Jim Kling

Large nonpedunculated rectal polyps (LNPRPs), defined as 20 mm or larger, are associated with a high risk of submucosal invasive cancer (SMIC). Although LNPRPs can be removed by distal colorectal surgery, this approach has an increased risk of morbidity, mortality, and permanent ostomy formation.

The first-line resection technique for LNPRPs is endoscopic mucosal resection (EMR); however, for larger lesions, piecemeal removal is required. When SMIC is revealed after piecemeal resection, surgery is generally recommended, since this is the only way to determine if R0 margins and curative oncologic resection have been achieved.

In such cases, an alternative is endoscopic submucosal dissection (ESD), but there is no current algorithm to choose between the two procedures based on lesion identity.

Optical methods can determine a lesion’s pit and microvascular pattern in real time to determine if SMIC is present, but the performance is modest. Researchers sought to bolster optical detection by combining it with SMIC risk stratification to streamline the choice between EMR and ESD for LNPRPs.

In a study published online in Clinical Gastroenterology and Hepatology, researchers led by Neal Shahidi, MD, of the division of gastroenterology, St. Paul’s Hospital, Vancouver, described a selective resection algorithm (SRA) that could assist gastroenterologists in determining the best procedure to use when confronted with an LNPRP.

“Cost-effectiveness analyses have shown that an SRA using EMR and ESD is the optimal approach. However, a mechanism to facilitate modality selection has not been delineated. To our knowledge, this study is the first to show that a rectum-specific SRA, based on real-time optical evaluation and covert SMIC risk stratification, increases the frequency of curative oncologic resection and minimizes the risk of piecemeal resection of malignant LNPRPs. ... Piecemeal resection of endoscopically curable malignant LNPRPs negates the very benefit that they are intended to provide. To avoid malignant piecemeal resection, optical evaluation of the lesion’s pit and microvascular surface pattern can be used to predict SMIC prior to resection technique selection,” the authors wrote.

The researchers conducted a prospective observational study of 480 LNPRPs that were detected between July 2008 and April 2021. They compared the performance of the SRA to that of a universal EMR algorithm (UEA) for procedure determination. The SRA flagged LNPRPs with features consistent with SMIC (< 1,000 mm or Kudo pit pattern Vi) for endoscopic dissection. The latter included Paris 0-Is or 0-IIa+Is nongranular, or 0-IIa+Is granular with a dominant nodule 10 mm or larger. Other LNPRPs were designated to undergo EMR.

The median patient age was 67 years, and 54.2% were men; 90.1% of participants were ASA I-II; 290 LNPRPs were evaluated with the UEA and 190 with the SRA. The median lesion size was 40 mm. Overall, 11.7% of LPNRPs were identified as containing SMIC.

In the SRA, only 1.0% of LNPRPs removed by EMR contained SMIC, while the UEA identified cancer in 12.1%, a significant difference (P = .001). The SRA led to 33.3% as curative oncologic resections, while the UEA achieved only 5.7% (P = .010).

There were no significant differences in technical success or adverse events between the two algorithms.

Procedures determined by SRA took longer than those decided by UEA (median resection duration, 45 vs. 29 minutes; P < .001). Among LNPRPs that were removed through EMR and margin thermal ablation, there was no significant difference in recurrence whether SRA or UEA was used to determine the procedure.

Compared with UEA, SRA was associated with higher rates of en bloc resection (90.5% vs. 11.4%; P < .001), R0 resection (85.7% vs. 5.7%; P < .001), and curative oncologic resection (33.3% vs. 5.7%; P = .010).

“In this study, using analogous optical evaluation and covert SMIC risk stratification criteria, only one (1.0%) [of] malignant LNPRP underwent piecemeal resection within the SRA. This is a pivotal advance in the application of minimally invasive endoscopic resection techniques. It demonstrates an effective approach to optical evaluation; thereby, delineating which LNPRPs can be effectively, efficiently, and safely managed by EMR, compared with those which may derive benefit from ESD,” the authors wrote.

The authors recommended ESD only be used for lesions with suspected superficial SMIC or when there is a heightened risk of SMIC.

A key finding of the study is the frequency of curative resection following ESD. “At 33.3%, this represents a critical improvement in patient outcomes and the application of minimally invasive endoscopic resection techniques; especially when taking into consideration the potential negative ramifications of distal colorectal surgery and evidence showing that endoscopic resection does not impair subsequent surgical intervention,” the authors wrote.

There was no significant difference in recurrence at surveillance colonoscopy between SRA and UEA when undergoing margin thermal ablation. The finding suggests that margin thermal ablation should be considered a vital component of EMR, according to the authors.

Dr. Shahidi received speaker honorarium from Boston Scientific and Pharmascience, and one coauthor received research support from Olympus, Cook Medical, and Boston Scientific.

Large nonpedunculated rectal polyps (LNPRPs), defined as 20 mm or larger, are associated with a high risk of submucosal invasive cancer (SMIC). Although LNPRPs can be removed by distal colorectal surgery, this approach has an increased risk of morbidity, mortality, and permanent ostomy formation.

The first-line resection technique for LNPRPs is endoscopic mucosal resection (EMR); however, for larger lesions, piecemeal removal is required. When SMIC is revealed after piecemeal resection, surgery is generally recommended, since this is the only way to determine if R0 margins and curative oncologic resection have been achieved.

In such cases, an alternative is endoscopic submucosal dissection (ESD), but there is no current algorithm to choose between the two procedures based on lesion identity.

Optical methods can determine a lesion’s pit and microvascular pattern in real time to determine if SMIC is present, but the performance is modest. Researchers sought to bolster optical detection by combining it with SMIC risk stratification to streamline the choice between EMR and ESD for LNPRPs.

In a study published online in Clinical Gastroenterology and Hepatology, researchers led by Neal Shahidi, MD, of the division of gastroenterology, St. Paul’s Hospital, Vancouver, described a selective resection algorithm (SRA) that could assist gastroenterologists in determining the best procedure to use when confronted with an LNPRP.

“Cost-effectiveness analyses have shown that an SRA using EMR and ESD is the optimal approach. However, a mechanism to facilitate modality selection has not been delineated. To our knowledge, this study is the first to show that a rectum-specific SRA, based on real-time optical evaluation and covert SMIC risk stratification, increases the frequency of curative oncologic resection and minimizes the risk of piecemeal resection of malignant LNPRPs. ... Piecemeal resection of endoscopically curable malignant LNPRPs negates the very benefit that they are intended to provide. To avoid malignant piecemeal resection, optical evaluation of the lesion’s pit and microvascular surface pattern can be used to predict SMIC prior to resection technique selection,” the authors wrote.

The researchers conducted a prospective observational study of 480 LNPRPs that were detected between July 2008 and April 2021. They compared the performance of the SRA to that of a universal EMR algorithm (UEA) for procedure determination. The SRA flagged LNPRPs with features consistent with SMIC (< 1,000 mm or Kudo pit pattern Vi) for endoscopic dissection. The latter included Paris 0-Is or 0-IIa+Is nongranular, or 0-IIa+Is granular with a dominant nodule 10 mm or larger. Other LNPRPs were designated to undergo EMR.

The median patient age was 67 years, and 54.2% were men; 90.1% of participants were ASA I-II; 290 LNPRPs were evaluated with the UEA and 190 with the SRA. The median lesion size was 40 mm. Overall, 11.7% of LPNRPs were identified as containing SMIC.

In the SRA, only 1.0% of LNPRPs removed by EMR contained SMIC, while the UEA identified cancer in 12.1%, a significant difference (P = .001). The SRA led to 33.3% as curative oncologic resections, while the UEA achieved only 5.7% (P = .010).

There were no significant differences in technical success or adverse events between the two algorithms.

Procedures determined by SRA took longer than those decided by UEA (median resection duration, 45 vs. 29 minutes; P < .001). Among LNPRPs that were removed through EMR and margin thermal ablation, there was no significant difference in recurrence whether SRA or UEA was used to determine the procedure.

Compared with UEA, SRA was associated with higher rates of en bloc resection (90.5% vs. 11.4%; P < .001), R0 resection (85.7% vs. 5.7%; P < .001), and curative oncologic resection (33.3% vs. 5.7%; P = .010).

“In this study, using analogous optical evaluation and covert SMIC risk stratification criteria, only one (1.0%) [of] malignant LNPRP underwent piecemeal resection within the SRA. This is a pivotal advance in the application of minimally invasive endoscopic resection techniques. It demonstrates an effective approach to optical evaluation; thereby, delineating which LNPRPs can be effectively, efficiently, and safely managed by EMR, compared with those which may derive benefit from ESD,” the authors wrote.

The authors recommended ESD only be used for lesions with suspected superficial SMIC or when there is a heightened risk of SMIC.

A key finding of the study is the frequency of curative resection following ESD. “At 33.3%, this represents a critical improvement in patient outcomes and the application of minimally invasive endoscopic resection techniques; especially when taking into consideration the potential negative ramifications of distal colorectal surgery and evidence showing that endoscopic resection does not impair subsequent surgical intervention,” the authors wrote.

There was no significant difference in recurrence at surveillance colonoscopy between SRA and UEA when undergoing margin thermal ablation. The finding suggests that margin thermal ablation should be considered a vital component of EMR, according to the authors.

Dr. Shahidi received speaker honorarium from Boston Scientific and Pharmascience, and one coauthor received research support from Olympus, Cook Medical, and Boston Scientific.

Large nonpedunculated rectal polyps (LNPRPs), defined as 20 mm or larger, are associated with a high risk of submucosal invasive cancer (SMIC). Although LNPRPs can be removed by distal colorectal surgery, this approach has an increased risk of morbidity, mortality, and permanent ostomy formation.

The first-line resection technique for LNPRPs is endoscopic mucosal resection (EMR); however, for larger lesions, piecemeal removal is required. When SMIC is revealed after piecemeal resection, surgery is generally recommended, since this is the only way to determine if R0 margins and curative oncologic resection have been achieved.

In such cases, an alternative is endoscopic submucosal dissection (ESD), but there is no current algorithm to choose between the two procedures based on lesion identity.

Optical methods can determine a lesion’s pit and microvascular pattern in real time to determine if SMIC is present, but the performance is modest. Researchers sought to bolster optical detection by combining it with SMIC risk stratification to streamline the choice between EMR and ESD for LNPRPs.

In a study published online in Clinical Gastroenterology and Hepatology, researchers led by Neal Shahidi, MD, of the division of gastroenterology, St. Paul’s Hospital, Vancouver, described a selective resection algorithm (SRA) that could assist gastroenterologists in determining the best procedure to use when confronted with an LNPRP.

“Cost-effectiveness analyses have shown that an SRA using EMR and ESD is the optimal approach. However, a mechanism to facilitate modality selection has not been delineated. To our knowledge, this study is the first to show that a rectum-specific SRA, based on real-time optical evaluation and covert SMIC risk stratification, increases the frequency of curative oncologic resection and minimizes the risk of piecemeal resection of malignant LNPRPs. ... Piecemeal resection of endoscopically curable malignant LNPRPs negates the very benefit that they are intended to provide. To avoid malignant piecemeal resection, optical evaluation of the lesion’s pit and microvascular surface pattern can be used to predict SMIC prior to resection technique selection,” the authors wrote.

The researchers conducted a prospective observational study of 480 LNPRPs that were detected between July 2008 and April 2021. They compared the performance of the SRA to that of a universal EMR algorithm (UEA) for procedure determination. The SRA flagged LNPRPs with features consistent with SMIC (< 1,000 mm or Kudo pit pattern Vi) for endoscopic dissection. The latter included Paris 0-Is or 0-IIa+Is nongranular, or 0-IIa+Is granular with a dominant nodule 10 mm or larger. Other LNPRPs were designated to undergo EMR.

The median patient age was 67 years, and 54.2% were men; 90.1% of participants were ASA I-II; 290 LNPRPs were evaluated with the UEA and 190 with the SRA. The median lesion size was 40 mm. Overall, 11.7% of LPNRPs were identified as containing SMIC.

In the SRA, only 1.0% of LNPRPs removed by EMR contained SMIC, while the UEA identified cancer in 12.1%, a significant difference (P = .001). The SRA led to 33.3% as curative oncologic resections, while the UEA achieved only 5.7% (P = .010).

There were no significant differences in technical success or adverse events between the two algorithms.

Procedures determined by SRA took longer than those decided by UEA (median resection duration, 45 vs. 29 minutes; P < .001). Among LNPRPs that were removed through EMR and margin thermal ablation, there was no significant difference in recurrence whether SRA or UEA was used to determine the procedure.

Compared with UEA, SRA was associated with higher rates of en bloc resection (90.5% vs. 11.4%; P < .001), R0 resection (85.7% vs. 5.7%; P < .001), and curative oncologic resection (33.3% vs. 5.7%; P = .010).

