Brandon May

While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.

Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.

According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).

Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.

To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.

Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase and aspartate transaminase as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.

The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.

In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.

Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.

The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.

The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.

This article was updated on Sep. 20, 2022.

While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.

Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.

According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).

Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.

To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.

Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase and aspartate transaminase as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.

The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.

In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.

Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.

The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.

The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.

This article was updated on Sep. 20, 2022.

While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.

Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.

According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).

Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.

To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.

Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase and aspartate transaminase as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.

The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.

In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.

Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.

The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.

The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.

This article was updated on Sep. 20, 2022.

Treatment with endoscopic submucosal dissection (ESD) is associated with higher rates of complete remission of dysplasia at 2 years compared with cap-assisted endoscopic mucosal resection (cEMR) in patients with Barrett’s esophagus with dysplasia or early-stage intramucosal esophageal adenocarcinoma (EAC), according to study findings.

Despite the seeming advantage of ESD over cEMR, the study found similar rates of complete remission of intestinal metaplasia (CRIM) between the treatment groups at 2 years.

The study authors explained that ESD, a recent development in endoscopic resection, allows for en bloc resection of larger lesions in dysplastic Barrett’s and EAC and features less diagnostic uncertainty compared with cEMR. Findings from the study highlight the importance of this newer technique but also emphasize the utility of both treatments. “In expert hands both sets of procedures appear to be safe and well tolerated,” wrote study authors Don Codipilly, MD, of the Mayo Clinic in Rochester, Minn., and colleagues in Clinical Gastroenterology and Hepatology.

Given the lack of comparative data on the long-term outcomes of cEMR versus ESD in patients with neoplasia associated with Barrett’s esophagus, Dr. Codipilly and colleagues examined histologic outcomes in a prospectively maintained database of 537 patients who underwent endoscopic eradication therapy for Barrett’s esophagus or EAC at the Mayo Clinic between 2006 and 2020. Only patients who had undergone either cEMR (n = 456) or ESD (n = 81) followed by endoscopic ablation were included in the analysis.

The primary endpoint of the study was the rate and time to complete remission of dysplasia (CRD), which was defined by the absence of dysplasia on biopsy from the gastroesophageal junction and tubular esophagus during ≥1 surveillance endoscopy. Researchers also examined the rates of complications, such as clinically significant intraprocedural or post-procedural bleeding that required hospitalization, perforation, receipt of red blood cells within 30 days of the initial procedure, and stricture formation that required dilation within 120 days of the index procedure.

Patients in the ESD group had a longer mean length of resected specimens (23.9 vs. 10.9 mm; P <.01) as well as higher rates of en bloc (97.5% vs. 41.9%; P <.01) and R0 resection (58% vs. 20.2%; P <.01). Patients were generally balanced on other basic baseline demographics, including age, sex distribution, and smoking status.

Over a median 11.2-year follow-up period, a total of 420 patients in the cEMR group achieved CRD. In the ESD group, 48 patients achieved CRD over a median 1.4-year follow-up period. The 2-year cumulative probability of CRD was lower in patients who received cEMR versus those who received ESD (75.8% vs. 85.6%, respectively). In a univariate analysis, the odds of achieving CRD were lower in cEMR versus ESD (hazard ratio, 0.41; 95% CI, 0.31-0.54; P <.01).

According to multivariate analysis, 2 independent predictors of CRD included ESD (hazard ratio, 2.38; P <.01) and shorter Barrett’s segment length (HR, 1.11; P <.01).

The investigators also assessed whether advancements made in cEMR technique have contributed to the findings in an analysis of patients who underwent cEMR (n = 48) with ESD (n = 80) from 2015 to 2019. In this analysis, the researchers found that the odds of CRD were lower than that of ESD (HR, 0.67; 95% CI, 0.45-0.99). Additionally, higher odds of achieving CRD in the cEMR group were observed in years between 2013 and 2019 (n = 129) compared with years 2006 and 2012 (n = 112) (HR, 2.09; 95% CI, 1.59-2.75; P <.01).

Demographic and clinical variables were incorporated into a Cox proportional hazard model to identify factors associated with decreased odds of CRD. This analysis found that decreased odds of CRD were associated with longer Barrett’s esophagus segment length (HR, 0.90; P <.01) and treatment with cEMR versus ESD (HR, 0.42; P <.01).

Over median follow-up periods of 7.8 years in the cEMR group and 1.1 years in the ESD group, approximately 78.5% and 40.7% of patients, respectively, achieved CRIM. While those in the ESD group achieved CRIM earlier, the cumulative probabilities of CRIM were similar by 2 years (59.3% vs. 50.6%; HR, 0.74; 95% CI, 0.52-1.07; P =.11). Shorter Barrett’s esophagus segment was the only independent predictor of CRIM (HR, 1.16; P <.01).

The researchers noted that the study population may have included patients with more severe disease than that in the general population, which may limit the generalizability of the findings. Additionally, the lack of a randomized design was cited as an additional study limitation.

In spite of their findings, the researchers explained that “continued monitoring for additional outcomes such as recurrence are required for further elucidation of the optimal role of these procedures in the management of” neoplasia associated with Barrett’s esophagus.”

The study was funded by the National Cancer Institute and the Freeman Foundation. The researchers reported no conflicts of interest with any pharmaceutical companies.

Treatment with endoscopic submucosal dissection (ESD) is associated with higher rates of complete remission of dysplasia at 2 years compared with cap-assisted endoscopic mucosal resection (cEMR) in patients with Barrett’s esophagus with dysplasia or early-stage intramucosal esophageal adenocarcinoma (EAC), according to study findings.

Despite the seeming advantage of ESD over cEMR, the study found similar rates of complete remission of intestinal metaplasia (CRIM) between the treatment groups at 2 years.

The study authors explained that ESD, a recent development in endoscopic resection, allows for en bloc resection of larger lesions in dysplastic Barrett’s and EAC and features less diagnostic uncertainty compared with cEMR. Findings from the study highlight the importance of this newer technique but also emphasize the utility of both treatments. “In expert hands both sets of procedures appear to be safe and well tolerated,” wrote study authors Don Codipilly, MD, of the Mayo Clinic in Rochester, Minn., and colleagues in Clinical Gastroenterology and Hepatology.

Given the lack of comparative data on the long-term outcomes of cEMR versus ESD in patients with neoplasia associated with Barrett’s esophagus, Dr. Codipilly and colleagues examined histologic outcomes in a prospectively maintained database of 537 patients who underwent endoscopic eradication therapy for Barrett’s esophagus or EAC at the Mayo Clinic between 2006 and 2020. Only patients who had undergone either cEMR (n = 456) or ESD (n = 81) followed by endoscopic ablation were included in the analysis.

The primary endpoint of the study was the rate and time to complete remission of dysplasia (CRD), which was defined by the absence of dysplasia on biopsy from the gastroesophageal junction and tubular esophagus during ≥1 surveillance endoscopy. Researchers also examined the rates of complications, such as clinically significant intraprocedural or post-procedural bleeding that required hospitalization, perforation, receipt of red blood cells within 30 days of the initial procedure, and stricture formation that required dilation within 120 days of the index procedure.

Patients in the ESD group had a longer mean length of resected specimens (23.9 vs. 10.9 mm; P <.01) as well as higher rates of en bloc (97.5% vs. 41.9%; P <.01) and R0 resection (58% vs. 20.2%; P <.01). Patients were generally balanced on other basic baseline demographics, including age, sex distribution, and smoking status.

Over a median 11.2-year follow-up period, a total of 420 patients in the cEMR group achieved CRD. In the ESD group, 48 patients achieved CRD over a median 1.4-year follow-up period. The 2-year cumulative probability of CRD was lower in patients who received cEMR versus those who received ESD (75.8% vs. 85.6%, respectively). In a univariate analysis, the odds of achieving CRD were lower in cEMR versus ESD (hazard ratio, 0.41; 95% CI, 0.31-0.54; P <.01).

According to multivariate analysis, 2 independent predictors of CRD included ESD (hazard ratio, 2.38; P <.01) and shorter Barrett’s segment length (HR, 1.11; P <.01).

The investigators also assessed whether advancements made in cEMR technique have contributed to the findings in an analysis of patients who underwent cEMR (n = 48) with ESD (n = 80) from 2015 to 2019. In this analysis, the researchers found that the odds of CRD were lower than that of ESD (HR, 0.67; 95% CI, 0.45-0.99). Additionally, higher odds of achieving CRD in the cEMR group were observed in years between 2013 and 2019 (n = 129) compared with years 2006 and 2012 (n = 112) (HR, 2.09; 95% CI, 1.59-2.75; P <.01).

Demographic and clinical variables were incorporated into a Cox proportional hazard model to identify factors associated with decreased odds of CRD. This analysis found that decreased odds of CRD were associated with longer Barrett’s esophagus segment length (HR, 0.90; P <.01) and treatment with cEMR versus ESD (HR, 0.42; P <.01).

Over median follow-up periods of 7.8 years in the cEMR group and 1.1 years in the ESD group, approximately 78.5% and 40.7% of patients, respectively, achieved CRIM. While those in the ESD group achieved CRIM earlier, the cumulative probabilities of CRIM were similar by 2 years (59.3% vs. 50.6%; HR, 0.74; 95% CI, 0.52-1.07; P =.11). Shorter Barrett’s esophagus segment was the only independent predictor of CRIM (HR, 1.16; P <.01).

The researchers noted that the study population may have included patients with more severe disease than that in the general population, which may limit the generalizability of the findings. Additionally, the lack of a randomized design was cited as an additional study limitation.

In spite of their findings, the researchers explained that “continued monitoring for additional outcomes such as recurrence are required for further elucidation of the optimal role of these procedures in the management of” neoplasia associated with Barrett’s esophagus.”

The study was funded by the National Cancer Institute and the Freeman Foundation. The researchers reported no conflicts of interest with any pharmaceutical companies.

Treatment with endoscopic submucosal dissection (ESD) is associated with higher rates of complete remission of dysplasia at 2 years compared with cap-assisted endoscopic mucosal resection (cEMR) in patients with Barrett’s esophagus with dysplasia or early-stage intramucosal esophageal adenocarcinoma (EAC), according to study findings.

Despite the seeming advantage of ESD over cEMR, the study found similar rates of complete remission of intestinal metaplasia (CRIM) between the treatment groups at 2 years.

The study authors explained that ESD, a recent development in endoscopic resection, allows for en bloc resection of larger lesions in dysplastic Barrett’s and EAC and features less diagnostic uncertainty compared with cEMR. Findings from the study highlight the importance of this newer technique but also emphasize the utility of both treatments. “In expert hands both sets of procedures appear to be safe and well tolerated,” wrote study authors Don Codipilly, MD, of the Mayo Clinic in Rochester, Minn., and colleagues in Clinical Gastroenterology and Hepatology.

Given the lack of comparative data on the long-term outcomes of cEMR versus ESD in patients with neoplasia associated with Barrett’s esophagus, Dr. Codipilly and colleagues examined histologic outcomes in a prospectively maintained database of 537 patients who underwent endoscopic eradication therapy for Barrett’s esophagus or EAC at the Mayo Clinic between 2006 and 2020. Only patients who had undergone either cEMR (n = 456) or ESD (n = 81) followed by endoscopic ablation were included in the analysis.

The primary endpoint of the study was the rate and time to complete remission of dysplasia (CRD), which was defined by the absence of dysplasia on biopsy from the gastroesophageal junction and tubular esophagus during ≥1 surveillance endoscopy. Researchers also examined the rates of complications, such as clinically significant intraprocedural or post-procedural bleeding that required hospitalization, perforation, receipt of red blood cells within 30 days of the initial procedure, and stricture formation that required dilation within 120 days of the index procedure.

Patients in the ESD group had a longer mean length of resected specimens (23.9 vs. 10.9 mm; P <.01) as well as higher rates of en bloc (97.5% vs. 41.9%; P <.01) and R0 resection (58% vs. 20.2%; P <.01). Patients were generally balanced on other basic baseline demographics, including age, sex distribution, and smoking status.

