Validation of an anti-α-Gal IgE fluoroenzyme-immunoassay for the screening of patients at risk of severe anaphylaxis to cetuximab.

BACKGROUND: The link between immediate hypersensitivity reactions (HSR) following the first cetuximab infusion and the IgE sensitization against anti-galactose-α-1,3-galactose (α-Gal) is now well-established. An automated Fluoroenzyme-Immunoassay (FEIA) is available and may facilitate the screening of patients with anti-α-Gal IgE before treatment. METHODS: This study aimed to evaluate its performances as compared to a previously validated anti-cetuximab IgE ELISA, using 185 samples from two previously studied cohorts. RESULTS: Despite 21.1% of discrepancies between the two techniques, FEIA discriminated better positive patients and similarly negative ones with a ≥ 0.525 kUA/L threshold. Sensitivity was 87.5% for both tests, specificity was better for FEIA (96.3% vs ELISA: 82.1%). FEIA had a higher positive likelihood ratio (23.9 vs ELISA: 4.89) and a similar negative likelihood ratio (0.13 vs ELISA: 0.15). In our population, the risk of severe HSR following a positive test was higher with FEIA (56.7% vs ELISA: 19.6%) and similar following a negative test (0.7% vs ELISA: 0.8%). CONCLUSION: Although the predictive value of the IgE screening before cetuximab infusion remains discussed, this automated commercial test can identify high-risk patients and is suitable for routine use in laboratories. It could help avoiding cetuximab-induced HSR by a systematic anti-α-Gal IgE screening before treatment.

New Histoprognostic Factors to Consider for the Staging of Colon Cancers: Tumor Deposits, Invasive Tumor Infiltration and High-Grade Budding.

Colorectal cancer is a major public health issue due to its high incidence and mortality. It is, therefore, essential to identify histological markers for prognostic purposes and to optimize the therapeutic management of patients. The main objective of our study was to analyze the impact of new histoprognostic factors, such as tumor deposits, budding, poorly differentiated clusters, mode of infiltration, the intensity of inflammatory infiltrate and the type of tumor stroma, on the survival of patients with colon cancer. Two hundred and twenty-nine resected colon cancers were fully histologically reviewed, and survival and recurrence data were collected. Survival was analyzed using Kaplan-Meier curves. A univariate and multivariate Cox model was constructed to identify prognostic factors for overall survival and recurrence-free survival. The median overall survival of the patients was 60.2 months and the median recurrence-free survival was 46.9 months. Overall survival and recurrence-free survival were significantly worse in the presence of isolated tumor deposits (log rank = 0.003 and 0.001, respectively) and for an infiltrative type of tumor invasion (log rank = 0.008 and 0.02, respectively). High-grade budding was associated with a poor prognosis, with no significant difference. We did not find a significant prognostic impact of the presence of poorly differentiated clusters, the intensity of the inflammatory infiltrate or the stromal type. In conclusion, the analysis of these recent histoprognostic factors, such as tumor deposits, mode of infiltration, and budding, could be integrated into the results of pathological reports of colon cancers. Thus, the therapeutic management of patients could be adjusted by providing more aggressive treatments in the presence of some of these factors.

Mouse HSA+ immature cardiomyocytes persist in the adult heart and expand after ischemic injury.

The assessment of the regenerative capacity of the heart has been compromised by the lack of surface signatures to characterize cardiomyocytes (CMs). Here, combined multiparametric surface marker analysis with single-cell transcriptional profiling and in vivo transplantation identify the main mouse fetal cardiac populations and their progenitors (PRGs). We found that CMs at different stages of differentiation coexist during development. We identified a population of immature heat stable antigen (HSA)/ cluster of differentiation 24 (CD24)+ CMs that persists throughout life and that, unlike other CM subsets, actively proliferates up to 1 week of age and engrafts cardiac tissue upon transplantation. In the adult heart, a discrete population of HSA/CD24+ CMs appears as mononucleated cells that increase in frequency after infarction. Our work identified cell surface signatures that allow the prospective isolation of CMs at all developmental stages and the detection of a subset of immature CMs throughout life that, although at reduced frequencies, are poised for activation in response to ischemic stimuli. This work opens new perspectives in the understanding and treatment of heart pathologies.

