The U.S. Senate voted to confirm Rep. Tom Price, MD, as secretary of the Department of Health & Human Services.

The final tally, recorded in the early hours of Feb. 10, was a strict party-line vote, with all 52 Republicans voting in favor of Rep. Price (R-Ga.) and 47 Democrats voting against. One Democrat, Sen. Claire McCaskill of Missouri, did not vote. Only a simple majority is needed to confirm cabinet members to their posts.
 

The confirmation comes amid ongoing concerns presented by Senate Democrats on Dr. Price’s stock purchases, particularly of Australia-based Innate Immunotherapeutics. Dr. Price was serving as a representative from Georgia at the time of his nomination, and there have been questions of possible ethics violations related to this and other securities purchases.

Wikimedia Commons/District office of Tom Price/Creative Commons License

[email protected]

The U.S. Senate voted to confirm Rep. Tom Price, MD, as secretary of the Department of Health & Human Services.

The final tally, recorded in the early hours of Feb. 10, was a strict party-line vote, with all 52 Republicans voting in favor of Rep. Price (R-Ga.) and 47 Democrats voting against. One Democrat, Sen. Claire McCaskill of Missouri, did not vote. Only a simple majority is needed to confirm cabinet members to their posts.
 

The confirmation comes amid ongoing concerns presented by Senate Democrats on Dr. Price’s stock purchases, particularly of Australia-based Innate Immunotherapeutics. Dr. Price was serving as a representative from Georgia at the time of his nomination, and there have been questions of possible ethics violations related to this and other securities purchases.

Wikimedia Commons/District office of Tom Price/Creative Commons License

[email protected]

The U.S. Senate voted to confirm Rep. Tom Price, MD, as secretary of the Department of Health & Human Services.

The final tally, recorded in the early hours of Feb. 10, was a strict party-line vote, with all 52 Republicans voting in favor of Rep. Price (R-Ga.) and 47 Democrats voting against. One Democrat, Sen. Claire McCaskill of Missouri, did not vote. Only a simple majority is needed to confirm cabinet members to their posts.
 

The confirmation comes amid ongoing concerns presented by Senate Democrats on Dr. Price’s stock purchases, particularly of Australia-based Innate Immunotherapeutics. Dr. Price was serving as a representative from Georgia at the time of his nomination, and there have been questions of possible ethics violations related to this and other securities purchases.

Wikimedia Commons/District office of Tom Price/Creative Commons License

[email protected]

SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).

“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.

“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.

In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).

There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.

So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).

The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.

Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.

Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.

[email protected]

SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).

“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.

“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.

In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).

There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.

So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).

The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.

Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.

Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.

[email protected]

SNOWMASS, COLO. – Glucocorticoids remain the first-line therapy in immunoglobulin G4-related disease, but it’s essential to bear in mind that their long-term efficacy in this immune-mediated fibroinflammatory disease is the exception rather than the rule, John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.

Dr. Stone, professor of medicine at Harvard Medical School, Boston, was a coauthor of an international expert consensus statement on the treatment of IgG4-related disease (IgG4-RD) which emphasized that point (Arthritis Rheumatol. 2015 Jul;67[7]:1688-99).

“I typically start with prednisone at 40 mg/day, and there’s a dramatic response in these patients. Then I taper them off after 2-3 months. If 2-3 months doesn’t put them into a long-term sustained remission, it’s time to go to something else,” said Dr. Stone, who also serves as director of clinical rheumatology at Massachusetts General Hospital, Boston.

“Glucocorticoids are rapidly effective, but initial reports were overoptimistic about their long-term efficacy. They don’t cure this disease any more than they cure giant cell arteritis in most of our patients, or ANCA-associated vasculitis. And since patients with IgG4-related disease are often older and may already have disease-induced damage to the pancreas and other organs, the morbidity from steroids in this population is formidable,” the rheumatologist explained.

In his series of 125 patients with biopsy-proven IgG4-RD, 83% responded to steroids initially, but 77% of steroid-treated patients failed to achieve a stable steroid-free remission after treatment discontinuation (Arthritis Rheumatol. 2015 Sep;67[9]:2466-75).

There is no evidence at all to indicate that conventional steroid-sparing drugs such as methotrexate, azathioprine, and mycophenolate mofetil are effective in IgG4-RD, the rheumatologist noted.

So what’s the next move, then, after steroids fail? Dr. Stone was a pioneer in the strikingly successful use of B cell depletion via rituximab (Rituxan) in patients with IgG4-RD. First he and his coinvestigators demonstrated that this off-label use of rituximab led to rapid clinical and histologic improvement (Ann Rheum Dis. 2015 Jun; 74[6]:1171-7), then they showed it also causes levels of circulating plasmablasts, serum IgG4, and biomarkers of fibrosis to plunge, suggesting B cell depletion may halt the destructive process of collagen deposition that characterizes this immune-related disease (Ann Rheum Dis. 2015 Dec;74[12]:2236-43). They have also reported that patients with very elevated baseline serum IgG4 levels are at more than sixfold increased risk of relapse at a median of 244 days from their first rituximab infusion (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).