Over a median 11.2-year follow-up period, a total of 420 patients in the cEMR group achieved CRD. In the ESD group, 48 patients achieved CRD over a median 1.4-year follow-up period. The 2-year cumulative probability of CRD was lower in patients who received cEMR versus those who received ESD (75.8% vs. 85.6%, respectively). In a univariate analysis, the odds of achieving CRD were lower in cEMR versus ESD (hazard ratio, 0.41; 95% CI, 0.31-0.54; P <.01).

According to multivariate analysis, 2 independent predictors of CRD included ESD (hazard ratio, 2.38; P <.01) and shorter Barrett’s segment length (HR, 1.11; P <.01).

The investigators also assessed whether advancements made in cEMR technique have contributed to the findings in an analysis of patients who underwent cEMR (n = 48) with ESD (n = 80) from 2015 to 2019. In this analysis, the researchers found that the odds of CRD were lower than that of ESD (HR, 0.67; 95% CI, 0.45-0.99). Additionally, higher odds of achieving CRD in the cEMR group were observed in years between 2013 and 2019 (n = 129) compared with years 2006 and 2012 (n = 112) (HR, 2.09; 95% CI, 1.59-2.75; P <.01).

Demographic and clinical variables were incorporated into a Cox proportional hazard model to identify factors associated with decreased odds of CRD. This analysis found that decreased odds of CRD were associated with longer Barrett’s esophagus segment length (HR, 0.90; P <.01) and treatment with cEMR versus ESD (HR, 0.42; P <.01).

Over median follow-up periods of 7.8 years in the cEMR group and 1.1 years in the ESD group, approximately 78.5% and 40.7% of patients, respectively, achieved CRIM. While those in the ESD group achieved CRIM earlier, the cumulative probabilities of CRIM were similar by 2 years (59.3% vs. 50.6%; HR, 0.74; 95% CI, 0.52-1.07; P =.11). Shorter Barrett’s esophagus segment was the only independent predictor of CRIM (HR, 1.16; P <.01).

The researchers noted that the study population may have included patients with more severe disease than that in the general population, which may limit the generalizability of the findings. Additionally, the lack of a randomized design was cited as an additional study limitation.

In spite of their findings, the researchers explained that “continued monitoring for additional outcomes such as recurrence are required for further elucidation of the optimal role of these procedures in the management of” neoplasia associated with Barrett’s esophagus.”

The study was funded by the National Cancer Institute and the Freeman Foundation. The researchers reported no conflicts of interest with any pharmaceutical companies.

While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.

Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.

According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).

Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.

To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.

Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase (ALT) and aspartate transaminase (AST) as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.

The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.

In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.

Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.

The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.

The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.

This article was updated on Sep. 20, 2022.

While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.

Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.

According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).

Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.

To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.

Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase (ALT) and aspartate transaminase (AST) as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.

The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.

In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.

Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.

The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.

The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.

This article was updated on Sep. 20, 2022.

While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.

Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.

According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).

Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.

To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.

Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase (ALT) and aspartate transaminase (AST) as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.

The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.

In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.

Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.

The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.

The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.

This article was updated on Sep. 20, 2022.

Patients with immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease and rheumatic conditions, have a reduced serologic response to a 2-dose vaccination regimen with mRNA COVID-19 vaccines, according to the findings of a meta-analysis.

“These results suggest that IMID patients receiving mRNA vaccines should complete the vaccine series without delay and support the strategy of providing a third dose of the vaccine,” wrote study authors Atsushi Sakuraba, MD, of the University of Chicago Medicine, and colleagues in Gastroenterology.

During the COVID-19 pandemic, concerns were raised about the susceptibility of patients with pre-existing conditions to infection with the novel coronavirus, the authors noted. Likewise, ongoing concerns have centered on the risk of worse COVID-19–related outcomes among patients with IMIDs who are treated with immunosuppressive agents.

Since the onset of the pandemic, several registries have been established to gauge the incidence and prognosis of COVID-19 in patients with IMID, including the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE)–Inflammatory Bowel Disease (IBD) registry and the COVID-19 Global Rheumatology Alliance 75 (C19-GRA), which includes patients with rheumatic diseases.

Authorization of COVID-19 mRNA vaccines provided hope that the COVID-19 pandemic could soon come to an end given the overwhelming safety and efficacy data supporting the use of these vaccines for preventing hospitalization and death. Despite these data, little is known regarding the efficacy of mRNA COVID-19 vaccines in patients with IMIDs and/or patients treated with immunosuppressive therapies, as these patients were excluded from the regulatory vaccine studies.

The study by Dr. Sakuraba and colleagues was a meta-analysis of 25 observational studies that reported serologic response rates to COVID-19 vaccination in a pooled cohort of 5,360 patients with IMIDs. Data regarding the reference population, medications, vaccination, and proportion of patients who achieved a serologic response were extracted from the observational studies and included in the meta-analysis.

In the analyzed studies, serologic response was evaluated separately after one or two vaccine doses. The researchers also examined the post-vaccine serologic response rate in patients with IMIDs versus controls without IMIDs.

A total of 23 studies used the BNT162b2 or mRNA-1273 vaccines, while 3 studies reported that 50% to 75.9% of patients received the AZD1222 vaccine. Some studies also included patients who received other COVID-19 vaccines, including CoronaVac, BBV152, and Ad26.COV2.S.

While 6 studies assessed serologic response to COVID-19 after just 1 dose, 20 studies assessed the post-vaccination serologic response following 2 doses. In most cases, researchers evaluated serologic response at 2 to 3 weeks after the first dose. After the second vaccine dose, most studies examined serologic response at 1 to 3 weeks.

The serologic response after 1 dose of the mRNA vaccines was 73.2% (95% CI 65.7-79.5). In a multivariate meta-regression analysis, the researchers found that a significantly greater proportion of patients with IMIDs who took anti-tumor necrosis factor (anti-TNF) therapies had a lower serologic response rate (coefficient, –2.60; 95% CI –4.49 to –0.72; P =.0069). The investigators indicated this “likely contributed to the difference in serologic response rates and overall heterogeneity.”

Studies with patients with IBD reported a lower serologic response rate compared with studies that included patients with rheumatoid arthritis (49.2% vs. 65.0%, respectively), which the investigators explained was likely reflective of the increased use of anti-TNF agents in patients with IBD.

After 2 doses of the mRNA vaccines, the pooled serologic response was 83.4% (95% CI, 76.8%-88.4%). Multivariate meta-regression found that a significantly greater proportion of patients who took anti-CD20 treatments had a lower serologic response (coefficient, -6.08; 95% CI -9.40 to -2.76; P <.001). The investigators found that older age was significantly associated with lower serologic response after 2 doses (coefficient, -0.044; 95% CI -0.083 to -0.0050; P =.027).

For the non-mRNA COVID-19 vaccines, the rates of serologic response after 2 doses were 93.5% with AZD1222, 22.9% with CoronaVac, and 55.6% with BBV152.

Compared with controls without IMIDs, those with IMIDs were significantly less likely to achieve a serologic response following 2 mRNA vaccine doses (odds ratio, 0.086; 95% CI 0.036-0.206; P <.001). The investigators noted that there were not enough studies to examine and compare serologic response rates to adenoviral or inactivated vaccines between patients and controls.

In terms of limitations, the researchers wrote that additional studies examining humoral and cellular immunity to COVID-19 vaccines are needed to determine vaccine efficacy and durability in patients with IMIDs. Additionally, there is a need for studies with larger patient populations to determine serologic response to COVID-19 vaccines in the broader IMID population.

The researchers reported no funding for the study and no relevant conflicts of interest with the pharmaceutical industry.

Patients with immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease and rheumatic conditions, have a reduced serologic response to a 2-dose vaccination regimen with mRNA COVID-19 vaccines, according to the findings of a meta-analysis.

“These results suggest that IMID patients receiving mRNA vaccines should complete the vaccine series without delay and support the strategy of providing a third dose of the vaccine,” wrote study authors Atsushi Sakuraba, MD, of the University of Chicago Medicine, and colleagues in Gastroenterology.

During the COVID-19 pandemic, concerns were raised about the susceptibility of patients with pre-existing conditions to infection with the novel coronavirus, the authors noted. Likewise, ongoing concerns have centered on the risk of worse COVID-19–related outcomes among patients with IMIDs who are treated with immunosuppressive agents.

Since the onset of the pandemic, several registries have been established to gauge the incidence and prognosis of COVID-19 in patients with IMID, including the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE)–Inflammatory Bowel Disease (IBD) registry and the COVID-19 Global Rheumatology Alliance 75 (C19-GRA), which includes patients with rheumatic diseases.

Authorization of COVID-19 mRNA vaccines provided hope that the COVID-19 pandemic could soon come to an end given the overwhelming safety and efficacy data supporting the use of these vaccines for preventing hospitalization and death. Despite these data, little is known regarding the efficacy of mRNA COVID-19 vaccines in patients with IMIDs and/or patients treated with immunosuppressive therapies, as these patients were excluded from the regulatory vaccine studies.

The study by Dr. Sakuraba and colleagues was a meta-analysis of 25 observational studies that reported serologic response rates to COVID-19 vaccination in a pooled cohort of 5,360 patients with IMIDs. Data regarding the reference population, medications, vaccination, and proportion of patients who achieved a serologic response were extracted from the observational studies and included in the meta-analysis.

In the analyzed studies, serologic response was evaluated separately after one or two vaccine doses. The researchers also examined the post-vaccine serologic response rate in patients with IMIDs versus controls without IMIDs.

A total of 23 studies used the BNT162b2 or mRNA-1273 vaccines, while 3 studies reported that 50% to 75.9% of patients received the AZD1222 vaccine. Some studies also included patients who received other COVID-19 vaccines, including CoronaVac, BBV152, and Ad26.COV2.S.

While 6 studies assessed serologic response to COVID-19 after just 1 dose, 20 studies assessed the post-vaccination serologic response following 2 doses. In most cases, researchers evaluated serologic response at 2 to 3 weeks after the first dose. After the second vaccine dose, most studies examined serologic response at 1 to 3 weeks.

The serologic response after 1 dose of the mRNA vaccines was 73.2% (95% CI 65.7-79.5). In a multivariate meta-regression analysis, the researchers found that a significantly greater proportion of patients with IMIDs who took anti-tumor necrosis factor (anti-TNF) therapies had a lower serologic response rate (coefficient, –2.60; 95% CI –4.49 to –0.72; P =.0069). The investigators indicated this “likely contributed to the difference in serologic response rates and overall heterogeneity.”

Studies with patients with IBD reported a lower serologic response rate compared with studies that included patients with rheumatoid arthritis (49.2% vs. 65.0%, respectively), which the investigators explained was likely reflective of the increased use of anti-TNF agents in patients with IBD.

After 2 doses of the mRNA vaccines, the pooled serologic response was 83.4% (95% CI, 76.8%-88.4%). Multivariate meta-regression found that a significantly greater proportion of patients who took anti-CD20 treatments had a lower serologic response (coefficient, -6.08; 95% CI -9.40 to -2.76; P <.001). The investigators found that older age was significantly associated with lower serologic response after 2 doses (coefficient, -0.044; 95% CI -0.083 to -0.0050; P =.027).

For the non-mRNA COVID-19 vaccines, the rates of serologic response after 2 doses were 93.5% with AZD1222, 22.9% with CoronaVac, and 55.6% with BBV152.

Compared with controls without IMIDs, those with IMIDs were significantly less likely to achieve a serologic response following 2 mRNA vaccine doses (odds ratio, 0.086; 95% CI 0.036-0.206; P <.001). The investigators noted that there were not enough studies to examine and compare serologic response rates to adenoviral or inactivated vaccines between patients and controls.

In terms of limitations, the researchers wrote that additional studies examining humoral and cellular immunity to COVID-19 vaccines are needed to determine vaccine efficacy and durability in patients with IMIDs. Additionally, there is a need for studies with larger patient populations to determine serologic response to COVID-19 vaccines in the broader IMID population.

