When it joined with 15 other medical specialty societies at a Feb. 21 press conference to announce updates to the ABIM Foundation’s Choosing Wisely campaign to combat cost and waste reduction in healthcare , SHM leaders said they hoped the hospitalist-focused quality guidelines would trickle down from the national level to clinicians in the field (see “Stop! Think Twice Before You Order"). The lists of treatments adult and pediatric hospitalists should consider questioning in the absence of evidence or protocols include the urinary catheters, blood transfusions, telemetry monitoring outside of the ICU, and certain lab tests and medications for preventing stress ulcers.

Ian Jenkins, MD, a hospitalist at the University of California, San Diego, who presented during both Choosing Wisely sessions, said hospitalists are at the intersection of healthcare cost and quality improvement. “People recognize the moral imperatives,” he said.

Pre-course participants split into four teams and drilled deeper into questionable treatments and practices outlined by the campaign. SHM plans to make results of those small-group discussions available to its members, along with enhanced reference lists and best practices from the field. “We can contribute a bunch of stuff,” Dr. Jenkins told pre-course participants. “Tell us what you can contribute, and what you’d like to see from us.”

Hospitalist George Dimitriou, MD, of Allegheny General Hospital in Pittsburgh, said his hospital has spent the past couple of years working on several of the same hospital-focused quality issues outlined in the Choosing Wisely campaign.

“Our transfusion initiative was driven by the local blood bank, knowing we were over-transfusing,” he said. “We had an order set, but we recently put in place a more restrictive transfusion policy, following national guidelines.

“Our Foley catheter protocol was in response to the national recommendations to reduce urinary tract infections, mostly driven by our infectious disease department,” Dr. Dimitriou added. The hospital has not yet tackled the problem of overuse of telemetry services, “although that’s something I have wanted to do for a long time.”

Another hot-button issue, the daily ordering of lab tests, should be rectified by simply “taking it out of the electronic medical record as a default option.”

According to SHM staff, a Choosing Wisely case study competition will be held next year, with $10,000 in cash prizes awarded for adult and pediatric quality initiatives showing improvement in utilization, innovation, sustainability, and institutional commitment. An independent review panel will develop evaluation criteria, with a projected application deadline of Fall 2014. The competition is supported by a $50,000 grant from the ABIM Foundation. TH

Larry Beresford is a freelance writer in Oakland, Calif.

When it joined with 15 other medical specialty societies at a Feb. 21 press conference to announce updates to the ABIM Foundation’s Choosing Wisely campaign to combat cost and waste reduction in healthcare , SHM leaders said they hoped the hospitalist-focused quality guidelines would trickle down from the national level to clinicians in the field (see “Stop! Think Twice Before You Order"). The lists of treatments adult and pediatric hospitalists should consider questioning in the absence of evidence or protocols include the urinary catheters, blood transfusions, telemetry monitoring outside of the ICU, and certain lab tests and medications for preventing stress ulcers.

Ian Jenkins, MD, a hospitalist at the University of California, San Diego, who presented during both Choosing Wisely sessions, said hospitalists are at the intersection of healthcare cost and quality improvement. “People recognize the moral imperatives,” he said.

Pre-course participants split into four teams and drilled deeper into questionable treatments and practices outlined by the campaign. SHM plans to make results of those small-group discussions available to its members, along with enhanced reference lists and best practices from the field. “We can contribute a bunch of stuff,” Dr. Jenkins told pre-course participants. “Tell us what you can contribute, and what you’d like to see from us.”

Hospitalist George Dimitriou, MD, of Allegheny General Hospital in Pittsburgh, said his hospital has spent the past couple of years working on several of the same hospital-focused quality issues outlined in the Choosing Wisely campaign.

“Our transfusion initiative was driven by the local blood bank, knowing we were over-transfusing,” he said. “We had an order set, but we recently put in place a more restrictive transfusion policy, following national guidelines.

“Our Foley catheter protocol was in response to the national recommendations to reduce urinary tract infections, mostly driven by our infectious disease department,” Dr. Dimitriou added. The hospital has not yet tackled the problem of overuse of telemetry services, “although that’s something I have wanted to do for a long time.”

