Key clinical point: Tofacitinib vs. tocilizumab was more likely to induce and maintain improvement in clinical disease activity index (CDAI) and remission during the first 12 months of therapy in biological disease-modifying antirheumatic drugs (bDMARD)-naïve patients with methotrexate-refractory rheumatoid arthritis (RA).

Major finding: Likelihood of achieving and maintaining 85% or more (adjusted odds ratio [aOR], 3.88; P less than .001), 70% or more (aOR, 2.89; P = .003) improvement in CDAI, and remission (aOR, 3.31; P less than .001) in the first 12 months was higher with tofacitinib vs. tocilizumab in bDMARD-naïve patients but not in patients with previous bDMARD failure.

Study details: This was a multicenter cohort study of 464 patients with methotrexate-refractory RA who had high to moderate CDAI and initiated treatment with tofacitinib (n=247) or tocilizumab (n=217).

Disclosures: This study was supported by research funds from the National Hospital Organization, Japan. The authors including the leading author reported receiving lecture fees from various sources.

Source: Mori S et al. RMD Open. 2021 May 6. doi: 10.1136/rmdopen-2021-001601.

Key clinical point: Tofacitinib vs. tocilizumab was more likely to induce and maintain improvement in clinical disease activity index (CDAI) and remission during the first 12 months of therapy in biological disease-modifying antirheumatic drugs (bDMARD)-naïve patients with methotrexate-refractory rheumatoid arthritis (RA).

Major finding: Likelihood of achieving and maintaining 85% or more (adjusted odds ratio [aOR], 3.88; P less than .001), 70% or more (aOR, 2.89; P = .003) improvement in CDAI, and remission (aOR, 3.31; P less than .001) in the first 12 months was higher with tofacitinib vs. tocilizumab in bDMARD-naïve patients but not in patients with previous bDMARD failure.

Study details: This was a multicenter cohort study of 464 patients with methotrexate-refractory RA who had high to moderate CDAI and initiated treatment with tofacitinib (n=247) or tocilizumab (n=217).

Disclosures: This study was supported by research funds from the National Hospital Organization, Japan. The authors including the leading author reported receiving lecture fees from various sources.

Source: Mori S et al. RMD Open. 2021 May 6. doi: 10.1136/rmdopen-2021-001601.

Key clinical point: Tofacitinib vs. tocilizumab was more likely to induce and maintain improvement in clinical disease activity index (CDAI) and remission during the first 12 months of therapy in biological disease-modifying antirheumatic drugs (bDMARD)-naïve patients with methotrexate-refractory rheumatoid arthritis (RA).

Major finding: Likelihood of achieving and maintaining 85% or more (adjusted odds ratio [aOR], 3.88; P less than .001), 70% or more (aOR, 2.89; P = .003) improvement in CDAI, and remission (aOR, 3.31; P less than .001) in the first 12 months was higher with tofacitinib vs. tocilizumab in bDMARD-naïve patients but not in patients with previous bDMARD failure.

Study details: This was a multicenter cohort study of 464 patients with methotrexate-refractory RA who had high to moderate CDAI and initiated treatment with tofacitinib (n=247) or tocilizumab (n=217).

Disclosures: This study was supported by research funds from the National Hospital Organization, Japan. The authors including the leading author reported receiving lecture fees from various sources.

Source: Mori S et al. RMD Open. 2021 May 6. doi: 10.1136/rmdopen-2021-001601.

Key clinical point: A 3-dose regimen of intravenous tranexamic acid (IV-TXA) was more effective than a single dose in reducing postoperative blood loss in patients with rheumatoid arthritis (RA) who underwent primary unilateral total knee arthroplasty (TKA).

Major finding: Decrease in total blood loss (P = .038), hidden blood loss (P = .036), and maximum hemoglobin drop (P less than .001) was significantly lower with 3 vs. a single dose of postoperative IV-TXA. Additionally, levels of D-dimer on postoperative day 1 were significantly lower with 3 vs. a single dose of IV-TXA (P less than .001). Incidences of thromboembolic events were similar between groups.

Study details: This was a single-center, randomized controlled trial of 104 patients who underwent primary unilateral TKA for RA and were randomly allocated to receive either a single dose of IV-TXA (1 g; n=52) 3 hours postoperatively or 3 doses of IV-TXA (1 g; n=52) 3, 6, and 12 hours postoperatively.

Disclosures: This study was supported by the Foundation of Health and Family planning Commission of Shanghai, China. The authors declared no conflicts of interest.

Source: Kang BX et al. BMC Musculoskelet Disord. 2021 May 7. doi: 10.1186/s12891-021-04307-4.

Key clinical point: A 3-dose regimen of intravenous tranexamic acid (IV-TXA) was more effective than a single dose in reducing postoperative blood loss in patients with rheumatoid arthritis (RA) who underwent primary unilateral total knee arthroplasty (TKA).

Major finding: Decrease in total blood loss (P = .038), hidden blood loss (P = .036), and maximum hemoglobin drop (P less than .001) was significantly lower with 3 vs. a single dose of postoperative IV-TXA. Additionally, levels of D-dimer on postoperative day 1 were significantly lower with 3 vs. a single dose of IV-TXA (P less than .001). Incidences of thromboembolic events were similar between groups.

Study details: This was a single-center, randomized controlled trial of 104 patients who underwent primary unilateral TKA for RA and were randomly allocated to receive either a single dose of IV-TXA (1 g; n=52) 3 hours postoperatively or 3 doses of IV-TXA (1 g; n=52) 3, 6, and 12 hours postoperatively.

Disclosures: This study was supported by the Foundation of Health and Family planning Commission of Shanghai, China. The authors declared no conflicts of interest.

Source: Kang BX et al. BMC Musculoskelet Disord. 2021 May 7. doi: 10.1186/s12891-021-04307-4.

Key clinical point: A 3-dose regimen of intravenous tranexamic acid (IV-TXA) was more effective than a single dose in reducing postoperative blood loss in patients with rheumatoid arthritis (RA) who underwent primary unilateral total knee arthroplasty (TKA).

Major finding: Decrease in total blood loss (P = .038), hidden blood loss (P = .036), and maximum hemoglobin drop (P less than .001) was significantly lower with 3 vs. a single dose of postoperative IV-TXA. Additionally, levels of D-dimer on postoperative day 1 were significantly lower with 3 vs. a single dose of IV-TXA (P less than .001). Incidences of thromboembolic events were similar between groups.

Study details: This was a single-center, randomized controlled trial of 104 patients who underwent primary unilateral TKA for RA and were randomly allocated to receive either a single dose of IV-TXA (1 g; n=52) 3 hours postoperatively or 3 doses of IV-TXA (1 g; n=52) 3, 6, and 12 hours postoperatively.

Disclosures: This study was supported by the Foundation of Health and Family planning Commission of Shanghai, China. The authors declared no conflicts of interest.

Source: Kang BX et al. BMC Musculoskelet Disord. 2021 May 7. doi: 10.1186/s12891-021-04307-4.

Key clinical point: Treatment with the half dose vs. stable dose of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was associated with increased rates of flares over 12 months in patients with rheumatoid arthritis (RA) in remission.

Major finding: At 12 months, the proportion of patients with at least 1 flare was significantly higher with half-dose vs. stable-dose csDMARDs (25% vs. 6%; risk difference, 18%; P = .003), thereby not meeting the noninferiority criterion of a 20% difference. There were 54 vs. 75 adverse events in the half-dose vs. stable-dose group.

Study details: Findings are from ARCTIC REWIND, a 36-month noninferiority trial of 160 patients with RA in remission for 12 months who were receiving stable csDMARDs. Patients were randomly allocated to either half-dose (n=80) or stable-dose (n=80) csDMARDs.

Disclosures: ARCTIC REWIND study was funded by the Research Council of Norway and South-Eastern Norway Regional Health Authority. The authors including the lead author reported receiving grants, personal fees, and nonfinancial support from various sources.