“In this study, using analogous optical evaluation and covert SMIC risk stratification criteria, only one (1.0%) [of] malignant LNPRP underwent piecemeal resection within the SRA. This is a pivotal advance in the application of minimally invasive endoscopic resection techniques. It demonstrates an effective approach to optical evaluation; thereby, delineating which LNPRPs can be effectively, efficiently, and safely managed by EMR, compared with those which may derive benefit from ESD,” the authors wrote.

The authors recommended ESD only be used for lesions with suspected superficial SMIC or when there is a heightened risk of SMIC.

A key finding of the study is the frequency of curative resection following ESD. “At 33.3%, this represents a critical improvement in patient outcomes and the application of minimally invasive endoscopic resection techniques; especially when taking into consideration the potential negative ramifications of distal colorectal surgery and evidence showing that endoscopic resection does not impair subsequent surgical intervention,” the authors wrote.

There was no significant difference in recurrence at surveillance colonoscopy between SRA and UEA when undergoing margin thermal ablation. The finding suggests that margin thermal ablation should be considered a vital component of EMR, according to the authors.

Dr. Shahidi received speaker honorarium from Boston Scientific and Pharmascience, and one coauthor received research support from Olympus, Cook Medical, and Boston Scientific.

A new clinical practice update from the American Gastroenterological Association focuses on new technology for the diagnosis of Barrett’s esophagus (BE). It also suggests that patients with no symptoms of chronic reflux can be considered for screening, which could significantly increase the number of people eligible for screening.

Current AGA guidelines support endoscopic screening for BE followed by surveillance for the early detection of BE, dysplasia, and neoplasia. However, fewer than 20% of patients eventually diagnosed with esophageal adenocarcinoma (EAC) were previously diagnosed with BE, suggesting that many opportunities for early detection are missed.

The clinical practice update, published online in Clinical Gastroenterology and Hepatology, represents an effort to highlight advances in screening and surveillance with the goal of improving uptake. The main thrust of the document is risk factors other than gastroesophageal reflux disease (GERD) when considering candidates for screening.

In practice, physicians are already starting to employ other risk factors to select patients for screening, according to coauthor Srinadh Komanduri, MD, who is a professor of medicine and surgery at Northwestern University, Chicago. Specifically, the update suggests screening for individuals with at least three established risk factors for EAC and BE. Risk factors include male sex, non-Hispanic White race, age over 50 years, history of smoking, chronic GERD, obesity, or a family history of BE or EAC.

Another purpose of the update is to highlight noninvasive screening tools, especially nonendoscopic cell collection devices. The authors stress that upper endoscopy with biopsies remains the preferred method for BE diagnosis, but methods that are simple, patient-friendly, and cost-effective have the potential to increase the screened population. One option is transnasal endoscopy, which can be performed in the office with no sedation, but this is expensive and requires expertise.

Recently developed nonendoscopic cell collection devices include Cytosponge (Medtronic GI Solutions), EsoCheck (Lucid Diagnostics), and EsophaCap (Capnostics). All are safe and well-tolerated, and they have good sensitivity for BE. The Cytosponge consists of a swallowable piece of polyurethane foam fitted into a capsule that is attached to suture. The capsule dissolves and the foam expands, collecting cells, and is then withdrawn. It has undergone extensive testing in BE screening in the United Kingdom and was found to have a sensitivity of 80% and specificity of 92.2%. A primary care study showed a 10-fold increase in BE detection compared with usual care.

The EsophaCap works similarly to the Cytosponge but with a smaller diameter. It has 93% sensitivity and 93% specificity for intestinal metaplasia when combined with a panel of five methylated DNA biomarkers.

The EsoCheck device consists of a balloon attached to a catheter, which is inflated and withdrawn. Ridges on the balloon surface capture cells for analysis. A pilot study using two biomarkers found a 90.3% sensitivity and 91.7% specificity.

The update also advises use of high-definition white light endoscopy (HD-WLE) and virtual chromoendoscopy (VC) for screening and surveillance. An updated meta-analysis showed the two methods combined led to a higher detection rate of high grade dysplasia/EAC than HD-WLE alone (14.7% versus 10.1%; relative risk, 1.44). VC and traditional chromoendoscopy have similar dysplasia detection rates, but the former is recommended since it is readily available, requires no extra costs, and avoids issues that can affect dye-based chromoendoscopy. VC from any manufacturer is acceptable, but most data supporting its utility focuses on narrow-band imaging only.

The authors of the update did not suggest a minimum procedure time because of insufficient data, but they noted that the European Society for Gastrointestinal Endoscopy and United European Gastroenterology recommend a minimum of 7 minutes for upper endoscopy and a minimum of 1 minute per centimeter of the circumferential extent of the Barrett’s mucosa.

The update advises use of the Seattle biopsy protocol for sample during screening and surveillance exams. This includes four-quadrant biopsies taken every 1-2 cm, as well as biopsies from visible lesions. This protocol, however, is not followed in up to 20% of procedures, according to one study. Conceding that fact, the authors also suggest the use of wide area transepithelial sampling (WATS-3D) as a supplementary technique for BE segment sampling.

The Seattle biopsy protocol is associated with a higher dysplasia detection rate (RR, 2.75). This criterion can still be met even if an endoscopist chooses to send a patient for endoscopic resection rather than sample a visible lesion.
 

A new clinical practice update from the American Gastroenterological Association focuses on new technology for the diagnosis of Barrett’s esophagus (BE). It also suggests that patients with no symptoms of chronic reflux can be considered for screening, which could significantly increase the number of people eligible for screening.

Current AGA guidelines support endoscopic screening for BE followed by surveillance for the early detection of BE, dysplasia, and neoplasia. However, fewer than 20% of patients eventually diagnosed with esophageal adenocarcinoma (EAC) were previously diagnosed with BE, suggesting that many opportunities for early detection are missed.

The clinical practice update, published online in Clinical Gastroenterology and Hepatology, represents an effort to highlight advances in screening and surveillance with the goal of improving uptake. The main thrust of the document is risk factors other than gastroesophageal reflux disease (GERD) when considering candidates for screening.

In practice, physicians are already starting to employ other risk factors to select patients for screening, according to coauthor Srinadh Komanduri, MD, who is a professor of medicine and surgery at Northwestern University, Chicago. Specifically, the update suggests screening for individuals with at least three established risk factors for EAC and BE. Risk factors include male sex, non-Hispanic White race, age over 50 years, history of smoking, chronic GERD, obesity, or a family history of BE or EAC.

Another purpose of the update is to highlight noninvasive screening tools, especially nonendoscopic cell collection devices. The authors stress that upper endoscopy with biopsies remains the preferred method for BE diagnosis, but methods that are simple, patient-friendly, and cost-effective have the potential to increase the screened population. One option is transnasal endoscopy, which can be performed in the office with no sedation, but this is expensive and requires expertise.

Recently developed nonendoscopic cell collection devices include Cytosponge (Medtronic GI Solutions), EsoCheck (Lucid Diagnostics), and EsophaCap (Capnostics). All are safe and well-tolerated, and they have good sensitivity for BE. The Cytosponge consists of a swallowable piece of polyurethane foam fitted into a capsule that is attached to suture. The capsule dissolves and the foam expands, collecting cells, and is then withdrawn. It has undergone extensive testing in BE screening in the United Kingdom and was found to have a sensitivity of 80% and specificity of 92.2%. A primary care study showed a 10-fold increase in BE detection compared with usual care.

The EsophaCap works similarly to the Cytosponge but with a smaller diameter. It has 93% sensitivity and 93% specificity for intestinal metaplasia when combined with a panel of five methylated DNA biomarkers.

The EsoCheck device consists of a balloon attached to a catheter, which is inflated and withdrawn. Ridges on the balloon surface capture cells for analysis. A pilot study using two biomarkers found a 90.3% sensitivity and 91.7% specificity.

The update also advises use of high-definition white light endoscopy (HD-WLE) and virtual chromoendoscopy (VC) for screening and surveillance. An updated meta-analysis showed the two methods combined led to a higher detection rate of high grade dysplasia/EAC than HD-WLE alone (14.7% versus 10.1%; relative risk, 1.44). VC and traditional chromoendoscopy have similar dysplasia detection rates, but the former is recommended since it is readily available, requires no extra costs, and avoids issues that can affect dye-based chromoendoscopy. VC from any manufacturer is acceptable, but most data supporting its utility focuses on narrow-band imaging only.

The authors of the update did not suggest a minimum procedure time because of insufficient data, but they noted that the European Society for Gastrointestinal Endoscopy and United European Gastroenterology recommend a minimum of 7 minutes for upper endoscopy and a minimum of 1 minute per centimeter of the circumferential extent of the Barrett’s mucosa.

The update advises use of the Seattle biopsy protocol for sample during screening and surveillance exams. This includes four-quadrant biopsies taken every 1-2 cm, as well as biopsies from visible lesions. This protocol, however, is not followed in up to 20% of procedures, according to one study. Conceding that fact, the authors also suggest the use of wide area transepithelial sampling (WATS-3D) as a supplementary technique for BE segment sampling.

The Seattle biopsy protocol is associated with a higher dysplasia detection rate (RR, 2.75). This criterion can still be met even if an endoscopist chooses to send a patient for endoscopic resection rather than sample a visible lesion.
 

A new clinical practice update from the American Gastroenterological Association focuses on new technology for the diagnosis of Barrett’s esophagus (BE). It also suggests that patients with no symptoms of chronic reflux can be considered for screening, which could significantly increase the number of people eligible for screening.

Current AGA guidelines support endoscopic screening for BE followed by surveillance for the early detection of BE, dysplasia, and neoplasia. However, fewer than 20% of patients eventually diagnosed with esophageal adenocarcinoma (EAC) were previously diagnosed with BE, suggesting that many opportunities for early detection are missed.

The clinical practice update, published online in Clinical Gastroenterology and Hepatology, represents an effort to highlight advances in screening and surveillance with the goal of improving uptake. The main thrust of the document is risk factors other than gastroesophageal reflux disease (GERD) when considering candidates for screening.

In practice, physicians are already starting to employ other risk factors to select patients for screening, according to coauthor Srinadh Komanduri, MD, who is a professor of medicine and surgery at Northwestern University, Chicago. Specifically, the update suggests screening for individuals with at least three established risk factors for EAC and BE. Risk factors include male sex, non-Hispanic White race, age over 50 years, history of smoking, chronic GERD, obesity, or a family history of BE or EAC.

Another purpose of the update is to highlight noninvasive screening tools, especially nonendoscopic cell collection devices. The authors stress that upper endoscopy with biopsies remains the preferred method for BE diagnosis, but methods that are simple, patient-friendly, and cost-effective have the potential to increase the screened population. One option is transnasal endoscopy, which can be performed in the office with no sedation, but this is expensive and requires expertise.

Recently developed nonendoscopic cell collection devices include Cytosponge (Medtronic GI Solutions), EsoCheck (Lucid Diagnostics), and EsophaCap (Capnostics). All are safe and well-tolerated, and they have good sensitivity for BE. The Cytosponge consists of a swallowable piece of polyurethane foam fitted into a capsule that is attached to suture. The capsule dissolves and the foam expands, collecting cells, and is then withdrawn. It has undergone extensive testing in BE screening in the United Kingdom and was found to have a sensitivity of 80% and specificity of 92.2%. A primary care study showed a 10-fold increase in BE detection compared with usual care.

The EsophaCap works similarly to the Cytosponge but with a smaller diameter. It has 93% sensitivity and 93% specificity for intestinal metaplasia when combined with a panel of five methylated DNA biomarkers.

The EsoCheck device consists of a balloon attached to a catheter, which is inflated and withdrawn. Ridges on the balloon surface capture cells for analysis. A pilot study using two biomarkers found a 90.3% sensitivity and 91.7% specificity.

The update also advises use of high-definition white light endoscopy (HD-WLE) and virtual chromoendoscopy (VC) for screening and surveillance. An updated meta-analysis showed the two methods combined led to a higher detection rate of high grade dysplasia/EAC than HD-WLE alone (14.7% versus 10.1%; relative risk, 1.44). VC and traditional chromoendoscopy have similar dysplasia detection rates, but the former is recommended since it is readily available, requires no extra costs, and avoids issues that can affect dye-based chromoendoscopy. VC from any manufacturer is acceptable, but most data supporting its utility focuses on narrow-band imaging only.

The authors of the update did not suggest a minimum procedure time because of insufficient data, but they noted that the European Society for Gastrointestinal Endoscopy and United European Gastroenterology recommend a minimum of 7 minutes for upper endoscopy and a minimum of 1 minute per centimeter of the circumferential extent of the Barrett’s mucosa.

The update advises use of the Seattle biopsy protocol for sample during screening and surveillance exams. This includes four-quadrant biopsies taken every 1-2 cm, as well as biopsies from visible lesions. This protocol, however, is not followed in up to 20% of procedures, according to one study. Conceding that fact, the authors also suggest the use of wide area transepithelial sampling (WATS-3D) as a supplementary technique for BE segment sampling.