The researchers reported no funding for the study and no relevant conflicts of interest with the pharmaceutical industry.

Patients with immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease and rheumatic conditions, have a reduced serologic response to a 2-dose vaccination regimen with mRNA COVID-19 vaccines, according to the findings of a meta-analysis.

“These results suggest that IMID patients receiving mRNA vaccines should complete the vaccine series without delay and support the strategy of providing a third dose of the vaccine,” wrote study authors Atsushi Sakuraba, MD, of the University of Chicago Medicine, and colleagues in Gastroenterology.

During the COVID-19 pandemic, concerns were raised about the susceptibility of patients with pre-existing conditions to infection with the novel coronavirus, the authors noted. Likewise, ongoing concerns have centered on the risk of worse COVID-19–related outcomes among patients with IMIDs who are treated with immunosuppressive agents.

Since the onset of the pandemic, several registries have been established to gauge the incidence and prognosis of COVID-19 in patients with IMID, including the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE)–Inflammatory Bowel Disease (IBD) registry and the COVID-19 Global Rheumatology Alliance 75 (C19-GRA), which includes patients with rheumatic diseases.

Authorization of COVID-19 mRNA vaccines provided hope that the COVID-19 pandemic could soon come to an end given the overwhelming safety and efficacy data supporting the use of these vaccines for preventing hospitalization and death. Despite these data, little is known regarding the efficacy of mRNA COVID-19 vaccines in patients with IMIDs and/or patients treated with immunosuppressive therapies, as these patients were excluded from the regulatory vaccine studies.

The study by Dr. Sakuraba and colleagues was a meta-analysis of 25 observational studies that reported serologic response rates to COVID-19 vaccination in a pooled cohort of 5,360 patients with IMIDs. Data regarding the reference population, medications, vaccination, and proportion of patients who achieved a serologic response were extracted from the observational studies and included in the meta-analysis.

In the analyzed studies, serologic response was evaluated separately after one or two vaccine doses. The researchers also examined the post-vaccine serologic response rate in patients with IMIDs versus controls without IMIDs.

A total of 23 studies used the BNT162b2 or mRNA-1273 vaccines, while 3 studies reported that 50% to 75.9% of patients received the AZD1222 vaccine. Some studies also included patients who received other COVID-19 vaccines, including CoronaVac, BBV152, and Ad26.COV2.S.

While 6 studies assessed serologic response to COVID-19 after just 1 dose, 20 studies assessed the post-vaccination serologic response following 2 doses. In most cases, researchers evaluated serologic response at 2 to 3 weeks after the first dose. After the second vaccine dose, most studies examined serologic response at 1 to 3 weeks.

The serologic response after 1 dose of the mRNA vaccines was 73.2% (95% CI 65.7-79.5). In a multivariate meta-regression analysis, the researchers found that a significantly greater proportion of patients with IMIDs who took anti-tumor necrosis factor (anti-TNF) therapies had a lower serologic response rate (coefficient, –2.60; 95% CI –4.49 to –0.72; P =.0069). The investigators indicated this “likely contributed to the difference in serologic response rates and overall heterogeneity.”

Studies with patients with IBD reported a lower serologic response rate compared with studies that included patients with rheumatoid arthritis (49.2% vs. 65.0%, respectively), which the investigators explained was likely reflective of the increased use of anti-TNF agents in patients with IBD.

After 2 doses of the mRNA vaccines, the pooled serologic response was 83.4% (95% CI, 76.8%-88.4%). Multivariate meta-regression found that a significantly greater proportion of patients who took anti-CD20 treatments had a lower serologic response (coefficient, -6.08; 95% CI -9.40 to -2.76; P <.001). The investigators found that older age was significantly associated with lower serologic response after 2 doses (coefficient, -0.044; 95% CI -0.083 to -0.0050; P =.027).

For the non-mRNA COVID-19 vaccines, the rates of serologic response after 2 doses were 93.5% with AZD1222, 22.9% with CoronaVac, and 55.6% with BBV152.

Compared with controls without IMIDs, those with IMIDs were significantly less likely to achieve a serologic response following 2 mRNA vaccine doses (odds ratio, 0.086; 95% CI 0.036-0.206; P <.001). The investigators noted that there were not enough studies to examine and compare serologic response rates to adenoviral or inactivated vaccines between patients and controls.

In terms of limitations, the researchers wrote that additional studies examining humoral and cellular immunity to COVID-19 vaccines are needed to determine vaccine efficacy and durability in patients with IMIDs. Additionally, there is a need for studies with larger patient populations to determine serologic response to COVID-19 vaccines in the broader IMID population.

The researchers reported no funding for the study and no relevant conflicts of interest with the pharmaceutical industry.

Despite the clinical value of medical devices, there is a potential for these products to cause adverse skin reactions in some patients. Findings from a European retrospective study, published in the European Journal of Allergy and Clinical Immunology, show that nearly one-quarter of patients with suspected allergic contact dermatitis were referred for patch testing for contact allergies associated with medical devices, highlighting the possibility of a high prevalence of contact allergens in these devices.

“We found it important to publish these findings, because up until now no clear figures have been reported regarding this particular clinical problem,” said study author Olivier Aerts, MD, a researcher in the contact allergy unit at the University Hospital Antwerp, Belgium, in an interview with this news organization.

For the study, Dr. Aerts and colleagues conducted a retrospective analysis of medical device users with suspected allergic contact dermatitis. All patients had been patch tested at a tertiary European clinic between 2018 and 2020.

The cohort included patients who experienced suspected contact allergy from medical adhesives (n = 57), gloves (n = 38), topical and surface medical devices (n = 38), glucose sensors and insulin pumps (n = 74), and prostheses (n = 75). Other medical products associated with contact allergy in another 44 patients included surgical glues, face masks, compression stockings, condoms, and suture materials.

Overall, 326 patients had been patch-tested during the 30-month study period. Approximately 25.8% of all patients – including 299 adults and 27 children – were referred for contact allergy associated with medical devices.

Acrylates were the most frequently encountered contact allergens and were found in diabetes devices and medical adhesives. Potential skin sensitizers included colophonium-related substances, D-limonene, isothiazolinone derivatives, salicylates, and sulphites, all of which were identified across most products.

According to the investigators, many of the labels for the medical devices made no mention of the potential skin sensitizers, except in the cases of some topical and surface disinfectants. And many topical products are often marketed as medical devices rather than cosmetics, further complicating labeling issues, according to Dr. Aerts.

“What should be done to help any patient suffering from allergic contact due to medical devices is that these devices should be labeled with all their components, or at the very least with the potential skin sensitizers these may contain,” Dr. Aerts explained. He added that manufacturers should “establish more cooperation with physicians/dermatologists who evaluate such patients,” a cooperation that often exists with cosmetic companies.

Dr. Aerts noted that while it’s important for patch testers and dermatologists to be aware of the prevalence of allergic contact dermatitis in medical device users, companies producing these devices should also be aware of these potential issues. “Additionally, legislators/regulators should perhaps focus some more on the cutaneous side effects these products may provoke,” he said, “as this awareness may hopefully also serve as a stimulant to perform more clinical allergy research in this field.”

Leonard Bielory, MD, an allergist at Robert Wood Johnson University Hospital in Rahway, New Jersey, told this news organization that the findings are “alarming” and should heighten clinicians’ awareness of the possibility of allergic contact dermatitis among medical device users.

Dr. Bielory, who wasn’t involved in the research, noted that the findings from this study may not be entirely generalizable to the U.S., given the study was performed in Europe. “In contrast to other countries, the U.S. is very conscientious about allergic responses to items being used in hospitals,” he added, “or such that the issue here is that many of these things would be an adverse reaction, which you have to report.” He suggested that further research in this field is needed to determine the prevalence of possible skin sensitizers in products specifically developed and marketed in the U.S.

The study had no specific funding. Dr. Aerts and Dr. Bielory have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Despite the clinical value of medical devices, there is a potential for these products to cause adverse skin reactions in some patients. Findings from a European retrospective study, published in the European Journal of Allergy and Clinical Immunology, show that nearly one-quarter of patients with suspected allergic contact dermatitis were referred for patch testing for contact allergies associated with medical devices, highlighting the possibility of a high prevalence of contact allergens in these devices.

“We found it important to publish these findings, because up until now no clear figures have been reported regarding this particular clinical problem,” said study author Olivier Aerts, MD, a researcher in the contact allergy unit at the University Hospital Antwerp, Belgium, in an interview with this news organization.

For the study, Dr. Aerts and colleagues conducted a retrospective analysis of medical device users with suspected allergic contact dermatitis. All patients had been patch tested at a tertiary European clinic between 2018 and 2020.

The cohort included patients who experienced suspected contact allergy from medical adhesives (n = 57), gloves (n = 38), topical and surface medical devices (n = 38), glucose sensors and insulin pumps (n = 74), and prostheses (n = 75). Other medical products associated with contact allergy in another 44 patients included surgical glues, face masks, compression stockings, condoms, and suture materials.

Overall, 326 patients had been patch-tested during the 30-month study period. Approximately 25.8% of all patients – including 299 adults and 27 children – were referred for contact allergy associated with medical devices.

Acrylates were the most frequently encountered contact allergens and were found in diabetes devices and medical adhesives. Potential skin sensitizers included colophonium-related substances, D-limonene, isothiazolinone derivatives, salicylates, and sulphites, all of which were identified across most products.

According to the investigators, many of the labels for the medical devices made no mention of the potential skin sensitizers, except in the cases of some topical and surface disinfectants. And many topical products are often marketed as medical devices rather than cosmetics, further complicating labeling issues, according to Dr. Aerts.

“What should be done to help any patient suffering from allergic contact due to medical devices is that these devices should be labeled with all their components, or at the very least with the potential skin sensitizers these may contain,” Dr. Aerts explained. He added that manufacturers should “establish more cooperation with physicians/dermatologists who evaluate such patients,” a cooperation that often exists with cosmetic companies.

Dr. Aerts noted that while it’s important for patch testers and dermatologists to be aware of the prevalence of allergic contact dermatitis in medical device users, companies producing these devices should also be aware of these potential issues. “Additionally, legislators/regulators should perhaps focus some more on the cutaneous side effects these products may provoke,” he said, “as this awareness may hopefully also serve as a stimulant to perform more clinical allergy research in this field.”

Leonard Bielory, MD, an allergist at Robert Wood Johnson University Hospital in Rahway, New Jersey, told this news organization that the findings are “alarming” and should heighten clinicians’ awareness of the possibility of allergic contact dermatitis among medical device users.

Dr. Bielory, who wasn’t involved in the research, noted that the findings from this study may not be entirely generalizable to the U.S., given the study was performed in Europe. “In contrast to other countries, the U.S. is very conscientious about allergic responses to items being used in hospitals,” he added, “or such that the issue here is that many of these things would be an adverse reaction, which you have to report.” He suggested that further research in this field is needed to determine the prevalence of possible skin sensitizers in products specifically developed and marketed in the U.S.

The study had no specific funding. Dr. Aerts and Dr. Bielory have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Despite the clinical value of medical devices, there is a potential for these products to cause adverse skin reactions in some patients. Findings from a European retrospective study, published in the European Journal of Allergy and Clinical Immunology, show that nearly one-quarter of patients with suspected allergic contact dermatitis were referred for patch testing for contact allergies associated with medical devices, highlighting the possibility of a high prevalence of contact allergens in these devices.

“We found it important to publish these findings, because up until now no clear figures have been reported regarding this particular clinical problem,” said study author Olivier Aerts, MD, a researcher in the contact allergy unit at the University Hospital Antwerp, Belgium, in an interview with this news organization.

For the study, Dr. Aerts and colleagues conducted a retrospective analysis of medical device users with suspected allergic contact dermatitis. All patients had been patch tested at a tertiary European clinic between 2018 and 2020.