Source: Lillegraven S et al. JAMA. 2021 May 4. doi: 10.1001/jama.2021.4542.

Key clinical point: Treatment with the half dose vs. stable dose of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was associated with increased rates of flares over 12 months in patients with rheumatoid arthritis (RA) in remission.

Major finding: At 12 months, the proportion of patients with at least 1 flare was significantly higher with half-dose vs. stable-dose csDMARDs (25% vs. 6%; risk difference, 18%; P = .003), thereby not meeting the noninferiority criterion of a 20% difference. There were 54 vs. 75 adverse events in the half-dose vs. stable-dose group.

Study details: Findings are from ARCTIC REWIND, a 36-month noninferiority trial of 160 patients with RA in remission for 12 months who were receiving stable csDMARDs. Patients were randomly allocated to either half-dose (n=80) or stable-dose (n=80) csDMARDs.

Disclosures: ARCTIC REWIND study was funded by the Research Council of Norway and South-Eastern Norway Regional Health Authority. The authors including the lead author reported receiving grants, personal fees, and nonfinancial support from various sources.

Source: Lillegraven S et al. JAMA. 2021 May 4. doi: 10.1001/jama.2021.4542.

Key clinical point: Treatment with the half dose vs. stable dose of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was associated with increased rates of flares over 12 months in patients with rheumatoid arthritis (RA) in remission.

Major finding: At 12 months, the proportion of patients with at least 1 flare was significantly higher with half-dose vs. stable-dose csDMARDs (25% vs. 6%; risk difference, 18%; P = .003), thereby not meeting the noninferiority criterion of a 20% difference. There were 54 vs. 75 adverse events in the half-dose vs. stable-dose group.

Study details: Findings are from ARCTIC REWIND, a 36-month noninferiority trial of 160 patients with RA in remission for 12 months who were receiving stable csDMARDs. Patients were randomly allocated to either half-dose (n=80) or stable-dose (n=80) csDMARDs.

Disclosures: ARCTIC REWIND study was funded by the Research Council of Norway and South-Eastern Norway Regional Health Authority. The authors including the lead author reported receiving grants, personal fees, and nonfinancial support from various sources.

Source: Lillegraven S et al. JAMA. 2021 May 4. doi: 10.1001/jama.2021.4542.

Veterans with chronic headaches had a greater risk of a suicide attempt than that of veterans suffering from chronic neck or back pain, according to findings presented at the American Headache Society’s 2021 annual meeting. Risk rose even more in those with chronic headache pain and a comorbid traumatic brain injury (TBI).

“In addition, as expected, veterans with psychiatric conditions have increased risk of suicide attempt with the exception of anxiety in men and dependent personality in women,” said X. Michelle Androulakis, MD, associate professor of neurology at the University of South Carolina, Columbia.
 

‘Surprising’ findings

“These findings are eye-opening but not surprising since we know that veterans in general and people with chronic pain are at higher risk for suicidal behaviors compared with their civilian counterparts,” said Amy. S Grinberg, PhD, a clinical health psychologist who practices in New Rochelle, N.Y. Dr. Grinberg, who also works at VA Connecticut Healthcare System, was not involved in the study.

“It is, however, very interesting that suicidal attempts are higher in veterans with chronic headache compared with other chronic pain disorders, such as chronic neck and back pain,” Dr Grinberg said. “This really highlights the impact of living with a chronic headache disorder, and emphasizes the continued efforts that should be put into place to support veterans with chronic headache, including improved access to a range of treatment options and continued funding for future research.”
 

Veterans with chronic pain

The researchers retrospectively analyzed Veterans Health Administration electronic health records of 3,252,704 veterans, predominantly male and White, who had been diagnosed with any type of chronic pain from 2000 to 2010.

The researchers looked at overall headache diagnoses instead of specific diagnoses, such as migraine, cluster headache, or posttraumatic headache, since specific headache disorders are frequently underdiagnosed.

The population included 14.7% of patients with chronic headache, 14.9% with chronic neck pain, 59.2% with chronic back pain, and 60.2% with other types of chronic pain, including arthritis, fibromyalgia, joint pain, and reflex sympathetic dystrophy.

Traumatic brain injury occurred in 11.2% of those with chronic headaches, compared with 6.8% of those with chronic back pain, 8.5% of those with chronic neck pain, and 5.9% of those with other chronic pain.

More than half (56.4%) of those with chronic headache had depression, the most common comorbidity in the group, followed by 31.5% who had posttraumatic stress disorder (PTSD), and 21.8% who had adjustment disorder. Other rates of psychiatric disorders were all below 10%. Prevalence of depression occurred in 44.5% of those with back pain, 52.4% of those with neck pain, and 39% of those with other chronic pain. PTSD rates were also lower in those with back (22%), neck (27.2%), or other chronic pain (18.6%).

“Interestingly, this study found that those veterans with a history of traumatic brain injury and psychiatric comorbidities, such as depression, are at greater risk for suicide attempts,” said Dr. Grinberg. “The good news is that these are modifiable risk factors, and evidence-based treatments for depression, PTSD, and headache, for example, are widely disseminated within the VA.”

The majority of headache diagnoses were not otherwise specified (80.1%). Half (50.2%) were migraine headaches while rates were much lower for tension-type headache (8.8%), trigeminal neuralgia (5%), cluster headache (0.8%), and posttraumatic headache (0.7%).

The highest incidence of suicide attempts occurred among those with chronic headaches, ranging from 329 to 396 per 100,000, aside from a peak of 482 per 100,000 in 2005. Suicide attempts peaked among all patients with chronic pain in 2005, “likely related to the deployment and policy changes in the Veterans Health Administration,” Dr. Androulakis said.

Those with neck pain had the next highest rate of suicide attempts, ranging from 263 to 314 per 100,000, excluding the peak of 398 per 100,000 in 2005.

Male veterans with chronic headaches had a 1.5 times greater likelihood of a suicide attempt than did those with back or neck pain (relative risk [RR] = 1.5), which increased to a relative risk of 2.8 greater for those with concurrent TBI. Among female veterans, chronic headache was associated with a 1.6 times greater risk of a suicide attempt, which rose to 2.15 times greater with concurrent TBI.

“Knowing that veterans with chronic headache disorders have an elevated rate of suicide, it is imperative that doctors and other clinical providers continue to conduct in-depth risk assessments and implement strategies to support those veterans who are at risk,” said Dr. Grinberg. “Clinical providers should continue in their efforts to reduce stigma associated with headache disorders and mental health treatment in order to effectively engage veterans in evidence-based treatments that are likely a step towards reducing symptoms and suicidal attempts.”

No external funding was noted. Dr. Androulakis and Dr. Grinberg had no disclosures.

Veterans with chronic headaches had a greater risk of a suicide attempt than that of veterans suffering from chronic neck or back pain, according to findings presented at the American Headache Society’s 2021 annual meeting. Risk rose even more in those with chronic headache pain and a comorbid traumatic brain injury (TBI).

“In addition, as expected, veterans with psychiatric conditions have increased risk of suicide attempt with the exception of anxiety in men and dependent personality in women,” said X. Michelle Androulakis, MD, associate professor of neurology at the University of South Carolina, Columbia.
 

‘Surprising’ findings

“These findings are eye-opening but not surprising since we know that veterans in general and people with chronic pain are at higher risk for suicidal behaviors compared with their civilian counterparts,” said Amy. S Grinberg, PhD, a clinical health psychologist who practices in New Rochelle, N.Y. Dr. Grinberg, who also works at VA Connecticut Healthcare System, was not involved in the study.

“It is, however, very interesting that suicidal attempts are higher in veterans with chronic headache compared with other chronic pain disorders, such as chronic neck and back pain,” Dr Grinberg said. “This really highlights the impact of living with a chronic headache disorder, and emphasizes the continued efforts that should be put into place to support veterans with chronic headache, including improved access to a range of treatment options and continued funding for future research.”
 

