Jim Kling

In a real-world test, tofacitinib had a similar safety profile to what was seen in clinical trials. The majority of adverse events seen were infections, and few were serious; however, the study did find evidence of rare venous thromboembolism (VTE) in patients with preexisting risk factors, which suggests that precaution is warranted in this group.

Tofacitinib, a Janus kinase inhibitor, was approved by the Food and Drug Administration in 2018 for adults with moderate to severe ulcerative colitis (UC). Three phase 3 clinical trials and an open-label, long-term extension trial found that the drug was associated with increased infection rates and higher lipid levels.

In rheumatoid arthritis patients, an interim analysis of a safety clinical trial of twice-daily doses of 10 mg tofacitinib showed increased rates of pulmonary embolism and all-cause mortality, compared to treatment with a dose of 5 mg or a tumor necrosis factor antagonist. That finding led to a black box label warning against thrombosis.

The current study, led by Parakkal Deepak, MBBS, MS, and colleagues and published in Clinical Gastroenterology and Hepatology, included patients from six centers in the United States.

The findings suggest that patients should be counseled about the potential risk for herpes zoster (HZ) reactivation, especially older patients taking corticosteroids. The authors also recommended vaccination with an inactivated HZ vaccine. “Our data suggest a careful risk-benefit discussion before starting tofacitinib, especially in patients with preexisting risk factors for VTE, dose deescalation to the lowest clinically feasible dose, and monitoring for clinical signs of VTE, especially among those who continue on a dose of 10 mg twice a day,” the authors wrote.

The researchers followed 260 patients over a median of 6 months (median age, 38 years; 58.1% male; 71.9% non-Hispanic). Overall, 88.5% had previously received treatment with a biologic, most often an anti–TNF-alpha agent (76.5%). During follow-up, 15.7% experienced adverse events, most commonly infections (5.0%) and rash (3.5%). Joint pain (1.5%) and anemia (1.5%) also occurred. The incidence rate for any adverse event was 27.2 per 100 person-years. Adverse events occurred more often in older patients (mean age, 42 vs. 37 years; P = .02) and those who had not undergone previous anti-TNF therapy (63.4% vs 79.8%; P = .03). There was no association between concomitant steroid use and adverse events on univariate analysis. Of the overall cohort, 5.8% experienced a severe adverse event, with the most common being herpes zoster rash (26.7% of severe adverse events). Therapy was discontinued by 4.6%.

Five patients developed herpes zoster (3.29 per 100 person-years; 95% CI, 1.37-7.90). Risk factors for VTE were seen in 31.2% of the cohort, and two cases of VTE occurred during follow-up (1.32 per 100 person-years; 95% CI, 0.33-5.28), both in patients with extensive UC. There was no increased risk of complications following abdominal surgery.

At baseline, 38.4% had an abnormal lipid profile, and this increased to 48.3% following 8 weeks of treatment.

Overall, 45% of patients were anemic at baseline. Females experienced a significant improvement by week 26 (median hemoglobin level, 13.0 g/dL; interquartile range, 12.5-13.8), while a similar improvement occurred by week 52 in males (median hemoglobin level, 13.6 g/dL; IQR, 12.57-14.0). At 52 weeks, the mean increase in hemoglobin was 5% (IQR, 0%-11.1%). The increase was greater in females (7.7%; IQR, 4.2%-11.7%) than in males (2.1%; IQR, –0.5% to 11.3%).

Limitations of the study include its retrospective nature and that the tools by which data were collected could have missed some adverse events because they were not adequately captured in the treating clinician’s notes. However, the data trend similarly to a prospective study.

“In summary, we report safety signals on a real-world cohort of patients with UC initiated on tofacitinib in whom increasing age is a risk factor for AEs and consistent with recent reports of a dose-dependent risk of HZ reactivation and VTE events in patients with a risk factor for VTE on the 10-mg twice-daily dosing,” the authors concluded.

The study was funded by the American College of Gastroenterology, the Crohn’s and Colitis Foundation, the Givin’ it all for Guts Foundation, and the Lawrence C. Pakula, MD, Inflammatory Bowel Disease Research Innovation and Education Fund. The authors have financial ties with various pharmaceutical companies.

This article was updated July 19, 2021.

In a real-world test, tofacitinib had a similar safety profile to what was seen in clinical trials. The majority of adverse events seen were infections, and few were serious; however, the study did find evidence of rare venous thromboembolism (VTE) in patients with preexisting risk factors, which suggests that precaution is warranted in this group.

Tofacitinib, a Janus kinase inhibitor, was approved by the Food and Drug Administration in 2018 for adults with moderate to severe ulcerative colitis (UC). Three phase 3 clinical trials and an open-label, long-term extension trial found that the drug was associated with increased infection rates and higher lipid levels.

In rheumatoid arthritis patients, an interim analysis of a safety clinical trial of twice-daily doses of 10 mg tofacitinib showed increased rates of pulmonary embolism and all-cause mortality, compared to treatment with a dose of 5 mg or a tumor necrosis factor antagonist. That finding led to a black box label warning against thrombosis.

The current study, led by Parakkal Deepak, MBBS, MS, and colleagues and published in Clinical Gastroenterology and Hepatology, included patients from six centers in the United States.

The findings suggest that patients should be counseled about the potential risk for herpes zoster (HZ) reactivation, especially older patients taking corticosteroids. The authors also recommended vaccination with an inactivated HZ vaccine. “Our data suggest a careful risk-benefit discussion before starting tofacitinib, especially in patients with preexisting risk factors for VTE, dose deescalation to the lowest clinically feasible dose, and monitoring for clinical signs of VTE, especially among those who continue on a dose of 10 mg twice a day,” the authors wrote.

The researchers followed 260 patients over a median of 6 months (median age, 38 years; 58.1% male; 71.9% non-Hispanic). Overall, 88.5% had previously received treatment with a biologic, most often an anti–TNF-alpha agent (76.5%). During follow-up, 15.7% experienced adverse events, most commonly infections (5.0%) and rash (3.5%). Joint pain (1.5%) and anemia (1.5%) also occurred. The incidence rate for any adverse event was 27.2 per 100 person-years. Adverse events occurred more often in older patients (mean age, 42 vs. 37 years; P = .02) and those who had not undergone previous anti-TNF therapy (63.4% vs 79.8%; P = .03). There was no association between concomitant steroid use and adverse events on univariate analysis. Of the overall cohort, 5.8% experienced a severe adverse event, with the most common being herpes zoster rash (26.7% of severe adverse events). Therapy was discontinued by 4.6%.

Five patients developed herpes zoster (3.29 per 100 person-years; 95% CI, 1.37-7.90). Risk factors for VTE were seen in 31.2% of the cohort, and two cases of VTE occurred during follow-up (1.32 per 100 person-years; 95% CI, 0.33-5.28), both in patients with extensive UC. There was no increased risk of complications following abdominal surgery.

At baseline, 38.4% had an abnormal lipid profile, and this increased to 48.3% following 8 weeks of treatment.

Overall, 45% of patients were anemic at baseline. Females experienced a significant improvement by week 26 (median hemoglobin level, 13.0 g/dL; interquartile range, 12.5-13.8), while a similar improvement occurred by week 52 in males (median hemoglobin level, 13.6 g/dL; IQR, 12.57-14.0). At 52 weeks, the mean increase in hemoglobin was 5% (IQR, 0%-11.1%). The increase was greater in females (7.7%; IQR, 4.2%-11.7%) than in males (2.1%; IQR, –0.5% to 11.3%).

Limitations of the study include its retrospective nature and that the tools by which data were collected could have missed some adverse events because they were not adequately captured in the treating clinician’s notes. However, the data trend similarly to a prospective study.

“In summary, we report safety signals on a real-world cohort of patients with UC initiated on tofacitinib in whom increasing age is a risk factor for AEs and consistent with recent reports of a dose-dependent risk of HZ reactivation and VTE events in patients with a risk factor for VTE on the 10-mg twice-daily dosing,” the authors concluded.

The study was funded by the American College of Gastroenterology, the Crohn’s and Colitis Foundation, the Givin’ it all for Guts Foundation, and the Lawrence C. Pakula, MD, Inflammatory Bowel Disease Research Innovation and Education Fund. The authors have financial ties with various pharmaceutical companies.

This article was updated July 19, 2021.

In a real-world test, tofacitinib had a similar safety profile to what was seen in clinical trials. The majority of adverse events seen were infections, and few were serious; however, the study did find evidence of rare venous thromboembolism (VTE) in patients with preexisting risk factors, which suggests that precaution is warranted in this group.

Tofacitinib, a Janus kinase inhibitor, was approved by the Food and Drug Administration in 2018 for adults with moderate to severe ulcerative colitis (UC). Three phase 3 clinical trials and an open-label, long-term extension trial found that the drug was associated with increased infection rates and higher lipid levels.

In rheumatoid arthritis patients, an interim analysis of a safety clinical trial of twice-daily doses of 10 mg tofacitinib showed increased rates of pulmonary embolism and all-cause mortality, compared to treatment with a dose of 5 mg or a tumor necrosis factor antagonist. That finding led to a black box label warning against thrombosis.

The current study, led by Parakkal Deepak, MBBS, MS, and colleagues and published in Clinical Gastroenterology and Hepatology, included patients from six centers in the United States.

The findings suggest that patients should be counseled about the potential risk for herpes zoster (HZ) reactivation, especially older patients taking corticosteroids. The authors also recommended vaccination with an inactivated HZ vaccine. “Our data suggest a careful risk-benefit discussion before starting tofacitinib, especially in patients with preexisting risk factors for VTE, dose deescalation to the lowest clinically feasible dose, and monitoring for clinical signs of VTE, especially among those who continue on a dose of 10 mg twice a day,” the authors wrote.

The researchers followed 260 patients over a median of 6 months (median age, 38 years; 58.1% male; 71.9% non-Hispanic). Overall, 88.5% had previously received treatment with a biologic, most often an anti–TNF-alpha agent (76.5%). During follow-up, 15.7% experienced adverse events, most commonly infections (5.0%) and rash (3.5%). Joint pain (1.5%) and anemia (1.5%) also occurred. The incidence rate for any adverse event was 27.2 per 100 person-years. Adverse events occurred more often in older patients (mean age, 42 vs. 37 years; P = .02) and those who had not undergone previous anti-TNF therapy (63.4% vs 79.8%; P = .03). There was no association between concomitant steroid use and adverse events on univariate analysis. Of the overall cohort, 5.8% experienced a severe adverse event, with the most common being herpes zoster rash (26.7% of severe adverse events). Therapy was discontinued by 4.6%.

Five patients developed herpes zoster (3.29 per 100 person-years; 95% CI, 1.37-7.90). Risk factors for VTE were seen in 31.2% of the cohort, and two cases of VTE occurred during follow-up (1.32 per 100 person-years; 95% CI, 0.33-5.28), both in patients with extensive UC. There was no increased risk of complications following abdominal surgery.

At baseline, 38.4% had an abnormal lipid profile, and this increased to 48.3% following 8 weeks of treatment.

Overall, 45% of patients were anemic at baseline. Females experienced a significant improvement by week 26 (median hemoglobin level, 13.0 g/dL; interquartile range, 12.5-13.8), while a similar improvement occurred by week 52 in males (median hemoglobin level, 13.6 g/dL; IQR, 12.57-14.0). At 52 weeks, the mean increase in hemoglobin was 5% (IQR, 0%-11.1%). The increase was greater in females (7.7%; IQR, 4.2%-11.7%) than in males (2.1%; IQR, –0.5% to 11.3%).

Limitations of the study include its retrospective nature and that the tools by which data were collected could have missed some adverse events because they were not adequately captured in the treating clinician’s notes. However, the data trend similarly to a prospective study.

“In summary, we report safety signals on a real-world cohort of patients with UC initiated on tofacitinib in whom increasing age is a risk factor for AEs and consistent with recent reports of a dose-dependent risk of HZ reactivation and VTE events in patients with a risk factor for VTE on the 10-mg twice-daily dosing,” the authors concluded.

The study was funded by the American College of Gastroenterology, the Crohn’s and Colitis Foundation, the Givin’ it all for Guts Foundation, and the Lawrence C. Pakula, MD, Inflammatory Bowel Disease Research Innovation and Education Fund. The authors have financial ties with various pharmaceutical companies.

This article was updated July 19, 2021.

A network meta-analysis of current first-line dual, triple, and quadruple therapies for Helicobacter pylori infection found that vonoprazan triple therapy was most effective, while standard triple therapy of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin was least effective. Levofloxacin-containing triple therapy performed best in Western countries and West Asia, while reverse hybrid therapy was most effective in East Asia.

The results “[suggest that] a new approach concerning H. pylori treatment is now needed and that the time for transitioning from trial and error to antimicrobial stewardship [of H. pylori infection] has arrived,” wrote Theodore Rokkas, PhD, MD, of the European University of Cyprus in Engomi, and colleagues. Their study was published online April 8 in Gastroenterology.

H. pylori infection is the primary cause of gastritis, peptic ulcer disease, gastric mucosa–associated lymphoid tissue lymphoma, and gastric cancer.

Since H. pylori infection was first recognized, physicians have employed a range of drugs in double, triple, and quadruple combinations to combat it.

Despite those efforts, treatment success is lower than with many other infectious diseases. A newcomer is the potassium-competing acid blocker vonoprazan, which increases efficacy of amoxicillin combination therapies and has, thereby, generated renewed interest in all combination therapies, according to the study authors. Vonoprazan is currently available in some Asian countries, but not the United States or Europe.

Current guidelines for H. pylori treatment relied on randomized controlled trials and relevant pair-wise meta-analyses, but no previous pairwise analysis has included all currently available medications, the authors noted. Network meta-analyses can help fill this evidence gap: They incorporate both direct and indirect evidence from a collection of randomized controlled trials to estimate the comparative effectiveness of three or more regimens.