The cohort included patients who experienced suspected contact allergy from medical adhesives (n = 57), gloves (n = 38), topical and surface medical devices (n = 38), glucose sensors and insulin pumps (n = 74), and prostheses (n = 75). Other medical products associated with contact allergy in another 44 patients included surgical glues, face masks, compression stockings, condoms, and suture materials.

Overall, 326 patients had been patch-tested during the 30-month study period. Approximately 25.8% of all patients – including 299 adults and 27 children – were referred for contact allergy associated with medical devices.

Acrylates were the most frequently encountered contact allergens and were found in diabetes devices and medical adhesives. Potential skin sensitizers included colophonium-related substances, D-limonene, isothiazolinone derivatives, salicylates, and sulphites, all of which were identified across most products.

According to the investigators, many of the labels for the medical devices made no mention of the potential skin sensitizers, except in the cases of some topical and surface disinfectants. And many topical products are often marketed as medical devices rather than cosmetics, further complicating labeling issues, according to Dr. Aerts.

“What should be done to help any patient suffering from allergic contact due to medical devices is that these devices should be labeled with all their components, or at the very least with the potential skin sensitizers these may contain,” Dr. Aerts explained. He added that manufacturers should “establish more cooperation with physicians/dermatologists who evaluate such patients,” a cooperation that often exists with cosmetic companies.

Dr. Aerts noted that while it’s important for patch testers and dermatologists to be aware of the prevalence of allergic contact dermatitis in medical device users, companies producing these devices should also be aware of these potential issues. “Additionally, legislators/regulators should perhaps focus some more on the cutaneous side effects these products may provoke,” he said, “as this awareness may hopefully also serve as a stimulant to perform more clinical allergy research in this field.”

Leonard Bielory, MD, an allergist at Robert Wood Johnson University Hospital in Rahway, New Jersey, told this news organization that the findings are “alarming” and should heighten clinicians’ awareness of the possibility of allergic contact dermatitis among medical device users.

Dr. Bielory, who wasn’t involved in the research, noted that the findings from this study may not be entirely generalizable to the U.S., given the study was performed in Europe. “In contrast to other countries, the U.S. is very conscientious about allergic responses to items being used in hospitals,” he added, “or such that the issue here is that many of these things would be an adverse reaction, which you have to report.” He suggested that further research in this field is needed to determine the prevalence of possible skin sensitizers in products specifically developed and marketed in the U.S.

The study had no specific funding. Dr. Aerts and Dr. Bielory have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A blood-based biomarker panel that includes DNA and protein markers featured a 71% sensitivity at 90% specificity for the detection of early-stage hepatocellular carcinoma (HCC) compared with the GALAD (gender, age, a-fetoprotein [AFP], Lens culinaris agglutinin-reactive AFP [AFP-L3], and des-gamma-carboxy-prothrombin [DCP]) score or AFP alone, according to research findings. The panel reportedly performed well in certain subgroups based on sex, presence of cirrhosis, and liver disease etiology.

Jezperklauzen/ThinkStock

The study, which included inpatients with HCC and controls without HCC but underlying liver disease, suggests the panel could be utilized in the detection of early stage disease in patients with well-established risk factors for HCC. Ultimately, this may lead to earlier treatment initiation and potentially improved clinical outcomes.

“A blood-based marker panel that detects early-stage HCC with higher sensitivity than current biomarker-based approaches could substantially benefit patients undergoing HCC surveillance,” wrote study authors Naga Chalasani, MD, of Indiana University, Indianapolis, and colleagues. Their report is in Clinical Gastroenterology and Hepatology.

HCC, which accounts for most primary liver cancers, generally occurs in patients with several established risk factors, including alcoholic liver disease or nonalcoholic fatty liver disease as well as chronic hepatitis B virus or hepatitis C virus infection. Current guidelines, such as those from the European Association for the Study of the Liver and those from the American Association for the Study of Liver Diseases, recommend surveillance of at-risk patients every 6 months by ultrasound with or without AFP measurement. When caught early, HCC is typically treatable and is associated with a higher rate of survival compared with late-stage disease. According to Dr. Chalasani and colleagues, however, the effectiveness of current recommended surveillance for very early stage or early stage HCC is poor, characterized by a 45% sensitivity for ultrasound and a 63% sensitivity for ultrasound coupled with AFP measurement.

The investigators of the multicenter, case-control study collected blood specimens from 135 patients with HCC as well as 302 age-matched controls with underlying liver disease but no HCC. Very early or early stage disease was seen in approximately 56.3% of patients with HCC, and intermediate, advanced, or terminal stage disease was seen in 43.7% of patients.

To predict cases of HCC, the researchers used a logistic regression algorithm to analyze 10 methylated DNA markers (MDMs) associated with HCC, methylated B3GALT6 (reference DNA marker), and 3 candidate proteins. Finally, the researchers compared the accuracy of the developed blood-based biomarker panel with other blood-based biomarkers – including the GALAD, AFP, AFP-L3, DCP – for the detection of HCC.

The multitarget HCC panel included 3 MDMs – HOXA1, EMX1, and TSPYL5. In addition, the panel included methylation reference marker B3GALT6 and the protein markers AFP and AFP-L3. The biomarker panel featured a higher sensitivity (71%; 95% confidence interval, 60-81) at 90% specificity for the detection of early stage HCC compared with the GALAD score (41%; 95% CI, 30-53) or AFP ≥ 7.32 ng/mL (45%; 95% CI, 33-57). The area under the curve for the novel HCC panel for the detection of any stage HCC was 0.92 vs. 0.87 for the GALAD and 0.81 for the AFP measurement alone. The researchers found that the performance of the test was similar between men and women in terms of sensitivity (79% and 84%, respectively). Moreover, the panel performed similarly well among subgroups based on presence of cirrhosis and liver disease etiology.

A potential limitation of this study was the inclusion of controls who were largely confirmed HCC negative by ultrasound, a technique that lacks sensitivity for detecting early stage HCC, the researchers noted. Given this limitation, the researchers suggest that some of the control participants may have had underlying HCC that was missed by ultrasound. Furthermore, the findings indicate that the cross-sectional nature of the study may also mean some of the control participants had HCCs that were undetectable at initial screening.

Despite the limitations of the study, the researchers reported that the novel, blood-based marker panel’s sensitivity for detecting early stage HCC likely supports its use “among at-risk patients to enhance HCC surveillance and improve early cancer detection.”

The study was funded by the Exact Sciences Corporation. The researchers reported conflicts of interest with several pharmaceutical companies.

A blood-based biomarker panel that includes DNA and protein markers featured a 71% sensitivity at 90% specificity for the detection of early-stage hepatocellular carcinoma (HCC) compared with the GALAD (gender, age, a-fetoprotein [AFP], Lens culinaris agglutinin-reactive AFP [AFP-L3], and des-gamma-carboxy-prothrombin [DCP]) score or AFP alone, according to research findings. The panel reportedly performed well in certain subgroups based on sex, presence of cirrhosis, and liver disease etiology.

Jezperklauzen/ThinkStock

The study, which included inpatients with HCC and controls without HCC but underlying liver disease, suggests the panel could be utilized in the detection of early stage disease in patients with well-established risk factors for HCC. Ultimately, this may lead to earlier treatment initiation and potentially improved clinical outcomes.

“A blood-based marker panel that detects early-stage HCC with higher sensitivity than current biomarker-based approaches could substantially benefit patients undergoing HCC surveillance,” wrote study authors Naga Chalasani, MD, of Indiana University, Indianapolis, and colleagues. Their report is in Clinical Gastroenterology and Hepatology.

HCC, which accounts for most primary liver cancers, generally occurs in patients with several established risk factors, including alcoholic liver disease or nonalcoholic fatty liver disease as well as chronic hepatitis B virus or hepatitis C virus infection. Current guidelines, such as those from the European Association for the Study of the Liver and those from the American Association for the Study of Liver Diseases, recommend surveillance of at-risk patients every 6 months by ultrasound with or without AFP measurement. When caught early, HCC is typically treatable and is associated with a higher rate of survival compared with late-stage disease. According to Dr. Chalasani and colleagues, however, the effectiveness of current recommended surveillance for very early stage or early stage HCC is poor, characterized by a 45% sensitivity for ultrasound and a 63% sensitivity for ultrasound coupled with AFP measurement.

The investigators of the multicenter, case-control study collected blood specimens from 135 patients with HCC as well as 302 age-matched controls with underlying liver disease but no HCC. Very early or early stage disease was seen in approximately 56.3% of patients with HCC, and intermediate, advanced, or terminal stage disease was seen in 43.7% of patients.

To predict cases of HCC, the researchers used a logistic regression algorithm to analyze 10 methylated DNA markers (MDMs) associated with HCC, methylated B3GALT6 (reference DNA marker), and 3 candidate proteins. Finally, the researchers compared the accuracy of the developed blood-based biomarker panel with other blood-based biomarkers – including the GALAD, AFP, AFP-L3, DCP – for the detection of HCC.

The multitarget HCC panel included 3 MDMs – HOXA1, EMX1, and TSPYL5. In addition, the panel included methylation reference marker B3GALT6 and the protein markers AFP and AFP-L3. The biomarker panel featured a higher sensitivity (71%; 95% confidence interval, 60-81) at 90% specificity for the detection of early stage HCC compared with the GALAD score (41%; 95% CI, 30-53) or AFP ≥ 7.32 ng/mL (45%; 95% CI, 33-57). The area under the curve for the novel HCC panel for the detection of any stage HCC was 0.92 vs. 0.87 for the GALAD and 0.81 for the AFP measurement alone. The researchers found that the performance of the test was similar between men and women in terms of sensitivity (79% and 84%, respectively). Moreover, the panel performed similarly well among subgroups based on presence of cirrhosis and liver disease etiology.

A potential limitation of this study was the inclusion of controls who were largely confirmed HCC negative by ultrasound, a technique that lacks sensitivity for detecting early stage HCC, the researchers noted. Given this limitation, the researchers suggest that some of the control participants may have had underlying HCC that was missed by ultrasound. Furthermore, the findings indicate that the cross-sectional nature of the study may also mean some of the control participants had HCCs that were undetectable at initial screening.

Despite the limitations of the study, the researchers reported that the novel, blood-based marker panel’s sensitivity for detecting early stage HCC likely supports its use “among at-risk patients to enhance HCC surveillance and improve early cancer detection.”

The study was funded by the Exact Sciences Corporation. The researchers reported conflicts of interest with several pharmaceutical companies.

A blood-based biomarker panel that includes DNA and protein markers featured a 71% sensitivity at 90% specificity for the detection of early-stage hepatocellular carcinoma (HCC) compared with the GALAD (gender, age, a-fetoprotein [AFP], Lens culinaris agglutinin-reactive AFP [AFP-L3], and des-gamma-carboxy-prothrombin [DCP]) score or AFP alone, according to research findings. The panel reportedly performed well in certain subgroups based on sex, presence of cirrhosis, and liver disease etiology.

Jezperklauzen/ThinkStock

The study, which included inpatients with HCC and controls without HCC but underlying liver disease, suggests the panel could be utilized in the detection of early stage disease in patients with well-established risk factors for HCC. Ultimately, this may lead to earlier treatment initiation and potentially improved clinical outcomes.

“A blood-based marker panel that detects early-stage HCC with higher sensitivity than current biomarker-based approaches could substantially benefit patients undergoing HCC surveillance,” wrote study authors Naga Chalasani, MD, of Indiana University, Indianapolis, and colleagues. Their report is in Clinical Gastroenterology and Hepatology.

HCC, which accounts for most primary liver cancers, generally occurs in patients with several established risk factors, including alcoholic liver disease or nonalcoholic fatty liver disease as well as chronic hepatitis B virus or hepatitis C virus infection. Current guidelines, such as those from the European Association for the Study of the Liver and those from the American Association for the Study of Liver Diseases, recommend surveillance of at-risk patients every 6 months by ultrasound with or without AFP measurement. When caught early, HCC is typically treatable and is associated with a higher rate of survival compared with late-stage disease. According to Dr. Chalasani and colleagues, however, the effectiveness of current recommended surveillance for very early stage or early stage HCC is poor, characterized by a 45% sensitivity for ultrasound and a 63% sensitivity for ultrasound coupled with AFP measurement.