Another hot-button issue, the daily ordering of lab tests, should be rectified by simply “taking it out of the electronic medical record as a default option.”

According to SHM staff, a Choosing Wisely case study competition will be held next year, with $10,000 in cash prizes awarded for adult and pediatric quality initiatives showing improvement in utilization, innovation, sustainability, and institutional commitment. An independent review panel will develop evaluation criteria, with a projected application deadline of Fall 2014. The competition is supported by a $50,000 grant from the ABIM Foundation. TH

Larry Beresford is a freelance writer in Oakland, Calif.

When it joined with 15 other medical specialty societies at a Feb. 21 press conference to announce updates to the ABIM Foundation’s Choosing Wisely campaign to combat cost and waste reduction in healthcare , SHM leaders said they hoped the hospitalist-focused quality guidelines would trickle down from the national level to clinicians in the field (see “Stop! Think Twice Before You Order"). The lists of treatments adult and pediatric hospitalists should consider questioning in the absence of evidence or protocols include the urinary catheters, blood transfusions, telemetry monitoring outside of the ICU, and certain lab tests and medications for preventing stress ulcers.

Ian Jenkins, MD, a hospitalist at the University of California, San Diego, who presented during both Choosing Wisely sessions, said hospitalists are at the intersection of healthcare cost and quality improvement. “People recognize the moral imperatives,” he said.

Pre-course participants split into four teams and drilled deeper into questionable treatments and practices outlined by the campaign. SHM plans to make results of those small-group discussions available to its members, along with enhanced reference lists and best practices from the field. “We can contribute a bunch of stuff,” Dr. Jenkins told pre-course participants. “Tell us what you can contribute, and what you’d like to see from us.”

Hospitalist George Dimitriou, MD, of Allegheny General Hospital in Pittsburgh, said his hospital has spent the past couple of years working on several of the same hospital-focused quality issues outlined in the Choosing Wisely campaign.

“Our transfusion initiative was driven by the local blood bank, knowing we were over-transfusing,” he said. “We had an order set, but we recently put in place a more restrictive transfusion policy, following national guidelines.

“Our Foley catheter protocol was in response to the national recommendations to reduce urinary tract infections, mostly driven by our infectious disease department,” Dr. Dimitriou added. The hospital has not yet tackled the problem of overuse of telemetry services, “although that’s something I have wanted to do for a long time.”

Another hot-button issue, the daily ordering of lab tests, should be rectified by simply “taking it out of the electronic medical record as a default option.”

According to SHM staff, a Choosing Wisely case study competition will be held next year, with $10,000 in cash prizes awarded for adult and pediatric quality initiatives showing improvement in utilization, innovation, sustainability, and institutional commitment. An independent review panel will develop evaluation criteria, with a projected application deadline of Fall 2014. The competition is supported by a $50,000 grant from the ABIM Foundation. TH

Larry Beresford is a freelance writer in Oakland, Calif.

When my children were in school and got head lice, I learned the full metaphorical scope of words like "lousy" and "nit-picking." I also learned that school nurses didn’t give a hoot for my opinions.

Despite my boards in pediatrics and dermatology, my protests against schools’ policies of dragging parents out of work to pick up a kid on whom the nurse found a nit, or thought she did, even after multiple treatments and fine-tooth combing (another nice, real-life metaphor) went unheard.

In vain did I cite policy statements by august professional organizations that no-nit policies were unnecessary. No sir – they find one dead egg case, and Johnny goes home. His parents are obviously irresponsible anyway, not to mention unhygienic. So I gave up, and my children grew up.

What reawakened these memories was my annual visit to Marcie, my eye doctor. "I really like your PA," she said. "Jared saw her when the school nurse sent him home with a rash. Your PA asked him why he was there. ‘The nurse sent me home,’ he said. ‘OK,’ said your PA, ‘now you can go back.’

"They once sent Jared home because of a chalazion," Marcie continued. "I called them up. ‘He’s on tobramycin,’ I told them. ‘And a chalazion isn’t contagious anyway.’ But they didn’t believe me!

