Jim Kling

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

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.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

A phase 3, sham-controlled clinical trial of an external trigeminal nerve stimulation (e-TNS) device showed confirmed superiority over a sham device and eliminated the most bothersome migraine symptoms after 2 hours of use. The study also demonstrated that the device, manufactured by Cefaly and cleared in 2020 by the Food and Drug Administration for over-the-counter use, can be safely and effectively used at home.

The study also explored the benefits of 2 hours of use, rather than the 1 hour of use tested in a previous study. “The programming on the device is currently [set to] turn off at 1 hour. As a result of this study, I tell patients if they don’t have adequate relief, and they’re tolerating it, that they can activate it again for a second hour,” Stewart Tepper, MD, said in an interview. Dr. Tepper is a professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., and a coauthor of the study that was presented by Deena Kuruvilla, MD, at the American Headache Society’s 2021 annual meeting. Dr. Kuruvilla is a neurologist and director of the Westport (Conn.) Headache Institute.

The improvements seen over the sham were significant but not overwhelming, according to Deborah Friedman, MD, MPH, professor of neurology and ophthalmology at the University of Texas, Dallas.

“The numbers are not super impressive when you compare them with other devices. I thought it was interesting that the most bothersome symptom went away in a much higher percentage of people than the headache. That was actually pretty impressive,” said Dr. Friedman, who was asked to comment on the study. She also wondered if the sham device may have inadvertently provided a small amount of stimulation, which could explain the smaller than expected efficacy difference. “It just kind of makes me wonder because I would expect to see a larger separation, even though it was statistically significant.”

The study was an overall success according to Dr. Tepper, who noted that the efficacy of pain freedom was comparable with what has been seen with calcitonin gene-related peptide receptor antagonists (gepants), as well as relieving the most bothersome symptom at 2 hours. The device failed to reduce the usage of rescue medication, suggesting that it might be a candidate to combine with rescue medications. “I think the main thing is it works. It works in a sham-controlled trial, it works at home, and it works comparably to acute medication. And it is further evidence that the lack of access is something that needs to be addressed,” said Dr. Tepper.

Access will depend on insurance companies, who have so far been reluctant to pay for the device. Dr. Tepper is not optimistic they will come around on their own. “My feeling about it is that the only way that payers will finally start to cover this is with a concerted, organized advocacy campaign by patients. The analogy is that when the disease-modifying therapies became available for multiple sclerosis, the National MS Society organized the MS patients and they demanded that the payers cover the disease modifying therapies. That’s the kind of intense focus of advocacy that needs to be done for these noninvasive neuromodulation devices,” said Dr. Tepper.

The TEAM study was a double blind, randomized, sham-controlled trial of 538 patients who were asked to use neurostimulation for a 2-hour, continuous session within 4 hours of a moderate to severe migraine accompanied by at least one migraine-associated symptom. At 2 hours, 25.5% of those using the device achieved pain freedom, compared with 18.3% of those using the sham (P < .05). Among those using the device, 56.4% had freedom from most bothersome symptom, compared with 42.3% of those using the sham (P < .01).

Pain relief at 2 hours was more common in the device group (69.5% vs. 55.2%; P < .01), as was absence of all migraine-associated symptoms at 2 hours (42.5% vs. 34.1%; P < .05), sustained pain freedom at 24 hours (22.8% vs. 15.8%; P < .05), and sustained pain relief at 24 hours (45.9% vs. 34.4%; P < .01). There was no statistically significant between-group difference in use of rescue medications.

In the device group, 8.5% of patients experienced an adverse event, versus 2.9% in the sham group (P = .004). The only adverse reaction that occurred more frequently in the device group was forehead paresthesia, discomfort, and burning (3.5% vs. 0.4%; P = .009).

The study was funded by Cefaly. Dr. Tepper and Dr. Friedman have no relevant financial disclosures.

A phase 3, sham-controlled clinical trial of an external trigeminal nerve stimulation (e-TNS) device showed confirmed superiority over a sham device and eliminated the most bothersome migraine symptoms after 2 hours of use. The study also demonstrated that the device, manufactured by Cefaly and cleared in 2020 by the Food and Drug Administration for over-the-counter use, can be safely and effectively used at home.

The study also explored the benefits of 2 hours of use, rather than the 1 hour of use tested in a previous study. “The programming on the device is currently [set to] turn off at 1 hour. As a result of this study, I tell patients if they don’t have adequate relief, and they’re tolerating it, that they can activate it again for a second hour,” Stewart Tepper, MD, said in an interview. Dr. Tepper is a professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., and a coauthor of the study that was presented by Deena Kuruvilla, MD, at the American Headache Society’s 2021 annual meeting. Dr. Kuruvilla is a neurologist and director of the Westport (Conn.) Headache Institute.

The improvements seen over the sham were significant but not overwhelming, according to Deborah Friedman, MD, MPH, professor of neurology and ophthalmology at the University of Texas, Dallas.

“The numbers are not super impressive when you compare them with other devices. I thought it was interesting that the most bothersome symptom went away in a much higher percentage of people than the headache. That was actually pretty impressive,” said Dr. Friedman, who was asked to comment on the study. She also wondered if the sham device may have inadvertently provided a small amount of stimulation, which could explain the smaller than expected efficacy difference. “It just kind of makes me wonder because I would expect to see a larger separation, even though it was statistically significant.”

The study was an overall success according to Dr. Tepper, who noted that the efficacy of pain freedom was comparable with what has been seen with calcitonin gene-related peptide receptor antagonists (gepants), as well as relieving the most bothersome symptom at 2 hours. The device failed to reduce the usage of rescue medication, suggesting that it might be a candidate to combine with rescue medications. “I think the main thing is it works. It works in a sham-controlled trial, it works at home, and it works comparably to acute medication. And it is further evidence that the lack of access is something that needs to be addressed,” said Dr. Tepper.

Access will depend on insurance companies, who have so far been reluctant to pay for the device. Dr. Tepper is not optimistic they will come around on their own. “My feeling about it is that the only way that payers will finally start to cover this is with a concerted, organized advocacy campaign by patients. The analogy is that when the disease-modifying therapies became available for multiple sclerosis, the National MS Society organized the MS patients and they demanded that the payers cover the disease modifying therapies. That’s the kind of intense focus of advocacy that needs to be done for these noninvasive neuromodulation devices,” said Dr. Tepper.

The TEAM study was a double blind, randomized, sham-controlled trial of 538 patients who were asked to use neurostimulation for a 2-hour, continuous session within 4 hours of a moderate to severe migraine accompanied by at least one migraine-associated symptom. At 2 hours, 25.5% of those using the device achieved pain freedom, compared with 18.3% of those using the sham (P < .05). Among those using the device, 56.4% had freedom from most bothersome symptom, compared with 42.3% of those using the sham (P < .01).

Pain relief at 2 hours was more common in the device group (69.5% vs. 55.2%; P < .01), as was absence of all migraine-associated symptoms at 2 hours (42.5% vs. 34.1%; P < .05), sustained pain freedom at 24 hours (22.8% vs. 15.8%; P < .05), and sustained pain relief at 24 hours (45.9% vs. 34.4%; P < .01). There was no statistically significant between-group difference in use of rescue medications.