The investigators of the multicenter, case-control study collected blood specimens from 135 patients with HCC as well as 302 age-matched controls with underlying liver disease but no HCC. Very early or early stage disease was seen in approximately 56.3% of patients with HCC, and intermediate, advanced, or terminal stage disease was seen in 43.7% of patients.

To predict cases of HCC, the researchers used a logistic regression algorithm to analyze 10 methylated DNA markers (MDMs) associated with HCC, methylated B3GALT6 (reference DNA marker), and 3 candidate proteins. Finally, the researchers compared the accuracy of the developed blood-based biomarker panel with other blood-based biomarkers – including the GALAD, AFP, AFP-L3, DCP – for the detection of HCC.

The multitarget HCC panel included 3 MDMs – HOXA1, EMX1, and TSPYL5. In addition, the panel included methylation reference marker B3GALT6 and the protein markers AFP and AFP-L3. The biomarker panel featured a higher sensitivity (71%; 95% confidence interval, 60-81) at 90% specificity for the detection of early stage HCC compared with the GALAD score (41%; 95% CI, 30-53) or AFP ≥ 7.32 ng/mL (45%; 95% CI, 33-57). The area under the curve for the novel HCC panel for the detection of any stage HCC was 0.92 vs. 0.87 for the GALAD and 0.81 for the AFP measurement alone. The researchers found that the performance of the test was similar between men and women in terms of sensitivity (79% and 84%, respectively). Moreover, the panel performed similarly well among subgroups based on presence of cirrhosis and liver disease etiology.

A potential limitation of this study was the inclusion of controls who were largely confirmed HCC negative by ultrasound, a technique that lacks sensitivity for detecting early stage HCC, the researchers noted. Given this limitation, the researchers suggest that some of the control participants may have had underlying HCC that was missed by ultrasound. Furthermore, the findings indicate that the cross-sectional nature of the study may also mean some of the control participants had HCCs that were undetectable at initial screening.

Despite the limitations of the study, the researchers reported that the novel, blood-based marker panel’s sensitivity for detecting early stage HCC likely supports its use “among at-risk patients to enhance HCC surveillance and improve early cancer detection.”

The study was funded by the Exact Sciences Corporation. The researchers reported conflicts of interest with several pharmaceutical companies.

In a new study, researchers stimulated immune cells to assemble into tertiary lymphoid structures that improved the efficacy of chemotherapy in a preclinical model of pancreatic cancer.

Overall, the evidence generated by the study supports the notion that induction of tertiary lymphoid structures may potentiate chemotherapy’s antitumor activity, at least in a murine model of pancreatic ductal adenocarcinoma (PDAC). A more detailed understanding of tertiary lymphoid structure “kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immuno-oncology,” Francesca Delvecchio of Queen Mary University of London and colleagues wrote in Cellular and Molecular Gastroenterology and Hepatology.

While the immune system can play a role in combating cancer, a dense stroma surrounds pancreatic cancer cells, often blocking the ability of certain immune cells, such as T cells, from accessing the tumor. As shown by Young and colleagues, this causes immunotherapies to have very little success in the management of most pancreatic cancers, despite the efficacy of these therapies in other types of cancer.

In a proportion of patients with pancreatic cancer, clusters of immune cells can assemble tertiary lymphoid structures within the stroma that surrounds pancreatic cancer. These structures are associated with improved survival in PDAC. In the study, Mr. Delvecchio and colleagues sought to further elucidate the role of tertiary lymphoid structures in PDAC, particularly the structures’ antitumor potential.

The investigators analyzed donated tissue samples from patients to identify the presence of the structures within chemotherapy-naive human pancreatic cancer. Tertiary lymphoid structures were defined by the presence of tissue zones that were rich in T cells, B cells, and dendritic cells. Staining techniques were used to visualize the various cell types in the samples, revealing tertiary lymphoid structures in approximately 30% of tissue microarrays and 42% of the full section.

Multicolor immunofluorescence and immunohistochemistry were also used to characterize tertiary lymphoid structures in murine models of pancreatic cancer. Additionally, the investigators developed an orthotopic murine model to assess the development of the structures and their role in improving the therapeutic effects of chemotherapy. While tertiary lymphoid structures were not initially present in the preclinical murine model, B cells and T cells subsequently infiltrated into the tumor site following injection of lymphoid chemokines. These cells consequently assembled into the tertiary lymphoid structures.

In addition, the researchers combined chemotherapy gemcitabine with the intratumoral lymphoid chemokine and injected this combination treatment into orthotopic tumors. Following injection, the researchers observed “altered immune cell infiltration,” which facilitated the induction of tertiary lymphoid structures and potentiated antitumor activity of the chemotherapy. As a result, there was a significant reduction in the tumors, an effect the researchers did not find following the use of either treatment alone.

According to the investigators, the antitumor activity observed following induction of the tertiary lymphoid structures within the cancer is associated with B cell–mediated activation of dendritic cells, a key cell type involved in initiating an immune response.

Based on the findings, the researchers concluded that the combination of chemotherapy and lymphoid chemokines might be a viable strategy for promoting an antitumor immune response in pancreatic cancer. In turn, the researchers suggest this strategy may result in better clinical outcomes for patients with the disease. Additionally, the researchers wrote that mature tertiary lymphoid structures in PDAC prior to an immune treatment could “be used as a biomarker to define inclusion criteria of patients in immunotherapy protocols, with the aim to boost the ongoing antitumor immune response.”

The study relied on a mouse model and for this reason, it remains unclear at this time if the findings will be generalizable to humans. In the context of PDAC, the researchers wrote that further investigation and understanding of the formation of tertiary lymphoid structures may support the development of tailored treatments, including those that take advantage of the body’s immune system, to combat cancer and improve patient outcomes.

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

In a new study, researchers stimulated immune cells to assemble into tertiary lymphoid structures that improved the efficacy of chemotherapy in a preclinical model of pancreatic cancer.

Overall, the evidence generated by the study supports the notion that induction of tertiary lymphoid structures may potentiate chemotherapy’s antitumor activity, at least in a murine model of pancreatic ductal adenocarcinoma (PDAC). A more detailed understanding of tertiary lymphoid structure “kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immuno-oncology,” Francesca Delvecchio of Queen Mary University of London and colleagues wrote in Cellular and Molecular Gastroenterology and Hepatology.

While the immune system can play a role in combating cancer, a dense stroma surrounds pancreatic cancer cells, often blocking the ability of certain immune cells, such as T cells, from accessing the tumor. As shown by Young and colleagues, this causes immunotherapies to have very little success in the management of most pancreatic cancers, despite the efficacy of these therapies in other types of cancer.

In a proportion of patients with pancreatic cancer, clusters of immune cells can assemble tertiary lymphoid structures within the stroma that surrounds pancreatic cancer. These structures are associated with improved survival in PDAC. In the study, Mr. Delvecchio and colleagues sought to further elucidate the role of tertiary lymphoid structures in PDAC, particularly the structures’ antitumor potential.

The investigators analyzed donated tissue samples from patients to identify the presence of the structures within chemotherapy-naive human pancreatic cancer. Tertiary lymphoid structures were defined by the presence of tissue zones that were rich in T cells, B cells, and dendritic cells. Staining techniques were used to visualize the various cell types in the samples, revealing tertiary lymphoid structures in approximately 30% of tissue microarrays and 42% of the full section.

Multicolor immunofluorescence and immunohistochemistry were also used to characterize tertiary lymphoid structures in murine models of pancreatic cancer. Additionally, the investigators developed an orthotopic murine model to assess the development of the structures and their role in improving the therapeutic effects of chemotherapy. While tertiary lymphoid structures were not initially present in the preclinical murine model, B cells and T cells subsequently infiltrated into the tumor site following injection of lymphoid chemokines. These cells consequently assembled into the tertiary lymphoid structures.

In addition, the researchers combined chemotherapy gemcitabine with the intratumoral lymphoid chemokine and injected this combination treatment into orthotopic tumors. Following injection, the researchers observed “altered immune cell infiltration,” which facilitated the induction of tertiary lymphoid structures and potentiated antitumor activity of the chemotherapy. As a result, there was a significant reduction in the tumors, an effect the researchers did not find following the use of either treatment alone.

According to the investigators, the antitumor activity observed following induction of the tertiary lymphoid structures within the cancer is associated with B cell–mediated activation of dendritic cells, a key cell type involved in initiating an immune response.

Based on the findings, the researchers concluded that the combination of chemotherapy and lymphoid chemokines might be a viable strategy for promoting an antitumor immune response in pancreatic cancer. In turn, the researchers suggest this strategy may result in better clinical outcomes for patients with the disease. Additionally, the researchers wrote that mature tertiary lymphoid structures in PDAC prior to an immune treatment could “be used as a biomarker to define inclusion criteria of patients in immunotherapy protocols, with the aim to boost the ongoing antitumor immune response.”

The study relied on a mouse model and for this reason, it remains unclear at this time if the findings will be generalizable to humans. In the context of PDAC, the researchers wrote that further investigation and understanding of the formation of tertiary lymphoid structures may support the development of tailored treatments, including those that take advantage of the body’s immune system, to combat cancer and improve patient outcomes.

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

In a new study, researchers stimulated immune cells to assemble into tertiary lymphoid structures that improved the efficacy of chemotherapy in a preclinical model of pancreatic cancer.

Overall, the evidence generated by the study supports the notion that induction of tertiary lymphoid structures may potentiate chemotherapy’s antitumor activity, at least in a murine model of pancreatic ductal adenocarcinoma (PDAC). A more detailed understanding of tertiary lymphoid structure “kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immuno-oncology,” Francesca Delvecchio of Queen Mary University of London and colleagues wrote in Cellular and Molecular Gastroenterology and Hepatology.

While the immune system can play a role in combating cancer, a dense stroma surrounds pancreatic cancer cells, often blocking the ability of certain immune cells, such as T cells, from accessing the tumor. As shown by Young and colleagues, this causes immunotherapies to have very little success in the management of most pancreatic cancers, despite the efficacy of these therapies in other types of cancer.

In a proportion of patients with pancreatic cancer, clusters of immune cells can assemble tertiary lymphoid structures within the stroma that surrounds pancreatic cancer. These structures are associated with improved survival in PDAC. In the study, Mr. Delvecchio and colleagues sought to further elucidate the role of tertiary lymphoid structures in PDAC, particularly the structures’ antitumor potential.

The investigators analyzed donated tissue samples from patients to identify the presence of the structures within chemotherapy-naive human pancreatic cancer. Tertiary lymphoid structures were defined by the presence of tissue zones that were rich in T cells, B cells, and dendritic cells. Staining techniques were used to visualize the various cell types in the samples, revealing tertiary lymphoid structures in approximately 30% of tissue microarrays and 42% of the full section.

Multicolor immunofluorescence and immunohistochemistry were also used to characterize tertiary lymphoid structures in murine models of pancreatic cancer. Additionally, the investigators developed an orthotopic murine model to assess the development of the structures and their role in improving the therapeutic effects of chemotherapy. While tertiary lymphoid structures were not initially present in the preclinical murine model, B cells and T cells subsequently infiltrated into the tumor site following injection of lymphoid chemokines. These cells consequently assembled into the tertiary lymphoid structures.

In addition, the researchers combined chemotherapy gemcitabine with the intratumoral lymphoid chemokine and injected this combination treatment into orthotopic tumors. Following injection, the researchers observed “altered immune cell infiltration,” which facilitated the induction of tertiary lymphoid structures and potentiated antitumor activity of the chemotherapy. As a result, there was a significant reduction in the tumors, an effect the researchers did not find following the use of either treatment alone.

According to the investigators, the antitumor activity observed following induction of the tertiary lymphoid structures within the cancer is associated with B cell–mediated activation of dendritic cells, a key cell type involved in initiating an immune response.