Countering Distrust in Illicit Online Networks: The Dispute Resolution Strategies of Cybercriminals.

The core of this article is a detailed investigation of the dispute resolution system contained within Darkode, an elite cybercriminal forum. Extracting the dedicated disputes section from within the marketplace, where users can report bad behavior and register complaints, we carry out content analysis on these threads. This involves both descriptive statistics across the data set and qualitative analysis of particular posts of interest, leading to a number of new insights. First, the overall level of disputes is quite high, even though members are vetted for entry in the first instance. Second, the lower ranked members of the marketplace are the most highly represented category for both the plaintiffs and defendants. Third, vendors are accused of malfeasance far more often than buyers, and their "crimes" are most commonly either not providing the product/service or providing a poor one. Fourth, the monetary size of the disputes is surprisingly small. Finally, only 23.1% of disputes reach a clear outcome.

Transhepatic forceps biopsy combined with biliary drainage in obstructive jaundice: safety and accuracy.

PURPOSE: This study was conducted in order to investigate the safety and accuracy of percutaneous transluminal forceps biopsy (PTFB) during percutaneous biliary drainage (PTBD) in patients with a suspicion of malignant biliary stricture. MATERIAL AND METHODS: Fifty consecutive patients with obstructive jaundice underwent PTFB during PTBD. Biopsy specimens were obtained using 5.2-F flexible biopsy forceps and these specimens were independently analysed by two pathologists. Consensus was obtained in case of discrepancy. Biopsy was considered as a true positive when tumour cells were retrieved. In the absence of tumour cells, comparison with available surgical findings and/or endoscopic ultrasound fine-needle aspiration (EUS-FNA) and/or percutaneous liver biopsy and/or imaging or clinical follow-up was made to distinguish true and false negatives. Specificity, sensitivity, positive predictive value, negative predictive value and accuracy were calculated. Influence of tumour location and pre-operative imaging findings was evaluated. Adverse events were reported. RESULTS: Biliary drainage and tissue sampling were achieved in 100% of patients. Sensitivity and specificity were 70 and 100%, respectively, while overall accuracy was 72%. After excluding the first 25 patients, accuracy and sensitivity for tissue sampling reached 80 and 78%, respectively. Sensitivity was better (87%) if stenosis was located at the upper part of the biliary tree, compared to the lower part (55%). In case of cholangiocarcinoma or intraductal invasion suspected on imaging, biopsy was contributive in 84 and 81% of patients, respectively. Four complications occurred consisting of one bile leak, two haemobilia and one pneumoperitoneum. CONCLUSION: PTFB combined with PTBD is a safe and effective technique for both histopathological diagnosis and biliary decompression of biliary strictures. KEY POINTS: Implications for patient care: • Percutaneous transbiliary forceps biopsy is technically feasible (100% of tissue sampling in our study) and is a safe technique. • Radiological management combining PTFB plus PTBD may allow diagnosis and treatment of the biliary stricture at the same time. • Sensitivity and accuracy for PTFB reached 78 and 80%, respectively, with a 100% specificity.

Proposal of a novel MELD exception point system for hepatocellular carcinoma based on tumor characteristics and dynamics.

BACKGROUND & AIMS: Patients listed with exception points for hepatocellular carcinoma (HCC) have been more likely to be transplanted than those listed for chronic liver failure (LF) based on the model for end-stage liver disease (MELD) score. The aim of this study was to determine outcomes in the 5-year experience of a scoring system designed to reflect heterogeneity of tumor load of patients listed for HCC. METHODS: A novel MELD exception point system based on size and number of HCC was implemented in July 2009. This system allows stratification of patients based on risk of dropping out from the waiting list according to Milan criteria. LF patients were listed according to biological MELD sodium score; HCC patients were reassigned points every three months upon repeat imaging. RESULTS: Among 624 patients listed for liver transplant (LT), 505 were eligible. 94 (18.6%) were assigned MELD HCC points. Only 24.7% required changes in allocated points over time. Transplantation rates (HCC 83% vs. LF 73%, p=0.04) and waiting time in days (HCC 258 vs. LF 325; p=0.07) were similar. The method of competing risk analysis revealed that HCC patients were more likely to be transplanted than LF during the 5-year period preceding implementation, whereas transplant rates became equivalent for HCC and non-HCC in 2009-2014. One- and two-year survivals were similar between the two groups. CONCLUSIONS: Our study demonstrates that a novel MELD point system for HCC, taking into account dynamics in tumor size and number, allows for equitable liver allocation without compromising graft and patient survival. LAY SUMMARY: It has historically been difficult to achieve equitable liver allocation for liver cancer and chronic liver failure with the allocation systems currently in place in many countries worldwide. We designed a new system to help improve access to organs for liver failure patients in Québec, Canada. Our 5-year experience demonstrates that this unique system renders access to transplant similar for both liver cancer and liver failure indications.