In the device group, 8.5% of patients experienced an adverse event, versus 2.9% in the sham group (P = .004). The only adverse reaction that occurred more frequently in the device group was forehead paresthesia, discomfort, and burning (3.5% vs. 0.4%; P = .009).

The study was funded by Cefaly. Dr. Tepper and Dr. Friedman have no relevant financial disclosures.

A phase 3, sham-controlled clinical trial of an external trigeminal nerve stimulation (e-TNS) device showed confirmed superiority over a sham device and eliminated the most bothersome migraine symptoms after 2 hours of use. The study also demonstrated that the device, manufactured by Cefaly and cleared in 2020 by the Food and Drug Administration for over-the-counter use, can be safely and effectively used at home.

The study also explored the benefits of 2 hours of use, rather than the 1 hour of use tested in a previous study. “The programming on the device is currently [set to] turn off at 1 hour. As a result of this study, I tell patients if they don’t have adequate relief, and they’re tolerating it, that they can activate it again for a second hour,” Stewart Tepper, MD, said in an interview. Dr. Tepper is a professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., and a coauthor of the study that was presented by Deena Kuruvilla, MD, at the American Headache Society’s 2021 annual meeting. Dr. Kuruvilla is a neurologist and director of the Westport (Conn.) Headache Institute.

The improvements seen over the sham were significant but not overwhelming, according to Deborah Friedman, MD, MPH, professor of neurology and ophthalmology at the University of Texas, Dallas.

“The numbers are not super impressive when you compare them with other devices. I thought it was interesting that the most bothersome symptom went away in a much higher percentage of people than the headache. That was actually pretty impressive,” said Dr. Friedman, who was asked to comment on the study. She also wondered if the sham device may have inadvertently provided a small amount of stimulation, which could explain the smaller than expected efficacy difference. “It just kind of makes me wonder because I would expect to see a larger separation, even though it was statistically significant.”

The study was an overall success according to Dr. Tepper, who noted that the efficacy of pain freedom was comparable with what has been seen with calcitonin gene-related peptide receptor antagonists (gepants), as well as relieving the most bothersome symptom at 2 hours. The device failed to reduce the usage of rescue medication, suggesting that it might be a candidate to combine with rescue medications. “I think the main thing is it works. It works in a sham-controlled trial, it works at home, and it works comparably to acute medication. And it is further evidence that the lack of access is something that needs to be addressed,” said Dr. Tepper.

Access will depend on insurance companies, who have so far been reluctant to pay for the device. Dr. Tepper is not optimistic they will come around on their own. “My feeling about it is that the only way that payers will finally start to cover this is with a concerted, organized advocacy campaign by patients. The analogy is that when the disease-modifying therapies became available for multiple sclerosis, the National MS Society organized the MS patients and they demanded that the payers cover the disease modifying therapies. That’s the kind of intense focus of advocacy that needs to be done for these noninvasive neuromodulation devices,” said Dr. Tepper.

The TEAM study was a double blind, randomized, sham-controlled trial of 538 patients who were asked to use neurostimulation for a 2-hour, continuous session within 4 hours of a moderate to severe migraine accompanied by at least one migraine-associated symptom. At 2 hours, 25.5% of those using the device achieved pain freedom, compared with 18.3% of those using the sham (P < .05). Among those using the device, 56.4% had freedom from most bothersome symptom, compared with 42.3% of those using the sham (P < .01).

Pain relief at 2 hours was more common in the device group (69.5% vs. 55.2%; P < .01), as was absence of all migraine-associated symptoms at 2 hours (42.5% vs. 34.1%; P < .05), sustained pain freedom at 24 hours (22.8% vs. 15.8%; P < .05), and sustained pain relief at 24 hours (45.9% vs. 34.4%; P < .01). There was no statistically significant between-group difference in use of rescue medications.

In the device group, 8.5% of patients experienced an adverse event, versus 2.9% in the sham group (P = .004). The only adverse reaction that occurred more frequently in the device group was forehead paresthesia, discomfort, and burning (3.5% vs. 0.4%; P = .009).

The study was funded by Cefaly. Dr. Tepper and Dr. Friedman have no relevant financial disclosures.

OnabotulinumtoxinA alone provides relief from chronic migraine, and addition of anti-calcitonin gene-related peptide (CGRP) antibodies may boost the benefit, according to a large retrospective analysis. The results lend hope that the combination may be synergistic, according to Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad. Dr. Blumenfeld presented at the American Headache Society’s 2021 annual meeting. The study was published online April 21 in Pain Therapy.

The retrospective analysis showed a 4-day reduction in headache days per month. In contrast, in the pivotal study for erenumab, the most commonly used anti-CGRP antibody among subjects in the study, showed a 2-day benefit in a subanalysis of patients who had failed at least two oral preventives.

There is mechanistic evidence to suggest the two therapies could be synergistic. OnabotulinumtoxinA is believed to inhibit the release of CGRP, and antibodies reduce CGRP levels. OnabotulinumtoxinA prevents activation of C-fibers in the trigeminal sensory afferents, but does not affect A-delta fibers.

On the other hand, most data indicate that the anti-CGRP antibody fremanezumab prevents activation of A-delta but not C-fibers, and a recent review argues that CGRP antibody nonresponders may have migraines driven by C-fibers or other pathways. “Thus, concomitant use of medications blocking the activation of meningeal C-fibers may provide a synergistic effect on the trigeminal nociceptive pathway,” the authors wrote.
 

Study finding match clinical practice

The results of the new study strengthen the case that the combination is effective, though proof would require prospective, randomized trials. “I think that it really gives credibility to what we are seeing in practice, which is that combined therapy often is much better than therapy with onabotulinumtoxinA alone, said Deborah Friedman, MD, MPH, who was asked to comment on the findings. Dr. Friedman is professor of neurology and ophthalmology at the University of Texas, Dallas.

The extra 4 migraine-free days per month is a significant benefit, said Stewart Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H. “It’s an extra month and a half of no disability per year, and that’s on top of what onabotulinumtoxinA does. So it’s really a very important clinical finding,” Dr. Tepper said in an interview.

Improvements with combination therapy

The study was a chart review of 257 patients who started on onabotulinumtoxinA and later initiated anti-CGRP antibody therapy. A total of 104 completed four visits after initiation of anti-CGRP antibody therapy (completers). Before starting any therapy, patients reported an average of 21 headache days per month in the overall group, and 22 among completers. That frequency dropped to 12 in both groups after onabotulinumtoxinA therapy (overall group difference, –9 days; 95% confidence interval, –8 to –11 days; completers group difference, –10; 95% CI, –7 to –12 days).

A total of 77.8% of subjects in the overall cohort took erenumab, 16.3% took galcanezumab, and 5.8% took fremanezumab. In the completers cohort, the percentages were 84.5%, 10.7%, and 4.9%, respectively.

