incidence rates from the target cohort. However, they assume the same covariate distribution across cohorts and when the assumption is violated, the recalibrated model can be substantially biased. Further, recalibration is also complicated by the two-phase sampling design that is commonly used for developing risk prediction models. In this paper, we develop a weighted estimating-equation approach accounting for the two-phase design and combine it with a weighted empirical likelihood that leverages the summary information on both disease incidence rates and covariates from the target cohort. We provide a resampling-based inference procedure. Our extensive simulation results show that using the summary information from the target population, the proposed recalibration method yields nearly unbiased risk estimates under a wide range of scenarios. An application to a colorectal cancer study also illustrates that the proposed method yields a well-calibrated model in the target cohort.

Risk Projection for Time-to-event Outcome Leveraging Summary Statistics With Source Individual-level Data.

Predicting risks of chronic diseases has become increasingly important in clinical practice. When a prediction model is developed in a cohort, there is a great interest to apply the model to other cohorts. Due to potential discrepancy in baseline disease incidences between different cohorts and shifts in patient composition, the risk predicted by the model built in the source cohort often under- or over-estimates the risk in a new cohort. In this article, we assume the relative risks of predictors are the same between the two cohorts, and propose a novel weighted estimating equation approach to re-calibrating the projected risk for the targeted population through updating the baseline risk. The recalibration leverages the knowledge about survival probabilities for the disease of interest and competing events, and summary information of risk factors from the target population. We establish the consistency and asymptotic normality of the proposed estimators. Extensive simulation demonstrate that the proposed estimators are robust, even if the risk factor distributions differ between the source and target populations, and gain efficiency if they are the same, as long as the information from the target is precise. The method is illustrated with a recalibration of colorectal cancer prediction model.

Usefulness of metagenomic next-generation sequencing in adenovirus 7-induced acute respiratory distress syndrome: A case report.

BACKGROUND: Direct metagenomic next-generation sequencing (mNGS) of clinical samples is an effective method for the molecular diagnosis of infection. However, its role in the diagnosis of patients with acute respiratory distress syndrome (ARDS) of an unknown infectious etiology remains unclear. CASE SUMMARY: A 33-year-old man was admitted to our center for a cough and febrile sensation. Shortly after admission, the patient was diagnosed with ARDS and treated in the intensive care unit. Subsequently, chest computed tomography features suggested an infection. mNGS was performed and the results were indicative of an infection caused by adenovirus type 7. The patient recovered after receiving appropriate treatment. CONCLUSION: mNGS is a promising tool for the diagnosis of ARDS caused by infectious agents. However, further studies are required to develop strategies for incorporating mNGS into the current diagnostic process for the disease.

IL-17A Neutralization Improves the Neurological Outcome of Mice With Ischemic Stroke and Inhibits Caspase-12-Dependent Apoptosis.

We previously reported that the levels of astrocyte-derived interleukin-17A (IL-17A) increased both in the peri-infarct region and cerebrospinal fluid (CSF) of mice with 1-h middle cerebral artery (MCA) occlusion/12-h reperfusion (1-h MCAO/R 12 h)-induced ischemic stroke. However, the effects of IL-17A neutralization on the neurological outcome of mice with ischemic stroke and its underlying molecular mechanism are unclear. In this study, we found that the intracerebroventricular injection of IL-17A-neutralizing monoclonal antibody (mAb; 2.0 µg) could reduce the infarct volume, alleviate neuron loss, and improve the neurological outcomes of mice with 1-h MCAO/R 24-h- or 3-day-induced ischemic-stroke mice. The IL-17A neutralization could also significantly inhibit the increase of pro-caspase-3 cleavage through caspase-12-dependent cell apoptosis, as well as preventing the decrease of antiapoptotic factor B-cell lymphoma 2 (Bcl-2) and the increase of proapoptotic Bcl-2-associated X protein (Bax) in the peri-infarct region of mice following ischemic stroke. In addition, we confirmed that the recombinant mouse (rm) IL-17A could significantly aggravate 1-h oxygen-glucose deprivation/24-h reoxygenation (1-h OGD/R 24 h)-induced ischemic injuries in cortical neurons in a dose-dependent manner, and the rmIL-17A could also exacerbate neuronal apoptosis through caspase-12 (not caspase-8 or caspase-9)-dependent pathway. These results suggest that IL-17A neutralization could improve the neurological outcome of mice with ischemic stroke through inhibiting caspase-12-dependent neuronal apoptosis.