Veterans with chronic pain

The researchers retrospectively analyzed Veterans Health Administration electronic health records of 3,252,704 veterans, predominantly male and White, who had been diagnosed with any type of chronic pain from 2000 to 2010.

The researchers looked at overall headache diagnoses instead of specific diagnoses, such as migraine, cluster headache, or posttraumatic headache, since specific headache disorders are frequently underdiagnosed.

The population included 14.7% of patients with chronic headache, 14.9% with chronic neck pain, 59.2% with chronic back pain, and 60.2% with other types of chronic pain, including arthritis, fibromyalgia, joint pain, and reflex sympathetic dystrophy.

Traumatic brain injury occurred in 11.2% of those with chronic headaches, compared with 6.8% of those with chronic back pain, 8.5% of those with chronic neck pain, and 5.9% of those with other chronic pain.

More than half (56.4%) of those with chronic headache had depression, the most common comorbidity in the group, followed by 31.5% who had posttraumatic stress disorder (PTSD), and 21.8% who had adjustment disorder. Other rates of psychiatric disorders were all below 10%. Prevalence of depression occurred in 44.5% of those with back pain, 52.4% of those with neck pain, and 39% of those with other chronic pain. PTSD rates were also lower in those with back (22%), neck (27.2%), or other chronic pain (18.6%).

“Interestingly, this study found that those veterans with a history of traumatic brain injury and psychiatric comorbidities, such as depression, are at greater risk for suicide attempts,” said Dr. Grinberg. “The good news is that these are modifiable risk factors, and evidence-based treatments for depression, PTSD, and headache, for example, are widely disseminated within the VA.”

The majority of headache diagnoses were not otherwise specified (80.1%). Half (50.2%) were migraine headaches while rates were much lower for tension-type headache (8.8%), trigeminal neuralgia (5%), cluster headache (0.8%), and posttraumatic headache (0.7%).

The highest incidence of suicide attempts occurred among those with chronic headaches, ranging from 329 to 396 per 100,000, aside from a peak of 482 per 100,000 in 2005. Suicide attempts peaked among all patients with chronic pain in 2005, “likely related to the deployment and policy changes in the Veterans Health Administration,” Dr. Androulakis said.

Those with neck pain had the next highest rate of suicide attempts, ranging from 263 to 314 per 100,000, excluding the peak of 398 per 100,000 in 2005.

Male veterans with chronic headaches had a 1.5 times greater likelihood of a suicide attempt than did those with back or neck pain (relative risk [RR] = 1.5), which increased to a relative risk of 2.8 greater for those with concurrent TBI. Among female veterans, chronic headache was associated with a 1.6 times greater risk of a suicide attempt, which rose to 2.15 times greater with concurrent TBI.

“Knowing that veterans with chronic headache disorders have an elevated rate of suicide, it is imperative that doctors and other clinical providers continue to conduct in-depth risk assessments and implement strategies to support those veterans who are at risk,” said Dr. Grinberg. “Clinical providers should continue in their efforts to reduce stigma associated with headache disorders and mental health treatment in order to effectively engage veterans in evidence-based treatments that are likely a step towards reducing symptoms and suicidal attempts.”

No external funding was noted. Dr. Androulakis and Dr. Grinberg had no disclosures.

Veterans with chronic headaches had a greater risk of a suicide attempt than that of veterans suffering from chronic neck or back pain, according to findings presented at the American Headache Society’s 2021 annual meeting. Risk rose even more in those with chronic headache pain and a comorbid traumatic brain injury (TBI).

“In addition, as expected, veterans with psychiatric conditions have increased risk of suicide attempt with the exception of anxiety in men and dependent personality in women,” said X. Michelle Androulakis, MD, associate professor of neurology at the University of South Carolina, Columbia.
 

‘Surprising’ findings

“These findings are eye-opening but not surprising since we know that veterans in general and people with chronic pain are at higher risk for suicidal behaviors compared with their civilian counterparts,” said Amy. S Grinberg, PhD, a clinical health psychologist who practices in New Rochelle, N.Y. Dr. Grinberg, who also works at VA Connecticut Healthcare System, was not involved in the study.

“It is, however, very interesting that suicidal attempts are higher in veterans with chronic headache compared with other chronic pain disorders, such as chronic neck and back pain,” Dr Grinberg said. “This really highlights the impact of living with a chronic headache disorder, and emphasizes the continued efforts that should be put into place to support veterans with chronic headache, including improved access to a range of treatment options and continued funding for future research.”
 

Veterans with chronic pain

The researchers retrospectively analyzed Veterans Health Administration electronic health records of 3,252,704 veterans, predominantly male and White, who had been diagnosed with any type of chronic pain from 2000 to 2010.

The researchers looked at overall headache diagnoses instead of specific diagnoses, such as migraine, cluster headache, or posttraumatic headache, since specific headache disorders are frequently underdiagnosed.

The population included 14.7% of patients with chronic headache, 14.9% with chronic neck pain, 59.2% with chronic back pain, and 60.2% with other types of chronic pain, including arthritis, fibromyalgia, joint pain, and reflex sympathetic dystrophy.

Traumatic brain injury occurred in 11.2% of those with chronic headaches, compared with 6.8% of those with chronic back pain, 8.5% of those with chronic neck pain, and 5.9% of those with other chronic pain.

More than half (56.4%) of those with chronic headache had depression, the most common comorbidity in the group, followed by 31.5% who had posttraumatic stress disorder (PTSD), and 21.8% who had adjustment disorder. Other rates of psychiatric disorders were all below 10%. Prevalence of depression occurred in 44.5% of those with back pain, 52.4% of those with neck pain, and 39% of those with other chronic pain. PTSD rates were also lower in those with back (22%), neck (27.2%), or other chronic pain (18.6%).

“Interestingly, this study found that those veterans with a history of traumatic brain injury and psychiatric comorbidities, such as depression, are at greater risk for suicide attempts,” said Dr. Grinberg. “The good news is that these are modifiable risk factors, and evidence-based treatments for depression, PTSD, and headache, for example, are widely disseminated within the VA.”

The majority of headache diagnoses were not otherwise specified (80.1%). Half (50.2%) were migraine headaches while rates were much lower for tension-type headache (8.8%), trigeminal neuralgia (5%), cluster headache (0.8%), and posttraumatic headache (0.7%).

The highest incidence of suicide attempts occurred among those with chronic headaches, ranging from 329 to 396 per 100,000, aside from a peak of 482 per 100,000 in 2005. Suicide attempts peaked among all patients with chronic pain in 2005, “likely related to the deployment and policy changes in the Veterans Health Administration,” Dr. Androulakis said.

Those with neck pain had the next highest rate of suicide attempts, ranging from 263 to 314 per 100,000, excluding the peak of 398 per 100,000 in 2005.

Male veterans with chronic headaches had a 1.5 times greater likelihood of a suicide attempt than did those with back or neck pain (relative risk [RR] = 1.5), which increased to a relative risk of 2.8 greater for those with concurrent TBI. Among female veterans, chronic headache was associated with a 1.6 times greater risk of a suicide attempt, which rose to 2.15 times greater with concurrent TBI.

“Knowing that veterans with chronic headache disorders have an elevated rate of suicide, it is imperative that doctors and other clinical providers continue to conduct in-depth risk assessments and implement strategies to support those veterans who are at risk,” said Dr. Grinberg. “Clinical providers should continue in their efforts to reduce stigma associated with headache disorders and mental health treatment in order to effectively engage veterans in evidence-based treatments that are likely a step towards reducing symptoms and suicidal attempts.”

No external funding was noted. Dr. Androulakis and Dr. Grinberg had no 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.

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.