Compared with baseline, both completers and noncompleters had clinically significant improvements in disability, as measured by at least a 5-point improvement in Migraine Disability Assessment (MIDAS) score at the 3-month visit (–5.8 for completers and –6.3 for the overall cohort group), the 6-month visit (–6.6 and –11.1), the 9-month visit (–8.3 and –6.1), and 1 year (–12.7 and –8.4).

At the first visit, 33.0% of completers had at least a 5-point reduction in MIDAS, as did 36.0% of the overall cohort group, and the trend continued at 6 months (39.8% and 45.1%), 9 months (43.7% and 43.7%), and at 1 year (45.3% and 44.8%).

The study was funded by Allergan. Dr. Blumenfeld has served on advisory boards for Aeon, AbbVie, Amgen, Alder, Biohaven, Teva, Supernus, Promius, Eaglet, and Lilly, and has received funding for speaking from AbbVie, Amgen, Pernix, Supernus, Depomed, Avanir, Promius, Teva, Eli Lilly, Lundbeck, Novartis, and Theranica. Dr. Tepper has consulted for Teva. Dr. Friedman has been on the advisory board for Allergan, Amgen, Lundbeck, Eli Lilly, and Teva Pharmaceuticals, and has received grant support from Allergan and Eli Lilly.

OnabotulinumtoxinA alone provides relief from chronic migraine, and addition of anti-calcitonin gene-related peptide (CGRP) antibodies may boost the benefit, according to a large retrospective analysis. The results lend hope that the combination may be synergistic, according to Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad. Dr. Blumenfeld presented at the American Headache Society’s 2021 annual meeting. The study was published online April 21 in Pain Therapy.

The retrospective analysis showed a 4-day reduction in headache days per month. In contrast, in the pivotal study for erenumab, the most commonly used anti-CGRP antibody among subjects in the study, showed a 2-day benefit in a subanalysis of patients who had failed at least two oral preventives.

There is mechanistic evidence to suggest the two therapies could be synergistic. OnabotulinumtoxinA is believed to inhibit the release of CGRP, and antibodies reduce CGRP levels. OnabotulinumtoxinA prevents activation of C-fibers in the trigeminal sensory afferents, but does not affect A-delta fibers.

On the other hand, most data indicate that the anti-CGRP antibody fremanezumab prevents activation of A-delta but not C-fibers, and a recent review argues that CGRP antibody nonresponders may have migraines driven by C-fibers or other pathways. “Thus, concomitant use of medications blocking the activation of meningeal C-fibers may provide a synergistic effect on the trigeminal nociceptive pathway,” the authors wrote.
 

Study finding match clinical practice

The results of the new study strengthen the case that the combination is effective, though proof would require prospective, randomized trials. “I think that it really gives credibility to what we are seeing in practice, which is that combined therapy often is much better than therapy with onabotulinumtoxinA alone, said Deborah Friedman, MD, MPH, who was asked to comment on the findings. Dr. Friedman is professor of neurology and ophthalmology at the University of Texas, Dallas.

The extra 4 migraine-free days per month is a significant benefit, said Stewart Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H. “It’s an extra month and a half of no disability per year, and that’s on top of what onabotulinumtoxinA does. So it’s really a very important clinical finding,” Dr. Tepper said in an interview.

Improvements with combination therapy

The study was a chart review of 257 patients who started on onabotulinumtoxinA and later initiated anti-CGRP antibody therapy. A total of 104 completed four visits after initiation of anti-CGRP antibody therapy (completers). Before starting any therapy, patients reported an average of 21 headache days per month in the overall group, and 22 among completers. That frequency dropped to 12 in both groups after onabotulinumtoxinA therapy (overall group difference, –9 days; 95% confidence interval, –8 to –11 days; completers group difference, –10; 95% CI, –7 to –12 days).

A total of 77.8% of subjects in the overall cohort took erenumab, 16.3% took galcanezumab, and 5.8% took fremanezumab. In the completers cohort, the percentages were 84.5%, 10.7%, and 4.9%, respectively.

Compared with baseline, both completers and noncompleters had clinically significant improvements in disability, as measured by at least a 5-point improvement in Migraine Disability Assessment (MIDAS) score at the 3-month visit (–5.8 for completers and –6.3 for the overall cohort group), the 6-month visit (–6.6 and –11.1), the 9-month visit (–8.3 and –6.1), and 1 year (–12.7 and –8.4).

At the first visit, 33.0% of completers had at least a 5-point reduction in MIDAS, as did 36.0% of the overall cohort group, and the trend continued at 6 months (39.8% and 45.1%), 9 months (43.7% and 43.7%), and at 1 year (45.3% and 44.8%).

The study was funded by Allergan. Dr. Blumenfeld has served on advisory boards for Aeon, AbbVie, Amgen, Alder, Biohaven, Teva, Supernus, Promius, Eaglet, and Lilly, and has received funding for speaking from AbbVie, Amgen, Pernix, Supernus, Depomed, Avanir, Promius, Teva, Eli Lilly, Lundbeck, Novartis, and Theranica. Dr. Tepper has consulted for Teva. Dr. Friedman has been on the advisory board for Allergan, Amgen, Lundbeck, Eli Lilly, and Teva Pharmaceuticals, and has received grant support from Allergan and Eli Lilly.

OnabotulinumtoxinA alone provides relief from chronic migraine, and addition of anti-calcitonin gene-related peptide (CGRP) antibodies may boost the benefit, according to a large retrospective analysis. The results lend hope that the combination may be synergistic, according to Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad. Dr. Blumenfeld presented at the American Headache Society’s 2021 annual meeting. The study was published online April 21 in Pain Therapy.

The retrospective analysis showed a 4-day reduction in headache days per month. In contrast, in the pivotal study for erenumab, the most commonly used anti-CGRP antibody among subjects in the study, showed a 2-day benefit in a subanalysis of patients who had failed at least two oral preventives.

There is mechanistic evidence to suggest the two therapies could be synergistic. OnabotulinumtoxinA is believed to inhibit the release of CGRP, and antibodies reduce CGRP levels. OnabotulinumtoxinA prevents activation of C-fibers in the trigeminal sensory afferents, but does not affect A-delta fibers.

On the other hand, most data indicate that the anti-CGRP antibody fremanezumab prevents activation of A-delta but not C-fibers, and a recent review argues that CGRP antibody nonresponders may have migraines driven by C-fibers or other pathways. “Thus, concomitant use of medications blocking the activation of meningeal C-fibers may provide a synergistic effect on the trigeminal nociceptive pathway,” the authors wrote.
 

Study finding match clinical practice

The results of the new study strengthen the case that the combination is effective, though proof would require prospective, randomized trials. “I think that it really gives credibility to what we are seeing in practice, which is that combined therapy often is much better than therapy with onabotulinumtoxinA alone, said Deborah Friedman, MD, MPH, who was asked to comment on the findings. Dr. Friedman is professor of neurology and ophthalmology at the University of Texas, Dallas.

The extra 4 migraine-free days per month is a significant benefit, said Stewart Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H. “It’s an extra month and a half of no disability per year, and that’s on top of what onabotulinumtoxinA does. So it’s really a very important clinical finding,” Dr. Tepper said in an interview.