Utility of serum anti-cetuximab immunoglobulin E levels to identify patients at a high risk of severe hypersensitivity reaction to cetuximab.

AIM: Cetuximab is an anti-epidermal growth factor receptor antibody used for the treatment of metastatic colorectal cancer and head and neck cancer. Hypersensitivity reactions (HSRs) are associated with cetuximab use. The aim of the study was to evaluate the utility of anti-cetuximab immunoglobulin E (IgE) detection in order to identify patients at risk of HSR to cetuximab. METHODS: We included patients ready to receive a first cetuximab infusion in a prospective cohort carried out at nine French centres. Pretreatment anti-cetuximab IgE levels were measured. We compared the proportion of severe HSRs in the low anti-cetuximab IgE levels (≤29 IgE arbitrary units) subgroup with that in a historical cohort of 213 patients extracted from a previous study. RESULTS: Of the 301 assessable patients (mean age: 60.9 ± 9.3 years, head-and-neck cancer: 77%), 66 patients (22%) had high anti-cetuximab IgE levels, and 247 patients received cetuximab (including 38 with high anti-cetuximab levels). Severe HSRs occurred in eight patients (five grade 3 and three grade 4). The proportion of severe HSRs was lower in the low anti-cetuximab IgE levels subgroup vs. the historical cohort (3/209 [1.4%] vs. 11/213 [5.2%], odds ratio, 0.27, 95% confidence interval, 0.07-0.97), and higher in high vs. low anti-cetuximab IgE levels subgroup (5/38 [13.2%] vs. 3/209 [1.4%]; odds ratio, 10.4, 95% confidence interval, 2.4-45.6). Patients with severe HSRs had higher anti-cetuximab IgE levels than patients without reaction (median, 45 vs. 2 IgE arbitrary units, P = 0.006). CONCLUSIONS: Detection of pretreatment anti-cetuximab IgE is feasible and helpful to identify patients at risk of severe cetuximab-induced HSRs.

Preoperative Biliary Drainage in Patients with Resectable Perihilar Cholangiocarcinoma: Is Percutaneous Transhepatic Biliary Drainage Safer and More Effective than Endoscopic Biliary Drainage? A Meta-Analysis.

PURPOSE: To determine the best initial procedure for performing preoperative biliary drainage in patients with resectable perihilar cholangiocarcinoma (PHCC). MATERIALS AND METHODS: MEDLINE/PubMed and the Cochrane database were searched for all studies published until June 2016 comparing endoscopic biliary drainage (EBD) and percutaneous transhepatic biliary drainage (PTBD) for preoperative biliary drainage. Meta-analysis was performed by using Review Manager 5.3 software. RESULTS: Four retrospective studies were identified that met the criteria. The analysis was performed on 433 patients who underwent preoperative biliary drainage for resectable PHCC. Of those, 275 (63.5%) had EBD and 158 (36.5%) had PTBD as the initial procedure. The overall procedure-related morbidity rate was significantly lower in the PTBD group than in the EBD group (39 of 147 [26.5%] vs 82 of 185 [44.3%]; odds ratio [OR], 2.23; 95% confidence interval [CI], 1.39-3.57; P = .0009). The rate of conversion from one procedure to the other was significantly lower in the PTBD group than in the EBD group (8 of 158 [5.0%] vs 73 of 275 [26.5%]; odds ratio, 4.76; 95% CI, 2.71-8.36; P < .00001). Pancreatitis occurred only in the EBD group (25 of 275 [9.0%] vs 0 of 158; OR, 7.46; 95% CI, 3.02-18.44; P < .0001). The cholangitis rate was significantly lower in the PTBD group than in the EBD group (12 of 158 [7.6%] vs 93 of 275 [33.8%]; OR, 5.41; 95% CI, 2.75-10.63; P < .00001). CONCLUSIONS: This meta-analysis shows that PTBD has a lower rate of complications than EBD as the initial procedure to perform preoperative biliary drainage in resectable PHCC. PTBD is associated with less conversion and lower rates of pancreatitis and cholangitis.