A New Comprehensive Colorectal Cancer Risk Prediction Model Incorporating Family History, Personal Characteristics, and Environmental Factors.

PURPOSE: Reducing colorectal cancer incidence and mortality through early detection would improve efficacy if targeted. We developed a colorectal cancer risk prediction model incorporating personal, family, genetic, and environmental risk factors to enhance prevention. METHODS: A familial risk profile (FRP) was calculated to summarize individuals' risk based on detailed cancer family history (FH), family structure, probabilities of mutation in major colorectal cancer susceptibility genes, and a polygenic component. We developed risk models, including individuals' FRP or binary colorectal cancer FH, and colorectal cancer risk factors collected at enrollment using population-based colorectal cancer cases (N = 4,445) and controls (N = 3,967) recruited by the Colon Cancer Family Registry Cohort (CCFRC). Model validation used CCFRC follow-up data for population-based (N = 12,052) and clinic-based (N = 5,584) relatives with no cancer history at recruitment to assess model calibration [expected/observed rate ratio (E/O)] and discrimination [area under the receiver-operating-characteristic curve (AUC)]. RESULTS: The E/O [95% confidence interval (CI)] for FRP models for population-based relatives were 1.04 (0.74-1.45) for men and 0.86 (0.64-1.20) for women, and for clinic-based relatives were 1.15 (0.87-1.58) for men and 1.04 (0.76-1.45) for women. The age-adjusted AUCs (95% CI) for FRP models for population-based relatives were 0.69 (0.60-0.78) for men and 0.70 (0.62-0.77) for women, and for clinic-based relatives were 0.77 (0.69-0.84) for men and 0.68 (0.60-0.76) for women. The incremental values of AUC for FRP over FH models for population-based relatives were 0.08 (0.01-0.15) for men and 0.10 (0.04-0.16) for women, and for clinic-based relatives were 0.11 (0.05-0.17) for men and 0.11 (0.06-0.17) for women. CONCLUSIONS: Both models calibrated well. The FRP-based model provided better risk stratification and risk discrimination than the FH-based model. IMPACT: Our findings suggest detailed FH may be useful for targeted risk-based screening and clinical management.

Adjusted time-varying population attributable hazard in case-control studies.

Population attributable fraction is a widely used measure for quantifying the disease burden associated with a modifiable exposure of interest at the population level. It has been extended to a time-varying measure, population attributable hazard function, to provide additional information on when and how the exposure's impact varies over time. However, like the classic population attributable fraction, the population attributable hazard is generally biased if confounders are present. In this article, we provide a natural definition of adjusted population attributable hazard to take into account the effects of confounders, and its alternative that is identifiable from case-control studies under the rare disease assumption. We propose a novel estimator, which combines the odds ratio estimator from logistic regression model, and the conditional density function estimator of the exposure and confounding variables distribution given the failure times of cases or the current times of controls from a kernel smoother. We show that the proposed estimators are consistent and asymptotically normal with variance that can be estimated empirically from the data. Simulation studies demonstrate that the proposed estimators perform well in finite sample sizes. Finally, we illustrate the method by an analysis of a case-control study of colorectal cancer. Supplementary materials for this article are available online.

Inconsistencies in Colonic Tattooing Practice: Differences in Reported and Actual Practices at a Tertiary Medical Center.

