Conference Coverage

PHM20 session title

The Incidentaloma: Common Incidental Findings Seen on Pediatric Imaging

Presenters

Jill Azok, MD; Amanda Lansell, MD; Allayne Stephans, MD; and Erin Frank, MD

Session summary

Dr. Azok, Dr. Lansell, and Dr. Frank of University Hospitals Rainbow Babies & Children’s Hospital, Cleveland, described one to three common, incidentally noted findings in central nervous system, thoracic, abdominopelvic, and musculoskeletal imaging. The presenters explained the indications for further work-up and/or intervention of these findings, and the importance of judicious use of imaging in pediatric patients.

Dr. Frank discussed incidental findings seen on imaging of the central nervous system, using cases to focus on benign enlargement of the subarachnoid space, lipomas of the filum terminale, and pituitary abnormalities. Dr. Lansell continued by discussing possible clinical models for management of incidentally found pulmonary nodules and renal cysts. Dr. Azok completed the session with a discussion of the appearance and management of nonossifying fibromas and cortical fibrous defects. Common threads shared by all presenters were how frequent incidental findings are and the need for providers to be comfortable with a level of uncertainty.
 

Key takeaways

• Incidental findings are very common in pediatric imaging, occurring on up to one-third of CT scans, 25% of brain MRIs, and 21% of knee radiographs.
• An infant with personal and family history of macrocephaly, normal development, and increased extra-axial CSF on MRI likely has benign enlargement of the arachnoid space and does not need further evaluation.
• A hyperintensity of filum terminale on MRI is consistent with lipoma of the filum terminale and does not require follow-up unless symptoms of tethered cord are present.
• Pituitary abnormalities are common and call for dedicated history, physical exam, and an endocrine screening with imaging surveillance if screening is normal.
• Patient history and appearance of pulmonary nodules are important in determining appropriate follow-up.
• No single feature of renal lesions predicts future behavior, but larger lesions deserve more work-up.
• Nonossifying fibromas are well-demarcated intracortical radiolucencies of long bone metaphyses that do not require treatment or further evaluation unless they are large, painful, or occur in the proximal femur.

Dr. Miller is a second-year pediatric hospital medicine fellow at Cleveland Clinic Children’s. His academic interests include medical education, quality improvement, and high value care.

PHM20 session title

The Incidentaloma: Common Incidental Findings Seen on Pediatric Imaging

Presenters

Jill Azok, MD; Amanda Lansell, MD; Allayne Stephans, MD; and Erin Frank, MD

Session summary

Dr. Azok, Dr. Lansell, and Dr. Frank of University Hospitals Rainbow Babies & Children’s Hospital, Cleveland, described one to three common, incidentally noted findings in central nervous system, thoracic, abdominopelvic, and musculoskeletal imaging. The presenters explained the indications for further work-up and/or intervention of these findings, and the importance of judicious use of imaging in pediatric patients.

Dr. Frank discussed incidental findings seen on imaging of the central nervous system, using cases to focus on benign enlargement of the subarachnoid space, lipomas of the filum terminale, and pituitary abnormalities. Dr. Lansell continued by discussing possible clinical models for management of incidentally found pulmonary nodules and renal cysts. Dr. Azok completed the session with a discussion of the appearance and management of nonossifying fibromas and cortical fibrous defects. Common threads shared by all presenters were how frequent incidental findings are and the need for providers to be comfortable with a level of uncertainty.
 

Key takeaways

• Incidental findings are very common in pediatric imaging, occurring on up to one-third of CT scans, 25% of brain MRIs, and 21% of knee radiographs.
• An infant with personal and family history of macrocephaly, normal development, and increased extra-axial CSF on MRI likely has benign enlargement of the arachnoid space and does not need further evaluation.
• A hyperintensity of filum terminale on MRI is consistent with lipoma of the filum terminale and does not require follow-up unless symptoms of tethered cord are present.
• Pituitary abnormalities are common and call for dedicated history, physical exam, and an endocrine screening with imaging surveillance if screening is normal.
• Patient history and appearance of pulmonary nodules are important in determining appropriate follow-up.
• No single feature of renal lesions predicts future behavior, but larger lesions deserve more work-up.
• Nonossifying fibromas are well-demarcated intracortical radiolucencies of long bone metaphyses that do not require treatment or further evaluation unless they are large, painful, or occur in the proximal femur.

Dr. Miller is a second-year pediatric hospital medicine fellow at Cleveland Clinic Children’s. His academic interests include medical education, quality improvement, and high value care.

PHM20 session title

The Incidentaloma: Common Incidental Findings Seen on Pediatric Imaging

Presenters

Jill Azok, MD; Amanda Lansell, MD; Allayne Stephans, MD; and Erin Frank, MD

Session summary

Dr. Azok, Dr. Lansell, and Dr. Frank of University Hospitals Rainbow Babies & Children’s Hospital, Cleveland, described one to three common, incidentally noted findings in central nervous system, thoracic, abdominopelvic, and musculoskeletal imaging. The presenters explained the indications for further work-up and/or intervention of these findings, and the importance of judicious use of imaging in pediatric patients.

Dr. Frank discussed incidental findings seen on imaging of the central nervous system, using cases to focus on benign enlargement of the subarachnoid space, lipomas of the filum terminale, and pituitary abnormalities. Dr. Lansell continued by discussing possible clinical models for management of incidentally found pulmonary nodules and renal cysts. Dr. Azok completed the session with a discussion of the appearance and management of nonossifying fibromas and cortical fibrous defects. Common threads shared by all presenters were how frequent incidental findings are and the need for providers to be comfortable with a level of uncertainty.
 

Key takeaways

• Incidental findings are very common in pediatric imaging, occurring on up to one-third of CT scans, 25% of brain MRIs, and 21% of knee radiographs.
• An infant with personal and family history of macrocephaly, normal development, and increased extra-axial CSF on MRI likely has benign enlargement of the arachnoid space and does not need further evaluation.
• A hyperintensity of filum terminale on MRI is consistent with lipoma of the filum terminale and does not require follow-up unless symptoms of tethered cord are present.
• Pituitary abnormalities are common and call for dedicated history, physical exam, and an endocrine screening with imaging surveillance if screening is normal.
• Patient history and appearance of pulmonary nodules are important in determining appropriate follow-up.
• No single feature of renal lesions predicts future behavior, but larger lesions deserve more work-up.
• Nonossifying fibromas are well-demarcated intracortical radiolucencies of long bone metaphyses that do not require treatment or further evaluation unless they are large, painful, or occur in the proximal femur.

Dr. Miller is a second-year pediatric hospital medicine fellow at Cleveland Clinic Children’s. His academic interests include medical education, quality improvement, and high value care.

As hospitalists and other physicians at the University of Texas at Austin considered how to treat COVID-19 patients in the early weeks of the pandemic, one question they had to consider was: What about convalescent plasma?

All they had to go on were small case series in Ebola, SARS, and MERS and a few small, nonrandomized COVID-19 studies showing a possible benefit and minimal risk, but the evidence was only “toward the middle or bottom” of the evidence pyramid, said Johanna Busch, MD, of the department of internal medicine at Dell Medical Center at the university.

The center’s COVID-19 committee asked a few of its members – infectious disease and internal medicine physicians – to analyze the literature and other factors. In the end, the committee – which meets regularly and also includes pulmonology–critical care experts, nursing experts, and others – recommended using convalescent plasma because of the evidence and the available supply. But in subsequent meetings, as the pandemic surged in the South and the supply dwindled, the committee changed its recommendation for convalescent plasma to more limited use, she said during the virtual annual meeting of the Society of Hospital Medicine.

Dell’s experience with the therapy is one example of how the center had to quickly develop protocols for managing a pandemic with essentially no solid evidence for treatment and a system that had never been challenged before to the same degree.

“It’s all about teamwork,” said W. Michael Brode, MD, of the department of internal medicine at Dell. “The interprofessional team members know their roles and have shared expectations because they have a common understanding of the protocol.” It’s okay to deviate from the protocol, he said, as long as the language exists to communicate these deviations.

“Maybe the approach is more important than the actual content,” he said.

What Dr. Brode and Dr. Busch described was in large part a fine-tuning of communication – being available to communicate in real time and being aware of when certain specialists should be contacted – for instance, to determine at what oxygenation level internal medicine staff should get in touch with the pulmonary–critical care team.

Dr. Brode said that the groundwork is laid for productive meetings, with agendas announced ahead of time and readings assigned and presenters ready with near-finished products at meeting time, “with a clear path for operationalizing it.”

“We don’t want people kind of riffing off the top of their heads,” he said.

Committee members are encouraged to be as specific as possible when giving input into COVID-19 care decisions, he said.

“We’re so used to dealing with uncertainty, but that doesn’t really help when we’re trying to make tough decisions,” Dr. Brode said. They might be asked, “What are you going to write in your consult note template?” or “It’s 1:00 a.m. and your intern’s panicked and calling you – what are you going to tell them to do over the phone?”

The recommendations have to go into writing and are incorporated into the electronic medical record, a process that required some workarounds, he said. He also noted that the committee learned early on that they should assume that no one reads the e-mails – especially after being off for a period of time – so they likely won’t digest updates on an email-by-email basis.

“We quickly learned,” Dr. Brode said, “that this information needs to live on a Web site or [be] linked to the most up-to-date version in a cloud-sharing platform.”

In a question-and-answer discussion, session viewers expressed enthusiasm for the presenters’ one-page summary of protocols – much more, they said, and it could feel overwhelming.

Dr. Busch and Dr. Brode were asked how standardized order sets for COVID patients could be justified without comparison to a control group that didn’t use the standard order set.

Dr. Busch responded that, while there was no controlled trial, the order sets they use have evolved based on experience.

“At the beginning, we were following every inflammatory marker known to mankind, and then we realized as we gained more experience with COVID and COVID patients that some of those markers were not really informing any of our clinical decisions,” she said. “Obviously, as literature comes out we may reevaluate what goes into that standard order set and how frequently we follow labs.”

Dr. Brode said the context – a pandemic – has to be considered.

“In an ideal world, we could show that the intervention is superior through a randomized fashion with a control group, but really our thought process behind it is just, what is the default?” he said. “I looked at the order sets [as] not that they’re going to be dictating care, but it’s really like the guardrails of what’s reasonable. And when you’re in the middle of a surge, what is usually reasonable and easiest is what is going to be done.”

Dr. Busch and Dr. Brode reported no relevant financial relationships.

As hospitalists and other physicians at the University of Texas at Austin considered how to treat COVID-19 patients in the early weeks of the pandemic, one question they had to consider was: What about convalescent plasma?

All they had to go on were small case series in Ebola, SARS, and MERS and a few small, nonrandomized COVID-19 studies showing a possible benefit and minimal risk, but the evidence was only “toward the middle or bottom” of the evidence pyramid, said Johanna Busch, MD, of the department of internal medicine at Dell Medical Center at the university.

The center’s COVID-19 committee asked a few of its members – infectious disease and internal medicine physicians – to analyze the literature and other factors. In the end, the committee – which meets regularly and also includes pulmonology–critical care experts, nursing experts, and others – recommended using convalescent plasma because of the evidence and the available supply. But in subsequent meetings, as the pandemic surged in the South and the supply dwindled, the committee changed its recommendation for convalescent plasma to more limited use, she said during the virtual annual meeting of the Society of Hospital Medicine.

Dell’s experience with the therapy is one example of how the center had to quickly develop protocols for managing a pandemic with essentially no solid evidence for treatment and a system that had never been challenged before to the same degree.

“It’s all about teamwork,” said W. Michael Brode, MD, of the department of internal medicine at Dell. “The interprofessional team members know their roles and have shared expectations because they have a common understanding of the protocol.” It’s okay to deviate from the protocol, he said, as long as the language exists to communicate these deviations.

“Maybe the approach is more important than the actual content,” he said.

What Dr. Brode and Dr. Busch described was in large part a fine-tuning of communication – being available to communicate in real time and being aware of when certain specialists should be contacted – for instance, to determine at what oxygenation level internal medicine staff should get in touch with the pulmonary–critical care team.

Dr. Brode said that the groundwork is laid for productive meetings, with agendas announced ahead of time and readings assigned and presenters ready with near-finished products at meeting time, “with a clear path for operationalizing it.”

“We don’t want people kind of riffing off the top of their heads,” he said.

Committee members are encouraged to be as specific as possible when giving input into COVID-19 care decisions, he said.

“We’re so used to dealing with uncertainty, but that doesn’t really help when we’re trying to make tough decisions,” Dr. Brode said. They might be asked, “What are you going to write in your consult note template?” or “It’s 1:00 a.m. and your intern’s panicked and calling you – what are you going to tell them to do over the phone?”

The recommendations have to go into writing and are incorporated into the electronic medical record, a process that required some workarounds, he said. He also noted that the committee learned early on that they should assume that no one reads the e-mails – especially after being off for a period of time – so they likely won’t digest updates on an email-by-email basis.

“We quickly learned,” Dr. Brode said, “that this information needs to live on a Web site or [be] linked to the most up-to-date version in a cloud-sharing platform.”

In a question-and-answer discussion, session viewers expressed enthusiasm for the presenters’ one-page summary of protocols – much more, they said, and it could feel overwhelming.

Dr. Busch and Dr. Brode were asked how standardized order sets for COVID patients could be justified without comparison to a control group that didn’t use the standard order set.

Dr. Busch responded that, while there was no controlled trial, the order sets they use have evolved based on experience.

“At the beginning, we were following every inflammatory marker known to mankind, and then we realized as we gained more experience with COVID and COVID patients that some of those markers were not really informing any of our clinical decisions,” she said. “Obviously, as literature comes out we may reevaluate what goes into that standard order set and how frequently we follow labs.”

Dr. Brode said the context – a pandemic – has to be considered.

“In an ideal world, we could show that the intervention is superior through a randomized fashion with a control group, but really our thought process behind it is just, what is the default?” he said. “I looked at the order sets [as] not that they’re going to be dictating care, but it’s really like the guardrails of what’s reasonable. And when you’re in the middle of a surge, what is usually reasonable and easiest is what is going to be done.”

Dr. Busch and Dr. Brode reported no relevant financial relationships.

As hospitalists and other physicians at the University of Texas at Austin considered how to treat COVID-19 patients in the early weeks of the pandemic, one question they had to consider was: What about convalescent plasma?

All they had to go on were small case series in Ebola, SARS, and MERS and a few small, nonrandomized COVID-19 studies showing a possible benefit and minimal risk, but the evidence was only “toward the middle or bottom” of the evidence pyramid, said Johanna Busch, MD, of the department of internal medicine at Dell Medical Center at the university.

The center’s COVID-19 committee asked a few of its members – infectious disease and internal medicine physicians – to analyze the literature and other factors. In the end, the committee – which meets regularly and also includes pulmonology–critical care experts, nursing experts, and others – recommended using convalescent plasma because of the evidence and the available supply. But in subsequent meetings, as the pandemic surged in the South and the supply dwindled, the committee changed its recommendation for convalescent plasma to more limited use, she said during the virtual annual meeting of the Society of Hospital Medicine.

Dell’s experience with the therapy is one example of how the center had to quickly develop protocols for managing a pandemic with essentially no solid evidence for treatment and a system that had never been challenged before to the same degree.

“It’s all about teamwork,” said W. Michael Brode, MD, of the department of internal medicine at Dell. “The interprofessional team members know their roles and have shared expectations because they have a common understanding of the protocol.” It’s okay to deviate from the protocol, he said, as long as the language exists to communicate these deviations.

“Maybe the approach is more important than the actual content,” he said.

What Dr. Brode and Dr. Busch described was in large part a fine-tuning of communication – being available to communicate in real time and being aware of when certain specialists should be contacted – for instance, to determine at what oxygenation level internal medicine staff should get in touch with the pulmonary–critical care team.