Improvements with combination therapy

The study was a chart review of 257 patients who started on onabotulinumtoxinA and later initiated anti-CGRP antibody therapy. A total of 104 completed four visits after initiation of anti-CGRP antibody therapy (completers). Before starting any therapy, patients reported an average of 21 headache days per month in the overall group, and 22 among completers. That frequency dropped to 12 in both groups after onabotulinumtoxinA therapy (overall group difference, –9 days; 95% confidence interval, –8 to –11 days; completers group difference, –10; 95% CI, –7 to –12 days).

A total of 77.8% of subjects in the overall cohort took erenumab, 16.3% took galcanezumab, and 5.8% took fremanezumab. In the completers cohort, the percentages were 84.5%, 10.7%, and 4.9%, respectively.

Compared with baseline, both completers and noncompleters had clinically significant improvements in disability, as measured by at least a 5-point improvement in Migraine Disability Assessment (MIDAS) score at the 3-month visit (–5.8 for completers and –6.3 for the overall cohort group), the 6-month visit (–6.6 and –11.1), the 9-month visit (–8.3 and –6.1), and 1 year (–12.7 and –8.4).

At the first visit, 33.0% of completers had at least a 5-point reduction in MIDAS, as did 36.0% of the overall cohort group, and the trend continued at 6 months (39.8% and 45.1%), 9 months (43.7% and 43.7%), and at 1 year (45.3% and 44.8%).

The study was funded by Allergan. Dr. Blumenfeld has served on advisory boards for Aeon, AbbVie, Amgen, Alder, Biohaven, Teva, Supernus, Promius, Eaglet, and Lilly, and has received funding for speaking from AbbVie, Amgen, Pernix, Supernus, Depomed, Avanir, Promius, Teva, Eli Lilly, Lundbeck, Novartis, and Theranica. Dr. Tepper has consulted for Teva. Dr. Friedman has been on the advisory board for Allergan, Amgen, Lundbeck, Eli Lilly, and Teva Pharmaceuticals, and has received grant support from Allergan and Eli Lilly.

A phase 2 study of the anti-calcitonin gene–related peptide (CGRP) antibody fremanezumab found no benefit of treatment in persistent posttraumatic headache. Anti-CGRP therapy had been predicted to be effective, given its history of improving other forms of headache, and preclinical studies had suggested that CGRP plays a role in late pain sensitization that can occur after mild brain injuries.

“There was a decrease in migraine headache days of moderate or severe intensity in both groups. But the difference between fremanezumab and placebo treatment was not statistically significant, either looking at that on a monthly basis or over the total 12 weeks of treatment,” Egilius L.H. Spierings, MD, PhD, said during his presentation of the results at the American Headache Society’s 2021 annual meeting. Dr. Spierings is medical director of the Boston Headache Institute.
 

Disappointing findings

“That’s sad. It’s just dreadful news,” Stewart J. Tepper, MD, professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., said in an interview. Dr. Tepper was not involved in the study. The results suggest that CGRP mechanisms may not be relevant to persistent posttraumatic headache, but it could still play a role at onset. “We have to rethink this. Either it’s that chronic, persistent posttraumatic headache does not have a CGRP biology, or it’s that you have to get to them earlier [in the disease process],” he said.

The negative results were surprising, according to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and former president of the International Headache Society. He noted that the study was small, and the researchers were unable to conduct subgroup analyses. “Posttraumatic headaches are usually broken down into those that phenotypically look like migraine, or phenotypically look like tension-type headache. It would have been nice to know if most of them had what clinically appears to be tension-type headache, and maybe that’s why they didn’t respond. Or did most of them have a migraine phenotype, and then it would be a little more surprising that they didn’t respond,” Dr. Rapoport said in an interview.

As a result, he believes that further studies might show that fremanezumab is an effective treatment for posttraumatic headache. “I would not give up on it. I expect that a larger study with better power, and a better idea of exactly what was wrong with the patients, might end up being a positive study,” he said.

Although most posttraumatic headaches resolve within weeks or months, some can linger or become chronic for years. Pain medication is often prescribed but should not be, according to Dr. Rapoport, because it can lead to medication overuse headache that worsens the problem. “So we badly need a good temporary preventive treatment. The thought of giving our newest, most effective preventive medications, with few adverse events, is a good one. It just didn’t seem to work in this fairly small and underpowered study,” he said.
 

The phase 2 trial

The trial included 87 patients with new-onset or significant worsening of headache following a minor traumatic brain injury or concussion, who were randomized to treatment with 675 mg subcutaneous fremanezumab once monthly, or placebo. The average elapsed time since the trauma was 8.1 years in the placebo group and 9.3 years in the fremanezumab arm. The average number of moderate to severe headache days was 18.5 days in the placebo group and 18.4 days in the fremanezumab group. The initial 12-week randomized period was followed by an open-label period in which patients on placebo received the study drug.

After 12 weeks of treatment, there was a greater decrease in moderate to severe headache days in the placebo arm, though the difference was not statistically significant (–5.1 versus –3.6 days; P = .1876). At 1 month, the two groups were similar (–4 days placebo versus –3.6 days fremanezumab), but there was a greater reduction in the placebo arm at 2 months (–6.7 versus –3.7 days) and 3 months (–7.21 versus –5.2 days).

A secondary endpoint was the proportion of patients who experienced a 50% or greater reduction in moderate to severe headache days, and there was no significant difference between placebo and fremanezumab after 12 weeks (26% versus 21%) or at month 1 (26% versus 19%), month 2 (33% versus 19%), or month 3 (28% versus 33%).

Adverse events occurred more often in the placebo group (81% versus 72%), and all were mild or moderate, with the exception of one that occurred in the placebo group. There were no deaths, and no meaningful changes in laboratory or clinical examinations.

Dr. Spierings is on the advisory board for Satsuma, is a speaker for Teva, Amgen, Novartis, Eli Lilly, Lundbeck, Biohaven, and AbbVie, and has been a clinical trial principal investigator for Teva, Novartis, Eli Lilly, Biohaven, and Satsuma. Dr. Tepper has been a consultant for Teva. Dr. Rapoport has consulted for Teva and has been a speaker for Teva.

A phase 2 study of the anti-calcitonin gene–related peptide (CGRP) antibody fremanezumab found no benefit of treatment in persistent posttraumatic headache. Anti-CGRP therapy had been predicted to be effective, given its history of improving other forms of headache, and preclinical studies had suggested that CGRP plays a role in late pain sensitization that can occur after mild brain injuries.

“There was a decrease in migraine headache days of moderate or severe intensity in both groups. But the difference between fremanezumab and placebo treatment was not statistically significant, either looking at that on a monthly basis or over the total 12 weeks of treatment,” Egilius L.H. Spierings, MD, PhD, said during his presentation of the results at the American Headache Society’s 2021 annual meeting. Dr. Spierings is medical director of the Boston Headache Institute.
 

