Jim Kling

Autologous hematopoietic stem cell transplant (AHSCT) is more effective than fingolimod and natalizumab for patients with highly active relapsing-remitting multiple sclerosis (MS), data indicate.

In a multicenter study that emulated pairwise trials, AHSCT was associated with a higher likelihood of disability improvement, compared with fingolimod (hazard ratio, 2.70).

Once the immune system is reconstituted, it can contribute to the healing process. AHSCT thus provides the possibility of improvement in MS. Disease-modifying therapies that require continued use, however, could inhibit that process.

“If you can stop the inflammation that’s driving this disease fairly early on, [patients] do have the capacity to repair,” said study author Mark Freedman, MD, a professor of neurology at the University of Ottawa. “And we start to see that especially in a treatment [like AHSCT] where you don’t maintain the hit on the immune system.”

The study was published online in JAMA Neurology.
 

Pairwise analyses

Single-arm studies and an open-label, randomized trial have suggested that AHSCT has efficacy. The regimen is associated with a 0.3%-2.0% risk for mortality, but this risk has declined with better patient selection and clinical experience, according to the researchers. Comparative studies of AHSCT and DMTs are needed, but they are difficult to carry out, which is why the current team chose a propensity-score matched case–control design, according to lead author Tomas Kalincik, MD, PhD, head of the University of Melbourne’s Clinical Outcomes Research Unit.

The researchers examined data from 4,915 patients with relapsing-remitting MS. Of this population, 3.4% received AHSCT, 52.0% received fingolimod, 30.3% received natalizumab, and 14.2% received ocrelizumab. The proportion of women in the treatment groups ranged from 65% to 70%.

The researchers used pairwise matching to simulate the randomized, controlled trials comparing AHSCT with fingolimod, natalizumab, and ocrelizumab. Patients were matched on the basis of sex, age, disability, relapse events at 12 and 24 months before baseline, time from first symptoms to baseline, the most effective previous DMT, and geographical region.

Compared with fingolimod, AHSCT was associated with fewer relapses (annualized relapse rate, 0.09 vs. 0.20; P < .001). This finding was confirmed by a reduced cumulative hazard of relapse (HR, 0.26).

Compared with natalizumab, AHSCT had only a modestly greater effect on annualized relapse rates (ARR, 0.08 vs. 0.10; P = .03), with a cumulative HR for relapses of 0.51.

There was no significant difference in the risk for relapse between treatment with AHSCT and with ocrelizumab (ARR, 0.09 vs. 0.06; P = .86), nor was the risk of cumulative relapses significantly different between these treatments.

Among patients included in the pairwise analyses who received AHSCT, 23.3% developed febrile neutropenia during mobilization, 11.3% developed serum sickness, and 8.8% were admitted to an intensive care unit. There were 82 serious adverse events among 58 patients after they were discharged post AHSCT treatment, including infections (59.8% of adverse events) that were primarily due to viral sources (41.5% of adverse events). There was one death (0.6%) due to veno-occlusive disease of the liver following busulfan exposure.

Some AHSCT protocols are stronger than others, and milder immune ablative measures are less likely to produce lasting effects. “We completely remove the old immune system and put in a brand new one,” said Dr. Freedman, referring to the practice at his center. “That’s a fairly horrendous procedure, and, not surprisingly, we’ve had a slight increase in the types of side effects, compared with other groups who don’t use that heavy-duty conditioning regimen, but we’ve had absolutely zero return of inflammatory events over 23 years that we’ve been doing this. Nobody’s had another attack, no one has even developed a single new MRI lesion.”

The so-called medium and light conditioning regimens are associated with a return of disease activity in about 25% of patients within 3 years, Dr. Freedman added. “You start to see new MRI lesions form and relapses occurring. It’s still better than any of the higher efficacy therapies, but it’s not stopped the disease.”

A key limitation of the study is that its efficacy analysis did not distinguish between different intensities of AHSCT regimens, according to the authors.
 

Encouraging results

AHSCT is highly effective at temporarily eliminating inflammation in the central nervous system, according to Jeffrey Cohen, MD, director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research, and Anne Cross, MD, professor of neurology at Washington University, St. Louis, who wrote an editorial that accompanied the study. As many as 35% of patients require DMTs at some point after AHSCT.

The results of the new study are encouraging, but plenty of unanswered questions remain, Dr. Cohen said. “Many studies demonstrate AHSCT to have potent durable efficacy that appears to be greater than that of the available DMTs, but some studies – for example, this one – suggest that AHSCT may be superior to some but not all DMTs. Therefore, where to place AHSCT in the overall treatment sequence remains uncertain.” Randomized, controlled trials that are now in process “hopefully will clarify,” he added.

The study was supported by the National Health and Medical Research Council of Australia, Multiple Sclerosis Australia, and the MS Foundation of Canada. Dr. Kalincik has financial relationships with Eisai, Novartis, Biogen, Merck, Roche, Sanofi Genzyme, Teva, Celgene, Bristol-Myers Squibb, and Janssen. Dr. Freedman has financial relationships with Sanofi-Genzyme Canada, Alexion, Atara Biotherapeutics, Bayer Healthcare, Beigene, BMS (Celgene), EMD, Hoffmann-La Roche, Janssen, Merck Serono, Quanterix, Novartis, Sanofi-Genzyme, Teva Canada Innovation, Celestra Health, McKesson, and EMD Serono. Dr. Cohen has financial relationships with Biogen, Convelo, EMD Serono, Gossamer Bio, Mylan, and PSI.

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

Autologous hematopoietic stem cell transplant (AHSCT) is more effective than fingolimod and natalizumab for patients with highly active relapsing-remitting multiple sclerosis (MS), data indicate.

In a multicenter study that emulated pairwise trials, AHSCT was associated with a higher likelihood of disability improvement, compared with fingolimod (hazard ratio, 2.70).

Once the immune system is reconstituted, it can contribute to the healing process. AHSCT thus provides the possibility of improvement in MS. Disease-modifying therapies that require continued use, however, could inhibit that process.

“If you can stop the inflammation that’s driving this disease fairly early on, [patients] do have the capacity to repair,” said study author Mark Freedman, MD, a professor of neurology at the University of Ottawa. “And we start to see that especially in a treatment [like AHSCT] where you don’t maintain the hit on the immune system.”

The study was published online in JAMA Neurology.
 

Pairwise analyses

Single-arm studies and an open-label, randomized trial have suggested that AHSCT has efficacy. The regimen is associated with a 0.3%-2.0% risk for mortality, but this risk has declined with better patient selection and clinical experience, according to the researchers. Comparative studies of AHSCT and DMTs are needed, but they are difficult to carry out, which is why the current team chose a propensity-score matched case–control design, according to lead author Tomas Kalincik, MD, PhD, head of the University of Melbourne’s Clinical Outcomes Research Unit.

The researchers examined data from 4,915 patients with relapsing-remitting MS. Of this population, 3.4% received AHSCT, 52.0% received fingolimod, 30.3% received natalizumab, and 14.2% received ocrelizumab. The proportion of women in the treatment groups ranged from 65% to 70%.

The researchers used pairwise matching to simulate the randomized, controlled trials comparing AHSCT with fingolimod, natalizumab, and ocrelizumab. Patients were matched on the basis of sex, age, disability, relapse events at 12 and 24 months before baseline, time from first symptoms to baseline, the most effective previous DMT, and geographical region.

Compared with fingolimod, AHSCT was associated with fewer relapses (annualized relapse rate, 0.09 vs. 0.20; P < .001). This finding was confirmed by a reduced cumulative hazard of relapse (HR, 0.26).

Compared with natalizumab, AHSCT had only a modestly greater effect on annualized relapse rates (ARR, 0.08 vs. 0.10; P = .03), with a cumulative HR for relapses of 0.51.

There was no significant difference in the risk for relapse between treatment with AHSCT and with ocrelizumab (ARR, 0.09 vs. 0.06; P = .86), nor was the risk of cumulative relapses significantly different between these treatments.

Among patients included in the pairwise analyses who received AHSCT, 23.3% developed febrile neutropenia during mobilization, 11.3% developed serum sickness, and 8.8% were admitted to an intensive care unit. There were 82 serious adverse events among 58 patients after they were discharged post AHSCT treatment, including infections (59.8% of adverse events) that were primarily due to viral sources (41.5% of adverse events). There was one death (0.6%) due to veno-occlusive disease of the liver following busulfan exposure.

Some AHSCT protocols are stronger than others, and milder immune ablative measures are less likely to produce lasting effects. “We completely remove the old immune system and put in a brand new one,” said Dr. Freedman, referring to the practice at his center. “That’s a fairly horrendous procedure, and, not surprisingly, we’ve had a slight increase in the types of side effects, compared with other groups who don’t use that heavy-duty conditioning regimen, but we’ve had absolutely zero return of inflammatory events over 23 years that we’ve been doing this. Nobody’s had another attack, no one has even developed a single new MRI lesion.”

The so-called medium and light conditioning regimens are associated with a return of disease activity in about 25% of patients within 3 years, Dr. Freedman added. “You start to see new MRI lesions form and relapses occurring. It’s still better than any of the higher efficacy therapies, but it’s not stopped the disease.”

A key limitation of the study is that its efficacy analysis did not distinguish between different intensities of AHSCT regimens, according to the authors.
 

Encouraging results

AHSCT is highly effective at temporarily eliminating inflammation in the central nervous system, according to Jeffrey Cohen, MD, director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research, and Anne Cross, MD, professor of neurology at Washington University, St. Louis, who wrote an editorial that accompanied the study. As many as 35% of patients require DMTs at some point after AHSCT.

The results of the new study are encouraging, but plenty of unanswered questions remain, Dr. Cohen said. “Many studies demonstrate AHSCT to have potent durable efficacy that appears to be greater than that of the available DMTs, but some studies – for example, this one – suggest that AHSCT may be superior to some but not all DMTs. Therefore, where to place AHSCT in the overall treatment sequence remains uncertain.” Randomized, controlled trials that are now in process “hopefully will clarify,” he added.

The study was supported by the National Health and Medical Research Council of Australia, Multiple Sclerosis Australia, and the MS Foundation of Canada. Dr. Kalincik has financial relationships with Eisai, Novartis, Biogen, Merck, Roche, Sanofi Genzyme, Teva, Celgene, Bristol-Myers Squibb, and Janssen. Dr. Freedman has financial relationships with Sanofi-Genzyme Canada, Alexion, Atara Biotherapeutics, Bayer Healthcare, Beigene, BMS (Celgene), EMD, Hoffmann-La Roche, Janssen, Merck Serono, Quanterix, Novartis, Sanofi-Genzyme, Teva Canada Innovation, Celestra Health, McKesson, and EMD Serono. Dr. Cohen has financial relationships with Biogen, Convelo, EMD Serono, Gossamer Bio, Mylan, and PSI.

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

Autologous hematopoietic stem cell transplant (AHSCT) is more effective than fingolimod and natalizumab for patients with highly active relapsing-remitting multiple sclerosis (MS), data indicate.

In a multicenter study that emulated pairwise trials, AHSCT was associated with a higher likelihood of disability improvement, compared with fingolimod (hazard ratio, 2.70).

Once the immune system is reconstituted, it can contribute to the healing process. AHSCT thus provides the possibility of improvement in MS. Disease-modifying therapies that require continued use, however, could inhibit that process.

“If you can stop the inflammation that’s driving this disease fairly early on, [patients] do have the capacity to repair,” said study author Mark Freedman, MD, a professor of neurology at the University of Ottawa. “And we start to see that especially in a treatment [like AHSCT] where you don’t maintain the hit on the immune system.”

The study was published online in JAMA Neurology.
 

Pairwise analyses

Single-arm studies and an open-label, randomized trial have suggested that AHSCT has efficacy. The regimen is associated with a 0.3%-2.0% risk for mortality, but this risk has declined with better patient selection and clinical experience, according to the researchers. Comparative studies of AHSCT and DMTs are needed, but they are difficult to carry out, which is why the current team chose a propensity-score matched case–control design, according to lead author Tomas Kalincik, MD, PhD, head of the University of Melbourne’s Clinical Outcomes Research Unit.

The researchers examined data from 4,915 patients with relapsing-remitting MS. Of this population, 3.4% received AHSCT, 52.0% received fingolimod, 30.3% received natalizumab, and 14.2% received ocrelizumab. The proportion of women in the treatment groups ranged from 65% to 70%.

The researchers used pairwise matching to simulate the randomized, controlled trials comparing AHSCT with fingolimod, natalizumab, and ocrelizumab. Patients were matched on the basis of sex, age, disability, relapse events at 12 and 24 months before baseline, time from first symptoms to baseline, the most effective previous DMT, and geographical region.

Compared with fingolimod, AHSCT was associated with fewer relapses (annualized relapse rate, 0.09 vs. 0.20; P < .001). This finding was confirmed by a reduced cumulative hazard of relapse (HR, 0.26).

Compared with natalizumab, AHSCT had only a modestly greater effect on annualized relapse rates (ARR, 0.08 vs. 0.10; P = .03), with a cumulative HR for relapses of 0.51.

There was no significant difference in the risk for relapse between treatment with AHSCT and with ocrelizumab (ARR, 0.09 vs. 0.06; P = .86), nor was the risk of cumulative relapses significantly different between these treatments.

Among patients included in the pairwise analyses who received AHSCT, 23.3% developed febrile neutropenia during mobilization, 11.3% developed serum sickness, and 8.8% were admitted to an intensive care unit. There were 82 serious adverse events among 58 patients after they were discharged post AHSCT treatment, including infections (59.8% of adverse events) that were primarily due to viral sources (41.5% of adverse events). There was one death (0.6%) due to veno-occlusive disease of the liver following busulfan exposure.

Some AHSCT protocols are stronger than others, and milder immune ablative measures are less likely to produce lasting effects. “We completely remove the old immune system and put in a brand new one,” said Dr. Freedman, referring to the practice at his center. “That’s a fairly horrendous procedure, and, not surprisingly, we’ve had a slight increase in the types of side effects, compared with other groups who don’t use that heavy-duty conditioning regimen, but we’ve had absolutely zero return of inflammatory events over 23 years that we’ve been doing this. Nobody’s had another attack, no one has even developed a single new MRI lesion.”

The so-called medium and light conditioning regimens are associated with a return of disease activity in about 25% of patients within 3 years, Dr. Freedman added. “You start to see new MRI lesions form and relapses occurring. It’s still better than any of the higher efficacy therapies, but it’s not stopped the disease.”

A key limitation of the study is that its efficacy analysis did not distinguish between different intensities of AHSCT regimens, according to the authors.
 

Encouraging results

AHSCT is highly effective at temporarily eliminating inflammation in the central nervous system, according to Jeffrey Cohen, MD, director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research, and Anne Cross, MD, professor of neurology at Washington University, St. Louis, who wrote an editorial that accompanied the study. As many as 35% of patients require DMTs at some point after AHSCT.

The results of the new study are encouraging, but plenty of unanswered questions remain, Dr. Cohen said. “Many studies demonstrate AHSCT to have potent durable efficacy that appears to be greater than that of the available DMTs, but some studies – for example, this one – suggest that AHSCT may be superior to some but not all DMTs. Therefore, where to place AHSCT in the overall treatment sequence remains uncertain.” Randomized, controlled trials that are now in process “hopefully will clarify,” he added.

The study was supported by the National Health and Medical Research Council of Australia, Multiple Sclerosis Australia, and the MS Foundation of Canada. Dr. Kalincik has financial relationships with Eisai, Novartis, Biogen, Merck, Roche, Sanofi Genzyme, Teva, Celgene, Bristol-Myers Squibb, and Janssen. Dr. Freedman has financial relationships with Sanofi-Genzyme Canada, Alexion, Atara Biotherapeutics, Bayer Healthcare, Beigene, BMS (Celgene), EMD, Hoffmann-La Roche, Janssen, Merck Serono, Quanterix, Novartis, Sanofi-Genzyme, Teva Canada Innovation, Celestra Health, McKesson, and EMD Serono. Dr. Cohen has financial relationships with Biogen, Convelo, EMD Serono, Gossamer Bio, Mylan, and PSI.

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

A new review article highlights approaches for mechanical circulatory support in patients with high-risk acute pulmonary embolism (PE). Mechanical support has become an important treatment option for refractory shock resulting from acute right ventricular failure (RVF).

Pulmonary embolism with hemodynamic significance is widely underdiagnosed, and the mortality rate can be as high as 30%, but new therapeutic developments offer promise. “Over the past few years, a renewed interest in mechanical circulatory support (MCS; both percutaneous and surgical) for acute RVF has emerged, increasing viable treatment options for high-risk acute PE,” wrote the authors of the review, which was published online in Interventional Cardiology Clinics.

Poor outcomes are often driven by RVF, which is tricky to diagnose and manage, and it stems from a sudden increase in pulmonary vascular resistance (PVR) following PE. “The mechanism for increased PVR in acute PE is multifactorial, including direct blood flow impedance, local hypoxia-induced vasoconstriction, and platelet/thrombin-induced release of vasoactive peptides. The cascade of events that then leads to RVF includes decreased RV stoke volume, increased RV wall tension, and RV dilation,” the authors wrote.