"My husband called them. ‘My wife is an eye doctor,’ he said. ‘Oh,’ they said, ‘We didn’t know what kind of doctor she was.’ "

Probably the most egregious example of high-handed school medical behavior I have ever seen played out in my office just last month. The Hightowers brought in 4-year-old Jeffrey with an impetiginized rash. We started cephalexin, pending culture results. When these showed MRSA on Friday afternoon, we called the family to switch Jeffrey to trimethoprim-sulfamethoxazole.

Janice Hightower became very upset. "Should I call the school?" We suggested she use her discretion, because by Monday Jeffrey would no longer be contagious. "But I’m a teacher," she said. "I feel responsible." So she did.

The next day, Jeffrey’s dad, Brian Hightower, came to school to coach baseball (his kids stayed home). During the game, all the parents got text messages informing them: "Someone in the school is infected with MRSA, and school is closed until further notice." He then sat in stunned silence as the other parents commiserated with each other about what happens when their children have to hang around with other kids whose parents are irresponsible, dirty, and a lot of other unpleasant things.

On Monday, Brian Hightower brought Jeffrey’s older brother, Jason, to the office. Jason had no skin lesions at all. "My wife won’t let me go home without antibiotics for him," insisted Brian. We told him there was nothing to treat, and he left. Later, Janice Hightower called. "This is like ‘The Scarlet Letter,’ " she said. "We’ll never be able to show our faces in the community again."

We tried to reassure her (the MRSA culprit’s identity had mercifully not been divulged), but she pressed on. "When he grows up and kisses his first girl," she asked, "will he have to tell her about this?"

Things went downhill from there. Several days and many phone calls later, the Hightowers began to calm down. Jeffrey and Jason returned to school, which had somehow managed to reopen. I have no idea which medical authority authorized the reopening, any more than I know who told them to close it in the first place. Jeffrey hasn’t been sighted kissing any girls yet, other than possibly Aunt Susie.

What this episode says about how people judge and treat others who are ill, not to mention how ancient ideas about disease persist long after they are supposed to have been discarded, doesn’t need to be spelled out. Better to take polite notice and move on.

But it also says quite a lot about the limitations of our professional authority outside the spheres where we’re in charge. In the office, people may or may not listen to us, but at least they act as though they might.

But outside the office, in schools for instance, what we have to say often doesn’t count for much. Or anything.

Dr. Rockoff practices dermatology in Brookline, Mass. To respond to this column, e-mail him at our editorial offices at [email protected].

When my children were in school and got head lice, I learned the full metaphorical scope of words like "lousy" and "nit-picking." I also learned that school nurses didn’t give a hoot for my opinions.

Despite my boards in pediatrics and dermatology, my protests against schools’ policies of dragging parents out of work to pick up a kid on whom the nurse found a nit, or thought she did, even after multiple treatments and fine-tooth combing (another nice, real-life metaphor) went unheard.

In vain did I cite policy statements by august professional organizations that no-nit policies were unnecessary. No sir – they find one dead egg case, and Johnny goes home. His parents are obviously irresponsible anyway, not to mention unhygienic. So I gave up, and my children grew up.

What reawakened these memories was my annual visit to Marcie, my eye doctor. "I really like your PA," she said. "Jared saw her when the school nurse sent him home with a rash. Your PA asked him why he was there. ‘The nurse sent me home,’ he said. ‘OK,’ said your PA, ‘now you can go back.’

"They once sent Jared home because of a chalazion," Marcie continued. "I called them up. ‘He’s on tobramycin,’ I told them. ‘And a chalazion isn’t contagious anyway.’ But they didn’t believe me!

"My husband called them. ‘My wife is an eye doctor,’ he said. ‘Oh,’ they said, ‘We didn’t know what kind of doctor she was.’ "

Probably the most egregious example of high-handed school medical behavior I have ever seen played out in my office just last month. The Hightowers brought in 4-year-old Jeffrey with an impetiginized rash. We started cephalexin, pending culture results. When these showed MRSA on Friday afternoon, we called the family to switch Jeffrey to trimethoprim-sulfamethoxazole.

Janice Hightower became very upset. "Should I call the school?" We suggested she use her discretion, because by Monday Jeffrey would no longer be contagious. "But I’m a teacher," she said. "I feel responsible." So she did.