The Seattle biopsy protocol is associated with a higher dysplasia detection rate (RR, 2.75). This criterion can still be met even if an endoscopist chooses to send a patient for endoscopic resection rather than sample a visible lesion.
 

In a phase 2 clinical trial of the soluble lymphocyte-activation gene 3 (LAG-3) as a potential treatment for non–small cell lung cancer (NSCLC), the drug performed well across all levels of PD-L1 expression.

“We observed a very encouraging response rate. Responses were seen across PD-L1 status,” said Wade Iams, MD, at a press conference held in advance of the annual meeting of the Society for Immunotherapy of Cancer. Dr. Iams is a professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn.

“The study was not loaded to PD-L1–high patients. We had a good breakdown across all of our three typical groups in the [NSCLC] treatment setting. Across histology types between squamous and nonsquamous, the median duration of response was almost 22 months. This is very encouraging compared to historical controls,” he said.

Eftilagimod alpha is a soluble form of the LAG-3 protein, which is a stimulator of antigen-presenting cells and CD8+ T cells through its action on MHC class 2 molecules. It suppresses the activation of T cells and therefore has the potential to boost the effect of anti–PD-1 therapy. LAG-3 can have both stimulatory and inhibitor immune effects, leading Immutep, which sponsored the study with Merck Sharp and Dohme, to pursue it in both cancer immunotherapy and autoimmune diseases.

The drug is a departure from other drugs which are LAG-3 antagonists. Those therapies interfere with the interaction between LAG-3 on the surface of activated T cells and MHC class 2 molecules on the surface of resting dendritic cells, which would otherwise dampen immune response in the tumor microenvironment. On the other hand, LAG-3 (or eftilagimod alpha) interacts with MHC class 2 on the surface of activated dendritic cells and monocytes to stimulate production of cytotoxic CD8+ T cells. These in turn can be unleashed further by the downstream action of pembrolizumab.

The phase 2 trial included three parts: In part A, 114 patients with NSCLC received the combination of eftilagimod alpha and pembrolizumab being given as a first-line therapy. Part B looked at the combination in 36 patents who were resistant to PD-1/PD-L1 therapies. Part C included 39 patients with head and neck squamous cell carcinoma who had previously received platinum-based chemotherapy. Patients received combination therapy for up to 1 year, then monotherapy with pembrolizumab for up to another year.

The primary endpoint of the study was a comparison of overall response rate to historical controls, with success set at 35% or higher. In the intent-to-treat analysis of the treatment-naive NSCLC population, ORR was 39.5% (95% confidence interval, 30.5%-49.1%) and the interim median progression-free survival was 6.9 months (95% CI, 4.9-9.3 months). Among 40 responders, the median duration of response was 21.6 months (95% CI, 17.3-30.0 months). ORRs were similar between squamous and nonsquamous subtypes.

In his presentation of the results, Dr. Iams said that 75% of participants had PD-L1 levels below 50%. The ORR was highest at 55% in the PD-L1 greater than 50% group, 44.7% in the PD-L1 1%-49% group, and 31.1% in the PD-L1 less than 1% group. It was a “very impressive response rate” for the low PD-L1 group, Dr. Iams said. Interim median progression-free survival followed a similar trend, with values of 11.4 months, 8.3 months, and 4.2 months, respectively.

Asked about the efficacy across subgroups, Dr. Iams responded that other immune stimulating agents have shown a stepwise improvement across PD-L1 expression levels, similar to what was observed in the current study. “My personal opinion as to why it was still effective at low PD-L1 is in part that PD-L1 is an imperfect biomarker. We know that there’s tumor heterogeneity, and perhaps it’s not fully representative of a one-site evaluation, but also in combination, and we have seen this in patients with [NSCLC] treated with both PD-L1 and CTLA-4 agents of increased efficacy in the PD-L1–low patients. So these combination immunotherapy strategies may be uniquely opportune for the low PD-L1 patients,” Dr. Iams said.

The study was funded by Immutep and Merck Sharp and Dohme. Dr. Iams has financial relationships with Merck.

In a phase 2 clinical trial of the soluble lymphocyte-activation gene 3 (LAG-3) as a potential treatment for non–small cell lung cancer (NSCLC), the drug performed well across all levels of PD-L1 expression.

“We observed a very encouraging response rate. Responses were seen across PD-L1 status,” said Wade Iams, MD, at a press conference held in advance of the annual meeting of the Society for Immunotherapy of Cancer. Dr. Iams is a professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn.

“The study was not loaded to PD-L1–high patients. We had a good breakdown across all of our three typical groups in the [NSCLC] treatment setting. Across histology types between squamous and nonsquamous, the median duration of response was almost 22 months. This is very encouraging compared to historical controls,” he said.

Eftilagimod alpha is a soluble form of the LAG-3 protein, which is a stimulator of antigen-presenting cells and CD8+ T cells through its action on MHC class 2 molecules. It suppresses the activation of T cells and therefore has the potential to boost the effect of anti–PD-1 therapy. LAG-3 can have both stimulatory and inhibitor immune effects, leading Immutep, which sponsored the study with Merck Sharp and Dohme, to pursue it in both cancer immunotherapy and autoimmune diseases.

The drug is a departure from other drugs which are LAG-3 antagonists. Those therapies interfere with the interaction between LAG-3 on the surface of activated T cells and MHC class 2 molecules on the surface of resting dendritic cells, which would otherwise dampen immune response in the tumor microenvironment. On the other hand, LAG-3 (or eftilagimod alpha) interacts with MHC class 2 on the surface of activated dendritic cells and monocytes to stimulate production of cytotoxic CD8+ T cells. These in turn can be unleashed further by the downstream action of pembrolizumab.

The phase 2 trial included three parts: In part A, 114 patients with NSCLC received the combination of eftilagimod alpha and pembrolizumab being given as a first-line therapy. Part B looked at the combination in 36 patents who were resistant to PD-1/PD-L1 therapies. Part C included 39 patients with head and neck squamous cell carcinoma who had previously received platinum-based chemotherapy. Patients received combination therapy for up to 1 year, then monotherapy with pembrolizumab for up to another year.

The primary endpoint of the study was a comparison of overall response rate to historical controls, with success set at 35% or higher. In the intent-to-treat analysis of the treatment-naive NSCLC population, ORR was 39.5% (95% confidence interval, 30.5%-49.1%) and the interim median progression-free survival was 6.9 months (95% CI, 4.9-9.3 months). Among 40 responders, the median duration of response was 21.6 months (95% CI, 17.3-30.0 months). ORRs were similar between squamous and nonsquamous subtypes.

In his presentation of the results, Dr. Iams said that 75% of participants had PD-L1 levels below 50%. The ORR was highest at 55% in the PD-L1 greater than 50% group, 44.7% in the PD-L1 1%-49% group, and 31.1% in the PD-L1 less than 1% group. It was a “very impressive response rate” for the low PD-L1 group, Dr. Iams said. Interim median progression-free survival followed a similar trend, with values of 11.4 months, 8.3 months, and 4.2 months, respectively.

Asked about the efficacy across subgroups, Dr. Iams responded that other immune stimulating agents have shown a stepwise improvement across PD-L1 expression levels, similar to what was observed in the current study. “My personal opinion as to why it was still effective at low PD-L1 is in part that PD-L1 is an imperfect biomarker. We know that there’s tumor heterogeneity, and perhaps it’s not fully representative of a one-site evaluation, but also in combination, and we have seen this in patients with [NSCLC] treated with both PD-L1 and CTLA-4 agents of increased efficacy in the PD-L1–low patients. So these combination immunotherapy strategies may be uniquely opportune for the low PD-L1 patients,” Dr. Iams said.

The study was funded by Immutep and Merck Sharp and Dohme. Dr. Iams has financial relationships with Merck.

In a phase 2 clinical trial of the soluble lymphocyte-activation gene 3 (LAG-3) as a potential treatment for non–small cell lung cancer (NSCLC), the drug performed well across all levels of PD-L1 expression.

“We observed a very encouraging response rate. Responses were seen across PD-L1 status,” said Wade Iams, MD, at a press conference held in advance of the annual meeting of the Society for Immunotherapy of Cancer. Dr. Iams is a professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn.

“The study was not loaded to PD-L1–high patients. We had a good breakdown across all of our three typical groups in the [NSCLC] treatment setting. Across histology types between squamous and nonsquamous, the median duration of response was almost 22 months. This is very encouraging compared to historical controls,” he said.

Eftilagimod alpha is a soluble form of the LAG-3 protein, which is a stimulator of antigen-presenting cells and CD8+ T cells through its action on MHC class 2 molecules. It suppresses the activation of T cells and therefore has the potential to boost the effect of anti–PD-1 therapy. LAG-3 can have both stimulatory and inhibitor immune effects, leading Immutep, which sponsored the study with Merck Sharp and Dohme, to pursue it in both cancer immunotherapy and autoimmune diseases.

The drug is a departure from other drugs which are LAG-3 antagonists. Those therapies interfere with the interaction between LAG-3 on the surface of activated T cells and MHC class 2 molecules on the surface of resting dendritic cells, which would otherwise dampen immune response in the tumor microenvironment. On the other hand, LAG-3 (or eftilagimod alpha) interacts with MHC class 2 on the surface of activated dendritic cells and monocytes to stimulate production of cytotoxic CD8+ T cells. These in turn can be unleashed further by the downstream action of pembrolizumab.

The phase 2 trial included three parts: In part A, 114 patients with NSCLC received the combination of eftilagimod alpha and pembrolizumab being given as a first-line therapy. Part B looked at the combination in 36 patents who were resistant to PD-1/PD-L1 therapies. Part C included 39 patients with head and neck squamous cell carcinoma who had previously received platinum-based chemotherapy. Patients received combination therapy for up to 1 year, then monotherapy with pembrolizumab for up to another year.

The primary endpoint of the study was a comparison of overall response rate to historical controls, with success set at 35% or higher. In the intent-to-treat analysis of the treatment-naive NSCLC population, ORR was 39.5% (95% confidence interval, 30.5%-49.1%) and the interim median progression-free survival was 6.9 months (95% CI, 4.9-9.3 months). Among 40 responders, the median duration of response was 21.6 months (95% CI, 17.3-30.0 months). ORRs were similar between squamous and nonsquamous subtypes.

In his presentation of the results, Dr. Iams said that 75% of participants had PD-L1 levels below 50%. The ORR was highest at 55% in the PD-L1 greater than 50% group, 44.7% in the PD-L1 1%-49% group, and 31.1% in the PD-L1 less than 1% group. It was a “very impressive response rate” for the low PD-L1 group, Dr. Iams said. Interim median progression-free survival followed a similar trend, with values of 11.4 months, 8.3 months, and 4.2 months, respectively.

Asked about the efficacy across subgroups, Dr. Iams responded that other immune stimulating agents have shown a stepwise improvement across PD-L1 expression levels, similar to what was observed in the current study. “My personal opinion as to why it was still effective at low PD-L1 is in part that PD-L1 is an imperfect biomarker. We know that there’s tumor heterogeneity, and perhaps it’s not fully representative of a one-site evaluation, but also in combination, and we have seen this in patients with [NSCLC] treated with both PD-L1 and CTLA-4 agents of increased efficacy in the PD-L1–low patients. So these combination immunotherapy strategies may be uniquely opportune for the low PD-L1 patients,” Dr. Iams said.

The study was funded by Immutep and Merck Sharp and Dohme. Dr. Iams has financial relationships with Merck.

A systematic review of immune checkpoint inhibitor (ICI) combinations for advanced renal cancer finds that treatment with ICIs has a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib. The combination treatment should be made readily available worldwide to patients with advanced renal cell carcinoma (RCC), the authors said.

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials have examined ICIs in combination with VEGF-directed therapies.

In a review published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and 1 each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared to sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate poor-risk patients compared to sunitinib, but the combination led to more frequent discontinuation due to toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation due to toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation due to toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggest that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual ICI combination therapy were similar to those seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors noted that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, International Metastatic RCC Database Consortium (IMDC) risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

A systematic review of immune checkpoint inhibitor (ICI) combinations for advanced renal cancer finds that treatment with ICIs has a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib. The combination treatment should be made readily available worldwide to patients with advanced renal cell carcinoma (RCC), the authors said.

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials have examined ICIs in combination with VEGF-directed therapies.

In a review published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and 1 each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared to sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate poor-risk patients compared to sunitinib, but the combination led to more frequent discontinuation due to toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation due to toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation due to toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggest that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual ICI combination therapy were similar to those seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors noted that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, International Metastatic RCC Database Consortium (IMDC) risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

A systematic review of immune checkpoint inhibitor (ICI) combinations for advanced renal cancer finds that treatment with ICIs has a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib. The combination treatment should be made readily available worldwide to patients with advanced renal cell carcinoma (RCC), the authors said.

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials have examined ICIs in combination with VEGF-directed therapies.