The authors noted that diuretics help to correct changes to RV geometry and can improve left ventricle filling, which improves hemodynamics. Diuretics can be used in patients who are hypotensive and volume overloaded, but vasopressors should be employed to support blood pressure.

When using mechanical ventilation, strategies such as low tidal volumes, minimization of positive end expiratory pressure, and prevention of hypoxemia and acidemia should be employed to prevent an increase of pulmonary vascular resistance, which can worsen RV failure.

Pulmonary vasodilators aren’t recommended for acute PE, but inhaled pulmonary vasodilators may be considered in hemodynamically unstable patients.

Surgically implanted right ventricle assistance device are generally not used for acute RV failure in high-risk PE, unless the patient has not improved after medical management.
 

Percutaneous devices

Percutaneous mechanical circulatory support devices can be used for patients experiencing refractory shock. The review highlighted three such devices, including the Impella RP, tandem-heart right ventricular assist devices (TH-RVAD) or Protek Duo, and venoarterial extracorporeal membrane oxygenation (VA-ECMO), but they are not without limitations. “Challenges to using these devices in patients with acute PE include clot dislodgement, vascular complications, infections, device migration, and fracture of individual elements,” the authors wrote.

The Impella RP is easy to deploy and bypasses the RV, but it can’t provide blood oxygenation and may cause bleeding or hemolysis. TH-RVAD oxygenates the blood and bypasses the RV, but suffers from a large sheath size. VA-ECMO oxygenates the blood but may cause bleeding.

There are important differences among the mechanical support devices, according to Jonathan Ludmir, MD, who was asked to comment. “In reality, if someone has a large pulmonary embolism burden, to put in the Impella RP or the Protek Duo would be a little bit risky, because you’d be sometimes putting the device right where the clot is. At least what we do in our institution, when someone is in extremis despite using [intravenous] medications like vasopressors or inotropes, VA-ECMO is kind of the go to. This is both the quickest and probably most effective way to support the patient. I say the quickest because this is a procedure you can do at the bedside.”
 

Benefits of PERT

One message that the review only briefly mentions, but Dr. Ludmir believes is key, is employing a pulmonary embolism response team. “That’s been looked at extensively, and it’s a really key part of any decision-making. If someone presents to the emergency room or someone inside the hospital has an acute pulmonary embolism, you have a team of people that can respond and help assess the next step. Typically, that involves a cardiologist or an interventional cardiologist, a hematologist, vascular surgeon, often a cardiac surgeon, so it’s a whole slew of people. Based on the patient assessment they can quickly decide, can this patient just be okay with a blood thinner like heparin? Does this patient need something more aggressive, like a thrombectomy? Or is this a serious case where you involve the shock team or the ECMO team, and you have to stabilize the patient on mechanical circulatory support, so you can accomplish what you need to do to get rid of the pulmonary embolism,” said Dr. Ludmir, who is an assistant professor of medicine at Corrigan Minehan Heart Center at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“Every case is individualized, hence the importance of having a team of a variety of different backgrounds and thoughts to approach it. And I think that’s kind of like the key takeaway. Yes, you have to be familiar with all the therapies, but at the end of the day, not every patient is going to fit into the algorithm for how you approach pulmonary embolism,” said Dr. Ludmir.

Dr. Ludmir has no relevant conflicts of interest.

A new review article highlights approaches for mechanical circulatory support in patients with high-risk acute pulmonary embolism (PE). Mechanical support has become an important treatment option for refractory shock resulting from acute right ventricular failure (RVF).

Pulmonary embolism with hemodynamic significance is widely underdiagnosed, and the mortality rate can be as high as 30%, but new therapeutic developments offer promise. “Over the past few years, a renewed interest in mechanical circulatory support (MCS; both percutaneous and surgical) for acute RVF has emerged, increasing viable treatment options for high-risk acute PE,” wrote the authors of the review, which was published online in Interventional Cardiology Clinics.

Poor outcomes are often driven by RVF, which is tricky to diagnose and manage, and it stems from a sudden increase in pulmonary vascular resistance (PVR) following PE. “The mechanism for increased PVR in acute PE is multifactorial, including direct blood flow impedance, local hypoxia-induced vasoconstriction, and platelet/thrombin-induced release of vasoactive peptides. The cascade of events that then leads to RVF includes decreased RV stoke volume, increased RV wall tension, and RV dilation,” the authors wrote.

The authors noted that diuretics help to correct changes to RV geometry and can improve left ventricle filling, which improves hemodynamics. Diuretics can be used in patients who are hypotensive and volume overloaded, but vasopressors should be employed to support blood pressure.

When using mechanical ventilation, strategies such as low tidal volumes, minimization of positive end expiratory pressure, and prevention of hypoxemia and acidemia should be employed to prevent an increase of pulmonary vascular resistance, which can worsen RV failure.

Pulmonary vasodilators aren’t recommended for acute PE, but inhaled pulmonary vasodilators may be considered in hemodynamically unstable patients.

Surgically implanted right ventricle assistance device are generally not used for acute RV failure in high-risk PE, unless the patient has not improved after medical management.
 

Percutaneous devices

Percutaneous mechanical circulatory support devices can be used for patients experiencing refractory shock. The review highlighted three such devices, including the Impella RP, tandem-heart right ventricular assist devices (TH-RVAD) or Protek Duo, and venoarterial extracorporeal membrane oxygenation (VA-ECMO), but they are not without limitations. “Challenges to using these devices in patients with acute PE include clot dislodgement, vascular complications, infections, device migration, and fracture of individual elements,” the authors wrote.

The Impella RP is easy to deploy and bypasses the RV, but it can’t provide blood oxygenation and may cause bleeding or hemolysis. TH-RVAD oxygenates the blood and bypasses the RV, but suffers from a large sheath size. VA-ECMO oxygenates the blood but may cause bleeding.

There are important differences among the mechanical support devices, according to Jonathan Ludmir, MD, who was asked to comment. “In reality, if someone has a large pulmonary embolism burden, to put in the Impella RP or the Protek Duo would be a little bit risky, because you’d be sometimes putting the device right where the clot is. At least what we do in our institution, when someone is in extremis despite using [intravenous] medications like vasopressors or inotropes, VA-ECMO is kind of the go to. This is both the quickest and probably most effective way to support the patient. I say the quickest because this is a procedure you can do at the bedside.”
 

Benefits of PERT

One message that the review only briefly mentions, but Dr. Ludmir believes is key, is employing a pulmonary embolism response team. “That’s been looked at extensively, and it’s a really key part of any decision-making. If someone presents to the emergency room or someone inside the hospital has an acute pulmonary embolism, you have a team of people that can respond and help assess the next step. Typically, that involves a cardiologist or an interventional cardiologist, a hematologist, vascular surgeon, often a cardiac surgeon, so it’s a whole slew of people. Based on the patient assessment they can quickly decide, can this patient just be okay with a blood thinner like heparin? Does this patient need something more aggressive, like a thrombectomy? Or is this a serious case where you involve the shock team or the ECMO team, and you have to stabilize the patient on mechanical circulatory support, so you can accomplish what you need to do to get rid of the pulmonary embolism,” said Dr. Ludmir, who is an assistant professor of medicine at Corrigan Minehan Heart Center at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“Every case is individualized, hence the importance of having a team of a variety of different backgrounds and thoughts to approach it. And I think that’s kind of like the key takeaway. Yes, you have to be familiar with all the therapies, but at the end of the day, not every patient is going to fit into the algorithm for how you approach pulmonary embolism,” said Dr. Ludmir.

Dr. Ludmir has no relevant conflicts of interest.

A new review article highlights approaches for mechanical circulatory support in patients with high-risk acute pulmonary embolism (PE). Mechanical support has become an important treatment option for refractory shock resulting from acute right ventricular failure (RVF).

Pulmonary embolism with hemodynamic significance is widely underdiagnosed, and the mortality rate can be as high as 30%, but new therapeutic developments offer promise. “Over the past few years, a renewed interest in mechanical circulatory support (MCS; both percutaneous and surgical) for acute RVF has emerged, increasing viable treatment options for high-risk acute PE,” wrote the authors of the review, which was published online in Interventional Cardiology Clinics.

Poor outcomes are often driven by RVF, which is tricky to diagnose and manage, and it stems from a sudden increase in pulmonary vascular resistance (PVR) following PE. “The mechanism for increased PVR in acute PE is multifactorial, including direct blood flow impedance, local hypoxia-induced vasoconstriction, and platelet/thrombin-induced release of vasoactive peptides. The cascade of events that then leads to RVF includes decreased RV stoke volume, increased RV wall tension, and RV dilation,” the authors wrote.

The authors noted that diuretics help to correct changes to RV geometry and can improve left ventricle filling, which improves hemodynamics. Diuretics can be used in patients who are hypotensive and volume overloaded, but vasopressors should be employed to support blood pressure.

When using mechanical ventilation, strategies such as low tidal volumes, minimization of positive end expiratory pressure, and prevention of hypoxemia and acidemia should be employed to prevent an increase of pulmonary vascular resistance, which can worsen RV failure.

Pulmonary vasodilators aren’t recommended for acute PE, but inhaled pulmonary vasodilators may be considered in hemodynamically unstable patients.

Surgically implanted right ventricle assistance device are generally not used for acute RV failure in high-risk PE, unless the patient has not improved after medical management.
 

Percutaneous devices

Percutaneous mechanical circulatory support devices can be used for patients experiencing refractory shock. The review highlighted three such devices, including the Impella RP, tandem-heart right ventricular assist devices (TH-RVAD) or Protek Duo, and venoarterial extracorporeal membrane oxygenation (VA-ECMO), but they are not without limitations. “Challenges to using these devices in patients with acute PE include clot dislodgement, vascular complications, infections, device migration, and fracture of individual elements,” the authors wrote.

The Impella RP is easy to deploy and bypasses the RV, but it can’t provide blood oxygenation and may cause bleeding or hemolysis. TH-RVAD oxygenates the blood and bypasses the RV, but suffers from a large sheath size. VA-ECMO oxygenates the blood but may cause bleeding.

There are important differences among the mechanical support devices, according to Jonathan Ludmir, MD, who was asked to comment. “In reality, if someone has a large pulmonary embolism burden, to put in the Impella RP or the Protek Duo would be a little bit risky, because you’d be sometimes putting the device right where the clot is. At least what we do in our institution, when someone is in extremis despite using [intravenous] medications like vasopressors or inotropes, VA-ECMO is kind of the go to. This is both the quickest and probably most effective way to support the patient. I say the quickest because this is a procedure you can do at the bedside.”
 

Benefits of PERT

One message that the review only briefly mentions, but Dr. Ludmir believes is key, is employing a pulmonary embolism response team. “That’s been looked at extensively, and it’s a really key part of any decision-making. If someone presents to the emergency room or someone inside the hospital has an acute pulmonary embolism, you have a team of people that can respond and help assess the next step. Typically, that involves a cardiologist or an interventional cardiologist, a hematologist, vascular surgeon, often a cardiac surgeon, so it’s a whole slew of people. Based on the patient assessment they can quickly decide, can this patient just be okay with a blood thinner like heparin? Does this patient need something more aggressive, like a thrombectomy? Or is this a serious case where you involve the shock team or the ECMO team, and you have to stabilize the patient on mechanical circulatory support, so you can accomplish what you need to do to get rid of the pulmonary embolism,” said Dr. Ludmir, who is an assistant professor of medicine at Corrigan Minehan Heart Center at Massachusetts General Hospital and Harvard Medical School, both in Boston.

“Every case is individualized, hence the importance of having a team of a variety of different backgrounds and thoughts to approach it. And I think that’s kind of like the key takeaway. Yes, you have to be familiar with all the therapies, but at the end of the day, not every patient is going to fit into the algorithm for how you approach pulmonary embolism,” said Dr. Ludmir.

Dr. Ludmir has no relevant conflicts of interest.

Psyllium fiber offered protection against colitis in mice models through its effect on bile acid metabolism, which in turn reduces proinflammatory signaling through activation of the farnesoid X receptor (FXR), shows a study recently published in Cellular and Molecular Gastroenterology and Hepatology

“Our results support the notion that pharmacologic FXR activation might be useful in managing IBD [inflammatory bowel disease], and thus, further investigation of its mechanisms of action are warranted,” wrote the authors, led by Andrew Gewirtz, of the Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta.

Dr. Andrew Gewirtz

Dietary fiber has long been understood to be a key component to a healthy diet by promoting intestinal and metabolic health, but it is unclear whether dietary fiber benefits IBD, specifically Crohn’s disease and ulcerative colitis, and if so, what fiber types are best for these conditions. Some studies have suggested an association between fiber-rich diets and reduced incidence of IBD, but some IBD patients experience intolerance to fiber-rich foods and associated fiber-rich foods with disease flares. In mouse models with colitis, semi-purified fibers have been associated with both the easing and exacerbation of IBD symptoms, with soluble/fermentable fibers like inulin and pectin generally worsening colitis.

The study had two goals: Identify specific fibers that might ameliorate two models of experimental colitis in mice models and to better understand the mechanism by which fiber(s) might suppress inflammation.

Mice were fed high-fiber grain-based chow or diets enriched with semi-purified fibers that included inulin, cellulose, pectin, glucomannan, and psyllium, but only psyllium, a semi-soluble derived from Plantago seeds, improved colitis, and metabolic syndrome. The other fibers often protected against obesity but worsened colitis.

Consuming diets enriched with psyllium were found to “markedly” protected against both dextran sulfate sodium– and T-cell transfer–induced colitis. The protection was independent of fermentation and occurred in animals with minimal microbiota. The animals had increased expression of genes that influence bile acid secretion, and the researchers noted increased levels of both fecal and serum BA.

The increased serum levels prompted the researchers to investigate psyllium’s role in signaling activation through BA receptors, especially FXR. An FXR agonist also reduced colitis severity, while an FXR antagonist worsened it. FXR-deficient mice gained little benefit from psyllium supplementation, further suggesting that FXR mediates psyllium’s effect.

All soluble fibers impacted gut microbiota composition, but none more than psyllium which protected mice from developing dextran sulfate sodium colitis. While other soluble fibers increased in the abundance of bacteria (that is, fecal/luminal bacterial density), psyllium decreased in this area, which may explain why some fermentable fibers, including inulin, exacerbate colitis.

“These results indicate that psyllium’s protection against colitis involves its ability to increase circulating bile acid levels, thus activating FXR signaling,” the authors wrote.

Researchers found some evidence that prolonged psyllium supplementation could lead to mild elevations in AST and ALT, suggesting that the ability of psyllium to chelate BA could lead to lipid deficiency, especially in the presence of a low-fat diet.

“We suggest that future studies of psyllium in humans measure serum BA and consider roles for FXR activation in mediating impacts of this fiber,” the authors wrote.

The study was supported by the National Institutes of Health and the Crohn’s and Colitis Foundation. The authors disclosed no conflicts.

Psyllium fiber offered protection against colitis in mice models through its effect on bile acid metabolism, which in turn reduces proinflammatory signaling through activation of the farnesoid X receptor (FXR), shows a study recently published in Cellular and Molecular Gastroenterology and Hepatology

“Our results support the notion that pharmacologic FXR activation might be useful in managing IBD [inflammatory bowel disease], and thus, further investigation of its mechanisms of action are warranted,” wrote the authors, led by Andrew Gewirtz, of the Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta.

Dr. Andrew Gewirtz

Dietary fiber has long been understood to be a key component to a healthy diet by promoting intestinal and metabolic health, but it is unclear whether dietary fiber benefits IBD, specifically Crohn’s disease and ulcerative colitis, and if so, what fiber types are best for these conditions. Some studies have suggested an association between fiber-rich diets and reduced incidence of IBD, but some IBD patients experience intolerance to fiber-rich foods and associated fiber-rich foods with disease flares. In mouse models with colitis, semi-purified fibers have been associated with both the easing and exacerbation of IBD symptoms, with soluble/fermentable fibers like inulin and pectin generally worsening colitis.

The study had two goals: Identify specific fibers that might ameliorate two models of experimental colitis in mice models and to better understand the mechanism by which fiber(s) might suppress inflammation.

Mice were fed high-fiber grain-based chow or diets enriched with semi-purified fibers that included inulin, cellulose, pectin, glucomannan, and psyllium, but only psyllium, a semi-soluble derived from Plantago seeds, improved colitis, and metabolic syndrome. The other fibers often protected against obesity but worsened colitis.

Consuming diets enriched with psyllium were found to “markedly” protected against both dextran sulfate sodium– and T-cell transfer–induced colitis. The protection was independent of fermentation and occurred in animals with minimal microbiota. The animals had increased expression of genes that influence bile acid secretion, and the researchers noted increased levels of both fecal and serum BA.

The increased serum levels prompted the researchers to investigate psyllium’s role in signaling activation through BA receptors, especially FXR. An FXR agonist also reduced colitis severity, while an FXR antagonist worsened it. FXR-deficient mice gained little benefit from psyllium supplementation, further suggesting that FXR mediates psyllium’s effect.