The researchers conducted a network meta-analysis that included 68 randomized, controlled trials totaling 22,975 patients. The following regimens were included in the analysis: Concomitant quadruple bismuth treatment (bismuth quadruple therapy), concomitant quadruple nonbismuth treatment (nonbismuth quadruple therapy), high-dose amoxicillin double treatment (Amox-dual therapy), levofloxacin-containing treatment (Levo-therapy), reverse hybrid therapy (R-hybrid therapy), sequential quadruple treatment (sequential therapy), standard triple treatment (triple therapy), and vonoprazan-containing therapy (Vono-triple therapy).

Statistically significant results were found with Vono-triple therapy versus triple therapy (odds ratio, 3.80; 95% confidence interval, 1.62-8.94), sequential therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53), nonbismuth quadruple therapy versus triple therapy (OR, 2.08; 95% CI, 1.45-2.98), bismuth quadruple therapy versus triple therapy (OR, 1.47; 95% CI, 1.02-2.11), and Levo-therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53).

In the overall data, mean cure rates greater than 90% were seen only in Vono-triple therapy (91.4%; 95% CI, 88.5-93.5%) and R-hybrid therapy (93.6%; 95% CI, 90.4-96.8%). Cure rates were lower for Nonbismuth quadruple therapy (84.3%; 95% CI, 82.7-85.8%), Levo-therapy (83.8%; 95% CI, 82.1-85.4%), Sequential therapy (83.7%; 95% CI, 82.7-84.7%), bismuth quadruple therapy (81.3%; 95% CI, 79.5-83.1%), Amox-dual therapy (80.2%; 75.3%-84.4%), and triple therapy (75.7%; 95% CI, 74.9-76.4%). Levo-therapy performed best in Western countries (88.5%; 95% CI, 86.5-90.5%) and West Asia (88.4%; 95% CI, 84.6-91.1%). R-hybrid therapy performed best in East Asia (93.6%; 95% CI, 90.4-96.8%).

A surface under the cumulative ranking (SUCRA) value, which represents the efficacy of the intervention compared to an ideal intervention, was 92.4% for Vono-triple therapy. The second highest SUCRA value was for 68.8% for nonbismuth quadruple therapy. The SUCRA value of standard triple therapy was 4.7%.

A key limitation to the study is that Vono-triple therapy was tested only in Japan, and requires additional study in other geographic regions.

The study received support from the Department of Veteran Affairs. The authors have consulted for and received research funding from various pharmaceutical companies.

A network meta-analysis of current first-line dual, triple, and quadruple therapies for Helicobacter pylori infection found that vonoprazan triple therapy was most effective, while standard triple therapy of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin was least effective. Levofloxacin-containing triple therapy performed best in Western countries and West Asia, while reverse hybrid therapy was most effective in East Asia.

The results “[suggest that] a new approach concerning H. pylori treatment is now needed and that the time for transitioning from trial and error to antimicrobial stewardship [of H. pylori infection] has arrived,” wrote Theodore Rokkas, PhD, MD, of the European University of Cyprus in Engomi, and colleagues. Their study was published online April 8 in Gastroenterology.

H. pylori infection is the primary cause of gastritis, peptic ulcer disease, gastric mucosa–associated lymphoid tissue lymphoma, and gastric cancer.

Since H. pylori infection was first recognized, physicians have employed a range of drugs in double, triple, and quadruple combinations to combat it.

Despite those efforts, treatment success is lower than with many other infectious diseases. A newcomer is the potassium-competing acid blocker vonoprazan, which increases efficacy of amoxicillin combination therapies and has, thereby, generated renewed interest in all combination therapies, according to the study authors. Vonoprazan is currently available in some Asian countries, but not the United States or Europe.

Current guidelines for H. pylori treatment relied on randomized controlled trials and relevant pair-wise meta-analyses, but no previous pairwise analysis has included all currently available medications, the authors noted. Network meta-analyses can help fill this evidence gap: They incorporate both direct and indirect evidence from a collection of randomized controlled trials to estimate the comparative effectiveness of three or more regimens.

The researchers conducted a network meta-analysis that included 68 randomized, controlled trials totaling 22,975 patients. The following regimens were included in the analysis: Concomitant quadruple bismuth treatment (bismuth quadruple therapy), concomitant quadruple nonbismuth treatment (nonbismuth quadruple therapy), high-dose amoxicillin double treatment (Amox-dual therapy), levofloxacin-containing treatment (Levo-therapy), reverse hybrid therapy (R-hybrid therapy), sequential quadruple treatment (sequential therapy), standard triple treatment (triple therapy), and vonoprazan-containing therapy (Vono-triple therapy).

Statistically significant results were found with Vono-triple therapy versus triple therapy (odds ratio, 3.80; 95% confidence interval, 1.62-8.94), sequential therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53), nonbismuth quadruple therapy versus triple therapy (OR, 2.08; 95% CI, 1.45-2.98), bismuth quadruple therapy versus triple therapy (OR, 1.47; 95% CI, 1.02-2.11), and Levo-therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53).

In the overall data, mean cure rates greater than 90% were seen only in Vono-triple therapy (91.4%; 95% CI, 88.5-93.5%) and R-hybrid therapy (93.6%; 95% CI, 90.4-96.8%). Cure rates were lower for Nonbismuth quadruple therapy (84.3%; 95% CI, 82.7-85.8%), Levo-therapy (83.8%; 95% CI, 82.1-85.4%), Sequential therapy (83.7%; 95% CI, 82.7-84.7%), bismuth quadruple therapy (81.3%; 95% CI, 79.5-83.1%), Amox-dual therapy (80.2%; 75.3%-84.4%), and triple therapy (75.7%; 95% CI, 74.9-76.4%). Levo-therapy performed best in Western countries (88.5%; 95% CI, 86.5-90.5%) and West Asia (88.4%; 95% CI, 84.6-91.1%). R-hybrid therapy performed best in East Asia (93.6%; 95% CI, 90.4-96.8%).

A surface under the cumulative ranking (SUCRA) value, which represents the efficacy of the intervention compared to an ideal intervention, was 92.4% for Vono-triple therapy. The second highest SUCRA value was for 68.8% for nonbismuth quadruple therapy. The SUCRA value of standard triple therapy was 4.7%.

A key limitation to the study is that Vono-triple therapy was tested only in Japan, and requires additional study in other geographic regions.

The study received support from the Department of Veteran Affairs. The authors have consulted for and received research funding from various pharmaceutical companies.

A network meta-analysis of current first-line dual, triple, and quadruple therapies for Helicobacter pylori infection found that vonoprazan triple therapy was most effective, while standard triple therapy of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin was least effective. Levofloxacin-containing triple therapy performed best in Western countries and West Asia, while reverse hybrid therapy was most effective in East Asia.

The results “[suggest that] a new approach concerning H. pylori treatment is now needed and that the time for transitioning from trial and error to antimicrobial stewardship [of H. pylori infection] has arrived,” wrote Theodore Rokkas, PhD, MD, of the European University of Cyprus in Engomi, and colleagues. Their study was published online April 8 in Gastroenterology.

H. pylori infection is the primary cause of gastritis, peptic ulcer disease, gastric mucosa–associated lymphoid tissue lymphoma, and gastric cancer.

Since H. pylori infection was first recognized, physicians have employed a range of drugs in double, triple, and quadruple combinations to combat it.

Despite those efforts, treatment success is lower than with many other infectious diseases. A newcomer is the potassium-competing acid blocker vonoprazan, which increases efficacy of amoxicillin combination therapies and has, thereby, generated renewed interest in all combination therapies, according to the study authors. Vonoprazan is currently available in some Asian countries, but not the United States or Europe.

Current guidelines for H. pylori treatment relied on randomized controlled trials and relevant pair-wise meta-analyses, but no previous pairwise analysis has included all currently available medications, the authors noted. Network meta-analyses can help fill this evidence gap: They incorporate both direct and indirect evidence from a collection of randomized controlled trials to estimate the comparative effectiveness of three or more regimens.

The researchers conducted a network meta-analysis that included 68 randomized, controlled trials totaling 22,975 patients. The following regimens were included in the analysis: Concomitant quadruple bismuth treatment (bismuth quadruple therapy), concomitant quadruple nonbismuth treatment (nonbismuth quadruple therapy), high-dose amoxicillin double treatment (Amox-dual therapy), levofloxacin-containing treatment (Levo-therapy), reverse hybrid therapy (R-hybrid therapy), sequential quadruple treatment (sequential therapy), standard triple treatment (triple therapy), and vonoprazan-containing therapy (Vono-triple therapy).

Statistically significant results were found with Vono-triple therapy versus triple therapy (odds ratio, 3.80; 95% confidence interval, 1.62-8.94), sequential therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53), nonbismuth quadruple therapy versus triple therapy (OR, 2.08; 95% CI, 1.45-2.98), bismuth quadruple therapy versus triple therapy (OR, 1.47; 95% CI, 1.02-2.11), and Levo-therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53).

In the overall data, mean cure rates greater than 90% were seen only in Vono-triple therapy (91.4%; 95% CI, 88.5-93.5%) and R-hybrid therapy (93.6%; 95% CI, 90.4-96.8%). Cure rates were lower for Nonbismuth quadruple therapy (84.3%; 95% CI, 82.7-85.8%), Levo-therapy (83.8%; 95% CI, 82.1-85.4%), Sequential therapy (83.7%; 95% CI, 82.7-84.7%), bismuth quadruple therapy (81.3%; 95% CI, 79.5-83.1%), Amox-dual therapy (80.2%; 75.3%-84.4%), and triple therapy (75.7%; 95% CI, 74.9-76.4%). Levo-therapy performed best in Western countries (88.5%; 95% CI, 86.5-90.5%) and West Asia (88.4%; 95% CI, 84.6-91.1%). R-hybrid therapy performed best in East Asia (93.6%; 95% CI, 90.4-96.8%).

A surface under the cumulative ranking (SUCRA) value, which represents the efficacy of the intervention compared to an ideal intervention, was 92.4% for Vono-triple therapy. The second highest SUCRA value was for 68.8% for nonbismuth quadruple therapy. The SUCRA value of standard triple therapy was 4.7%.

A key limitation to the study is that Vono-triple therapy was tested only in Japan, and requires additional study in other geographic regions.

The study received support from the Department of Veteran Affairs. The authors have consulted for and received research funding from various pharmaceutical companies.

In a small study of Hirschsprung’s disease (HSCR) patients, those with a low-fiber colonic mucosal acetylcholinesterase-positive (AChE+) innervation phenotype were more likely to suffer from postoperative enterocolitis, which can be life-threatening.

The study lends insight into crosstalk between the human enteric nervous and immune systems. It suggests a role for acetylcholine-secreting (cholinergic) nerve fibers in aganglionic sections of colon in patients with HSCR, which is a congenital disorder marked by the absence of enteric neuronal cells in the distal part of the gut.

There are also potential clinical implications. “These observations suggest that HSCR patients with low-fiber phenotype might have a higher risk of developing postoperative enterocolitis and that the fiber phenotype could serve as a predictive marker for development of prophylactic therapy,” wrote Simone Keck, PhD,  of the University of Basel (Switzerland) and colleagues in a study published in Cellular and Molecular Gastroenterology and Hepatology.

HSCR is a multigenetic congenital condition that includes a lack of enteric ganglia cells (aganglionosis) in the distal part of the colon, leading to intestinal obstruction and prestenotic megacolon. Treatment consists of pull-through surgery to remove the aganglionic portion of the bowel, but 20%-50% of patients develop life-threatening HSCR-associated enterocolitis before or after surgery. Although the mechanism of the complication is uncertain, immune cells, intestinal barrier function, and the microbiome may play a role.

Mouse models have shown connections between the immune and nervous system, but it has been challenging to study the effects of specific neurotransmitters in humans. There are more than 30 separate neurotransmitters in the enteric nervous system, making it difficult to tease apart individual functions. But there are comparatively few enteric nervous system neurotransmitters in patients with HSCR and the aganglionic colon in these patients contains enlarged AChE+ nerve fibers, “neuronal cholinergic function can be examined particularly well” among these patients. .

The researchers of the current study from analyzed tissue from 44 pediatric HSCR patients who underwent pull-through surgery, along with 6 non-HSCR controls who had surgery for various other reasons. Tissue samples were semiquantitatively categorized according to the extent of colonic mucosal AChE+ innervation: Low-fiber rectosigmoid tissue lacked intrinsic nerve cell bodies and mucosal ACHe+ innervation, while high-fiber tissue lacked nerve cell bodies but had mucosal AChE+ innervation. The researchers also determined tissue cytokine profile and immune cell frequencies, and used confocal immunofluorescence microscopy to determine proximity of macrophages to nerve fibers and 16S-rDNA sequencing to determine microbial populations.

They found that aganglionic low-fiber samples had higher levels of inflammatory cytokines such as interleukin-17, IL-1-beta, and IL6. Levels of these cytokines were lower in both ganglionic sections of the colon and in high-fiber samples with mucosal AChE+ nerve fibers. Low-fiber samples also had elevated Th17 T cells, compared with high-fiber, aganglionic, and ganglionic distal colon samples. Regulatory T cells were highest in cholinergic high-fiber segments.

Out of 42 patients, 9 developed enterocolitis within 1 year of surgery; 7 had a low-fiber phenotype, while 2 were high-fiber. This difference was not statistically significant, but the researchers then performed a retrospective analysis of 29 HSCR patients to validate the findings. Of these, 14 developed enterocolitis after surgery, with 12 of the cases occurring among children with the low-fiber phenotype, and 2 cases occurred among those with the high-fiber phenotype.

The findings could help guide postsurgical management of HSCR by allowing clinicians to employ preventive measures against enterocolitis, such as high-volume enemas, antibiotics, prebiotics, probiotics, or dietary changes. Th17 cells are known to migrate to nearby mesenteric lymph nodes, where they may promote enterocolitis, and this site is usually not removed during HSCR surgery. Fiber phenotype could prompt a surgeon to also remove mesenteric lymph nodes to reduce enterocolitis risk. A potential therapeutic strategy is to target IL-17 or IL-23.

The study was funded by the University of Basel. The authors have no relevant financial disclosures.

In a small study of Hirschsprung’s disease (HSCR) patients, those with a low-fiber colonic mucosal acetylcholinesterase-positive (AChE+) innervation phenotype were more likely to suffer from postoperative enterocolitis, which can be life-threatening.