Risk factors associated with hypersensitivity reactions to cetuximab: anti-cetuximab IgE detection as screening test.

AIM: To describe the factors associated with a high risk of a hypersensitivity reaction to cetuximab. PATIENTS & METHODS: We retrospectively studied a cohort of patients living in Normandy (France) treated with cetuximab. RESULTS: Among the 229 treated patients, 24 (10.5%) had a hypersensitivity reaction to cetuximab, including 11 grade 3-5 reactions. Detection of anti-cetuximab IgE could be performed in 108 patients. Anti-cetuximab IgE was found in 13 of 17 patients (76.5%) who had a hypersensitivity reaction to cetuximab compared with 17 of 91 control patients (18.7%; adjusted odds ratio: 14.99; 95% CI: 3.59-62.63). No clinical criteria predicted the risk of allergy to cetuximab. CONCLUSION: Anti-cetuximab IgE may help physicians identify patients at risk of a hypersensitivity reaction to cetuximab.

Functional sequelae after pancreatic resection for cancer.

The morbidity and mortality of pancreatic cancer surgery has seen substantial improvement due to the standardization of surgical techniques, the optimization of perioperative multidisciplinary management and the organization of specialized care systems. The identification and treatment of postoperative functional and nutritional sequelae have thereby become major issues in patients who undergo pancreatic surgery. This review addresses the functional sequelae of pancreatic resection for cancerous and pre-cancerous lesions (excluding chronic pancreatitis). Its aim is to specify the prevalence and severity of sequelae according to the type of pancreatic resection and to document, where appropriate, the therapeutic management. Exocrine pancreatic insufficiency (ExPI) is observed in nearly one out of three patients at one year after surgery, and endocrine pancreatic insufficiency (EnPI) is present in one out of five patients after pancreatoduodenectomy (PD) and one out of three patients after distal pancreatectomy (DP). In addition, digestive functional disorders may appear, such as delayed gastric emptying (DGE), which affects 10 to 45% of patients after PD and nearly 8% after DP. Beyond these functional sequelae, pancreatic surgery can also induce nutritional and vitamin deficiencies secondary to a lack of uptake for certain vitamins or to the loss of absorption site in the duodenum. In addition to the treatment of ExPI with oral pancreatic enzymes, nutritional management is based on a high-calorie, high-protein diet with normal lipid intake in frequent small feedings, combined with vitamin supplementation adapted to monitored deficiencies. Better knowledge of the functional consequences of pancreatic cancer surgery can improve the overall management of patients.

Impact of sarcopenic obesity on predicting the severity of acute pancreatitis.

BACKGROUND AND AIMS: This work aimed to evaluate the impact of sarcopenia and sarcopenic obesity on the occurrence of severe pancreatitis and to study the performance of anthropometric indices to predict severe forms. METHODS: We conducted a single-center retrospective study at Caen University Hospital between 2014 and 2017. Sarcopenia was assessed by measuring the psoas area on an abdominal scan. The psoas area /body mass index ratio reflected sarcopenic obesity. By normalizing the value to the body surface, we obtained an index called sarcopancreatic index, avoiding sex differences in measurements. RESULTS: Among 467 included patients, 65 (13.9%) developed severe pancreatitis. The sarcopancreatic index was independently associated with the occurrence of severe pancreatitis (1.455 95% CI [1.028-2.061]; p = 0.035), as was the Visual Analog Scale, creatinine or albumin. The complication rate was not different depending on sarcopancreatic index value. Based on variables independently associated with the occurrence of severe pancreatitis, we constructed a score called Sarcopenia Severity Index. This score presented an area under the receiver operating characteristics curve of 0.84, comparable to the Ranson score (0.87) and superior to body mass index or the sarcopancreatic index to predict a severe form of acute pancreatitis. CONCLUSIONS: Sarcopenic obesity seems to be associated with severe acute pancreatitis.