OBJECTIVES: Accurate localization of a colonic lesion is crucial to successful resection. Although colonic tattooing is a widely accepted technique to mark lesions for future identification surgery or repeat colonoscopy, no consensus guidelines exist. The objective of this study was to determine whether the current tattooing practice at a tertiary medical center differs from recommendations in the literature and self-reported provider practice. METHODS: The study consisted of an observational retrospective chart review of patients who received colonic tattoos, as well as a provider survey of reported tattooing practices at a tertiary academic medical center. A total of 747 patients older than 18 years of age who underwent colonoscopy with tattoo were included. Forty-four gastroenterologists performing endoscopy were surveyed on tattooing techniques. RESULTS: In the majority of cases, neither the number of tattoos, location of the tattoo nor the distance from the lesion was specified within the report. Following the index procedure, a tattoo was detected in 75% of surgical resections and 73% of endoscopies. At the time of surgery, however, the tattoo and/or the lesion was detected approximately 94% of the time. Twenty-five endoscopists (56.8%) completed the survey. Differences were seen the between the chart review and reported practice. Most providers report placing ≥2 marks (87.2%); however, chart review revealed that only 56.2 % were tattooed with ≥2 marks. CONCLUSIONS: Variation exists between the reported tattooing practice and actual practice. Despite this, most tattoos are identified at the time of surgery or repeat endoscopy. Further research is needed to determine whether a standardized approach to tattooing and reporting could improve localization at repeat endoscopy.

Association Between Left Atrial Appendage Occlusion and Readmission for Thromboembolism Among Patients With Atrial Fibrillation Undergoing Concomitant Cardiac Surgery.

Importance: The left atrial appendage is a key site of thrombus formation in atrial fibrillation (AF) and can be occluded or removed at the time of cardiac surgery. There is limited evidence regarding the effectiveness of surgical left atrial appendage occlusion (S-LAAO) for reducing the risk of thromboembolism. Objective: To evaluate the association of S-LAAO vs no receipt of S-LAAO with the risk of thromboembolism among older patients undergoing cardiac surgery. Design, Setting, and Participants: Retrospective cohort study of a nationally representative Medicare-linked cohort from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (2011-2012). Patients aged 65 years and older with AF undergoing cardiac surgery (coronary artery bypass grafting [CABG], mitral valve surgery with or without CABG, or aortic valve surgery with or without CABG) with and without concomitant S-LAAO were followed up until December 31, 2014. Exposures: S-LAAO vs no S-LAAO. Main Outcomes and Measures: The primary outcome was readmission for thromboembolism (stroke, transient ischemic attack, or systemic embolism) at up to 3 years of follow-up, as defined by Medicare claims data. Secondary end points included hemorrhagic stroke, all-cause mortality, and a composite end point (thromboembolism, hemorrhagic stroke, or all-cause mortality). Results: Among 10 524 patients undergoing surgery (median age, 76 years; 39% female; median CHA2DS2-VASc score, 4), 3892 (37%) underwent S-LAAO. Overall, at a mean follow-up of 2.6 years, thromboembolism occurred in 5.4%, hemorrhagic stroke in 0.9%, all-cause mortality in 21.5%, and the composite end point in 25.7%. S-LAAO, compared with no S-LAAO, was associated with lower unadjusted rates of thromboembolism (4.2% vs 6.2%), all-cause mortality (17.3% vs 23.9%), and the composite end point (20.5% vs 28.7%) but no significant difference in rates of hemorrhagic stroke (0.9% vs 0.9%). After inverse probability-weighted adjustment, S-LAAO was associated with a significantly lower rate of thromboembolism (subdistribution hazard ratio [HR], 0.67; 95% CI, 0.56-0.81; P < .001), all-cause mortality (HR, 0.88; 95% CI, 0.79-0.97; P = .001), and the composite end point (HR, 0.83; 95% CI, 0.76-0.91; P < .001) but not hemorrhagic stroke (subdistribution HR, 0.84; 95% CI, 0.53-1.32; P = .44). S-LAAO, compared with no S-LAAO, was associated with a lower risk of thromboembolism among patients discharged without anticoagulation (unadjusted rate, 4.2% vs 6.0%; adjusted subdistribution HR, 0.26; 95% CI, 0.17-0.40; P < .001), but not among patients discharged with anticoagulation (unadjusted rate, 4.1% vs 6.3%; adjusted subdistribution HR, 0.88; 95% CI, 0.56-1.39; P = .59). Conclusions and Relevance: Among older patients with AF undergoing concomitant cardiac surgery, S-LAAO, compared with no S-LAAO, was associated with a lower risk of readmission for thromboembolism over 3 years. These findings support the use of S-LAAO, but randomized trials are necessary to provide definitive evidence.