The study lends insight into crosstalk between the human enteric nervous and immune systems. It suggests a role for acetylcholine-secreting (cholinergic) nerve fibers in aganglionic sections of colon in patients with HSCR, which is a congenital disorder marked by the absence of enteric neuronal cells in the distal part of the gut.

There are also potential clinical implications. “These observations suggest that HSCR patients with low-fiber phenotype might have a higher risk of developing postoperative enterocolitis and that the fiber phenotype could serve as a predictive marker for development of prophylactic therapy,” wrote Simone Keck, PhD,  of the University of Basel (Switzerland) and colleagues in a study published in Cellular and Molecular Gastroenterology and Hepatology.

HSCR is a multigenetic congenital condition that includes a lack of enteric ganglia cells (aganglionosis) in the distal part of the colon, leading to intestinal obstruction and prestenotic megacolon. Treatment consists of pull-through surgery to remove the aganglionic portion of the bowel, but 20%-50% of patients develop life-threatening HSCR-associated enterocolitis before or after surgery. Although the mechanism of the complication is uncertain, immune cells, intestinal barrier function, and the microbiome may play a role.

Mouse models have shown connections between the immune and nervous system, but it has been challenging to study the effects of specific neurotransmitters in humans. There are more than 30 separate neurotransmitters in the enteric nervous system, making it difficult to tease apart individual functions. But there are comparatively few enteric nervous system neurotransmitters in patients with HSCR and the aganglionic colon in these patients contains enlarged AChE+ nerve fibers, “neuronal cholinergic function can be examined particularly well” among these patients. .

The researchers of the current study from analyzed tissue from 44 pediatric HSCR patients who underwent pull-through surgery, along with 6 non-HSCR controls who had surgery for various other reasons. Tissue samples were semiquantitatively categorized according to the extent of colonic mucosal AChE+ innervation: Low-fiber rectosigmoid tissue lacked intrinsic nerve cell bodies and mucosal ACHe+ innervation, while high-fiber tissue lacked nerve cell bodies but had mucosal AChE+ innervation. The researchers also determined tissue cytokine profile and immune cell frequencies, and used confocal immunofluorescence microscopy to determine proximity of macrophages to nerve fibers and 16S-rDNA sequencing to determine microbial populations.

They found that aganglionic low-fiber samples had higher levels of inflammatory cytokines such as interleukin-17, IL-1-beta, and IL6. Levels of these cytokines were lower in both ganglionic sections of the colon and in high-fiber samples with mucosal AChE+ nerve fibers. Low-fiber samples also had elevated Th17 T cells, compared with high-fiber, aganglionic, and ganglionic distal colon samples. Regulatory T cells were highest in cholinergic high-fiber segments.

Out of 42 patients, 9 developed enterocolitis within 1 year of surgery; 7 had a low-fiber phenotype, while 2 were high-fiber. This difference was not statistically significant, but the researchers then performed a retrospective analysis of 29 HSCR patients to validate the findings. Of these, 14 developed enterocolitis after surgery, with 12 of the cases occurring among children with the low-fiber phenotype, and 2 cases occurred among those with the high-fiber phenotype.

The findings could help guide postsurgical management of HSCR by allowing clinicians to employ preventive measures against enterocolitis, such as high-volume enemas, antibiotics, prebiotics, probiotics, or dietary changes. Th17 cells are known to migrate to nearby mesenteric lymph nodes, where they may promote enterocolitis, and this site is usually not removed during HSCR surgery. Fiber phenotype could prompt a surgeon to also remove mesenteric lymph nodes to reduce enterocolitis risk. A potential therapeutic strategy is to target IL-17 or IL-23.

The study was funded by the University of Basel. The authors have no relevant financial disclosures.

In a small study of Hirschsprung’s disease (HSCR) patients, those with a low-fiber colonic mucosal acetylcholinesterase-positive (AChE+) innervation phenotype were more likely to suffer from postoperative enterocolitis, which can be life-threatening.

The study lends insight into crosstalk between the human enteric nervous and immune systems. It suggests a role for acetylcholine-secreting (cholinergic) nerve fibers in aganglionic sections of colon in patients with HSCR, which is a congenital disorder marked by the absence of enteric neuronal cells in the distal part of the gut.

There are also potential clinical implications. “These observations suggest that HSCR patients with low-fiber phenotype might have a higher risk of developing postoperative enterocolitis and that the fiber phenotype could serve as a predictive marker for development of prophylactic therapy,” wrote Simone Keck, PhD,  of the University of Basel (Switzerland) and colleagues in a study published in Cellular and Molecular Gastroenterology and Hepatology.

HSCR is a multigenetic congenital condition that includes a lack of enteric ganglia cells (aganglionosis) in the distal part of the colon, leading to intestinal obstruction and prestenotic megacolon. Treatment consists of pull-through surgery to remove the aganglionic portion of the bowel, but 20%-50% of patients develop life-threatening HSCR-associated enterocolitis before or after surgery. Although the mechanism of the complication is uncertain, immune cells, intestinal barrier function, and the microbiome may play a role.

Mouse models have shown connections between the immune and nervous system, but it has been challenging to study the effects of specific neurotransmitters in humans. There are more than 30 separate neurotransmitters in the enteric nervous system, making it difficult to tease apart individual functions. But there are comparatively few enteric nervous system neurotransmitters in patients with HSCR and the aganglionic colon in these patients contains enlarged AChE+ nerve fibers, “neuronal cholinergic function can be examined particularly well” among these patients. .

The researchers of the current study from analyzed tissue from 44 pediatric HSCR patients who underwent pull-through surgery, along with 6 non-HSCR controls who had surgery for various other reasons. Tissue samples were semiquantitatively categorized according to the extent of colonic mucosal AChE+ innervation: Low-fiber rectosigmoid tissue lacked intrinsic nerve cell bodies and mucosal ACHe+ innervation, while high-fiber tissue lacked nerve cell bodies but had mucosal AChE+ innervation. The researchers also determined tissue cytokine profile and immune cell frequencies, and used confocal immunofluorescence microscopy to determine proximity of macrophages to nerve fibers and 16S-rDNA sequencing to determine microbial populations.

They found that aganglionic low-fiber samples had higher levels of inflammatory cytokines such as interleukin-17, IL-1-beta, and IL6. Levels of these cytokines were lower in both ganglionic sections of the colon and in high-fiber samples with mucosal AChE+ nerve fibers. Low-fiber samples also had elevated Th17 T cells, compared with high-fiber, aganglionic, and ganglionic distal colon samples. Regulatory T cells were highest in cholinergic high-fiber segments.

Out of 42 patients, 9 developed enterocolitis within 1 year of surgery; 7 had a low-fiber phenotype, while 2 were high-fiber. This difference was not statistically significant, but the researchers then performed a retrospective analysis of 29 HSCR patients to validate the findings. Of these, 14 developed enterocolitis after surgery, with 12 of the cases occurring among children with the low-fiber phenotype, and 2 cases occurred among those with the high-fiber phenotype.

The findings could help guide postsurgical management of HSCR by allowing clinicians to employ preventive measures against enterocolitis, such as high-volume enemas, antibiotics, prebiotics, probiotics, or dietary changes. Th17 cells are known to migrate to nearby mesenteric lymph nodes, where they may promote enterocolitis, and this site is usually not removed during HSCR surgery. Fiber phenotype could prompt a surgeon to also remove mesenteric lymph nodes to reduce enterocolitis risk. A potential therapeutic strategy is to target IL-17 or IL-23.

The study was funded by the University of Basel. The authors have no relevant financial disclosures.

In a real-world test, tofacitinib had a similar safety profile to what was seen in clinical trials. The majority of adverse events seen were infections, and few were serious; however, the study did find evidence of rare venous thromboembolism (VTE) in patients with preexisting risk factors, which suggests that precaution is warranted in this group.

Tofacitinib, a Janus kinase inhibitor, was approved by the Food and Drug Administration in 2018 for adults with moderate to severe ulcerative colitis (UC). Three phase 3 clinical trials and an open-label, long-term extension trial found that the drug was associated with increased infection rates and higher lipid levels.

In rheumatoid arthritis patients, an interim analysis of a safety clinical trial of twice-daily doses of 10 mg tofacitinib showed increased rates of pulmonary embolism and all-cause mortality, compared to treatment with a dose of 5 mg or a tumor necrosis factor antagonist. That finding led to a black box label warning against thrombosis.

The current study, published in Clinical Gastroenterology and Hepatology, included patients from six centers in the United States.

The findings suggest that patients should be counseled about the potential risk for herpes zoster (HZ) reactivation, especially older patients taking corticosteroids. The authors also recommended vaccination with an inactivated HZ vaccine. “Our data suggest a careful risk-benefit discussion before starting tofacitinib, especially in patients with preexisting risk factors for VTE, dose deescalation to the lowest clinically feasible dose, and monitoring for clinical signs of VTE, especially among those who continue on a dose of 10 mg twice a day,” the authors wrote.

The researchers followed 260 patients over a median of 6 months (median age, 38 years; 58.1% male; 71.9% non-Hispanic). Overall, 88.5% had previously received treatment with a biologic, most often an anti–TNF-alpha agent (76.5%). During follow-up, 15.7% experienced adverse events, most commonly infections (5.0%) and rash (3.5%). Joint pain (1.5%) and anemia (1.5%) also occurred. The incidence rate for any adverse event was 27.2 per 100 person-years. Adverse events occurred more often in older patients (mean age, 42 vs. 37 years; P = .02) and those who had not undergone previous anti-TNF therapy (63.4% vs 79.8%; P = .03). There was no association between concomitant steroid use and adverse events on univariate analysis. Of the overall cohort, 5.8% experienced a severe adverse event, with the most common being herpes zoster rash (26.7% of severe adverse events). Therapy was discontinued by 4.6%.

Five patients developed herpes zoster (3.29 per 100 person-years; 95% CI, 1.37-7.90). Risk factors for VTE were seen in 31.2% of the cohort, and two cases of VTE occurred during follow-up (1.32 per 100 person-years; 95% CI, 0.33-5.28), both in patients with extensive UC. There was no increased risk of complications following abdominal surgery.

At baseline, 38.4% had an abnormal lipid profile, and this increased to 48.3% following 8 weeks of treatment.

Overall, 45% of patients were anemic at baseline. Females experienced a significant improvement by week 26 (median hemoglobin level, 13.0 g/dL; interquartile range, 12.5-13.8), while a similar improvement occurred by week 52 in males (median hemoglobin level, 13.6 g/dL; IQR, 12.57-14.0). At 52 weeks, the mean increase in hemoglobin was 5% (IQR, 0%-11.1%). The increase was greater in females (7.7%; IQR, 4.2%-11.7%) than in males (2.1%; IQR, –0.5% to 11.3%).

Limitations of the study include its retrospective nature and that the tools by which data were collected could have missed some adverse events because they were not adequately captured in the treating clinician’s notes. However, the data trend similarly to a prospective study.

“In summary, we report safety signals on a real-world cohort of patients with UC initiated on tofacitinib in whom increasing age is a risk factor for AEs and consistent with recent reports of a dose-dependent risk of HZ reactivation and VTE events in patients with a risk factor for VTE on the 10-mg twice-daily dosing,” the authors concluded.

The study was funded by the American College of Gastroenterology, the Crohn’s and Colitis Foundation, the Givin’ it all for Guts Foundation, and the Lawrence C. Pakula, MD, Inflammatory Bowel Disease Research Innovation and Education Fund. The authors have financial ties with various pharmaceutical companies.

This article was updated July 19, 2021.

In a real-world test, tofacitinib had a similar safety profile to what was seen in clinical trials. The majority of adverse events seen were infections, and few were serious; however, the study did find evidence of rare venous thromboembolism (VTE) in patients with preexisting risk factors, which suggests that precaution is warranted in this group.

Tofacitinib, a Janus kinase inhibitor, was approved by the Food and Drug Administration in 2018 for adults with moderate to severe ulcerative colitis (UC). Three phase 3 clinical trials and an open-label, long-term extension trial found that the drug was associated with increased infection rates and higher lipid levels.

In rheumatoid arthritis patients, an interim analysis of a safety clinical trial of twice-daily doses of 10 mg tofacitinib showed increased rates of pulmonary embolism and all-cause mortality, compared to treatment with a dose of 5 mg or a tumor necrosis factor antagonist. That finding led to a black box label warning against thrombosis.

The current study, published in Clinical Gastroenterology and Hepatology, included patients from six centers in the United States.

The findings suggest that patients should be counseled about the potential risk for herpes zoster (HZ) reactivation, especially older patients taking corticosteroids. The authors also recommended vaccination with an inactivated HZ vaccine. “Our data suggest a careful risk-benefit discussion before starting tofacitinib, especially in patients with preexisting risk factors for VTE, dose deescalation to the lowest clinically feasible dose, and monitoring for clinical signs of VTE, especially among those who continue on a dose of 10 mg twice a day,” the authors wrote.

The researchers followed 260 patients over a median of 6 months (median age, 38 years; 58.1% male; 71.9% non-Hispanic). Overall, 88.5% had previously received treatment with a biologic, most often an anti–TNF-alpha agent (76.5%). During follow-up, 15.7% experienced adverse events, most commonly infections (5.0%) and rash (3.5%). Joint pain (1.5%) and anemia (1.5%) also occurred. The incidence rate for any adverse event was 27.2 per 100 person-years. Adverse events occurred more often in older patients (mean age, 42 vs. 37 years; P = .02) and those who had not undergone previous anti-TNF therapy (63.4% vs 79.8%; P = .03). There was no association between concomitant steroid use and adverse events on univariate analysis. Of the overall cohort, 5.8% experienced a severe adverse event, with the most common being herpes zoster rash (26.7% of severe adverse events). Therapy was discontinued by 4.6%.

Five patients developed herpes zoster (3.29 per 100 person-years; 95% CI, 1.37-7.90). Risk factors for VTE were seen in 31.2% of the cohort, and two cases of VTE occurred during follow-up (1.32 per 100 person-years; 95% CI, 0.33-5.28), both in patients with extensive UC. There was no increased risk of complications following abdominal surgery.