Dr. Brode said that the groundwork is laid for productive meetings, with agendas announced ahead of time and readings assigned and presenters ready with near-finished products at meeting time, “with a clear path for operationalizing it.”

“We don’t want people kind of riffing off the top of their heads,” he said.

Committee members are encouraged to be as specific as possible when giving input into COVID-19 care decisions, he said.

“We’re so used to dealing with uncertainty, but that doesn’t really help when we’re trying to make tough decisions,” Dr. Brode said. They might be asked, “What are you going to write in your consult note template?” or “It’s 1:00 a.m. and your intern’s panicked and calling you – what are you going to tell them to do over the phone?”

The recommendations have to go into writing and are incorporated into the electronic medical record, a process that required some workarounds, he said. He also noted that the committee learned early on that they should assume that no one reads the e-mails – especially after being off for a period of time – so they likely won’t digest updates on an email-by-email basis.

“We quickly learned,” Dr. Brode said, “that this information needs to live on a Web site or [be] linked to the most up-to-date version in a cloud-sharing platform.”

In a question-and-answer discussion, session viewers expressed enthusiasm for the presenters’ one-page summary of protocols – much more, they said, and it could feel overwhelming.

Dr. Busch and Dr. Brode were asked how standardized order sets for COVID patients could be justified without comparison to a control group that didn’t use the standard order set.

Dr. Busch responded that, while there was no controlled trial, the order sets they use have evolved based on experience.

“At the beginning, we were following every inflammatory marker known to mankind, and then we realized as we gained more experience with COVID and COVID patients that some of those markers were not really informing any of our clinical decisions,” she said. “Obviously, as literature comes out we may reevaluate what goes into that standard order set and how frequently we follow labs.”

Dr. Brode said the context – a pandemic – has to be considered.

“In an ideal world, we could show that the intervention is superior through a randomized fashion with a control group, but really our thought process behind it is just, what is the default?” he said. “I looked at the order sets [as] not that they’re going to be dictating care, but it’s really like the guardrails of what’s reasonable. And when you’re in the middle of a surge, what is usually reasonable and easiest is what is going to be done.”

Dr. Busch and Dr. Brode reported no relevant financial relationships.

Fractional flow reserve derived noninvasively from coronary CT angiography is a safe and accurate method for assessing the significance of coronary artery disease in patients with severe aortic stenosis who are headed for transcatheter aortic valve replacement (TAVR), according to results of the CAST-FFR prospective study.

Indeed, utilization of coronary CT angiography–derived fractional flow reserve (CT-FFR) for this purpose offers the advantage of using a single noninvasive imaging method to replace two invasive procedures: coronary angiography to assess the anatomy of coronary lesions, and conventional FFR using a pressure wire to determine the functional significance of a given coronary stenosis as a cause of ischemia, Michael Michail, MBBS, explained in reporting the results at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Because up to 50% of patients with severe aortic stenosis undergoing TAVR have coexisting coronary artery disease, it remains common practice to perform prior invasive coronary angiography. However, this is associated with inherent risks, particularly in an elderly cohort with comorbidities. Additionally, coronary angiography provides no information on the functional impact of coronary stenoses, which may be important in guiding revascularization decisions prior to TAVR,” noted Dr. Michail, a cardiologist at Monash University, Melbourne.
 

Simulating FFR: ‘A one-stop shop cardiac CT’

Dr. Michail presented the results of the prospective CAST-FFR study, the first evaluation of CT-FFR for assessment of coronary arteries in patients with severe symptomatic aortic stenosis. This method uses computational fluid dynamics to transform data obtained noninvasively from a standard coronary CT angiography acquisition into a simulated FFR. And it offers the potential to streamline patient care.

“In current practice we see elderly patients with a long pre-TAVR assessment period, with numerous appointments and invasive procedures. Our vision is a one-stop shop cardiac CT that will provide the cardiologist with a complete assessment of the annular measurements, peripheral vasculature, and the coronary arteries ahead of their procedure,” according to Dr. Michail.

“We believe the ability to perform the requisite coronary assessment using CT-FFR will translate to improved patient care in several ways,” he continued. “Firstly, this will shorten the number of tests and overall diagnostic journey for patients. It will reduce the risk from unnecessary invasive procedures, and this will also reduce discomfort for the patient. Based on emerging evidence on the adverse prognostic impact of functionally significant coronary disease in aortic stenosis, this data has the potential to improve procedural risk stratification. And finally, contingent on further data, this may improve lesion selection for upfront revascularization.”

The CAST-FFR study was a small, single-center, proof-of-concept study in which 42 patients with severe aortic stenosis underwent both coronary CT angiography and conventional FFR with a pressure wire. The CT data was sent to a core laboratory for conversion into CT-FFR by evaluators blinded to the conventional FFR values.

Of the 42 participants, 39 (93%) had usable CT-FFR data on 60 coronary vessels. Dr. Michail and coinvestigators found a strong correlation between the conventional pressure wire FFR and CT-FFR findings, with a receiver operating characteristic area under the curve of 0.83 per vessel. CT-FFR had a diagnostic sensitivity and specificity of 73.9% and 78.4%, respectively, with a positive predictive value of 68%, a negative predictive value of 82.9%, and a diagnostic accuracy of 76.7%.

He cited as study limitations the small size, the fact that patients with previous revascularization or significant left ventricular impairment were excluded, and the study cohort’s relative youth.

“With a mean age of 76.2 years, it’s unclear whether these results can be extrapolated to very elderly patients with more calcified arteries undergoing TAVR. Encouragingly, though, a subgroup analysis based on calcium score showed no effect on accuracy,” according to the cardiologist.

CT-FFR may ‘shorten the diagnostic journey’ for fragile patients

Discussant Daniele Andreini, MD, PhD, praised the investigators’ concept of integrating the functional assessment provided by CT-FFR into a one-stop shop examination by cardiac CT angiography for TAVR planning.

“I would like to underline one of Dr. Michail’s messages: It’s really important to shorten the diagnostic journey for these fragile, older patients with aortic stenosis in order to improve safety, use less contrast, and avoid complications,” said Dr. Andreini, a cardiologist at the University of Milan and director of the cardiovascular CT and radiology unit at Monzino Cardiology Center, also in Milan.

Both Dr. Michail and Dr. Andreini reported having no financial conflicts of interest.

bjancin@mdedge.com

Fractional flow reserve derived noninvasively from coronary CT angiography is a safe and accurate method for assessing the significance of coronary artery disease in patients with severe aortic stenosis who are headed for transcatheter aortic valve replacement (TAVR), according to results of the CAST-FFR prospective study.

Indeed, utilization of coronary CT angiography–derived fractional flow reserve (CT-FFR) for this purpose offers the advantage of using a single noninvasive imaging method to replace two invasive procedures: coronary angiography to assess the anatomy of coronary lesions, and conventional FFR using a pressure wire to determine the functional significance of a given coronary stenosis as a cause of ischemia, Michael Michail, MBBS, explained in reporting the results at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Because up to 50% of patients with severe aortic stenosis undergoing TAVR have coexisting coronary artery disease, it remains common practice to perform prior invasive coronary angiography. However, this is associated with inherent risks, particularly in an elderly cohort with comorbidities. Additionally, coronary angiography provides no information on the functional impact of coronary stenoses, which may be important in guiding revascularization decisions prior to TAVR,” noted Dr. Michail, a cardiologist at Monash University, Melbourne.
 

Simulating FFR: ‘A one-stop shop cardiac CT’

Dr. Michail presented the results of the prospective CAST-FFR study, the first evaluation of CT-FFR for assessment of coronary arteries in patients with severe symptomatic aortic stenosis. This method uses computational fluid dynamics to transform data obtained noninvasively from a standard coronary CT angiography acquisition into a simulated FFR. And it offers the potential to streamline patient care.

“In current practice we see elderly patients with a long pre-TAVR assessment period, with numerous appointments and invasive procedures. Our vision is a one-stop shop cardiac CT that will provide the cardiologist with a complete assessment of the annular measurements, peripheral vasculature, and the coronary arteries ahead of their procedure,” according to Dr. Michail.

“We believe the ability to perform the requisite coronary assessment using CT-FFR will translate to improved patient care in several ways,” he continued. “Firstly, this will shorten the number of tests and overall diagnostic journey for patients. It will reduce the risk from unnecessary invasive procedures, and this will also reduce discomfort for the patient. Based on emerging evidence on the adverse prognostic impact of functionally significant coronary disease in aortic stenosis, this data has the potential to improve procedural risk stratification. And finally, contingent on further data, this may improve lesion selection for upfront revascularization.”

The CAST-FFR study was a small, single-center, proof-of-concept study in which 42 patients with severe aortic stenosis underwent both coronary CT angiography and conventional FFR with a pressure wire. The CT data was sent to a core laboratory for conversion into CT-FFR by evaluators blinded to the conventional FFR values.

Of the 42 participants, 39 (93%) had usable CT-FFR data on 60 coronary vessels. Dr. Michail and coinvestigators found a strong correlation between the conventional pressure wire FFR and CT-FFR findings, with a receiver operating characteristic area under the curve of 0.83 per vessel. CT-FFR had a diagnostic sensitivity and specificity of 73.9% and 78.4%, respectively, with a positive predictive value of 68%, a negative predictive value of 82.9%, and a diagnostic accuracy of 76.7%.

He cited as study limitations the small size, the fact that patients with previous revascularization or significant left ventricular impairment were excluded, and the study cohort’s relative youth.

“With a mean age of 76.2 years, it’s unclear whether these results can be extrapolated to very elderly patients with more calcified arteries undergoing TAVR. Encouragingly, though, a subgroup analysis based on calcium score showed no effect on accuracy,” according to the cardiologist.

CT-FFR may ‘shorten the diagnostic journey’ for fragile patients

Discussant Daniele Andreini, MD, PhD, praised the investigators’ concept of integrating the functional assessment provided by CT-FFR into a one-stop shop examination by cardiac CT angiography for TAVR planning.

“I would like to underline one of Dr. Michail’s messages: It’s really important to shorten the diagnostic journey for these fragile, older patients with aortic stenosis in order to improve safety, use less contrast, and avoid complications,” said Dr. Andreini, a cardiologist at the University of Milan and director of the cardiovascular CT and radiology unit at Monzino Cardiology Center, also in Milan.

Both Dr. Michail and Dr. Andreini reported having no financial conflicts of interest.

bjancin@mdedge.com

Fractional flow reserve derived noninvasively from coronary CT angiography is a safe and accurate method for assessing the significance of coronary artery disease in patients with severe aortic stenosis who are headed for transcatheter aortic valve replacement (TAVR), according to results of the CAST-FFR prospective study.

Indeed, utilization of coronary CT angiography–derived fractional flow reserve (CT-FFR) for this purpose offers the advantage of using a single noninvasive imaging method to replace two invasive procedures: coronary angiography to assess the anatomy of coronary lesions, and conventional FFR using a pressure wire to determine the functional significance of a given coronary stenosis as a cause of ischemia, Michael Michail, MBBS, explained in reporting the results at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“Because up to 50% of patients with severe aortic stenosis undergoing TAVR have coexisting coronary artery disease, it remains common practice to perform prior invasive coronary angiography. However, this is associated with inherent risks, particularly in an elderly cohort with comorbidities. Additionally, coronary angiography provides no information on the functional impact of coronary stenoses, which may be important in guiding revascularization decisions prior to TAVR,” noted Dr. Michail, a cardiologist at Monash University, Melbourne.
 

Simulating FFR: ‘A one-stop shop cardiac CT’

Dr. Michail presented the results of the prospective CAST-FFR study, the first evaluation of CT-FFR for assessment of coronary arteries in patients with severe symptomatic aortic stenosis. This method uses computational fluid dynamics to transform data obtained noninvasively from a standard coronary CT angiography acquisition into a simulated FFR. And it offers the potential to streamline patient care.

“In current practice we see elderly patients with a long pre-TAVR assessment period, with numerous appointments and invasive procedures. Our vision is a one-stop shop cardiac CT that will provide the cardiologist with a complete assessment of the annular measurements, peripheral vasculature, and the coronary arteries ahead of their procedure,” according to Dr. Michail.

“We believe the ability to perform the requisite coronary assessment using CT-FFR will translate to improved patient care in several ways,” he continued. “Firstly, this will shorten the number of tests and overall diagnostic journey for patients. It will reduce the risk from unnecessary invasive procedures, and this will also reduce discomfort for the patient. Based on emerging evidence on the adverse prognostic impact of functionally significant coronary disease in aortic stenosis, this data has the potential to improve procedural risk stratification. And finally, contingent on further data, this may improve lesion selection for upfront revascularization.”

The CAST-FFR study was a small, single-center, proof-of-concept study in which 42 patients with severe aortic stenosis underwent both coronary CT angiography and conventional FFR with a pressure wire. The CT data was sent to a core laboratory for conversion into CT-FFR by evaluators blinded to the conventional FFR values.

Of the 42 participants, 39 (93%) had usable CT-FFR data on 60 coronary vessels. Dr. Michail and coinvestigators found a strong correlation between the conventional pressure wire FFR and CT-FFR findings, with a receiver operating characteristic area under the curve of 0.83 per vessel. CT-FFR had a diagnostic sensitivity and specificity of 73.9% and 78.4%, respectively, with a positive predictive value of 68%, a negative predictive value of 82.9%, and a diagnostic accuracy of 76.7%.

He cited as study limitations the small size, the fact that patients with previous revascularization or significant left ventricular impairment were excluded, and the study cohort’s relative youth.

“With a mean age of 76.2 years, it’s unclear whether these results can be extrapolated to very elderly patients with more calcified arteries undergoing TAVR. Encouragingly, though, a subgroup analysis based on calcium score showed no effect on accuracy,” according to the cardiologist.

CT-FFR may ‘shorten the diagnostic journey’ for fragile patients

Discussant Daniele Andreini, MD, PhD, praised the investigators’ concept of integrating the functional assessment provided by CT-FFR into a one-stop shop examination by cardiac CT angiography for TAVR planning.

“I would like to underline one of Dr. Michail’s messages: It’s really important to shorten the diagnostic journey for these fragile, older patients with aortic stenosis in order to improve safety, use less contrast, and avoid complications,” said Dr. Andreini, a cardiologist at the University of Milan and director of the cardiovascular CT and radiology unit at Monzino Cardiology Center, also in Milan.

Both Dr. Michail and Dr. Andreini reported having no financial conflicts of interest.

bjancin@mdedge.com

The investigational anti-PD-1 antibody sintilimab (Tyvyt, Innovent Biologics and Eli Lilly) has shown that it improves the efficacy of platinum-based chemotherapy in the first-line treatment of patients with advanced nonsquamous non–small cell lung cancer (NSCLC) in a phase 3 trial dubbed ORIENT-11.

The study was presented at the World Congress on Lung Cancer 2020 Virtual Presidential Symposium, held virtually due to the COVID-19 pandemic, on August 8. It was also published simultaneously in the Journal of Thoracic Oncology.

Sintilimab is a fully human IgG4 monoclonal antibody that blocks the binding of programmed death (PD)-1 to PD-ligand 1 (PD-L1) or PD-L2 with high affinity, and has received market authorization in China for the treatment of Hodgkin lymphoma.

For ORIENT-11, almost 400 patients with advanced nonsquamous NSCLC were randomly assigned to sintilimab or placebo plus pemetrexed and platinum-based chemotherapy in a 2:1 ratio.

“The addition of sintilimab to pemetrexed and platinum significantly improved PFS [progression-free survival], compared to placebo,” reducing progression rates by 52%, noted lead investigator Li Zhang, MD, professor of medical oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Crucially, this benefit “was seen across key clinical subgroups,” he added.