Disappointing findings

“That’s sad. It’s just dreadful news,” Stewart J. Tepper, MD, professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., said in an interview. Dr. Tepper was not involved in the study. The results suggest that CGRP mechanisms may not be relevant to persistent posttraumatic headache, but it could still play a role at onset. “We have to rethink this. Either it’s that chronic, persistent posttraumatic headache does not have a CGRP biology, or it’s that you have to get to them earlier [in the disease process],” he said.

The negative results were surprising, according to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and former president of the International Headache Society. He noted that the study was small, and the researchers were unable to conduct subgroup analyses. “Posttraumatic headaches are usually broken down into those that phenotypically look like migraine, or phenotypically look like tension-type headache. It would have been nice to know if most of them had what clinically appears to be tension-type headache, and maybe that’s why they didn’t respond. Or did most of them have a migraine phenotype, and then it would be a little more surprising that they didn’t respond,” Dr. Rapoport said in an interview.

As a result, he believes that further studies might show that fremanezumab is an effective treatment for posttraumatic headache. “I would not give up on it. I expect that a larger study with better power, and a better idea of exactly what was wrong with the patients, might end up being a positive study,” he said.

Although most posttraumatic headaches resolve within weeks or months, some can linger or become chronic for years. Pain medication is often prescribed but should not be, according to Dr. Rapoport, because it can lead to medication overuse headache that worsens the problem. “So we badly need a good temporary preventive treatment. The thought of giving our newest, most effective preventive medications, with few adverse events, is a good one. It just didn’t seem to work in this fairly small and underpowered study,” he said.
 

The phase 2 trial

The trial included 87 patients with new-onset or significant worsening of headache following a minor traumatic brain injury or concussion, who were randomized to treatment with 675 mg subcutaneous fremanezumab once monthly, or placebo. The average elapsed time since the trauma was 8.1 years in the placebo group and 9.3 years in the fremanezumab arm. The average number of moderate to severe headache days was 18.5 days in the placebo group and 18.4 days in the fremanezumab group. The initial 12-week randomized period was followed by an open-label period in which patients on placebo received the study drug.

After 12 weeks of treatment, there was a greater decrease in moderate to severe headache days in the placebo arm, though the difference was not statistically significant (–5.1 versus –3.6 days; P = .1876). At 1 month, the two groups were similar (–4 days placebo versus –3.6 days fremanezumab), but there was a greater reduction in the placebo arm at 2 months (–6.7 versus –3.7 days) and 3 months (–7.21 versus –5.2 days).

A secondary endpoint was the proportion of patients who experienced a 50% or greater reduction in moderate to severe headache days, and there was no significant difference between placebo and fremanezumab after 12 weeks (26% versus 21%) or at month 1 (26% versus 19%), month 2 (33% versus 19%), or month 3 (28% versus 33%).

Adverse events occurred more often in the placebo group (81% versus 72%), and all were mild or moderate, with the exception of one that occurred in the placebo group. There were no deaths, and no meaningful changes in laboratory or clinical examinations.

Dr. Spierings is on the advisory board for Satsuma, is a speaker for Teva, Amgen, Novartis, Eli Lilly, Lundbeck, Biohaven, and AbbVie, and has been a clinical trial principal investigator for Teva, Novartis, Eli Lilly, Biohaven, and Satsuma. Dr. Tepper has been a consultant for Teva. Dr. Rapoport has consulted for Teva and has been a speaker for Teva.

A phase 2 study of the anti-calcitonin gene–related peptide (CGRP) antibody fremanezumab found no benefit of treatment in persistent posttraumatic headache. Anti-CGRP therapy had been predicted to be effective, given its history of improving other forms of headache, and preclinical studies had suggested that CGRP plays a role in late pain sensitization that can occur after mild brain injuries.

“There was a decrease in migraine headache days of moderate or severe intensity in both groups. But the difference between fremanezumab and placebo treatment was not statistically significant, either looking at that on a monthly basis or over the total 12 weeks of treatment,” Egilius L.H. Spierings, MD, PhD, said during his presentation of the results at the American Headache Society’s 2021 annual meeting. Dr. Spierings is medical director of the Boston Headache Institute.
 

Disappointing findings

“That’s sad. It’s just dreadful news,” Stewart J. Tepper, MD, professor of neurology at Geisel School of Medicine at Dartmouth, Hanover, N.H., said in an interview. Dr. Tepper was not involved in the study. The results suggest that CGRP mechanisms may not be relevant to persistent posttraumatic headache, but it could still play a role at onset. “We have to rethink this. Either it’s that chronic, persistent posttraumatic headache does not have a CGRP biology, or it’s that you have to get to them earlier [in the disease process],” he said.

The negative results were surprising, according to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and former president of the International Headache Society. He noted that the study was small, and the researchers were unable to conduct subgroup analyses. “Posttraumatic headaches are usually broken down into those that phenotypically look like migraine, or phenotypically look like tension-type headache. It would have been nice to know if most of them had what clinically appears to be tension-type headache, and maybe that’s why they didn’t respond. Or did most of them have a migraine phenotype, and then it would be a little more surprising that they didn’t respond,” Dr. Rapoport said in an interview.

As a result, he believes that further studies might show that fremanezumab is an effective treatment for posttraumatic headache. “I would not give up on it. I expect that a larger study with better power, and a better idea of exactly what was wrong with the patients, might end up being a positive study,” he said.

Although most posttraumatic headaches resolve within weeks or months, some can linger or become chronic for years. Pain medication is often prescribed but should not be, according to Dr. Rapoport, because it can lead to medication overuse headache that worsens the problem. “So we badly need a good temporary preventive treatment. The thought of giving our newest, most effective preventive medications, with few adverse events, is a good one. It just didn’t seem to work in this fairly small and underpowered study,” he said.
 

The phase 2 trial

The trial included 87 patients with new-onset or significant worsening of headache following a minor traumatic brain injury or concussion, who were randomized to treatment with 675 mg subcutaneous fremanezumab once monthly, or placebo. The average elapsed time since the trauma was 8.1 years in the placebo group and 9.3 years in the fremanezumab arm. The average number of moderate to severe headache days was 18.5 days in the placebo group and 18.4 days in the fremanezumab group. The initial 12-week randomized period was followed by an open-label period in which patients on placebo received the study drug.

After 12 weeks of treatment, there was a greater decrease in moderate to severe headache days in the placebo arm, though the difference was not statistically significant (–5.1 versus –3.6 days; P = .1876). At 1 month, the two groups were similar (–4 days placebo versus –3.6 days fremanezumab), but there was a greater reduction in the placebo arm at 2 months (–6.7 versus –3.7 days) and 3 months (–7.21 versus –5.2 days).

A secondary endpoint was the proportion of patients who experienced a 50% or greater reduction in moderate to severe headache days, and there was no significant difference between placebo and fremanezumab after 12 weeks (26% versus 21%) or at month 1 (26% versus 19%), month 2 (33% versus 19%), or month 3 (28% versus 33%).

Adverse events occurred more often in the placebo group (81% versus 72%), and all were mild or moderate, with the exception of one that occurred in the placebo group. There were no deaths, and no meaningful changes in laboratory or clinical examinations.