At baseline, 38.4% had an abnormal lipid profile, and this increased to 48.3% following 8 weeks of treatment.

Overall, 45% of patients were anemic at baseline. Females experienced a significant improvement by week 26 (median hemoglobin level, 13.0 g/dL; interquartile range, 12.5-13.8), while a similar improvement occurred by week 52 in males (median hemoglobin level, 13.6 g/dL; IQR, 12.57-14.0). At 52 weeks, the mean increase in hemoglobin was 5% (IQR, 0%-11.1%). The increase was greater in females (7.7%; IQR, 4.2%-11.7%) than in males (2.1%; IQR, –0.5% to 11.3%).

Limitations of the study include its retrospective nature and that the tools by which data were collected could have missed some adverse events because they were not adequately captured in the treating clinician’s notes. However, the data trend similarly to a prospective study.

“In summary, we report safety signals on a real-world cohort of patients with UC initiated on tofacitinib in whom increasing age is a risk factor for AEs and consistent with recent reports of a dose-dependent risk of HZ reactivation and VTE events in patients with a risk factor for VTE on the 10-mg twice-daily dosing,” the authors concluded.

The study was funded by the American College of Gastroenterology, the Crohn’s and Colitis Foundation, the Givin’ it all for Guts Foundation, and the Lawrence C. Pakula, MD, Inflammatory Bowel Disease Research Innovation and Education Fund. The authors have financial ties with various pharmaceutical companies.

This article was updated July 19, 2021.

In a real-world test, tofacitinib had a similar safety profile to what was seen in clinical trials. The majority of adverse events seen were infections, and few were serious; however, the study did find evidence of rare venous thromboembolism (VTE) in patients with preexisting risk factors, which suggests that precaution is warranted in this group.

Tofacitinib, a Janus kinase inhibitor, was approved by the Food and Drug Administration in 2018 for adults with moderate to severe ulcerative colitis (UC). Three phase 3 clinical trials and an open-label, long-term extension trial found that the drug was associated with increased infection rates and higher lipid levels.

In rheumatoid arthritis patients, an interim analysis of a safety clinical trial of twice-daily doses of 10 mg tofacitinib showed increased rates of pulmonary embolism and all-cause mortality, compared to treatment with a dose of 5 mg or a tumor necrosis factor antagonist. That finding led to a black box label warning against thrombosis.

The current study, published in Clinical Gastroenterology and Hepatology, included patients from six centers in the United States.

The findings suggest that patients should be counseled about the potential risk for herpes zoster (HZ) reactivation, especially older patients taking corticosteroids. The authors also recommended vaccination with an inactivated HZ vaccine. “Our data suggest a careful risk-benefit discussion before starting tofacitinib, especially in patients with preexisting risk factors for VTE, dose deescalation to the lowest clinically feasible dose, and monitoring for clinical signs of VTE, especially among those who continue on a dose of 10 mg twice a day,” the authors wrote.

The researchers followed 260 patients over a median of 6 months (median age, 38 years; 58.1% male; 71.9% non-Hispanic). Overall, 88.5% had previously received treatment with a biologic, most often an anti–TNF-alpha agent (76.5%). During follow-up, 15.7% experienced adverse events, most commonly infections (5.0%) and rash (3.5%). Joint pain (1.5%) and anemia (1.5%) also occurred. The incidence rate for any adverse event was 27.2 per 100 person-years. Adverse events occurred more often in older patients (mean age, 42 vs. 37 years; P = .02) and those who had not undergone previous anti-TNF therapy (63.4% vs 79.8%; P = .03). There was no association between concomitant steroid use and adverse events on univariate analysis. Of the overall cohort, 5.8% experienced a severe adverse event, with the most common being herpes zoster rash (26.7% of severe adverse events). Therapy was discontinued by 4.6%.

Five patients developed herpes zoster (3.29 per 100 person-years; 95% CI, 1.37-7.90). Risk factors for VTE were seen in 31.2% of the cohort, and two cases of VTE occurred during follow-up (1.32 per 100 person-years; 95% CI, 0.33-5.28), both in patients with extensive UC. There was no increased risk of complications following abdominal surgery.

At baseline, 38.4% had an abnormal lipid profile, and this increased to 48.3% following 8 weeks of treatment.

Overall, 45% of patients were anemic at baseline. Females experienced a significant improvement by week 26 (median hemoglobin level, 13.0 g/dL; interquartile range, 12.5-13.8), while a similar improvement occurred by week 52 in males (median hemoglobin level, 13.6 g/dL; IQR, 12.57-14.0). At 52 weeks, the mean increase in hemoglobin was 5% (IQR, 0%-11.1%). The increase was greater in females (7.7%; IQR, 4.2%-11.7%) than in males (2.1%; IQR, –0.5% to 11.3%).

Limitations of the study include its retrospective nature and that the tools by which data were collected could have missed some adverse events because they were not adequately captured in the treating clinician’s notes. However, the data trend similarly to a prospective study.

“In summary, we report safety signals on a real-world cohort of patients with UC initiated on tofacitinib in whom increasing age is a risk factor for AEs and consistent with recent reports of a dose-dependent risk of HZ reactivation and VTE events in patients with a risk factor for VTE on the 10-mg twice-daily dosing,” the authors concluded.

The study was funded by the American College of Gastroenterology, the Crohn’s and Colitis Foundation, the Givin’ it all for Guts Foundation, and the Lawrence C. Pakula, MD, Inflammatory Bowel Disease Research Innovation and Education Fund. The authors have financial ties with various pharmaceutical companies.

This article was updated July 19, 2021.

A network meta-analysis of current first-line dual, triple, and quadruple therapies for Helicobacter pylori infection found that vonoprazan triple therapy was most effective, while standard triple therapy of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin was least effective. Levofloxacin-containing triple therapy performed best in Western countries and West Asia, while reverse hybrid therapy was most effective in East Asia.

The results “[suggest that] a new approach concerning H. pylori treatment is now needed and that the time for transitioning from trial and error to antimicrobial stewardship [of H. pylori infection] has arrived,” wrote Theodore Rokkas, PhD, MD, of the European University of Cyprus in Engomi, and colleagues. Their study was published in Gastroenterology.

H. pylori infection is the primary cause of gastritis, peptic ulcer disease, gastric mucosa–associated lymphoid tissue lymphoma, and gastric cancer.

Since H. pylori infection was first recognized, physicians have employed a range of drugs in double, triple, and quadruple combinations to combat it.

Despite those efforts, treatment success is lower than with many other infectious diseases. A newcomer is the potassium-competing acid blocker vonoprazan, which increases efficacy of amoxicillin combination therapies and has, thereby, generated renewed interest in all combination therapies, according to the study authors. Vonoprazan is currently available in some Asian countries, but not the United States or Europe.

Current guidelines for H. pylori treatment relied on randomized controlled trials and relevant pair-wise meta-analyses, but no previous pairwise analysis has included all currently available medications, the authors noted. Network meta-analyses can help fill this evidence gap: They incorporate both direct and indirect evidence from a collection of randomized controlled trials to estimate the comparative effectiveness of three or more regimens.

The researchers conducted a network meta-analysis that included 68 randomized, controlled trials totaling 22,975 patients. The following regimens were included in the analysis: Concomitant quadruple bismuth treatment (bismuth quadruple therapy), concomitant quadruple nonbismuth treatment (nonbismuth quadruple therapy), high-dose amoxicillin double treatment (Amox-dual therapy), levofloxacin-containing treatment (Levo-therapy), reverse hybrid therapy (R-hybrid therapy), sequential quadruple treatment (sequential therapy), standard triple treatment (triple therapy), and vonoprazan-containing therapy (Vono-triple therapy).

Statistically significant results were found with Vono-triple therapy versus triple therapy (odds ratio, 3.80; 95% confidence interval, 1.62-8.94), sequential therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53), nonbismuth quadruple therapy versus triple therapy (OR, 2.08; 95% CI, 1.45-2.98), bismuth quadruple therapy versus triple therapy (OR, 1.47; 95% CI, 1.02-2.11), and Levo-therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53).

In the overall data, mean cure rates greater than 90% were seen only in Vono-triple therapy (91.4%; 95% CI, 88.5-93.5%) and R-hybrid therapy (93.6%; 95% CI, 90.4-96.8%). Cure rates were lower for Nonbismuth quadruple therapy (84.3%; 95% CI, 82.7-85.8%), Levo-therapy (83.8%; 95% CI, 82.1-85.4%), Sequential therapy (83.7%; 95% CI, 82.7-84.7%), bismuth quadruple therapy (81.3%; 95% CI, 79.5-83.1%), Amox-dual therapy (80.2%; 75.3%-84.4%), and triple therapy (75.7%; 95% CI, 74.9-76.4%). Levo-therapy performed best in Western countries (88.5%; 95% CI, 86.5-90.5%) and West Asia (88.4%; 95% CI, 84.6-91.1%). R-hybrid therapy performed best in East Asia (93.6%; 95% CI, 90.4-96.8%).

A surface under the cumulative ranking (SUCRA) value, which represents the efficacy of the intervention compared to an ideal intervention, was 92.4% for Vono-triple therapy. The second highest SUCRA value was for 68.8% for nonbismuth quadruple therapy. The SUCRA value of standard triple therapy was 4.7%.

A key limitation to the study is that Vono-triple therapy was tested only in Japan, and requires additional study in other geographic regions.

The study received support from the Department of Veteran Affairs. The authors have consulted for and received research funding from various pharmaceutical companies.

A network meta-analysis of current first-line dual, triple, and quadruple therapies for Helicobacter pylori infection found that vonoprazan triple therapy was most effective, while standard triple therapy of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin was least effective. Levofloxacin-containing triple therapy performed best in Western countries and West Asia, while reverse hybrid therapy was most effective in East Asia.

The results “[suggest that] a new approach concerning H. pylori treatment is now needed and that the time for transitioning from trial and error to antimicrobial stewardship [of H. pylori infection] has arrived,” wrote Theodore Rokkas, PhD, MD, of the European University of Cyprus in Engomi, and colleagues. Their study was published in Gastroenterology.

H. pylori infection is the primary cause of gastritis, peptic ulcer disease, gastric mucosa–associated lymphoid tissue lymphoma, and gastric cancer.

Since H. pylori infection was first recognized, physicians have employed a range of drugs in double, triple, and quadruple combinations to combat it.

Despite those efforts, treatment success is lower than with many other infectious diseases. A newcomer is the potassium-competing acid blocker vonoprazan, which increases efficacy of amoxicillin combination therapies and has, thereby, generated renewed interest in all combination therapies, according to the study authors. Vonoprazan is currently available in some Asian countries, but not the United States or Europe.

Current guidelines for H. pylori treatment relied on randomized controlled trials and relevant pair-wise meta-analyses, but no previous pairwise analysis has included all currently available medications, the authors noted. Network meta-analyses can help fill this evidence gap: They incorporate both direct and indirect evidence from a collection of randomized controlled trials to estimate the comparative effectiveness of three or more regimens.

The researchers conducted a network meta-analysis that included 68 randomized, controlled trials totaling 22,975 patients. The following regimens were included in the analysis: Concomitant quadruple bismuth treatment (bismuth quadruple therapy), concomitant quadruple nonbismuth treatment (nonbismuth quadruple therapy), high-dose amoxicillin double treatment (Amox-dual therapy), levofloxacin-containing treatment (Levo-therapy), reverse hybrid therapy (R-hybrid therapy), sequential quadruple treatment (sequential therapy), standard triple treatment (triple therapy), and vonoprazan-containing therapy (Vono-triple therapy).

Statistically significant results were found with Vono-triple therapy versus triple therapy (odds ratio, 3.80; 95% confidence interval, 1.62-8.94), sequential therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53), nonbismuth quadruple therapy versus triple therapy (OR, 2.08; 95% CI, 1.45-2.98), bismuth quadruple therapy versus triple therapy (OR, 1.47; 95% CI, 1.02-2.11), and Levo-therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53).

In the overall data, mean cure rates greater than 90% were seen only in Vono-triple therapy (91.4%; 95% CI, 88.5-93.5%) and R-hybrid therapy (93.6%; 95% CI, 90.4-96.8%). Cure rates were lower for Nonbismuth quadruple therapy (84.3%; 95% CI, 82.7-85.8%), Levo-therapy (83.8%; 95% CI, 82.1-85.4%), Sequential therapy (83.7%; 95% CI, 82.7-84.7%), bismuth quadruple therapy (81.3%; 95% CI, 79.5-83.1%), Amox-dual therapy (80.2%; 75.3%-84.4%), and triple therapy (75.7%; 95% CI, 74.9-76.4%). Levo-therapy performed best in Western countries (88.5%; 95% CI, 86.5-90.5%) and West Asia (88.4%; 95% CI, 84.6-91.1%). R-hybrid therapy performed best in East Asia (93.6%; 95% CI, 90.4-96.8%).

A surface under the cumulative ranking (SUCRA) value, which represents the efficacy of the intervention compared to an ideal intervention, was 92.4% for Vono-triple therapy. The second highest SUCRA value was for 68.8% for nonbismuth quadruple therapy. The SUCRA value of standard triple therapy was 4.7%.

A key limitation to the study is that Vono-triple therapy was tested only in Japan, and requires additional study in other geographic regions.

The study received support from the Department of Veteran Affairs. The authors have consulted for and received research funding from various pharmaceutical companies.

A network meta-analysis of current first-line dual, triple, and quadruple therapies for Helicobacter pylori infection found that vonoprazan triple therapy was most effective, while standard triple therapy of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin was least effective. Levofloxacin-containing triple therapy performed best in Western countries and West Asia, while reverse hybrid therapy was most effective in East Asia.

The results “[suggest that] a new approach concerning H. pylori treatment is now needed and that the time for transitioning from trial and error to antimicrobial stewardship [of H. pylori infection] has arrived,” wrote Theodore Rokkas, PhD, MD, of the European University of Cyprus in Engomi, and colleagues. Their study was published in Gastroenterology.