The next day, Jeffrey’s dad, Brian Hightower, came to school to coach baseball (his kids stayed home). During the game, all the parents got text messages informing them: "Someone in the school is infected with MRSA, and school is closed until further notice." He then sat in stunned silence as the other parents commiserated with each other about what happens when their children have to hang around with other kids whose parents are irresponsible, dirty, and a lot of other unpleasant things.

On Monday, Brian Hightower brought Jeffrey’s older brother, Jason, to the office. Jason had no skin lesions at all. "My wife won’t let me go home without antibiotics for him," insisted Brian. We told him there was nothing to treat, and he left. Later, Janice Hightower called. "This is like ‘The Scarlet Letter,’ " she said. "We’ll never be able to show our faces in the community again."

We tried to reassure her (the MRSA culprit’s identity had mercifully not been divulged), but she pressed on. "When he grows up and kisses his first girl," she asked, "will he have to tell her about this?"

Things went downhill from there. Several days and many phone calls later, the Hightowers began to calm down. Jeffrey and Jason returned to school, which had somehow managed to reopen. I have no idea which medical authority authorized the reopening, any more than I know who told them to close it in the first place. Jeffrey hasn’t been sighted kissing any girls yet, other than possibly Aunt Susie.

What this episode says about how people judge and treat others who are ill, not to mention how ancient ideas about disease persist long after they are supposed to have been discarded, doesn’t need to be spelled out. Better to take polite notice and move on.

But it also says quite a lot about the limitations of our professional authority outside the spheres where we’re in charge. In the office, people may or may not listen to us, but at least they act as though they might.

But outside the office, in schools for instance, what we have to say often doesn’t count for much. Or anything.

Dr. Rockoff practices dermatology in Brookline, Mass. To respond to this column, e-mail him at our editorial offices at [email protected].

When my children were in school and got head lice, I learned the full metaphorical scope of words like "lousy" and "nit-picking." I also learned that school nurses didn’t give a hoot for my opinions.

Despite my boards in pediatrics and dermatology, my protests against schools’ policies of dragging parents out of work to pick up a kid on whom the nurse found a nit, or thought she did, even after multiple treatments and fine-tooth combing (another nice, real-life metaphor) went unheard.

In vain did I cite policy statements by august professional organizations that no-nit policies were unnecessary. No sir – they find one dead egg case, and Johnny goes home. His parents are obviously irresponsible anyway, not to mention unhygienic. So I gave up, and my children grew up.

What reawakened these memories was my annual visit to Marcie, my eye doctor. "I really like your PA," she said. "Jared saw her when the school nurse sent him home with a rash. Your PA asked him why he was there. ‘The nurse sent me home,’ he said. ‘OK,’ said your PA, ‘now you can go back.’

"They once sent Jared home because of a chalazion," Marcie continued. "I called them up. ‘He’s on tobramycin,’ I told them. ‘And a chalazion isn’t contagious anyway.’ But they didn’t believe me!

"My husband called them. ‘My wife is an eye doctor,’ he said. ‘Oh,’ they said, ‘We didn’t know what kind of doctor she was.’ "

Probably the most egregious example of high-handed school medical behavior I have ever seen played out in my office just last month. The Hightowers brought in 4-year-old Jeffrey with an impetiginized rash. We started cephalexin, pending culture results. When these showed MRSA on Friday afternoon, we called the family to switch Jeffrey to trimethoprim-sulfamethoxazole.

Janice Hightower became very upset. "Should I call the school?" We suggested she use her discretion, because by Monday Jeffrey would no longer be contagious. "But I’m a teacher," she said. "I feel responsible." So she did.

The next day, Jeffrey’s dad, Brian Hightower, came to school to coach baseball (his kids stayed home). During the game, all the parents got text messages informing them: "Someone in the school is infected with MRSA, and school is closed until further notice." He then sat in stunned silence as the other parents commiserated with each other about what happens when their children have to hang around with other kids whose parents are irresponsible, dirty, and a lot of other unpleasant things.