In a review published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and 1 each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared to sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate poor-risk patients compared to sunitinib, but the combination led to more frequent discontinuation due to toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation due to toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation due to toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggest that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual ICI combination therapy were similar to those seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors noted that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, International Metastatic RCC Database Consortium (IMDC) risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

Artificial intelligence (AI) is impacting many aspects of health care, and radiation oncology is no exception. It has the potential to cut costs and streamline work flows ranging from image analysis to treatment plan formulation, but its specific place in clinical practice is still being debated.

In a session at the annual meeting of the American Society for Radiation Oncology, researchers discussed some of the ways that AI is or will soon be relevant to the clinic. The general consensus was that AI provides a useful supplement but is no threat to replace the role of radiation oncologists.

In his talk, Sanjay Aneja, MD focused on practical applications of AI that are in the clinic or close to being ready. One example is image classification. “There has been recent evidence that suggests in a variety of different kind of scenarios, deep-learning models can be very good at image classification in automated ways,” said Dr. Aneja, who is a professor of radiology at Yale University, New Haven, Conn. He described one study that used AI to classify 14 different pathologies on chest x-ray images.

Dr. Aneja described the open-source nnU-net tool, which automatically configures itself and segments biomedical images for research or clinical purposes, including therapy planning support, intraoperative support, and tumor growth monitoring. The researchers who developed it also created a “recipe” to systematize configuration of nnU-net, making it useful as an out-of-the-box tool for image segmentation.

He predicted that AI will improve radiology oncology by assisting in the determination of disease extent, including microscopic areas of disease. It could also help plan treatment volume and monitor treatment response. “I think that these are the types of things that will be moving toward the clinic in the future; very specific applications and models trained on very specific scenarios that will help us answer a very important clinical question,” Dr. Aneja said.

He expects AI to contribute to auto-segmenting and clinical contouring, “but I will caution everyone that these algorithms have not been proven to be better than physician contours. They very frequently fail in the specific use cases when anatomy is distorted by, I don’t know, say a tumor. And so a lot of times, we don’t actually have the ability to just make it an automated process. I think it’ll be something that physicians will use to help them but not necessarily replace their contouring ability,” Dr. Aneja said.

Another, potentially more useful application, is in adaptive radiation planning. “I think that AI auto-contouring will be very helpful in establishing contours in a situation in which a physician doing them would not be feasible. We need to have nimble and computationally efficient auto segmentation algorithms that will be able to be easily deployed at the linear accelerator,” he said.
 

AI in pathology and treatment selection

In another talk, Osama Mohamad, MD talked about AI in pathology, and specifically treatment selection. He described research from his group that digitized pathology data from 5,500 patients drawn from five randomized, clinical trials. They used AI on data from four of the clinical trials to identify a prognostic biomarker for distant metastasis, then validated it on data from the remaining clinical trial, which compared radiation versus radiation plus short-term hormone therapy in prostate cancer.

The results suggested that most patients should receive hormone therapy, but the AI suggested a more nuanced answer. “Patients who had AI biomarker negative do not see any benefit from adding 4 months of hormone therapy ... whereas patients who have biomarker positive have significant difference and improvement in distant metastasis at 10 years and 15 years. This means that we can save a significant proportion of patients from getting [androgen deprivation therapy], which is hormonal therapy and has very well-known side effects, because they simply they will not benefit,” said Dr. Mohamad, who is an assistant professor of radiation oncology at University of California, San Francisco.

That study relied on the ArteraAI prostate cancer test, which is available through a Clinical Laboratory Improvement Amendment–certified laboratory in Florida.

Another example of AI used to plan treatment is On-line Real-time Benchmarking Informatics Technology for Radiotherapy (ORBIT-RT), developed at the University of California, San Diego. It focuses on radiotherapy treatment plan quality control, and has two main components: creating clinically validated plan routines and a free radiotherapy plan quality control system.

No matter how impressive the technical advances may be, AI contributions won’t impact clinical practice if radiation oncologists, physicians, and patients don’t accept AI. Dr. Aneja’s group surveyed patients about which health field they would feel more comfortable with AI having an important role. Most said they were extremely uncomfortable when it came to cancer. “Now, does that mean that we can’t use AI in oncology? No, I think it just means that we have to be a little bit more nuanced in our approach and how we develop AI solutions for cancer patients,” Dr. Aneja said.

Physicians also show reluctance, according to Alejandro Berlin, MD, who is an affiliate scientist at Princess Margaret Cancer Centre in Toronto. He discussed some research looking at physician acceptance of machine learning. His group looked at physician acceptance of treatment plans for prostate cancer that were generated by physicians and in parallel by machine learning. In a theoretical phase, physicians generally agreed that the machine learning plans were better, but when it came to a phase of the study in which physicians chose which plan to implement in a real patient, the acceptance of machine learning-generated plans dropped by 20%.

This tendency to trust humans over machines is what Dr. Berlin called “automation bias,” and he called for a more collaborative approach to implement AI. “In some cases, [machine learning] is going to be good and sufficient. And in some cases, you will need the expertise of a human.”

Dr. Aneja, who also moderated the session, expressed a similar sentiment when summing up the day’s talks: “I do feel like it’s a disruptive technology ... but I think there will still be a need for us to have people who are trained in order to evaluate and make sure that these algorithms are working correctly and efficiently.”

Dr. Aneja, Dr. Mohamad, and Dr. Berlin have no relevant financial disclosures.

* This article was updated on Nov. 15, 2022.

Artificial intelligence (AI) is impacting many aspects of health care, and radiation oncology is no exception. It has the potential to cut costs and streamline work flows ranging from image analysis to treatment plan formulation, but its specific place in clinical practice is still being debated.

In a session at the annual meeting of the American Society for Radiation Oncology, researchers discussed some of the ways that AI is or will soon be relevant to the clinic. The general consensus was that AI provides a useful supplement but is no threat to replace the role of radiation oncologists.

In his talk, Sanjay Aneja, MD focused on practical applications of AI that are in the clinic or close to being ready. One example is image classification. “There has been recent evidence that suggests in a variety of different kind of scenarios, deep-learning models can be very good at image classification in automated ways,” said Dr. Aneja, who is a professor of radiology at Yale University, New Haven, Conn. He described one study that used AI to classify 14 different pathologies on chest x-ray images.

Dr. Aneja described the open-source nnU-net tool, which automatically configures itself and segments biomedical images for research or clinical purposes, including therapy planning support, intraoperative support, and tumor growth monitoring. The researchers who developed it also created a “recipe” to systematize configuration of nnU-net, making it useful as an out-of-the-box tool for image segmentation.

He predicted that AI will improve radiology oncology by assisting in the determination of disease extent, including microscopic areas of disease. It could also help plan treatment volume and monitor treatment response. “I think that these are the types of things that will be moving toward the clinic in the future; very specific applications and models trained on very specific scenarios that will help us answer a very important clinical question,” Dr. Aneja said.

He expects AI to contribute to auto-segmenting and clinical contouring, “but I will caution everyone that these algorithms have not been proven to be better than physician contours. They very frequently fail in the specific use cases when anatomy is distorted by, I don’t know, say a tumor. And so a lot of times, we don’t actually have the ability to just make it an automated process. I think it’ll be something that physicians will use to help them but not necessarily replace their contouring ability,” Dr. Aneja said.

Another, potentially more useful application, is in adaptive radiation planning. “I think that AI auto-contouring will be very helpful in establishing contours in a situation in which a physician doing them would not be feasible. We need to have nimble and computationally efficient auto segmentation algorithms that will be able to be easily deployed at the linear accelerator,” he said.
 

AI in pathology and treatment selection

In another talk, Osama Mohamad, MD talked about AI in pathology, and specifically treatment selection. He described research from his group that digitized pathology data from 5,500 patients drawn from five randomized, clinical trials. They used AI on data from four of the clinical trials to identify a prognostic biomarker for distant metastasis, then validated it on data from the remaining clinical trial, which compared radiation versus radiation plus short-term hormone therapy in prostate cancer.

The results suggested that most patients should receive hormone therapy, but the AI suggested a more nuanced answer. “Patients who had AI biomarker negative do not see any benefit from adding 4 months of hormone therapy ... whereas patients who have biomarker positive have significant difference and improvement in distant metastasis at 10 years and 15 years. This means that we can save a significant proportion of patients from getting [androgen deprivation therapy], which is hormonal therapy and has very well-known side effects, because they simply they will not benefit,” said Dr. Mohamad, who is an assistant professor of radiation oncology at University of California, San Francisco.

That study relied on the ArteraAI prostate cancer test, which is available through a Clinical Laboratory Improvement Amendment–certified laboratory in Florida.

Another example of AI used to plan treatment is On-line Real-time Benchmarking Informatics Technology for Radiotherapy (ORBIT-RT), developed at the University of California, San Diego. It focuses on radiotherapy treatment plan quality control, and has two main components: creating clinically validated plan routines and a free radiotherapy plan quality control system.

No matter how impressive the technical advances may be, AI contributions won’t impact clinical practice if radiation oncologists, physicians, and patients don’t accept AI. Dr. Aneja’s group surveyed patients about which health field they would feel more comfortable with AI having an important role. Most said they were extremely uncomfortable when it came to cancer. “Now, does that mean that we can’t use AI in oncology? No, I think it just means that we have to be a little bit more nuanced in our approach and how we develop AI solutions for cancer patients,” Dr. Aneja said.

Physicians also show reluctance, according to Alejandro Berlin, MD, who is an affiliate scientist at Princess Margaret Cancer Centre in Toronto. He discussed some research looking at physician acceptance of machine learning. His group looked at physician acceptance of treatment plans for prostate cancer that were generated by physicians and in parallel by machine learning. In a theoretical phase, physicians generally agreed that the machine learning plans were better, but when it came to a phase of the study in which physicians chose which plan to implement in a real patient, the acceptance of machine learning-generated plans dropped by 20%.

This tendency to trust humans over machines is what Dr. Berlin called “automation bias,” and he called for a more collaborative approach to implement AI. “In some cases, [machine learning] is going to be good and sufficient. And in some cases, you will need the expertise of a human.”

Dr. Aneja, who also moderated the session, expressed a similar sentiment when summing up the day’s talks: “I do feel like it’s a disruptive technology ... but I think there will still be a need for us to have people who are trained in order to evaluate and make sure that these algorithms are working correctly and efficiently.”

Dr. Aneja, Dr. Mohamad, and Dr. Berlin have no relevant financial disclosures.

* This article was updated on Nov. 15, 2022.

Artificial intelligence (AI) is impacting many aspects of health care, and radiation oncology is no exception. It has the potential to cut costs and streamline work flows ranging from image analysis to treatment plan formulation, but its specific place in clinical practice is still being debated.

In a session at the annual meeting of the American Society for Radiation Oncology, researchers discussed some of the ways that AI is or will soon be relevant to the clinic. The general consensus was that AI provides a useful supplement but is no threat to replace the role of radiation oncologists.

In his talk, Sanjay Aneja, MD focused on practical applications of AI that are in the clinic or close to being ready. One example is image classification. “There has been recent evidence that suggests in a variety of different kind of scenarios, deep-learning models can be very good at image classification in automated ways,” said Dr. Aneja, who is a professor of radiology at Yale University, New Haven, Conn. He described one study that used AI to classify 14 different pathologies on chest x-ray images.

Dr. Aneja described the open-source nnU-net tool, which automatically configures itself and segments biomedical images for research or clinical purposes, including therapy planning support, intraoperative support, and tumor growth monitoring. The researchers who developed it also created a “recipe” to systematize configuration of nnU-net, making it useful as an out-of-the-box tool for image segmentation.

He predicted that AI will improve radiology oncology by assisting in the determination of disease extent, including microscopic areas of disease. It could also help plan treatment volume and monitor treatment response. “I think that these are the types of things that will be moving toward the clinic in the future; very specific applications and models trained on very specific scenarios that will help us answer a very important clinical question,” Dr. Aneja said.

He expects AI to contribute to auto-segmenting and clinical contouring, “but I will caution everyone that these algorithms have not been proven to be better than physician contours. They very frequently fail in the specific use cases when anatomy is distorted by, I don’t know, say a tumor. And so a lot of times, we don’t actually have the ability to just make it an automated process. I think it’ll be something that physicians will use to help them but not necessarily replace their contouring ability,” Dr. Aneja said.

Another, potentially more useful application, is in adaptive radiation planning. “I think that AI auto-contouring will be very helpful in establishing contours in a situation in which a physician doing them would not be feasible. We need to have nimble and computationally efficient auto segmentation algorithms that will be able to be easily deployed at the linear accelerator,” he said.
 

AI in pathology and treatment selection

In another talk, Osama Mohamad, MD talked about AI in pathology, and specifically treatment selection. He described research from his group that digitized pathology data from 5,500 patients drawn from five randomized, clinical trials. They used AI on data from four of the clinical trials to identify a prognostic biomarker for distant metastasis, then validated it on data from the remaining clinical trial, which compared radiation versus radiation plus short-term hormone therapy in prostate cancer.