As summer approaches, so does the risk of Lyme disease.

According to the Centers for Disease Control and Prevention, Lyme disease is the fastest growing vector-borne disease, affecting approximately 300,000 Americans every year. It is caused by the spirochete, Borrelia burgdorferi which is transmitted to humans by the deer tick. Lyme disease is often an overlooked diagnosis for myriad reasons, including inaccurate test results.

Infection prevention

We all know that the best way to treat any disease is by preventing it. The following measures are recommended as tools to prevent infection: personal protective wear, repellents, and removal of the attached tick. Recommended repellents include DEET, picaridin, IR3535, oil of lemon, eucalyptus, para-Menthane-3,8-diol (PMD), 2-undecanone, and permethrin. If a tick is found, it should be removed promptly by mechanical measures, such as with tweezers. The tweezers should be inserted between the tick body and skin to ensure removal of the entire tick. Burning an attached tick or applying a noxious chemical to the tick is not recommended.

Diagnosis

Diagnosing Lyme disease is often difficult given that tests can be negative for some time after a tick bite, even when the infection is present. There is good evidence to show that submitting the removed tick for identification is good practice. However, there is no evidence supporting testing the removed tick for the presence of Borrelia burgdorferi as it does not reliably predict infection in humans. It also is recommended to avoid testing asymptomatic people following a tick bite.

Following a high-risk tick bite, adults and children can be given prophylactic antibiotics within 72 hours. It is not helpful for low-risk bites. If the risk level is uncertain, it is better to observe before giving antibiotics. For adults, a single 200-mg dose of doxycycline can be given. In children, 4.4 mg per kg of body weight, up to 200 mg max, can be used for those under 45 kg.

For patients with a tick exposure and erythema migrans, a clinical diagnosis of Lyme disease can be made without further testing. If the clinical presentation is not typical, it is recommended to do an antibody test on an acute phase serum sample followed by a convalescent serum sample in 2-3 weeks if the initial test is negative. Recommended antibiotics for treatment include doxycycline for 10 days or amoxicillin or cefuroxime for 14 days. If a patient is unable to take these, azithromycin may be used for 7 days.

The guidelines also make recommendations regarding testing for Lyme neuroborreliosis, for which neurologic presentations, for adults with psychiatric illnesses, and for children with developmental/behavioral/psychiatric disorders. They further make recommendations for treatment of Lyme disease involving the brain or spinal column, facial nerve palsy, carditis, cardiomyopathy, and arthritis, which are beyond the scope of this discussion.

As family doctors, we are often the first ones patients call upon after a tick bite. We are the ones who diagnosis and treat Lyme disease, so it is imperative that we stay up to date with current clinical guidelines and practice evidence-based medicine. These most recent guidelines from several specialty societies can provide the answers to many of our patients’ questions. They also serve as a great tool to help with our clinical decision-making regarding tick bites. Lyme disease can be a scary infection for patients but, if we offer them the recommended measures, it doesn’t have to be.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

As summer approaches, so does the risk of Lyme disease.

According to the Centers for Disease Control and Prevention, Lyme disease is the fastest growing vector-borne disease, affecting approximately 300,000 Americans every year. It is caused by the spirochete, Borrelia burgdorferi which is transmitted to humans by the deer tick. Lyme disease is often an overlooked diagnosis for myriad reasons, including inaccurate test results.

Infection prevention

We all know that the best way to treat any disease is by preventing it. The following measures are recommended as tools to prevent infection: personal protective wear, repellents, and removal of the attached tick. Recommended repellents include DEET, picaridin, IR3535, oil of lemon, eucalyptus, para-Menthane-3,8-diol (PMD), 2-undecanone, and permethrin. If a tick is found, it should be removed promptly by mechanical measures, such as with tweezers. The tweezers should be inserted between the tick body and skin to ensure removal of the entire tick. Burning an attached tick or applying a noxious chemical to the tick is not recommended.

Diagnosis

Diagnosing Lyme disease is often difficult given that tests can be negative for some time after a tick bite, even when the infection is present. There is good evidence to show that submitting the removed tick for identification is good practice. However, there is no evidence supporting testing the removed tick for the presence of Borrelia burgdorferi as it does not reliably predict infection in humans. It also is recommended to avoid testing asymptomatic people following a tick bite.

Following a high-risk tick bite, adults and children can be given prophylactic antibiotics within 72 hours. It is not helpful for low-risk bites. If the risk level is uncertain, it is better to observe before giving antibiotics. For adults, a single 200-mg dose of doxycycline can be given. In children, 4.4 mg per kg of body weight, up to 200 mg max, can be used for those under 45 kg.

For patients with a tick exposure and erythema migrans, a clinical diagnosis of Lyme disease can be made without further testing. If the clinical presentation is not typical, it is recommended to do an antibody test on an acute phase serum sample followed by a convalescent serum sample in 2-3 weeks if the initial test is negative. Recommended antibiotics for treatment include doxycycline for 10 days or amoxicillin or cefuroxime for 14 days. If a patient is unable to take these, azithromycin may be used for 7 days.

The guidelines also make recommendations regarding testing for Lyme neuroborreliosis, for which neurologic presentations, for adults with psychiatric illnesses, and for children with developmental/behavioral/psychiatric disorders. They further make recommendations for treatment of Lyme disease involving the brain or spinal column, facial nerve palsy, carditis, cardiomyopathy, and arthritis, which are beyond the scope of this discussion.

As family doctors, we are often the first ones patients call upon after a tick bite. We are the ones who diagnosis and treat Lyme disease, so it is imperative that we stay up to date with current clinical guidelines and practice evidence-based medicine. These most recent guidelines from several specialty societies can provide the answers to many of our patients’ questions. They also serve as a great tool to help with our clinical decision-making regarding tick bites. Lyme disease can be a scary infection for patients but, if we offer them the recommended measures, it doesn’t have to be.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

As summer approaches, so does the risk of Lyme disease.

According to the Centers for Disease Control and Prevention, Lyme disease is the fastest growing vector-borne disease, affecting approximately 300,000 Americans every year. It is caused by the spirochete, Borrelia burgdorferi which is transmitted to humans by the deer tick. Lyme disease is often an overlooked diagnosis for myriad reasons, including inaccurate test results.

Infection prevention

We all know that the best way to treat any disease is by preventing it. The following measures are recommended as tools to prevent infection: personal protective wear, repellents, and removal of the attached tick. Recommended repellents include DEET, picaridin, IR3535, oil of lemon, eucalyptus, para-Menthane-3,8-diol (PMD), 2-undecanone, and permethrin. If a tick is found, it should be removed promptly by mechanical measures, such as with tweezers. The tweezers should be inserted between the tick body and skin to ensure removal of the entire tick. Burning an attached tick or applying a noxious chemical to the tick is not recommended.

Diagnosis

Diagnosing Lyme disease is often difficult given that tests can be negative for some time after a tick bite, even when the infection is present. There is good evidence to show that submitting the removed tick for identification is good practice. However, there is no evidence supporting testing the removed tick for the presence of Borrelia burgdorferi as it does not reliably predict infection in humans. It also is recommended to avoid testing asymptomatic people following a tick bite.

Following a high-risk tick bite, adults and children can be given prophylactic antibiotics within 72 hours. It is not helpful for low-risk bites. If the risk level is uncertain, it is better to observe before giving antibiotics. For adults, a single 200-mg dose of doxycycline can be given. In children, 4.4 mg per kg of body weight, up to 200 mg max, can be used for those under 45 kg.

For patients with a tick exposure and erythema migrans, a clinical diagnosis of Lyme disease can be made without further testing. If the clinical presentation is not typical, it is recommended to do an antibody test on an acute phase serum sample followed by a convalescent serum sample in 2-3 weeks if the initial test is negative. Recommended antibiotics for treatment include doxycycline for 10 days or amoxicillin or cefuroxime for 14 days. If a patient is unable to take these, azithromycin may be used for 7 days.