He noted that the overall response rate “was also improved, with a durable response,” while the results, which are not yet mature, suggest the experimental arm was associated with an overall survival (OS) benefit.

Study discussant Misako Nagasaka, MD, a thoracic oncologist and clinical investigator at Karmanos Cancer Institute, Detroit, said that the PFS benefit seen in the study is “certainly encouraging.”

Adding a note of caution, she continued: “But we have seen studies with PFS improvement which did not translate into OS improvement.

“Longer follow-up would allow events to mature and we will ultimately see if there would be a significant OS benefit,” she said.

Dr. Nagasaka also pointed out that the greater benefit with sintilimab seen in patients with high PD-L1 begs the question as to what would be the preferred regimen in those with higher or lower expression.

And, she said, this is not just about what regimen to choose but “more importantly, why?”

“Perhaps you’d like to use something with the best response rate, perhaps you’re sticking to a single agent immunotherapy because the toxicity profile is more favorable, or perhaps you [are] convinced with a certain regimen because of the robust PFS and OS data,” she said.

“Whatever you chose, there was a reason for your choice,” she said, adding that the sintilimab combination would have to “fulfill those reasons for you to consider choosing this regimen.”

Study details

Dr. Zhang began his presentation by noting that previous phase 1b studies have shown that sintilimab plus pemetrexed and platinum-based chemotherapy has a “tolerable safety profile and promising efficacy” in previously untreated non-squamous NSCLC.

They therefore conducted ORIENT-11, a randomized, double-blind, phase 3 study involving 397 patients with untreated stage IIIB/C or IV nonsquamous NSCLC who had neither EGFR nor ALK gene alterations.

The patients were randomly assigned in a 2:1 fashion to sintilimab plus pemetrexed and platinum-based chemotherapy (n = 266) or placebo plus pemetrexed and chemo (n = 131) for four cycles, followed by sintilimab or placebo plus pemetrexed for up to 24 months.

Thirty-five patients in the placebo arm crossed over to sintilimab monotherapy, representing 31.3% of the intention-to-treat population.

At the data cutoff of Nov. 15, 2019, 198 events had occurred, at a median follow-up of 8.9 months.

The team found that median PFS was significantly higher with sintilimab than placebo combination therapy, at 8.9 months vs. 5.0 months, or a hazard ratio of 0.482 (P < .00001).

Dr. Zhang noted that the benefit with sintilimab plus pemetrexed and platinum-based chemotherapy was seen across all subgroups.

However, it was notable that the impact of adding sintilimab on PFS was greater in patients with a tumor proportion score (TPS) ≥50%.

The HR for progression vs. the placebo treatment arm was 0.310, with median PFS not reached, which decreased to 0.503 in patients with a TPS of 1%-49% and 0.664 among those with a TPS <1%.

The results also showed that there was a “nominally significant improvement” in overall survival with sintilimab versus placebo, at a HR of 0.609 (P = 0.01921).

The ORR was markedly different between the sintilimab and placebo groups, at 51.9% vs. 29.8%, with the duration of response not reached in the sintilimab arm compared with 5.5 months in the placebo arm.

The sintilimab arm included three (1.1%) complete responses, which was not observed with pemetrexed and platinum-based chemotherapy alone.

Finally, Dr. Zhang observed that the safety profiles of the sintilimab and placebo arms were similar, with comparable rates of any, grade 3-5, and serious adverse events largely driven by high rates of chemotherapy-related events.

While there were fewer adverse events that led to death with sintilimab, at 2.3% vs. 6.9% with placebo, there were, as expected, more immune-related adverse events, at 43.2% vs. 36.6%, respectively.

Comparison with pembrolizumab

In her discussion, Dr. Nagasaka said that the first question that came to mind when she saw the results was: “How does the ORIENT-11 data compare with KEYNOTE-189?”

For that study, pembrolizumab (Keytruda, Merck) was added to pemetrexed plus carboplatin chemotherapy and compared with standard of care alone in patients with untreated metastatic nonsquamous NSCLC.

As reported by Medscape Medical News, pembrolizumab was associated with a 48% reduced risk of disease progression, as well as improved overall survival.

Dr. Nagasaka said that ORIENT-11 “had patients that tended to be younger, there were more males, more with performance status 1, and those who had never smoked” than those in KEYNOTE-189.

“But most importantly, KEYNOTE-189 had a very small number of patients from East Asia, only 1% in the pembro arm and 2.9% in the placebo arm.”

In contrast, all the patients included in ORIENT-11 were from East Asia, making the study of “high importance.”

She added that, “while across-trial comparisons must be taken with caution, the medium PFS of ORIENT-11 ... appears comparable to those of KEYNOTE-189,” while the HR “appears identical.”

This is despite median follow-up time in ORIENT-11 of “only” 8.9 months vs. a median of 23.1 months in the updated KEYNOTE-189 data.

There are plans to register the sintilimab combination therapy in China for the treatment of nonsquamous NSCLC, where it will go up against pembrolizumab as well as, potentially, tislelizumab (BeiGene).

The study was sponsored by Innovent Biologics and Eli Lilly. Dr. Zhang disclosed research grants from Eli Lilly and Pfizer. Dr. Nagasaka disclosed serving on the advisory boards of AstraZeneca, Daiichi Sankyo, Takeda, Novartis, and EMD Serono; as a consultant for Caris Life Sciences; and receiving travel support from An Hearts Therapeutics.

This article first appeared on Medscape.com.

The investigational anti-PD-1 antibody sintilimab (Tyvyt, Innovent Biologics and Eli Lilly) has shown that it improves the efficacy of platinum-based chemotherapy in the first-line treatment of patients with advanced nonsquamous non–small cell lung cancer (NSCLC) in a phase 3 trial dubbed ORIENT-11.

The study was presented at the World Congress on Lung Cancer 2020 Virtual Presidential Symposium, held virtually due to the COVID-19 pandemic, on August 8. It was also published simultaneously in the Journal of Thoracic Oncology.

Sintilimab is a fully human IgG4 monoclonal antibody that blocks the binding of programmed death (PD)-1 to PD-ligand 1 (PD-L1) or PD-L2 with high affinity, and has received market authorization in China for the treatment of Hodgkin lymphoma.

For ORIENT-11, almost 400 patients with advanced nonsquamous NSCLC were randomly assigned to sintilimab or placebo plus pemetrexed and platinum-based chemotherapy in a 2:1 ratio.

“The addition of sintilimab to pemetrexed and platinum significantly improved PFS [progression-free survival], compared to placebo,” reducing progression rates by 52%, noted lead investigator Li Zhang, MD, professor of medical oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Crucially, this benefit “was seen across key clinical subgroups,” he added.

He noted that the overall response rate “was also improved, with a durable response,” while the results, which are not yet mature, suggest the experimental arm was associated with an overall survival (OS) benefit.

Study discussant Misako Nagasaka, MD, a thoracic oncologist and clinical investigator at Karmanos Cancer Institute, Detroit, said that the PFS benefit seen in the study is “certainly encouraging.”

Adding a note of caution, she continued: “But we have seen studies with PFS improvement which did not translate into OS improvement.

“Longer follow-up would allow events to mature and we will ultimately see if there would be a significant OS benefit,” she said.

Dr. Nagasaka also pointed out that the greater benefit with sintilimab seen in patients with high PD-L1 begs the question as to what would be the preferred regimen in those with higher or lower expression.

And, she said, this is not just about what regimen to choose but “more importantly, why?”

“Perhaps you’d like to use something with the best response rate, perhaps you’re sticking to a single agent immunotherapy because the toxicity profile is more favorable, or perhaps you [are] convinced with a certain regimen because of the robust PFS and OS data,” she said.

“Whatever you chose, there was a reason for your choice,” she said, adding that the sintilimab combination would have to “fulfill those reasons for you to consider choosing this regimen.”

Study details

Dr. Zhang began his presentation by noting that previous phase 1b studies have shown that sintilimab plus pemetrexed and platinum-based chemotherapy has a “tolerable safety profile and promising efficacy” in previously untreated non-squamous NSCLC.

They therefore conducted ORIENT-11, a randomized, double-blind, phase 3 study involving 397 patients with untreated stage IIIB/C or IV nonsquamous NSCLC who had neither EGFR nor ALK gene alterations.

The patients were randomly assigned in a 2:1 fashion to sintilimab plus pemetrexed and platinum-based chemotherapy (n = 266) or placebo plus pemetrexed and chemo (n = 131) for four cycles, followed by sintilimab or placebo plus pemetrexed for up to 24 months.

Thirty-five patients in the placebo arm crossed over to sintilimab monotherapy, representing 31.3% of the intention-to-treat population.

At the data cutoff of Nov. 15, 2019, 198 events had occurred, at a median follow-up of 8.9 months.

The team found that median PFS was significantly higher with sintilimab than placebo combination therapy, at 8.9 months vs. 5.0 months, or a hazard ratio of 0.482 (P < .00001).

Dr. Zhang noted that the benefit with sintilimab plus pemetrexed and platinum-based chemotherapy was seen across all subgroups.

However, it was notable that the impact of adding sintilimab on PFS was greater in patients with a tumor proportion score (TPS) ≥50%.

The HR for progression vs. the placebo treatment arm was 0.310, with median PFS not reached, which decreased to 0.503 in patients with a TPS of 1%-49% and 0.664 among those with a TPS <1%.

The results also showed that there was a “nominally significant improvement” in overall survival with sintilimab versus placebo, at a HR of 0.609 (P = 0.01921).

The ORR was markedly different between the sintilimab and placebo groups, at 51.9% vs. 29.8%, with the duration of response not reached in the sintilimab arm compared with 5.5 months in the placebo arm.

The sintilimab arm included three (1.1%) complete responses, which was not observed with pemetrexed and platinum-based chemotherapy alone.

Finally, Dr. Zhang observed that the safety profiles of the sintilimab and placebo arms were similar, with comparable rates of any, grade 3-5, and serious adverse events largely driven by high rates of chemotherapy-related events.

While there were fewer adverse events that led to death with sintilimab, at 2.3% vs. 6.9% with placebo, there were, as expected, more immune-related adverse events, at 43.2% vs. 36.6%, respectively.

Comparison with pembrolizumab

In her discussion, Dr. Nagasaka said that the first question that came to mind when she saw the results was: “How does the ORIENT-11 data compare with KEYNOTE-189?”

For that study, pembrolizumab (Keytruda, Merck) was added to pemetrexed plus carboplatin chemotherapy and compared with standard of care alone in patients with untreated metastatic nonsquamous NSCLC.

As reported by Medscape Medical News, pembrolizumab was associated with a 48% reduced risk of disease progression, as well as improved overall survival.

Dr. Nagasaka said that ORIENT-11 “had patients that tended to be younger, there were more males, more with performance status 1, and those who had never smoked” than those in KEYNOTE-189.

“But most importantly, KEYNOTE-189 had a very small number of patients from East Asia, only 1% in the pembro arm and 2.9% in the placebo arm.”

In contrast, all the patients included in ORIENT-11 were from East Asia, making the study of “high importance.”

She added that, “while across-trial comparisons must be taken with caution, the medium PFS of ORIENT-11 ... appears comparable to those of KEYNOTE-189,” while the HR “appears identical.”

This is despite median follow-up time in ORIENT-11 of “only” 8.9 months vs. a median of 23.1 months in the updated KEYNOTE-189 data.

There are plans to register the sintilimab combination therapy in China for the treatment of nonsquamous NSCLC, where it will go up against pembrolizumab as well as, potentially, tislelizumab (BeiGene).

The study was sponsored by Innovent Biologics and Eli Lilly. Dr. Zhang disclosed research grants from Eli Lilly and Pfizer. Dr. Nagasaka disclosed serving on the advisory boards of AstraZeneca, Daiichi Sankyo, Takeda, Novartis, and EMD Serono; as a consultant for Caris Life Sciences; and receiving travel support from An Hearts Therapeutics.

This article first appeared on Medscape.com.

The investigational anti-PD-1 antibody sintilimab (Tyvyt, Innovent Biologics and Eli Lilly) has shown that it improves the efficacy of platinum-based chemotherapy in the first-line treatment of patients with advanced nonsquamous non–small cell lung cancer (NSCLC) in a phase 3 trial dubbed ORIENT-11.

The study was presented at the World Congress on Lung Cancer 2020 Virtual Presidential Symposium, held virtually due to the COVID-19 pandemic, on August 8. It was also published simultaneously in the Journal of Thoracic Oncology.

Sintilimab is a fully human IgG4 monoclonal antibody that blocks the binding of programmed death (PD)-1 to PD-ligand 1 (PD-L1) or PD-L2 with high affinity, and has received market authorization in China for the treatment of Hodgkin lymphoma.

For ORIENT-11, almost 400 patients with advanced nonsquamous NSCLC were randomly assigned to sintilimab or placebo plus pemetrexed and platinum-based chemotherapy in a 2:1 ratio.

“The addition of sintilimab to pemetrexed and platinum significantly improved PFS [progression-free survival], compared to placebo,” reducing progression rates by 52%, noted lead investigator Li Zhang, MD, professor of medical oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Crucially, this benefit “was seen across key clinical subgroups,” he added.

He noted that the overall response rate “was also improved, with a durable response,” while the results, which are not yet mature, suggest the experimental arm was associated with an overall survival (OS) benefit.

Study discussant Misako Nagasaka, MD, a thoracic oncologist and clinical investigator at Karmanos Cancer Institute, Detroit, said that the PFS benefit seen in the study is “certainly encouraging.”

Adding a note of caution, she continued: “But we have seen studies with PFS improvement which did not translate into OS improvement.

“Longer follow-up would allow events to mature and we will ultimately see if there would be a significant OS benefit,” she said.

Dr. Nagasaka also pointed out that the greater benefit with sintilimab seen in patients with high PD-L1 begs the question as to what would be the preferred regimen in those with higher or lower expression.

And, she said, this is not just about what regimen to choose but “more importantly, why?”

“Perhaps you’d like to use something with the best response rate, perhaps you’re sticking to a single agent immunotherapy because the toxicity profile is more favorable, or perhaps you [are] convinced with a certain regimen because of the robust PFS and OS data,” she said.

“Whatever you chose, there was a reason for your choice,” she said, adding that the sintilimab combination would have to “fulfill those reasons for you to consider choosing this regimen.”

Study details

Dr. Zhang began his presentation by noting that previous phase 1b studies have shown that sintilimab plus pemetrexed and platinum-based chemotherapy has a “tolerable safety profile and promising efficacy” in previously untreated non-squamous NSCLC.

They therefore conducted ORIENT-11, a randomized, double-blind, phase 3 study involving 397 patients with untreated stage IIIB/C or IV nonsquamous NSCLC who had neither EGFR nor ALK gene alterations.

The patients were randomly assigned in a 2:1 fashion to sintilimab plus pemetrexed and platinum-based chemotherapy (n = 266) or placebo plus pemetrexed and chemo (n = 131) for four cycles, followed by sintilimab or placebo plus pemetrexed for up to 24 months.

Thirty-five patients in the placebo arm crossed over to sintilimab monotherapy, representing 31.3% of the intention-to-treat population.

At the data cutoff of Nov. 15, 2019, 198 events had occurred, at a median follow-up of 8.9 months.

The team found that median PFS was significantly higher with sintilimab than placebo combination therapy, at 8.9 months vs. 5.0 months, or a hazard ratio of 0.482 (P < .00001).

Dr. Zhang noted that the benefit with sintilimab plus pemetrexed and platinum-based chemotherapy was seen across all subgroups.

However, it was notable that the impact of adding sintilimab on PFS was greater in patients with a tumor proportion score (TPS) ≥50%.

The HR for progression vs. the placebo treatment arm was 0.310, with median PFS not reached, which decreased to 0.503 in patients with a TPS of 1%-49% and 0.664 among those with a TPS <1%.