On Monday, Brian Hightower brought Jeffrey’s older brother, Jason, to the office. Jason had no skin lesions at all. "My wife won’t let me go home without antibiotics for him," insisted Brian. We told him there was nothing to treat, and he left. Later, Janice Hightower called. "This is like ‘The Scarlet Letter,’ " she said. "We’ll never be able to show our faces in the community again."

We tried to reassure her (the MRSA culprit’s identity had mercifully not been divulged), but she pressed on. "When he grows up and kisses his first girl," she asked, "will he have to tell her about this?"

Things went downhill from there. Several days and many phone calls later, the Hightowers began to calm down. Jeffrey and Jason returned to school, which had somehow managed to reopen. I have no idea which medical authority authorized the reopening, any more than I know who told them to close it in the first place. Jeffrey hasn’t been sighted kissing any girls yet, other than possibly Aunt Susie.

What this episode says about how people judge and treat others who are ill, not to mention how ancient ideas about disease persist long after they are supposed to have been discarded, doesn’t need to be spelled out. Better to take polite notice and move on.

But it also says quite a lot about the limitations of our professional authority outside the spheres where we’re in charge. In the office, people may or may not listen to us, but at least they act as though they might.

But outside the office, in schools for instance, what we have to say often doesn’t count for much. Or anything.

Dr. Rockoff practices dermatology in Brookline, Mass. To respond to this column, e-mail him at our editorial offices at [email protected].

PLEASE VIEW THE FULL-TEXT PDF.

PLEASE VIEW THE FULL-TEXT PDF.

PLEASE VIEW THE FULL-TEXT PDF.

CHICAGO – A novel technique for ferreting out DNA mutations in circulating plasma appears to be more sensitive than is conventional pathology at detecting drug-resistant mutations in patients with gastrointestinal stromal tumors, said an investigator at the annual meeting of the American Society of Clinical Oncology.

Secondary KIT mutations associated with resistance to tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec) were detected in 47% of plasma samples using "BEAMing" (beads, emulsions, amplification, magnetics) technology, compared with only 12% of tissue biopsy specimens, said Dr. George D. Demetri, director of the center for sarcoma and bone oncology at the Dana-Farber Cancer Institute in Boston.

"We know that tumor cells are constantly turning over, apoptosing, dying, and releasing free DNA into the bloodstream. I want to emphasize that this is not looking at circulating tumor cells; this is looking at free circulating DNA in the plasma, and by looking at that circulating DNA, we may be able to get a more comprehensive assessment of all the mutations from across all tumor burden in any given patient," Dr. Demetri said.

The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 in plasma, according to the American Association for Cancer Research.

Dr. Demetri and his colleagues used the technology to retrospectively study mutations from patient samples in the GRID (GIST-Regorafenib in Progressive Disease) phase III study. In that trial, regorafenib (Stivarga), a multikinase inhibitor, significantly improved progression-free survival (PFS) compared with placebo (hazard ratio, 0.27; P less than .0001) in patients with metastatic GIST after failure of both standard and targeted therapies, including imatinib and sunitinib (Sutent).

The investigators looked for primary and secondary mutations in KIT in both plasma samples (available for 163 of 199 patients in GRID) and tumor tissue (from 102 patients), and found that BEAMing detected mutations in 58% of plasma samples, compared with 66% of tumor samples analyzed by the Sanger DNA sequencing method.

In addition, BEAMing detected mutations in PDGFRA in 1% of samples, and in KRAS in one of two samples, compared with 3% and 1%, respectively, for sequencing. Neither analysis method detected any BRAF mutations, and the numbers of PDGFRA and KRAS mutations were too small for researchers to draw meaningful conclusions.

When it came to KIT, however, there was a high degree of concordance between the tests where both types of samples from individual patients were available, including 100% agreement for primary KIT exon 9 mutations, 79% for primary KIT exon 11 mutations, and 84% overall for primary KIT exon 9 and 11 mutations.

The BEAMing technology can help determine prognosis of patients with GIST, Dr. Demetri said, noting that in the GRID trial, patients in the placebo arm who had secondary KIT mutations had shorter PFS than did patients without KIT mutations (HR, 1.82; P = .05). Patients with KIT exon 9 mutations had received a shorter course of imatinib than did the rest of the study population (HR, 2.02; P = .002) and a longer course of sunitinib (HR, 0.54; P = .005).