H. pylori infection is the primary cause of gastritis, peptic ulcer disease, gastric mucosa–associated lymphoid tissue lymphoma, and gastric cancer.

Since H. pylori infection was first recognized, physicians have employed a range of drugs in double, triple, and quadruple combinations to combat it.

Despite those efforts, treatment success is lower than with many other infectious diseases. A newcomer is the potassium-competing acid blocker vonoprazan, which increases efficacy of amoxicillin combination therapies and has, thereby, generated renewed interest in all combination therapies, according to the study authors. Vonoprazan is currently available in some Asian countries, but not the United States or Europe.

Current guidelines for H. pylori treatment relied on randomized controlled trials and relevant pair-wise meta-analyses, but no previous pairwise analysis has included all currently available medications, the authors noted. Network meta-analyses can help fill this evidence gap: They incorporate both direct and indirect evidence from a collection of randomized controlled trials to estimate the comparative effectiveness of three or more regimens.

The researchers conducted a network meta-analysis that included 68 randomized, controlled trials totaling 22,975 patients. The following regimens were included in the analysis: Concomitant quadruple bismuth treatment (bismuth quadruple therapy), concomitant quadruple nonbismuth treatment (nonbismuth quadruple therapy), high-dose amoxicillin double treatment (Amox-dual therapy), levofloxacin-containing treatment (Levo-therapy), reverse hybrid therapy (R-hybrid therapy), sequential quadruple treatment (sequential therapy), standard triple treatment (triple therapy), and vonoprazan-containing therapy (Vono-triple therapy).

Statistically significant results were found with Vono-triple therapy versus triple therapy (odds ratio, 3.80; 95% confidence interval, 1.62-8.94), sequential therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53), nonbismuth quadruple therapy versus triple therapy (OR, 2.08; 95% CI, 1.45-2.98), bismuth quadruple therapy versus triple therapy (OR, 1.47; 95% CI, 1.02-2.11), and Levo-therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53).

In the overall data, mean cure rates greater than 90% were seen only in Vono-triple therapy (91.4%; 95% CI, 88.5-93.5%) and R-hybrid therapy (93.6%; 95% CI, 90.4-96.8%). Cure rates were lower for Nonbismuth quadruple therapy (84.3%; 95% CI, 82.7-85.8%), Levo-therapy (83.8%; 95% CI, 82.1-85.4%), Sequential therapy (83.7%; 95% CI, 82.7-84.7%), bismuth quadruple therapy (81.3%; 95% CI, 79.5-83.1%), Amox-dual therapy (80.2%; 75.3%-84.4%), and triple therapy (75.7%; 95% CI, 74.9-76.4%). Levo-therapy performed best in Western countries (88.5%; 95% CI, 86.5-90.5%) and West Asia (88.4%; 95% CI, 84.6-91.1%). R-hybrid therapy performed best in East Asia (93.6%; 95% CI, 90.4-96.8%).

A surface under the cumulative ranking (SUCRA) value, which represents the efficacy of the intervention compared to an ideal intervention, was 92.4% for Vono-triple therapy. The second highest SUCRA value was for 68.8% for nonbismuth quadruple therapy. The SUCRA value of standard triple therapy was 4.7%.

A key limitation to the study is that Vono-triple therapy was tested only in Japan, and requires additional study in other geographic regions.

The study received support from the Department of Veteran Affairs. The authors have consulted for and received research funding from various pharmaceutical companies.

In a small study of Hirschsprung’s disease (HSCR) patients, those with a low-fiber colonic mucosal acetylcholinesterase-positive (AChE+) innervation phenotype were more likely to suffer from postoperative enterocolitis, which can be life-threatening.

The study lends insight into crosstalk between the human enteric nervous and immune systems. It suggests a role for acetylcholine-secreting (cholinergic) nerve fibers in aganglionic sections of colon in patients with HSCR, which is a congenital disorder marked by the absence of enteric neuronal cells in the distal part of the gut.

There are also potential clinical implications. “These observations suggest that HSCR patients with low-fiber phenotype might have a higher risk of developing postoperative enterocolitis and that the fiber phenotype could serve as a predictive marker for development of prophylactic therapy,” wrote Simone Keck of the University of Basel (Switzerland) and colleagues in a study published in Cellular and Molecular Gastroenterology and Hepatology.

HSCR is a multigenetic congenital condition that includes a lack of enteric ganglia cells (aganglionosis) in the distal part of the colon, leading to intestinal obstruction and prestenotic megacolon. Treatment consists of pull-through surgery to remove the aganglionic portion of the bowel, but 20%-50% of patients develop life-threatening HSCR-associated enterocolitis before or after surgery. Although the mechanism of the complication is uncertain, immune cells, intestinal barrier function, and the microbiome may play a role.

Mouse models have shown connections between the immune and nervous system, but it has been challenging to study the effects of specific neurotransmitters in humans. There are more than 30 separate neurotransmitters in the enteric nervous system, making it difficult to tease apart individual functions. But there are comparatively few enteric nervous system neurotransmitters in patients with HSCR and the aganglionic colon in these patients contains enlarged AChE+ nerve fibers, “neuronal cholinergic function can be examined particularly well” among these patients. .

The researchers of the current study from analyzed tissue from 44 pediatric HSCR patients who underwent pull-through surgery, along with 6 non-HSCR controls who had surgery for various other reasons. Tissue samples were semiquantitatively categorized according to the extent of colonic mucosal AChE+ innervation: Low-fiber rectosigmoid tissue lacked intrinsic nerve cell bodies and mucosal ACHe+ innervation, while high-fiber tissue lacked nerve cell bodies but had mucosal AChE+ innervation. The researchers also determined tissue cytokine profile and immune cell frequencies, and used confocal immunofluorescence microscopy to determine proximity of macrophages to nerve fibers and 16S-rDNA sequencing to determine microbial populations.

They found that aganglionic low-fiber samples had higher levels of inflammatory cytokines such as interleukin-17, IL-1-beta, and IL6. Levels of these cytokines were lower in both ganglionic sections of the colon and in high-fiber samples with mucosal AChE+ nerve fibers. Low-fiber samples also had elevated Th17 T cells, compared with high-fiber, aganglionic, and ganglionic distal colon samples. Regulatory T cells were highest in cholinergic high-fiber segments.

Out of 42 patients, 9 developed enterocolitis within 1 year of surgery; 7 had a low-fiber phenotype, while 2 were high-fiber. This difference was not statistically significant, but the researchers then performed a retrospective analysis of 29 HSCR patients to validate the findings. Of these, 14 developed enterocolitis after surgery, with 12 of the cases occurring among children with the low-fiber phenotype, and 2 cases occurred among those with the high-fiber phenotype.

The findings could help guide postsurgical management of HSCR by allowing clinicians to employ preventive measures against enterocolitis, such as high-volume enemas, antibiotics, prebiotics, probiotics, or dietary changes. Th17 cells are known to migrate to nearby mesenteric lymph nodes, where they may promote enterocolitis, and this site is usually not removed during HSCR surgery. Fiber phenotype could prompt a surgeon to also remove mesenteric lymph nodes to reduce enterocolitis risk. A potential therapeutic strategy is to target IL-17 or IL-23.

The study was funded by the University of Basel. The authors have no relevant financial disclosures.

In a small study of Hirschsprung’s disease (HSCR) patients, those with a low-fiber colonic mucosal acetylcholinesterase-positive (AChE+) innervation phenotype were more likely to suffer from postoperative enterocolitis, which can be life-threatening.

The study lends insight into crosstalk between the human enteric nervous and immune systems. It suggests a role for acetylcholine-secreting (cholinergic) nerve fibers in aganglionic sections of colon in patients with HSCR, which is a congenital disorder marked by the absence of enteric neuronal cells in the distal part of the gut.

There are also potential clinical implications. “These observations suggest that HSCR patients with low-fiber phenotype might have a higher risk of developing postoperative enterocolitis and that the fiber phenotype could serve as a predictive marker for development of prophylactic therapy,” wrote Simone Keck of the University of Basel (Switzerland) and colleagues in a study published in Cellular and Molecular Gastroenterology and Hepatology.

HSCR is a multigenetic congenital condition that includes a lack of enteric ganglia cells (aganglionosis) in the distal part of the colon, leading to intestinal obstruction and prestenotic megacolon. Treatment consists of pull-through surgery to remove the aganglionic portion of the bowel, but 20%-50% of patients develop life-threatening HSCR-associated enterocolitis before or after surgery. Although the mechanism of the complication is uncertain, immune cells, intestinal barrier function, and the microbiome may play a role.

Mouse models have shown connections between the immune and nervous system, but it has been challenging to study the effects of specific neurotransmitters in humans. There are more than 30 separate neurotransmitters in the enteric nervous system, making it difficult to tease apart individual functions. But there are comparatively few enteric nervous system neurotransmitters in patients with HSCR and the aganglionic colon in these patients contains enlarged AChE+ nerve fibers, “neuronal cholinergic function can be examined particularly well” among these patients. .

The researchers of the current study from analyzed tissue from 44 pediatric HSCR patients who underwent pull-through surgery, along with 6 non-HSCR controls who had surgery for various other reasons. Tissue samples were semiquantitatively categorized according to the extent of colonic mucosal AChE+ innervation: Low-fiber rectosigmoid tissue lacked intrinsic nerve cell bodies and mucosal ACHe+ innervation, while high-fiber tissue lacked nerve cell bodies but had mucosal AChE+ innervation. The researchers also determined tissue cytokine profile and immune cell frequencies, and used confocal immunofluorescence microscopy to determine proximity of macrophages to nerve fibers and 16S-rDNA sequencing to determine microbial populations.

They found that aganglionic low-fiber samples had higher levels of inflammatory cytokines such as interleukin-17, IL-1-beta, and IL6. Levels of these cytokines were lower in both ganglionic sections of the colon and in high-fiber samples with mucosal AChE+ nerve fibers. Low-fiber samples also had elevated Th17 T cells, compared with high-fiber, aganglionic, and ganglionic distal colon samples. Regulatory T cells were highest in cholinergic high-fiber segments.

Out of 42 patients, 9 developed enterocolitis within 1 year of surgery; 7 had a low-fiber phenotype, while 2 were high-fiber. This difference was not statistically significant, but the researchers then performed a retrospective analysis of 29 HSCR patients to validate the findings. Of these, 14 developed enterocolitis after surgery, with 12 of the cases occurring among children with the low-fiber phenotype, and 2 cases occurred among those with the high-fiber phenotype.

The findings could help guide postsurgical management of HSCR by allowing clinicians to employ preventive measures against enterocolitis, such as high-volume enemas, antibiotics, prebiotics, probiotics, or dietary changes. Th17 cells are known to migrate to nearby mesenteric lymph nodes, where they may promote enterocolitis, and this site is usually not removed during HSCR surgery. Fiber phenotype could prompt a surgeon to also remove mesenteric lymph nodes to reduce enterocolitis risk. A potential therapeutic strategy is to target IL-17 or IL-23.

The study was funded by the University of Basel. The authors have no relevant financial disclosures.

In a small study of Hirschsprung’s disease (HSCR) patients, those with a low-fiber colonic mucosal acetylcholinesterase-positive (AChE+) innervation phenotype were more likely to suffer from postoperative enterocolitis, which can be life-threatening.

The study lends insight into crosstalk between the human enteric nervous and immune systems. It suggests a role for acetylcholine-secreting (cholinergic) nerve fibers in aganglionic sections of colon in patients with HSCR, which is a congenital disorder marked by the absence of enteric neuronal cells in the distal part of the gut.

There are also potential clinical implications. “These observations suggest that HSCR patients with low-fiber phenotype might have a higher risk of developing postoperative enterocolitis and that the fiber phenotype could serve as a predictive marker for development of prophylactic therapy,” wrote Simone Keck of the University of Basel (Switzerland) and colleagues in a study published in Cellular and Molecular Gastroenterology and Hepatology.

HSCR is a multigenetic congenital condition that includes a lack of enteric ganglia cells (aganglionosis) in the distal part of the colon, leading to intestinal obstruction and prestenotic megacolon. Treatment consists of pull-through surgery to remove the aganglionic portion of the bowel, but 20%-50% of patients develop life-threatening HSCR-associated enterocolitis before or after surgery. Although the mechanism of the complication is uncertain, immune cells, intestinal barrier function, and the microbiome may play a role.

Mouse models have shown connections between the immune and nervous system, but it has been challenging to study the effects of specific neurotransmitters in humans. There are more than 30 separate neurotransmitters in the enteric nervous system, making it difficult to tease apart individual functions. But there are comparatively few enteric nervous system neurotransmitters in patients with HSCR and the aganglionic colon in these patients contains enlarged AChE+ nerve fibers, “neuronal cholinergic function can be examined particularly well” among these patients. .

The researchers of the current study from analyzed tissue from 44 pediatric HSCR patients who underwent pull-through surgery, along with 6 non-HSCR controls who had surgery for various other reasons. Tissue samples were semiquantitatively categorized according to the extent of colonic mucosal AChE+ innervation: Low-fiber rectosigmoid tissue lacked intrinsic nerve cell bodies and mucosal ACHe+ innervation, while high-fiber tissue lacked nerve cell bodies but had mucosal AChE+ innervation. The researchers also determined tissue cytokine profile and immune cell frequencies, and used confocal immunofluorescence microscopy to determine proximity of macrophages to nerve fibers and 16S-rDNA sequencing to determine microbial populations.

They found that aganglionic low-fiber samples had higher levels of inflammatory cytokines such as interleukin-17, IL-1-beta, and IL6. Levels of these cytokines were lower in both ganglionic sections of the colon and in high-fiber samples with mucosal AChE+ nerve fibers. Low-fiber samples also had elevated Th17 T cells, compared with high-fiber, aganglionic, and ganglionic distal colon samples. Regulatory T cells were highest in cholinergic high-fiber segments.

Out of 42 patients, 9 developed enterocolitis within 1 year of surgery; 7 had a low-fiber phenotype, while 2 were high-fiber. This difference was not statistically significant, but the researchers then performed a retrospective analysis of 29 HSCR patients to validate the findings. Of these, 14 developed enterocolitis after surgery, with 12 of the cases occurring among children with the low-fiber phenotype, and 2 cases occurred among those with the high-fiber phenotype.