The guidelines also make recommendations regarding testing for Lyme neuroborreliosis, for which neurologic presentations, for adults with psychiatric illnesses, and for children with developmental/behavioral/psychiatric disorders. They further make recommendations for treatment of Lyme disease involving the brain or spinal column, facial nerve palsy, carditis, cardiomyopathy, and arthritis, which are beyond the scope of this discussion.

As family doctors, we are often the first ones patients call upon after a tick bite. We are the ones who diagnosis and treat Lyme disease, so it is imperative that we stay up to date with current clinical guidelines and practice evidence-based medicine. These most recent guidelines from several specialty societies can provide the answers to many of our patients’ questions. They also serve as a great tool to help with our clinical decision-making regarding tick bites. Lyme disease can be a scary infection for patients but, if we offer them the recommended measures, it doesn’t have to be.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, N.J. You can contact her at [email protected].

The relationship between adherence and benefit for those prescribed continuous positive airway pressure (CPAP) devices is clear. However, a Medicare-reimbursement rule that demands adherence blind to circumstances appears to be denying access to many low-income patients, according to an analysis delivered at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.

Over the past several years, adherence to CPAP has improved substantially following a series of studies that demonstrated the device must be used at least 4 hours per night to achieve improved outcomes. Medicare defines adherence as using the device more than 4 hours per night for 70% of nights (21 nights) during a consecutive 30-day period any time in the first 3 months of initial usage.

However, the studies that show improved adherence show a lag among those in the lowest income quartile, according to Sairam Parthasarathy, MD, director of the Center for Sleep and Circadian Sciences at the University of Arizona, Tucson.

When patients are followed for a year after being prescribed CPAP, the lag for the low-income patients is not seen immediately. Rather, adherence studies show a steady climb in adherence in all income groups initially, but ”right at 90 days there is a marked change,” said Dr. Parthasarathy.

This change happens to coincide with Medicare policy that denies reimbursement for CPAP after 90 days if patients are not using CPAP at least 4 hours per night, which is the threshold associated with benefit.

The correlation between this policy and income disparity is “observational” rather than proven, but Dr. Parthasarathy is confident it is valid. He believes it is a prime example of a health inequity driven by poorly conceived policy.

“The 90-day rule needs to go,” he said, calling the choice of threshold “man-made.” He added: “This is the only disease condition for which a therapy is withheld if it is not used according to some magical threshold. I cannot think of a more draconian policy.”

In an effort to illustrate the problem, he likened this policy to withholding insulin in a diabetes patient judged nonadherent because of a persistently elevated Hb1Ac.

At 90 days, adherence rates remain at a relatively early point in their upwards trajectory in all income groups. One year later, adherence rates are more than twice as high in the highest income relative to the lowest quartile and approaching twofold greater in quartiles 2 and 3.

“It takes time to get used to these devices,” Dr. Parthasarathy explained. Given studies demonstrating that “more is better” with CPAP, whether measured by sleep scales or quality of life, Dr. Parthasarathy advocates strategies to improve adherence, but he questioned an approach that penalizes low-income patients for a definition of nonadherence at an arbitrary point in time. He suggested it is just one example of health policies that ultimately penalize individuals with lower incomes.

“There are millions of dollars spent every year on understanding the genetics of disease, but the biggest influence on how long you live is the ZIP code of where you live,” said Dr. Parthasarathy, referring to ZIP codes as a surrogate for socioeconomic status.

This is not to imply, however, that genetics are irrelevant, Dr. Parthasarathy said. He pointed to data linking genetic traits that determine melanin levels and circadian rhythms. He noted one genotype associated with later bedtimes that is more commonly found in African-Americans and Hispanics. This has relevance to a variety of sleep disorders and other health conditions, but it might serve as a fundamental disadvantage for children with this genotype, Dr. Parthasarathy maintained. He cited a study conducted at his center that found Hispanic children sleep on average 30 minutes less than White children (Sleep Med 2016;18:61-6). The reason was simple. Hispanic children went to bed 30 minutes later but rose at the same time.

The later bedtimes and reduced sleep could potentially be one obstacle among many, such as the need for lower-income patients to hold several jobs, that prevent these patients from becoming accustomed to CPAP at the same speed as wealthier patients, according to Dr. Parthasarathy.

The current Medicare policy that withholds CPAP on the basis of a single definition of nonadherence appears to lead directly to an inequity in treatment of sleep apnea, he maintained. Dr. Parthasarathy, who was a coauthor of a recently published paper on addressing disparities in sleep health (Chest 2021;159:1232-40), described this issue as part of a larger problem of the failure to deliver health care that is sensitive to the cultural and racial differences underlying these inequities.

Kathleen Sarmiento, MD, FCCP, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System, agreed. “This type of issue is exactly what our committee would like to address,” said Dr. Sarmiento, a member of the CHEST Health Policy and Advocacy Committee and the moderator of the session in which Dr. Parthasarathy presented his data.

Courtesy Dr. Sarmiento

The relationship between adherence and benefit for those prescribed continuous positive airway pressure (CPAP) devices is clear. However, a Medicare-reimbursement rule that demands adherence blind to circumstances appears to be denying access to many low-income patients, according to an analysis delivered at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.

Over the past several years, adherence to CPAP has improved substantially following a series of studies that demonstrated the device must be used at least 4 hours per night to achieve improved outcomes. Medicare defines adherence as using the device more than 4 hours per night for 70% of nights (21 nights) during a consecutive 30-day period any time in the first 3 months of initial usage.

However, the studies that show improved adherence show a lag among those in the lowest income quartile, according to Sairam Parthasarathy, MD, director of the Center for Sleep and Circadian Sciences at the University of Arizona, Tucson.

When patients are followed for a year after being prescribed CPAP, the lag for the low-income patients is not seen immediately. Rather, adherence studies show a steady climb in adherence in all income groups initially, but ”right at 90 days there is a marked change,” said Dr. Parthasarathy.

This change happens to coincide with Medicare policy that denies reimbursement for CPAP after 90 days if patients are not using CPAP at least 4 hours per night, which is the threshold associated with benefit.

The correlation between this policy and income disparity is “observational” rather than proven, but Dr. Parthasarathy is confident it is valid. He believes it is a prime example of a health inequity driven by poorly conceived policy.

“The 90-day rule needs to go,” he said, calling the choice of threshold “man-made.” He added: “This is the only disease condition for which a therapy is withheld if it is not used according to some magical threshold. I cannot think of a more draconian policy.”

In an effort to illustrate the problem, he likened this policy to withholding insulin in a diabetes patient judged nonadherent because of a persistently elevated Hb1Ac.

At 90 days, adherence rates remain at a relatively early point in their upwards trajectory in all income groups. One year later, adherence rates are more than twice as high in the highest income relative to the lowest quartile and approaching twofold greater in quartiles 2 and 3.

“It takes time to get used to these devices,” Dr. Parthasarathy explained. Given studies demonstrating that “more is better” with CPAP, whether measured by sleep scales or quality of life, Dr. Parthasarathy advocates strategies to improve adherence, but he questioned an approach that penalizes low-income patients for a definition of nonadherence at an arbitrary point in time. He suggested it is just one example of health policies that ultimately penalize individuals with lower incomes.

“There are millions of dollars spent every year on understanding the genetics of disease, but the biggest influence on how long you live is the ZIP code of where you live,” said Dr. Parthasarathy, referring to ZIP codes as a surrogate for socioeconomic status.

This is not to imply, however, that genetics are irrelevant, Dr. Parthasarathy said. He pointed to data linking genetic traits that determine melanin levels and circadian rhythms. He noted one genotype associated with later bedtimes that is more commonly found in African-Americans and Hispanics. This has relevance to a variety of sleep disorders and other health conditions, but it might serve as a fundamental disadvantage for children with this genotype, Dr. Parthasarathy maintained. He cited a study conducted at his center that found Hispanic children sleep on average 30 minutes less than White children (Sleep Med 2016;18:61-6). The reason was simple. Hispanic children went to bed 30 minutes later but rose at the same time.