All soluble fibers impacted gut microbiota composition, but none more than psyllium which protected mice from developing dextran sulfate sodium colitis. While other soluble fibers increased in the abundance of bacteria (that is, fecal/luminal bacterial density), psyllium decreased in this area, which may explain why some fermentable fibers, including inulin, exacerbate colitis.

“These results indicate that psyllium’s protection against colitis involves its ability to increase circulating bile acid levels, thus activating FXR signaling,” the authors wrote.

Researchers found some evidence that prolonged psyllium supplementation could lead to mild elevations in AST and ALT, suggesting that the ability of psyllium to chelate BA could lead to lipid deficiency, especially in the presence of a low-fat diet.

“We suggest that future studies of psyllium in humans measure serum BA and consider roles for FXR activation in mediating impacts of this fiber,” the authors wrote.

The study was supported by the National Institutes of Health and the Crohn’s and Colitis Foundation. The authors disclosed no conflicts.

Psyllium fiber offered protection against colitis in mice models through its effect on bile acid metabolism, which in turn reduces proinflammatory signaling through activation of the farnesoid X receptor (FXR), shows a study recently published in Cellular and Molecular Gastroenterology and Hepatology

“Our results support the notion that pharmacologic FXR activation might be useful in managing IBD [inflammatory bowel disease], and thus, further investigation of its mechanisms of action are warranted,” wrote the authors, led by Andrew Gewirtz, of the Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta.

Dr. Andrew Gewirtz

Dietary fiber has long been understood to be a key component to a healthy diet by promoting intestinal and metabolic health, but it is unclear whether dietary fiber benefits IBD, specifically Crohn’s disease and ulcerative colitis, and if so, what fiber types are best for these conditions. Some studies have suggested an association between fiber-rich diets and reduced incidence of IBD, but some IBD patients experience intolerance to fiber-rich foods and associated fiber-rich foods with disease flares. In mouse models with colitis, semi-purified fibers have been associated with both the easing and exacerbation of IBD symptoms, with soluble/fermentable fibers like inulin and pectin generally worsening colitis.

The study had two goals: Identify specific fibers that might ameliorate two models of experimental colitis in mice models and to better understand the mechanism by which fiber(s) might suppress inflammation.

Mice were fed high-fiber grain-based chow or diets enriched with semi-purified fibers that included inulin, cellulose, pectin, glucomannan, and psyllium, but only psyllium, a semi-soluble derived from Plantago seeds, improved colitis, and metabolic syndrome. The other fibers often protected against obesity but worsened colitis.

Consuming diets enriched with psyllium were found to “markedly” protected against both dextran sulfate sodium– and T-cell transfer–induced colitis. The protection was independent of fermentation and occurred in animals with minimal microbiota. The animals had increased expression of genes that influence bile acid secretion, and the researchers noted increased levels of both fecal and serum BA.

The increased serum levels prompted the researchers to investigate psyllium’s role in signaling activation through BA receptors, especially FXR. An FXR agonist also reduced colitis severity, while an FXR antagonist worsened it. FXR-deficient mice gained little benefit from psyllium supplementation, further suggesting that FXR mediates psyllium’s effect.

All soluble fibers impacted gut microbiota composition, but none more than psyllium which protected mice from developing dextran sulfate sodium colitis. While other soluble fibers increased in the abundance of bacteria (that is, fecal/luminal bacterial density), psyllium decreased in this area, which may explain why some fermentable fibers, including inulin, exacerbate colitis.

“These results indicate that psyllium’s protection against colitis involves its ability to increase circulating bile acid levels, thus activating FXR signaling,” the authors wrote.

Researchers found some evidence that prolonged psyllium supplementation could lead to mild elevations in AST and ALT, suggesting that the ability of psyllium to chelate BA could lead to lipid deficiency, especially in the presence of a low-fat diet.

“We suggest that future studies of psyllium in humans measure serum BA and consider roles for FXR activation in mediating impacts of this fiber,” the authors wrote.

The study was supported by the National Institutes of Health and the Crohn’s and Colitis Foundation. The authors disclosed no conflicts.

Individuals who are carriers of germline pathogenic variants in susceptibility genes for pancreatic ductal adenocarcinoma (PDAC), or have a strong family history of PDAC, benefit from having annual MRIs, shows a new study published in Gastroenterology.

While other studies have shown potential benefit in screening high-risk individuals, “a concern is that in absence of sufficiently large control groups with unscreened controls,” the outcomes may be influenced by lead-time bias. The current study is the first to address that important limitation.

The study, which was led by Derk C.F. Klatte, MD, of the department of gastroenterology and hepatology at Leiden University Medical Center, the Netherlands, included 43,762 patients from the Netherlands Cancer Registry who were diagnosed with PDAC between January 2000 and December 2020. Using a 1:5 ratio, researchers matched 31 patients who were diagnosed in the pancreatic cancer surveillance cohort against 155 patients in the non-surveillance group.

Leiden University Medical Center

“We show that surveillance for PDAC in high-risk individuals results in significant earlier detection, increased resectability, and improved survival as compared with average-risk individuals diagnosed with PDAC not under surveillance. This reaffirms that pancreatic surveillance for certain in high-risk individuals is beneficial and could have a meaningful impact on disease course,” the authors wrote.

PDAC has the worst outcomes all cancers and is on pace to become the second-leading cause of cancer-related mortality. By the time a tumor is detected, it is usually unresectable or has developed distant metastases. In principle, early detection could improve outcomes, but there is no test that is adequate for population-wide screening. Surveillance must therefore concentrate on individuals deemed to be at heightened risk. Prospective studies have shown a benefit of pancreatic cancer screening in patients who are at high-risk. Such studies may be misleading, however, due to the potential for lead-time bias. This can occur when a condition is detected at an earlier time than it would have been identified based on clinical signs, as usually occurs in nonscreened populations, and this asymptomatic lag time between diagnosis and initial symptoms does not get incorporated into a survival analysis. The result can be an artificially longer survival time following diagnosis in the screened population.

Guidelines from the International Cancer of the Pancreas Screening (CAPS) consortium, the American Society for Gastrointestinal Endoscopy, and American Society of Clinical Oncology recommend surveillance in high-risk cases.

In this study, researchers conducted a propensity score matched cohort analysis of patients from the general population with primary PDAC who were diagnosed outside of a screening program, with carriers of a germline CDKN2A/p16 mutation who were diagnosed after surveillance.

The surveillance group received a stage 1 diagnosis in 38.7% of cases, versus 5.8% of those outside of surveillance (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04-0.19). Surgical resection occurred in 71.0% of surveillance patients, versus 18.7% of non-surveillance patients (OR, 10.62; 95% CI, 4.56-26.63), and stage 4 diagnoses were much more common in the nonsurveillance population (61.3% versus 9.7%). Among the patients who did not undergo surveillance, 61.3% were diagnosed with stage 4 disease compared with 9.7% of those in the surveillance group.

The 5-year survival rate (unadjusted for lead-time) in the surveillance group was 32.4% and 4.3% in the nonsurveillance group. The median overall survival was 26.8 months in the surveillance group compared with 5.2 months in the nonsurveillance group, (hazard ratio, 0.22; 95% CI, 0.14-0.36). The mortality rate per 100 person-years was 114.5 (95% CI, 96.2–135.3) in nonsurveillance patients and 21.9 (95% CI, 13.4–33.8) in surveillance patients.

Despite the apparent benefit of screening, there is room for improvement. “Although the outcomes presented here are encouraging and endorse our earlier findings, a significant proportion of surveillance patients (61%) still had poor outcomes because of diagnosis in a late stage (T2–4N0M0 and nodal or distant metastatic PDAC), with a 5-year survival of 16%,” the authors wrote.

The study received no funding and the authors declared no conflicts.

Individuals who are carriers of germline pathogenic variants in susceptibility genes for pancreatic ductal adenocarcinoma (PDAC), or have a strong family history of PDAC, benefit from having annual MRIs, shows a new study published in Gastroenterology.

While other studies have shown potential benefit in screening high-risk individuals, “a concern is that in absence of sufficiently large control groups with unscreened controls,” the outcomes may be influenced by lead-time bias. The current study is the first to address that important limitation.

The study, which was led by Derk C.F. Klatte, MD, of the department of gastroenterology and hepatology at Leiden University Medical Center, the Netherlands, included 43,762 patients from the Netherlands Cancer Registry who were diagnosed with PDAC between January 2000 and December 2020. Using a 1:5 ratio, researchers matched 31 patients who were diagnosed in the pancreatic cancer surveillance cohort against 155 patients in the non-surveillance group.

Leiden University Medical Center

“We show that surveillance for PDAC in high-risk individuals results in significant earlier detection, increased resectability, and improved survival as compared with average-risk individuals diagnosed with PDAC not under surveillance. This reaffirms that pancreatic surveillance for certain in high-risk individuals is beneficial and could have a meaningful impact on disease course,” the authors wrote.

PDAC has the worst outcomes all cancers and is on pace to become the second-leading cause of cancer-related mortality. By the time a tumor is detected, it is usually unresectable or has developed distant metastases. In principle, early detection could improve outcomes, but there is no test that is adequate for population-wide screening. Surveillance must therefore concentrate on individuals deemed to be at heightened risk. Prospective studies have shown a benefit of pancreatic cancer screening in patients who are at high-risk. Such studies may be misleading, however, due to the potential for lead-time bias. This can occur when a condition is detected at an earlier time than it would have been identified based on clinical signs, as usually occurs in nonscreened populations, and this asymptomatic lag time between diagnosis and initial symptoms does not get incorporated into a survival analysis. The result can be an artificially longer survival time following diagnosis in the screened population.

Guidelines from the International Cancer of the Pancreas Screening (CAPS) consortium, the American Society for Gastrointestinal Endoscopy, and American Society of Clinical Oncology recommend surveillance in high-risk cases.

In this study, researchers conducted a propensity score matched cohort analysis of patients from the general population with primary PDAC who were diagnosed outside of a screening program, with carriers of a germline CDKN2A/p16 mutation who were diagnosed after surveillance.

The surveillance group received a stage 1 diagnosis in 38.7% of cases, versus 5.8% of those outside of surveillance (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04-0.19). Surgical resection occurred in 71.0% of surveillance patients, versus 18.7% of non-surveillance patients (OR, 10.62; 95% CI, 4.56-26.63), and stage 4 diagnoses were much more common in the nonsurveillance population (61.3% versus 9.7%). Among the patients who did not undergo surveillance, 61.3% were diagnosed with stage 4 disease compared with 9.7% of those in the surveillance group.

The 5-year survival rate (unadjusted for lead-time) in the surveillance group was 32.4% and 4.3% in the nonsurveillance group. The median overall survival was 26.8 months in the surveillance group compared with 5.2 months in the nonsurveillance group, (hazard ratio, 0.22; 95% CI, 0.14-0.36). The mortality rate per 100 person-years was 114.5 (95% CI, 96.2–135.3) in nonsurveillance patients and 21.9 (95% CI, 13.4–33.8) in surveillance patients.

Despite the apparent benefit of screening, there is room for improvement. “Although the outcomes presented here are encouraging and endorse our earlier findings, a significant proportion of surveillance patients (61%) still had poor outcomes because of diagnosis in a late stage (T2–4N0M0 and nodal or distant metastatic PDAC), with a 5-year survival of 16%,” the authors wrote.

The study received no funding and the authors declared no conflicts.

Individuals who are carriers of germline pathogenic variants in susceptibility genes for pancreatic ductal adenocarcinoma (PDAC), or have a strong family history of PDAC, benefit from having annual MRIs, shows a new study published in Gastroenterology.

While other studies have shown potential benefit in screening high-risk individuals, “a concern is that in absence of sufficiently large control groups with unscreened controls,” the outcomes may be influenced by lead-time bias. The current study is the first to address that important limitation.

The study, which was led by Derk C.F. Klatte, MD, of the department of gastroenterology and hepatology at Leiden University Medical Center, the Netherlands, included 43,762 patients from the Netherlands Cancer Registry who were diagnosed with PDAC between January 2000 and December 2020. Using a 1:5 ratio, researchers matched 31 patients who were diagnosed in the pancreatic cancer surveillance cohort against 155 patients in the non-surveillance group.

Leiden University Medical Center

“We show that surveillance for PDAC in high-risk individuals results in significant earlier detection, increased resectability, and improved survival as compared with average-risk individuals diagnosed with PDAC not under surveillance. This reaffirms that pancreatic surveillance for certain in high-risk individuals is beneficial and could have a meaningful impact on disease course,” the authors wrote.

PDAC has the worst outcomes all cancers and is on pace to become the second-leading cause of cancer-related mortality. By the time a tumor is detected, it is usually unresectable or has developed distant metastases. In principle, early detection could improve outcomes, but there is no test that is adequate for population-wide screening. Surveillance must therefore concentrate on individuals deemed to be at heightened risk. Prospective studies have shown a benefit of pancreatic cancer screening in patients who are at high-risk. Such studies may be misleading, however, due to the potential for lead-time bias. This can occur when a condition is detected at an earlier time than it would have been identified based on clinical signs, as usually occurs in nonscreened populations, and this asymptomatic lag time between diagnosis and initial symptoms does not get incorporated into a survival analysis. The result can be an artificially longer survival time following diagnosis in the screened population.

Guidelines from the International Cancer of the Pancreas Screening (CAPS) consortium, the American Society for Gastrointestinal Endoscopy, and American Society of Clinical Oncology recommend surveillance in high-risk cases.

In this study, researchers conducted a propensity score matched cohort analysis of patients from the general population with primary PDAC who were diagnosed outside of a screening program, with carriers of a germline CDKN2A/p16 mutation who were diagnosed after surveillance.

The surveillance group received a stage 1 diagnosis in 38.7% of cases, versus 5.8% of those outside of surveillance (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04-0.19). Surgical resection occurred in 71.0% of surveillance patients, versus 18.7% of non-surveillance patients (OR, 10.62; 95% CI, 4.56-26.63), and stage 4 diagnoses were much more common in the nonsurveillance population (61.3% versus 9.7%). Among the patients who did not undergo surveillance, 61.3% were diagnosed with stage 4 disease compared with 9.7% of those in the surveillance group.

The 5-year survival rate (unadjusted for lead-time) in the surveillance group was 32.4% and 4.3% in the nonsurveillance group. The median overall survival was 26.8 months in the surveillance group compared with 5.2 months in the nonsurveillance group, (hazard ratio, 0.22; 95% CI, 0.14-0.36). The mortality rate per 100 person-years was 114.5 (95% CI, 96.2–135.3) in nonsurveillance patients and 21.9 (95% CI, 13.4–33.8) in surveillance patients.

Despite the apparent benefit of screening, there is room for improvement. “Although the outcomes presented here are encouraging and endorse our earlier findings, a significant proportion of surveillance patients (61%) still had poor outcomes because of diagnosis in a late stage (T2–4N0M0 and nodal or distant metastatic PDAC), with a 5-year survival of 16%,” the authors wrote.

The study received no funding and the authors declared no conflicts.

Extraesophageal reflux (EER) symptoms are a subset of gastroesophageal reflux disease (GERD) that can be difficult to diagnose because of its heterogeneous nature and symptoms that overlap with other conditions.

That puts the onus on physicians to take all symptoms into account and work across disciplines to diagnose, manage, and treat the condition, according to a new clinical practice update from the American Gastroenterological Association, which was published in Clinical Gastroenterology and Hepatology.

University of Michigan Health

GERD is becoming increasingly common, which in turn has led to greater awareness and consideration of EER symptoms. EER symptoms can present a challenge because they may vary considerably and are not unique to GERD. The symptoms often do not respond well to proton pump inhibitor (PPI) therapy.

EER symptoms can include cough, laryngeal hoarseness, dysphonia, pulmonary fibrosis, asthma, dental erosions/caries, sinus disease, ear disease, postnasal drip, and throat clearing. Some patients with EER symptoms do not report heartburn or regurgitation, which leaves it up to the physician to determine if acid reflux is present and contributing to symptoms.

“The concept of extraesophageal symptoms secondary to GERD is complex and often controversial, leading to diagnostic and therapeutic challenges. Several extraesophageal symptoms have been associated with GERD, although the strength of evidence to support a causal relation varies,” wrote the authors, who were led by Joan W. Chen, MD, MS, a gastroenterologist with the University of Michigan, Ann Arbor.

There is also debate over whether fluid refluxate is the source of damage that causes EER symptoms, and if so, whether it is sufficient that the fluid be acidic or that pepsin be present, or if the cause is related to neurogenic signaling and resulting inflammation. Because of these questions, a PPI trial will not necessarily provide insight into the role of acid reflux in EER symptoms.

American Gastroenterological Association

To guide physicians in diagnosing and managing EER symptoms, the authors created 10 advice statements based on a review of the published literature and expert opinion.

Best practice advice 1: The authors emphasized that gastroenterologists need to be aware of the potential extraesophageal symptoms of GERD. They should inquire with GERD patients to determine if laryngitis, chronic cough, asthma, and dental erosions are present.

Best practice advice 2: Consider a multidisciplinary approach to EER manifestations. Cases may require input from non-GI specialties. Tests performed by other specialists, such as bronchoscopy, thoracic imaging, or laryngoscopy, should be taken into account, since patients will also seek out multiple specialists to address their symptoms.