The results also showed that there was a “nominally significant improvement” in overall survival with sintilimab versus placebo, at a HR of 0.609 (P = 0.01921).

The ORR was markedly different between the sintilimab and placebo groups, at 51.9% vs. 29.8%, with the duration of response not reached in the sintilimab arm compared with 5.5 months in the placebo arm.

The sintilimab arm included three (1.1%) complete responses, which was not observed with pemetrexed and platinum-based chemotherapy alone.

Finally, Dr. Zhang observed that the safety profiles of the sintilimab and placebo arms were similar, with comparable rates of any, grade 3-5, and serious adverse events largely driven by high rates of chemotherapy-related events.

While there were fewer adverse events that led to death with sintilimab, at 2.3% vs. 6.9% with placebo, there were, as expected, more immune-related adverse events, at 43.2% vs. 36.6%, respectively.

Comparison with pembrolizumab

In her discussion, Dr. Nagasaka said that the first question that came to mind when she saw the results was: “How does the ORIENT-11 data compare with KEYNOTE-189?”

For that study, pembrolizumab (Keytruda, Merck) was added to pemetrexed plus carboplatin chemotherapy and compared with standard of care alone in patients with untreated metastatic nonsquamous NSCLC.

As reported by Medscape Medical News, pembrolizumab was associated with a 48% reduced risk of disease progression, as well as improved overall survival.

Dr. Nagasaka said that ORIENT-11 “had patients that tended to be younger, there were more males, more with performance status 1, and those who had never smoked” than those in KEYNOTE-189.

“But most importantly, KEYNOTE-189 had a very small number of patients from East Asia, only 1% in the pembro arm and 2.9% in the placebo arm.”

In contrast, all the patients included in ORIENT-11 were from East Asia, making the study of “high importance.”

She added that, “while across-trial comparisons must be taken with caution, the medium PFS of ORIENT-11 ... appears comparable to those of KEYNOTE-189,” while the HR “appears identical.”

This is despite median follow-up time in ORIENT-11 of “only” 8.9 months vs. a median of 23.1 months in the updated KEYNOTE-189 data.

There are plans to register the sintilimab combination therapy in China for the treatment of nonsquamous NSCLC, where it will go up against pembrolizumab as well as, potentially, tislelizumab (BeiGene).

The study was sponsored by Innovent Biologics and Eli Lilly. Dr. Zhang disclosed research grants from Eli Lilly and Pfizer. Dr. Nagasaka disclosed serving on the advisory boards of AstraZeneca, Daiichi Sankyo, Takeda, Novartis, and EMD Serono; as a consultant for Caris Life Sciences; and receiving travel support from An Hearts Therapeutics.

This article first appeared on Medscape.com.

Patients with untreated mesothelioma may be able to avoid chemotherapy, say researchers reporting new survival data with the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy).

The two approaches were compared in more than 600 patients with treatment-naive mesothelioma in the phase 3 CheckMate 743 trial, which was supported by the manufacturer of both immunotherapies, Bristol-Myers Squibb.

The trial “met its primary endpoint of statistically improving overall survival for the experimental arm vs chemotherapy in a prespecified interim analysis,” reported Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, The Netherlands,

The combined nivo+ipi immunotherapy regimen was associated with a 26% improvement in overall survival. At 2 years, 41% of patients in the immunotherapy arm were still alive, vs 27% in the chemotherapy group.

“This is the first positive randomized trial of dual immunotherapy in the first-line treatment of patients with mesothelioma,” he said. He suggested that it should therefore “be considered as a new standard of care.”

The data were presented on August 8 in the presidential symposium of the World Congress on Lung Cancer 2020, which was held online because of the COVID-19 pandemic.

A key analysis for the study was by histologic subgroup. It is known that standard-of-care chemotherapy performs better in patients with epithelioid as opposed to nonepithelioid tumor subtypes.

Bass highlighted that the performance of nivo+ipi was “almost the same” in patients with epithelioid and nonepithelioid tumors, at a median overall survival of 18.7 months and 18.1 months, respectively.

In contrast, overall survival in the chemotherapy arm was markedly lower in patients with nonepithelioid tumors, at 8.8 months vs 16.5 months among those with epithelioid tumors.

This was reflected in the hazard ratios for overall survival vs nivo+ipi, at 0.46 and 0.86, respectively, the latter nonsignificantly different from combination immunotherapy.

For study discussant Dean A. Fennell, MD, PhD, professor and consultant in thoracic medical oncology, University of Leicester, United Kingdom, the epithet of a “new standard of care” for nivo+ipi should be reserved for nonepithelioid disease.

In this setting, he described the overall survival improvement as “transformative,” considering the “marked chemo resistance” of nonepithelioid tumors, which is “almost certainly” associated with epithelial-to-mesenchymal transition (EMT).

In the future, he suggested, combinations of chemotherapy and immunotherapy involving all histologies or selective targeting of nonepithelioid mesothelioma “could further extend the benefit for patients.”
 

Improving survival in mesothelioma

“We have been trying to improve the overall survival of patients with mesothelioma now for many decades,” Bass commented. Platinum-based chemotherapy plus pemetrexed is a standard of care, although the 5-year survival rate «is still below 10%,” he noted.

Randomized trials of single-agent immune checkpoint inhibitor therapy in the second-line treatment of patients with mesothelioma have not shown any significant benefits.

However, nivolumab and ipilimumab have a “complementary mechanism of action,” and two previous reports have indicated that together, they have clinical activity in the second-line setting.

The team conducted CheckMate 743 to determine the efficacy of the combination in the first-line setting.

The study involved 605 patients with pleural mesothelioma who had received no prior systemic therapy and had good performance status.

They were randomly assigned in a 1:1 ratio to receive nivo+ipi for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin until disease progression or unacceptable toxicity occurred.

“Patients could have a subsequent therapy,” Bass noted; 44.0% of patients in the experimental arm received subsequent therapy, vs 44.1% of those in the chemotherapy arm.

Of the latter, 20% received an immune checkpoint inhibitor as subsequent therapy.

The minimum follow-up for overall survival was 22.1 months; the median follow-up was 29.7 months.

Nivo+ipi was associated with a significant improvement in overall survival vs standard-of-care chemotherapy, at a median overall survival of 18.1 months vs 14.1 months, with a hazard ratio of 0.74 (P = .0020).

The results indicated that overall survival was similar across key subgroups, which suggests that “no subgroup was harmed” by nivo+ipi, Bass said.
 

Stratification by PD-LI expression

Stratifying the patients by the absence or presence of programmed cell death–ligand-1 (PD-L1) expression, the team found that the performance of nivo+ipi was “the same” as that of chemotherapy, Bass said.

“But in cases where there is any expression of PD-L1, the experimental arm performs better,” at an overall survival 18.0 months vs 13.3 months for chemotherapy and a hazard ratio of 0.69, he said.

There was no difference between the two treatment arms in progression-free survival. Chemotherapy performed better in the first 6 months of treatment, after which the nivo+ipi arm had lower event rates.

Nivo+ipi was also associated with a greater duration of response, at a median of 11.0 months vs 6.7 months for standard-of-care chemotherapy.

Moreover, at 24 months, 32% of nivo+ipi patients were still experiencing a response, whereas 8% of those in the chemotherapy arm were.

Treatment-related adverse events rates were almost identical between the two treatment groups, although treatment with nivo+ipi was associated with more grade 3/4 serious treatment-related adverse events, at 15 vs six for chemotherapy.
 

Choosing immunotherapy vs. chemotherapy

In his discussion of the new study, Fennell compared the current results with those from two studies, INITIATE and MAPS2. “What’s very clear is the response rate is slightly higher,” as is the disease control rate, he said.

This, he explained, “is perhaps not surprising, given that these two previous trials were in the relapse setting.”

He pointed out, however, that the progression-free survival data from those previous trials were “not a million miles away” from results seen in CheckMate 743, “suggesting that this immunotherapy does have significant activity in the relapse setting.”

For Fennell, the “pivotal data” are in patients with nonepithelioid tumors, particularly inasmuch as chemotherapy performed “poorly” in this setting, whereas it performs “as expected” in epithelioid mesothelioma.

He believes that the driver for this is the poor prognosis associated with sarcomatoid biphasic disease, a subtype characterized by increased expression of vimentin and ZEB1, proteins both associated with EMT.

“What does this mean?” Fennell asked.

“If you have have enrichment of EMT, what you see is increased drug resistance, increased invasiveness, something we know well with sarcomatoid mesotheliomas in particular, and this drug-resistance phenotype may account for the drug resistance that we see in CheckMate 743 with chemotherapy.

“This does not appear, however, to impact in any way the efficacy of the immunotherapy,” he noted.

Fennell believes that, with regard to both efficacy and safety, the balance is “very much in favor” of nivo+ipi in epithelioid mesothelioma, although there is less to choose between immunotherapy and chemotherapy in the nonepithelioid setting.

Indeed, the choice is “possible tilting slightly towards chemotherapy” in patients with the nonepithelioid tumors, owing to the lower rates of grade 3/4 serious treatment-related adverse events in comparison with combination immunotherapy.

The study was supported by Bristol-Myers Squibb. Bass has served on the advisory boards of MSD, AstraZeneca, and Takeda. Fennell has received research support from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, MSD, and Roche; research funding from Astex Therapeutics, Bayer, and Boehringer Ingelheim; has served on the speaker bureau of AstraZeneca, Boehringer Ingelheim, and Roche; has acted as a consultant for Bayer and Lab 21; and has served on the advisory board of Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

This article first appeared on Medscape.com.

Patients with untreated mesothelioma may be able to avoid chemotherapy, say researchers reporting new survival data with the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy).

The two approaches were compared in more than 600 patients with treatment-naive mesothelioma in the phase 3 CheckMate 743 trial, which was supported by the manufacturer of both immunotherapies, Bristol-Myers Squibb.

The trial “met its primary endpoint of statistically improving overall survival for the experimental arm vs chemotherapy in a prespecified interim analysis,” reported Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, The Netherlands,

The combined nivo+ipi immunotherapy regimen was associated with a 26% improvement in overall survival. At 2 years, 41% of patients in the immunotherapy arm were still alive, vs 27% in the chemotherapy group.

“This is the first positive randomized trial of dual immunotherapy in the first-line treatment of patients with mesothelioma,” he said. He suggested that it should therefore “be considered as a new standard of care.”

The data were presented on August 8 in the presidential symposium of the World Congress on Lung Cancer 2020, which was held online because of the COVID-19 pandemic.

A key analysis for the study was by histologic subgroup. It is known that standard-of-care chemotherapy performs better in patients with epithelioid as opposed to nonepithelioid tumor subtypes.

Bass highlighted that the performance of nivo+ipi was “almost the same” in patients with epithelioid and nonepithelioid tumors, at a median overall survival of 18.7 months and 18.1 months, respectively.

In contrast, overall survival in the chemotherapy arm was markedly lower in patients with nonepithelioid tumors, at 8.8 months vs 16.5 months among those with epithelioid tumors.

This was reflected in the hazard ratios for overall survival vs nivo+ipi, at 0.46 and 0.86, respectively, the latter nonsignificantly different from combination immunotherapy.

For study discussant Dean A. Fennell, MD, PhD, professor and consultant in thoracic medical oncology, University of Leicester, United Kingdom, the epithet of a “new standard of care” for nivo+ipi should be reserved for nonepithelioid disease.

In this setting, he described the overall survival improvement as “transformative,” considering the “marked chemo resistance” of nonepithelioid tumors, which is “almost certainly” associated with epithelial-to-mesenchymal transition (EMT).

In the future, he suggested, combinations of chemotherapy and immunotherapy involving all histologies or selective targeting of nonepithelioid mesothelioma “could further extend the benefit for patients.”
 

Improving survival in mesothelioma

“We have been trying to improve the overall survival of patients with mesothelioma now for many decades,” Bass commented. Platinum-based chemotherapy plus pemetrexed is a standard of care, although the 5-year survival rate «is still below 10%,” he noted.

Randomized trials of single-agent immune checkpoint inhibitor therapy in the second-line treatment of patients with mesothelioma have not shown any significant benefits.

However, nivolumab and ipilimumab have a “complementary mechanism of action,” and two previous reports have indicated that together, they have clinical activity in the second-line setting.

The team conducted CheckMate 743 to determine the efficacy of the combination in the first-line setting.

The study involved 605 patients with pleural mesothelioma who had received no prior systemic therapy and had good performance status.

They were randomly assigned in a 1:1 ratio to receive nivo+ipi for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin until disease progression or unacceptable toxicity occurred.

“Patients could have a subsequent therapy,” Bass noted; 44.0% of patients in the experimental arm received subsequent therapy, vs 44.1% of those in the chemotherapy arm.

Of the latter, 20% received an immune checkpoint inhibitor as subsequent therapy.

The minimum follow-up for overall survival was 22.1 months; the median follow-up was 29.7 months.

Nivo+ipi was associated with a significant improvement in overall survival vs standard-of-care chemotherapy, at a median overall survival of 18.1 months vs 14.1 months, with a hazard ratio of 0.74 (P = .0020).

The results indicated that overall survival was similar across key subgroups, which suggests that “no subgroup was harmed” by nivo+ipi, Bass said.
 

Stratification by PD-LI expression

Stratifying the patients by the absence or presence of programmed cell death–ligand-1 (PD-L1) expression, the team found that the performance of nivo+ipi was “the same” as that of chemotherapy, Bass said.

“But in cases where there is any expression of PD-L1, the experimental arm performs better,” at an overall survival 18.0 months vs 13.3 months for chemotherapy and a hazard ratio of 0.69, he said.

There was no difference between the two treatment arms in progression-free survival. Chemotherapy performed better in the first 6 months of treatment, after which the nivo+ipi arm had lower event rates.

Nivo+ipi was also associated with a greater duration of response, at a median of 11.0 months vs 6.7 months for standard-of-care chemotherapy.

Moreover, at 24 months, 32% of nivo+ipi patients were still experiencing a response, whereas 8% of those in the chemotherapy arm were.

Treatment-related adverse events rates were almost identical between the two treatment groups, although treatment with nivo+ipi was associated with more grade 3/4 serious treatment-related adverse events, at 15 vs six for chemotherapy.
 

Choosing immunotherapy vs. chemotherapy

In his discussion of the new study, Fennell compared the current results with those from two studies, INITIATE and MAPS2. “What’s very clear is the response rate is slightly higher,” as is the disease control rate, he said.

This, he explained, “is perhaps not surprising, given that these two previous trials were in the relapse setting.”

He pointed out, however, that the progression-free survival data from those previous trials were “not a million miles away” from results seen in CheckMate 743, “suggesting that this immunotherapy does have significant activity in the relapse setting.”

For Fennell, the “pivotal data” are in patients with nonepithelioid tumors, particularly inasmuch as chemotherapy performed “poorly” in this setting, whereas it performs “as expected” in epithelioid mesothelioma.

He believes that the driver for this is the poor prognosis associated with sarcomatoid biphasic disease, a subtype characterized by increased expression of vimentin and ZEB1, proteins both associated with EMT.

“What does this mean?” Fennell asked.

“If you have have enrichment of EMT, what you see is increased drug resistance, increased invasiveness, something we know well with sarcomatoid mesotheliomas in particular, and this drug-resistance phenotype may account for the drug resistance that we see in CheckMate 743 with chemotherapy.

“This does not appear, however, to impact in any way the efficacy of the immunotherapy,” he noted.

Fennell believes that, with regard to both efficacy and safety, the balance is “very much in favor” of nivo+ipi in epithelioid mesothelioma, although there is less to choose between immunotherapy and chemotherapy in the nonepithelioid setting.