The results suggested that most patients should receive hormone therapy, but the AI suggested a more nuanced answer. “Patients who had AI biomarker negative do not see any benefit from adding 4 months of hormone therapy ... whereas patients who have biomarker positive have significant difference and improvement in distant metastasis at 10 years and 15 years. This means that we can save a significant proportion of patients from getting [androgen deprivation therapy], which is hormonal therapy and has very well-known side effects, because they simply they will not benefit,” said Dr. Mohamad, who is an assistant professor of radiation oncology at University of California, San Francisco.

That study relied on the ArteraAI prostate cancer test, which is available through a Clinical Laboratory Improvement Amendment–certified laboratory in Florida.

Another example of AI used to plan treatment is On-line Real-time Benchmarking Informatics Technology for Radiotherapy (ORBIT-RT), developed at the University of California, San Diego. It focuses on radiotherapy treatment plan quality control, and has two main components: creating clinically validated plan routines and a free radiotherapy plan quality control system.

No matter how impressive the technical advances may be, AI contributions won’t impact clinical practice if radiation oncologists, physicians, and patients don’t accept AI. Dr. Aneja’s group surveyed patients about which health field they would feel more comfortable with AI having an important role. Most said they were extremely uncomfortable when it came to cancer. “Now, does that mean that we can’t use AI in oncology? No, I think it just means that we have to be a little bit more nuanced in our approach and how we develop AI solutions for cancer patients,” Dr. Aneja said.

Physicians also show reluctance, according to Alejandro Berlin, MD, who is an affiliate scientist at Princess Margaret Cancer Centre in Toronto. He discussed some research looking at physician acceptance of machine learning. His group looked at physician acceptance of treatment plans for prostate cancer that were generated by physicians and in parallel by machine learning. In a theoretical phase, physicians generally agreed that the machine learning plans were better, but when it came to a phase of the study in which physicians chose which plan to implement in a real patient, the acceptance of machine learning-generated plans dropped by 20%.

This tendency to trust humans over machines is what Dr. Berlin called “automation bias,” and he called for a more collaborative approach to implement AI. “In some cases, [machine learning] is going to be good and sufficient. And in some cases, you will need the expertise of a human.”

Dr. Aneja, who also moderated the session, expressed a similar sentiment when summing up the day’s talks: “I do feel like it’s a disruptive technology ... but I think there will still be a need for us to have people who are trained in order to evaluate and make sure that these algorithms are working correctly and efficiently.”

Dr. Aneja, Dr. Mohamad, and Dr. Berlin have no relevant financial disclosures.

* This article was updated on Nov. 15, 2022.

The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.

It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.

Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.

To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.

Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”

In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.

In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.

After adjustment, the researchers found that a high allostatic load was linked to a 14% increased risk of cancer death overall (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.

Dr. Moore has no relevant financial disclosures.

The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.

It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.

Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.

To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.

Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”

In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.

In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.

After adjustment, the researchers found that a high allostatic load was linked to a 14% increased risk of cancer death overall (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.

Dr. Moore has no relevant financial disclosures.

The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.

It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.

Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.

To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.

Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”

In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.

In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.

After adjustment, the researchers found that a high allostatic load was linked to a 14% increased risk of cancer death overall (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.

Dr. Moore has no relevant financial disclosures.

A third dose of coronavirus booster vaccine is effective in reducing death and hospitalization among people with cancer, though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.

People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.

The research was published in the November issue of the European Journal of Cancer.

Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.

Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.

The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.

“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.

Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.

The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.

The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).

Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).

Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).

Dr. Lee has no relevant financial disclosures.

A third dose of coronavirus booster vaccine is effective in reducing death and hospitalization among people with cancer, though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.

People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.

The research was published in the November issue of the European Journal of Cancer.

Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.

Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.

The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.

“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.

Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.

The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.

The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).

Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).

Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).

Dr. Lee has no relevant financial disclosures.

A third dose of coronavirus booster vaccine is effective in reducing death and hospitalization among people with cancer, though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.

People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.

The research was published in the November issue of the European Journal of Cancer.

Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.

Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.

The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.

“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.

Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.

The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.

The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).

Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).

Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).

Dr. Lee has no relevant financial disclosures.

In two retrospective studies that drew from the international MSBase registry, autologous hematopoietic stem cell therapy (AHSCT) did not outperform a disease-modifying therapy (DMT) in patients with multiple sclerosis. One study looked at progressive MS and found no evidence of superiority. Another study in relapsing-remitting MS showed a reduction in relapses compared with treatment with the immune reconstitution therapies alemtuzumab and cladribine, though the results were not definitive.

Scant evidence supporting AHSCT for progressive MS

Some previous, small retrospective studies had suggested that AHSCT could benefit progressive MS. For example, a study published in Neurology looked at outcomes following AHSCT in 210 patients with MS and found a disability worsening–free survival of 85.5% at 5 years in relapsing-remitting MS and 71.0% in progressive MS. However, such studies are prone to bias, according to Bruce Cree, MD, PhD, who was asked to comment on the progressive MS study. Both studies were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

AHSCT has attracted interest as a treatment for both relapsing-remitting and progressive MS, and some retrospective studies have reported signals of efficacy for both. Despite that, the biology of progressive MS is inconsistent with an expectation of success, said Tomas Kalincik, MD, PhD, who presented the two studies. “AHSCT is primarily a very potent anti-inflammatory therapy. Therefore, it is assumed that where localized, episodic inflammation is not part of the clinical picture, such as nonactive progressive MS forms, AHSCT should not be more effective than standard DMTs. In fact, in these scenarios, the potent DMTs also show at best marginal effect on disability outcomes. Therefore, the lack of evidence for superiority of the effectiveness of AHSCT over natalizumab in progressive MS is not surprising. The clinical implications of our study therefore are that the use of AHSCT in inactive progressive MS cannot be justified based on the presently available data,” said Dr. Kalincik, who is head of neuroimmunology at Royal Melbourne Hospital and head of the Clinical Outcomes Research Unit at the University of Melbourne, in an email exchange.

Dr. Cree agreed. “Right now, based on this very, very large data set that MSBase can afford, there really doesn’t seem to be a basis for this presumption that you’re going to get the therapeutic bang for the buck that you want to see with HSCT,” he said.

Despite the scientific attention that AHSCT has received, Dr. Cree has never been convinced that AHSCT is likely to be broadly useful in MS. “The simple concept is that MS is an autoimmune disease, so if you can reset the immune system, that you would eradicate MS in that individual, and then that individual would be fine thereafter. It’s a bit naive, but nonetheless, it’s an OK concept to begin a series of studies for investigation. I think there’s a potential place for this in relapsing disease, but when it comes to a cure for progressive MS, everything that we understand about this disease is pointing away from a peripheral immune system inflammatory etiology as the driver for what is causing progression, and so we have to, in my opinion, think about other possible etiologies for what might be driving and underlying disability worsening in progressive MS,” said Dr. Cree.
 

Two studies

In the progressive MS study, the researchers conducted a propensity-matched analysis of 39 patients treated with AHSCT and 65 who were treated with natalizumab. There were no significant differences between the two groups in overall annualized relapse rate or annual relapse rate by year. Disability outcomes were also similar, with no differences in worsening or improvement.

In the relapsing-remitting MS study, Dr. Kalincik’s group drew on data from 6 centers as well as the MSBase registry. They compared outcomes following AHSCT with outcomes of patients taking the immune-reconstitution DMTs mitoxantrone, alemtuzumab, and cladribine. The study included matched cohorts of 135 patients treated with AHSCT versus 312 treated with alemtuzumab, 72 treated with AHSCT versus 164 treated with cladribine, and 30 treated with AHSCT versus 100 treated with mitoxantrone. All groups had similar outcomes, with the exception of a greater likelihood of confirmed disability improvement in treatment with AHSCT versus alemtuzumab (hazard ratio, 1.63; P = .02). The cumulative probability of improvement was higher in the AHSCT group both at year 2 (28% versus 19%) and year 4 (30% versus 22%).

“The analysis suggested trends that may favor the effectiveness AHSCT over alemtuzumab, cladribine, and mitoxantrone, but the analysis was not fully powered. More research with larger cohorts is needed,” said Dr. Kalincik.

Dr. Cree has consulted for Biogen. Dr. Kalincik has financial relationships with Merck, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Biogen, Eisai, Teva, BioCSL, and Celgene.
 

In two retrospective studies that drew from the international MSBase registry, autologous hematopoietic stem cell therapy (AHSCT) did not outperform a disease-modifying therapy (DMT) in patients with multiple sclerosis. One study looked at progressive MS and found no evidence of superiority. Another study in relapsing-remitting MS showed a reduction in relapses compared with treatment with the immune reconstitution therapies alemtuzumab and cladribine, though the results were not definitive.

Scant evidence supporting AHSCT for progressive MS

Some previous, small retrospective studies had suggested that AHSCT could benefit progressive MS. For example, a study published in Neurology looked at outcomes following AHSCT in 210 patients with MS and found a disability worsening–free survival of 85.5% at 5 years in relapsing-remitting MS and 71.0% in progressive MS. However, such studies are prone to bias, according to Bruce Cree, MD, PhD, who was asked to comment on the progressive MS study. Both studies were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

AHSCT has attracted interest as a treatment for both relapsing-remitting and progressive MS, and some retrospective studies have reported signals of efficacy for both. Despite that, the biology of progressive MS is inconsistent with an expectation of success, said Tomas Kalincik, MD, PhD, who presented the two studies. “AHSCT is primarily a very potent anti-inflammatory therapy. Therefore, it is assumed that where localized, episodic inflammation is not part of the clinical picture, such as nonactive progressive MS forms, AHSCT should not be more effective than standard DMTs. In fact, in these scenarios, the potent DMTs also show at best marginal effect on disability outcomes. Therefore, the lack of evidence for superiority of the effectiveness of AHSCT over natalizumab in progressive MS is not surprising. The clinical implications of our study therefore are that the use of AHSCT in inactive progressive MS cannot be justified based on the presently available data,” said Dr. Kalincik, who is head of neuroimmunology at Royal Melbourne Hospital and head of the Clinical Outcomes Research Unit at the University of Melbourne, in an email exchange.

Dr. Cree agreed. “Right now, based on this very, very large data set that MSBase can afford, there really doesn’t seem to be a basis for this presumption that you’re going to get the therapeutic bang for the buck that you want to see with HSCT,” he said.

Despite the scientific attention that AHSCT has received, Dr. Cree has never been convinced that AHSCT is likely to be broadly useful in MS. “The simple concept is that MS is an autoimmune disease, so if you can reset the immune system, that you would eradicate MS in that individual, and then that individual would be fine thereafter. It’s a bit naive, but nonetheless, it’s an OK concept to begin a series of studies for investigation. I think there’s a potential place for this in relapsing disease, but when it comes to a cure for progressive MS, everything that we understand about this disease is pointing away from a peripheral immune system inflammatory etiology as the driver for what is causing progression, and so we have to, in my opinion, think about other possible etiologies for what might be driving and underlying disability worsening in progressive MS,” said Dr. Cree.
 

Two studies

In the progressive MS study, the researchers conducted a propensity-matched analysis of 39 patients treated with AHSCT and 65 who were treated with natalizumab. There were no significant differences between the two groups in overall annualized relapse rate or annual relapse rate by year. Disability outcomes were also similar, with no differences in worsening or improvement.

In the relapsing-remitting MS study, Dr. Kalincik’s group drew on data from 6 centers as well as the MSBase registry. They compared outcomes following AHSCT with outcomes of patients taking the immune-reconstitution DMTs mitoxantrone, alemtuzumab, and cladribine. The study included matched cohorts of 135 patients treated with AHSCT versus 312 treated with alemtuzumab, 72 treated with AHSCT versus 164 treated with cladribine, and 30 treated with AHSCT versus 100 treated with mitoxantrone. All groups had similar outcomes, with the exception of a greater likelihood of confirmed disability improvement in treatment with AHSCT versus alemtuzumab (hazard ratio, 1.63; P = .02). The cumulative probability of improvement was higher in the AHSCT group both at year 2 (28% versus 19%) and year 4 (30% versus 22%).

“The analysis suggested trends that may favor the effectiveness AHSCT over alemtuzumab, cladribine, and mitoxantrone, but the analysis was not fully powered. More research with larger cohorts is needed,” said Dr. Kalincik.

Dr. Cree has consulted for Biogen. Dr. Kalincik has financial relationships with Merck, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Biogen, Eisai, Teva, BioCSL, and Celgene.
 

In two retrospective studies that drew from the international MSBase registry, autologous hematopoietic stem cell therapy (AHSCT) did not outperform a disease-modifying therapy (DMT) in patients with multiple sclerosis. One study looked at progressive MS and found no evidence of superiority. Another study in relapsing-remitting MS showed a reduction in relapses compared with treatment with the immune reconstitution therapies alemtuzumab and cladribine, though the results were not definitive.