The findings could help guide postsurgical management of HSCR by allowing clinicians to employ preventive measures against enterocolitis, such as high-volume enemas, antibiotics, prebiotics, probiotics, or dietary changes. Th17 cells are known to migrate to nearby mesenteric lymph nodes, where they may promote enterocolitis, and this site is usually not removed during HSCR surgery. Fiber phenotype could prompt a surgeon to also remove mesenteric lymph nodes to reduce enterocolitis risk. A potential therapeutic strategy is to target IL-17 or IL-23.

The study was funded by the University of Basel. The authors have no relevant financial disclosures.

Among patients with atherosclerotic cardiovascular disease (ASCVD), 2 years after release of treat-to-target guidelines from the American Heart Association and the European Society of Cardiology and European Atherosclerosis Society, most patients with LDL cholesterol higher than 70 mg/dL did not receive intensification of therapy, and two-thirds continued to have LDL levels above that level, according to a prospective registry study.

Both guidelines recommend driving LDL-C levels to 50% or below of baseline levels; results from the Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) registry suggest this is rarely achieved. “Unfortunately it’s not a total surprise, but it’s disappointing,” said Christopher Cannon, MD, the study’s lead author.

“Therapeutic inertia seems to be the rule in clinical practice,” said Jennifer G. Robinson, MD, MPH, who was asked to comment on the study. Dr. Robinson is professor epidemiology and cardiology at the University of Iowa, Iowa City.

Patients hesitant

Changes in practice following guidelines can often be slow, but in this case may have been complicated by the fact that statins have a reputation for causing side effects, so some patients may be refusing treatment based on what they’ve seen on the Internet. Even though the study looked at all lipid-lowering agents, the misinformation around statins may be spilling over, according to Dr. Cannon. “There’s in general so much misinformation around COVID and every other topic in the world. That makes people question what is real [about] anything,” said Dr. Cannon, a cardiologist at Brigham and Women’s hospital and professor of medicine at Harvard Medical School, both in Boston.

Patient characteristics may partly explain slow uptake. “Clinicians may not think further LDL-C lowering is a high enough priority in terms of potential benefit for a given patient in light of the effort being expended to take care of all their other issues and chronic health problems. If the clinician does bring it up to the patient, there may be barriers in terms of additional medication burden, cost, or acquisition issues,” said Dr. Robinson.

The answer may be better evidence and a more personalized approach. Clinical trials that explore defined patient populations could convince patients of a benefit, and payers to reimburse, according to Dr. Robinson.
 

Changing guidance

Another complication is that both the guidelines and the field are rapidly changing. The 2013 AHA guidelines did not include a treatment to goal and focused instead on use of high-dose statins. But the 2018 update reversed course after randomized studies demonstrated a benefit to treating to target. The researchers found no increase in the frequency of treating to target after the release of the 2018 guidelines. “Publication and announcement of guidelines doesn’t mean that people are getting treated better. We really have to implement them,” said Dr. Cannon.

On a positive note, the GOULD researchers found high acceptance of the new proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors, with over 90% of patients continuing those medications after 2 years. “That’s nice and high. If people do get onto the very intensive lipid-lowing therapies, they tend to stay on them,” said Dr. Cannon.
 

What’s next

Still, the lack of intensification is concerning, and the findings led to some consternation in Twitter exchanges, said Dr. Cannon. “People posted ‘Well, what do we do now?’ ” Dr. Cannon’s team is addressing the issue with an algorithm-based risk management program with prospective enrollment. They have conducted educational webinars and provided site-specific reports on LDL status among patients at each center compared to others, and hope that information will improve compliance. In 2020, the group published an interim analysis of the first 5,000 enrollees, and Dr. Cannon expects to finish that study by the end of the year.

Dr. Navar agreed that physicians need to do a better job of testing LDL-C levels after treatment to identify patients who require more aggressive therapy. That can be deferred in some primary prevention patients with high LDL-C but normal particle numbers as measured with ApoB. “But in those at high risk for disease and those with established CVD who are not at goal, as long as they don’t have a life-limiting condition, we should always up-titrate therapy. It’s one of the safest, most effective ways to lower cardiovascular risk,” said Dr. Navar.

Key study results

The prospective study included 5,006 patients at 119 centers with a mean age of 68 years. About 40% were women, and 86.1% were White. All had ASCVD and LDL levels of at least 70 mg/dL. After 2 years, 17% had undergone intensification of lipid-lowering therapy (LLT). Among patients with LDL-C levels ≥ 100 mg/dL, 22% underwent LLT intensification, compared with 14% of patients with LDL-C levels of 70-99 mg/dL.

The vast majority, 92%, of patients who underwent LLT via addition of PCSK9 inhibitors were still taking the drug after 2 years.

Three-quarters (3,768) had lipid level measurements at least once during follow-up, and median LDL-C levels dropped from 120 to 95 mg/dL in the ≥100-mg/dL cohort (P < .001), and from 82 to 77 mg/dL in the 70- to 99-mg/dL cohort (P <. 001). There was no significant difference in the median values in the patients on PCSK9 inhibitors.

In all, 21% of the ≥100-mg/dL cohort achieved LDL-C levels <70 mg/dL at 2 years, versus 34% in the 77- to 99-mg/dL cohort and 52% of patients taking PCSK9 inhibitors.

Patients seen at teaching hospitals were more likely to undergo LLT intensification compared to nonteaching hospitals (25% versus 17%; P < .001), as were those where lipid protocols were in place (22% versus 15%; P < .001), and those treated in cardiology (22%) compared to treatment in internal or family medicine (12%; P <.001). The study was published online June 16 in JAMA Cardiology.

Dr. Cannon, Dr. Navar, and Dr. Robinson disclosed ties with Amgen, which funded the study, and other companies.

Among patients with atherosclerotic cardiovascular disease (ASCVD), 2 years after release of treat-to-target guidelines from the American Heart Association and the European Society of Cardiology and European Atherosclerosis Society, most patients with LDL cholesterol higher than 70 mg/dL did not receive intensification of therapy, and two-thirds continued to have LDL levels above that level, according to a prospective registry study.

Both guidelines recommend driving LDL-C levels to 50% or below of baseline levels; results from the Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) registry suggest this is rarely achieved. “Unfortunately it’s not a total surprise, but it’s disappointing,” said Christopher Cannon, MD, the study’s lead author.

“Therapeutic inertia seems to be the rule in clinical practice,” said Jennifer G. Robinson, MD, MPH, who was asked to comment on the study. Dr. Robinson is professor epidemiology and cardiology at the University of Iowa, Iowa City.

Patients hesitant

Changes in practice following guidelines can often be slow, but in this case may have been complicated by the fact that statins have a reputation for causing side effects, so some patients may be refusing treatment based on what they’ve seen on the Internet. Even though the study looked at all lipid-lowering agents, the misinformation around statins may be spilling over, according to Dr. Cannon. “There’s in general so much misinformation around COVID and every other topic in the world. That makes people question what is real [about] anything,” said Dr. Cannon, a cardiologist at Brigham and Women’s hospital and professor of medicine at Harvard Medical School, both in Boston.

Patient characteristics may partly explain slow uptake. “Clinicians may not think further LDL-C lowering is a high enough priority in terms of potential benefit for a given patient in light of the effort being expended to take care of all their other issues and chronic health problems. If the clinician does bring it up to the patient, there may be barriers in terms of additional medication burden, cost, or acquisition issues,” said Dr. Robinson.

The answer may be better evidence and a more personalized approach. Clinical trials that explore defined patient populations could convince patients of a benefit, and payers to reimburse, according to Dr. Robinson.
 

Changing guidance

Another complication is that both the guidelines and the field are rapidly changing. The 2013 AHA guidelines did not include a treatment to goal and focused instead on use of high-dose statins. But the 2018 update reversed course after randomized studies demonstrated a benefit to treating to target. The researchers found no increase in the frequency of treating to target after the release of the 2018 guidelines. “Publication and announcement of guidelines doesn’t mean that people are getting treated better. We really have to implement them,” said Dr. Cannon.

On a positive note, the GOULD researchers found high acceptance of the new proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors, with over 90% of patients continuing those medications after 2 years. “That’s nice and high. If people do get onto the very intensive lipid-lowing therapies, they tend to stay on them,” said Dr. Cannon.
 

What’s next

Still, the lack of intensification is concerning, and the findings led to some consternation in Twitter exchanges, said Dr. Cannon. “People posted ‘Well, what do we do now?’ ” Dr. Cannon’s team is addressing the issue with an algorithm-based risk management program with prospective enrollment. They have conducted educational webinars and provided site-specific reports on LDL status among patients at each center compared to others, and hope that information will improve compliance. In 2020, the group published an interim analysis of the first 5,000 enrollees, and Dr. Cannon expects to finish that study by the end of the year.

Dr. Navar agreed that physicians need to do a better job of testing LDL-C levels after treatment to identify patients who require more aggressive therapy. That can be deferred in some primary prevention patients with high LDL-C but normal particle numbers as measured with ApoB. “But in those at high risk for disease and those with established CVD who are not at goal, as long as they don’t have a life-limiting condition, we should always up-titrate therapy. It’s one of the safest, most effective ways to lower cardiovascular risk,” said Dr. Navar.

Key study results

The prospective study included 5,006 patients at 119 centers with a mean age of 68 years. About 40% were women, and 86.1% were White. All had ASCVD and LDL levels of at least 70 mg/dL. After 2 years, 17% had undergone intensification of lipid-lowering therapy (LLT). Among patients with LDL-C levels ≥ 100 mg/dL, 22% underwent LLT intensification, compared with 14% of patients with LDL-C levels of 70-99 mg/dL.

The vast majority, 92%, of patients who underwent LLT via addition of PCSK9 inhibitors were still taking the drug after 2 years.

Three-quarters (3,768) had lipid level measurements at least once during follow-up, and median LDL-C levels dropped from 120 to 95 mg/dL in the ≥100-mg/dL cohort (P < .001), and from 82 to 77 mg/dL in the 70- to 99-mg/dL cohort (P <. 001). There was no significant difference in the median values in the patients on PCSK9 inhibitors.

In all, 21% of the ≥100-mg/dL cohort achieved LDL-C levels <70 mg/dL at 2 years, versus 34% in the 77- to 99-mg/dL cohort and 52% of patients taking PCSK9 inhibitors.

Patients seen at teaching hospitals were more likely to undergo LLT intensification compared to nonteaching hospitals (25% versus 17%; P < .001), as were those where lipid protocols were in place (22% versus 15%; P < .001), and those treated in cardiology (22%) compared to treatment in internal or family medicine (12%; P <.001). The study was published online June 16 in JAMA Cardiology.

Dr. Cannon, Dr. Navar, and Dr. Robinson disclosed ties with Amgen, which funded the study, and other companies.

Among patients with atherosclerotic cardiovascular disease (ASCVD), 2 years after release of treat-to-target guidelines from the American Heart Association and the European Society of Cardiology and European Atherosclerosis Society, most patients with LDL cholesterol higher than 70 mg/dL did not receive intensification of therapy, and two-thirds continued to have LDL levels above that level, according to a prospective registry study.

Both guidelines recommend driving LDL-C levels to 50% or below of baseline levels; results from the Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) registry suggest this is rarely achieved. “Unfortunately it’s not a total surprise, but it’s disappointing,” said Christopher Cannon, MD, the study’s lead author.

“Therapeutic inertia seems to be the rule in clinical practice,” said Jennifer G. Robinson, MD, MPH, who was asked to comment on the study. Dr. Robinson is professor epidemiology and cardiology at the University of Iowa, Iowa City.

Patients hesitant

Changes in practice following guidelines can often be slow, but in this case may have been complicated by the fact that statins have a reputation for causing side effects, so some patients may be refusing treatment based on what they’ve seen on the Internet. Even though the study looked at all lipid-lowering agents, the misinformation around statins may be spilling over, according to Dr. Cannon. “There’s in general so much misinformation around COVID and every other topic in the world. That makes people question what is real [about] anything,” said Dr. Cannon, a cardiologist at Brigham and Women’s hospital and professor of medicine at Harvard Medical School, both in Boston.

Patient characteristics may partly explain slow uptake. “Clinicians may not think further LDL-C lowering is a high enough priority in terms of potential benefit for a given patient in light of the effort being expended to take care of all their other issues and chronic health problems. If the clinician does bring it up to the patient, there may be barriers in terms of additional medication burden, cost, or acquisition issues,” said Dr. Robinson.

The answer may be better evidence and a more personalized approach. Clinical trials that explore defined patient populations could convince patients of a benefit, and payers to reimburse, according to Dr. Robinson.
 

Changing guidance

Another complication is that both the guidelines and the field are rapidly changing. The 2013 AHA guidelines did not include a treatment to goal and focused instead on use of high-dose statins. But the 2018 update reversed course after randomized studies demonstrated a benefit to treating to target. The researchers found no increase in the frequency of treating to target after the release of the 2018 guidelines. “Publication and announcement of guidelines doesn’t mean that people are getting treated better. We really have to implement them,” said Dr. Cannon.

On a positive note, the GOULD researchers found high acceptance of the new proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors, with over 90% of patients continuing those medications after 2 years. “That’s nice and high. If people do get onto the very intensive lipid-lowing therapies, they tend to stay on them,” said Dr. Cannon.
 

What’s next

Still, the lack of intensification is concerning, and the findings led to some consternation in Twitter exchanges, said Dr. Cannon. “People posted ‘Well, what do we do now?’ ” Dr. Cannon’s team is addressing the issue with an algorithm-based risk management program with prospective enrollment. They have conducted educational webinars and provided site-specific reports on LDL status among patients at each center compared to others, and hope that information will improve compliance. In 2020, the group published an interim analysis of the first 5,000 enrollees, and Dr. Cannon expects to finish that study by the end of the year.