Outcomes of liver retransplantation in patients with primary sclerosing cholangitis.

Liver retransplantation in patients with primary sclerosing cholangitis (PSC) has not been well studied. The aims of this study were to characterize patients with PSC listed for and undergoing retransplantation and to describe the outcomes in these patients. The United Network for Organ Sharing/Organ Procurement and Transplantation Network database was used to identify all primary liver transplantations and subsequent relistings and first retransplantations in adults with PSC between 1987 and 2015. A total of 5080 adults underwent primary transplantation for PSC during this period, and of the 1803 who experienced graft failure (GF), 762 were relisted, and 636 underwent retransplantation. Younger patients and patients with GF due to vascular thrombosis or biliary complications were more likely to be relisted, whereas those with Medicaid insurance or GF due to infection were less likely. Both 5-year graft and patient survival after retransplantation were inferior to primary transplantation (P < 0.001). Five-year survival after retransplantation for disease recurrence (REC), however, was similar to primary transplantation (graft survival, P = 0.45; patient survival, P = 0.09) and superior to other indications for retransplantation (graft and patient survival, P < 0.001). On multivariate analysis, mechanical ventilation, creatinine, bilirubin, albumin, advanced donor age, and a living donor were associated with poorer outcomes after retransplantation. In conclusion, although survival after liver retransplantation in patients with PSC was overall inferior to primary transplantation, outcomes after retransplantation for PSC REC were similar to primary transplantation at 5 years. Retransplantation may therefore represent a treatment option with the potential for excellent outcomes in patients with REC of PSC in the appropriate clinical circumstances. Liver Transplantation 23 769-780 2017 AASLD.

Impact of intra-operative cell salvage on blood coagulation in high-bleeding-risk patients undergoing cardiac surgery with cardiopulmonary bypass: a prospective randomized and controlled trial.

BACKGROUND: Intra-operative cell salvage (CS) was reported to have no impairment on blood coagulation in low-bleeding-risk cardiac surgery with cardiopulmonary bypass (CPB), but studies in high-bleeding-risk cardiac surgery are limited. The objective of this study is to evaluate the impact of CS on blood coagulation in high-bleeding-risk cardiac surgery with CPB. METHODS: One hundred and ten patients were randomly assigned to either with intra-operative CS group (Group CS) or without intra-operative CS group (Group C). Study endpoints included the incidence of impairment of blood coagulation during perioperative period (peri-op) and the incidence of adverse events during postoperative period (post-op). Peri-op was defined as the period from beginning of anesthesia (anesthesia induction) to 24 h after end of surgery. Post-op was defined as the period from the end of surgery to 24 h after end of surgery. The types of impairment of blood coagulation included heparin residual, coagulopathy due to low PLT, coagulopathy due to low FIB, coagulopathy due to low coagulation factors, hyperfibrinolytic. The sum of above five types was total impairment of blood coagulation. Adverse events included excessive bleeding, resternotomy, etc. RESULTS: The incidence of heparin residual measured both at the end of surgery and during post-op were significantly higher in Group CS than in Group C (15.09 vs 4.00, 13.21 vs 2.00 %; p = 0.024, 0.010, respectively). Similarly, the incidence of total impairment of blood coagulation at the end of surgery and during post-op were significantly higher in Group CS than in Group C (32.08 vs 18.00, 26.42 vs 12.00 %; p = 0.043, 0.040, respectively). The incidence of excessive bleeding during post-op was 32.08 % in Group CS compared with 16.00 % in Group C (p = 0.038). Intriguingly, CS was associated with a significantly increase in the relative risk ratios for heparin residual and excessive bleeding (p = 0.034, 0.049, respectively). CONCLUSIONS: Intra-operative CS could impair blood coagulation in the scenario of high-risk-bleeding cardiac surgery with CPB.