Based on the findings, the researchers concluded that the combination of chemotherapy and lymphoid chemokines might be a viable strategy for promoting an antitumor immune response in pancreatic cancer. In turn, the researchers suggest this strategy may result in better clinical outcomes for patients with the disease. Additionally, the researchers wrote that mature tertiary lymphoid structures in PDAC prior to an immune treatment could “be used as a biomarker to define inclusion criteria of patients in immunotherapy protocols, with the aim to boost the ongoing antitumor immune response.”

The study relied on a mouse model and for this reason, it remains unclear at this time if the findings will be generalizable to humans. In the context of PDAC, the researchers wrote that further investigation and understanding of the formation of tertiary lymphoid structures may support the development of tailored treatments, including those that take advantage of the body’s immune system, to combat cancer and improve patient outcomes.

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

A newly updated version of the Model for End-Stage Liver Disease (MELD) score was effective for predicting short-term mortality in patients with end-stage liver disease and addressed important determinants of wait list outcomes that haven’t been addressed in previous versions, according to findings from a recent study. The new model, termed MELD 3.0, includes new variables such as female sex, serum albumin, and updated creatinine cutoffs.

Thomas Northcut/Getty Images

“We believe that the new model represents an opportunity to lower wait list mortality in the United States and propose it to be considered to replace the current version of MELD in determining allocation priorities in liver transplantation,” wrote study authors W. Ray Kim, MD, of Stanford (Calif.) University and colleagues in Gastroenterology.

In patients with end-stage liver disease, the MELD score was shown to be a reliable predictor of short-term survival, according to the researchers. The original version of MELD consists of international normalized ratio of prothrombin time and serum concentrations of bilirubin and creatinine; MELDNa consists of the same with the addition of serum concentrations of total sodium. Since 2016, MELDNa has been utilized in the United States to allocate livers for transplant.

Despite the utility of the current MELD score, questions have been raised concerning the accuracy of the tool’s ability to predict mortality, including a study by Sumeet K. Asrani, MD, MSc, and colleagues. Changes in liver disease epidemiology, the introduction of newer therapies that alter prognosis, as well as increasing age and prevalence of comorbidities in transplant-eligible patients are several drivers for these concerns, according to Dr. Kim and colleagues. Also, there is an increasing concern regarding women and their potential disadvantages in the current system: At least one study has suggested that serum creatinine may overestimate renal function and consequently underestimate mortality risk in female patients, compared with men with the same creatinine level.

Dr. Kim and colleagues sought to further optimize the fit of the current MELD score by considering alternative interactions and including other variables relevant to predicting short-term mortality in patients awaiting liver transplant. The study included patients who are registered on the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files newly wait-listed from 2016 through 2018. The full cohort was divided 70:30 into a development set (n = 20,587) and a validation set (n = 8,823); there were no significant differences between the sets in respect to age, sex, race, or liver disease severity.

The investigators used univariable and multivariable regression models to predict 90-day survival following wait list registration. The 90-day Kaplan-Meier survival rate in the development set was 91.3%. Additionally, model fit was tested, and the investigators used the Liver Simulated Allocation Model to estimate the impact of replacing the current version of the MELD with MELD 3.0.

In the final MELD 3.0 model, the researchers included several additional variables such as female sex and serum albumin. Additionally, the final model was characterized by interactions between bilirubin and sodium as well as between albumin and creatinine. Also, an adjustment to the current version of MELD lowering the upper bound for creatinine from 4.0 mg/dL to 3.0 mg/dL.

The MELD 3.0 featured significantly better discrimination, compared with the MELDNa (C-statistic = 0.8693 vs. 0.8622, respectively; P < .01). In addition, the researchers wrote that the new MELD 3.0 score “correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplantation, particularly in women.” The MELD 3.0 score with albumin also led to fewer wait-list deaths, compared with the MELDNa, according to the Liver Simulated Allocation Model analysis (P = .02); the number for MELD 3.0 without albumin was not statistically significant.

According to the investigators, a cause of concern for the MELD 3.0 was the addition of albumin, as this variable may be vulnerable to manipulation. In addition, the researchers note that, while differences in wait list mortality and survival based on race/ethnicity were observed in the study, they were unable to describe the exact root causes of worse outcomes among patients belonging to minority groups. “Thus, inclusion in a risk prediction score without fully understanding the underlying reasons for the racial disparity may have unintended consequences,” the researchers wrote.

“Based on recent data consisting of liver transplant candidates in the United States, we identify additional variables that are meaningfully associated with short-term mortality, including female sex and serum albumin. We also found evidence to support lowering the serum creatinine ceiling to 3 mg/dL,” they wrote. “Based on these data, we created an updated version of the MELD score, which improves mortality prediction compared to the current MELDNa model, including the recognition of female sex as a risk factor for death.”

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

A newly updated version of the Model for End-Stage Liver Disease (MELD) score was effective for predicting short-term mortality in patients with end-stage liver disease and addressed important determinants of wait list outcomes that haven’t been addressed in previous versions, according to findings from a recent study. The new model, termed MELD 3.0, includes new variables such as female sex, serum albumin, and updated creatinine cutoffs.

Thomas Northcut/Getty Images

“We believe that the new model represents an opportunity to lower wait list mortality in the United States and propose it to be considered to replace the current version of MELD in determining allocation priorities in liver transplantation,” wrote study authors W. Ray Kim, MD, of Stanford (Calif.) University and colleagues in Gastroenterology.

In patients with end-stage liver disease, the MELD score was shown to be a reliable predictor of short-term survival, according to the researchers. The original version of MELD consists of international normalized ratio of prothrombin time and serum concentrations of bilirubin and creatinine; MELDNa consists of the same with the addition of serum concentrations of total sodium. Since 2016, MELDNa has been utilized in the United States to allocate livers for transplant.

Despite the utility of the current MELD score, questions have been raised concerning the accuracy of the tool’s ability to predict mortality, including a study by Sumeet K. Asrani, MD, MSc, and colleagues. Changes in liver disease epidemiology, the introduction of newer therapies that alter prognosis, as well as increasing age and prevalence of comorbidities in transplant-eligible patients are several drivers for these concerns, according to Dr. Kim and colleagues. Also, there is an increasing concern regarding women and their potential disadvantages in the current system: At least one study has suggested that serum creatinine may overestimate renal function and consequently underestimate mortality risk in female patients, compared with men with the same creatinine level.

Dr. Kim and colleagues sought to further optimize the fit of the current MELD score by considering alternative interactions and including other variables relevant to predicting short-term mortality in patients awaiting liver transplant. The study included patients who are registered on the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files newly wait-listed from 2016 through 2018. The full cohort was divided 70:30 into a development set (n = 20,587) and a validation set (n = 8,823); there were no significant differences between the sets in respect to age, sex, race, or liver disease severity.

The investigators used univariable and multivariable regression models to predict 90-day survival following wait list registration. The 90-day Kaplan-Meier survival rate in the development set was 91.3%. Additionally, model fit was tested, and the investigators used the Liver Simulated Allocation Model to estimate the impact of replacing the current version of the MELD with MELD 3.0.

In the final MELD 3.0 model, the researchers included several additional variables such as female sex and serum albumin. Additionally, the final model was characterized by interactions between bilirubin and sodium as well as between albumin and creatinine. Also, an adjustment to the current version of MELD lowering the upper bound for creatinine from 4.0 mg/dL to 3.0 mg/dL.

The MELD 3.0 featured significantly better discrimination, compared with the MELDNa (C-statistic = 0.8693 vs. 0.8622, respectively; P < .01). In addition, the researchers wrote that the new MELD 3.0 score “correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplantation, particularly in women.” The MELD 3.0 score with albumin also led to fewer wait-list deaths, compared with the MELDNa, according to the Liver Simulated Allocation Model analysis (P = .02); the number for MELD 3.0 without albumin was not statistically significant.

According to the investigators, a cause of concern for the MELD 3.0 was the addition of albumin, as this variable may be vulnerable to manipulation. In addition, the researchers note that, while differences in wait list mortality and survival based on race/ethnicity were observed in the study, they were unable to describe the exact root causes of worse outcomes among patients belonging to minority groups. “Thus, inclusion in a risk prediction score without fully understanding the underlying reasons for the racial disparity may have unintended consequences,” the researchers wrote.

“Based on recent data consisting of liver transplant candidates in the United States, we identify additional variables that are meaningfully associated with short-term mortality, including female sex and serum albumin. We also found evidence to support lowering the serum creatinine ceiling to 3 mg/dL,” they wrote. “Based on these data, we created an updated version of the MELD score, which improves mortality prediction compared to the current MELDNa model, including the recognition of female sex as a risk factor for death.”

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

A newly updated version of the Model for End-Stage Liver Disease (MELD) score was effective for predicting short-term mortality in patients with end-stage liver disease and addressed important determinants of wait list outcomes that haven’t been addressed in previous versions, according to findings from a recent study. The new model, termed MELD 3.0, includes new variables such as female sex, serum albumin, and updated creatinine cutoffs.

Thomas Northcut/Getty Images

“We believe that the new model represents an opportunity to lower wait list mortality in the United States and propose it to be considered to replace the current version of MELD in determining allocation priorities in liver transplantation,” wrote study authors W. Ray Kim, MD, of Stanford (Calif.) University and colleagues in Gastroenterology.

In patients with end-stage liver disease, the MELD score was shown to be a reliable predictor of short-term survival, according to the researchers. The original version of MELD consists of international normalized ratio of prothrombin time and serum concentrations of bilirubin and creatinine; MELDNa consists of the same with the addition of serum concentrations of total sodium. Since 2016, MELDNa has been utilized in the United States to allocate livers for transplant.

Despite the utility of the current MELD score, questions have been raised concerning the accuracy of the tool’s ability to predict mortality, including a study by Sumeet K. Asrani, MD, MSc, and colleagues. Changes in liver disease epidemiology, the introduction of newer therapies that alter prognosis, as well as increasing age and prevalence of comorbidities in transplant-eligible patients are several drivers for these concerns, according to Dr. Kim and colleagues. Also, there is an increasing concern regarding women and their potential disadvantages in the current system: At least one study has suggested that serum creatinine may overestimate renal function and consequently underestimate mortality risk in female patients, compared with men with the same creatinine level.

Dr. Kim and colleagues sought to further optimize the fit of the current MELD score by considering alternative interactions and including other variables relevant to predicting short-term mortality in patients awaiting liver transplant. The study included patients who are registered on the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files newly wait-listed from 2016 through 2018. The full cohort was divided 70:30 into a development set (n = 20,587) and a validation set (n = 8,823); there were no significant differences between the sets in respect to age, sex, race, or liver disease severity.

The investigators used univariable and multivariable regression models to predict 90-day survival following wait list registration. The 90-day Kaplan-Meier survival rate in the development set was 91.3%. Additionally, model fit was tested, and the investigators used the Liver Simulated Allocation Model to estimate the impact of replacing the current version of the MELD with MELD 3.0.

In the final MELD 3.0 model, the researchers included several additional variables such as female sex and serum albumin. Additionally, the final model was characterized by interactions between bilirubin and sodium as well as between albumin and creatinine. Also, an adjustment to the current version of MELD lowering the upper bound for creatinine from 4.0 mg/dL to 3.0 mg/dL.

The MELD 3.0 featured significantly better discrimination, compared with the MELDNa (C-statistic = 0.8693 vs. 0.8622, respectively; P < .01). In addition, the researchers wrote that the new MELD 3.0 score “correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplantation, particularly in women.” The MELD 3.0 score with albumin also led to fewer wait-list deaths, compared with the MELDNa, according to the Liver Simulated Allocation Model analysis (P = .02); the number for MELD 3.0 without albumin was not statistically significant.

According to the investigators, a cause of concern for the MELD 3.0 was the addition of albumin, as this variable may be vulnerable to manipulation. In addition, the researchers note that, while differences in wait list mortality and survival based on race/ethnicity were observed in the study, they were unable to describe the exact root causes of worse outcomes among patients belonging to minority groups. “Thus, inclusion in a risk prediction score without fully understanding the underlying reasons for the racial disparity may have unintended consequences,” the researchers wrote.