Scant evidence supporting AHSCT for progressive MS

Some previous, small retrospective studies had suggested that AHSCT could benefit progressive MS. For example, a study published in Neurology looked at outcomes following AHSCT in 210 patients with MS and found a disability worsening–free survival of 85.5% at 5 years in relapsing-remitting MS and 71.0% in progressive MS. However, such studies are prone to bias, according to Bruce Cree, MD, PhD, who was asked to comment on the progressive MS study. Both studies were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

AHSCT has attracted interest as a treatment for both relapsing-remitting and progressive MS, and some retrospective studies have reported signals of efficacy for both. Despite that, the biology of progressive MS is inconsistent with an expectation of success, said Tomas Kalincik, MD, PhD, who presented the two studies. “AHSCT is primarily a very potent anti-inflammatory therapy. Therefore, it is assumed that where localized, episodic inflammation is not part of the clinical picture, such as nonactive progressive MS forms, AHSCT should not be more effective than standard DMTs. In fact, in these scenarios, the potent DMTs also show at best marginal effect on disability outcomes. Therefore, the lack of evidence for superiority of the effectiveness of AHSCT over natalizumab in progressive MS is not surprising. The clinical implications of our study therefore are that the use of AHSCT in inactive progressive MS cannot be justified based on the presently available data,” said Dr. Kalincik, who is head of neuroimmunology at Royal Melbourne Hospital and head of the Clinical Outcomes Research Unit at the University of Melbourne, in an email exchange.

Dr. Cree agreed. “Right now, based on this very, very large data set that MSBase can afford, there really doesn’t seem to be a basis for this presumption that you’re going to get the therapeutic bang for the buck that you want to see with HSCT,” he said.

Despite the scientific attention that AHSCT has received, Dr. Cree has never been convinced that AHSCT is likely to be broadly useful in MS. “The simple concept is that MS is an autoimmune disease, so if you can reset the immune system, that you would eradicate MS in that individual, and then that individual would be fine thereafter. It’s a bit naive, but nonetheless, it’s an OK concept to begin a series of studies for investigation. I think there’s a potential place for this in relapsing disease, but when it comes to a cure for progressive MS, everything that we understand about this disease is pointing away from a peripheral immune system inflammatory etiology as the driver for what is causing progression, and so we have to, in my opinion, think about other possible etiologies for what might be driving and underlying disability worsening in progressive MS,” said Dr. Cree.
 

Two studies

In the progressive MS study, the researchers conducted a propensity-matched analysis of 39 patients treated with AHSCT and 65 who were treated with natalizumab. There were no significant differences between the two groups in overall annualized relapse rate or annual relapse rate by year. Disability outcomes were also similar, with no differences in worsening or improvement.

In the relapsing-remitting MS study, Dr. Kalincik’s group drew on data from 6 centers as well as the MSBase registry. They compared outcomes following AHSCT with outcomes of patients taking the immune-reconstitution DMTs mitoxantrone, alemtuzumab, and cladribine. The study included matched cohorts of 135 patients treated with AHSCT versus 312 treated with alemtuzumab, 72 treated with AHSCT versus 164 treated with cladribine, and 30 treated with AHSCT versus 100 treated with mitoxantrone. All groups had similar outcomes, with the exception of a greater likelihood of confirmed disability improvement in treatment with AHSCT versus alemtuzumab (hazard ratio, 1.63; P = .02). The cumulative probability of improvement was higher in the AHSCT group both at year 2 (28% versus 19%) and year 4 (30% versus 22%).

“The analysis suggested trends that may favor the effectiveness AHSCT over alemtuzumab, cladribine, and mitoxantrone, but the analysis was not fully powered. More research with larger cohorts is needed,” said Dr. Kalincik.

Dr. Cree has consulted for Biogen. Dr. Kalincik has financial relationships with Merck, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Biogen, Eisai, Teva, BioCSL, and Celgene.
 

Epstein-Barr Virus (EBV) is a suspect in the development of multiple sclerosis (MS), and recent research developments have strengthened that connection. In 2022, two studies received quite a bit of attention. One showed that EBV seroconversion occurs in the years prior to MS diagnosis in virtually every patient, and that serum levels of the neuronal damage biomarker neurofilament light (NfL) rose following EBV infection. Another paper showed anti-EBNA (Epstein-Barr nuclear antigen) antibodies in the cerebrospinal fluid cross-react with the central nervous system antigen GlialCAM in some MS patients.

Based on those studies, “it’s tempting to speculate that primary EBV infection could be a trigger to the autoimmune process suspected for MS,” said Tilman Schneider-Hohendorf, PhD, during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Dr. Schneider-Hohendorf, who is a postdoctoral fellow at the University of Münster, Germany, presented a new study that added more evidence that EBV may be a key player in MS pathogenesis. He and colleagues conducted a genetic analysis of patient T cells and found evidence that EBV viral activity may be occurring during MS.
 

A viral pathway to MS

Asked for comment, Bruce Cree, MD, PhD, said: “I think it is a very interesting one, because what we know about EBV is that it’s a risk factor for MS. So many studies performed over the last 20 years have shown a very strong association between EBV infection and the occurrence of MS. Studies have shown quite conclusively that EBV infection precedes MS in almost every patient, and that EBV infection is followed by a rise in serum NfL, which is a biomarker of neuronal damage. You have EBV infection, and then typically several years later a rise in serum concentrations of this marker of neuronal injury, and this is all in a presymptomatic state. Then that is followed by the onset of clinical symptoms in MS. That temporal sequence, I think, is very convincing,” said Dr. Cree, who is a professor of clinical neurology at the University of California, San Francisco.

He pointed out that EBV is not the sole causal pathway of MS, since genetic and environmental factors are known to be involved. “Nonetheless, it’s very strong evidence to indicate that this virus is involved in disease pathogenesis,” said Dr. Cree.

The new research takes the work a step further by revealing a population of T cells in MS patients that appear to be responding directly to EBV during active viral disease. That could be telling because most people who experience an EBV infection and experience mononucleosis recover, and some never even realize they have been infected. As a herpes virus, EBV remains in a latent state in B cells and other immune cells. “We know that you need an EBV infection (to trigger MS), but is EBV in some way continuing to be active in MS?” said Dr. Cree.

Other groups have looked for such evidence, but results have been mixed. Dr. Cree’s own group looked for evidence of EBV in spinal fluid of MS patients when they first present with symptoms, and could find no evidence. On the other hand, an autopsy study of MS patients has found evidence of chronic EBV infection in and around the brain, including the meninges, which could implicate the B cells found in that region. Another study found EBV-targeting antibodies that cross react with neuronal antigens in the cerebral spinal fluid of MS patients. “So depending on the assay used and the types of investigation, there is variable evidence to indicate that EBV has a role in ongoing MS pathogenesis – that it isn’t just a risk factor for MS that triggers the disease but potentially has a role in determining the course of MS,” said Dr. Cree.
 

IS EBV part of MS pathogenesis?

The new study presented at ECTRIMS by Dr. Schneider-Hohendorf offered evidence that MS patients have excess CD8-positive T cells that recognize EBV antigens typically shed during active viral infection. The results suggest “that the immune system is responding to that chronic infection,” said Dr. Cree.

The findings have some implications for a clinical study now in progress, called EMBOLD, which is looking at whether a heterologous infusion of T cells that have been primed to attack EBV could improve symptoms of progressive MS. “The hypothesis there is that chronically infected cells within the body are causing progressive MS and that if we could eradicate those cells, both within the central nervous system and within the periphery, perhaps we could see improvement in MS functional outcomes,” said Dr. Cree, who is a co-investigator for the EMBOLD study. The trial is using T cells from donors that are matched for the human leukocyte antigen complex, which is hoped will target and kill EBV-infected cells.

The study presented by Dr. Schneider-Hohendorf supports the approach. “There is an implication from this study that the trial that that’s currently being conducted might actually possibly have a benefit in the sense that there’s now another piece of evidence to indicate that EBV is not only a risk factor for MS, but may actually participate during the course of the disease as part of the pathogenesis,” said Dr. Cree.

In the new study, the researchers sequenced the T-cell receptor variable beta-chain (TRBV) peripheral repertoire among three cohorts of MS patients: A discovery cohort with 1,336 patients with MS and 229 controls; a validation cohort with 59 patients with MS and 51 controls; and 35 monozygotic twins who were discordant for MS. They identified sequences known to bind to EBV, SARS-CoV-2, cytomegalovirus, and influenza A, and used the latter three viruses as a proof of concept to demonstrate the validity of the approach. EBV-specific MHC-1 restricted CD8 TRBV in the serum of MS patients, with large effect sizes in the discovery (+2.2), validation (+2.1), and MS twin (+1.6) populations. The findings in the twin population rule out a genetic or environmental explanation for the findings in the discovery and validation cohorts, according to Dr. Schneider-Hohendorf.

The researchers also sequenced CSF among six healthy donors and five patients with MS and found significant differences. The T-cell populations had more lytic properties that suggested ongoing immune surveillance. “We can conclude that we found a broader response that could indicate an aberrant immune response. This could be a remnant of disease triggering an event or it could indicate an ongoing immune response to EBV. Is this EBV activity? We really don’t know. To find out, we would expand our pathogen-specific sequences, we would assess CNS tissue and lesions, and we would define the primary response in pediatric cohorts to better understand what might go wrong,” Dr. Schneider-Hohendorf concluded.

Dr. Cree has a financial relationship with Biogen and is a co-investigator for the EMBOLD trial. Dr. Schneider-Hohendorf has financial relationships with Biogen, Novartis, and Roche.

Epstein-Barr Virus (EBV) is a suspect in the development of multiple sclerosis (MS), and recent research developments have strengthened that connection. In 2022, two studies received quite a bit of attention. One showed that EBV seroconversion occurs in the years prior to MS diagnosis in virtually every patient, and that serum levels of the neuronal damage biomarker neurofilament light (NfL) rose following EBV infection. Another paper showed anti-EBNA (Epstein-Barr nuclear antigen) antibodies in the cerebrospinal fluid cross-react with the central nervous system antigen GlialCAM in some MS patients.

Based on those studies, “it’s tempting to speculate that primary EBV infection could be a trigger to the autoimmune process suspected for MS,” said Tilman Schneider-Hohendorf, PhD, during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Dr. Schneider-Hohendorf, who is a postdoctoral fellow at the University of Münster, Germany, presented a new study that added more evidence that EBV may be a key player in MS pathogenesis. He and colleagues conducted a genetic analysis of patient T cells and found evidence that EBV viral activity may be occurring during MS.
 

A viral pathway to MS

Asked for comment, Bruce Cree, MD, PhD, said: “I think it is a very interesting one, because what we know about EBV is that it’s a risk factor for MS. So many studies performed over the last 20 years have shown a very strong association between EBV infection and the occurrence of MS. Studies have shown quite conclusively that EBV infection precedes MS in almost every patient, and that EBV infection is followed by a rise in serum NfL, which is a biomarker of neuronal damage. You have EBV infection, and then typically several years later a rise in serum concentrations of this marker of neuronal injury, and this is all in a presymptomatic state. Then that is followed by the onset of clinical symptoms in MS. That temporal sequence, I think, is very convincing,” said Dr. Cree, who is a professor of clinical neurology at the University of California, San Francisco.

He pointed out that EBV is not the sole causal pathway of MS, since genetic and environmental factors are known to be involved. “Nonetheless, it’s very strong evidence to indicate that this virus is involved in disease pathogenesis,” said Dr. Cree.

The new research takes the work a step further by revealing a population of T cells in MS patients that appear to be responding directly to EBV during active viral disease. That could be telling because most people who experience an EBV infection and experience mononucleosis recover, and some never even realize they have been infected. As a herpes virus, EBV remains in a latent state in B cells and other immune cells. “We know that you need an EBV infection (to trigger MS), but is EBV in some way continuing to be active in MS?” said Dr. Cree.

Other groups have looked for such evidence, but results have been mixed. Dr. Cree’s own group looked for evidence of EBV in spinal fluid of MS patients when they first present with symptoms, and could find no evidence. On the other hand, an autopsy study of MS patients has found evidence of chronic EBV infection in and around the brain, including the meninges, which could implicate the B cells found in that region. Another study found EBV-targeting antibodies that cross react with neuronal antigens in the cerebral spinal fluid of MS patients. “So depending on the assay used and the types of investigation, there is variable evidence to indicate that EBV has a role in ongoing MS pathogenesis – that it isn’t just a risk factor for MS that triggers the disease but potentially has a role in determining the course of MS,” said Dr. Cree.
 

IS EBV part of MS pathogenesis?

The new study presented at ECTRIMS by Dr. Schneider-Hohendorf offered evidence that MS patients have excess CD8-positive T cells that recognize EBV antigens typically shed during active viral infection. The results suggest “that the immune system is responding to that chronic infection,” said Dr. Cree.