Indeed, the choice is “possible tilting slightly towards chemotherapy” in patients with the nonepithelioid tumors, owing to the lower rates of grade 3/4 serious treatment-related adverse events in comparison with combination immunotherapy.

The study was supported by Bristol-Myers Squibb. Bass has served on the advisory boards of MSD, AstraZeneca, and Takeda. Fennell has received research support from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, MSD, and Roche; research funding from Astex Therapeutics, Bayer, and Boehringer Ingelheim; has served on the speaker bureau of AstraZeneca, Boehringer Ingelheim, and Roche; has acted as a consultant for Bayer and Lab 21; and has served on the advisory board of Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

This article first appeared on Medscape.com.

Patients with untreated mesothelioma may be able to avoid chemotherapy, say researchers reporting new survival data with the immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy).

The two approaches were compared in more than 600 patients with treatment-naive mesothelioma in the phase 3 CheckMate 743 trial, which was supported by the manufacturer of both immunotherapies, Bristol-Myers Squibb.

The trial “met its primary endpoint of statistically improving overall survival for the experimental arm vs chemotherapy in a prespecified interim analysis,” reported Paul Baas, MD, PhD, Netherlands Cancer Institute, Amsterdam, The Netherlands,

The combined nivo+ipi immunotherapy regimen was associated with a 26% improvement in overall survival. At 2 years, 41% of patients in the immunotherapy arm were still alive, vs 27% in the chemotherapy group.

“This is the first positive randomized trial of dual immunotherapy in the first-line treatment of patients with mesothelioma,” he said. He suggested that it should therefore “be considered as a new standard of care.”

The data were presented on August 8 in the presidential symposium of the World Congress on Lung Cancer 2020, which was held online because of the COVID-19 pandemic.

A key analysis for the study was by histologic subgroup. It is known that standard-of-care chemotherapy performs better in patients with epithelioid as opposed to nonepithelioid tumor subtypes.

Bass highlighted that the performance of nivo+ipi was “almost the same” in patients with epithelioid and nonepithelioid tumors, at a median overall survival of 18.7 months and 18.1 months, respectively.

In contrast, overall survival in the chemotherapy arm was markedly lower in patients with nonepithelioid tumors, at 8.8 months vs 16.5 months among those with epithelioid tumors.

This was reflected in the hazard ratios for overall survival vs nivo+ipi, at 0.46 and 0.86, respectively, the latter nonsignificantly different from combination immunotherapy.

For study discussant Dean A. Fennell, MD, PhD, professor and consultant in thoracic medical oncology, University of Leicester, United Kingdom, the epithet of a “new standard of care” for nivo+ipi should be reserved for nonepithelioid disease.

In this setting, he described the overall survival improvement as “transformative,” considering the “marked chemo resistance” of nonepithelioid tumors, which is “almost certainly” associated with epithelial-to-mesenchymal transition (EMT).

In the future, he suggested, combinations of chemotherapy and immunotherapy involving all histologies or selective targeting of nonepithelioid mesothelioma “could further extend the benefit for patients.”
 

Improving survival in mesothelioma

“We have been trying to improve the overall survival of patients with mesothelioma now for many decades,” Bass commented. Platinum-based chemotherapy plus pemetrexed is a standard of care, although the 5-year survival rate «is still below 10%,” he noted.

Randomized trials of single-agent immune checkpoint inhibitor therapy in the second-line treatment of patients with mesothelioma have not shown any significant benefits.

However, nivolumab and ipilimumab have a “complementary mechanism of action,” and two previous reports have indicated that together, they have clinical activity in the second-line setting.

The team conducted CheckMate 743 to determine the efficacy of the combination in the first-line setting.

The study involved 605 patients with pleural mesothelioma who had received no prior systemic therapy and had good performance status.

They were randomly assigned in a 1:1 ratio to receive nivo+ipi for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin until disease progression or unacceptable toxicity occurred.

“Patients could have a subsequent therapy,” Bass noted; 44.0% of patients in the experimental arm received subsequent therapy, vs 44.1% of those in the chemotherapy arm.

Of the latter, 20% received an immune checkpoint inhibitor as subsequent therapy.

The minimum follow-up for overall survival was 22.1 months; the median follow-up was 29.7 months.

Nivo+ipi was associated with a significant improvement in overall survival vs standard-of-care chemotherapy, at a median overall survival of 18.1 months vs 14.1 months, with a hazard ratio of 0.74 (P = .0020).

The results indicated that overall survival was similar across key subgroups, which suggests that “no subgroup was harmed” by nivo+ipi, Bass said.
 

Stratification by PD-LI expression

Stratifying the patients by the absence or presence of programmed cell death–ligand-1 (PD-L1) expression, the team found that the performance of nivo+ipi was “the same” as that of chemotherapy, Bass said.

“But in cases where there is any expression of PD-L1, the experimental arm performs better,” at an overall survival 18.0 months vs 13.3 months for chemotherapy and a hazard ratio of 0.69, he said.

There was no difference between the two treatment arms in progression-free survival. Chemotherapy performed better in the first 6 months of treatment, after which the nivo+ipi arm had lower event rates.

Nivo+ipi was also associated with a greater duration of response, at a median of 11.0 months vs 6.7 months for standard-of-care chemotherapy.

Moreover, at 24 months, 32% of nivo+ipi patients were still experiencing a response, whereas 8% of those in the chemotherapy arm were.

Treatment-related adverse events rates were almost identical between the two treatment groups, although treatment with nivo+ipi was associated with more grade 3/4 serious treatment-related adverse events, at 15 vs six for chemotherapy.
 

Choosing immunotherapy vs. chemotherapy

In his discussion of the new study, Fennell compared the current results with those from two studies, INITIATE and MAPS2. “What’s very clear is the response rate is slightly higher,” as is the disease control rate, he said.

This, he explained, “is perhaps not surprising, given that these two previous trials were in the relapse setting.”

He pointed out, however, that the progression-free survival data from those previous trials were “not a million miles away” from results seen in CheckMate 743, “suggesting that this immunotherapy does have significant activity in the relapse setting.”

For Fennell, the “pivotal data” are in patients with nonepithelioid tumors, particularly inasmuch as chemotherapy performed “poorly” in this setting, whereas it performs “as expected” in epithelioid mesothelioma.

He believes that the driver for this is the poor prognosis associated with sarcomatoid biphasic disease, a subtype characterized by increased expression of vimentin and ZEB1, proteins both associated with EMT.

“What does this mean?” Fennell asked.

“If you have have enrichment of EMT, what you see is increased drug resistance, increased invasiveness, something we know well with sarcomatoid mesotheliomas in particular, and this drug-resistance phenotype may account for the drug resistance that we see in CheckMate 743 with chemotherapy.

“This does not appear, however, to impact in any way the efficacy of the immunotherapy,” he noted.

Fennell believes that, with regard to both efficacy and safety, the balance is “very much in favor” of nivo+ipi in epithelioid mesothelioma, although there is less to choose between immunotherapy and chemotherapy in the nonepithelioid setting.

Indeed, the choice is “possible tilting slightly towards chemotherapy” in patients with the nonepithelioid tumors, owing to the lower rates of grade 3/4 serious treatment-related adverse events in comparison with combination immunotherapy.

The study was supported by Bristol-Myers Squibb. Bass has served on the advisory boards of MSD, AstraZeneca, and Takeda. Fennell has received research support from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, MSD, and Roche; research funding from Astex Therapeutics, Bayer, and Boehringer Ingelheim; has served on the speaker bureau of AstraZeneca, Boehringer Ingelheim, and Roche; has acted as a consultant for Bayer and Lab 21; and has served on the advisory board of Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

This article first appeared on Medscape.com.

A methodical, constructive, goal-oriented rapid repetition of emergency response simulations has emerged as a dominant strategy for pediatric readiness in the hospital setting, according to a detailed description of one such program at the virtual Pediatric Hospital Medicine.

Rather than a single run-through followed by a lengthy debriefing, which has been a traditional approach, short simulations done rapidly and repeatedly until skills are mastered improve skill development, according to Jeanmarie Schied, MD, of the department of pediatrics, University of Chicago Medicine.

A methodical, constructive, goal-oriented rapid repetition of emergency response simulations has emerged as a dominant strategy for pediatric readiness in the hospital setting, according to a detailed description of one such program at the virtual Pediatric Hospital Medicine.

Rather than a single run-through followed by a lengthy debriefing, which has been a traditional approach, short simulations done rapidly and repeatedly until skills are mastered improve skill development, according to Jeanmarie Schied, MD, of the department of pediatrics, University of Chicago Medicine.

A methodical, constructive, goal-oriented rapid repetition of emergency response simulations has emerged as a dominant strategy for pediatric readiness in the hospital setting, according to a detailed description of one such program at the virtual Pediatric Hospital Medicine.

Rather than a single run-through followed by a lengthy debriefing, which has been a traditional approach, short simulations done rapidly and repeatedly until skills are mastered improve skill development, according to Jeanmarie Schied, MD, of the department of pediatrics, University of Chicago Medicine.

Precision medicine is driven by technologies such as rapid genome sequencing and artificial intelligence (AI), according to a presentation at the AACR virtual meeting II.

AI can be applied to the sequencing information derived from advanced cancers to make highly personalized treatment recommendations for patients, said Olivier Elemento, PhD, of Weill Cornell Medicine, New York.

Dr. Elemento described such work during the opening plenary session of the meeting.

Dr. Elemento advocated for whole-genome sequencing (WGS) of metastatic sites, as it can reveal “branched evolution” as tumors progress from localized to metastatic (Nat Genet. 2016 Dec;48[12]:1490-9).

The metastases share common mutations with the primaries from which they arise but also develop their own mutational profiles, which facilitate site-of-origin-agnostic, predictive treatment choices.

As examples, Dr. Elemento mentioned HER2 amplification found in a patient with urothelial cancer (J Natl Compr Canc Netw. 2019 Mar 1;17[3]:194-200) and a patient with uterine serous carcinoma (Gynecol Oncol Rep. 2019 Feb 21;28:54-7), both of whom experienced long-lasting remissions to HER2-targeted therapy.

Dr. Elemento also noted that WGS can reveal complex structural variants in lung adenocarcinomas that lack alterations in the RTK/RAS/RAF pathway (unpublished data).
 

Application of machine learning

One study suggested that microRNA expression and machine learning can be used to identify malignant thyroid lesions (Clin Cancer Res. 2012 Apr 1;18[7]:2032-8). The approach diagnosed malignant lesions with 90% accuracy, 100% sensitivity, and 86% specificity.

Dr. Elemento and colleagues used a similar approach to predict response to immunotherapy in melanoma (unpublished data).

The idea was to mine the cancer genome and transcriptome, allowing for identification of signals from neoantigens, immune gene expression, immune cell composition, and T-cell receptor repertoires, Dr. Elemento said. Integrating these signals with clinical outcome data via machine learning technology enabled the researchers to predict immunotherapy response in malignant melanoma with nearly 90% accuracy.

AI and image analysis

Studies have indicated that AI can be applied to medical images to improve diagnosis and treatment. The approach has been shown to:

• Facilitate correct diagnoses of malignant skin lesions (Nature. 2017 Feb 2;542[7639]:115-8).
• Distinguish lung adenocarcinoma from squamous cell cancer with 100% accuracy (EBioMedicine. 2018 Jan;27:317-28).
• Recognize distinct breast cancer subtypes (ductal, lobular, mucinous, papillary) and biomarkers (bioRxiv 242818. doi: 10.1101/242818; EBioMedicine. 2018 Jan;27:317-28)
• Predict mesothelioma prognosis (Nat Med. 2019 Oct;25[10]:1519-25).
• Predict prostate biopsy results (unpublished data) and calculate Gleason scores that can predict survival in prostate cancer patients (AACR 2020, Abstract 867).

Drug development through applied AI

In another study, Dr. Elemento and colleagues used a Bayesian machine learning approach to predict targets of molecules without a known mechanism of action (Nat Commun. 2019 Nov 19;10[1]:5221).

The method involved using data on gene expression profiles, cell line viability, side effects in animals, and structures of the molecules. The researchers applied this method to a large library of orphan small molecules and found it could predict targets in about 40% of cases.

Of 24 AI-predicted microtubule-targeting molecules, 14 depolymerized microtubules in the lab. Five of these molecules were effective in cell lines that were resistant to other microtubule-targeted drugs.

Dr. Elemento went on to describe how Oncoceutics was developing an antineoplastic agent called ONC201, but the company lacked information about the agent’s target. Using AI, the target was identified as dopamine receptor 2 (DRD2; Clin Cancer Res. 2019 Apr 1;25[7]:2305-13).

With that information, Oncoceutics initiated trials of ONC201 in tumors expressing high levels of DRD2, including a highly resistant glioma (J Neurooncol. 2019 Oct;145[1]:97-105). Responses were seen, and ONC201 is now being tested against other DRD2-expressing cancers.
 

Challenges to acknowledge

Potential benefits of AI in the clinic are exciting, but there are many bench-to-bedside challenges.

A clinically obvious example of AI’s applications is radiographic image analysis. There is no biologic rationale for our RECIST “cut values” for partial response, minimal response, and stable disease.

If AI can measure subtle changes on imaging that correlate with tumor biology (i.e., radiomics), we stand a better chance of predicting treatment outcomes than we can with conventional measurements of shrinkage of arbitrarily selected “target lesions.”

A tremendous amount of work is needed to build the required large image banks. During that time, AI will only improve – and without the human risks of fatigue, inconsistency, or burnout.

Those human frailties notwithstanding, AI cannot substitute for the key discussions between patient and clinician regarding goals of care, trade-offs of risks and benefits, and shared decision-making regarding management options.

At least initially (but painfully), complex technologies like WGS and digital image analysis via AI may further disadvantage patients who are medically disadvantaged by geography or socioeconomic circumstances.

In the discussion period, AACR President Antoni Ribas, MD, of University of California, Los Angeles, asked whether AI can simulate crosstalk between gene pathways so that unique treatment combinations can be identified. Dr. Elemento said those simulations are the subject of ongoing investigation.

The theme of the opening plenary session at the AACR virtual meeting II was “Turning Science into Life-Saving Care.” Applications of AI to optimize personalized use of genomics, digital image analysis, and drug development show great promise for being among the technologies that can help to realize AACR’s thematic vision.

Dr. Elemento disclosed relationships with Volastra Therapeutics, OneThree Biotech, Owkin, Freenome, Genetic Intelligence, Acuamark Diagnostics, Eli Lilly, Janssen, and Sanofi.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Precision medicine is driven by technologies such as rapid genome sequencing and artificial intelligence (AI), according to a presentation at the AACR virtual meeting II.

AI can be applied to the sequencing information derived from advanced cancers to make highly personalized treatment recommendations for patients, said Olivier Elemento, PhD, of Weill Cornell Medicine, New York.

Dr. Elemento described such work during the opening plenary session of the meeting.

Dr. Elemento advocated for whole-genome sequencing (WGS) of metastatic sites, as it can reveal “branched evolution” as tumors progress from localized to metastatic (Nat Genet. 2016 Dec;48[12]:1490-9).

The metastases share common mutations with the primaries from which they arise but also develop their own mutational profiles, which facilitate site-of-origin-agnostic, predictive treatment choices.

As examples, Dr. Elemento mentioned HER2 amplification found in a patient with urothelial cancer (J Natl Compr Canc Netw. 2019 Mar 1;17[3]:194-200) and a patient with uterine serous carcinoma (Gynecol Oncol Rep. 2019 Feb 21;28:54-7), both of whom experienced long-lasting remissions to HER2-targeted therapy.

Dr. Elemento also noted that WGS can reveal complex structural variants in lung adenocarcinomas that lack alterations in the RTK/RAS/RAF pathway (unpublished data).
 