Dr. Navar agreed that physicians need to do a better job of testing LDL-C levels after treatment to identify patients who require more aggressive therapy. That can be deferred in some primary prevention patients with high LDL-C but normal particle numbers as measured with ApoB. “But in those at high risk for disease and those with established CVD who are not at goal, as long as they don’t have a life-limiting condition, we should always up-titrate therapy. It’s one of the safest, most effective ways to lower cardiovascular risk,” said Dr. Navar.

Key study results

The prospective study included 5,006 patients at 119 centers with a mean age of 68 years. About 40% were women, and 86.1% were White. All had ASCVD and LDL levels of at least 70 mg/dL. After 2 years, 17% had undergone intensification of lipid-lowering therapy (LLT). Among patients with LDL-C levels ≥ 100 mg/dL, 22% underwent LLT intensification, compared with 14% of patients with LDL-C levels of 70-99 mg/dL.

The vast majority, 92%, of patients who underwent LLT via addition of PCSK9 inhibitors were still taking the drug after 2 years.

Three-quarters (3,768) had lipid level measurements at least once during follow-up, and median LDL-C levels dropped from 120 to 95 mg/dL in the ≥100-mg/dL cohort (P < .001), and from 82 to 77 mg/dL in the 70- to 99-mg/dL cohort (P <. 001). There was no significant difference in the median values in the patients on PCSK9 inhibitors.

In all, 21% of the ≥100-mg/dL cohort achieved LDL-C levels <70 mg/dL at 2 years, versus 34% in the 77- to 99-mg/dL cohort and 52% of patients taking PCSK9 inhibitors.

Patients seen at teaching hospitals were more likely to undergo LLT intensification compared to nonteaching hospitals (25% versus 17%; P < .001), as were those where lipid protocols were in place (22% versus 15%; P < .001), and those treated in cardiology (22%) compared to treatment in internal or family medicine (12%; P <.001). The study was published online June 16 in JAMA Cardiology.

Dr. Cannon, Dr. Navar, and Dr. Robinson disclosed ties with Amgen, which funded the study, and other companies.

When it comes to measuring gut transit time, blue dye could be a cost-effective and simple alternative to other, more burdensome methods.

James Griffiths PhotographyiStock/Getty Images Plus

The approach, which only requires fasting followed by eating dyed food, revealed an association between microbiome composition and transit time in healthy individuals, according to authors led by Francisco Asnicar, PhD, of the University of Trento (Italy). The researchers chose the blue food coloring over carmine red dye partly because of its vegetable origin and because the blue color makes it unlikely the recipient would mistake the coloring in stool as originating from some other food, such as beetroot.

Gut motility is connected to digestion, the immune system, the endocrine system, and gut microbiota, according to the authors. For example, some have suggested that transit time may affect postprandial glycemia and lipemia through a potential effect on nutrient absorption and gut microbiome composition. “[This blue dye’s] use therefore has the potential to provide another piece of the puzzle to advance precision medicine,” the authors wrote.

Validated methods to measure transit time include scintigraphy, wireless motility capsule, radio-opaque markers and breath testing, but they require specialized equipment and staff, participants must make at least one in-person visit, and they can be expensive.
 

Transit time’s position in research

Those limitations may explain why the effect of transit time has been understudied, though it has gained momentum in recent years, according to Henrik Roager, PhD, who was asked to comment on the study. “I think it has become clear that it is probably one of the most important factors that explain the [microbiota] differences that we see from individual to individual,” said Dr. Roager, of the department of nutrition, exercise, and sports at the University of Copenhagen.

The relationship is complex, since gut microbes may be releasing metabolites that can affect motility, which in turn would affect the microbes. “The speed by which nutrients pass through a fermenter in the lab will have a huge impact on microbial physiology and metabolism. It’s basically the same principle in humans,” added Dr. Roager, who is engaged in research to identify such microbial metabolites.

To better understand those relationships will require epidemiological studies in healthy populations. Blue dye is one approach. Another is sweet corn, which individuals can obtain even more easily. Dye has one advantage in that it’s unlikely to impact transit time, while the quantity of sweet corn eaten could have an effect. “I definitely think that either this or sweet corn would be standard in many studies in the future,” said Dr. Roager.

Epidemiological studies made easier by dye or sweet corn could also reveal how diet interacts with the microbiome by including transit time as a variable. Transit time can vary from day to day, and Dr. Roager believes those variations may be linked to changes in the gut microbiome. With simpler techniques for measuring transit time, “I think we might be able to better identify effects of diets or drugs or lifestyle on the microbiome.”
 

How the blue dye fared

The researchers analyzed data from 866 twins and unrelated adults from the United States and the United Kingdom who were enrolled in the PREDICT 1 study, which quantified metabolic responses to standardized meals. Participants underwent fasting and then ate two blue muffins, along with a glass of chocolate milk, then logged the first sign of blue coloring in their stool using an app. Participants also answered a questionnaire detailing the frequency and consistency of bowel movements. The researchers also conducted sequencing of stool samples to determine microbiome profile.

There was a strong correlation between stool consistency and frequency, as well as microbial diversity and the composition of the gut microbiome. The dye measurement identified different fast and slow transit time clusters (area under the receiver operating characteristic curve, 0.82), which were associated with the composition of the gut microbiome, including species like Akkermansia muciniphila, Bacteroides species, and Alistipes species (false discovery rate–adjusted P values < .01). Transit times measured with the blue dye was a better predictor of gut function than either stool consistency and stool frequency, suggesting that the dye may be a more useful method for large cohorts of healthy individuals.

Although associations with diet and cardiometabolic factors were more modest, longer transit times appear predictive of greater visceral fat and higher postprandial responses, “which are key measures of health.”

The authors cited some limitations, including the fact that the blue-dye method has not yet been compared with other transit methodologies. However, the gut transit time in this study was found to be strongly correlated with stool consistency and frequency.

“To conclude, our findings indicate that the blue dye method is a novel, inexpensive and scalable method of gut transit assessment providing valuable gut health and metabolic insights,” they wrote. “Its wide use in both research and clinical settings could facilitate the advancement of our understanding of gut function and its determinants, as well as the complex interactions between gut physiology and health outcomes.”

The study authors received funding from a wide range of nonindustry sources. Dr. Roager had no relevant financial disclosures.

When it comes to measuring gut transit time, blue dye could be a cost-effective and simple alternative to other, more burdensome methods.

James Griffiths PhotographyiStock/Getty Images Plus

The approach, which only requires fasting followed by eating dyed food, revealed an association between microbiome composition and transit time in healthy individuals, according to authors led by Francisco Asnicar, PhD, of the University of Trento (Italy). The researchers chose the blue food coloring over carmine red dye partly because of its vegetable origin and because the blue color makes it unlikely the recipient would mistake the coloring in stool as originating from some other food, such as beetroot.

Gut motility is connected to digestion, the immune system, the endocrine system, and gut microbiota, according to the authors. For example, some have suggested that transit time may affect postprandial glycemia and lipemia through a potential effect on nutrient absorption and gut microbiome composition. “[This blue dye’s] use therefore has the potential to provide another piece of the puzzle to advance precision medicine,” the authors wrote.

Validated methods to measure transit time include scintigraphy, wireless motility capsule, radio-opaque markers and breath testing, but they require specialized equipment and staff, participants must make at least one in-person visit, and they can be expensive.
 

Transit time’s position in research

Those limitations may explain why the effect of transit time has been understudied, though it has gained momentum in recent years, according to Henrik Roager, PhD, who was asked to comment on the study. “I think it has become clear that it is probably one of the most important factors that explain the [microbiota] differences that we see from individual to individual,” said Dr. Roager, of the department of nutrition, exercise, and sports at the University of Copenhagen.

The relationship is complex, since gut microbes may be releasing metabolites that can affect motility, which in turn would affect the microbes. “The speed by which nutrients pass through a fermenter in the lab will have a huge impact on microbial physiology and metabolism. It’s basically the same principle in humans,” added Dr. Roager, who is engaged in research to identify such microbial metabolites.

To better understand those relationships will require epidemiological studies in healthy populations. Blue dye is one approach. Another is sweet corn, which individuals can obtain even more easily. Dye has one advantage in that it’s unlikely to impact transit time, while the quantity of sweet corn eaten could have an effect. “I definitely think that either this or sweet corn would be standard in many studies in the future,” said Dr. Roager.

Epidemiological studies made easier by dye or sweet corn could also reveal how diet interacts with the microbiome by including transit time as a variable. Transit time can vary from day to day, and Dr. Roager believes those variations may be linked to changes in the gut microbiome. With simpler techniques for measuring transit time, “I think we might be able to better identify effects of diets or drugs or lifestyle on the microbiome.”
 

How the blue dye fared

The researchers analyzed data from 866 twins and unrelated adults from the United States and the United Kingdom who were enrolled in the PREDICT 1 study, which quantified metabolic responses to standardized meals. Participants underwent fasting and then ate two blue muffins, along with a glass of chocolate milk, then logged the first sign of blue coloring in their stool using an app. Participants also answered a questionnaire detailing the frequency and consistency of bowel movements. The researchers also conducted sequencing of stool samples to determine microbiome profile.

There was a strong correlation between stool consistency and frequency, as well as microbial diversity and the composition of the gut microbiome. The dye measurement identified different fast and slow transit time clusters (area under the receiver operating characteristic curve, 0.82), which were associated with the composition of the gut microbiome, including species like Akkermansia muciniphila, Bacteroides species, and Alistipes species (false discovery rate–adjusted P values < .01). Transit times measured with the blue dye was a better predictor of gut function than either stool consistency and stool frequency, suggesting that the dye may be a more useful method for large cohorts of healthy individuals.

Although associations with diet and cardiometabolic factors were more modest, longer transit times appear predictive of greater visceral fat and higher postprandial responses, “which are key measures of health.”

The authors cited some limitations, including the fact that the blue-dye method has not yet been compared with other transit methodologies. However, the gut transit time in this study was found to be strongly correlated with stool consistency and frequency.

“To conclude, our findings indicate that the blue dye method is a novel, inexpensive and scalable method of gut transit assessment providing valuable gut health and metabolic insights,” they wrote. “Its wide use in both research and clinical settings could facilitate the advancement of our understanding of gut function and its determinants, as well as the complex interactions between gut physiology and health outcomes.”

The study authors received funding from a wide range of nonindustry sources. Dr. Roager had no relevant financial disclosures.

When it comes to measuring gut transit time, blue dye could be a cost-effective and simple alternative to other, more burdensome methods.

James Griffiths PhotographyiStock/Getty Images Plus

The approach, which only requires fasting followed by eating dyed food, revealed an association between microbiome composition and transit time in healthy individuals, according to authors led by Francisco Asnicar, PhD, of the University of Trento (Italy). The researchers chose the blue food coloring over carmine red dye partly because of its vegetable origin and because the blue color makes it unlikely the recipient would mistake the coloring in stool as originating from some other food, such as beetroot.

Gut motility is connected to digestion, the immune system, the endocrine system, and gut microbiota, according to the authors. For example, some have suggested that transit time may affect postprandial glycemia and lipemia through a potential effect on nutrient absorption and gut microbiome composition. “[This blue dye’s] use therefore has the potential to provide another piece of the puzzle to advance precision medicine,” the authors wrote.

Validated methods to measure transit time include scintigraphy, wireless motility capsule, radio-opaque markers and breath testing, but they require specialized equipment and staff, participants must make at least one in-person visit, and they can be expensive.
 

Transit time’s position in research

Those limitations may explain why the effect of transit time has been understudied, though it has gained momentum in recent years, according to Henrik Roager, PhD, who was asked to comment on the study. “I think it has become clear that it is probably one of the most important factors that explain the [microbiota] differences that we see from individual to individual,” said Dr. Roager, of the department of nutrition, exercise, and sports at the University of Copenhagen.

The relationship is complex, since gut microbes may be releasing metabolites that can affect motility, which in turn would affect the microbes. “The speed by which nutrients pass through a fermenter in the lab will have a huge impact on microbial physiology and metabolism. It’s basically the same principle in humans,” added Dr. Roager, who is engaged in research to identify such microbial metabolites.

To better understand those relationships will require epidemiological studies in healthy populations. Blue dye is one approach. Another is sweet corn, which individuals can obtain even more easily. Dye has one advantage in that it’s unlikely to impact transit time, while the quantity of sweet corn eaten could have an effect. “I definitely think that either this or sweet corn would be standard in many studies in the future,” said Dr. Roager.

Epidemiological studies made easier by dye or sweet corn could also reveal how diet interacts with the microbiome by including transit time as a variable. Transit time can vary from day to day, and Dr. Roager believes those variations may be linked to changes in the gut microbiome. With simpler techniques for measuring transit time, “I think we might be able to better identify effects of diets or drugs or lifestyle on the microbiome.”
 

How the blue dye fared

The researchers analyzed data from 866 twins and unrelated adults from the United States and the United Kingdom who were enrolled in the PREDICT 1 study, which quantified metabolic responses to standardized meals. Participants underwent fasting and then ate two blue muffins, along with a glass of chocolate milk, then logged the first sign of blue coloring in their stool using an app. Participants also answered a questionnaire detailing the frequency and consistency of bowel movements. The researchers also conducted sequencing of stool samples to determine microbiome profile.

There was a strong correlation between stool consistency and frequency, as well as microbial diversity and the composition of the gut microbiome. The dye measurement identified different fast and slow transit time clusters (area under the receiver operating characteristic curve, 0.82), which were associated with the composition of the gut microbiome, including species like Akkermansia muciniphila, Bacteroides species, and Alistipes species (false discovery rate–adjusted P values < .01). Transit times measured with the blue dye was a better predictor of gut function than either stool consistency and stool frequency, suggesting that the dye may be a more useful method for large cohorts of healthy individuals.

Although associations with diet and cardiometabolic factors were more modest, longer transit times appear predictive of greater visceral fat and higher postprandial responses, “which are key measures of health.”

The authors cited some limitations, including the fact that the blue-dye method has not yet been compared with other transit methodologies. However, the gut transit time in this study was found to be strongly correlated with stool consistency and frequency.

“To conclude, our findings indicate that the blue dye method is a novel, inexpensive and scalable method of gut transit assessment providing valuable gut health and metabolic insights,” they wrote. “Its wide use in both research and clinical settings could facilitate the advancement of our understanding of gut function and its determinants, as well as the complex interactions between gut physiology and health outcomes.”