“Based on recent data consisting of liver transplant candidates in the United States, we identify additional variables that are meaningfully associated with short-term mortality, including female sex and serum albumin. We also found evidence to support lowering the serum creatinine ceiling to 3 mg/dL,” they wrote. “Based on these data, we created an updated version of the MELD score, which improves mortality prediction compared to the current MELDNa model, including the recognition of female sex as a risk factor for death.”

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

A blood-based biomarker panel that includes DNA and protein markers featured a 71% sensitivity at 90% specificity for the detection of early-stage hepatocellular carcinoma (HCC) compared with the GALAD (gender, age, a-fetoprotein [AFP], Lens culinaris agglutinin-reactive AFP [AFP-L3], and des-gamma-carboxy-prothrombin [DCP]) score or AFP alone, according to research findings. The panel reportedly performed well in certain subgroups based on sex, presence of cirrhosis, and liver disease etiology.

Jezperklauzen/ThinkStock

The study, which included inpatients with HCC and controls without HCC but underlying liver disease, suggests the panel could be utilized in the detection of early stage disease in patients with well-established risk factors for HCC. Ultimately, this may lead to earlier treatment initiation and potentially improved clinical outcomes.

“A blood-based marker panel that detects early-stage HCC with higher sensitivity than current biomarker-based approaches could substantially benefit patients undergoing HCC surveillance,” wrote study authors Naga Chalasani, MD, of Indiana University, Indianapolis, and colleagues. Their report is in Clinical Gastroenterology and Hepatology.

HCC, which accounts for most primary liver cancers, generally occurs in patients with several established risk factors, including alcoholic liver disease or nonalcoholic fatty liver disease as well as chronic hepatitis B virus or hepatitis C virus infection. Current guidelines, such as those from the European Association for the Study of the Liver and those from the American Association for the Study of Liver Diseases, recommend surveillance of at-risk patients every 6 months by ultrasound with or without AFP measurement. When caught early, HCC is typically treatable and is associated with a higher rate of survival compared with late-stage disease. According to Dr. Chalasani and colleagues, however, the effectiveness of current recommended surveillance for very early stage or early stage HCC is poor, characterized by a 45% sensitivity for ultrasound and a 63% sensitivity for ultrasound coupled with AFP measurement.

The investigators of the multicenter, case-control study collected blood specimens from 135 patients with HCC as well as 302 age-matched controls with underlying liver disease but no HCC. Very early or early stage disease was seen in approximately 56.3% of patients with HCC, and intermediate, advanced, or terminal stage disease was seen in 43.7% of patients.

To predict cases of HCC, the researchers used a logistic regression algorithm to analyze 10 methylated DNA markers (MDMs) associated with HCC, methylated B3GALT6 (reference DNA marker), and 3 candidate proteins. Finally, the researchers compared the accuracy of the developed blood-based biomarker panel with other blood-based biomarkers – including the GALAD, AFP, AFP-L3, DCP – for the detection of HCC.

The multitarget HCC panel included 3 MDMs – HOXA1, EMX1, and TSPYL5. In addition, the panel included methylation reference marker B3GALT6 and the protein markers AFP and AFP-L3. The biomarker panel featured a higher sensitivity (71%; 95% confidence interval, 60-81) at 90% specificity for the detection of early stage HCC compared with the GALAD score (41%; 95% CI, 30-53) or AFP ≥ 7.32 ng/mL (45%; 95% CI, 33-57). The area under the curve for the novel HCC panel for the detection of any stage HCC was 0.92 vs. 0.87 for the GALAD and 0.81 for the AFP measurement alone. The researchers found that the performance of the test was similar between men and women in terms of sensitivity (79% and 84%, respectively). Moreover, the panel performed similarly well among subgroups based on presence of cirrhosis and liver disease etiology.

A potential limitation of this study was the inclusion of controls who were largely confirmed HCC negative by ultrasound, a technique that lacks sensitivity for detecting early stage HCC, the researchers noted. Given this limitation, the researchers suggest that some of the control participants may have had underlying HCC that was missed by ultrasound. Furthermore, the findings indicate that the cross-sectional nature of the study may also mean some of the control participants had HCCs that were undetectable at initial screening.

Despite the limitations of the study, the researchers reported that the novel, blood-based marker panel’s sensitivity for detecting early stage HCC likely supports its use “among at-risk patients to enhance HCC surveillance and improve early cancer detection.”

The study was funded by the Exact Sciences Corporation. The researchers reported conflicts of interest with several pharmaceutical companies.

A blood-based biomarker panel that includes DNA and protein markers featured a 71% sensitivity at 90% specificity for the detection of early-stage hepatocellular carcinoma (HCC) compared with the GALAD (gender, age, a-fetoprotein [AFP], Lens culinaris agglutinin-reactive AFP [AFP-L3], and des-gamma-carboxy-prothrombin [DCP]) score or AFP alone, according to research findings. The panel reportedly performed well in certain subgroups based on sex, presence of cirrhosis, and liver disease etiology.

Jezperklauzen/ThinkStock

The study, which included inpatients with HCC and controls without HCC but underlying liver disease, suggests the panel could be utilized in the detection of early stage disease in patients with well-established risk factors for HCC. Ultimately, this may lead to earlier treatment initiation and potentially improved clinical outcomes.

“A blood-based marker panel that detects early-stage HCC with higher sensitivity than current biomarker-based approaches could substantially benefit patients undergoing HCC surveillance,” wrote study authors Naga Chalasani, MD, of Indiana University, Indianapolis, and colleagues. Their report is in Clinical Gastroenterology and Hepatology.

HCC, which accounts for most primary liver cancers, generally occurs in patients with several established risk factors, including alcoholic liver disease or nonalcoholic fatty liver disease as well as chronic hepatitis B virus or hepatitis C virus infection. Current guidelines, such as those from the European Association for the Study of the Liver and those from the American Association for the Study of Liver Diseases, recommend surveillance of at-risk patients every 6 months by ultrasound with or without AFP measurement. When caught early, HCC is typically treatable and is associated with a higher rate of survival compared with late-stage disease. According to Dr. Chalasani and colleagues, however, the effectiveness of current recommended surveillance for very early stage or early stage HCC is poor, characterized by a 45% sensitivity for ultrasound and a 63% sensitivity for ultrasound coupled with AFP measurement.

The investigators of the multicenter, case-control study collected blood specimens from 135 patients with HCC as well as 302 age-matched controls with underlying liver disease but no HCC. Very early or early stage disease was seen in approximately 56.3% of patients with HCC, and intermediate, advanced, or terminal stage disease was seen in 43.7% of patients.

To predict cases of HCC, the researchers used a logistic regression algorithm to analyze 10 methylated DNA markers (MDMs) associated with HCC, methylated B3GALT6 (reference DNA marker), and 3 candidate proteins. Finally, the researchers compared the accuracy of the developed blood-based biomarker panel with other blood-based biomarkers – including the GALAD, AFP, AFP-L3, DCP – for the detection of HCC.

The multitarget HCC panel included 3 MDMs – HOXA1, EMX1, and TSPYL5. In addition, the panel included methylation reference marker B3GALT6 and the protein markers AFP and AFP-L3. The biomarker panel featured a higher sensitivity (71%; 95% confidence interval, 60-81) at 90% specificity for the detection of early stage HCC compared with the GALAD score (41%; 95% CI, 30-53) or AFP ≥ 7.32 ng/mL (45%; 95% CI, 33-57). The area under the curve for the novel HCC panel for the detection of any stage HCC was 0.92 vs. 0.87 for the GALAD and 0.81 for the AFP measurement alone. The researchers found that the performance of the test was similar between men and women in terms of sensitivity (79% and 84%, respectively). Moreover, the panel performed similarly well among subgroups based on presence of cirrhosis and liver disease etiology.

A potential limitation of this study was the inclusion of controls who were largely confirmed HCC negative by ultrasound, a technique that lacks sensitivity for detecting early stage HCC, the researchers noted. Given this limitation, the researchers suggest that some of the control participants may have had underlying HCC that was missed by ultrasound. Furthermore, the findings indicate that the cross-sectional nature of the study may also mean some of the control participants had HCCs that were undetectable at initial screening.

Despite the limitations of the study, the researchers reported that the novel, blood-based marker panel’s sensitivity for detecting early stage HCC likely supports its use “among at-risk patients to enhance HCC surveillance and improve early cancer detection.”

The study was funded by the Exact Sciences Corporation. The researchers reported conflicts of interest with several pharmaceutical companies.

A blood-based biomarker panel that includes DNA and protein markers featured a 71% sensitivity at 90% specificity for the detection of early-stage hepatocellular carcinoma (HCC) compared with the GALAD (gender, age, a-fetoprotein [AFP], Lens culinaris agglutinin-reactive AFP [AFP-L3], and des-gamma-carboxy-prothrombin [DCP]) score or AFP alone, according to research findings. The panel reportedly performed well in certain subgroups based on sex, presence of cirrhosis, and liver disease etiology.

Jezperklauzen/ThinkStock

The study, which included inpatients with HCC and controls without HCC but underlying liver disease, suggests the panel could be utilized in the detection of early stage disease in patients with well-established risk factors for HCC. Ultimately, this may lead to earlier treatment initiation and potentially improved clinical outcomes.

“A blood-based marker panel that detects early-stage HCC with higher sensitivity than current biomarker-based approaches could substantially benefit patients undergoing HCC surveillance,” wrote study authors Naga Chalasani, MD, of Indiana University, Indianapolis, and colleagues. Their report is in Clinical Gastroenterology and Hepatology.

HCC, which accounts for most primary liver cancers, generally occurs in patients with several established risk factors, including alcoholic liver disease or nonalcoholic fatty liver disease as well as chronic hepatitis B virus or hepatitis C virus infection. Current guidelines, such as those from the European Association for the Study of the Liver and those from the American Association for the Study of Liver Diseases, recommend surveillance of at-risk patients every 6 months by ultrasound with or without AFP measurement. When caught early, HCC is typically treatable and is associated with a higher rate of survival compared with late-stage disease. According to Dr. Chalasani and colleagues, however, the effectiveness of current recommended surveillance for very early stage or early stage HCC is poor, characterized by a 45% sensitivity for ultrasound and a 63% sensitivity for ultrasound coupled with AFP measurement.

The investigators of the multicenter, case-control study collected blood specimens from 135 patients with HCC as well as 302 age-matched controls with underlying liver disease but no HCC. Very early or early stage disease was seen in approximately 56.3% of patients with HCC, and intermediate, advanced, or terminal stage disease was seen in 43.7% of patients.

To predict cases of HCC, the researchers used a logistic regression algorithm to analyze 10 methylated DNA markers (MDMs) associated with HCC, methylated B3GALT6 (reference DNA marker), and 3 candidate proteins. Finally, the researchers compared the accuracy of the developed blood-based biomarker panel with other blood-based biomarkers – including the GALAD, AFP, AFP-L3, DCP – for the detection of HCC.

The multitarget HCC panel included 3 MDMs – HOXA1, EMX1, and TSPYL5. In addition, the panel included methylation reference marker B3GALT6 and the protein markers AFP and AFP-L3. The biomarker panel featured a higher sensitivity (71%; 95% confidence interval, 60-81) at 90% specificity for the detection of early stage HCC compared with the GALAD score (41%; 95% CI, 30-53) or AFP ≥ 7.32 ng/mL (45%; 95% CI, 33-57). The area under the curve for the novel HCC panel for the detection of any stage HCC was 0.92 vs. 0.87 for the GALAD and 0.81 for the AFP measurement alone. The researchers found that the performance of the test was similar between men and women in terms of sensitivity (79% and 84%, respectively). Moreover, the panel performed similarly well among subgroups based on presence of cirrhosis and liver disease etiology.