Application of machine learning

One study suggested that microRNA expression and machine learning can be used to identify malignant thyroid lesions (Clin Cancer Res. 2012 Apr 1;18[7]:2032-8). The approach diagnosed malignant lesions with 90% accuracy, 100% sensitivity, and 86% specificity.

Dr. Elemento and colleagues used a similar approach to predict response to immunotherapy in melanoma (unpublished data).

The idea was to mine the cancer genome and transcriptome, allowing for identification of signals from neoantigens, immune gene expression, immune cell composition, and T-cell receptor repertoires, Dr. Elemento said. Integrating these signals with clinical outcome data via machine learning technology enabled the researchers to predict immunotherapy response in malignant melanoma with nearly 90% accuracy.

AI and image analysis

Studies have indicated that AI can be applied to medical images to improve diagnosis and treatment. The approach has been shown to:

• Facilitate correct diagnoses of malignant skin lesions (Nature. 2017 Feb 2;542[7639]:115-8).
• Distinguish lung adenocarcinoma from squamous cell cancer with 100% accuracy (EBioMedicine. 2018 Jan;27:317-28).
• Recognize distinct breast cancer subtypes (ductal, lobular, mucinous, papillary) and biomarkers (bioRxiv 242818. doi: 10.1101/242818; EBioMedicine. 2018 Jan;27:317-28)
• Predict mesothelioma prognosis (Nat Med. 2019 Oct;25[10]:1519-25).
• Predict prostate biopsy results (unpublished data) and calculate Gleason scores that can predict survival in prostate cancer patients (AACR 2020, Abstract 867).

Drug development through applied AI

In another study, Dr. Elemento and colleagues used a Bayesian machine learning approach to predict targets of molecules without a known mechanism of action (Nat Commun. 2019 Nov 19;10[1]:5221).

The method involved using data on gene expression profiles, cell line viability, side effects in animals, and structures of the molecules. The researchers applied this method to a large library of orphan small molecules and found it could predict targets in about 40% of cases.

Of 24 AI-predicted microtubule-targeting molecules, 14 depolymerized microtubules in the lab. Five of these molecules were effective in cell lines that were resistant to other microtubule-targeted drugs.

Dr. Elemento went on to describe how Oncoceutics was developing an antineoplastic agent called ONC201, but the company lacked information about the agent’s target. Using AI, the target was identified as dopamine receptor 2 (DRD2; Clin Cancer Res. 2019 Apr 1;25[7]:2305-13).

With that information, Oncoceutics initiated trials of ONC201 in tumors expressing high levels of DRD2, including a highly resistant glioma (J Neurooncol. 2019 Oct;145[1]:97-105). Responses were seen, and ONC201 is now being tested against other DRD2-expressing cancers.
 

Challenges to acknowledge

Potential benefits of AI in the clinic are exciting, but there are many bench-to-bedside challenges.

A clinically obvious example of AI’s applications is radiographic image analysis. There is no biologic rationale for our RECIST “cut values” for partial response, minimal response, and stable disease.

If AI can measure subtle changes on imaging that correlate with tumor biology (i.e., radiomics), we stand a better chance of predicting treatment outcomes than we can with conventional measurements of shrinkage of arbitrarily selected “target lesions.”

A tremendous amount of work is needed to build the required large image banks. During that time, AI will only improve – and without the human risks of fatigue, inconsistency, or burnout.

Those human frailties notwithstanding, AI cannot substitute for the key discussions between patient and clinician regarding goals of care, trade-offs of risks and benefits, and shared decision-making regarding management options.

At least initially (but painfully), complex technologies like WGS and digital image analysis via AI may further disadvantage patients who are medically disadvantaged by geography or socioeconomic circumstances.

In the discussion period, AACR President Antoni Ribas, MD, of University of California, Los Angeles, asked whether AI can simulate crosstalk between gene pathways so that unique treatment combinations can be identified. Dr. Elemento said those simulations are the subject of ongoing investigation.

The theme of the opening plenary session at the AACR virtual meeting II was “Turning Science into Life-Saving Care.” Applications of AI to optimize personalized use of genomics, digital image analysis, and drug development show great promise for being among the technologies that can help to realize AACR’s thematic vision.

Dr. Elemento disclosed relationships with Volastra Therapeutics, OneThree Biotech, Owkin, Freenome, Genetic Intelligence, Acuamark Diagnostics, Eli Lilly, Janssen, and Sanofi.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Precision medicine is driven by technologies such as rapid genome sequencing and artificial intelligence (AI), according to a presentation at the AACR virtual meeting II.

AI can be applied to the sequencing information derived from advanced cancers to make highly personalized treatment recommendations for patients, said Olivier Elemento, PhD, of Weill Cornell Medicine, New York.

Dr. Elemento described such work during the opening plenary session of the meeting.

Dr. Elemento advocated for whole-genome sequencing (WGS) of metastatic sites, as it can reveal “branched evolution” as tumors progress from localized to metastatic (Nat Genet. 2016 Dec;48[12]:1490-9).

The metastases share common mutations with the primaries from which they arise but also develop their own mutational profiles, which facilitate site-of-origin-agnostic, predictive treatment choices.

As examples, Dr. Elemento mentioned HER2 amplification found in a patient with urothelial cancer (J Natl Compr Canc Netw. 2019 Mar 1;17[3]:194-200) and a patient with uterine serous carcinoma (Gynecol Oncol Rep. 2019 Feb 21;28:54-7), both of whom experienced long-lasting remissions to HER2-targeted therapy.

Dr. Elemento also noted that WGS can reveal complex structural variants in lung adenocarcinomas that lack alterations in the RTK/RAS/RAF pathway (unpublished data).
 

Application of machine learning

One study suggested that microRNA expression and machine learning can be used to identify malignant thyroid lesions (Clin Cancer Res. 2012 Apr 1;18[7]:2032-8). The approach diagnosed malignant lesions with 90% accuracy, 100% sensitivity, and 86% specificity.

Dr. Elemento and colleagues used a similar approach to predict response to immunotherapy in melanoma (unpublished data).

The idea was to mine the cancer genome and transcriptome, allowing for identification of signals from neoantigens, immune gene expression, immune cell composition, and T-cell receptor repertoires, Dr. Elemento said. Integrating these signals with clinical outcome data via machine learning technology enabled the researchers to predict immunotherapy response in malignant melanoma with nearly 90% accuracy.

AI and image analysis

Studies have indicated that AI can be applied to medical images to improve diagnosis and treatment. The approach has been shown to:

• Facilitate correct diagnoses of malignant skin lesions (Nature. 2017 Feb 2;542[7639]:115-8).
• Distinguish lung adenocarcinoma from squamous cell cancer with 100% accuracy (EBioMedicine. 2018 Jan;27:317-28).
• Recognize distinct breast cancer subtypes (ductal, lobular, mucinous, papillary) and biomarkers (bioRxiv 242818. doi: 10.1101/242818; EBioMedicine. 2018 Jan;27:317-28)
• Predict mesothelioma prognosis (Nat Med. 2019 Oct;25[10]:1519-25).
• Predict prostate biopsy results (unpublished data) and calculate Gleason scores that can predict survival in prostate cancer patients (AACR 2020, Abstract 867).

Drug development through applied AI

In another study, Dr. Elemento and colleagues used a Bayesian machine learning approach to predict targets of molecules without a known mechanism of action (Nat Commun. 2019 Nov 19;10[1]:5221).

The method involved using data on gene expression profiles, cell line viability, side effects in animals, and structures of the molecules. The researchers applied this method to a large library of orphan small molecules and found it could predict targets in about 40% of cases.

Of 24 AI-predicted microtubule-targeting molecules, 14 depolymerized microtubules in the lab. Five of these molecules were effective in cell lines that were resistant to other microtubule-targeted drugs.

Dr. Elemento went on to describe how Oncoceutics was developing an antineoplastic agent called ONC201, but the company lacked information about the agent’s target. Using AI, the target was identified as dopamine receptor 2 (DRD2; Clin Cancer Res. 2019 Apr 1;25[7]:2305-13).

With that information, Oncoceutics initiated trials of ONC201 in tumors expressing high levels of DRD2, including a highly resistant glioma (J Neurooncol. 2019 Oct;145[1]:97-105). Responses were seen, and ONC201 is now being tested against other DRD2-expressing cancers.
 

Challenges to acknowledge

Potential benefits of AI in the clinic are exciting, but there are many bench-to-bedside challenges.

A clinically obvious example of AI’s applications is radiographic image analysis. There is no biologic rationale for our RECIST “cut values” for partial response, minimal response, and stable disease.

If AI can measure subtle changes on imaging that correlate with tumor biology (i.e., radiomics), we stand a better chance of predicting treatment outcomes than we can with conventional measurements of shrinkage of arbitrarily selected “target lesions.”

A tremendous amount of work is needed to build the required large image banks. During that time, AI will only improve – and without the human risks of fatigue, inconsistency, or burnout.

Those human frailties notwithstanding, AI cannot substitute for the key discussions between patient and clinician regarding goals of care, trade-offs of risks and benefits, and shared decision-making regarding management options.

At least initially (but painfully), complex technologies like WGS and digital image analysis via AI may further disadvantage patients who are medically disadvantaged by geography or socioeconomic circumstances.

In the discussion period, AACR President Antoni Ribas, MD, of University of California, Los Angeles, asked whether AI can simulate crosstalk between gene pathways so that unique treatment combinations can be identified. Dr. Elemento said those simulations are the subject of ongoing investigation.

The theme of the opening plenary session at the AACR virtual meeting II was “Turning Science into Life-Saving Care.” Applications of AI to optimize personalized use of genomics, digital image analysis, and drug development show great promise for being among the technologies that can help to realize AACR’s thematic vision.

Dr. Elemento disclosed relationships with Volastra Therapeutics, OneThree Biotech, Owkin, Freenome, Genetic Intelligence, Acuamark Diagnostics, Eli Lilly, Janssen, and Sanofi.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

In the clinical experience of Libby Edwards, MD, the diagnosis of lichen sclerosus in a young girl often triggers worry from patients and parents alike.

“The parents are worried about the ramifications of genital diseases and they’re worried about scarring,” she said during the virtual annual meeting of the Society for Pediatric Dermatology.

Meanwhile, during the initial assessment, physicians tend to think about sexual abuse or sexually transmitted diseases as the primary culprit. “It’s really important that you consider those issues, but they’re not usually what’s going on,” said Dr. Edwards, a dermatologist who practices in Charlotte, N.C. “Also, for some reason we jump to yeast as a cause of diseases in the genital area. If the child is out of diapers and hasn’t reached puberty, it’s almost never yeast. Do a culture. Try and prove yeast. If it doesn’t respond to treatment for yeast, it’s not going to be yeast. Reassure, and don’t forget to reassure.”

The causes of lichen sclerosus in young girls are not completely understood, she continued, but a main factor is autoimmune-related, which can cause a distinctive rash that usually affects the genital skin around the vulva and anus. Lichen sclerosus presents classically as white, fragile plaques. “Textbooks say that there is cigarette paper-like crinkling of skin,” Dr. Edwards said. “I think of it being more like cellophane paper. In children, we often see it as smooth, kind of waxy and shiny, compared to adults. Children usually present with pruritus and irritation.”

Lichen sclerosus often starts in the clitoral area and on the perineum, and often with an edematous clitoral hood. “It often eventuates into clitoral phimosis, meaning that there is midline adhesion so that the clitoris is buried,” she said. “In adults, seeing this clitoral phimosis is a reliable sign of a scarring dermatosis – most often lichen sclerosus. But you can’t say that in children, because little girls will often have scarring over the clitoris. It’s just physiologic and means nothing, and it will go away at puberty. Certainly, sometimes this white discoloration can have crinkling. Purpura and tearing are common; if you look at lichen sclerosus histologically it looks like a thin epithelium that’s stretched over gelatin. Any rubbing and scratching can cause bleeding in the skin.”

Clinical appearance of well demarcated white skin with texture change drives the diagnosis. “It can be hard to tell from vitiligo at times, but there always should be texture change – whether it’s crinkling, whether it’s waxy, whether it’s smooth – and it’s symptomatic,” she said.

A biopsy is not usually required. “I think a good picture [of the affected area] or some sort of objective description in the chart is important, because most children do so well that in a few months there’s no sign of it, and the next provider [they see] may not believe that they ever had it,” she said.

The recommended initial treatment for lichen sclerosus in girls is a tiny amount of a superpotent topical corticosteroid ointment such as clobetasol or halobetasol one to two times daily until the skin is clear, which usually takes 2-4 months. “You do not treat these children until they’re comfortable, because that may be a week,” Dr. Edwards said. “You treat these children until the skin looks normal. Then you need to keep treating them, because if you don’t, the skin will relapse, even though they might not have symptoms.”

Following initial treatment, she recommends use of a superpotent corticosteroid once per day three times a week, or a midpotency steroid like triamcinolone ointment 0.1% every day. In her clinical experience, if lesions clear and remain clear with long-term treatment through puberty, the chances are good that they’ll stay clear if the medication is stopped.

“There are no studies on what to do after a patient clears,” said Dr. Edwards, chief of dermatology at Carolinas Medical Center, Charlotte, and adjunct clinical professor of dermatology at the University of North Carolina, Chapel Hill. “We have been informed by trial and error. If a child is totally clear after puberty, I will stop their medication and see them back every 3 months for about a year and a half. If they stay clear after a year and a half, I find that they stay clear. I wonder what happens at menopause. We surely don’t know.”

With consistent topical treatment, many patients will have clearing in one area of affected skin after a month or two, and it will take 3 or 4 months for the remaining area to clear. “I tend to see patients back every 6-8 weeks until they’re clear,” she said. “I do not like the idea of sending people out and saying, ‘use this medication twice a day for a month, then once a day for a month, then three times a week, then as needed.’

For patients concerned about the long-term use of topical steroids, the immunosuppressants tacrolimus and pimecrolimus are options. “They are often irritating on the vulva, but can work better than steroids for extragenital disease,” Dr. Edwards said. “Parents sometimes object to the use of a corticosteroid, but because these produce slower benefit and often burn with application, you can remind the parents that tacrolimus and pimecrolimus are not without side effects and are labeled as being associated with cancer. That often will prompt a parent to be willing to use a topical steroid. You can also point to studies that show the safety of topical steroids.”

Intralesional steroids are useful for thick lesions, but Dr. Edwards said that she has never had to use them in a child with lichen sclerosus. “I have found methotrexate to be useful in some people, but there is not one study on genital lichen sclerosus and methotrexate,” she said. “I find that about one in five patients with recalcitrant vulvar lichen sclerosus has had some benefit from methotrexate,” she added, noting that fractional CO₂ laser “is showing promise in these patients.”

Dr. Edwards concluded her remarks by noting that she has never cared for a child with vulvar lichen sclerosus who didn’t respond to topical super potent steroids, “except due to poor compliance.”

She reported having no relevant financial disclosures.

dbrunk@mdedge.com

In the clinical experience of Libby Edwards, MD, the diagnosis of lichen sclerosus in a young girl often triggers worry from patients and parents alike.

“The parents are worried about the ramifications of genital diseases and they’re worried about scarring,” she said during the virtual annual meeting of the Society for Pediatric Dermatology.

Meanwhile, during the initial assessment, physicians tend to think about sexual abuse or sexually transmitted diseases as the primary culprit. “It’s really important that you consider those issues, but they’re not usually what’s going on,” said Dr. Edwards, a dermatologist who practices in Charlotte, N.C. “Also, for some reason we jump to yeast as a cause of diseases in the genital area. If the child is out of diapers and hasn’t reached puberty, it’s almost never yeast. Do a culture. Try and prove yeast. If it doesn’t respond to treatment for yeast, it’s not going to be yeast. Reassure, and don’t forget to reassure.”