BEAMing analysis also showed that patients with secondary KIT mutations who received regorafenib had significantly better PFS than did patients in the placebo arm (HR, 0.22; P less than .001).

The data Dr. Demetri presented were "very exciting," said invited discussant Dr. Shreyaskumar R. Patel, professor of sarcoma oncology at the University of Texas MD Anderson Cancer Center in Houston.

"The important take-home messages are that there is some very good concordance between the tumor tissue analysis and the plasma analysis," and that regorafenib "appears to be totally agnostic to any of the mutational subsets and seems to equally benefit all patients," Dr. Patel said.

The study was supported in part by Bayer HealthCare. Dr. Demetri disclosed serving as a scientific consultant to the company. Dr. Patel reported having no disclosures relevant to the study.

CHICAGO – A novel technique for ferreting out DNA mutations in circulating plasma appears to be more sensitive than is conventional pathology at detecting drug-resistant mutations in patients with gastrointestinal stromal tumors, said an investigator at the annual meeting of the American Society of Clinical Oncology.

Secondary KIT mutations associated with resistance to tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec) were detected in 47% of plasma samples using "BEAMing" (beads, emulsions, amplification, magnetics) technology, compared with only 12% of tissue biopsy specimens, said Dr. George D. Demetri, director of the center for sarcoma and bone oncology at the Dana-Farber Cancer Institute in Boston.

"We know that tumor cells are constantly turning over, apoptosing, dying, and releasing free DNA into the bloodstream. I want to emphasize that this is not looking at circulating tumor cells; this is looking at free circulating DNA in the plasma, and by looking at that circulating DNA, we may be able to get a more comprehensive assessment of all the mutations from across all tumor burden in any given patient," Dr. Demetri said.

The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 in plasma, according to the American Association for Cancer Research.

Dr. Demetri and his colleagues used the technology to retrospectively study mutations from patient samples in the GRID (GIST-Regorafenib in Progressive Disease) phase III study. In that trial, regorafenib (Stivarga), a multikinase inhibitor, significantly improved progression-free survival (PFS) compared with placebo (hazard ratio, 0.27; P less than .0001) in patients with metastatic GIST after failure of both standard and targeted therapies, including imatinib and sunitinib (Sutent).

The investigators looked for primary and secondary mutations in KIT in both plasma samples (available for 163 of 199 patients in GRID) and tumor tissue (from 102 patients), and found that BEAMing detected mutations in 58% of plasma samples, compared with 66% of tumor samples analyzed by the Sanger DNA sequencing method.

In addition, BEAMing detected mutations in PDGFRA in 1% of samples, and in KRAS in one of two samples, compared with 3% and 1%, respectively, for sequencing. Neither analysis method detected any BRAF mutations, and the numbers of PDGFRA and KRAS mutations were too small for researchers to draw meaningful conclusions.

When it came to KIT, however, there was a high degree of concordance between the tests where both types of samples from individual patients were available, including 100% agreement for primary KIT exon 9 mutations, 79% for primary KIT exon 11 mutations, and 84% overall for primary KIT exon 9 and 11 mutations.

The BEAMing technology can help determine prognosis of patients with GIST, Dr. Demetri said, noting that in the GRID trial, patients in the placebo arm who had secondary KIT mutations had shorter PFS than did patients without KIT mutations (HR, 1.82; P = .05). Patients with KIT exon 9 mutations had received a shorter course of imatinib than did the rest of the study population (HR, 2.02; P = .002) and a longer course of sunitinib (HR, 0.54; P = .005).

BEAMing analysis also showed that patients with secondary KIT mutations who received regorafenib had significantly better PFS than did patients in the placebo arm (HR, 0.22; P less than .001).

The data Dr. Demetri presented were "very exciting," said invited discussant Dr. Shreyaskumar R. Patel, professor of sarcoma oncology at the University of Texas MD Anderson Cancer Center in Houston.