Dr. Spierings is on the advisory board for Satsuma, is a speaker for Teva, Amgen, Novartis, Eli Lilly, Lundbeck, Biohaven, and AbbVie, and has been a clinical trial principal investigator for Teva, Novartis, Eli Lilly, Biohaven, and Satsuma. Dr. Tepper has been a consultant for Teva. Dr. Rapoport has consulted for Teva and has been a speaker for Teva.

Apparent migraines experienced by 19th century factory workers remain relevant to clinical medicine today. Those workers were employed in the manufacture of nitroglycerine, and many became patients of a physician who in 1880 described them as experiencing headache with nausea, vomiting, and walking lightly on their toes. A majority of patients were women.

When researchers in the 1950s worked out how to use nitroglycerine to trigger migraine-like headaches, the chemical became an important experimental tool, Peter Goadsby, MD, PhD, said during a talk on the translational importance of nitroglycerine in headache medicine at the American Headache Society’s 2021 annual meeting.

Some neurologists view nitroglycerine with skepticism, but that’s not necessarily warranted, said Dr. Goadsby. “To me, it’s underappreciated, but it has matured. If you were talking about this topic a decade ago, then the criticism would be that somehow that it’s not migraine, or it’s got nothing really to do with migraine,” he said in an interview.

But varying lines of clinical and experimental research have strengthened the case that nitroglycerine-induced migraine is largely indistinguishable from natural-onset migraine, and that studies that use it can provide important insights into patient management. “If I said to a colleague, ‘I’ve got this patient with headaches, and they’ve got nausea, and they’re sensitive to light. And if they move their head about, it’s worse,’ that sounds like migraine, and that’s what they’d say. The patients will tell you it’s the same, and they have the same premonitory symptoms. They respond to the same medicines,” said Dr. Goadsby.

The method is also one of the few available to study premonitory symptoms, since it is difficult to predict naturally-occurring migraines. Once the minimal dose of nitroglycerine dose to trigger an attack was worked out, researchers could use functional imaging to monitor what happens before and during the episode. To support this point, Dr. Goadsby cited a 2005 study in Brain by his own group. They used positron-emission tomography (PET) scans to conclude that lateralized brain dysfunction is associated with lateralized pain during migraine.

The premonitory stage is characterized by symptoms such as neck stiffness, cognitive impairment, mood alterations, and fatigue, as well as homeostatic symptoms such as sleepiness and polyuria. Other possible symptoms include photophobia, phonophobia, nausea, and cranial autonomic symptoms. These symptoms can be studied and established with the use of nitroglycerin trigger studies.

Dr. Goadsby pointed out that triggered episodes can also be used to test therapeutics. Calcitonin gene-related peptide receptor antagonists, 5-HT1F receptor agonists, and substance P/neurokinin 1 receptor antagonists have all been tested against nitroglycerine-induced migraines.

Other studies have used repeat exposures to nitroglycerine to better understand the effects of chronic migraines. Dr. Goadsby cited an example by researchers at the University of Illinois at Chicago led by Amynah Pradhan, PhD, which administered nitroglycerine repeatedly to mice and found that it led to acute mechanical hyperalgesia and basal hyperalgesia. The latter effect was dose dependent and persistent after nitroglycerine administration stopped. The phosphodiesterase inhibitor sildenafil, which can trigger migraines in humans, made the effect worse, suggesting that nitric oxide may be the mediator.

Apparent migraines experienced by 19th century factory workers remain relevant to clinical medicine today. Those workers were employed in the manufacture of nitroglycerine, and many became patients of a physician who in 1880 described them as experiencing headache with nausea, vomiting, and walking lightly on their toes. A majority of patients were women.

When researchers in the 1950s worked out how to use nitroglycerine to trigger migraine-like headaches, the chemical became an important experimental tool, Peter Goadsby, MD, PhD, said during a talk on the translational importance of nitroglycerine in headache medicine at the American Headache Society’s 2021 annual meeting.

Some neurologists view nitroglycerine with skepticism, but that’s not necessarily warranted, said Dr. Goadsby. “To me, it’s underappreciated, but it has matured. If you were talking about this topic a decade ago, then the criticism would be that somehow that it’s not migraine, or it’s got nothing really to do with migraine,” he said in an interview.

But varying lines of clinical and experimental research have strengthened the case that nitroglycerine-induced migraine is largely indistinguishable from natural-onset migraine, and that studies that use it can provide important insights into patient management. “If I said to a colleague, ‘I’ve got this patient with headaches, and they’ve got nausea, and they’re sensitive to light. And if they move their head about, it’s worse,’ that sounds like migraine, and that’s what they’d say. The patients will tell you it’s the same, and they have the same premonitory symptoms. They respond to the same medicines,” said Dr. Goadsby.

The method is also one of the few available to study premonitory symptoms, since it is difficult to predict naturally-occurring migraines. Once the minimal dose of nitroglycerine dose to trigger an attack was worked out, researchers could use functional imaging to monitor what happens before and during the episode. To support this point, Dr. Goadsby cited a 2005 study in Brain by his own group. They used positron-emission tomography (PET) scans to conclude that lateralized brain dysfunction is associated with lateralized pain during migraine.

The premonitory stage is characterized by symptoms such as neck stiffness, cognitive impairment, mood alterations, and fatigue, as well as homeostatic symptoms such as sleepiness and polyuria. Other possible symptoms include photophobia, phonophobia, nausea, and cranial autonomic symptoms. These symptoms can be studied and established with the use of nitroglycerin trigger studies.

Dr. Goadsby pointed out that triggered episodes can also be used to test therapeutics. Calcitonin gene-related peptide receptor antagonists, 5-HT1F receptor agonists, and substance P/neurokinin 1 receptor antagonists have all been tested against nitroglycerine-induced migraines.

Other studies have used repeat exposures to nitroglycerine to better understand the effects of chronic migraines. Dr. Goadsby cited an example by researchers at the University of Illinois at Chicago led by Amynah Pradhan, PhD, which administered nitroglycerine repeatedly to mice and found that it led to acute mechanical hyperalgesia and basal hyperalgesia. The latter effect was dose dependent and persistent after nitroglycerine administration stopped. The phosphodiesterase inhibitor sildenafil, which can trigger migraines in humans, made the effect worse, suggesting that nitric oxide may be the mediator.

Apparent migraines experienced by 19th century factory workers remain relevant to clinical medicine today. Those workers were employed in the manufacture of nitroglycerine, and many became patients of a physician who in 1880 described them as experiencing headache with nausea, vomiting, and walking lightly on their toes. A majority of patients were women.

When researchers in the 1950s worked out how to use nitroglycerine to trigger migraine-like headaches, the chemical became an important experimental tool, Peter Goadsby, MD, PhD, said during a talk on the translational importance of nitroglycerine in headache medicine at the American Headache Society’s 2021 annual meeting.

Some neurologists view nitroglycerine with skepticism, but that’s not necessarily warranted, said Dr. Goadsby. “To me, it’s underappreciated, but it has matured. If you were talking about this topic a decade ago, then the criticism would be that somehow that it’s not migraine, or it’s got nothing really to do with migraine,” he said in an interview.