The causes of lichen sclerosus in young girls are not completely understood, she continued, but a main factor is autoimmune-related, which can cause a distinctive rash that usually affects the genital skin around the vulva and anus. Lichen sclerosus presents classically as white, fragile plaques. “Textbooks say that there is cigarette paper-like crinkling of skin,” Dr. Edwards said. “I think of it being more like cellophane paper. In children, we often see it as smooth, kind of waxy and shiny, compared to adults. Children usually present with pruritus and irritation.”

Lichen sclerosus often starts in the clitoral area and on the perineum, and often with an edematous clitoral hood. “It often eventuates into clitoral phimosis, meaning that there is midline adhesion so that the clitoris is buried,” she said. “In adults, seeing this clitoral phimosis is a reliable sign of a scarring dermatosis – most often lichen sclerosus. But you can’t say that in children, because little girls will often have scarring over the clitoris. It’s just physiologic and means nothing, and it will go away at puberty. Certainly, sometimes this white discoloration can have crinkling. Purpura and tearing are common; if you look at lichen sclerosus histologically it looks like a thin epithelium that’s stretched over gelatin. Any rubbing and scratching can cause bleeding in the skin.”

Clinical appearance of well demarcated white skin with texture change drives the diagnosis. “It can be hard to tell from vitiligo at times, but there always should be texture change – whether it’s crinkling, whether it’s waxy, whether it’s smooth – and it’s symptomatic,” she said.

A biopsy is not usually required. “I think a good picture [of the affected area] or some sort of objective description in the chart is important, because most children do so well that in a few months there’s no sign of it, and the next provider [they see] may not believe that they ever had it,” she said.

The recommended initial treatment for lichen sclerosus in girls is a tiny amount of a superpotent topical corticosteroid ointment such as clobetasol or halobetasol one to two times daily until the skin is clear, which usually takes 2-4 months. “You do not treat these children until they’re comfortable, because that may be a week,” Dr. Edwards said. “You treat these children until the skin looks normal. Then you need to keep treating them, because if you don’t, the skin will relapse, even though they might not have symptoms.”

Following initial treatment, she recommends use of a superpotent corticosteroid once per day three times a week, or a midpotency steroid like triamcinolone ointment 0.1% every day. In her clinical experience, if lesions clear and remain clear with long-term treatment through puberty, the chances are good that they’ll stay clear if the medication is stopped.

“There are no studies on what to do after a patient clears,” said Dr. Edwards, chief of dermatology at Carolinas Medical Center, Charlotte, and adjunct clinical professor of dermatology at the University of North Carolina, Chapel Hill. “We have been informed by trial and error. If a child is totally clear after puberty, I will stop their medication and see them back every 3 months for about a year and a half. If they stay clear after a year and a half, I find that they stay clear. I wonder what happens at menopause. We surely don’t know.”

With consistent topical treatment, many patients will have clearing in one area of affected skin after a month or two, and it will take 3 or 4 months for the remaining area to clear. “I tend to see patients back every 6-8 weeks until they’re clear,” she said. “I do not like the idea of sending people out and saying, ‘use this medication twice a day for a month, then once a day for a month, then three times a week, then as needed.’

For patients concerned about the long-term use of topical steroids, the immunosuppressants tacrolimus and pimecrolimus are options. “They are often irritating on the vulva, but can work better than steroids for extragenital disease,” Dr. Edwards said. “Parents sometimes object to the use of a corticosteroid, but because these produce slower benefit and often burn with application, you can remind the parents that tacrolimus and pimecrolimus are not without side effects and are labeled as being associated with cancer. That often will prompt a parent to be willing to use a topical steroid. You can also point to studies that show the safety of topical steroids.”

Intralesional steroids are useful for thick lesions, but Dr. Edwards said that she has never had to use them in a child with lichen sclerosus. “I have found methotrexate to be useful in some people, but there is not one study on genital lichen sclerosus and methotrexate,” she said. “I find that about one in five patients with recalcitrant vulvar lichen sclerosus has had some benefit from methotrexate,” she added, noting that fractional CO₂ laser “is showing promise in these patients.”

Dr. Edwards concluded her remarks by noting that she has never cared for a child with vulvar lichen sclerosus who didn’t respond to topical super potent steroids, “except due to poor compliance.”

She reported having no relevant financial disclosures.

dbrunk@mdedge.com

In the clinical experience of Libby Edwards, MD, the diagnosis of lichen sclerosus in a young girl often triggers worry from patients and parents alike.

“The parents are worried about the ramifications of genital diseases and they’re worried about scarring,” she said during the virtual annual meeting of the Society for Pediatric Dermatology.

Meanwhile, during the initial assessment, physicians tend to think about sexual abuse or sexually transmitted diseases as the primary culprit. “It’s really important that you consider those issues, but they’re not usually what’s going on,” said Dr. Edwards, a dermatologist who practices in Charlotte, N.C. “Also, for some reason we jump to yeast as a cause of diseases in the genital area. If the child is out of diapers and hasn’t reached puberty, it’s almost never yeast. Do a culture. Try and prove yeast. If it doesn’t respond to treatment for yeast, it’s not going to be yeast. Reassure, and don’t forget to reassure.”

The causes of lichen sclerosus in young girls are not completely understood, she continued, but a main factor is autoimmune-related, which can cause a distinctive rash that usually affects the genital skin around the vulva and anus. Lichen sclerosus presents classically as white, fragile plaques. “Textbooks say that there is cigarette paper-like crinkling of skin,” Dr. Edwards said. “I think of it being more like cellophane paper. In children, we often see it as smooth, kind of waxy and shiny, compared to adults. Children usually present with pruritus and irritation.”

Lichen sclerosus often starts in the clitoral area and on the perineum, and often with an edematous clitoral hood. “It often eventuates into clitoral phimosis, meaning that there is midline adhesion so that the clitoris is buried,” she said. “In adults, seeing this clitoral phimosis is a reliable sign of a scarring dermatosis – most often lichen sclerosus. But you can’t say that in children, because little girls will often have scarring over the clitoris. It’s just physiologic and means nothing, and it will go away at puberty. Certainly, sometimes this white discoloration can have crinkling. Purpura and tearing are common; if you look at lichen sclerosus histologically it looks like a thin epithelium that’s stretched over gelatin. Any rubbing and scratching can cause bleeding in the skin.”

Clinical appearance of well demarcated white skin with texture change drives the diagnosis. “It can be hard to tell from vitiligo at times, but there always should be texture change – whether it’s crinkling, whether it’s waxy, whether it’s smooth – and it’s symptomatic,” she said.

A biopsy is not usually required. “I think a good picture [of the affected area] or some sort of objective description in the chart is important, because most children do so well that in a few months there’s no sign of it, and the next provider [they see] may not believe that they ever had it,” she said.

The recommended initial treatment for lichen sclerosus in girls is a tiny amount of a superpotent topical corticosteroid ointment such as clobetasol or halobetasol one to two times daily until the skin is clear, which usually takes 2-4 months. “You do not treat these children until they’re comfortable, because that may be a week,” Dr. Edwards said. “You treat these children until the skin looks normal. Then you need to keep treating them, because if you don’t, the skin will relapse, even though they might not have symptoms.”

Following initial treatment, she recommends use of a superpotent corticosteroid once per day three times a week, or a midpotency steroid like triamcinolone ointment 0.1% every day. In her clinical experience, if lesions clear and remain clear with long-term treatment through puberty, the chances are good that they’ll stay clear if the medication is stopped.

“There are no studies on what to do after a patient clears,” said Dr. Edwards, chief of dermatology at Carolinas Medical Center, Charlotte, and adjunct clinical professor of dermatology at the University of North Carolina, Chapel Hill. “We have been informed by trial and error. If a child is totally clear after puberty, I will stop their medication and see them back every 3 months for about a year and a half. If they stay clear after a year and a half, I find that they stay clear. I wonder what happens at menopause. We surely don’t know.”

With consistent topical treatment, many patients will have clearing in one area of affected skin after a month or two, and it will take 3 or 4 months for the remaining area to clear. “I tend to see patients back every 6-8 weeks until they’re clear,” she said. “I do not like the idea of sending people out and saying, ‘use this medication twice a day for a month, then once a day for a month, then three times a week, then as needed.’

For patients concerned about the long-term use of topical steroids, the immunosuppressants tacrolimus and pimecrolimus are options. “They are often irritating on the vulva, but can work better than steroids for extragenital disease,” Dr. Edwards said. “Parents sometimes object to the use of a corticosteroid, but because these produce slower benefit and often burn with application, you can remind the parents that tacrolimus and pimecrolimus are not without side effects and are labeled as being associated with cancer. That often will prompt a parent to be willing to use a topical steroid. You can also point to studies that show the safety of topical steroids.”

Intralesional steroids are useful for thick lesions, but Dr. Edwards said that she has never had to use them in a child with lichen sclerosus. “I have found methotrexate to be useful in some people, but there is not one study on genital lichen sclerosus and methotrexate,” she said. “I find that about one in five patients with recalcitrant vulvar lichen sclerosus has had some benefit from methotrexate,” she added, noting that fractional CO₂ laser “is showing promise in these patients.”

Dr. Edwards concluded her remarks by noting that she has never cared for a child with vulvar lichen sclerosus who didn’t respond to topical super potent steroids, “except due to poor compliance.”

She reported having no relevant financial disclosures.

dbrunk@mdedge.com

All PASI 100 responses to psoriasis therapy are not the same, Andrew Blauvelt, MD, declared at the virtual annual meeting of the American Academy of Dermatology.

He presented a first-of-its-kind study that potentially opens the door to a new, more rigorous standard for treatment success in psoriasis: Not simply cleared lesional skin as captured by a Psoriasis Area and Severity Index (PASI) 100 response, but also clearance of residual psoriasis signs and symptoms – as well as what he termed “molecular clearance.”

“We’ve found that clearing skin with drugs utilizing different mechanisms of action may lead to differential consequences for our patients,” observed Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.

A PASI 100 response, traditionally considered an elusive goal for the great majority of patients with severe psoriasis, can now often be achieved using today’s top-tier, high-performance biologics. But Dr. Blauvelt and his coinvestigators are interested in pushing even beyond PASI 100 to a new frontier of therapeutic benefit.

He presented a secondary analysis of the previously reported VOYAGE 1 and 2 head-to-head randomized trials of guselkumab (Tremfya) versus adalimumab (Humira) for treatment of moderate to severe psoriasis. This new analysis, which focused exclusively on PASI 100 responders by week 24, demonstrated that patients with a PASI 100 response to guselkumab, an interleukin (IL)-23 inhibitor, had significantly fewer persistent symptoms and signs of psoriasis than those whose skin clearance was attained using adalimumab, a tumor necrosis factor (TNF) inhibitor.

Moreover, the investigators showed that the gene expression profile of PASI 100 responders who were free of signs and symptoms was more normalized than that of patients with residual symptoms despite their cleared skin.

The analysis included 16 participants in the VOYAGE trials who achieved PASI 100 at week 24 on guselkumab and 5 who did so on adalimumab. At baseline and again at week 24, these individuals completed the Psoriasis Symptoms and Signs Diary (PSSD). Also, biopsies of lesional and nonlesional skin were obtained at baseline and of cleared lesional skin at week 24 for transcriptomic microarray analysis of the expression of many thousands of genes.
 

Persistent psoriasis symptoms despite cleared skin

The PSSD involves patient ratings of various psoriasis symptoms and signs. Total scores can range from 0 (symptom- and sign-free) up to 100. At week 24, a significantly higher proportion of guselkumab-treated PASI 100 responders had a total PSSD score of zero: 55%, versus 43% in the adalimumab group. This was consistently true across the board for each of the individual signs and symptoms assessed. For example, 61% of the guselkumab group gave themselves a zero for itch, as did 50% of the adalimumab group. Sixty-four percent on guselkumab and 52% on adalimumab reported being free of redness. And 78% of the guselkumab group reported being pain-free, compared with 69% with adalimumab, Dr. Blauvelt reported.

Gene expression analysis

At baseline, more than 2,300 dysregulated genes were identified in lesional skin while functioning normally in nonlesional skin. The great majority of these initially dysregulated genes became normalized in cleared lesional skin in PASI 100 responders at week 24. However, 25 of the genes remained dysregulated in cleared lesional skin, meaning they displayed less than 75% of normal function. Ten of these 25 genes with dysregulated expression at follow-up showed abnormal function in patients with residual symptoms despite cleared skin, but they functioned normally in those without persistent symptoms. This raises the possibility that the residual symptoms of psoriasis were attributable to the abnormal gene functioning, according to Dr. Blauvelt.

Of note, 9 of the 10 dysregulated genes in cleared lesional skin of patients with residual symptoms were present in the adalimumab group; these included two genes localized to the epidermal differentiation complex as well as the psoriasis-specific proline-rich 9 gene known as PRR9, which is induced by IL-17A. In contrast, only four genes, none of which were localized to the epidermal differentiation complex, were insufficiently normalized in the cleared lesional skin of guselkumab-treated PASI-100 responders.

“Nothing like this analysis has ever been done before,” the dermatologist observed. “It’s a pilot study. Perhaps with more data like this, we’ll be using this type of information in clinical practice to go beyond clearing patients’ skin.”

Dr. Blauvelt reported serving as a scientific advisor to and paid clinical investigator for Janssen, which sponsored the study, as well as for roughly two dozen other pharmaceutical companies.

bjancin@mdedge.com

All PASI 100 responses to psoriasis therapy are not the same, Andrew Blauvelt, MD, declared at the virtual annual meeting of the American Academy of Dermatology.

He presented a first-of-its-kind study that potentially opens the door to a new, more rigorous standard for treatment success in psoriasis: Not simply cleared lesional skin as captured by a Psoriasis Area and Severity Index (PASI) 100 response, but also clearance of residual psoriasis signs and symptoms – as well as what he termed “molecular clearance.”

“We’ve found that clearing skin with drugs utilizing different mechanisms of action may lead to differential consequences for our patients,” observed Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.

A PASI 100 response, traditionally considered an elusive goal for the great majority of patients with severe psoriasis, can now often be achieved using today’s top-tier, high-performance biologics. But Dr. Blauvelt and his coinvestigators are interested in pushing even beyond PASI 100 to a new frontier of therapeutic benefit.

He presented a secondary analysis of the previously reported VOYAGE 1 and 2 head-to-head randomized trials of guselkumab (Tremfya) versus adalimumab (Humira) for treatment of moderate to severe psoriasis. This new analysis, which focused exclusively on PASI 100 responders by week 24, demonstrated that patients with a PASI 100 response to guselkumab, an interleukin (IL)-23 inhibitor, had significantly fewer persistent symptoms and signs of psoriasis than those whose skin clearance was attained using adalimumab, a tumor necrosis factor (TNF) inhibitor.

Moreover, the investigators showed that the gene expression profile of PASI 100 responders who were free of signs and symptoms was more normalized than that of patients with residual symptoms despite their cleared skin.

The analysis included 16 participants in the VOYAGE trials who achieved PASI 100 at week 24 on guselkumab and 5 who did so on adalimumab. At baseline and again at week 24, these individuals completed the Psoriasis Symptoms and Signs Diary (PSSD). Also, biopsies of lesional and nonlesional skin were obtained at baseline and of cleared lesional skin at week 24 for transcriptomic microarray analysis of the expression of many thousands of genes.
 

Persistent psoriasis symptoms despite cleared skin

The PSSD involves patient ratings of various psoriasis symptoms and signs. Total scores can range from 0 (symptom- and sign-free) up to 100. At week 24, a significantly higher proportion of guselkumab-treated PASI 100 responders had a total PSSD score of zero: 55%, versus 43% in the adalimumab group. This was consistently true across the board for each of the individual signs and symptoms assessed. For example, 61% of the guselkumab group gave themselves a zero for itch, as did 50% of the adalimumab group. Sixty-four percent on guselkumab and 52% on adalimumab reported being free of redness. And 78% of the guselkumab group reported being pain-free, compared with 69% with adalimumab, Dr. Blauvelt reported.