The findings have some implications for a clinical study now in progress, called EMBOLD, which is looking at whether a heterologous infusion of T cells that have been primed to attack EBV could improve symptoms of progressive MS. “The hypothesis there is that chronically infected cells within the body are causing progressive MS and that if we could eradicate those cells, both within the central nervous system and within the periphery, perhaps we could see improvement in MS functional outcomes,” said Dr. Cree, who is a co-investigator for the EMBOLD study. The trial is using T cells from donors that are matched for the human leukocyte antigen complex, which is hoped will target and kill EBV-infected cells.

The study presented by Dr. Schneider-Hohendorf supports the approach. “There is an implication from this study that the trial that that’s currently being conducted might actually possibly have a benefit in the sense that there’s now another piece of evidence to indicate that EBV is not only a risk factor for MS, but may actually participate during the course of the disease as part of the pathogenesis,” said Dr. Cree.

In the new study, the researchers sequenced the T-cell receptor variable beta-chain (TRBV) peripheral repertoire among three cohorts of MS patients: A discovery cohort with 1,336 patients with MS and 229 controls; a validation cohort with 59 patients with MS and 51 controls; and 35 monozygotic twins who were discordant for MS. They identified sequences known to bind to EBV, SARS-CoV-2, cytomegalovirus, and influenza A, and used the latter three viruses as a proof of concept to demonstrate the validity of the approach. EBV-specific MHC-1 restricted CD8 TRBV in the serum of MS patients, with large effect sizes in the discovery (+2.2), validation (+2.1), and MS twin (+1.6) populations. The findings in the twin population rule out a genetic or environmental explanation for the findings in the discovery and validation cohorts, according to Dr. Schneider-Hohendorf.

The researchers also sequenced CSF among six healthy donors and five patients with MS and found significant differences. The T-cell populations had more lytic properties that suggested ongoing immune surveillance. “We can conclude that we found a broader response that could indicate an aberrant immune response. This could be a remnant of disease triggering an event or it could indicate an ongoing immune response to EBV. Is this EBV activity? We really don’t know. To find out, we would expand our pathogen-specific sequences, we would assess CNS tissue and lesions, and we would define the primary response in pediatric cohorts to better understand what might go wrong,” Dr. Schneider-Hohendorf concluded.

Dr. Cree has a financial relationship with Biogen and is a co-investigator for the EMBOLD trial. Dr. Schneider-Hohendorf has financial relationships with Biogen, Novartis, and Roche.

Epstein-Barr Virus (EBV) is a suspect in the development of multiple sclerosis (MS), and recent research developments have strengthened that connection. In 2022, two studies received quite a bit of attention. One showed that EBV seroconversion occurs in the years prior to MS diagnosis in virtually every patient, and that serum levels of the neuronal damage biomarker neurofilament light (NfL) rose following EBV infection. Another paper showed anti-EBNA (Epstein-Barr nuclear antigen) antibodies in the cerebrospinal fluid cross-react with the central nervous system antigen GlialCAM in some MS patients.

Based on those studies, “it’s tempting to speculate that primary EBV infection could be a trigger to the autoimmune process suspected for MS,” said Tilman Schneider-Hohendorf, PhD, during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Dr. Schneider-Hohendorf, who is a postdoctoral fellow at the University of Münster, Germany, presented a new study that added more evidence that EBV may be a key player in MS pathogenesis. He and colleagues conducted a genetic analysis of patient T cells and found evidence that EBV viral activity may be occurring during MS.
 

A viral pathway to MS

Asked for comment, Bruce Cree, MD, PhD, said: “I think it is a very interesting one, because what we know about EBV is that it’s a risk factor for MS. So many studies performed over the last 20 years have shown a very strong association between EBV infection and the occurrence of MS. Studies have shown quite conclusively that EBV infection precedes MS in almost every patient, and that EBV infection is followed by a rise in serum NfL, which is a biomarker of neuronal damage. You have EBV infection, and then typically several years later a rise in serum concentrations of this marker of neuronal injury, and this is all in a presymptomatic state. Then that is followed by the onset of clinical symptoms in MS. That temporal sequence, I think, is very convincing,” said Dr. Cree, who is a professor of clinical neurology at the University of California, San Francisco.

He pointed out that EBV is not the sole causal pathway of MS, since genetic and environmental factors are known to be involved. “Nonetheless, it’s very strong evidence to indicate that this virus is involved in disease pathogenesis,” said Dr. Cree.

The new research takes the work a step further by revealing a population of T cells in MS patients that appear to be responding directly to EBV during active viral disease. That could be telling because most people who experience an EBV infection and experience mononucleosis recover, and some never even realize they have been infected. As a herpes virus, EBV remains in a latent state in B cells and other immune cells. “We know that you need an EBV infection (to trigger MS), but is EBV in some way continuing to be active in MS?” said Dr. Cree.

Other groups have looked for such evidence, but results have been mixed. Dr. Cree’s own group looked for evidence of EBV in spinal fluid of MS patients when they first present with symptoms, and could find no evidence. On the other hand, an autopsy study of MS patients has found evidence of chronic EBV infection in and around the brain, including the meninges, which could implicate the B cells found in that region. Another study found EBV-targeting antibodies that cross react with neuronal antigens in the cerebral spinal fluid of MS patients. “So depending on the assay used and the types of investigation, there is variable evidence to indicate that EBV has a role in ongoing MS pathogenesis – that it isn’t just a risk factor for MS that triggers the disease but potentially has a role in determining the course of MS,” said Dr. Cree.
 

IS EBV part of MS pathogenesis?

The new study presented at ECTRIMS by Dr. Schneider-Hohendorf offered evidence that MS patients have excess CD8-positive T cells that recognize EBV antigens typically shed during active viral infection. The results suggest “that the immune system is responding to that chronic infection,” said Dr. Cree.

The findings have some implications for a clinical study now in progress, called EMBOLD, which is looking at whether a heterologous infusion of T cells that have been primed to attack EBV could improve symptoms of progressive MS. “The hypothesis there is that chronically infected cells within the body are causing progressive MS and that if we could eradicate those cells, both within the central nervous system and within the periphery, perhaps we could see improvement in MS functional outcomes,” said Dr. Cree, who is a co-investigator for the EMBOLD study. The trial is using T cells from donors that are matched for the human leukocyte antigen complex, which is hoped will target and kill EBV-infected cells.

The study presented by Dr. Schneider-Hohendorf supports the approach. “There is an implication from this study that the trial that that’s currently being conducted might actually possibly have a benefit in the sense that there’s now another piece of evidence to indicate that EBV is not only a risk factor for MS, but may actually participate during the course of the disease as part of the pathogenesis,” said Dr. Cree.

In the new study, the researchers sequenced the T-cell receptor variable beta-chain (TRBV) peripheral repertoire among three cohorts of MS patients: A discovery cohort with 1,336 patients with MS and 229 controls; a validation cohort with 59 patients with MS and 51 controls; and 35 monozygotic twins who were discordant for MS. They identified sequences known to bind to EBV, SARS-CoV-2, cytomegalovirus, and influenza A, and used the latter three viruses as a proof of concept to demonstrate the validity of the approach. EBV-specific MHC-1 restricted CD8 TRBV in the serum of MS patients, with large effect sizes in the discovery (+2.2), validation (+2.1), and MS twin (+1.6) populations. The findings in the twin population rule out a genetic or environmental explanation for the findings in the discovery and validation cohorts, according to Dr. Schneider-Hohendorf.

The researchers also sequenced CSF among six healthy donors and five patients with MS and found significant differences. The T-cell populations had more lytic properties that suggested ongoing immune surveillance. “We can conclude that we found a broader response that could indicate an aberrant immune response. This could be a remnant of disease triggering an event or it could indicate an ongoing immune response to EBV. Is this EBV activity? We really don’t know. To find out, we would expand our pathogen-specific sequences, we would assess CNS tissue and lesions, and we would define the primary response in pediatric cohorts to better understand what might go wrong,” Dr. Schneider-Hohendorf concluded.

Dr. Cree has a financial relationship with Biogen and is a co-investigator for the EMBOLD trial. Dr. Schneider-Hohendorf has financial relationships with Biogen, Novartis, and Roche.

Neurofilament light chain (NfL) is a biomarker for both disease progression and treatment response in multiple sclerosis (MS), but the search continues for additional biomarkers to distinguish between disease activity and progression.

At a session of the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), researchers presented evidence that serum glial fibrillary acid protein (GFAP) could be a useful complement to NfL in MS, although it is not ready for the clinic. Acceptance of NfL wasn’t universal, either.

Patients with MS follow wide-ranging disease courses, and disability arises due to two partially independent mechanisms, according to Stephanie Meier, who presented results suggests from a study of two cohorts. “Firstly, the acute disease activity leading to relapse associated worsening or RAW (relapse-associated worsening), and secondly the chronic deterioration of neurologic functions leading to progression independent of relapse activity,” said Ms. Meier, a PhD student at University of Basel, Switzerland.
 

GFAP and NfL may be complementary biomarkers

NfL is a structural protein of neurons, while GFAP is a structure protein of astrocytes. NfL therefore reflects neuronal damage, while GFAP is an indicator of astrogliosis and astrocytic damage. GFAP has been shown to be increased in progressive MS and has been applied in traumatic brain injury and neuromyelitis optica spectrum disorder, according to Ms. Meier.

Her group examined data from two cohorts with “extreme” phenotypes. One cohort included 169 patients with stable MS and 184 with worsening disease progression but no sign of relapses. The other was a focal inflammation cohort that comprised paired samples from 66 patients: One sample from an active time point characterized by a relapse or at least one contrast-enhancing lesion (CEL) detected in the previous 30 days, and one remission sample when there was no relapse in the past year and no CEL in the previous 6 months.

The focal inflammation cohort demonstrated an association between raised NfL levels, with a 53% increase in predicted serum NfL during the active state after a multivariate analysis (P < .0001). GFAP values, on the other hand, were nearly identical.

In the progression cohort, there was more total yearly brain loss in the worsening group (0.42% vs. 0.14%; P = .0005). Baseline GFAP predicted gray matter atrophy (–0.24% per year, P < .0001) but NfL did not. The reverse was true for white matter atrophy, with NfL being predictive (–0.26% per year; P < .0001) but not GFAP.

“The use of biomarkers such as NfL and GFAP could be useful to understand the MS disease course by detecting disease activity that is not usually measurable with standard methods,” said Ms. Meier.

“We found that NfL was strongly associated with acute inflammation and prognosticated white matter volume loss, while GFAP has a potential as a prognostic biomarker for disease worsening, including progression independent of relapse activity, and baseline GFAP also prognosticated gray matter volume loss. From this we can conclude that serum GFAP is a promising biomarker reflecting progression in MS and it is complementary to NfL, as NfL is more strongly associated with acute inflammatory activity,” said Ms. Meier.
 

A biomarker of disease progression

In another presentation, Mark Wessels, MD, PhD, discussed use of GFAP as a biomarker of disease progression among patients treated with natalizumab. He noted that heightened levels of GFAP are found in astrocytes in chronic MS lesions. Serum GFAP also has been linked to lesion load and clinical outcomes in relapsing-remitting MS.

“The overall aim of our study was to evaluate the value of serum GFAP to monitor disability progression and treatment response in a natalizumab-treated cohort in which disease activity is effectively suppressed, and we did this by investigating GFAP as biomarker for progression despite suppression of inflammation,” said Dr. Wessels, a neurologist at Amsterdam University Medical Center.

The researchers evaluated data from an observational cohort at their institution in Amsterdam. GFAP decreased significantly after 3 months of treatment in both groups, then stabilized, but there was no difference between the groups. GFAP correlated with ventricle fraction at all time points with the exception of the last follow-up. It also correlated with lesion volume. However, GFAP did not correlate with whole brain parenchyma volume over time. There was no difference in GFAP among treatment responders and nonresponders.

Baseline serum GFAP predicted the annualized rate of ventricle volume change (P = .009). At 12 months it predicted both annualized rate of ventricle volume change (P = .009) and thalamus volume (P = .025).

“We’ve been struggling with how to interpret this data. We did see that GFAP and inflammation appear to be associated with each other. What supports this interpretation is that the GFAP decreased significantly after starting high efficacy treatments, namely natalizumab. We also found some clues that GFAP and brain atrophy may have a relationship with each other. Our conclusions weren’t entirely conclusive, possibly due to our smaller cohort sizes, and the use of various MRI scans over the years. And then the question of today was whether GFAP should be implemented in the clinic. Unfortunately, we couldn’t find evidence for use of GFAP as a disease progression biomarker, but we did find some clues of its use as both monitoring lesion volume and monitoring brain atrophy, making it still an interesting biomarker,” said Dr. Wessels.
 

What does it all mean?