The study authors received funding from a wide range of nonindustry sources. Dr. Roager had no relevant financial disclosures.

An in vitro study that used mouse endothelial cells to simulate the blood-brain barrier (BBB) suggests that specific proteins may be involved in destabilization of the protective barrier during a cortical spreading depression (CSD) event.

CSD has been linked to migraine aura, but a connection to pain symptoms is uncertain. “There’s just a lack of knowledge. We don’t understand migraine pathophysiology,” said Michael G. Harrington, MBChB, who was asked to comment on the study.

“The evidence for altered transport across the barrier in cortical spreading depression and the associated aura of migraine is pretty strong. The evidence for regular migraine, not so. In fact, there’s really no strong evidence for leakage in those people, and so it is still unresolved whether this initial cortical spreading depression that occurs in aura then triggers migraine afterwards, because it’s occurring during the aura. And in people who do not have the aura, is there a silent cortical spreading depression phenomenon with some leakage that triggers the migraine? That question is definitely not answered,” said Dr. Harrington, a research professor of neurology at the University of Southern California, Los Angeles.

Leakage of the BBB might allow passage of nociceptive compounds that could trigger migraine. Loss of BBB integrity has also been seen in other central nervous system pain disorders, suggesting that alterations to BBB functioning could have broader implications.

“In this model that we’re using, we’re seeing loss of overall barrier integrity, which lends itself to a whole cascade of further pathological possibilities,” Jared Wahl, a PhD candidate at the University of Arizona, Tucson, said in an interview. He presented the research at the American Headache Society’s 2021 annual meeting.

A leaky BBB could allow infiltration of a range of substances, but the potential for such a mechanism in migraine pathology is not well understood.

The researchers specifically investigated the potential role of claudin-5 in the tight junction (TJ) region of the BBB. The decision was made in part because the proteins involved in the BBB are difficult to study, and there is some familiarity with claudin-5, according to Mr. Wahl. ”Of all the proteins that are out there, for claudin-5 (there are) somewhat better techniques and products available to work with, and there’s been some previous research done to show that it’s implicated in blood brain barrier pathology. So it seemed like a good candidate to start with investigating this whole possible pathophysiological link between barrier disruption and migration of pronociceptive substances into the CNS during migraine attacks,” he said. The claudin proteins are also the major components of the tight junctions that seal off gaps between endothelial cells along the BBB.
 

Dynamic changes seen in the in vitro model

To simulate a CSD event, the researchers pulsed cultured cells for 5 minutes with astrocyte-conditioned media, artificial cerebrospinal fluid, KCl, glutamate, altered pH, or adenosine triphosphate (ATP). They used trans endothelial electrical resistance (TEER) to quickly and qualitatively screen for loss of barrier integrity, which is characterized by loss of electrical resistance. To quantify the magnitude of a breach, the researchers applied carbon-14 (C14)–labeled sucrose to one side of the barrier, and determined the amount of labeled sucrose transmitted to the other side of the barrier.

ATP and pH pulses that were outside normal physiological limits led to permeability. The team then used immunocytochemistry assays to visualize the condition of the model BBB, and found discontinuity of the tight junction membranes. Imaging of claudin-5 showed organizational changes within the tight junction, but there was no change in expression level, suggesting that the alterations were due to dynamic reorganization, according to Mr. Wahl.

Transient openings could allow passage of molecules such as bradykinin, calcitonin gene-related peptide (CGRP), and substance P, which could go on to affect the trigeminal nerve complex and trigger a migraine. “That’s sort of the crux of a lot of this migraine research, is gluing this physiological (mechanism) to how it is actually activating the CNS. And this is sort of where we’re going with it at the moment,” said Mr. Wahl.
 

Next steps

The researchers next plan to generate a cell line with claudin-5 linked to green fluorescent protein, then use confocal microscopy to image claudin-5 in real time as the BBB model responds to a simulated CSD.

Another important step will be to link physiological findings like those presented by Mr. Wahl to migraine-specific mechanisms. The results from this model will need to be expanded to include more than endothelial cells, especially astrocytes, pericytes, and neurons, as well as organoids, brain slices, or in vivo animal models, according to Dr. Harrington. “I think you could try and block the changes in occludin [another protein in the tight junction] or claudin-5 to see if, under the same provocation, that prevented the changes in a migraine model. That would be a direct way of connecting from CSD to migraine,” said Dr. Harrington.

If BBB disruption is confirmed to play an important role in migraine, and claudin-5 or other specific proteins are confirmed to be the cause, it could have clinical implications. A drug that could prevent those changes in the proteins and prevent a leak in the BBB could be a migraine preventative. “That could help prevent things like nociceptive substances migrating into the CNS, and could possibly be a well-tolerated drug target that doesn’t have the side effects or the overuse problems that a lot of stuff on the market has today,” said Mr. Wahl.

An in vitro study that used mouse endothelial cells to simulate the blood-brain barrier (BBB) suggests that specific proteins may be involved in destabilization of the protective barrier during a cortical spreading depression (CSD) event.

CSD has been linked to migraine aura, but a connection to pain symptoms is uncertain. “There’s just a lack of knowledge. We don’t understand migraine pathophysiology,” said Michael G. Harrington, MBChB, who was asked to comment on the study.

“The evidence for altered transport across the barrier in cortical spreading depression and the associated aura of migraine is pretty strong. The evidence for regular migraine, not so. In fact, there’s really no strong evidence for leakage in those people, and so it is still unresolved whether this initial cortical spreading depression that occurs in aura then triggers migraine afterwards, because it’s occurring during the aura. And in people who do not have the aura, is there a silent cortical spreading depression phenomenon with some leakage that triggers the migraine? That question is definitely not answered,” said Dr. Harrington, a research professor of neurology at the University of Southern California, Los Angeles.

Leakage of the BBB might allow passage of nociceptive compounds that could trigger migraine. Loss of BBB integrity has also been seen in other central nervous system pain disorders, suggesting that alterations to BBB functioning could have broader implications.

“In this model that we’re using, we’re seeing loss of overall barrier integrity, which lends itself to a whole cascade of further pathological possibilities,” Jared Wahl, a PhD candidate at the University of Arizona, Tucson, said in an interview. He presented the research at the American Headache Society’s 2021 annual meeting.

A leaky BBB could allow infiltration of a range of substances, but the potential for such a mechanism in migraine pathology is not well understood.

The researchers specifically investigated the potential role of claudin-5 in the tight junction (TJ) region of the BBB. The decision was made in part because the proteins involved in the BBB are difficult to study, and there is some familiarity with claudin-5, according to Mr. Wahl. ”Of all the proteins that are out there, for claudin-5 (there are) somewhat better techniques and products available to work with, and there’s been some previous research done to show that it’s implicated in blood brain barrier pathology. So it seemed like a good candidate to start with investigating this whole possible pathophysiological link between barrier disruption and migration of pronociceptive substances into the CNS during migraine attacks,” he said. The claudin proteins are also the major components of the tight junctions that seal off gaps between endothelial cells along the BBB.
 

Dynamic changes seen in the in vitro model

To simulate a CSD event, the researchers pulsed cultured cells for 5 minutes with astrocyte-conditioned media, artificial cerebrospinal fluid, KCl, glutamate, altered pH, or adenosine triphosphate (ATP). They used trans endothelial electrical resistance (TEER) to quickly and qualitatively screen for loss of barrier integrity, which is characterized by loss of electrical resistance. To quantify the magnitude of a breach, the researchers applied carbon-14 (C14)–labeled sucrose to one side of the barrier, and determined the amount of labeled sucrose transmitted to the other side of the barrier.

ATP and pH pulses that were outside normal physiological limits led to permeability. The team then used immunocytochemistry assays to visualize the condition of the model BBB, and found discontinuity of the tight junction membranes. Imaging of claudin-5 showed organizational changes within the tight junction, but there was no change in expression level, suggesting that the alterations were due to dynamic reorganization, according to Mr. Wahl.

Transient openings could allow passage of molecules such as bradykinin, calcitonin gene-related peptide (CGRP), and substance P, which could go on to affect the trigeminal nerve complex and trigger a migraine. “That’s sort of the crux of a lot of this migraine research, is gluing this physiological (mechanism) to how it is actually activating the CNS. And this is sort of where we’re going with it at the moment,” said Mr. Wahl.
 

Next steps

The researchers next plan to generate a cell line with claudin-5 linked to green fluorescent protein, then use confocal microscopy to image claudin-5 in real time as the BBB model responds to a simulated CSD.

Another important step will be to link physiological findings like those presented by Mr. Wahl to migraine-specific mechanisms. The results from this model will need to be expanded to include more than endothelial cells, especially astrocytes, pericytes, and neurons, as well as organoids, brain slices, or in vivo animal models, according to Dr. Harrington. “I think you could try and block the changes in occludin [another protein in the tight junction] or claudin-5 to see if, under the same provocation, that prevented the changes in a migraine model. That would be a direct way of connecting from CSD to migraine,” said Dr. Harrington.

If BBB disruption is confirmed to play an important role in migraine, and claudin-5 or other specific proteins are confirmed to be the cause, it could have clinical implications. A drug that could prevent those changes in the proteins and prevent a leak in the BBB could be a migraine preventative. “That could help prevent things like nociceptive substances migrating into the CNS, and could possibly be a well-tolerated drug target that doesn’t have the side effects or the overuse problems that a lot of stuff on the market has today,” said Mr. Wahl.

An in vitro study that used mouse endothelial cells to simulate the blood-brain barrier (BBB) suggests that specific proteins may be involved in destabilization of the protective barrier during a cortical spreading depression (CSD) event.

CSD has been linked to migraine aura, but a connection to pain symptoms is uncertain. “There’s just a lack of knowledge. We don’t understand migraine pathophysiology,” said Michael G. Harrington, MBChB, who was asked to comment on the study.

“The evidence for altered transport across the barrier in cortical spreading depression and the associated aura of migraine is pretty strong. The evidence for regular migraine, not so. In fact, there’s really no strong evidence for leakage in those people, and so it is still unresolved whether this initial cortical spreading depression that occurs in aura then triggers migraine afterwards, because it’s occurring during the aura. And in people who do not have the aura, is there a silent cortical spreading depression phenomenon with some leakage that triggers the migraine? That question is definitely not answered,” said Dr. Harrington, a research professor of neurology at the University of Southern California, Los Angeles.

Leakage of the BBB might allow passage of nociceptive compounds that could trigger migraine. Loss of BBB integrity has also been seen in other central nervous system pain disorders, suggesting that alterations to BBB functioning could have broader implications.

“In this model that we’re using, we’re seeing loss of overall barrier integrity, which lends itself to a whole cascade of further pathological possibilities,” Jared Wahl, a PhD candidate at the University of Arizona, Tucson, said in an interview. He presented the research at the American Headache Society’s 2021 annual meeting.

A leaky BBB could allow infiltration of a range of substances, but the potential for such a mechanism in migraine pathology is not well understood.

The researchers specifically investigated the potential role of claudin-5 in the tight junction (TJ) region of the BBB. The decision was made in part because the proteins involved in the BBB are difficult to study, and there is some familiarity with claudin-5, according to Mr. Wahl. ”Of all the proteins that are out there, for claudin-5 (there are) somewhat better techniques and products available to work with, and there’s been some previous research done to show that it’s implicated in blood brain barrier pathology. So it seemed like a good candidate to start with investigating this whole possible pathophysiological link between barrier disruption and migration of pronociceptive substances into the CNS during migraine attacks,” he said. The claudin proteins are also the major components of the tight junctions that seal off gaps between endothelial cells along the BBB.
 

Dynamic changes seen in the in vitro model

To simulate a CSD event, the researchers pulsed cultured cells for 5 minutes with astrocyte-conditioned media, artificial cerebrospinal fluid, KCl, glutamate, altered pH, or adenosine triphosphate (ATP). They used trans endothelial electrical resistance (TEER) to quickly and qualitatively screen for loss of barrier integrity, which is characterized by loss of electrical resistance. To quantify the magnitude of a breach, the researchers applied carbon-14 (C14)–labeled sucrose to one side of the barrier, and determined the amount of labeled sucrose transmitted to the other side of the barrier.

ATP and pH pulses that were outside normal physiological limits led to permeability. The team then used immunocytochemistry assays to visualize the condition of the model BBB, and found discontinuity of the tight junction membranes. Imaging of claudin-5 showed organizational changes within the tight junction, but there was no change in expression level, suggesting that the alterations were due to dynamic reorganization, according to Mr. Wahl.

Transient openings could allow passage of molecules such as bradykinin, calcitonin gene-related peptide (CGRP), and substance P, which could go on to affect the trigeminal nerve complex and trigger a migraine. “That’s sort of the crux of a lot of this migraine research, is gluing this physiological (mechanism) to how it is actually activating the CNS. And this is sort of where we’re going with it at the moment,” said Mr. Wahl.
 

Next steps

The researchers next plan to generate a cell line with claudin-5 linked to green fluorescent protein, then use confocal microscopy to image claudin-5 in real time as the BBB model responds to a simulated CSD.

Another important step will be to link physiological findings like those presented by Mr. Wahl to migraine-specific mechanisms. The results from this model will need to be expanded to include more than endothelial cells, especially astrocytes, pericytes, and neurons, as well as organoids, brain slices, or in vivo animal models, according to Dr. Harrington. “I think you could try and block the changes in occludin [another protein in the tight junction] or claudin-5 to see if, under the same provocation, that prevented the changes in a migraine model. That would be a direct way of connecting from CSD to migraine,” said Dr. Harrington.

If BBB disruption is confirmed to play an important role in migraine, and claudin-5 or other specific proteins are confirmed to be the cause, it could have clinical implications. A drug that could prevent those changes in the proteins and prevent a leak in the BBB could be a migraine preventative. “That could help prevent things like nociceptive substances migrating into the CNS, and could possibly be a well-tolerated drug target that doesn’t have the side effects or the overuse problems that a lot of stuff on the market has today,” said Mr. Wahl.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.