Best practice advice 3: There is no specific diagnostic test available to determine if GER is the cause of EER symptoms. Instead, physicians should interpret patient symptoms, response to GER therapy, and input from endoscopy and reflux tests.

Best practice advice 4: Rather than subject the patient to the cost and potential for even rare adverse events of a PPI trial, physicians should first consider conducting reflux testing. A PPI trial has clinical value but is insufficient on its own to help diagnose or manage EER. Initial single-dose PPI trial, titrating up to twice daily in those with typical GERD symptoms, is reasonable.

Best practice advice 5: The inconsistent therapeutic response to PPI therapy means that positive effects of PPI therapy on EER symptoms can’t confirm a GERD diagnosis because a placebo effect may be involved, and because symptom improvement can occur through mechanisms other than acid suppression. A meta-analysis found that a PPI trial has a sensitivity of 71%-78% and a specificity of 41%-54% with typical symptoms of heartburn and regurgitation. “Considering the greater variation expected with PPI response for extraesophageal symptoms, the diagnostic performance of empiric PPI trial for a diagnosis of EER would be anticipated to be substantially lower,” the authors wrote.

Best practice advice 6: When EER symptoms related to GERD are suspected and a PPI trial of up to 12 weeks does not lead to adequate improvement, the physician should consider testing for pathologic GER. Additional trials employing other PPIs are unlikely to succeed.

Best practice advice 7: Initial testing to evaluate for reflux should be tailored to patients’ clinical presentation. Potential methods to evaluate reflux include upper endoscopy and ambulatory reflux monitoring studies of acid suppressive therapy, which can assist with a GERD diagnosis, particularly when nonerosive reflux is present.

Best practice advice 8: About 50%-60% of patients with EER symptoms will not have GERD. Testing can be considered for those with an established objective diagnosis of GERD who do not respond well to high doses of acid suppression. Cost-effectiveness studies have confirmed the value of starting with ambulatory reflux monitoring, which can include a catheter-based pH sensor, pH impedance, or wireless pH capsule.

Ambulatory esophageal pH monitoring can also assist in making a GERD diagnosis, but it does not indicate whether GERD may be contributing to EER symptoms.

“Whichever the reflux testing modality, the strongest confidence for EER is achieved after ambulatory reflux testing showing pathologic acid exposure and a positive symptom-reflux association for EER symptoms,” the authors wrote. They also pointed out that ambulatory reflux monitoring in EER patients should be done in the absence of acid suppression unless there is already objective evidence for the presence of GERD.

Best practice advice 9: Aside from acid suppression, EER symptoms can also be managed through other means, including lifestyle modifications, such as eating avoidance prior to lying down, elevation of the head of the bed, sleeping on the left side, and weight loss. Or, alginate containing antacids, external upper esophageal sphincter compression device, cognitive behavioral therapy, and neuromodulators.

Best practice advice 10: In cases where the EER patient has objectively defined evidence of GERD, physicians should employ shared decision-making before considering anti-reflux surgery. If the patient did not respond to PPI therapy, this predicts a lack of response to antireflux surgery.

All four authors reported financial ties to multiple pharmaceutical companies.

Extraesophageal reflux (EER) symptoms are a subset of gastroesophageal reflux disease (GERD) that can be difficult to diagnose because of its heterogeneous nature and symptoms that overlap with other conditions.

That puts the onus on physicians to take all symptoms into account and work across disciplines to diagnose, manage, and treat the condition, according to a new clinical practice update from the American Gastroenterological Association, which was published in Clinical Gastroenterology and Hepatology.

University of Michigan Health

GERD is becoming increasingly common, which in turn has led to greater awareness and consideration of EER symptoms. EER symptoms can present a challenge because they may vary considerably and are not unique to GERD. The symptoms often do not respond well to proton pump inhibitor (PPI) therapy.

EER symptoms can include cough, laryngeal hoarseness, dysphonia, pulmonary fibrosis, asthma, dental erosions/caries, sinus disease, ear disease, postnasal drip, and throat clearing. Some patients with EER symptoms do not report heartburn or regurgitation, which leaves it up to the physician to determine if acid reflux is present and contributing to symptoms.

“The concept of extraesophageal symptoms secondary to GERD is complex and often controversial, leading to diagnostic and therapeutic challenges. Several extraesophageal symptoms have been associated with GERD, although the strength of evidence to support a causal relation varies,” wrote the authors, who were led by Joan W. Chen, MD, MS, a gastroenterologist with the University of Michigan, Ann Arbor.

There is also debate over whether fluid refluxate is the source of damage that causes EER symptoms, and if so, whether it is sufficient that the fluid be acidic or that pepsin be present, or if the cause is related to neurogenic signaling and resulting inflammation. Because of these questions, a PPI trial will not necessarily provide insight into the role of acid reflux in EER symptoms.

American Gastroenterological Association

To guide physicians in diagnosing and managing EER symptoms, the authors created 10 advice statements based on a review of the published literature and expert opinion.

Best practice advice 1: The authors emphasized that gastroenterologists need to be aware of the potential extraesophageal symptoms of GERD. They should inquire with GERD patients to determine if laryngitis, chronic cough, asthma, and dental erosions are present.

Best practice advice 2: Consider a multidisciplinary approach to EER manifestations. Cases may require input from non-GI specialties. Tests performed by other specialists, such as bronchoscopy, thoracic imaging, or laryngoscopy, should be taken into account, since patients will also seek out multiple specialists to address their symptoms.

Best practice advice 3: There is no specific diagnostic test available to determine if GER is the cause of EER symptoms. Instead, physicians should interpret patient symptoms, response to GER therapy, and input from endoscopy and reflux tests.

Best practice advice 4: Rather than subject the patient to the cost and potential for even rare adverse events of a PPI trial, physicians should first consider conducting reflux testing. A PPI trial has clinical value but is insufficient on its own to help diagnose or manage EER. Initial single-dose PPI trial, titrating up to twice daily in those with typical GERD symptoms, is reasonable.

Best practice advice 5: The inconsistent therapeutic response to PPI therapy means that positive effects of PPI therapy on EER symptoms can’t confirm a GERD diagnosis because a placebo effect may be involved, and because symptom improvement can occur through mechanisms other than acid suppression. A meta-analysis found that a PPI trial has a sensitivity of 71%-78% and a specificity of 41%-54% with typical symptoms of heartburn and regurgitation. “Considering the greater variation expected with PPI response for extraesophageal symptoms, the diagnostic performance of empiric PPI trial for a diagnosis of EER would be anticipated to be substantially lower,” the authors wrote.

Best practice advice 6: When EER symptoms related to GERD are suspected and a PPI trial of up to 12 weeks does not lead to adequate improvement, the physician should consider testing for pathologic GER. Additional trials employing other PPIs are unlikely to succeed.

Best practice advice 7: Initial testing to evaluate for reflux should be tailored to patients’ clinical presentation. Potential methods to evaluate reflux include upper endoscopy and ambulatory reflux monitoring studies of acid suppressive therapy, which can assist with a GERD diagnosis, particularly when nonerosive reflux is present.

Best practice advice 8: About 50%-60% of patients with EER symptoms will not have GERD. Testing can be considered for those with an established objective diagnosis of GERD who do not respond well to high doses of acid suppression. Cost-effectiveness studies have confirmed the value of starting with ambulatory reflux monitoring, which can include a catheter-based pH sensor, pH impedance, or wireless pH capsule.

Ambulatory esophageal pH monitoring can also assist in making a GERD diagnosis, but it does not indicate whether GERD may be contributing to EER symptoms.

“Whichever the reflux testing modality, the strongest confidence for EER is achieved after ambulatory reflux testing showing pathologic acid exposure and a positive symptom-reflux association for EER symptoms,” the authors wrote. They also pointed out that ambulatory reflux monitoring in EER patients should be done in the absence of acid suppression unless there is already objective evidence for the presence of GERD.

Best practice advice 9: Aside from acid suppression, EER symptoms can also be managed through other means, including lifestyle modifications, such as eating avoidance prior to lying down, elevation of the head of the bed, sleeping on the left side, and weight loss. Or, alginate containing antacids, external upper esophageal sphincter compression device, cognitive behavioral therapy, and neuromodulators.

Best practice advice 10: In cases where the EER patient has objectively defined evidence of GERD, physicians should employ shared decision-making before considering anti-reflux surgery. If the patient did not respond to PPI therapy, this predicts a lack of response to antireflux surgery.

All four authors reported financial ties to multiple pharmaceutical companies.

Extraesophageal reflux (EER) symptoms are a subset of gastroesophageal reflux disease (GERD) that can be difficult to diagnose because of its heterogeneous nature and symptoms that overlap with other conditions.

That puts the onus on physicians to take all symptoms into account and work across disciplines to diagnose, manage, and treat the condition, according to a new clinical practice update from the American Gastroenterological Association, which was published in Clinical Gastroenterology and Hepatology.

University of Michigan Health

GERD is becoming increasingly common, which in turn has led to greater awareness and consideration of EER symptoms. EER symptoms can present a challenge because they may vary considerably and are not unique to GERD. The symptoms often do not respond well to proton pump inhibitor (PPI) therapy.

EER symptoms can include cough, laryngeal hoarseness, dysphonia, pulmonary fibrosis, asthma, dental erosions/caries, sinus disease, ear disease, postnasal drip, and throat clearing. Some patients with EER symptoms do not report heartburn or regurgitation, which leaves it up to the physician to determine if acid reflux is present and contributing to symptoms.

“The concept of extraesophageal symptoms secondary to GERD is complex and often controversial, leading to diagnostic and therapeutic challenges. Several extraesophageal symptoms have been associated with GERD, although the strength of evidence to support a causal relation varies,” wrote the authors, who were led by Joan W. Chen, MD, MS, a gastroenterologist with the University of Michigan, Ann Arbor.

There is also debate over whether fluid refluxate is the source of damage that causes EER symptoms, and if so, whether it is sufficient that the fluid be acidic or that pepsin be present, or if the cause is related to neurogenic signaling and resulting inflammation. Because of these questions, a PPI trial will not necessarily provide insight into the role of acid reflux in EER symptoms.

American Gastroenterological Association

To guide physicians in diagnosing and managing EER symptoms, the authors created 10 advice statements based on a review of the published literature and expert opinion.

Best practice advice 1: The authors emphasized that gastroenterologists need to be aware of the potential extraesophageal symptoms of GERD. They should inquire with GERD patients to determine if laryngitis, chronic cough, asthma, and dental erosions are present.

Best practice advice 2: Consider a multidisciplinary approach to EER manifestations. Cases may require input from non-GI specialties. Tests performed by other specialists, such as bronchoscopy, thoracic imaging, or laryngoscopy, should be taken into account, since patients will also seek out multiple specialists to address their symptoms.

Best practice advice 3: There is no specific diagnostic test available to determine if GER is the cause of EER symptoms. Instead, physicians should interpret patient symptoms, response to GER therapy, and input from endoscopy and reflux tests.

Best practice advice 4: Rather than subject the patient to the cost and potential for even rare adverse events of a PPI trial, physicians should first consider conducting reflux testing. A PPI trial has clinical value but is insufficient on its own to help diagnose or manage EER. Initial single-dose PPI trial, titrating up to twice daily in those with typical GERD symptoms, is reasonable.

Best practice advice 5: The inconsistent therapeutic response to PPI therapy means that positive effects of PPI therapy on EER symptoms can’t confirm a GERD diagnosis because a placebo effect may be involved, and because symptom improvement can occur through mechanisms other than acid suppression. A meta-analysis found that a PPI trial has a sensitivity of 71%-78% and a specificity of 41%-54% with typical symptoms of heartburn and regurgitation. “Considering the greater variation expected with PPI response for extraesophageal symptoms, the diagnostic performance of empiric PPI trial for a diagnosis of EER would be anticipated to be substantially lower,” the authors wrote.

Best practice advice 6: When EER symptoms related to GERD are suspected and a PPI trial of up to 12 weeks does not lead to adequate improvement, the physician should consider testing for pathologic GER. Additional trials employing other PPIs are unlikely to succeed.

Best practice advice 7: Initial testing to evaluate for reflux should be tailored to patients’ clinical presentation. Potential methods to evaluate reflux include upper endoscopy and ambulatory reflux monitoring studies of acid suppressive therapy, which can assist with a GERD diagnosis, particularly when nonerosive reflux is present.

Best practice advice 8: About 50%-60% of patients with EER symptoms will not have GERD. Testing can be considered for those with an established objective diagnosis of GERD who do not respond well to high doses of acid suppression. Cost-effectiveness studies have confirmed the value of starting with ambulatory reflux monitoring, which can include a catheter-based pH sensor, pH impedance, or wireless pH capsule.

Ambulatory esophageal pH monitoring can also assist in making a GERD diagnosis, but it does not indicate whether GERD may be contributing to EER symptoms.

“Whichever the reflux testing modality, the strongest confidence for EER is achieved after ambulatory reflux testing showing pathologic acid exposure and a positive symptom-reflux association for EER symptoms,” the authors wrote. They also pointed out that ambulatory reflux monitoring in EER patients should be done in the absence of acid suppression unless there is already objective evidence for the presence of GERD.

Best practice advice 9: Aside from acid suppression, EER symptoms can also be managed through other means, including lifestyle modifications, such as eating avoidance prior to lying down, elevation of the head of the bed, sleeping on the left side, and weight loss. Or, alginate containing antacids, external upper esophageal sphincter compression device, cognitive behavioral therapy, and neuromodulators.

Best practice advice 10: In cases where the EER patient has objectively defined evidence of GERD, physicians should employ shared decision-making before considering anti-reflux surgery. If the patient did not respond to PPI therapy, this predicts a lack of response to antireflux surgery.

All four authors reported financial ties to multiple pharmaceutical companies.

A genetic sequencing effort identified more patients to be carriers of risk genes for hereditary breast and ovarian cancer or Lynch syndrome than would have been discovered by following existing genetic testing guidelines, according to new research.

The authors of the clinical trial suggest that these guidelines may need to be revised.

Individuals with hereditary breast and ovarian cancer (HBOC) have an 80% lifetime risk of breast cancer and are at greater risk of ovarian cancer, pancreatic cancer, prostate cancer, and melanoma. Those with Lynch syndrome (LS) have an 80% lifetime risk of colorectal cancer, a 60% lifetime risk of endometrial cancer, and heightened risk of upper gastrointestinal, urinary tract, skin, and other tumors, said study coauthor N. Jewel Samadder, MD in a statement.

The National Cancer Control Network has guidelines for determining family risk for colorectal cancer and breast, ovarian, and pancreatic cancer to identify individuals who should be screened for LS and HBOC, but these rely on personal and family health histories.

“These criteria were created at a time when genetic testing was cost prohibitive and thus aimed to identify those at the greatest chance of being a mutation carrier in the absence of population-wide whole-exome sequencing. However, [LS and HBOC] are poorly identified in current practice, and many patients are not aware of their cancer risk,” said Dr. Samadder, professor of medicine and coleader of the precision oncology program at the Mayo Clinic Comprehensive Cancer Center, Phoenix, in the statement.

Whole-exome sequencing covers only protein-coding regions of the genome, which is less than 2% of the total genome but includes more than 85% of known disease-related genetic variants, according to Emily Gay, who presented the trial results (Abstract 5768) on April 18 at the annual meeting of the American Association for Cancer Research.

“In recent years, the cost of whole-exome sequencing has been rapidly decreasing, allowing us to complete this test on saliva samples from thousands, if not tens of thousands of patients covering large populations and large health systems,” said Ms. Gay, a genetic counseling graduate student at the University of Arizona, during her presentation.

She described results from the TAPESTRY clinical trial, with 44,306 participants from Mayo Clinic centers in Arizona, Florida, and Minnesota, who were identified as definitely or likely to be harboring pathogenic mutations and consented to whole-exome sequencing from saliva samples. They used electronic health records to determine whether patients would satisfy the testing criteria from NCCN guidelines.

The researchers identified 1.24% of participants to be carriers of HBOC or LS. Of the HBOC carriers, 62.8% were female, and of the LS carriers, 62.6% were female. The percentages of HBOC and LS carriers who were White were 88.6 and 94.5, respectively. The median age of both groups was 57 years. Of HBOC carriers, 47.3% had personal histories of cancers; for LS carries, the percentage was 44.2.

Of HBOC carriers, 49.1% had been previously unaware of their genetic condition, while an even higher percentage of patients with LS – 59.3% – fell into that category. Thirty-two percent of those with HBOC and 56.2% of those with LS would not have qualified for screening using the relevant NCCN guidelines.

“Most strikingly,” 63.8% of individuals with mutations in the MSH6 gene and 83.7% of those mutations in the PMS2 gene would not have met NCCN criteria, Ms. Gay said.

Having a cancer type not known to be related to a genetic syndrome was a reason for 58.6% of individuals failing to meet NCCN guidelines, while 60.5% did not meet the guidelines because of an insufficient number of relatives known to have a history of cancer, and 63.3% did not because they had no personal history of cancer. Among individuals with a pathogenic mutation who met NCCN criteria, 34% were not aware of their condition.