Ursodeoxycholic acid for the prevention of gallstones and subsequent cholecystectomy after bariatric surgery: a meta-analysis of randomized controlled trials.

BACKGROUND: This meta-analysis aimed to compare the incidence of gallstone formation, subsequent biliary disease and the need for cholecystectomy in untreated patients and patients treated with ursodeoxycholic acid (UDCA) following bariatric surgery. METHODS: Randomized controlled trials (RCTs) comparing UDCA and controls for the prevention of gallstone formation after bariatric surgery published until February 2022 were selected and subjected to a systematic review and meta-analysis. Articles were searched in the MEDLINE, Web of Science and Cochrane Trials Register databases. Meta-analysis was performed with Review Manager 5.0. RESULTS: Eleven randomized controlled studies were included, with a total of 2363 randomized patients and 2217 patients analysed in the UDCA group versus 1415 randomized patients and 1257 patients analysed in the control group. Considering analysed patients, prophylactic use of UDCA was significantly associated with decreased (i) gallstone formation (OR = 0.25, 95% CI = 0.21-0.31), (ii) symptomatic gallstone disease (GD) (OR = 0.29, 95% CI = 0.20-0.42) and consequently (iii) cholecystectomy rate (OR = 0.33, 95% CI = 0.20-0.55). The results were similar in ITT analysis, in the subgroup of patients undergoing sleeve gastrectomy or considering only randomized versus placebo studies. CONCLUSIONS: Prophylactic use of UDCA after bariatric surgery prevents both gallstone formation and symptomatic GD and reduces the need for cholecystectomy.

Systematic Review: Impact of Social Determinants of Health on the Management and Prognosis of Gallstone Disease.

Background: Due to its prevalence, gallstone disease is a major public health issue. It affects diverse patient populations across various socioeconomic levels. Socioeconomic and geographic deprivation may impact both morbidity and mortality associated with digestive diseases, such as biliary tract disease. Aim: The aim of this systematic review was to review the available data on the impact of socioeconomic determinants and geographic factors on gallstone disease and its complications. Methods: This systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The MEDLINE and Web of Science databases were searched by two investigators to retrieve studies about the impact of income, insurance status, hospital status, education level, living areas, and deprivation indices on gallstone disease. Thirty-seven studies were selected for this review. Results: Socially disadvantaged populations appear to be more frequently affected by complicated or severe forms of gallstone disease. The prognosis of biliary tract disease is poor in these populations regardless of patient status, and increased morbidity and mortality were observed for acute cholangitis or subsequent cholecystectomy. Limited or delayed access and low-quality therapeutic interventions could be among the potential causes for this poor prognosis. Conclusions: This systematic review suggests that socioeconomic determinants impact the management of gallstone disease. Enhanced knowledge of these parameters could contribute to improved public health policies to manage these diseases.

Development of a Score for Predicting Severe Acute Pancreatitis at Admission.

OBJECTIVES: The identification of patients at risk of developing a severe form of acute pancreatitis is a major issue. The goal of this study was to identify parameters at admission associated with severe pancreatitis to develop a predictive severity score. METHODS: We conducted a retrospective study at Caen University Hospital between January 2014 and December 2017, including 504 patients hospitalized for acute pancreatitis, of whom 74 had a severe form. We developed a predictive score named Admission Severe Acute Pancreatitis (ASAP) score based on parameters associated with a severe form in multivariate analysis. We validated our score in an independent validation cohort of 80 patients. RESULTS: Hypothermia, low oxygen saturation or albumin levels, and high creatinine levels were significantly associated with severe pancreatitis. The ASAP score showed notable predictive accuracy (area under receiver operating characteristic, 0.82), which was significantly higher than Sequential Organ Failure Assessment, persistent Systemic Inflammatory Response Syndrome, and Balthazar. Using the -2.1742 threshold, the ASAP score had a sensitivity and specificity of 74% and a negative predictive value of 95%. These predictive performances for ASAP score were confirmed in the validation cohort. CONCLUSIONS: The ASAP score demonstrates remarkable predictive accuracy in distinguishing severe forms of acute pancreatitis.