But varying lines of clinical and experimental research have strengthened the case that nitroglycerine-induced migraine is largely indistinguishable from natural-onset migraine, and that studies that use it can provide important insights into patient management. “If I said to a colleague, ‘I’ve got this patient with headaches, and they’ve got nausea, and they’re sensitive to light. And if they move their head about, it’s worse,’ that sounds like migraine, and that’s what they’d say. The patients will tell you it’s the same, and they have the same premonitory symptoms. They respond to the same medicines,” said Dr. Goadsby.

The method is also one of the few available to study premonitory symptoms, since it is difficult to predict naturally-occurring migraines. Once the minimal dose of nitroglycerine dose to trigger an attack was worked out, researchers could use functional imaging to monitor what happens before and during the episode. To support this point, Dr. Goadsby cited a 2005 study in Brain by his own group. They used positron-emission tomography (PET) scans to conclude that lateralized brain dysfunction is associated with lateralized pain during migraine.

The premonitory stage is characterized by symptoms such as neck stiffness, cognitive impairment, mood alterations, and fatigue, as well as homeostatic symptoms such as sleepiness and polyuria. Other possible symptoms include photophobia, phonophobia, nausea, and cranial autonomic symptoms. These symptoms can be studied and established with the use of nitroglycerin trigger studies.

Dr. Goadsby pointed out that triggered episodes can also be used to test therapeutics. Calcitonin gene-related peptide receptor antagonists, 5-HT1F receptor agonists, and substance P/neurokinin 1 receptor antagonists have all been tested against nitroglycerine-induced migraines.

Other studies have used repeat exposures to nitroglycerine to better understand the effects of chronic migraines. Dr. Goadsby cited an example by researchers at the University of Illinois at Chicago led by Amynah Pradhan, PhD, which administered nitroglycerine repeatedly to mice and found that it led to acute mechanical hyperalgesia and basal hyperalgesia. The latter effect was dose dependent and persistent after nitroglycerine administration stopped. The phosphodiesterase inhibitor sildenafil, which can trigger migraines in humans, made the effect worse, suggesting that nitric oxide may be the mediator.

New guidelines from the American College of Gastroenterology on idiosyncratic drug-induced liver injury (DILI) emphasize that idiosyncratic DILI is increasingly driven by the burgeoning popularity of herbal and dietary supplements, as well as tyrosine kinase inhibitors and immune checkpoint inhibitors used to treat cancer.

Sebastian Kaulitzki/Science Photo Library

The guidelines, which represent an update from 2014, are published in The American Journal of Gastroenterology.

DILI is commonly seen by gastroenterologists and hepatologists, but it is challenging to diagnose because there are many potential causes, and no objective diagnostic tests. Its incidence in the general population is low, but it must be considered when facing unexplained liver injury. Its potential presence should also be considered when prescribing gastrointestinal medications like azathioprine, anti–tumor necrosis factor agents, and sulfonamides.

DILI can be characterized as intrinsic or idiosyncratic. Intrinsic DILI is somewhat predictable, based on human or animal studies that have revealed the potential for liver toxicity at higher doses. The best-known example is acetaminophen. Idiosyncratic DILI is rarer and shows up in individuals with a preexisting susceptibility. Clinical signs of idiosyncratic DILI are more diverse than intrinsic DILI. The ACG guideline focuses on idiosyncratic DILI, since guidelines are already available for intrinsic DILI.

Idiosyncratic DILI diagnosis can have a wide range of presentations, including asymptomatic liver biochemistry, jaundice, liver failure, and chronic hepatitis. Diagnosis is made by eliminating other potential causes.

In the presence of hepatocellular jaundice, mortality can reach 10%. DILI patients who develop progressive jaundice, regardless of concomitant coagulopathy, should be sent to a tertiary center and may be a candidate for liver transplantation.

Corticosteroids may be considered when there is uncertainty if a liver injury is from DILI or autoimmune hepatitis, but this remains controversial because some studies have shown benefit, while others have not, according to Bubu Banini, MD, PhD, assistant professor of medicine and research director of the metabolic health and weight management program at Yale University, New Haven, Conn. “Large-scale randomized controlled trials are needed for further elucidation of the role of steroids in DILI. For now, the guideline recommends consideration of steroid therapy, particularly in patients with features of autoimmune hepatitis,” she added.

An important factor driving DILI is the increasing popularity of herbal supplements, as well as increased use of some cancer therapies. “With the advent of immune checkpoint inhibitors as effective therapies for a variety of malignancies, physicians need to be aware of the potential side effects of these agents and the possibility of immune checkpoint inhibitor–related drug induced liver injury,” Dr. Banini said. The updated ACG guideline summarizes current FDA-approved immune checkpoint inhibitors and their potential to cause DILI. The drugs can also lead to reactivation of hepatitis B infection. Studies have shown liver enzyme elevation occurs in about 30% of patients treated with immune checkpoint inhibitors.

The guidelines recommend assessing DILI patients for hepatitis B and C, and treating patients prior to, or in combination with, immune checkpoint inhibitors or other chemotherapy drugs. The recommendations are in line with preliminary data from the ICI field, according to Dr. Banini.

Dr. Banini also noted there has been an increase in the use of herbal and dietary supplements in the United States over the past decade, and these now account for about one-fifth of DILI cases. The guidelines recommend that severe cholestatic disease from these agents should be managed similarly to cases caused by prescription drugs, and patients should be considered for liver transplant if necessary.

A web-based 6-month mortality calculator for suspected DILI is available. It uses Model for End-Stage Liver Disease, Charlson comorbidity Index, and serum albumin data. Those variables predict mortality in liver disease, and an independent analysis showed they predict 6-month mortality in DILI.

DILI is difficult to diagnose, but physicians should keep it in mind when faced with a case of liver enzyme abnormality, where other possibilities have been excluded. “With over a thousand medications potentially causing DILI, physicians should be familiar with LiverTox as a very useful and practical resource. The DILI mortality calculator can serve as a clinical tool to predict 6-month mortality in patients with suspected DILI,” Dr. Banini said.

Some authors disclosed relationships with several pharmaceutical companies. Dr. Banini reports having nothing to disclose.

New guidelines from the American College of Gastroenterology on idiosyncratic drug-induced liver injury (DILI) emphasize that idiosyncratic DILI is increasingly driven by the burgeoning popularity of herbal and dietary supplements, as well as tyrosine kinase inhibitors and immune checkpoint inhibitors used to treat cancer.

Sebastian Kaulitzki/Science Photo Library

The guidelines, which represent an update from 2014, are published in The American Journal of Gastroenterology.

DILI is commonly seen by gastroenterologists and hepatologists, but it is challenging to diagnose because there are many potential causes, and no objective diagnostic tests. Its incidence in the general population is low, but it must be considered when facing unexplained liver injury. Its potential presence should also be considered when prescribing gastrointestinal medications like azathioprine, anti–tumor necrosis factor agents, and sulfonamides.