“This suggests that the NCCN guidelines are underutilized in clinical practice, potentially due to the busy schedule of clinicians or because the complexity of using these criteria,” said Ms. Gay.

The numbers were even more striking among minorities: “There is additional data analysis and research needed in this area, but based on our preliminary findings, we saw that nearly 50% of the individuals who are [part of an underrepresented minority group] did not meet criteria, compared with 32% of the white cohort,” said Ms. Gay.

Asked what new NCCN guidelines should be, Ms. Gay replied: “I think maybe limiting the number of relatives that you have to have with a certain type of cancer, especially as we see families get smaller and smaller, especially in the United States – that family data isn’t necessarily available or as useful. And then also, I think, incorporating in the size of a family into the calculation, so more of maybe a point-based system like we see with other genetic conditions rather than a ‘yes you meet or no, you don’t.’ More of a range to say ‘you fall on the low-risk, medium-risk, or high-risk stage,’” said Ms. Gay.

During the Q&A period, session cochair Andrew Godwin, PhD, who is a professor of molecular oncology and pathology at University of Kansas Medical Center, Kansas City, said he wondered if whole-exome sequencing was capable of picking up cancer risk mutations that standard targeted tests don’t look for.

Dr. Samadder, who was in the audience, answered the question, saying that targeted tests are actually better at picking up some types of mutations like intronic mutations, single-nucleotide polymorphisms, and deletions.

“There are some limitations to whole-exome sequencing. Our estimate here of 1.2% [of participants carrying HBOC or LS mutations] is probably an underestimate. There are additional variants that exome sequencing probably doesn’t pick up easily or as well. That’s why we qualify that exome sequencing is a screening test, not a diagnostic,” he continued.

Ms. Gay and Dr. Samadder have no relevant financial disclosures. Dr. Godwin has financial relationships with Clara Biotech, VITRAC Therapeutics, and Sinochips Diagnostics.

A genetic sequencing effort identified more patients to be carriers of risk genes for hereditary breast and ovarian cancer or Lynch syndrome than would have been discovered by following existing genetic testing guidelines, according to new research.

The authors of the clinical trial suggest that these guidelines may need to be revised.

Individuals with hereditary breast and ovarian cancer (HBOC) have an 80% lifetime risk of breast cancer and are at greater risk of ovarian cancer, pancreatic cancer, prostate cancer, and melanoma. Those with Lynch syndrome (LS) have an 80% lifetime risk of colorectal cancer, a 60% lifetime risk of endometrial cancer, and heightened risk of upper gastrointestinal, urinary tract, skin, and other tumors, said study coauthor N. Jewel Samadder, MD in a statement.

The National Cancer Control Network has guidelines for determining family risk for colorectal cancer and breast, ovarian, and pancreatic cancer to identify individuals who should be screened for LS and HBOC, but these rely on personal and family health histories.

“These criteria were created at a time when genetic testing was cost prohibitive and thus aimed to identify those at the greatest chance of being a mutation carrier in the absence of population-wide whole-exome sequencing. However, [LS and HBOC] are poorly identified in current practice, and many patients are not aware of their cancer risk,” said Dr. Samadder, professor of medicine and coleader of the precision oncology program at the Mayo Clinic Comprehensive Cancer Center, Phoenix, in the statement.

Whole-exome sequencing covers only protein-coding regions of the genome, which is less than 2% of the total genome but includes more than 85% of known disease-related genetic variants, according to Emily Gay, who presented the trial results (Abstract 5768) on April 18 at the annual meeting of the American Association for Cancer Research.

“In recent years, the cost of whole-exome sequencing has been rapidly decreasing, allowing us to complete this test on saliva samples from thousands, if not tens of thousands of patients covering large populations and large health systems,” said Ms. Gay, a genetic counseling graduate student at the University of Arizona, during her presentation.

She described results from the TAPESTRY clinical trial, with 44,306 participants from Mayo Clinic centers in Arizona, Florida, and Minnesota, who were identified as definitely or likely to be harboring pathogenic mutations and consented to whole-exome sequencing from saliva samples. They used electronic health records to determine whether patients would satisfy the testing criteria from NCCN guidelines.

The researchers identified 1.24% of participants to be carriers of HBOC or LS. Of the HBOC carriers, 62.8% were female, and of the LS carriers, 62.6% were female. The percentages of HBOC and LS carriers who were White were 88.6 and 94.5, respectively. The median age of both groups was 57 years. Of HBOC carriers, 47.3% had personal histories of cancers; for LS carries, the percentage was 44.2.

Of HBOC carriers, 49.1% had been previously unaware of their genetic condition, while an even higher percentage of patients with LS – 59.3% – fell into that category. Thirty-two percent of those with HBOC and 56.2% of those with LS would not have qualified for screening using the relevant NCCN guidelines.

“Most strikingly,” 63.8% of individuals with mutations in the MSH6 gene and 83.7% of those mutations in the PMS2 gene would not have met NCCN criteria, Ms. Gay said.

Having a cancer type not known to be related to a genetic syndrome was a reason for 58.6% of individuals failing to meet NCCN guidelines, while 60.5% did not meet the guidelines because of an insufficient number of relatives known to have a history of cancer, and 63.3% did not because they had no personal history of cancer. Among individuals with a pathogenic mutation who met NCCN criteria, 34% were not aware of their condition.

“This suggests that the NCCN guidelines are underutilized in clinical practice, potentially due to the busy schedule of clinicians or because the complexity of using these criteria,” said Ms. Gay.

The numbers were even more striking among minorities: “There is additional data analysis and research needed in this area, but based on our preliminary findings, we saw that nearly 50% of the individuals who are [part of an underrepresented minority group] did not meet criteria, compared with 32% of the white cohort,” said Ms. Gay.

Asked what new NCCN guidelines should be, Ms. Gay replied: “I think maybe limiting the number of relatives that you have to have with a certain type of cancer, especially as we see families get smaller and smaller, especially in the United States – that family data isn’t necessarily available or as useful. And then also, I think, incorporating in the size of a family into the calculation, so more of maybe a point-based system like we see with other genetic conditions rather than a ‘yes you meet or no, you don’t.’ More of a range to say ‘you fall on the low-risk, medium-risk, or high-risk stage,’” said Ms. Gay.

During the Q&A period, session cochair Andrew Godwin, PhD, who is a professor of molecular oncology and pathology at University of Kansas Medical Center, Kansas City, said he wondered if whole-exome sequencing was capable of picking up cancer risk mutations that standard targeted tests don’t look for.

Dr. Samadder, who was in the audience, answered the question, saying that targeted tests are actually better at picking up some types of mutations like intronic mutations, single-nucleotide polymorphisms, and deletions.

“There are some limitations to whole-exome sequencing. Our estimate here of 1.2% [of participants carrying HBOC or LS mutations] is probably an underestimate. There are additional variants that exome sequencing probably doesn’t pick up easily or as well. That’s why we qualify that exome sequencing is a screening test, not a diagnostic,” he continued.

Ms. Gay and Dr. Samadder have no relevant financial disclosures. Dr. Godwin has financial relationships with Clara Biotech, VITRAC Therapeutics, and Sinochips Diagnostics.

A genetic sequencing effort identified more patients to be carriers of risk genes for hereditary breast and ovarian cancer or Lynch syndrome than would have been discovered by following existing genetic testing guidelines, according to new research.

The authors of the clinical trial suggest that these guidelines may need to be revised.

Individuals with hereditary breast and ovarian cancer (HBOC) have an 80% lifetime risk of breast cancer and are at greater risk of ovarian cancer, pancreatic cancer, prostate cancer, and melanoma. Those with Lynch syndrome (LS) have an 80% lifetime risk of colorectal cancer, a 60% lifetime risk of endometrial cancer, and heightened risk of upper gastrointestinal, urinary tract, skin, and other tumors, said study coauthor N. Jewel Samadder, MD in a statement.

The National Cancer Control Network has guidelines for determining family risk for colorectal cancer and breast, ovarian, and pancreatic cancer to identify individuals who should be screened for LS and HBOC, but these rely on personal and family health histories.

“These criteria were created at a time when genetic testing was cost prohibitive and thus aimed to identify those at the greatest chance of being a mutation carrier in the absence of population-wide whole-exome sequencing. However, [LS and HBOC] are poorly identified in current practice, and many patients are not aware of their cancer risk,” said Dr. Samadder, professor of medicine and coleader of the precision oncology program at the Mayo Clinic Comprehensive Cancer Center, Phoenix, in the statement.

Whole-exome sequencing covers only protein-coding regions of the genome, which is less than 2% of the total genome but includes more than 85% of known disease-related genetic variants, according to Emily Gay, who presented the trial results (Abstract 5768) on April 18 at the annual meeting of the American Association for Cancer Research.

“In recent years, the cost of whole-exome sequencing has been rapidly decreasing, allowing us to complete this test on saliva samples from thousands, if not tens of thousands of patients covering large populations and large health systems,” said Ms. Gay, a genetic counseling graduate student at the University of Arizona, during her presentation.

She described results from the TAPESTRY clinical trial, with 44,306 participants from Mayo Clinic centers in Arizona, Florida, and Minnesota, who were identified as definitely or likely to be harboring pathogenic mutations and consented to whole-exome sequencing from saliva samples. They used electronic health records to determine whether patients would satisfy the testing criteria from NCCN guidelines.

The researchers identified 1.24% of participants to be carriers of HBOC or LS. Of the HBOC carriers, 62.8% were female, and of the LS carriers, 62.6% were female. The percentages of HBOC and LS carriers who were White were 88.6 and 94.5, respectively. The median age of both groups was 57 years. Of HBOC carriers, 47.3% had personal histories of cancers; for LS carries, the percentage was 44.2.

Of HBOC carriers, 49.1% had been previously unaware of their genetic condition, while an even higher percentage of patients with LS – 59.3% – fell into that category. Thirty-two percent of those with HBOC and 56.2% of those with LS would not have qualified for screening using the relevant NCCN guidelines.

“Most strikingly,” 63.8% of individuals with mutations in the MSH6 gene and 83.7% of those mutations in the PMS2 gene would not have met NCCN criteria, Ms. Gay said.

Having a cancer type not known to be related to a genetic syndrome was a reason for 58.6% of individuals failing to meet NCCN guidelines, while 60.5% did not meet the guidelines because of an insufficient number of relatives known to have a history of cancer, and 63.3% did not because they had no personal history of cancer. Among individuals with a pathogenic mutation who met NCCN criteria, 34% were not aware of their condition.

“This suggests that the NCCN guidelines are underutilized in clinical practice, potentially due to the busy schedule of clinicians or because the complexity of using these criteria,” said Ms. Gay.

The numbers were even more striking among minorities: “There is additional data analysis and research needed in this area, but based on our preliminary findings, we saw that nearly 50% of the individuals who are [part of an underrepresented minority group] did not meet criteria, compared with 32% of the white cohort,” said Ms. Gay.

Asked what new NCCN guidelines should be, Ms. Gay replied: “I think maybe limiting the number of relatives that you have to have with a certain type of cancer, especially as we see families get smaller and smaller, especially in the United States – that family data isn’t necessarily available or as useful. And then also, I think, incorporating in the size of a family into the calculation, so more of maybe a point-based system like we see with other genetic conditions rather than a ‘yes you meet or no, you don’t.’ More of a range to say ‘you fall on the low-risk, medium-risk, or high-risk stage,’” said Ms. Gay.

During the Q&A period, session cochair Andrew Godwin, PhD, who is a professor of molecular oncology and pathology at University of Kansas Medical Center, Kansas City, said he wondered if whole-exome sequencing was capable of picking up cancer risk mutations that standard targeted tests don’t look for.

Dr. Samadder, who was in the audience, answered the question, saying that targeted tests are actually better at picking up some types of mutations like intronic mutations, single-nucleotide polymorphisms, and deletions.

“There are some limitations to whole-exome sequencing. Our estimate here of 1.2% [of participants carrying HBOC or LS mutations] is probably an underestimate. There are additional variants that exome sequencing probably doesn’t pick up easily or as well. That’s why we qualify that exome sequencing is a screening test, not a diagnostic,” he continued.

Ms. Gay and Dr. Samadder have no relevant financial disclosures. Dr. Godwin has financial relationships with Clara Biotech, VITRAC Therapeutics, and Sinochips Diagnostics.

A deep learning artificial intelligence (AI) model that used only a single histopathological slide predicted the risk of distant recurrence among endometrial cancer patients in a new study.

Endometrial cancer is the most frequently occurring uterine cancer. Early-stage patients have about a 95% 5-year survival, but distant recurrence is associated with very poor survival, according to Sarah Fremond, MSc, an author of the research (Abstract 5695), which she presented at the annual meeting of the American Association for Cancer Research.

“Most patients with endometrial cancer have a good prognosis and would not require any adjuvant treatment, but there is a proportion that will develop distant recurrence. For those you want to recommend adjuvant chemotherapy, because currently in the adjuvant setting, that’s the only treatment that is known to lower the risk of distant recurrence. But that also causes morbidity. Therefore, our clinical question was how to accurately identify patients at low and high risk of distant recurrence to reduce under- and overtreatment,” said Ms. Fremond, a PhD candidate at Leiden (the Netherlands) University Medical Center.

Pathologists can attempt such predictions, but Ms. Fremond noted that there are challenges. “There is a lot of variability between pathologists, and we don’t even use the entire visual information present in the H&E [hematoxylin and eosin] tumor slide. When it comes to molecular testing, it is hampered by cost, turnaround time, and sometimes interpretation. It’s quite complex to combine those data to specifically target risk of distant recurrence for patients with endometrial cancer.”

In her presentation, Ms. Fremond described how she and her colleagues used digitized histopathological slides in their research. She and her coauthors developed the AI model as part of a collaboration that included the AIRMEC Consortium, Leiden University Medical Center, the TransPORTEC Consortium, and the University of Zürich.

The researchers used long-term follow-up data from 1,408 patients drawn from three clinical cohorts and participants in the PORTEC-1, PORTEC-2, and PORTEC-3 studies, which tested radiotherapy and adjuvant therapy outcomes in endometrial cancer. Patients who had received prior adjuvant chemotherapy were excluded. In the model development phase, the system analyzed a single representative histopathological slide image from each patient and compared it with the known time to distant recurrence to identify patterns.

Once the system had been trained, the researchers applied it to a novel group of 353 patients. It ranked 89 patients as having a low risk of recurrence, 175 at intermediate risk, and 89 at high risk of recurrence. The system performed well: 3.37% of low-risk patients experienced a distant recurrence, as did 15.43% of the intermediate-risk group and 36% of the high-risk group.

The researchers also employed an external validation group with 152 patients and three slides per patient, with a 2.8-year follow-up. The model performed with a C index of 0.805 (±0.0136) when a random slide was selected for each patient, and the median predicted risk score per patient was associated with differences in distant recurrence-free survival between the three risk groups with a C index of 0.816 (P < .0001).
 

Questions about research and their answers

Session moderator Kristin Swanson, PhD, asked if the AI could be used with the pathology slide’s visible features to learn more about the underlying biology and pathophysiology of tumors.

“Overlying the HECTOR on to the tissue seems like a logical opportunity to go and then explore the biology and what’s attributed as a high-risk region,” said Dr. Swanson, who is director of the Mathematical NeuroOncology Lab and codirector of the Precision NeuroTherapeutics Innovation Program at Mayo Clinic Arizona, Phoenix.

Ms. Fremond agreed that the AI has the potential to be used that way.”

During the Q&A, an audience member asked how likely the model is to perform in populations that differ significantly from the populations used in her study.

Ms. Fremond responded that the populations used to develop and test the models were in or close to the Netherlands, and little information was available regarding patient ethnicity. “There is a possibility that perhaps we would have a different performance on a population that includes more minorities. That needs to be checked,” said Ms. Fremond.

The study is limited by its retrospective nature.

Ms. Fremond and Dr. Swanson have no relevant financial disclosures.

A deep learning artificial intelligence (AI) model that used only a single histopathological slide predicted the risk of distant recurrence among endometrial cancer patients in a new study.

Endometrial cancer is the most frequently occurring uterine cancer. Early-stage patients have about a 95% 5-year survival, but distant recurrence is associated with very poor survival, according to Sarah Fremond, MSc, an author of the research (Abstract 5695), which she presented at the annual meeting of the American Association for Cancer Research.

“Most patients with endometrial cancer have a good prognosis and would not require any adjuvant treatment, but there is a proportion that will develop distant recurrence. For those you want to recommend adjuvant chemotherapy, because currently in the adjuvant setting, that’s the only treatment that is known to lower the risk of distant recurrence. But that also causes morbidity. Therefore, our clinical question was how to accurately identify patients at low and high risk of distant recurrence to reduce under- and overtreatment,” said Ms. Fremond, a PhD candidate at Leiden (the Netherlands) University Medical Center.

Pathologists can attempt such predictions, but Ms. Fremond noted that there are challenges. “There is a lot of variability between pathologists, and we don’t even use the entire visual information present in the H&E [hematoxylin and eosin] tumor slide. When it comes to molecular testing, it is hampered by cost, turnaround time, and sometimes interpretation. It’s quite complex to combine those data to specifically target risk of distant recurrence for patients with endometrial cancer.”