The later bedtimes and reduced sleep could potentially be one obstacle among many, such as the need for lower-income patients to hold several jobs, that prevent these patients from becoming accustomed to CPAP at the same speed as wealthier patients, according to Dr. Parthasarathy.

The current Medicare policy that withholds CPAP on the basis of a single definition of nonadherence appears to lead directly to an inequity in treatment of sleep apnea, he maintained. Dr. Parthasarathy, who was a coauthor of a recently published paper on addressing disparities in sleep health (Chest 2021;159:1232-40), described this issue as part of a larger problem of the failure to deliver health care that is sensitive to the cultural and racial differences underlying these inequities.

Kathleen Sarmiento, MD, FCCP, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System, agreed. “This type of issue is exactly what our committee would like to address,” said Dr. Sarmiento, a member of the CHEST Health Policy and Advocacy Committee and the moderator of the session in which Dr. Parthasarathy presented his data.

Courtesy Dr. Sarmiento

The relationship between adherence and benefit for those prescribed continuous positive airway pressure (CPAP) devices is clear. However, a Medicare-reimbursement rule that demands adherence blind to circumstances appears to be denying access to many low-income patients, according to an analysis delivered at the annual health policy and advocacy conference sponsored by the American College of Chest Physicians.

Over the past several years, adherence to CPAP has improved substantially following a series of studies that demonstrated the device must be used at least 4 hours per night to achieve improved outcomes. Medicare defines adherence as using the device more than 4 hours per night for 70% of nights (21 nights) during a consecutive 30-day period any time in the first 3 months of initial usage.

However, the studies that show improved adherence show a lag among those in the lowest income quartile, according to Sairam Parthasarathy, MD, director of the Center for Sleep and Circadian Sciences at the University of Arizona, Tucson.

When patients are followed for a year after being prescribed CPAP, the lag for the low-income patients is not seen immediately. Rather, adherence studies show a steady climb in adherence in all income groups initially, but ”right at 90 days there is a marked change,” said Dr. Parthasarathy.

This change happens to coincide with Medicare policy that denies reimbursement for CPAP after 90 days if patients are not using CPAP at least 4 hours per night, which is the threshold associated with benefit.

The correlation between this policy and income disparity is “observational” rather than proven, but Dr. Parthasarathy is confident it is valid. He believes it is a prime example of a health inequity driven by poorly conceived policy.

“The 90-day rule needs to go,” he said, calling the choice of threshold “man-made.” He added: “This is the only disease condition for which a therapy is withheld if it is not used according to some magical threshold. I cannot think of a more draconian policy.”

In an effort to illustrate the problem, he likened this policy to withholding insulin in a diabetes patient judged nonadherent because of a persistently elevated Hb1Ac.

At 90 days, adherence rates remain at a relatively early point in their upwards trajectory in all income groups. One year later, adherence rates are more than twice as high in the highest income relative to the lowest quartile and approaching twofold greater in quartiles 2 and 3.

“It takes time to get used to these devices,” Dr. Parthasarathy explained. Given studies demonstrating that “more is better” with CPAP, whether measured by sleep scales or quality of life, Dr. Parthasarathy advocates strategies to improve adherence, but he questioned an approach that penalizes low-income patients for a definition of nonadherence at an arbitrary point in time. He suggested it is just one example of health policies that ultimately penalize individuals with lower incomes.

“There are millions of dollars spent every year on understanding the genetics of disease, but the biggest influence on how long you live is the ZIP code of where you live,” said Dr. Parthasarathy, referring to ZIP codes as a surrogate for socioeconomic status.

This is not to imply, however, that genetics are irrelevant, Dr. Parthasarathy said. He pointed to data linking genetic traits that determine melanin levels and circadian rhythms. He noted one genotype associated with later bedtimes that is more commonly found in African-Americans and Hispanics. This has relevance to a variety of sleep disorders and other health conditions, but it might serve as a fundamental disadvantage for children with this genotype, Dr. Parthasarathy maintained. He cited a study conducted at his center that found Hispanic children sleep on average 30 minutes less than White children (Sleep Med 2016;18:61-6). The reason was simple. Hispanic children went to bed 30 minutes later but rose at the same time.

The later bedtimes and reduced sleep could potentially be one obstacle among many, such as the need for lower-income patients to hold several jobs, that prevent these patients from becoming accustomed to CPAP at the same speed as wealthier patients, according to Dr. Parthasarathy.

The current Medicare policy that withholds CPAP on the basis of a single definition of nonadherence appears to lead directly to an inequity in treatment of sleep apnea, he maintained. Dr. Parthasarathy, who was a coauthor of a recently published paper on addressing disparities in sleep health (Chest 2021;159:1232-40), described this issue as part of a larger problem of the failure to deliver health care that is sensitive to the cultural and racial differences underlying these inequities.

Kathleen Sarmiento, MD, FCCP, director, VISN 21 Sleep Clinical Resource Hub for the San Francisco VA Health Care System, agreed. “This type of issue is exactly what our committee would like to address,” said Dr. Sarmiento, a member of the CHEST Health Policy and Advocacy Committee and the moderator of the session in which Dr. Parthasarathy presented his data.

Courtesy Dr. Sarmiento

Inhibiting granulocyte/macrophage–colony stimulating factor (GM-CSF) with mavrilimumab prevented some patients with severe COVID-19 pneumonia and hyperinflammation from needing mechanical ventilation and reduced their risk of dying versus placebo in a phase 2 study.

There was no difference in outcomes between the two doses of mavrilimumab used in the trial (6 mg/kg or 10 mg/kg) and combined data showed a higher percentage of patients achieving the primary endpoint of being alive and free of mechanical ventilation at 29 days, at 87%, versus placebo, at 74%.

The P value was 0.12, “which achieved the prespecified evidentiary standard of 0.2,” according to Lara Pupim, MD, vice president of clinical research and development at Kiniksa Pharmaceuticals in Lexington, Mass.

Importantly, there was a 61% reduction in the risk of dying if patients had received mavrilimumab rather than placebo, she reported at the annual European Congress of Rheumatology. Mortality at day 29 was 21% in the placebo arm but just 8% in the combined mavrilimumab arms (P = .07).

Hendrik Schulze-Koops, MD, called it a “surprising study” and that “the outcome is very spectacular” in his short appraisal of the study during the Clinical Highlights session on the final day of the congress.

Mavrilimumab was “a compound that we would not have thought that would have such an impact on the outcome of COVID-19 infected patients,” Dr. Schulze-Koops of Ludwig Maximilian University of Munich added.

In this small study, “there was a consistent suggestion of a biological effect across key endpoints,” Richard Conway, MBChB, PhD, a consultant rheumatologist at St. James’s Hospital in Dublin, pointed out in an interview.

“Similar to tocilizumab, the benefits with mavrilimumab appear to be in addition to those seen with glucocorticoids, as 96% of patients received dexamethasone,” Dr. Conway observed. Furthermore, nearly one-third received antiviral or remdesivir treatment.

“This study was likely underpowered to assess a clinically meaningful benefit,” he said, adding that “there is insufficient evidence at present to begin using mavrilimumab as an alternative to currently available agents.” That said, “these results are promising for future studies.”

Rationale for GM-CSF inhibition with mavrilimumab in COVID-19 pneumonia

“The cytokine GM-CSF is vital to both lung homeostasis and regulation of inflammation in autoimmunity,” Dr. Pupim explained.

She added that “GM-CSF is implicated in the mechanism of aberrant immune cell infiltration and activation in the lungs, and it may contribute to respiratory failure and death in patients with severe COVID-19 pneumonia and systemic hyperinflammation.”