A potential limitation of this study was the inclusion of controls who were largely confirmed HCC negative by ultrasound, a technique that lacks sensitivity for detecting early stage HCC, the researchers noted. Given this limitation, the researchers suggest that some of the control participants may have had underlying HCC that was missed by ultrasound. Furthermore, the findings indicate that the cross-sectional nature of the study may also mean some of the control participants had HCCs that were undetectable at initial screening.

Despite the limitations of the study, the researchers reported that the novel, blood-based marker panel’s sensitivity for detecting early stage HCC likely supports its use “among at-risk patients to enhance HCC surveillance and improve early cancer detection.”

The study was funded by the Exact Sciences Corporation. The researchers reported conflicts of interest with several pharmaceutical companies.

The diagnostic performance of optical evaluation for submucosal invasive cancer (SMIC) in patients with large (≥20 mm) nonpedunculated colorectal polyps (LNPCPs) may be dependent on lesion morphology. While optical evaluation featured excellent performance in the assessment of flat lesions, the assessment only featured decent performance in nodular lesions, underscoring the need for additional evaluation algorithms for these lesions.

Endoscopists rely on the accuracy of real-time optical evaluation to facilitate appropriate selection of treatment; however, in studies focusing on LNPCPs, the performance of optical evaluation is modest.

The stratification of optical evaluation by lesion morphology may enable more accurate “implementation of a selective resection algorithm by identifying lesion subgroups with accurate optical evaluation performance characteristics,” first authors Sergei Vosko, MD, and Neal Shahidi, MD, of the department of gastroenterology and hepatology, Westmead Hospital, Sydney, and colleagues wrote in Clinical Gastroenterology and Hepatology.

Given the potential importance of stratification in optical evaluation, Dr. Vosko and colleagues assessed the performance of the optical assessment modality based on lesion morphology in a prospective cohort of 1,583 LNPCPs measuring at least 20 mm in patients (median age, 69 years) referred for endoscopic resection.

In the observational cohort, centers performed optical evaluation before endoscopic resection. The optical prediction of SMIC was based on several different established features, including Kudo V pit pattern, depressed morphology, rigidity/fixation, and ulceration. The researchers calculated optical evaluation performance outcomes, which were reported by the dominant morphology, namely nodular (Paris 0–Is/0– IIaDIs) versus flat (Paris 0–IIa/0–IIb).

Across the overall cohort, the median lesion size was 35 mm. The investigators identified a total of 855 flat LNPCPs and 728 nodular LNPCPs, with 63.9% of LNPCPs considered granular. Additionally, the researchers reported submucosal invasive cancer in 146 LNPCPs (9.2%).

According to the investigators, the overall sensitivity of optical evaluation to diagnose submucosal invasive cancer was 67.1% (95% confidence interval, 59.2%-74.2%), while the overall specificity was 95.1% (95% CI, 93.9%-96.1%). The investigators reported significant differences between flat vs. nodular LNPCPs in terms of sensitivity (90.9% vs. 52.7%, respectively; P <.001) and specificity (96.3% vs. 93.7%; P =.027).

Overall, the SMIC miss rate was 3.0% (95% CI, 2.3%-4.0%). There was a significant difference in the SMIC miss rate between flat and nodular LNPCPs (0.6% vs. 5.9%, respectively; P < .001).

Independent predictors of missed SMIC on optical evaluation, as identified in the multiple logistic regression analysis, included nodular morphology (odds ratio, 7.2; 95% CI, 2.8-18.9; P < .001), rectosigmoid location (OR, 2.0; 95% CI, 1.1-3.7; P =.026), and size of at least 40 mm (OR, 2.0; 95% CI, 1.0-3.8; P =.039).

Based on the findings, the researchers suggested that all flat lesions, in the absence of optical features consistent with submucosal invasive cancer, should subsequently be removed by high-quality endoscopic mucosal resection, in conjunction with the application of “site-specific modifications and ancillary techniques where needed.”

One limitation of this study is how lesion morphology was classified, which can in some cases be subjective.

The researchers added that additional refinement is required “to robustly apply a selective resection algorithm irrespective of lesion morphology” given the modest performance value of optical evaluation in nodular lesions. “Nevertheless, it is imperative that all endoscopists embrace optical evaluation in everyday clinical practice, thus harnessing its proven ability to influence resection technique selection and the associated clinical and economic ramifications,” they concluded.

The study received financial support the Cancer Institute of New South Wales, in addition to funding from the Gallipoli Medical Research Foundation. One author reported receiving research support from Olympus Medical, Cook Medical, and Boston Scientific. The remaining authors disclosed no conflicts.

The diagnostic performance of optical evaluation for submucosal invasive cancer (SMIC) in patients with large (≥20 mm) nonpedunculated colorectal polyps (LNPCPs) may be dependent on lesion morphology. While optical evaluation featured excellent performance in the assessment of flat lesions, the assessment only featured decent performance in nodular lesions, underscoring the need for additional evaluation algorithms for these lesions.

Endoscopists rely on the accuracy of real-time optical evaluation to facilitate appropriate selection of treatment; however, in studies focusing on LNPCPs, the performance of optical evaluation is modest.

The stratification of optical evaluation by lesion morphology may enable more accurate “implementation of a selective resection algorithm by identifying lesion subgroups with accurate optical evaluation performance characteristics,” first authors Sergei Vosko, MD, and Neal Shahidi, MD, of the department of gastroenterology and hepatology, Westmead Hospital, Sydney, and colleagues wrote in Clinical Gastroenterology and Hepatology.

Given the potential importance of stratification in optical evaluation, Dr. Vosko and colleagues assessed the performance of the optical assessment modality based on lesion morphology in a prospective cohort of 1,583 LNPCPs measuring at least 20 mm in patients (median age, 69 years) referred for endoscopic resection.

In the observational cohort, centers performed optical evaluation before endoscopic resection. The optical prediction of SMIC was based on several different established features, including Kudo V pit pattern, depressed morphology, rigidity/fixation, and ulceration. The researchers calculated optical evaluation performance outcomes, which were reported by the dominant morphology, namely nodular (Paris 0–Is/0– IIaDIs) versus flat (Paris 0–IIa/0–IIb).

Across the overall cohort, the median lesion size was 35 mm. The investigators identified a total of 855 flat LNPCPs and 728 nodular LNPCPs, with 63.9% of LNPCPs considered granular. Additionally, the researchers reported submucosal invasive cancer in 146 LNPCPs (9.2%).

According to the investigators, the overall sensitivity of optical evaluation to diagnose submucosal invasive cancer was 67.1% (95% confidence interval, 59.2%-74.2%), while the overall specificity was 95.1% (95% CI, 93.9%-96.1%). The investigators reported significant differences between flat vs. nodular LNPCPs in terms of sensitivity (90.9% vs. 52.7%, respectively; P <.001) and specificity (96.3% vs. 93.7%; P =.027).

Overall, the SMIC miss rate was 3.0% (95% CI, 2.3%-4.0%). There was a significant difference in the SMIC miss rate between flat and nodular LNPCPs (0.6% vs. 5.9%, respectively; P < .001).

Independent predictors of missed SMIC on optical evaluation, as identified in the multiple logistic regression analysis, included nodular morphology (odds ratio, 7.2; 95% CI, 2.8-18.9; P < .001), rectosigmoid location (OR, 2.0; 95% CI, 1.1-3.7; P =.026), and size of at least 40 mm (OR, 2.0; 95% CI, 1.0-3.8; P =.039).

Based on the findings, the researchers suggested that all flat lesions, in the absence of optical features consistent with submucosal invasive cancer, should subsequently be removed by high-quality endoscopic mucosal resection, in conjunction with the application of “site-specific modifications and ancillary techniques where needed.”

One limitation of this study is how lesion morphology was classified, which can in some cases be subjective.

The researchers added that additional refinement is required “to robustly apply a selective resection algorithm irrespective of lesion morphology” given the modest performance value of optical evaluation in nodular lesions. “Nevertheless, it is imperative that all endoscopists embrace optical evaluation in everyday clinical practice, thus harnessing its proven ability to influence resection technique selection and the associated clinical and economic ramifications,” they concluded.

The study received financial support the Cancer Institute of New South Wales, in addition to funding from the Gallipoli Medical Research Foundation. One author reported receiving research support from Olympus Medical, Cook Medical, and Boston Scientific. The remaining authors disclosed no conflicts.

The diagnostic performance of optical evaluation for submucosal invasive cancer (SMIC) in patients with large (≥20 mm) nonpedunculated colorectal polyps (LNPCPs) may be dependent on lesion morphology. While optical evaluation featured excellent performance in the assessment of flat lesions, the assessment only featured decent performance in nodular lesions, underscoring the need for additional evaluation algorithms for these lesions.

Endoscopists rely on the accuracy of real-time optical evaluation to facilitate appropriate selection of treatment; however, in studies focusing on LNPCPs, the performance of optical evaluation is modest.

The stratification of optical evaluation by lesion morphology may enable more accurate “implementation of a selective resection algorithm by identifying lesion subgroups with accurate optical evaluation performance characteristics,” first authors Sergei Vosko, MD, and Neal Shahidi, MD, of the department of gastroenterology and hepatology, Westmead Hospital, Sydney, and colleagues wrote in Clinical Gastroenterology and Hepatology.

Given the potential importance of stratification in optical evaluation, Dr. Vosko and colleagues assessed the performance of the optical assessment modality based on lesion morphology in a prospective cohort of 1,583 LNPCPs measuring at least 20 mm in patients (median age, 69 years) referred for endoscopic resection.

In the observational cohort, centers performed optical evaluation before endoscopic resection. The optical prediction of SMIC was based on several different established features, including Kudo V pit pattern, depressed morphology, rigidity/fixation, and ulceration. The researchers calculated optical evaluation performance outcomes, which were reported by the dominant morphology, namely nodular (Paris 0–Is/0– IIaDIs) versus flat (Paris 0–IIa/0–IIb).

Across the overall cohort, the median lesion size was 35 mm. The investigators identified a total of 855 flat LNPCPs and 728 nodular LNPCPs, with 63.9% of LNPCPs considered granular. Additionally, the researchers reported submucosal invasive cancer in 146 LNPCPs (9.2%).

According to the investigators, the overall sensitivity of optical evaluation to diagnose submucosal invasive cancer was 67.1% (95% confidence interval, 59.2%-74.2%), while the overall specificity was 95.1% (95% CI, 93.9%-96.1%). The investigators reported significant differences between flat vs. nodular LNPCPs in terms of sensitivity (90.9% vs. 52.7%, respectively; P <.001) and specificity (96.3% vs. 93.7%; P =.027).

Overall, the SMIC miss rate was 3.0% (95% CI, 2.3%-4.0%). There was a significant difference in the SMIC miss rate between flat and nodular LNPCPs (0.6% vs. 5.9%, respectively; P < .001).

Independent predictors of missed SMIC on optical evaluation, as identified in the multiple logistic regression analysis, included nodular morphology (odds ratio, 7.2; 95% CI, 2.8-18.9; P < .001), rectosigmoid location (OR, 2.0; 95% CI, 1.1-3.7; P =.026), and size of at least 40 mm (OR, 2.0; 95% CI, 1.0-3.8; P =.039).

Based on the findings, the researchers suggested that all flat lesions, in the absence of optical features consistent with submucosal invasive cancer, should subsequently be removed by high-quality endoscopic mucosal resection, in conjunction with the application of “site-specific modifications and ancillary techniques where needed.”

One limitation of this study is how lesion morphology was classified, which can in some cases be subjective.

The researchers added that additional refinement is required “to robustly apply a selective resection algorithm irrespective of lesion morphology” given the modest performance value of optical evaluation in nodular lesions. “Nevertheless, it is imperative that all endoscopists embrace optical evaluation in everyday clinical practice, thus harnessing its proven ability to influence resection technique selection and the associated clinical and economic ramifications,” they concluded.

The study received financial support the Cancer Institute of New South Wales, in addition to funding from the Gallipoli Medical Research Foundation. One author reported receiving research support from Olympus Medical, Cook Medical, and Boston Scientific. The remaining authors disclosed no conflicts.