In her presentation, Ms. Fremond described how she and her colleagues used digitized histopathological slides in their research. She and her coauthors developed the AI model as part of a collaboration that included the AIRMEC Consortium, Leiden University Medical Center, the TransPORTEC Consortium, and the University of Zürich.

The researchers used long-term follow-up data from 1,408 patients drawn from three clinical cohorts and participants in the PORTEC-1, PORTEC-2, and PORTEC-3 studies, which tested radiotherapy and adjuvant therapy outcomes in endometrial cancer. Patients who had received prior adjuvant chemotherapy were excluded. In the model development phase, the system analyzed a single representative histopathological slide image from each patient and compared it with the known time to distant recurrence to identify patterns.

Once the system had been trained, the researchers applied it to a novel group of 353 patients. It ranked 89 patients as having a low risk of recurrence, 175 at intermediate risk, and 89 at high risk of recurrence. The system performed well: 3.37% of low-risk patients experienced a distant recurrence, as did 15.43% of the intermediate-risk group and 36% of the high-risk group.

The researchers also employed an external validation group with 152 patients and three slides per patient, with a 2.8-year follow-up. The model performed with a C index of 0.805 (±0.0136) when a random slide was selected for each patient, and the median predicted risk score per patient was associated with differences in distant recurrence-free survival between the three risk groups with a C index of 0.816 (P < .0001).
 

Questions about research and their answers

Session moderator Kristin Swanson, PhD, asked if the AI could be used with the pathology slide’s visible features to learn more about the underlying biology and pathophysiology of tumors.

“Overlying the HECTOR on to the tissue seems like a logical opportunity to go and then explore the biology and what’s attributed as a high-risk region,” said Dr. Swanson, who is director of the Mathematical NeuroOncology Lab and codirector of the Precision NeuroTherapeutics Innovation Program at Mayo Clinic Arizona, Phoenix.

Ms. Fremond agreed that the AI has the potential to be used that way.”

During the Q&A, an audience member asked how likely the model is to perform in populations that differ significantly from the populations used in her study.

Ms. Fremond responded that the populations used to develop and test the models were in or close to the Netherlands, and little information was available regarding patient ethnicity. “There is a possibility that perhaps we would have a different performance on a population that includes more minorities. That needs to be checked,” said Ms. Fremond.

The study is limited by its retrospective nature.

Ms. Fremond and Dr. Swanson have no relevant financial disclosures.

A deep learning artificial intelligence (AI) model that used only a single histopathological slide predicted the risk of distant recurrence among endometrial cancer patients in a new study.

Endometrial cancer is the most frequently occurring uterine cancer. Early-stage patients have about a 95% 5-year survival, but distant recurrence is associated with very poor survival, according to Sarah Fremond, MSc, an author of the research (Abstract 5695), which she presented at the annual meeting of the American Association for Cancer Research.

“Most patients with endometrial cancer have a good prognosis and would not require any adjuvant treatment, but there is a proportion that will develop distant recurrence. For those you want to recommend adjuvant chemotherapy, because currently in the adjuvant setting, that’s the only treatment that is known to lower the risk of distant recurrence. But that also causes morbidity. Therefore, our clinical question was how to accurately identify patients at low and high risk of distant recurrence to reduce under- and overtreatment,” said Ms. Fremond, a PhD candidate at Leiden (the Netherlands) University Medical Center.

Pathologists can attempt such predictions, but Ms. Fremond noted that there are challenges. “There is a lot of variability between pathologists, and we don’t even use the entire visual information present in the H&E [hematoxylin and eosin] tumor slide. When it comes to molecular testing, it is hampered by cost, turnaround time, and sometimes interpretation. It’s quite complex to combine those data to specifically target risk of distant recurrence for patients with endometrial cancer.”

In her presentation, Ms. Fremond described how she and her colleagues used digitized histopathological slides in their research. She and her coauthors developed the AI model as part of a collaboration that included the AIRMEC Consortium, Leiden University Medical Center, the TransPORTEC Consortium, and the University of Zürich.

The researchers used long-term follow-up data from 1,408 patients drawn from three clinical cohorts and participants in the PORTEC-1, PORTEC-2, and PORTEC-3 studies, which tested radiotherapy and adjuvant therapy outcomes in endometrial cancer. Patients who had received prior adjuvant chemotherapy were excluded. In the model development phase, the system analyzed a single representative histopathological slide image from each patient and compared it with the known time to distant recurrence to identify patterns.

Once the system had been trained, the researchers applied it to a novel group of 353 patients. It ranked 89 patients as having a low risk of recurrence, 175 at intermediate risk, and 89 at high risk of recurrence. The system performed well: 3.37% of low-risk patients experienced a distant recurrence, as did 15.43% of the intermediate-risk group and 36% of the high-risk group.

The researchers also employed an external validation group with 152 patients and three slides per patient, with a 2.8-year follow-up. The model performed with a C index of 0.805 (±0.0136) when a random slide was selected for each patient, and the median predicted risk score per patient was associated with differences in distant recurrence-free survival between the three risk groups with a C index of 0.816 (P < .0001).
 

Questions about research and their answers

Session moderator Kristin Swanson, PhD, asked if the AI could be used with the pathology slide’s visible features to learn more about the underlying biology and pathophysiology of tumors.

“Overlying the HECTOR on to the tissue seems like a logical opportunity to go and then explore the biology and what’s attributed as a high-risk region,” said Dr. Swanson, who is director of the Mathematical NeuroOncology Lab and codirector of the Precision NeuroTherapeutics Innovation Program at Mayo Clinic Arizona, Phoenix.

Ms. Fremond agreed that the AI has the potential to be used that way.”

During the Q&A, an audience member asked how likely the model is to perform in populations that differ significantly from the populations used in her study.

Ms. Fremond responded that the populations used to develop and test the models were in or close to the Netherlands, and little information was available regarding patient ethnicity. “There is a possibility that perhaps we would have a different performance on a population that includes more minorities. That needs to be checked,” said Ms. Fremond.

The study is limited by its retrospective nature.

Ms. Fremond and Dr. Swanson have no relevant financial disclosures.

Combination treatment with the poly ADP-ribose polymerase inhibitor, olaparib, and the novel ataxia telangiectasia–mutated Rad3-related (ATR) inhibitor, ceralasertib, was well tolerated and showed some promise in pediatric patients with tumors with DNA replication stress or DNA repair deficiencies, in a new study.

The small phase 1 trial also identified some molecular signatures in responders that may inform future clinical trials.

The results, presented at the annual meeting of the American Association of Cancer Research, came from a single arm of the European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (ESMART) trial. This trial matches pediatric, adolescent, and young adult cancer patients with treatment regimens based on the molecular profile of their tumors.

In over 220 children to date, the trial has investigated 15 different treatment regimens, most of which are combination therapies.

In adults, poly ADP-ribose polymerase (PARP) inhibitors have been shown to be effective in tumors with deficiencies in homologous repair, which is a DNA repair mechanism, with notable successes in patients carrying the BRCA1 and BRCA2 mutations. But BRCA1 and BRCA2 mutations are rare in pediatric cancer, and there is a belief that there may be primary resistance to PARP inhibitors in pediatric tumors, according to Susanne Gatz, MD, PhD, who presented the research at the meeting.

Previous research identified alterations in pediatric tumors that are candidates for patient selection. “These tumors have alterations which could potentially cause this resistance effect [against PARP inhibitors] and [also cause] sensitivity to ataxia telangiectasia–mutated Rad3-related inhibitors. This is how this arm [of the ESMART trial] was born,” said Dr. Gatz.

The phase 1 portion of the study included 18 pediatric and young adult patients with relapsed or treatment-refractory tumors. There were eight sarcomas, five central nervous system tumors, four neuroblastomas, and one carcinoma. Each had mutations thought to lead to HR deficiency or replication stress. The study included three dose levels of twice-daily oral olaparib that was given continuously, and ceralasertib, which was given day 1-14 of each 28-day cycle.

Patients underwent a median of 3.5 cycles of treatment. There were dose-limiting adverse events of thrombocytopenia and neutropenia in five patients, two of which occurred at the dose that was recommended for phase 2.

There were some positive clinical signs, including one partial response in a pineoblastoma patient who received treatment for 11 cycles. A neuroblastoma patient had stable disease until cycle 9 of treatment, and then converted to a partial response and is currently in cycle 12. Two other patients remain in treatment at cycle 8 and one is in treatment at cycle 15. None of the patients who experienced clinical benefit had BRCA mutations.

An important goal of the study was to understand molecular signature that might predict response to the drug combination. Although no firm conclusions could be drawn, there were some interesting patterns. In particular, five of the six worst responders had TP53 mutations. “It is striking ... so we need to learn what TP53 in this setting means if it’s mutated, and if it could be a resistance factor,” said Dr. Gatz, an associate clinical professor in pediatric oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham, during her talk.

Although the study is too small and included too many tumor types to identify tumor-based patterns of response, it did provide some hints as to biomarkers that could inform future studies, according to Julia Glade Bender, MD, who served as a discussant following the presentation and is a pediatric oncologist at Memorial Sloan Kettering Cancer Center, New York.

“The pediatric frequency of the common DNA damage repair biomarkers that have been [identified in] the adult literature – that is to say, BRCA1 and 2 and [ataxia-telangiectasia mutation] – are exceedingly rare in pediatrics,” said Dr. Bender during the session while serving as a discussant. She highlighted the following findings: Loss of the 11q region on chromosome 11 is common among the patients and that region contains three genes involved in the DNA damage response, along with a gene involved in homologous recombination, telomere maintenance, and double strand break repair.

She added that 11q deletion is also found in up to 40% of neuroblastomas, and is associated with poor prognosis, and the patients have multiple segmental chromosomal abnormalities. “That begs the question [of] whether chromosomal instability is another biomarker for pediatric cancer,” said Dr. Bender.

“The research highlights the complexity of pediatric cancers, whose distinct biology could make them more vulnerable to ATR [kinase], [checkpoint kinase 1], and WEE1 pathway inhibition with a PARP inhibitor used to induce replication stress and be the sensitizer. The biomarker profiles are going to be complex, context-dependent, and likely to reflect a constellation of findings that would be signatures or algorithms, rather than single gene alterations. The post hoc iterative analysis of responders and nonresponders is going to be absolutely critical to understanding those biomarkers and the role of DNA damage response inhibitors in pediatrics. Given the rarity of these diagnoses, and then the molecular subclasses, I think collaboration across ages and geography is absolutely critical, and I really congratulate the ESMART consortium for doing just that in Europe,” said Dr. Bender.

The study is limited by its small sample size and the fact that it was not randomized.

The study received funding from French Institut National de Cancer, Imagine for Margo, Fondation ARC, AstraZeneca France, AstraZeneca Global R&D, AstraZeneca UK, Cancer Research UK, Fondation Gustave Roussy, and Little Princess Trust/Children’s Cancer and Leukaemia Group. Dr. Gatz has no relevant financial disclosures. Dr. Bender has done paid consulting for Jazz Pharmaceuticals and has done unpaid work for Bristol-Myers Squibb, Eisai, Springworks Therapeutics, Merck Sharp & Dohme, and Pfizer. She has received research support from Eli Lilly, Loxo-oncology, Eisai, Cellectar, Bayer, Amgen, and Jazz Pharmaceuticals.

From American Association for Cancer Research (AACR) Annual Meeting 2023: Abstract CT019. Presented Tuesday, April 18.

Combination treatment with the poly ADP-ribose polymerase inhibitor, olaparib, and the novel ataxia telangiectasia–mutated Rad3-related (ATR) inhibitor, ceralasertib, was well tolerated and showed some promise in pediatric patients with tumors with DNA replication stress or DNA repair deficiencies, in a new study.

The small phase 1 trial also identified some molecular signatures in responders that may inform future clinical trials.

The results, presented at the annual meeting of the American Association of Cancer Research, came from a single arm of the European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (ESMART) trial. This trial matches pediatric, adolescent, and young adult cancer patients with treatment regimens based on the molecular profile of their tumors.

In over 220 children to date, the trial has investigated 15 different treatment regimens, most of which are combination therapies.

In adults, poly ADP-ribose polymerase (PARP) inhibitors have been shown to be effective in tumors with deficiencies in homologous repair, which is a DNA repair mechanism, with notable successes in patients carrying the BRCA1 and BRCA2 mutations. But BRCA1 and BRCA2 mutations are rare in pediatric cancer, and there is a belief that there may be primary resistance to PARP inhibitors in pediatric tumors, according to Susanne Gatz, MD, PhD, who presented the research at the meeting.

Previous research identified alterations in pediatric tumors that are candidates for patient selection. “These tumors have alterations which could potentially cause this resistance effect [against PARP inhibitors] and [also cause] sensitivity to ataxia telangiectasia–mutated Rad3-related inhibitors. This is how this arm [of the ESMART trial] was born,” said Dr. Gatz.

The phase 1 portion of the study included 18 pediatric and young adult patients with relapsed or treatment-refractory tumors. There were eight sarcomas, five central nervous system tumors, four neuroblastomas, and one carcinoma. Each had mutations thought to lead to HR deficiency or replication stress. The study included three dose levels of twice-daily oral olaparib that was given continuously, and ceralasertib, which was given day 1-14 of each 28-day cycle.

Patients underwent a median of 3.5 cycles of treatment. There were dose-limiting adverse events of thrombocytopenia and neutropenia in five patients, two of which occurred at the dose that was recommended for phase 2.

There were some positive clinical signs, including one partial response in a pineoblastoma patient who received treatment for 11 cycles. A neuroblastoma patient had stable disease until cycle 9 of treatment, and then converted to a partial response and is currently in cycle 12. Two other patients remain in treatment at cycle 8 and one is in treatment at cycle 15. None of the patients who experienced clinical benefit had BRCA mutations.

An important goal of the study was to understand molecular signature that might predict response to the drug combination. Although no firm conclusions could be drawn, there were some interesting patterns. In particular, five of the six worst responders had TP53 mutations. “It is striking ... so we need to learn what TP53 in this setting means if it’s mutated, and if it could be a resistance factor,” said Dr. Gatz, an associate clinical professor in pediatric oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham, during her talk.

Although the study is too small and included too many tumor types to identify tumor-based patterns of response, it did provide some hints as to biomarkers that could inform future studies, according to Julia Glade Bender, MD, who served as a discussant following the presentation and is a pediatric oncologist at Memorial Sloan Kettering Cancer Center, New York.

“The pediatric frequency of the common DNA damage repair biomarkers that have been [identified in] the adult literature – that is to say, BRCA1 and 2 and [ataxia-telangiectasia mutation] – are exceedingly rare in pediatrics,” said Dr. Bender during the session while serving as a discussant. She highlighted the following findings: Loss of the 11q region on chromosome 11 is common among the patients and that region contains three genes involved in the DNA damage response, along with a gene involved in homologous recombination, telomere maintenance, and double strand break repair.

She added that 11q deletion is also found in up to 40% of neuroblastomas, and is associated with poor prognosis, and the patients have multiple segmental chromosomal abnormalities. “That begs the question [of] whether chromosomal instability is another biomarker for pediatric cancer,” said Dr. Bender.

“The research highlights the complexity of pediatric cancers, whose distinct biology could make them more vulnerable to ATR [kinase], [checkpoint kinase 1], and WEE1 pathway inhibition with a PARP inhibitor used to induce replication stress and be the sensitizer. The biomarker profiles are going to be complex, context-dependent, and likely to reflect a constellation of findings that would be signatures or algorithms, rather than single gene alterations. The post hoc iterative analysis of responders and nonresponders is going to be absolutely critical to understanding those biomarkers and the role of DNA damage response inhibitors in pediatrics. Given the rarity of these diagnoses, and then the molecular subclasses, I think collaboration across ages and geography is absolutely critical, and I really congratulate the ESMART consortium for doing just that in Europe,” said Dr. Bender.

The study is limited by its small sample size and the fact that it was not randomized.

The study received funding from French Institut National de Cancer, Imagine for Margo, Fondation ARC, AstraZeneca France, AstraZeneca Global R&D, AstraZeneca UK, Cancer Research UK, Fondation Gustave Roussy, and Little Princess Trust/Children’s Cancer and Leukaemia Group. Dr. Gatz has no relevant financial disclosures. Dr. Bender has done paid consulting for Jazz Pharmaceuticals and has done unpaid work for Bristol-Myers Squibb, Eisai, Springworks Therapeutics, Merck Sharp & Dohme, and Pfizer. She has received research support from Eli Lilly, Loxo-oncology, Eisai, Cellectar, Bayer, Amgen, and Jazz Pharmaceuticals.

From American Association for Cancer Research (AACR) Annual Meeting 2023: Abstract CT019. Presented Tuesday, April 18.

Combination treatment with the poly ADP-ribose polymerase inhibitor, olaparib, and the novel ataxia telangiectasia–mutated Rad3-related (ATR) inhibitor, ceralasertib, was well tolerated and showed some promise in pediatric patients with tumors with DNA replication stress or DNA repair deficiencies, in a new study.