AGR2 is associated with gastric cancer progression and poor survival.

Anterior gradient protein 2 (AGR2) has been reported as a novel biomarker with a potential oncogenic role. However, its association with the prognosis and survival rate of gastric cancer (GC) has not yet been determined. Therefore, the present study aimed to examine the expression and prognostic significance of AGR2 in patients with GC. Immunohistochemistry was used to analyze AGR2 and cathepsin D (CTSD) protein expression in 436 clinicopathologically characterized GC cases and 92 noncancerous tissue samples. AGR2 and CTSD expression were both elevated in GC lesions compared with noncancerous tissues. In 204/436 (46.8%) GC patients, high expression of AGR2 was positively correlated with the expression of CTSD (r=0.577, P<0.01). Furthermore, several clinicopathological parameters were significantly associated with AGR2 expression level, including tumor size, depth of invasion and TNM stage (P<0.05). Using Kaplan-Meier survival analysis, it was determined that the mean survival time of patients with low levels of AGR2 expression was significantly longer than those with high ARG2 expression (in stages I, II and III; P<0.05). For stage IV disease, no significant difference in survival time was identified. Multivariate survival analysis demonstrated that AGR2 was an independent prognostic factor and was associated in the progression of GC. The findings of the present study indicate that AGR2 expression is significantly associated with location and size of GC, depth of invasion, TNM stage, lymphatic metastasis, vessel invasion, distant metastasis, Lauren's classification, high CTSD expression and poor prognosis. Thus, AGR2 may be a novel GC marker and may present a potential therapeutic target for GC.

The efficacy, safety and cost-effectiveness of intra-operative cell salvage in high-bleeding-risk cardiac surgery with cardiopulmonary bypass: a prospective randomized and controlled trial.

OBJECTIVE: Intra-operative cell salvage (CS) was reported to be ineffective, safe and not cost-effective in low-bleeding-risk cardiac surgery with cardiopulmonary bypass (CPB), but studies in high-bleeding-risk cardiac surgery are limited. The objective of this study is to evaluate the efficacy, safety and cost-effectiveness of intra-operative CS in high-bleeding-risk cardiac surgery with CPB. METHODS: One hundred and fifty patients were randomly assigned to either with intra-operative CS group (Group CS) or without intra-operative CS group (Group C). Study endpoints were defined as perioperative allogeneic red blood cell (RBC) transfusion, perioperative impairment of blood coagulative function, postoperative adverse events and costs of transfusion-related. RESULTS: Both the proportion and quantity of perioperative allogeneic RBC transfusion were significantly lower in Group CS than that in Group C (p=0.0002, <0.0001, respectively). The incidence of residual heparin and total impairment of blood coagulative function in the 24 hours after surgery, the incidence of postoperative excessive bleeding, were significantly higher in Group CS than that in Group C (p=0.018, 0.042, 0.034, respectively). Cost of both allogeneic RBC transfusion and total allogeneic blood transfusion were significantly lower in Group CS than that in Group C (p<0.001, =0.002, respectively). Cost of total blood transfusion was significantly higher in Group CS than that in Group C (p =0.001). CONCLUSION: Intra-operative CS in high-bleeding-risk cardiac surgery with CPB is effective, generally safe, and cost-effective in developed countries but not in China.