"The important take-home messages are that there is some very good concordance between the tumor tissue analysis and the plasma analysis," and that regorafenib "appears to be totally agnostic to any of the mutational subsets and seems to equally benefit all patients," Dr. Patel said.

The study was supported in part by Bayer HealthCare. Dr. Demetri disclosed serving as a scientific consultant to the company. Dr. Patel reported having no disclosures relevant to the study.

CHICAGO – A novel technique for ferreting out DNA mutations in circulating plasma appears to be more sensitive than is conventional pathology at detecting drug-resistant mutations in patients with gastrointestinal stromal tumors, said an investigator at the annual meeting of the American Society of Clinical Oncology.

Secondary KIT mutations associated with resistance to tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec) were detected in 47% of plasma samples using "BEAMing" (beads, emulsions, amplification, magnetics) technology, compared with only 12% of tissue biopsy specimens, said Dr. George D. Demetri, director of the center for sarcoma and bone oncology at the Dana-Farber Cancer Institute in Boston.

"We know that tumor cells are constantly turning over, apoptosing, dying, and releasing free DNA into the bloodstream. I want to emphasize that this is not looking at circulating tumor cells; this is looking at free circulating DNA in the plasma, and by looking at that circulating DNA, we may be able to get a more comprehensive assessment of all the mutations from across all tumor burden in any given patient," Dr. Demetri said.

The technique, which some investigators have dubbed "liquid biopsy," involves treating plasma with beads coated with DNA sequences that are complementary to target mutational sequences to create an emulsion polymerase chain reaction (PCR). The PCR amplifies the circulating DNA, which can then be identified with flow cytometry. The test can detect one circulating DNA molecule per 10,000 in plasma, according to the American Association for Cancer Research.

Dr. Demetri and his colleagues used the technology to retrospectively study mutations from patient samples in the GRID (GIST-Regorafenib in Progressive Disease) phase III study. In that trial, regorafenib (Stivarga), a multikinase inhibitor, significantly improved progression-free survival (PFS) compared with placebo (hazard ratio, 0.27; P less than .0001) in patients with metastatic GIST after failure of both standard and targeted therapies, including imatinib and sunitinib (Sutent).

The investigators looked for primary and secondary mutations in KIT in both plasma samples (available for 163 of 199 patients in GRID) and tumor tissue (from 102 patients), and found that BEAMing detected mutations in 58% of plasma samples, compared with 66% of tumor samples analyzed by the Sanger DNA sequencing method.

In addition, BEAMing detected mutations in PDGFRA in 1% of samples, and in KRAS in one of two samples, compared with 3% and 1%, respectively, for sequencing. Neither analysis method detected any BRAF mutations, and the numbers of PDGFRA and KRAS mutations were too small for researchers to draw meaningful conclusions.

When it came to KIT, however, there was a high degree of concordance between the tests where both types of samples from individual patients were available, including 100% agreement for primary KIT exon 9 mutations, 79% for primary KIT exon 11 mutations, and 84% overall for primary KIT exon 9 and 11 mutations.

The BEAMing technology can help determine prognosis of patients with GIST, Dr. Demetri said, noting that in the GRID trial, patients in the placebo arm who had secondary KIT mutations had shorter PFS than did patients without KIT mutations (HR, 1.82; P = .05). Patients with KIT exon 9 mutations had received a shorter course of imatinib than did the rest of the study population (HR, 2.02; P = .002) and a longer course of sunitinib (HR, 0.54; P = .005).

BEAMing analysis also showed that patients with secondary KIT mutations who received regorafenib had significantly better PFS than did patients in the placebo arm (HR, 0.22; P less than .001).

The data Dr. Demetri presented were "very exciting," said invited discussant Dr. Shreyaskumar R. Patel, professor of sarcoma oncology at the University of Texas MD Anderson Cancer Center in Houston.

"The important take-home messages are that there is some very good concordance between the tumor tissue analysis and the plasma analysis," and that regorafenib "appears to be totally agnostic to any of the mutational subsets and seems to equally benefit all patients," Dr. Patel said.

The study was supported in part by Bayer HealthCare. Dr. Demetri disclosed serving as a scientific consultant to the company. Dr. Patel reported having no disclosures relevant to the study.