The small phase 1 trial also identified some molecular signatures in responders that may inform future clinical trials.

The results, presented at the annual meeting of the American Association of Cancer Research, came from a single arm of the European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors (ESMART) trial. This trial matches pediatric, adolescent, and young adult cancer patients with treatment regimens based on the molecular profile of their tumors.

In over 220 children to date, the trial has investigated 15 different treatment regimens, most of which are combination therapies.

In adults, poly ADP-ribose polymerase (PARP) inhibitors have been shown to be effective in tumors with deficiencies in homologous repair, which is a DNA repair mechanism, with notable successes in patients carrying the BRCA1 and BRCA2 mutations. But BRCA1 and BRCA2 mutations are rare in pediatric cancer, and there is a belief that there may be primary resistance to PARP inhibitors in pediatric tumors, according to Susanne Gatz, MD, PhD, who presented the research at the meeting.

Previous research identified alterations in pediatric tumors that are candidates for patient selection. “These tumors have alterations which could potentially cause this resistance effect [against PARP inhibitors] and [also cause] sensitivity to ataxia telangiectasia–mutated Rad3-related inhibitors. This is how this arm [of the ESMART trial] was born,” said Dr. Gatz.

The phase 1 portion of the study included 18 pediatric and young adult patients with relapsed or treatment-refractory tumors. There were eight sarcomas, five central nervous system tumors, four neuroblastomas, and one carcinoma. Each had mutations thought to lead to HR deficiency or replication stress. The study included three dose levels of twice-daily oral olaparib that was given continuously, and ceralasertib, which was given day 1-14 of each 28-day cycle.

Patients underwent a median of 3.5 cycles of treatment. There were dose-limiting adverse events of thrombocytopenia and neutropenia in five patients, two of which occurred at the dose that was recommended for phase 2.

There were some positive clinical signs, including one partial response in a pineoblastoma patient who received treatment for 11 cycles. A neuroblastoma patient had stable disease until cycle 9 of treatment, and then converted to a partial response and is currently in cycle 12. Two other patients remain in treatment at cycle 8 and one is in treatment at cycle 15. None of the patients who experienced clinical benefit had BRCA mutations.

An important goal of the study was to understand molecular signature that might predict response to the drug combination. Although no firm conclusions could be drawn, there were some interesting patterns. In particular, five of the six worst responders had TP53 mutations. “It is striking ... so we need to learn what TP53 in this setting means if it’s mutated, and if it could be a resistance factor,” said Dr. Gatz, an associate clinical professor in pediatric oncology at the Institute of Cancer and Genomic Sciences of the University of Birmingham, during her talk.

Although the study is too small and included too many tumor types to identify tumor-based patterns of response, it did provide some hints as to biomarkers that could inform future studies, according to Julia Glade Bender, MD, who served as a discussant following the presentation and is a pediatric oncologist at Memorial Sloan Kettering Cancer Center, New York.

“The pediatric frequency of the common DNA damage repair biomarkers that have been [identified in] the adult literature – that is to say, BRCA1 and 2 and [ataxia-telangiectasia mutation] – are exceedingly rare in pediatrics,” said Dr. Bender during the session while serving as a discussant. She highlighted the following findings: Loss of the 11q region on chromosome 11 is common among the patients and that region contains three genes involved in the DNA damage response, along with a gene involved in homologous recombination, telomere maintenance, and double strand break repair.

She added that 11q deletion is also found in up to 40% of neuroblastomas, and is associated with poor prognosis, and the patients have multiple segmental chromosomal abnormalities. “That begs the question [of] whether chromosomal instability is another biomarker for pediatric cancer,” said Dr. Bender.

“The research highlights the complexity of pediatric cancers, whose distinct biology could make them more vulnerable to ATR [kinase], [checkpoint kinase 1], and WEE1 pathway inhibition with a PARP inhibitor used to induce replication stress and be the sensitizer. The biomarker profiles are going to be complex, context-dependent, and likely to reflect a constellation of findings that would be signatures or algorithms, rather than single gene alterations. The post hoc iterative analysis of responders and nonresponders is going to be absolutely critical to understanding those biomarkers and the role of DNA damage response inhibitors in pediatrics. Given the rarity of these diagnoses, and then the molecular subclasses, I think collaboration across ages and geography is absolutely critical, and I really congratulate the ESMART consortium for doing just that in Europe,” said Dr. Bender.

The study is limited by its small sample size and the fact that it was not randomized.

The study received funding from French Institut National de Cancer, Imagine for Margo, Fondation ARC, AstraZeneca France, AstraZeneca Global R&D, AstraZeneca UK, Cancer Research UK, Fondation Gustave Roussy, and Little Princess Trust/Children’s Cancer and Leukaemia Group. Dr. Gatz has no relevant financial disclosures. Dr. Bender has done paid consulting for Jazz Pharmaceuticals and has done unpaid work for Bristol-Myers Squibb, Eisai, Springworks Therapeutics, Merck Sharp & Dohme, and Pfizer. She has received research support from Eli Lilly, Loxo-oncology, Eisai, Cellectar, Bayer, Amgen, and Jazz Pharmaceuticals.

From American Association for Cancer Research (AACR) Annual Meeting 2023: Abstract CT019. Presented Tuesday, April 18.

Cancer screening remains challenging. There are screens available for a handful of solid tumors, but uptake is low caused in part by health care access barriers as well as the potential for unnecessary follow-up procedures, according to Phillip Febbo, MD.

These issues could threaten efforts like that of President Joe Biden’s Cancer Moonshot initiative, which aims to reduce cancer mortality by 50%. Advances in circulating tumor (ct) DNA analysis could help address these problems, but a lack of diversity among study participants needs to be addressed to ensure it has broad utility, continued Dr. Febbo, during his presentation at the annual meeting of the American Association for Cancer Research.

The problem is particularly acute among African American, Hispanic, and other underserved populations who often face health care barriers that can exacerbate the issue, said Dr. Febbo, who is chief medical officer for Illumina. The lack of access is compounded by the fact that there are only currently screens for lung, breast, colorectal, cervical, and prostate cancer, leaving a vast unmet need.

“We still do not have screening tests for 70% of the deaths that are due to cancer,” he said.

ctDNA released from dying cancer cells has the potential to reveal a wide range of cancer types and reduce barriers to access, because it is based on a blood test. It can be analyzed for various factors, including mutations, chromosomal rearrangements, methylation patterns, and other characteristics that hint at the presence of cancer. However, it can’t be successful without sufficient inclusion in research studies, Dr. Febbo explained.

“We have to ensure we have the right representation [of] populations when we develop these tests, when we go through the clinical trials, and as we bring these into communities,” he said.

During his presentation, Dr. Febbo shared a slide showing that about 78% of participants in published gene-association studies were White.

ctDNA showed promise in at least on recent study. Dr. Febbo discussed the ECLIPSE trial, which used the Guardant Health SHIELD assay for colorectal cancer (CRC). About 13% of its approximately 20,000 participants were Black or African American, 15% were Hispanic, and 7% were Asian Americans. It also included both urban and rural individuals. In results announced in December 2022, the researchers found a sensitivity of 83%, which was lower than the 92.3% found in standard CRC screening, but above the 74% threshold set by the Food and Drug Administration. The specificity was 90%.

One approach that could dramatically change the landscape of cancer screening is a multicancer early detection (MCED) test, according to Dr. Febbo. The CancerSeek MCED test, developed by Johns Hopkins Kimmel Cancer Center researchers, uses a series of genetic and protein biomarkers to detect all cancers, with the exception of leukemia, skin cancer, and central nervous system tumors. Among 10,006 women aged between 65 and 75 years with no history of cancer, it had a sensitivity of 27.1% and a specificity of 98.9%, with a positive predictive value of 19.4%. The study’s population was 95% non-Hispanic White.

He also discussed the Pathfinder study, sponsored by the Illumina subsidiary Grail, which included 6,662 individuals age 50 and over from seven sites in the United States, and grouped them into normal and increased risk; 92% were non-Hispanic White. It used the Galleri MCED test, which performed with a sensitivity of 29%, specificity of 99.1%, and a positive predictive value of 38.0%. False positives produced to limited burden, with 93% undergoing imaging, 28% nonsurgical invasive procedures, and 2% undergoing fruitless invasive surgical procedures.

Dr. Febbo touted the potential for such tests to greatly reduce cancer mortality, but only if there is adequate uptake of screening procedures, particularly in underserved groups. He put up a slide of a model showing that MCED has the potential to reduce cancer mortality by 20%, but only if the screen is widely accepted among all groups. “I’ve had my team model this. If we accept the current use of screening tests, and we don’t address disparities, and we don’t ensure everybody feels included and participates actively – not only in the research, but also in the testing and adoption, you would cut that potential benefit in half. That would be hundreds of thousands of lives lost because we didn’t address disparities.”
 

Successful recruiting of African Americans for research

Following Dr. Febbo’s talk, Karriem Watson, MS, spoke about some potential solutions to the issue, including his own experiences and success stories in recruiting African Americans to play active roles in research. He is chief engagement officer for the National Institute of Health’s All of Us Research Program, which aims to gather health data on at least 1 million residents of the United States. Mr. Watson has spent time reaching out to people living in communities in the Chicago area to encourage participation in breast cancer screening. An event at his church inspired his own sister to get a mammogram, and she was diagnosed with early-stage breast cancer.

“I’m a living witness that early engagement can lead to early detection,” said Mr. Watson during his talk.

He reported that the All of Us research program has succeeded in creating diversity within its data collection, as 46.7% of participants identify as racial and ethnic minorities.

Mr. Watson took issue with the common perception that underrepresented communities may be hard to reach.

“I want to challenge us to think outside the box and really ask ourselves: Are populations hard to reach, or are there opportunities for us to do better and more intentional engagement?” He went on to describe a program to recruit African American men as citizen scientists. He and his colleagues developed a network that included barbers, faith leaders, and fraternity and civic organization members to help recruit participants for a prostate cancer screening project. They exceeded their initial recruitment goal.

They went on to develop a network of barbers in the south and west sides of Chicago to recruit individuals to participate in studies of protein methylation and lung cancer screening, as well as a project that investigated associations between neighborhood of residence and lung cancer. The results of those efforts have also informed other projects, including a smoking cessation study. “We’ve not only included African American men in our research, but we’ve included them as part of our research team,” said Mr. Watson.

Dr. Febbo is also a stockholder of Illumina. Mr. Watson has no relevant financial disclosures.

From American Association for Cancer Research (AACR) Annual Meeting 2023: Improving cancer outcomes through equitable access to cfDNA tests. Presented Monday, April 17, 2023.

Cancer screening remains challenging. There are screens available for a handful of solid tumors, but uptake is low caused in part by health care access barriers as well as the potential for unnecessary follow-up procedures, according to Phillip Febbo, MD.

These issues could threaten efforts like that of President Joe Biden’s Cancer Moonshot initiative, which aims to reduce cancer mortality by 50%. Advances in circulating tumor (ct) DNA analysis could help address these problems, but a lack of diversity among study participants needs to be addressed to ensure it has broad utility, continued Dr. Febbo, during his presentation at the annual meeting of the American Association for Cancer Research.

The problem is particularly acute among African American, Hispanic, and other underserved populations who often face health care barriers that can exacerbate the issue, said Dr. Febbo, who is chief medical officer for Illumina. The lack of access is compounded by the fact that there are only currently screens for lung, breast, colorectal, cervical, and prostate cancer, leaving a vast unmet need.

“We still do not have screening tests for 70% of the deaths that are due to cancer,” he said.

ctDNA released from dying cancer cells has the potential to reveal a wide range of cancer types and reduce barriers to access, because it is based on a blood test. It can be analyzed for various factors, including mutations, chromosomal rearrangements, methylation patterns, and other characteristics that hint at the presence of cancer. However, it can’t be successful without sufficient inclusion in research studies, Dr. Febbo explained.

“We have to ensure we have the right representation [of] populations when we develop these tests, when we go through the clinical trials, and as we bring these into communities,” he said.

During his presentation, Dr. Febbo shared a slide showing that about 78% of participants in published gene-association studies were White.

ctDNA showed promise in at least on recent study. Dr. Febbo discussed the ECLIPSE trial, which used the Guardant Health SHIELD assay for colorectal cancer (CRC). About 13% of its approximately 20,000 participants were Black or African American, 15% were Hispanic, and 7% were Asian Americans. It also included both urban and rural individuals. In results announced in December 2022, the researchers found a sensitivity of 83%, which was lower than the 92.3% found in standard CRC screening, but above the 74% threshold set by the Food and Drug Administration. The specificity was 90%.

One approach that could dramatically change the landscape of cancer screening is a multicancer early detection (MCED) test, according to Dr. Febbo. The CancerSeek MCED test, developed by Johns Hopkins Kimmel Cancer Center researchers, uses a series of genetic and protein biomarkers to detect all cancers, with the exception of leukemia, skin cancer, and central nervous system tumors. Among 10,006 women aged between 65 and 75 years with no history of cancer, it had a sensitivity of 27.1% and a specificity of 98.9%, with a positive predictive value of 19.4%. The study’s population was 95% non-Hispanic White.

He also discussed the Pathfinder study, sponsored by the Illumina subsidiary Grail, which included 6,662 individuals age 50 and over from seven sites in the United States, and grouped them into normal and increased risk; 92% were non-Hispanic White. It used the Galleri MCED test, which performed with a sensitivity of 29%, specificity of 99.1%, and a positive predictive value of 38.0%. False positives produced to limited burden, with 93% undergoing imaging, 28% nonsurgical invasive procedures, and 2% undergoing fruitless invasive surgical procedures.

Dr. Febbo touted the potential for such tests to greatly reduce cancer mortality, but only if there is adequate uptake of screening procedures, particularly in underserved groups. He put up a slide of a model showing that MCED has the potential to reduce cancer mortality by 20%, but only if the screen is widely accepted among all groups. “I’ve had my team model this. If we accept the current use of screening tests, and we don’t address disparities, and we don’t ensure everybody feels included and participates actively – not only in the research, but also in the testing and adoption, you would cut that potential benefit in half. That would be hundreds of thousands of lives lost because we didn’t address disparities.”
 

Successful recruiting of African Americans for research

Following Dr. Febbo’s talk, Karriem Watson, MS, spoke about some potential solutions to the issue, including his own experiences and success stories in recruiting African Americans to play active roles in research. He is chief engagement officer for the National Institute of Health’s All of Us Research Program, which aims to gather health data on at least 1 million residents of the United States. Mr. Watson has spent time reaching out to people living in communities in the Chicago area to encourage participation in breast cancer screening. An event at his church inspired his own sister to get a mammogram, and she was diagnosed with early-stage breast cancer.

“I’m a living witness that early engagement can lead to early detection,” said Mr. Watson during his talk.

He reported that the All of Us research program has succeeded in creating diversity within its data collection, as 46.7% of participants identify as racial and ethnic minorities.

Mr. Watson took issue with the common perception that underrepresented communities may be hard to reach.

“I want to challenge us to think outside the box and really ask ourselves: Are populations hard to reach, or are there opportunities for us to do better and more intentional engagement?” He went on to describe a program to recruit African American men as citizen scientists. He and his colleagues developed a network that included barbers, faith leaders, and fraternity and civic organization members to help recruit participants for a prostate cancer screening project. They exceeded their initial recruitment goal.

They went on to develop a network of barbers in the south and west sides of Chicago to recruit individuals to participate in studies of protein methylation and lung cancer screening, as well as a project that investigated associations between neighborhood of residence and lung cancer. The results of those efforts have also informed other projects, including a smoking cessation study. “We’ve not only included African American men in our research, but we’ve included them as part of our research team,” said Mr. Watson.

Dr. Febbo is also a stockholder of Illumina. Mr. Watson has no relevant financial disclosures.

From American Association for Cancer Research (AACR) Annual Meeting 2023: Improving cancer outcomes through equitable access to cfDNA tests. Presented Monday, April 17, 2023.

Cancer screening remains challenging. There are screens available for a handful of solid tumors, but uptake is low caused in part by health care access barriers as well as the potential for unnecessary follow-up procedures, according to Phillip Febbo, MD.

These issues could threaten efforts like that of President Joe Biden’s Cancer Moonshot initiative, which aims to reduce cancer mortality by 50%. Advances in circulating tumor (ct) DNA analysis could help address these problems, but a lack of diversity among study participants needs to be addressed to ensure it has broad utility, continued Dr. Febbo, during his presentation at the annual meeting of the American Association for Cancer Research.

The problem is particularly acute among African American, Hispanic, and other underserved populations who often face health care barriers that can exacerbate the issue, said Dr. Febbo, who is chief medical officer for Illumina. The lack of access is compounded by the fact that there are only currently screens for lung, breast, colorectal, cervical, and prostate cancer, leaving a vast unmet need.

“We still do not have screening tests for 70% of the deaths that are due to cancer,” he said.

ctDNA released from dying cancer cells has the potential to reveal a wide range of cancer types and reduce barriers to access, because it is based on a blood test. It can be analyzed for various factors, including mutations, chromosomal rearrangements, methylation patterns, and other characteristics that hint at the presence of cancer. However, it can’t be successful without sufficient inclusion in research studies, Dr. Febbo explained.