The efficacy and safety of blocking GM-CSF with mavrilimumab have been shown previously in phase 2 studies in other diseases, Dr. Pupim noted. This includes patients with rheumatoid arthritis and those with giant cell arteritis.

“It was hypothesized that GM-CSF receptor–alpha blockade may reduce infiltration of pathogenic cells into the lung and may suppress inflammation in COVID-19 pneumonia in hyperinflammation,” she explained.

Study details and other outcome results

The study presented by Dr. Pupim was a phase 2/3 double-blind, placebo-controlled trial predominantly conducted in Brazil, the United States, and South Africa, with some participation in Peru and Chile.

Patients were eligible for inclusion if they had had a positive COVID-19 test within 14 days of randomization and had been hospitalized but not ventilated. Evidence of bilateral pneumonia on chest x-ray or CT scan and clinical laboratory evidence indicative of hyperinflammation were also prerequisites for study enrollment.

The ongoing study comprised two cohorts, Dr. Pupim explained: patients who have not been ventilated and those who have recently been ventilated. Dr. Pupim presented the data on the nonventilated cohort, noting that there was a total of 116 patients aged a mean of 57 years.

Patients were randomized to one of three treatment arms: two groups received a single intravenous infusion of mavrilimumab, either 6 mg/kg or 10 mg/kg, and the third group got a placebo.

“Using a time-to-event approach, looking at mechanical ventilation-free survival, mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death,” Dr. Pupim said (P = .0175).

“Separation in the Kaplan-Meier curves was evident very early after study drug administration,” she added.

There were trends toward a faster benefit with mavrilimumab than placebo in two other key secondary endpoints: the median time to achieving a two-point clinical improvement (7 vs. 11 days) and the median time to room air (7 vs. 9 days).

Timing of mavrilimumab administration and safety

Study coauthor and chief clinical development officer at Kiniksa, Arian Pano, MD, answered questions on the presentation. When asked about the timing of giving mavrilimumab, he said: “Based on these data it is before they go to ventilation, as soon as you have symptoms of hyperinflammation and a need for oxygen.”

Mavrilimumab is given as a single infusion “and has been well tolerated; virtually no interruptions occurred in this study.”

No serious adverse events related to mavrilimumab were seen, and adverse events, including secondary infections, which are known complications of COVID-19, occurred less frequently in mavrilimumab recipients, compared with placebo.

Dr. Pupim reported that there was a case of tuberculosis in one patient treated with mavrilimumab (10 mg/kg). That case had occurred in an “endemic area for tuberculosis,” and the patient had been screened before entry but only via a sputum sample.

“Prior to these events, the patient received high-dose corticosteroids, a known risk factor for reactivation of TB, and thus the potential additive contribution of mavrilimumab, if any, is uncertain.” Dr. Pupim said.

“Thrombotic events, another known complication of COVID-19, occurred in the placebo arm only,” she added.

Dr. Pano commented that the study has now “seamlessly continued to phase 3. So, basically, we did not stop the study. At the end of phase 2, we just locked the database and collected the data.” Both the 6 mg/kg and 10 mg/kg are being studied, but it’s “very likely [that] 6 mg/kg could be the dose that we may bring forward to the clinic in terms of registration, but that’s at this point in time. We will need to wait for the phase 3 data,” he observed. Those findings will hopefully be available later this year.

Kiniksa funded the study. Dr. Pupim, Dr. Pano, and multiple study coinvestigators are employees of the company.

Dr. Schulze-Koops was not involved in the study and had no specific disclosures. Dr. Conway had no financial disclosures to make in relation to his comments.

Inhibiting granulocyte/macrophage–colony stimulating factor (GM-CSF) with mavrilimumab prevented some patients with severe COVID-19 pneumonia and hyperinflammation from needing mechanical ventilation and reduced their risk of dying versus placebo in a phase 2 study.

There was no difference in outcomes between the two doses of mavrilimumab used in the trial (6 mg/kg or 10 mg/kg) and combined data showed a higher percentage of patients achieving the primary endpoint of being alive and free of mechanical ventilation at 29 days, at 87%, versus placebo, at 74%.

The P value was 0.12, “which achieved the prespecified evidentiary standard of 0.2,” according to Lara Pupim, MD, vice president of clinical research and development at Kiniksa Pharmaceuticals in Lexington, Mass.

Importantly, there was a 61% reduction in the risk of dying if patients had received mavrilimumab rather than placebo, she reported at the annual European Congress of Rheumatology. Mortality at day 29 was 21% in the placebo arm but just 8% in the combined mavrilimumab arms (P = .07).

Hendrik Schulze-Koops, MD, called it a “surprising study” and that “the outcome is very spectacular” in his short appraisal of the study during the Clinical Highlights session on the final day of the congress.

Mavrilimumab was “a compound that we would not have thought that would have such an impact on the outcome of COVID-19 infected patients,” Dr. Schulze-Koops of Ludwig Maximilian University of Munich added.

In this small study, “there was a consistent suggestion of a biological effect across key endpoints,” Richard Conway, MBChB, PhD, a consultant rheumatologist at St. James’s Hospital in Dublin, pointed out in an interview.

“Similar to tocilizumab, the benefits with mavrilimumab appear to be in addition to those seen with glucocorticoids, as 96% of patients received dexamethasone,” Dr. Conway observed. Furthermore, nearly one-third received antiviral or remdesivir treatment.

“This study was likely underpowered to assess a clinically meaningful benefit,” he said, adding that “there is insufficient evidence at present to begin using mavrilimumab as an alternative to currently available agents.” That said, “these results are promising for future studies.”

Rationale for GM-CSF inhibition with mavrilimumab in COVID-19 pneumonia

“The cytokine GM-CSF is vital to both lung homeostasis and regulation of inflammation in autoimmunity,” Dr. Pupim explained.

She added that “GM-CSF is implicated in the mechanism of aberrant immune cell infiltration and activation in the lungs, and it may contribute to respiratory failure and death in patients with severe COVID-19 pneumonia and systemic hyperinflammation.”

The efficacy and safety of blocking GM-CSF with mavrilimumab have been shown previously in phase 2 studies in other diseases, Dr. Pupim noted. This includes patients with rheumatoid arthritis and those with giant cell arteritis.

“It was hypothesized that GM-CSF receptor–alpha blockade may reduce infiltration of pathogenic cells into the lung and may suppress inflammation in COVID-19 pneumonia in hyperinflammation,” she explained.

Study details and other outcome results

The study presented by Dr. Pupim was a phase 2/3 double-blind, placebo-controlled trial predominantly conducted in Brazil, the United States, and South Africa, with some participation in Peru and Chile.

Patients were eligible for inclusion if they had had a positive COVID-19 test within 14 days of randomization and had been hospitalized but not ventilated. Evidence of bilateral pneumonia on chest x-ray or CT scan and clinical laboratory evidence indicative of hyperinflammation were also prerequisites for study enrollment.

The ongoing study comprised two cohorts, Dr. Pupim explained: patients who have not been ventilated and those who have recently been ventilated. Dr. Pupim presented the data on the nonventilated cohort, noting that there was a total of 116 patients aged a mean of 57 years.

Patients were randomized to one of three treatment arms: two groups received a single intravenous infusion of mavrilimumab, either 6 mg/kg or 10 mg/kg, and the third group got a placebo.

“Using a time-to-event approach, looking at mechanical ventilation-free survival, mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death,” Dr. Pupim said (P = .0175).

“Separation in the Kaplan-Meier curves was evident very early after study drug administration,” she added.

There were trends toward a faster benefit with mavrilimumab than placebo in two other key secondary endpoints: the median time to achieving a two-point clinical improvement (7 vs. 11 days) and the median time to room air (7 vs. 9 days).