In the Q&A session following the talks, one audience member challenged some of the assumptions behind the use of NfL and GFAP. “We don’t really know what these proteins actually do, and what they truly measure,” he said. Another criticism voiced by the commenter was that the platforms used to measure high and low values may be inconsistent. Finally, there are questions about the underlying theory. “I think our simplistic model for thinking that these are all just measurements of damage is potentially something that we have to reassess … or the assumption that these measures have to correlate to brain atrophy, as if that’s a gold standard. We all know that brain atrophy has totally failed us in the clinic and been incapable of giving us anything that’s useful for monitoring our patients,” said the questioner.

Elias Sotirchos, MD, who presented on NfL values and brain atrophy MS patients, agreed that it’s important to compare values across platforms to ensure consistency. He also cited potential issues with reference populations, since there may be a variety of contributors to neurotoxicity based on behaviors such as smoking, drinking, or comorbidities. “The selection of the reference population is important to be a representative of the MS population in which we are trying to apply that measurement of that normative value,” said Dr. Sotirchos, assistant professor of neurology at Johns Hopkins Medicine, Baltimore.

Ms. Basel and Dr. Wessels have no relevant financial disclosures. Dr. Sotirchos has financial relationships with Alexion, Viela Bio, Horizon Therapeutics, Genentech, Biogen, and Ad Scientiam.

Neurofilament light chain (NfL) is a biomarker for both disease progression and treatment response in multiple sclerosis (MS), but the search continues for additional biomarkers to distinguish between disease activity and progression.

At a session of the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), researchers presented evidence that serum glial fibrillary acid protein (GFAP) could be a useful complement to NfL in MS, although it is not ready for the clinic. Acceptance of NfL wasn’t universal, either.

Patients with MS follow wide-ranging disease courses, and disability arises due to two partially independent mechanisms, according to Stephanie Meier, who presented results suggests from a study of two cohorts. “Firstly, the acute disease activity leading to relapse associated worsening or RAW (relapse-associated worsening), and secondly the chronic deterioration of neurologic functions leading to progression independent of relapse activity,” said Ms. Meier, a PhD student at University of Basel, Switzerland.
 

GFAP and NfL may be complementary biomarkers

NfL is a structural protein of neurons, while GFAP is a structure protein of astrocytes. NfL therefore reflects neuronal damage, while GFAP is an indicator of astrogliosis and astrocytic damage. GFAP has been shown to be increased in progressive MS and has been applied in traumatic brain injury and neuromyelitis optica spectrum disorder, according to Ms. Meier.

Her group examined data from two cohorts with “extreme” phenotypes. One cohort included 169 patients with stable MS and 184 with worsening disease progression but no sign of relapses. The other was a focal inflammation cohort that comprised paired samples from 66 patients: One sample from an active time point characterized by a relapse or at least one contrast-enhancing lesion (CEL) detected in the previous 30 days, and one remission sample when there was no relapse in the past year and no CEL in the previous 6 months.

The focal inflammation cohort demonstrated an association between raised NfL levels, with a 53% increase in predicted serum NfL during the active state after a multivariate analysis (P < .0001). GFAP values, on the other hand, were nearly identical.

In the progression cohort, there was more total yearly brain loss in the worsening group (0.42% vs. 0.14%; P = .0005). Baseline GFAP predicted gray matter atrophy (–0.24% per year, P < .0001) but NfL did not. The reverse was true for white matter atrophy, with NfL being predictive (–0.26% per year; P < .0001) but not GFAP.

“The use of biomarkers such as NfL and GFAP could be useful to understand the MS disease course by detecting disease activity that is not usually measurable with standard methods,” said Ms. Meier.

“We found that NfL was strongly associated with acute inflammation and prognosticated white matter volume loss, while GFAP has a potential as a prognostic biomarker for disease worsening, including progression independent of relapse activity, and baseline GFAP also prognosticated gray matter volume loss. From this we can conclude that serum GFAP is a promising biomarker reflecting progression in MS and it is complementary to NfL, as NfL is more strongly associated with acute inflammatory activity,” said Ms. Meier.
 

A biomarker of disease progression

In another presentation, Mark Wessels, MD, PhD, discussed use of GFAP as a biomarker of disease progression among patients treated with natalizumab. He noted that heightened levels of GFAP are found in astrocytes in chronic MS lesions. Serum GFAP also has been linked to lesion load and clinical outcomes in relapsing-remitting MS.

“The overall aim of our study was to evaluate the value of serum GFAP to monitor disability progression and treatment response in a natalizumab-treated cohort in which disease activity is effectively suppressed, and we did this by investigating GFAP as biomarker for progression despite suppression of inflammation,” said Dr. Wessels, a neurologist at Amsterdam University Medical Center.

The researchers evaluated data from an observational cohort at their institution in Amsterdam. GFAP decreased significantly after 3 months of treatment in both groups, then stabilized, but there was no difference between the groups. GFAP correlated with ventricle fraction at all time points with the exception of the last follow-up. It also correlated with lesion volume. However, GFAP did not correlate with whole brain parenchyma volume over time. There was no difference in GFAP among treatment responders and nonresponders.

Baseline serum GFAP predicted the annualized rate of ventricle volume change (P = .009). At 12 months it predicted both annualized rate of ventricle volume change (P = .009) and thalamus volume (P = .025).

“We’ve been struggling with how to interpret this data. We did see that GFAP and inflammation appear to be associated with each other. What supports this interpretation is that the GFAP decreased significantly after starting high efficacy treatments, namely natalizumab. We also found some clues that GFAP and brain atrophy may have a relationship with each other. Our conclusions weren’t entirely conclusive, possibly due to our smaller cohort sizes, and the use of various MRI scans over the years. And then the question of today was whether GFAP should be implemented in the clinic. Unfortunately, we couldn’t find evidence for use of GFAP as a disease progression biomarker, but we did find some clues of its use as both monitoring lesion volume and monitoring brain atrophy, making it still an interesting biomarker,” said Dr. Wessels.
 

What does it all mean?

In the Q&A session following the talks, one audience member challenged some of the assumptions behind the use of NfL and GFAP. “We don’t really know what these proteins actually do, and what they truly measure,” he said. Another criticism voiced by the commenter was that the platforms used to measure high and low values may be inconsistent. Finally, there are questions about the underlying theory. “I think our simplistic model for thinking that these are all just measurements of damage is potentially something that we have to reassess … or the assumption that these measures have to correlate to brain atrophy, as if that’s a gold standard. We all know that brain atrophy has totally failed us in the clinic and been incapable of giving us anything that’s useful for monitoring our patients,” said the questioner.

Elias Sotirchos, MD, who presented on NfL values and brain atrophy MS patients, agreed that it’s important to compare values across platforms to ensure consistency. He also cited potential issues with reference populations, since there may be a variety of contributors to neurotoxicity based on behaviors such as smoking, drinking, or comorbidities. “The selection of the reference population is important to be a representative of the MS population in which we are trying to apply that measurement of that normative value,” said Dr. Sotirchos, assistant professor of neurology at Johns Hopkins Medicine, Baltimore.

Ms. Basel and Dr. Wessels have no relevant financial disclosures. Dr. Sotirchos has financial relationships with Alexion, Viela Bio, Horizon Therapeutics, Genentech, Biogen, and Ad Scientiam.

Neurofilament light chain (NfL) is a biomarker for both disease progression and treatment response in multiple sclerosis (MS), but the search continues for additional biomarkers to distinguish between disease activity and progression.

At a session of the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), researchers presented evidence that serum glial fibrillary acid protein (GFAP) could be a useful complement to NfL in MS, although it is not ready for the clinic. Acceptance of NfL wasn’t universal, either.

Patients with MS follow wide-ranging disease courses, and disability arises due to two partially independent mechanisms, according to Stephanie Meier, who presented results suggests from a study of two cohorts. “Firstly, the acute disease activity leading to relapse associated worsening or RAW (relapse-associated worsening), and secondly the chronic deterioration of neurologic functions leading to progression independent of relapse activity,” said Ms. Meier, a PhD student at University of Basel, Switzerland.
 

GFAP and NfL may be complementary biomarkers

NfL is a structural protein of neurons, while GFAP is a structure protein of astrocytes. NfL therefore reflects neuronal damage, while GFAP is an indicator of astrogliosis and astrocytic damage. GFAP has been shown to be increased in progressive MS and has been applied in traumatic brain injury and neuromyelitis optica spectrum disorder, according to Ms. Meier.

Her group examined data from two cohorts with “extreme” phenotypes. One cohort included 169 patients with stable MS and 184 with worsening disease progression but no sign of relapses. The other was a focal inflammation cohort that comprised paired samples from 66 patients: One sample from an active time point characterized by a relapse or at least one contrast-enhancing lesion (CEL) detected in the previous 30 days, and one remission sample when there was no relapse in the past year and no CEL in the previous 6 months.

The focal inflammation cohort demonstrated an association between raised NfL levels, with a 53% increase in predicted serum NfL during the active state after a multivariate analysis (P < .0001). GFAP values, on the other hand, were nearly identical.

In the progression cohort, there was more total yearly brain loss in the worsening group (0.42% vs. 0.14%; P = .0005). Baseline GFAP predicted gray matter atrophy (–0.24% per year, P < .0001) but NfL did not. The reverse was true for white matter atrophy, with NfL being predictive (–0.26% per year; P < .0001) but not GFAP.

“The use of biomarkers such as NfL and GFAP could be useful to understand the MS disease course by detecting disease activity that is not usually measurable with standard methods,” said Ms. Meier.

“We found that NfL was strongly associated with acute inflammation and prognosticated white matter volume loss, while GFAP has a potential as a prognostic biomarker for disease worsening, including progression independent of relapse activity, and baseline GFAP also prognosticated gray matter volume loss. From this we can conclude that serum GFAP is a promising biomarker reflecting progression in MS and it is complementary to NfL, as NfL is more strongly associated with acute inflammatory activity,” said Ms. Meier.
 

A biomarker of disease progression

In another presentation, Mark Wessels, MD, PhD, discussed use of GFAP as a biomarker of disease progression among patients treated with natalizumab. He noted that heightened levels of GFAP are found in astrocytes in chronic MS lesions. Serum GFAP also has been linked to lesion load and clinical outcomes in relapsing-remitting MS.

“The overall aim of our study was to evaluate the value of serum GFAP to monitor disability progression and treatment response in a natalizumab-treated cohort in which disease activity is effectively suppressed, and we did this by investigating GFAP as biomarker for progression despite suppression of inflammation,” said Dr. Wessels, a neurologist at Amsterdam University Medical Center.

The researchers evaluated data from an observational cohort at their institution in Amsterdam. GFAP decreased significantly after 3 months of treatment in both groups, then stabilized, but there was no difference between the groups. GFAP correlated with ventricle fraction at all time points with the exception of the last follow-up. It also correlated with lesion volume. However, GFAP did not correlate with whole brain parenchyma volume over time. There was no difference in GFAP among treatment responders and nonresponders.

Baseline serum GFAP predicted the annualized rate of ventricle volume change (P = .009). At 12 months it predicted both annualized rate of ventricle volume change (P = .009) and thalamus volume (P = .025).

“We’ve been struggling with how to interpret this data. We did see that GFAP and inflammation appear to be associated with each other. What supports this interpretation is that the GFAP decreased significantly after starting high efficacy treatments, namely natalizumab. We also found some clues that GFAP and brain atrophy may have a relationship with each other. Our conclusions weren’t entirely conclusive, possibly due to our smaller cohort sizes, and the use of various MRI scans over the years. And then the question of today was whether GFAP should be implemented in the clinic. Unfortunately, we couldn’t find evidence for use of GFAP as a disease progression biomarker, but we did find some clues of its use as both monitoring lesion volume and monitoring brain atrophy, making it still an interesting biomarker,” said Dr. Wessels.
 

What does it all mean?

In the Q&A session following the talks, one audience member challenged some of the assumptions behind the use of NfL and GFAP. “We don’t really know what these proteins actually do, and what they truly measure,” he said. Another criticism voiced by the commenter was that the platforms used to measure high and low values may be inconsistent. Finally, there are questions about the underlying theory. “I think our simplistic model for thinking that these are all just measurements of damage is potentially something that we have to reassess … or the assumption that these measures have to correlate to brain atrophy, as if that’s a gold standard. We all know that brain atrophy has totally failed us in the clinic and been incapable of giving us anything that’s useful for monitoring our patients,” said the questioner.

Elias Sotirchos, MD, who presented on NfL values and brain atrophy MS patients, agreed that it’s important to compare values across platforms to ensure consistency. He also cited potential issues with reference populations, since there may be a variety of contributors to neurotoxicity based on behaviors such as smoking, drinking, or comorbidities. “The selection of the reference population is important to be a representative of the MS population in which we are trying to apply that measurement of that normative value,” said Dr. Sotirchos, assistant professor of neurology at Johns Hopkins Medicine, Baltimore.

Ms. Basel and Dr. Wessels have no relevant financial disclosures. Dr. Sotirchos has financial relationships with Alexion, Viela Bio, Horizon Therapeutics, Genentech, Biogen, and Ad Scientiam.