“We have to ensure we have the right representation [of] populations when we develop these tests, when we go through the clinical trials, and as we bring these into communities,” he said.

During his presentation, Dr. Febbo shared a slide showing that about 78% of participants in published gene-association studies were White.

ctDNA showed promise in at least on recent study. Dr. Febbo discussed the ECLIPSE trial, which used the Guardant Health SHIELD assay for colorectal cancer (CRC). About 13% of its approximately 20,000 participants were Black or African American, 15% were Hispanic, and 7% were Asian Americans. It also included both urban and rural individuals. In results announced in December 2022, the researchers found a sensitivity of 83%, which was lower than the 92.3% found in standard CRC screening, but above the 74% threshold set by the Food and Drug Administration. The specificity was 90%.

One approach that could dramatically change the landscape of cancer screening is a multicancer early detection (MCED) test, according to Dr. Febbo. The CancerSeek MCED test, developed by Johns Hopkins Kimmel Cancer Center researchers, uses a series of genetic and protein biomarkers to detect all cancers, with the exception of leukemia, skin cancer, and central nervous system tumors. Among 10,006 women aged between 65 and 75 years with no history of cancer, it had a sensitivity of 27.1% and a specificity of 98.9%, with a positive predictive value of 19.4%. The study’s population was 95% non-Hispanic White.

He also discussed the Pathfinder study, sponsored by the Illumina subsidiary Grail, which included 6,662 individuals age 50 and over from seven sites in the United States, and grouped them into normal and increased risk; 92% were non-Hispanic White. It used the Galleri MCED test, which performed with a sensitivity of 29%, specificity of 99.1%, and a positive predictive value of 38.0%. False positives produced to limited burden, with 93% undergoing imaging, 28% nonsurgical invasive procedures, and 2% undergoing fruitless invasive surgical procedures.

Dr. Febbo touted the potential for such tests to greatly reduce cancer mortality, but only if there is adequate uptake of screening procedures, particularly in underserved groups. He put up a slide of a model showing that MCED has the potential to reduce cancer mortality by 20%, but only if the screen is widely accepted among all groups. “I’ve had my team model this. If we accept the current use of screening tests, and we don’t address disparities, and we don’t ensure everybody feels included and participates actively – not only in the research, but also in the testing and adoption, you would cut that potential benefit in half. That would be hundreds of thousands of lives lost because we didn’t address disparities.”
 

Successful recruiting of African Americans for research

Following Dr. Febbo’s talk, Karriem Watson, MS, spoke about some potential solutions to the issue, including his own experiences and success stories in recruiting African Americans to play active roles in research. He is chief engagement officer for the National Institute of Health’s All of Us Research Program, which aims to gather health data on at least 1 million residents of the United States. Mr. Watson has spent time reaching out to people living in communities in the Chicago area to encourage participation in breast cancer screening. An event at his church inspired his own sister to get a mammogram, and she was diagnosed with early-stage breast cancer.

“I’m a living witness that early engagement can lead to early detection,” said Mr. Watson during his talk.

He reported that the All of Us research program has succeeded in creating diversity within its data collection, as 46.7% of participants identify as racial and ethnic minorities.

Mr. Watson took issue with the common perception that underrepresented communities may be hard to reach.

“I want to challenge us to think outside the box and really ask ourselves: Are populations hard to reach, or are there opportunities for us to do better and more intentional engagement?” He went on to describe a program to recruit African American men as citizen scientists. He and his colleagues developed a network that included barbers, faith leaders, and fraternity and civic organization members to help recruit participants for a prostate cancer screening project. They exceeded their initial recruitment goal.

They went on to develop a network of barbers in the south and west sides of Chicago to recruit individuals to participate in studies of protein methylation and lung cancer screening, as well as a project that investigated associations between neighborhood of residence and lung cancer. The results of those efforts have also informed other projects, including a smoking cessation study. “We’ve not only included African American men in our research, but we’ve included them as part of our research team,” said Mr. Watson.

Dr. Febbo is also a stockholder of Illumina. Mr. Watson has no relevant financial disclosures.

From American Association for Cancer Research (AACR) Annual Meeting 2023: Improving cancer outcomes through equitable access to cfDNA tests. Presented Monday, April 17, 2023.

Among patients with unresectable desmoplastic melanoma (DM), a prospective trial showed that single-agent treatment with the programmed death 1 (PD-1) inhibitor pembrolizumab led to a dramatic overall response rate.

The findings could represent a new standard of treatment for this extremely rare tumor.

The study was inspired by a previous retrospective analysis which found an overall response rate of 77% and a complete response of 32% to anti–PD-1 monotherapy.

The ORR is about double what is seen in melanoma more generally, according to Kari Kendra, MD, PhD, who presented the study at the annual meeting of the American Association for Cancer Research.

“Our study was a positive study. Of note, in the retrospective study, they saw a complete response rate of 32%, which was amazingly similar to what we found. [The findings support] the use of single agent anti–PD-1 immunotherapy as first line treatment for most patients with unresectable desmoplastic melanoma. [There was 89% overall response and we saw] dramatic responses across the board,” said Dr. Kendra, who is a medical oncologist at Ohio State University Wexner Medical Center, Columbus.

The findings drew a strong reaction. “In a rare tumor session, to see response curves like that, it’s just outstanding,” said the session’s cochair Brian Van Tine, MD, PhD, who is a professor of medical oncology at Washington University in St. Louis.

“This really is one of the highest tumor response rates to immunotherapy that we are seeing in any cancer. And I think may also highlight the fact that we shouldn’t think of all cutaneous melanomas as one disease, given the heterogeneity in tumor responses based on some of the pathologic and molecular characteristics,” said Zeynep Aroglu, MD, who served as a discussant but was also one of the investigators who enrolled patients for the trial.

Desmoplastic melanoma represents about 4% of all cutaneous melanoma diagnoses, and its unique pathology can make it difficult to diagnose. That often leads to a late diagnosis, according to Dr. Aroglu. They typically occur in elderly patients, in the head and neck area, and are associated with sun exposure. DM also tends to have a high mutation burden, Dr. Aroglu said during the session.

It remains to be seen why there is such a high response rate in this tumor type, even among tumor types with mutation burdens that are nearly as high. DM tumors are often driven by neurofibromatosis type 1, but other tumors driven by NF-1 don’t have as high of a response rate to immunotherapy. The tumor environment could also play a role, she said.

“Is it a combination of all these factors? I think some of the ongoing analysis of tumor samples that Dr. Kendra mentioned may help to answer some of these questions,” Dr. Aroglu continued.

She also noted that the melanoma field is increasingly turning to combination of anti–PD-1 therapy with agents like that target LAG3 or CTLA4. Such combinations can achieve higher response rates, but at a cost of higher rates of grade 3-4 adverse events than anti–PD-1 inhibitors alone. “I wonder if for desmoplastic melanomas in light of this data, do we consider de-escalating therapy, given these very high response rates to PD-1 alone, given also the elderly age of many of these patients, because even the PD-1–LAG3 combo still has a higher rate of toxicity than PD-1 monotherapy. Perhaps the immunotherapy combinations can be reserved for those rare desmoplastic patients who are resistant to PD-1 alone,” said Dr. Aroglu.
 

Study details and adverse events

Twenty-seven patients were enrolled in the study; 93% were male, all were White, and 22% had elevated baseline lactate dehydrogenase. About 63% had disease located in the head and neck area, 33% experienced a complete response (P < .001), and 56% had a partial response for an ORR of 89%. The result surpassed the primary endpoint target of at least a 20% complete response rate.

The 2-year progression-free survival was 74%, and 2-year overall survival was 89%. The most common toxicities were fatigue (56%), diarrhea (33%), maculopapular rash (30%), pruritus (22%), anemia (19%), arthralgia (19%), and decreased lymphocyte count (19%). There were two grade 4 adverse events: a lipase increase and a lung infection accompanied by sepsis.

The researchers also carried out whole exome sequencing of biopsies and found that 67% had NF-1 loss of function mutations.

Dr. Aroglu has served on advisory boards for Pfizer, Array, Eisai, Genentech, Natera, Novartis, OncoSec, and Regeneron. She has received research support from Boehringer Ingelheim, Pfizer, and Novartis. Dr. Kendra has received institutional support from Bristol Myers-Squibb and trial support from CheckMate Pharmaceuticals, GlaxoSmithKline, Immunocore, Medspace, Merck, Novartis, and Varian Medical Systems. Dr. Van Tine has financial relationships with a wide range of pharmaceutical companies.

Among patients with unresectable desmoplastic melanoma (DM), a prospective trial showed that single-agent treatment with the programmed death 1 (PD-1) inhibitor pembrolizumab led to a dramatic overall response rate.

The findings could represent a new standard of treatment for this extremely rare tumor.

The study was inspired by a previous retrospective analysis which found an overall response rate of 77% and a complete response of 32% to anti–PD-1 monotherapy.

The ORR is about double what is seen in melanoma more generally, according to Kari Kendra, MD, PhD, who presented the study at the annual meeting of the American Association for Cancer Research.

“Our study was a positive study. Of note, in the retrospective study, they saw a complete response rate of 32%, which was amazingly similar to what we found. [The findings support] the use of single agent anti–PD-1 immunotherapy as first line treatment for most patients with unresectable desmoplastic melanoma. [There was 89% overall response and we saw] dramatic responses across the board,” said Dr. Kendra, who is a medical oncologist at Ohio State University Wexner Medical Center, Columbus.

The findings drew a strong reaction. “In a rare tumor session, to see response curves like that, it’s just outstanding,” said the session’s cochair Brian Van Tine, MD, PhD, who is a professor of medical oncology at Washington University in St. Louis.

“This really is one of the highest tumor response rates to immunotherapy that we are seeing in any cancer. And I think may also highlight the fact that we shouldn’t think of all cutaneous melanomas as one disease, given the heterogeneity in tumor responses based on some of the pathologic and molecular characteristics,” said Zeynep Aroglu, MD, who served as a discussant but was also one of the investigators who enrolled patients for the trial.

Desmoplastic melanoma represents about 4% of all cutaneous melanoma diagnoses, and its unique pathology can make it difficult to diagnose. That often leads to a late diagnosis, according to Dr. Aroglu. They typically occur in elderly patients, in the head and neck area, and are associated with sun exposure. DM also tends to have a high mutation burden, Dr. Aroglu said during the session.

It remains to be seen why there is such a high response rate in this tumor type, even among tumor types with mutation burdens that are nearly as high. DM tumors are often driven by neurofibromatosis type 1, but other tumors driven by NF-1 don’t have as high of a response rate to immunotherapy. The tumor environment could also play a role, she said.

“Is it a combination of all these factors? I think some of the ongoing analysis of tumor samples that Dr. Kendra mentioned may help to answer some of these questions,” Dr. Aroglu continued.

She also noted that the melanoma field is increasingly turning to combination of anti–PD-1 therapy with agents like that target LAG3 or CTLA4. Such combinations can achieve higher response rates, but at a cost of higher rates of grade 3-4 adverse events than anti–PD-1 inhibitors alone. “I wonder if for desmoplastic melanomas in light of this data, do we consider de-escalating therapy, given these very high response rates to PD-1 alone, given also the elderly age of many of these patients, because even the PD-1–LAG3 combo still has a higher rate of toxicity than PD-1 monotherapy. Perhaps the immunotherapy combinations can be reserved for those rare desmoplastic patients who are resistant to PD-1 alone,” said Dr. Aroglu.
 

Study details and adverse events

Twenty-seven patients were enrolled in the study; 93% were male, all were White, and 22% had elevated baseline lactate dehydrogenase. About 63% had disease located in the head and neck area, 33% experienced a complete response (P < .001), and 56% had a partial response for an ORR of 89%. The result surpassed the primary endpoint target of at least a 20% complete response rate.

The 2-year progression-free survival was 74%, and 2-year overall survival was 89%. The most common toxicities were fatigue (56%), diarrhea (33%), maculopapular rash (30%), pruritus (22%), anemia (19%), arthralgia (19%), and decreased lymphocyte count (19%). There were two grade 4 adverse events: a lipase increase and a lung infection accompanied by sepsis.

The researchers also carried out whole exome sequencing of biopsies and found that 67% had NF-1 loss of function mutations.

Dr. Aroglu has served on advisory boards for Pfizer, Array, Eisai, Genentech, Natera, Novartis, OncoSec, and Regeneron. She has received research support from Boehringer Ingelheim, Pfizer, and Novartis. Dr. Kendra has received institutional support from Bristol Myers-Squibb and trial support from CheckMate Pharmaceuticals, GlaxoSmithKline, Immunocore, Medspace, Merck, Novartis, and Varian Medical Systems. Dr. Van Tine has financial relationships with a wide range of pharmaceutical companies.

Among patients with unresectable desmoplastic melanoma (DM), a prospective trial showed that single-agent treatment with the programmed death 1 (PD-1) inhibitor pembrolizumab led to a dramatic overall response rate.

The findings could represent a new standard of treatment for this extremely rare tumor.

The study was inspired by a previous retrospective analysis which found an overall response rate of 77% and a complete response of 32% to anti–PD-1 monotherapy.

The ORR is about double what is seen in melanoma more generally, according to Kari Kendra, MD, PhD, who presented the study at the annual meeting of the American Association for Cancer Research.

“Our study was a positive study. Of note, in the retrospective study, they saw a complete response rate of 32%, which was amazingly similar to what we found. [The findings support] the use of single agent anti–PD-1 immunotherapy as first line treatment for most patients with unresectable desmoplastic melanoma. [There was 89% overall response and we saw] dramatic responses across the board,” said Dr. Kendra, who is a medical oncologist at Ohio State University Wexner Medical Center, Columbus.

The findings drew a strong reaction. “In a rare tumor session, to see response curves like that, it’s just outstanding,” said the session’s cochair Brian Van Tine, MD, PhD, who is a professor of medical oncology at Washington University in St. Louis.

“This really is one of the highest tumor response rates to immunotherapy that we are seeing in any cancer. And I think may also highlight the fact that we shouldn’t think of all cutaneous melanomas as one disease, given the heterogeneity in tumor responses based on some of the pathologic and molecular characteristics,” said Zeynep Aroglu, MD, who served as a discussant but was also one of the investigators who enrolled patients for the trial.

Desmoplastic melanoma represents about 4% of all cutaneous melanoma diagnoses, and its unique pathology can make it difficult to diagnose. That often leads to a late diagnosis, according to Dr. Aroglu. They typically occur in elderly patients, in the head and neck area, and are associated with sun exposure. DM also tends to have a high mutation burden, Dr. Aroglu said during the session.

It remains to be seen why there is such a high response rate in this tumor type, even among tumor types with mutation burdens that are nearly as high. DM tumors are often driven by neurofibromatosis type 1, but other tumors driven by NF-1 don’t have as high of a response rate to immunotherapy. The tumor environment could also play a role, she said.

“Is it a combination of all these factors? I think some of the ongoing analysis of tumor samples that Dr. Kendra mentioned may help to answer some of these questions,” Dr. Aroglu continued.

She also noted that the melanoma field is increasingly turning to combination of anti–PD-1 therapy with agents like that target LAG3 or CTLA4. Such combinations can achieve higher response rates, but at a cost of higher rates of grade 3-4 adverse events than anti–PD-1 inhibitors alone. “I wonder if for desmoplastic melanomas in light of this data, do we consider de-escalating therapy, given these very high response rates to PD-1 alone, given also the elderly age of many of these patients, because even the PD-1–LAG3 combo still has a higher rate of toxicity than PD-1 monotherapy. Perhaps the immunotherapy combinations can be reserved for those rare desmoplastic patients who are resistant to PD-1 alone,” said Dr. Aroglu.
 

Study details and adverse events

Twenty-seven patients were enrolled in the study; 93% were male, all were White, and 22% had elevated baseline lactate dehydrogenase. About 63% had disease located in the head and neck area, 33% experienced a complete response (P < .001), and 56% had a partial response for an ORR of 89%. The result surpassed the primary endpoint target of at least a 20% complete response rate.

The 2-year progression-free survival was 74%, and 2-year overall survival was 89%. The most common toxicities were fatigue (56%), diarrhea (33%), maculopapular rash (30%), pruritus (22%), anemia (19%), arthralgia (19%), and decreased lymphocyte count (19%). There were two grade 4 adverse events: a lipase increase and a lung infection accompanied by sepsis.

The researchers also carried out whole exome sequencing of biopsies and found that 67% had NF-1 loss of function mutations.

Dr. Aroglu has served on advisory boards for Pfizer, Array, Eisai, Genentech, Natera, Novartis, OncoSec, and Regeneron. She has received research support from Boehringer Ingelheim, Pfizer, and Novartis. Dr. Kendra has received institutional support from Bristol Myers-Squibb and trial support from CheckMate Pharmaceuticals, GlaxoSmithKline, Immunocore, Medspace, Merck, Novartis, and Varian Medical Systems. Dr. Van Tine has financial relationships with a wide range of pharmaceutical companies.