Timing of mavrilimumab administration and safety

Study coauthor and chief clinical development officer at Kiniksa, Arian Pano, MD, answered questions on the presentation. When asked about the timing of giving mavrilimumab, he said: “Based on these data it is before they go to ventilation, as soon as you have symptoms of hyperinflammation and a need for oxygen.”

Mavrilimumab is given as a single infusion “and has been well tolerated; virtually no interruptions occurred in this study.”

No serious adverse events related to mavrilimumab were seen, and adverse events, including secondary infections, which are known complications of COVID-19, occurred less frequently in mavrilimumab recipients, compared with placebo.

Dr. Pupim reported that there was a case of tuberculosis in one patient treated with mavrilimumab (10 mg/kg). That case had occurred in an “endemic area for tuberculosis,” and the patient had been screened before entry but only via a sputum sample.

“Prior to these events, the patient received high-dose corticosteroids, a known risk factor for reactivation of TB, and thus the potential additive contribution of mavrilimumab, if any, is uncertain.” Dr. Pupim said.

“Thrombotic events, another known complication of COVID-19, occurred in the placebo arm only,” she added.

Dr. Pano commented that the study has now “seamlessly continued to phase 3. So, basically, we did not stop the study. At the end of phase 2, we just locked the database and collected the data.” Both the 6 mg/kg and 10 mg/kg are being studied, but it’s “very likely [that] 6 mg/kg could be the dose that we may bring forward to the clinic in terms of registration, but that’s at this point in time. We will need to wait for the phase 3 data,” he observed. Those findings will hopefully be available later this year.

Kiniksa funded the study. Dr. Pupim, Dr. Pano, and multiple study coinvestigators are employees of the company.

Dr. Schulze-Koops was not involved in the study and had no specific disclosures. Dr. Conway had no financial disclosures to make in relation to his comments.

Inhibiting granulocyte/macrophage–colony stimulating factor (GM-CSF) with mavrilimumab prevented some patients with severe COVID-19 pneumonia and hyperinflammation from needing mechanical ventilation and reduced their risk of dying versus placebo in a phase 2 study.

There was no difference in outcomes between the two doses of mavrilimumab used in the trial (6 mg/kg or 10 mg/kg) and combined data showed a higher percentage of patients achieving the primary endpoint of being alive and free of mechanical ventilation at 29 days, at 87%, versus placebo, at 74%.

The P value was 0.12, “which achieved the prespecified evidentiary standard of 0.2,” according to Lara Pupim, MD, vice president of clinical research and development at Kiniksa Pharmaceuticals in Lexington, Mass.

Importantly, there was a 61% reduction in the risk of dying if patients had received mavrilimumab rather than placebo, she reported at the annual European Congress of Rheumatology. Mortality at day 29 was 21% in the placebo arm but just 8% in the combined mavrilimumab arms (P = .07).

Hendrik Schulze-Koops, MD, called it a “surprising study” and that “the outcome is very spectacular” in his short appraisal of the study during the Clinical Highlights session on the final day of the congress.

Mavrilimumab was “a compound that we would not have thought that would have such an impact on the outcome of COVID-19 infected patients,” Dr. Schulze-Koops of Ludwig Maximilian University of Munich added.

In this small study, “there was a consistent suggestion of a biological effect across key endpoints,” Richard Conway, MBChB, PhD, a consultant rheumatologist at St. James’s Hospital in Dublin, pointed out in an interview.

“Similar to tocilizumab, the benefits with mavrilimumab appear to be in addition to those seen with glucocorticoids, as 96% of patients received dexamethasone,” Dr. Conway observed. Furthermore, nearly one-third received antiviral or remdesivir treatment.

“This study was likely underpowered to assess a clinically meaningful benefit,” he said, adding that “there is insufficient evidence at present to begin using mavrilimumab as an alternative to currently available agents.” That said, “these results are promising for future studies.”

Rationale for GM-CSF inhibition with mavrilimumab in COVID-19 pneumonia

“The cytokine GM-CSF is vital to both lung homeostasis and regulation of inflammation in autoimmunity,” Dr. Pupim explained.

She added that “GM-CSF is implicated in the mechanism of aberrant immune cell infiltration and activation in the lungs, and it may contribute to respiratory failure and death in patients with severe COVID-19 pneumonia and systemic hyperinflammation.”

The efficacy and safety of blocking GM-CSF with mavrilimumab have been shown previously in phase 2 studies in other diseases, Dr. Pupim noted. This includes patients with rheumatoid arthritis and those with giant cell arteritis.

“It was hypothesized that GM-CSF receptor–alpha blockade may reduce infiltration of pathogenic cells into the lung and may suppress inflammation in COVID-19 pneumonia in hyperinflammation,” she explained.

Study details and other outcome results

The study presented by Dr. Pupim was a phase 2/3 double-blind, placebo-controlled trial predominantly conducted in Brazil, the United States, and South Africa, with some participation in Peru and Chile.

Patients were eligible for inclusion if they had had a positive COVID-19 test within 14 days of randomization and had been hospitalized but not ventilated. Evidence of bilateral pneumonia on chest x-ray or CT scan and clinical laboratory evidence indicative of hyperinflammation were also prerequisites for study enrollment.

The ongoing study comprised two cohorts, Dr. Pupim explained: patients who have not been ventilated and those who have recently been ventilated. Dr. Pupim presented the data on the nonventilated cohort, noting that there was a total of 116 patients aged a mean of 57 years.

Patients were randomized to one of three treatment arms: two groups received a single intravenous infusion of mavrilimumab, either 6 mg/kg or 10 mg/kg, and the third group got a placebo.

“Using a time-to-event approach, looking at mechanical ventilation-free survival, mavrilimumab recipients experienced a 65% reduction in the risk of mechanical ventilation or death,” Dr. Pupim said (P = .0175).

“Separation in the Kaplan-Meier curves was evident very early after study drug administration,” she added.

There were trends toward a faster benefit with mavrilimumab than placebo in two other key secondary endpoints: the median time to achieving a two-point clinical improvement (7 vs. 11 days) and the median time to room air (7 vs. 9 days).

Timing of mavrilimumab administration and safety

Study coauthor and chief clinical development officer at Kiniksa, Arian Pano, MD, answered questions on the presentation. When asked about the timing of giving mavrilimumab, he said: “Based on these data it is before they go to ventilation, as soon as you have symptoms of hyperinflammation and a need for oxygen.”

Mavrilimumab is given as a single infusion “and has been well tolerated; virtually no interruptions occurred in this study.”

No serious adverse events related to mavrilimumab were seen, and adverse events, including secondary infections, which are known complications of COVID-19, occurred less frequently in mavrilimumab recipients, compared with placebo.

Dr. Pupim reported that there was a case of tuberculosis in one patient treated with mavrilimumab (10 mg/kg). That case had occurred in an “endemic area for tuberculosis,” and the patient had been screened before entry but only via a sputum sample.

“Prior to these events, the patient received high-dose corticosteroids, a known risk factor for reactivation of TB, and thus the potential additive contribution of mavrilimumab, if any, is uncertain.” Dr. Pupim said.

“Thrombotic events, another known complication of COVID-19, occurred in the placebo arm only,” she added.

Dr. Pano commented that the study has now “seamlessly continued to phase 3. So, basically, we did not stop the study. At the end of phase 2, we just locked the database and collected the data.” Both the 6 mg/kg and 10 mg/kg are being studied, but it’s “very likely [that] 6 mg/kg could be the dose that we may bring forward to the clinic in terms of registration, but that’s at this point in time. We will need to wait for the phase 3 data,” he observed. Those findings will hopefully be available later this year.

Kiniksa funded the study. Dr. Pupim, Dr. Pano, and multiple study coinvestigators are employees of the company.

Dr. Schulze-Koops was not involved in the study and had no specific disclosures. Dr. Conway had no financial disclosures to make in relation to his comments.