Gene expression analysis

At baseline, more than 2,300 dysregulated genes were identified in lesional skin while functioning normally in nonlesional skin. The great majority of these initially dysregulated genes became normalized in cleared lesional skin in PASI 100 responders at week 24. However, 25 of the genes remained dysregulated in cleared lesional skin, meaning they displayed less than 75% of normal function. Ten of these 25 genes with dysregulated expression at follow-up showed abnormal function in patients with residual symptoms despite cleared skin, but they functioned normally in those without persistent symptoms. This raises the possibility that the residual symptoms of psoriasis were attributable to the abnormal gene functioning, according to Dr. Blauvelt.

Of note, 9 of the 10 dysregulated genes in cleared lesional skin of patients with residual symptoms were present in the adalimumab group; these included two genes localized to the epidermal differentiation complex as well as the psoriasis-specific proline-rich 9 gene known as PRR9, which is induced by IL-17A. In contrast, only four genes, none of which were localized to the epidermal differentiation complex, were insufficiently normalized in the cleared lesional skin of guselkumab-treated PASI-100 responders.

“Nothing like this analysis has ever been done before,” the dermatologist observed. “It’s a pilot study. Perhaps with more data like this, we’ll be using this type of information in clinical practice to go beyond clearing patients’ skin.”

Dr. Blauvelt reported serving as a scientific advisor to and paid clinical investigator for Janssen, which sponsored the study, as well as for roughly two dozen other pharmaceutical companies.

bjancin@mdedge.com

All PASI 100 responses to psoriasis therapy are not the same, Andrew Blauvelt, MD, declared at the virtual annual meeting of the American Academy of Dermatology.

He presented a first-of-its-kind study that potentially opens the door to a new, more rigorous standard for treatment success in psoriasis: Not simply cleared lesional skin as captured by a Psoriasis Area and Severity Index (PASI) 100 response, but also clearance of residual psoriasis signs and symptoms – as well as what he termed “molecular clearance.”

“We’ve found that clearing skin with drugs utilizing different mechanisms of action may lead to differential consequences for our patients,” observed Dr. Blauvelt, a dermatologist and clinical trialist who is president of the Oregon Medical Research Center, Portland.

A PASI 100 response, traditionally considered an elusive goal for the great majority of patients with severe psoriasis, can now often be achieved using today’s top-tier, high-performance biologics. But Dr. Blauvelt and his coinvestigators are interested in pushing even beyond PASI 100 to a new frontier of therapeutic benefit.

He presented a secondary analysis of the previously reported VOYAGE 1 and 2 head-to-head randomized trials of guselkumab (Tremfya) versus adalimumab (Humira) for treatment of moderate to severe psoriasis. This new analysis, which focused exclusively on PASI 100 responders by week 24, demonstrated that patients with a PASI 100 response to guselkumab, an interleukin (IL)-23 inhibitor, had significantly fewer persistent symptoms and signs of psoriasis than those whose skin clearance was attained using adalimumab, a tumor necrosis factor (TNF) inhibitor.

Moreover, the investigators showed that the gene expression profile of PASI 100 responders who were free of signs and symptoms was more normalized than that of patients with residual symptoms despite their cleared skin.

The analysis included 16 participants in the VOYAGE trials who achieved PASI 100 at week 24 on guselkumab and 5 who did so on adalimumab. At baseline and again at week 24, these individuals completed the Psoriasis Symptoms and Signs Diary (PSSD). Also, biopsies of lesional and nonlesional skin were obtained at baseline and of cleared lesional skin at week 24 for transcriptomic microarray analysis of the expression of many thousands of genes.
 

Persistent psoriasis symptoms despite cleared skin

The PSSD involves patient ratings of various psoriasis symptoms and signs. Total scores can range from 0 (symptom- and sign-free) up to 100. At week 24, a significantly higher proportion of guselkumab-treated PASI 100 responders had a total PSSD score of zero: 55%, versus 43% in the adalimumab group. This was consistently true across the board for each of the individual signs and symptoms assessed. For example, 61% of the guselkumab group gave themselves a zero for itch, as did 50% of the adalimumab group. Sixty-four percent on guselkumab and 52% on adalimumab reported being free of redness. And 78% of the guselkumab group reported being pain-free, compared with 69% with adalimumab, Dr. Blauvelt reported.

Gene expression analysis

At baseline, more than 2,300 dysregulated genes were identified in lesional skin while functioning normally in nonlesional skin. The great majority of these initially dysregulated genes became normalized in cleared lesional skin in PASI 100 responders at week 24. However, 25 of the genes remained dysregulated in cleared lesional skin, meaning they displayed less than 75% of normal function. Ten of these 25 genes with dysregulated expression at follow-up showed abnormal function in patients with residual symptoms despite cleared skin, but they functioned normally in those without persistent symptoms. This raises the possibility that the residual symptoms of psoriasis were attributable to the abnormal gene functioning, according to Dr. Blauvelt.

Of note, 9 of the 10 dysregulated genes in cleared lesional skin of patients with residual symptoms were present in the adalimumab group; these included two genes localized to the epidermal differentiation complex as well as the psoriasis-specific proline-rich 9 gene known as PRR9, which is induced by IL-17A. In contrast, only four genes, none of which were localized to the epidermal differentiation complex, were insufficiently normalized in the cleared lesional skin of guselkumab-treated PASI-100 responders.

“Nothing like this analysis has ever been done before,” the dermatologist observed. “It’s a pilot study. Perhaps with more data like this, we’ll be using this type of information in clinical practice to go beyond clearing patients’ skin.”

Dr. Blauvelt reported serving as a scientific advisor to and paid clinical investigator for Janssen, which sponsored the study, as well as for roughly two dozen other pharmaceutical companies.

bjancin@mdedge.com

In the wake of more than a decade of controversy over PSA testing, research is emerging that points to new approaches for the stratification of prostate cancer risk.

Two noninvasive tests — an assessment of spermine levels in urine and a blood test that combines free and total PSA and the (-2) pro-PSA isoform (p2PSA) — are much safer than historically risky biopsy and what is now considered to have been unnecessary surgery.

“We’ve ‘cured’ a lot of men,” Franklin Gaylis, MD, from the University of California, San Diego, told Medscape Medical News. “Even some who didn’t need to be cured.” Now, we are working to solve this dilemma, he said. “It’s time we determine who do you screen, [who do you] not screen, and how aggressively?”

Urine Spermine Test More Accurate Than PSA

Data from a highly predictive test that assesses spermine levels in urine were presented by Peter Ka-Fung Chiu, MD, from the University of Hong Kong, at the virtual annual congress of the European Association of Urology. Normal spermine levels are inversely associated with both prostate cancer (PCa) and high-grade prostate cancer (HGPCa).

To investigate the predictive value of spermine for any PCa or HGPCa (Gleason 7 or above), the researchers recruited 556 men from two centers and collected 30 mL of urine prior to prostate biopsy.

They analyzed data from 390 men and used decision-curve analyses for PCa and for HGPCa. The multivariate spermine score — which takes into account age, prostate volume, PSA level, and spermine level — provided net clinical benefit over PSA alone and over spermine score alone.

“At 90% sensitivity, this risk score actually had a negative predictive value of 96.7% and avoided about 50% of unnecessary biopsies,” Chiu explained. “This test predicts prostate cancer and high-grade prostate cancer well, without the need for prior prostate massage, offering improved predictive performance.”

PHI Reduces Need for MRI Screening

Another test, the PHI prostate cancer biomarker, is as predictive as multiparametric (mp)MRI, both with and without PSA scoring.

PHI scores from 554 men from five centers added to either PSA density or mpMRI improved the prediction of risk for ≥GG2 cancers to more than 0.81 and for ≥CPG3 cancers to more than 0.85, according to data from the multicenter PRIM (PHI to Refine MRI) study group recently published in BMC Medicine and presented at EAU.

With a PHI cut-off of 30, mpMRI referrals could be cut by 25%, and unnecessary biopsies could be cut by 40%, the PRIM group reports. PHI misses 8% of ≥GG2 cancers, whereas mpMRI misses 9%.

The PHI strategy reduces “mpMRI and biopsies without compromising detection of significant prostate cancers,” and also reduces costs, Nicholas Boxall, MB ChB, from Cambridge University Hospitals NHS Foundation Trust in the United Kingdom, explained during his presentation

“Instead of screening everyone, we’re risk-adapting who needs to be screened, identifying the right population and defaulting to MRI as an alternative to invasive biopsy, and doing secondary tests to look at biomarkers,” said Gerald Andriole, MD, from the Washington University School of Medicine in St. Louis, Missouri.

“We don’t have to auto-toggle to aggressive treatment,” he told Medscape Medical News. “We’re getting better than we were 10 years ago, but we need slightly better tests, and we also need better biopsies; urologists must be more careful.”

Chiu and Boxall report no relevant financial relationships. Gaylis is a scientific advisor for Stratify Genomics. Andriole is on the advisory board of Stratify Genomics.
 

This article first appeared on Medscape.com.

In the wake of more than a decade of controversy over PSA testing, research is emerging that points to new approaches for the stratification of prostate cancer risk.

Two noninvasive tests — an assessment of spermine levels in urine and a blood test that combines free and total PSA and the (-2) pro-PSA isoform (p2PSA) — are much safer than historically risky biopsy and what is now considered to have been unnecessary surgery.

“We’ve ‘cured’ a lot of men,” Franklin Gaylis, MD, from the University of California, San Diego, told Medscape Medical News. “Even some who didn’t need to be cured.” Now, we are working to solve this dilemma, he said. “It’s time we determine who do you screen, [who do you] not screen, and how aggressively?”

Urine Spermine Test More Accurate Than PSA

Data from a highly predictive test that assesses spermine levels in urine were presented by Peter Ka-Fung Chiu, MD, from the University of Hong Kong, at the virtual annual congress of the European Association of Urology. Normal spermine levels are inversely associated with both prostate cancer (PCa) and high-grade prostate cancer (HGPCa).

To investigate the predictive value of spermine for any PCa or HGPCa (Gleason 7 or above), the researchers recruited 556 men from two centers and collected 30 mL of urine prior to prostate biopsy.

They analyzed data from 390 men and used decision-curve analyses for PCa and for HGPCa. The multivariate spermine score — which takes into account age, prostate volume, PSA level, and spermine level — provided net clinical benefit over PSA alone and over spermine score alone.

“At 90% sensitivity, this risk score actually had a negative predictive value of 96.7% and avoided about 50% of unnecessary biopsies,” Chiu explained. “This test predicts prostate cancer and high-grade prostate cancer well, without the need for prior prostate massage, offering improved predictive performance.”

PHI Reduces Need for MRI Screening

Another test, the PHI prostate cancer biomarker, is as predictive as multiparametric (mp)MRI, both with and without PSA scoring.

PHI scores from 554 men from five centers added to either PSA density or mpMRI improved the prediction of risk for ≥GG2 cancers to more than 0.81 and for ≥CPG3 cancers to more than 0.85, according to data from the multicenter PRIM (PHI to Refine MRI) study group recently published in BMC Medicine and presented at EAU.

With a PHI cut-off of 30, mpMRI referrals could be cut by 25%, and unnecessary biopsies could be cut by 40%, the PRIM group reports. PHI misses 8% of ≥GG2 cancers, whereas mpMRI misses 9%.

The PHI strategy reduces “mpMRI and biopsies without compromising detection of significant prostate cancers,” and also reduces costs, Nicholas Boxall, MB ChB, from Cambridge University Hospitals NHS Foundation Trust in the United Kingdom, explained during his presentation

“Instead of screening everyone, we’re risk-adapting who needs to be screened, identifying the right population and defaulting to MRI as an alternative to invasive biopsy, and doing secondary tests to look at biomarkers,” said Gerald Andriole, MD, from the Washington University School of Medicine in St. Louis, Missouri.

“We don’t have to auto-toggle to aggressive treatment,” he told Medscape Medical News. “We’re getting better than we were 10 years ago, but we need slightly better tests, and we also need better biopsies; urologists must be more careful.”

Chiu and Boxall report no relevant financial relationships. Gaylis is a scientific advisor for Stratify Genomics. Andriole is on the advisory board of Stratify Genomics.
 

This article first appeared on Medscape.com.

In the wake of more than a decade of controversy over PSA testing, research is emerging that points to new approaches for the stratification of prostate cancer risk.

Two noninvasive tests — an assessment of spermine levels in urine and a blood test that combines free and total PSA and the (-2) pro-PSA isoform (p2PSA) — are much safer than historically risky biopsy and what is now considered to have been unnecessary surgery.

“We’ve ‘cured’ a lot of men,” Franklin Gaylis, MD, from the University of California, San Diego, told Medscape Medical News. “Even some who didn’t need to be cured.” Now, we are working to solve this dilemma, he said. “It’s time we determine who do you screen, [who do you] not screen, and how aggressively?”

Urine Spermine Test More Accurate Than PSA

Data from a highly predictive test that assesses spermine levels in urine were presented by Peter Ka-Fung Chiu, MD, from the University of Hong Kong, at the virtual annual congress of the European Association of Urology. Normal spermine levels are inversely associated with both prostate cancer (PCa) and high-grade prostate cancer (HGPCa).

To investigate the predictive value of spermine for any PCa or HGPCa (Gleason 7 or above), the researchers recruited 556 men from two centers and collected 30 mL of urine prior to prostate biopsy.

They analyzed data from 390 men and used decision-curve analyses for PCa and for HGPCa. The multivariate spermine score — which takes into account age, prostate volume, PSA level, and spermine level — provided net clinical benefit over PSA alone and over spermine score alone.

“At 90% sensitivity, this risk score actually had a negative predictive value of 96.7% and avoided about 50% of unnecessary biopsies,” Chiu explained. “This test predicts prostate cancer and high-grade prostate cancer well, without the need for prior prostate massage, offering improved predictive performance.”

PHI Reduces Need for MRI Screening

Another test, the PHI prostate cancer biomarker, is as predictive as multiparametric (mp)MRI, both with and without PSA scoring.

PHI scores from 554 men from five centers added to either PSA density or mpMRI improved the prediction of risk for ≥GG2 cancers to more than 0.81 and for ≥CPG3 cancers to more than 0.85, according to data from the multicenter PRIM (PHI to Refine MRI) study group recently published in BMC Medicine and presented at EAU.

With a PHI cut-off of 30, mpMRI referrals could be cut by 25%, and unnecessary biopsies could be cut by 40%, the PRIM group reports. PHI misses 8% of ≥GG2 cancers, whereas mpMRI misses 9%.

The PHI strategy reduces “mpMRI and biopsies without compromising detection of significant prostate cancers,” and also reduces costs, Nicholas Boxall, MB ChB, from Cambridge University Hospitals NHS Foundation Trust in the United Kingdom, explained during his presentation

“Instead of screening everyone, we’re risk-adapting who needs to be screened, identifying the right population and defaulting to MRI as an alternative to invasive biopsy, and doing secondary tests to look at biomarkers,” said Gerald Andriole, MD, from the Washington University School of Medicine in St. Louis, Missouri.

“We don’t have to auto-toggle to aggressive treatment,” he told Medscape Medical News. “We’re getting better than we were 10 years ago, but we need slightly better tests, and we also need better biopsies; urologists must be more careful.”

Chiu and Boxall report no relevant financial relationships. Gaylis is a scientific advisor for Stratify Genomics. Andriole is on the advisory board of Stratify Genomics.
 

This article first appeared on Medscape.com.