DILI can be characterized as intrinsic or idiosyncratic. Intrinsic DILI is somewhat predictable, based on human or animal studies that have revealed the potential for liver toxicity at higher doses. The best-known example is acetaminophen. Idiosyncratic DILI is rarer and shows up in individuals with a preexisting susceptibility. Clinical signs of idiosyncratic DILI are more diverse than intrinsic DILI. The ACG guideline focuses on idiosyncratic DILI, since guidelines are already available for intrinsic DILI.

Idiosyncratic DILI diagnosis can have a wide range of presentations, including asymptomatic liver biochemistry, jaundice, liver failure, and chronic hepatitis. Diagnosis is made by eliminating other potential causes.

In the presence of hepatocellular jaundice, mortality can reach 10%. DILI patients who develop progressive jaundice, regardless of concomitant coagulopathy, should be sent to a tertiary center and may be a candidate for liver transplantation.

Corticosteroids may be considered when there is uncertainty if a liver injury is from DILI or autoimmune hepatitis, but this remains controversial because some studies have shown benefit, while others have not, according to Bubu Banini, MD, PhD, assistant professor of medicine and research director of the metabolic health and weight management program at Yale University, New Haven, Conn. “Large-scale randomized controlled trials are needed for further elucidation of the role of steroids in DILI. For now, the guideline recommends consideration of steroid therapy, particularly in patients with features of autoimmune hepatitis,” she added.

An important factor driving DILI is the increasing popularity of herbal supplements, as well as increased use of some cancer therapies. “With the advent of immune checkpoint inhibitors as effective therapies for a variety of malignancies, physicians need to be aware of the potential side effects of these agents and the possibility of immune checkpoint inhibitor–related drug induced liver injury,” Dr. Banini said. The updated ACG guideline summarizes current FDA-approved immune checkpoint inhibitors and their potential to cause DILI. The drugs can also lead to reactivation of hepatitis B infection. Studies have shown liver enzyme elevation occurs in about 30% of patients treated with immune checkpoint inhibitors.

The guidelines recommend assessing DILI patients for hepatitis B and C, and treating patients prior to, or in combination with, immune checkpoint inhibitors or other chemotherapy drugs. The recommendations are in line with preliminary data from the ICI field, according to Dr. Banini.

Dr. Banini also noted there has been an increase in the use of herbal and dietary supplements in the United States over the past decade, and these now account for about one-fifth of DILI cases. The guidelines recommend that severe cholestatic disease from these agents should be managed similarly to cases caused by prescription drugs, and patients should be considered for liver transplant if necessary.

A web-based 6-month mortality calculator for suspected DILI is available. It uses Model for End-Stage Liver Disease, Charlson comorbidity Index, and serum albumin data. Those variables predict mortality in liver disease, and an independent analysis showed they predict 6-month mortality in DILI.

DILI is difficult to diagnose, but physicians should keep it in mind when faced with a case of liver enzyme abnormality, where other possibilities have been excluded. “With over a thousand medications potentially causing DILI, physicians should be familiar with LiverTox as a very useful and practical resource. The DILI mortality calculator can serve as a clinical tool to predict 6-month mortality in patients with suspected DILI,” Dr. Banini said.

Some authors disclosed relationships with several pharmaceutical companies. Dr. Banini reports having nothing to disclose.

New guidelines from the American College of Gastroenterology on idiosyncratic drug-induced liver injury (DILI) emphasize that idiosyncratic DILI is increasingly driven by the burgeoning popularity of herbal and dietary supplements, as well as tyrosine kinase inhibitors and immune checkpoint inhibitors used to treat cancer.

Sebastian Kaulitzki/Science Photo Library

The guidelines, which represent an update from 2014, are published in The American Journal of Gastroenterology.

DILI is commonly seen by gastroenterologists and hepatologists, but it is challenging to diagnose because there are many potential causes, and no objective diagnostic tests. Its incidence in the general population is low, but it must be considered when facing unexplained liver injury. Its potential presence should also be considered when prescribing gastrointestinal medications like azathioprine, anti–tumor necrosis factor agents, and sulfonamides.

DILI can be characterized as intrinsic or idiosyncratic. Intrinsic DILI is somewhat predictable, based on human or animal studies that have revealed the potential for liver toxicity at higher doses. The best-known example is acetaminophen. Idiosyncratic DILI is rarer and shows up in individuals with a preexisting susceptibility. Clinical signs of idiosyncratic DILI are more diverse than intrinsic DILI. The ACG guideline focuses on idiosyncratic DILI, since guidelines are already available for intrinsic DILI.

Idiosyncratic DILI diagnosis can have a wide range of presentations, including asymptomatic liver biochemistry, jaundice, liver failure, and chronic hepatitis. Diagnosis is made by eliminating other potential causes.

In the presence of hepatocellular jaundice, mortality can reach 10%. DILI patients who develop progressive jaundice, regardless of concomitant coagulopathy, should be sent to a tertiary center and may be a candidate for liver transplantation.

Corticosteroids may be considered when there is uncertainty if a liver injury is from DILI or autoimmune hepatitis, but this remains controversial because some studies have shown benefit, while others have not, according to Bubu Banini, MD, PhD, assistant professor of medicine and research director of the metabolic health and weight management program at Yale University, New Haven, Conn. “Large-scale randomized controlled trials are needed for further elucidation of the role of steroids in DILI. For now, the guideline recommends consideration of steroid therapy, particularly in patients with features of autoimmune hepatitis,” she added.

An important factor driving DILI is the increasing popularity of herbal supplements, as well as increased use of some cancer therapies. “With the advent of immune checkpoint inhibitors as effective therapies for a variety of malignancies, physicians need to be aware of the potential side effects of these agents and the possibility of immune checkpoint inhibitor–related drug induced liver injury,” Dr. Banini said. The updated ACG guideline summarizes current FDA-approved immune checkpoint inhibitors and their potential to cause DILI. The drugs can also lead to reactivation of hepatitis B infection. Studies have shown liver enzyme elevation occurs in about 30% of patients treated with immune checkpoint inhibitors.

The guidelines recommend assessing DILI patients for hepatitis B and C, and treating patients prior to, or in combination with, immune checkpoint inhibitors or other chemotherapy drugs. The recommendations are in line with preliminary data from the ICI field, according to Dr. Banini.

Dr. Banini also noted there has been an increase in the use of herbal and dietary supplements in the United States over the past decade, and these now account for about one-fifth of DILI cases. The guidelines recommend that severe cholestatic disease from these agents should be managed similarly to cases caused by prescription drugs, and patients should be considered for liver transplant if necessary.

A web-based 6-month mortality calculator for suspected DILI is available. It uses Model for End-Stage Liver Disease, Charlson comorbidity Index, and serum albumin data. Those variables predict mortality in liver disease, and an independent analysis showed they predict 6-month mortality in DILI.

DILI is difficult to diagnose, but physicians should keep it in mind when faced with a case of liver enzyme abnormality, where other possibilities have been excluded. “With over a thousand medications potentially causing DILI, physicians should be familiar with LiverTox as a very useful and practical resource. The DILI mortality calculator can serve as a clinical tool to predict 6-month mortality in patients with suspected DILI,” Dr. Banini said.

Some authors disclosed relationships with several pharmaceutical companies. Dr. Banini reports having nothing to disclose.