Exploring the Factors Associated With Rejection From a Closed Cybercrime Community.

Research examining the illicit online market for cybercrime services operating via web forums, such as malicious software, personal information, and hacking tools, has greatly improved our understanding of the practices of buyers and sellers, and the social forces that structure actor behavior. The majority of these studies are based on open markets, which can be accessed by anyone with minimal barriers to entry. There are, however, closed communities operating online that are thought to operate with greater trust and reliability between participants, as they must be vetted and approved by existing community members. The decision to allow individuals to join a forum may reflect restrictive deterrence practices on the part of existing members, as those applicants may threaten the security or operations of the group. This study utilized a quantitative analysis to understand the factors associated with rejection for individuals who sought membership in the organized and sophisticated closed forum run by and for cybercriminals called Darkode. The findings demonstrated that individuals whose perceived engagement with the hacker community and cybercrime marketplace were considered too risky for membership. The implications of this study for our understanding of restrictive deterrence theory, as well as criminal market operations on and offline were explored in depth.

Highlights of the Fourth Canadian Symposium on Hepatitis C: Moving towards a National Action Plan.

Hepatitis C virus (HCV) affects at least 268,000 Canadians and causes greater disease burden than any other infectious disease in the country. The Canadian Institutes of Health Research (CIHR) and the Public Health Agency of Canada (PHAC) have identified HCV-related liver disease as a priority. In 2015, the release of well-tolerated, short course treatments (~12 weeks) able to cure the majority of treated HCV patients revolutionized HCV therapy. However, treatment is extremely costly and puts a significant burden on the Canadian healthcare system. Thus, managing treatment costs and improving treatment engagement in those most in need will be a key challenge. Diagnosis and treatment uptake are currently poor in Canada due to financial, geographical, cultural, and social barriers. The United States, Australia, and Scotland all have National Action Plans to prevent, diagnose, and treat HCV in order to efficiently reduce the burden and costs associated with HCV-related liver disease. The theme of the 4th annual symposium held on Feb 27, 2015, "Strategies to Manage HCV Infection in Canada: Moving towards a National Action Plan," was aimed at identifying strategies to maximize the impact of highly effective therapies to reduce HCV disease burden and ultimately eliminate HCV in Canada.

Retrospective evaluation of prognostic score performances in cirrhotic patients admitted to an intermediate care unit.

BACKGROUND: The prognosis of cirrhotic patients in the Intensive Care Unit requires the development of predictive tools for mortality. We aimed to evaluate the ability of different prognostic scores to predict hospital mortality in these patients. METHODS: A single-centre retrospective analysis was conducted of 281 hospital stays of cirrhotic patients at an Intermediate Care Unit between June 2009 and December 2010. The performance of the Simplified Acute Physiology Score (SOFA), the Simplified Acute Physiology Score (SAPS) II or III, Child-Pugh, Model for End-Stage Liver Disease (MELD), MELD-Na and the Chronic Liver Failure-Consortium Acute-on-Chronic Liver Failure score (CLIF-C ACLF) in predicting hospital mortality were compared. RESULTS: Mean age was 58.2±12.1 years; 77% were male. The main cause of admission was acute gastrointestinal bleeding (47%). The in-hospital mortality rate was 25.3%. Receiver operating characteristic curve analyses demonstrated that SOFA (0.82) MELD-Na (0.82) or MELD (0.81) scores at admission predicted in-hospital mortality better than Child-Pugh (0.76), SAPS II (0.77), SAPS III (0.75) or CLIF-C ACLF (0.75). We then developed the cirrhosis prognostic score (Ci-Pro), which performed better (0.89) than SOFA. CONCLUSION: SOFA, MELD and especially the Ci-Pro score show the best performance in predicting hospital mortality of cirrhotic patients admitted to an Intermediate Care Unit.