The success with rituximab is just one example of how improved understanding of the pathophysiology of IgG4-RD has opened the door to novel treatments. Dr. Stone is the lead investigator in an ongoing phase II, open-label study in which 15 patients with active IgG4-RD will receive intravenous XmAb5871 every 2 weeks for 6 months to evaluate the effect on the IgG4-RD Responder Index. XmAb5871 is a monoclonal antibody that binds to CD19 and FCgammaRIIb in order to downregulate activated B cells and plasmablasts. It is also being developed for treatment of systemic lupus erythematosus.

Dr. Stone and his coinvestigators are working on a therapeutic approach to IgG4-RD that targets antigen presentation by activated B cells to CD4+ cytotoxic T cells at sites of disease. These CD4+ cytotoxic T cells contain signaling lymphocyte activation molecule F7 (SLAMF7) as a surface marker. Elotuzumab (Empliciti), an immunostimulatory humanized monoclonal antibody targeting SLAMF7, is already on the market for treatment of multiple myeloma, he noted.

Dr. Stone reported receiving IgG4-RD-related research funding from and serving as a consultant to Genentech and Xencor, which is developing XmAb5871.

[email protected]

B-cell gene expression in the peripheral blood strongly correlates with the extent of gluten-induced damage to the intestinal mucosa in patients with celiac disease, according to a report in Cellular and Molecular Gastroenterology and Hepatology.

If this finding from a single-center cohort study is validated in other patient populations, the B-cell signature may become a useful, minimally invasive tool for diagnosing celiac disease. Eventually, if biomarkers are developed from the peripheral B-cell signature, a simple blood test could be used for monitoring changes in gut inflammation over time as well as treatment response, said Mitchell E. Garber, PhD, of Alvine Pharmaceuticals, San Carlos, Calif., and the department of chemistry at Stanford University, and his associates.

However, it would be “premature but intriguing” to speculate about using this discovery to devise new, B cell–centered treatments for celiac disease, they added.

Noting that an inflammatory, gluten-induced immune response in the gut can be reflected in the peripheral blood, the investigators assessed whether a 6-week gluten challenge would induce damage to the small intestine that would show up in B-cell gene expression detected in blood samples. They assigned 73 patients at a single medical center in Finland to follow their usual gluten-free diets but to ingest an additional 6 g (20 patients), 3 g (26 patients), or 1.5 g (27 patients) of wheat gluten with a meal once per day for the study period.

The study participants (median age, 59 years; range, 23-74 years) underwent small-bowel biopsies obtained from the descending duodenum at baseline and after the gluten challenge. Damage to the intestinal mucosa was assessed by measuring the ratio of the height of the intestinal villi to the depth of the proliferative crypts at the base of the villi (villi height to crypt depth, or Vh:Cd). In celiac disease, gluten blunts the projection of the villi and causes hypertrophy or elongation of the crypts, resulting in flattened mucosa and a Vh:Cd approaching zero.

The study participants showed a wide variation in mucosal damage from the gluten exposure, with some patients showing no change and relatively healthy mucosa, and others showing extensive change and nearly flattened mucosa. The mucosal damage did not differ by gluten dose.

The largest change in Vh:Cd occurred in three patients who transitioned from relatively healthy intestinal mucosa (Vh:Cd 3.1) at baseline to nearly flat mucosa (Vh:Cd 0.2) after gluten exposure.

Patients with undamaged gut mucosa showed a relative increase in B-cell gene expression during the study period, while those who had increasing damage showed a relative decrease in B-cell expression. “The peripheral B cell therefore tracked with oral tolerance across the full spectrum of intestinal damage, from no change to a nearly flat mucosa,” Dr. Garber and his associates said (Cell Molec Gastroenterol Hepatol. 2017. doi: 10.1016/j.jcmgh.2017.01.011).

“The net increase in B-cell gene expression from baseline to 6 weeks in patients with little to no intestinal damage [suggests] that these individuals may have mounted a B-cell immune response to maintain mucosal homeostasis and circumvent inflammation,” they added.

Further study is needed to determine whether peripheral B cells are a marker that indicates tolerance to gluten but doesn’t play a functional role in the inflammatory process, or whether B cells may actually promote immune tolerance, the investigators said.

This study was funded by Alvine Pharmaceuticals, the American Recovery and Reinvestment Act, Tampere (Finland) University Hospital, the Academy of Finland Research Council for Health, and the U.S. National Institutes of Health. Dr. Garber reported ties to Alvine Pharmaceuticals, and his associates reported ties to ImmusanT, Celimmune, and ImmunogenX.

B-cell gene expression in the peripheral blood strongly correlates with the extent of gluten-induced damage to the intestinal mucosa in patients with celiac disease, according to a report in Cellular and Molecular Gastroenterology and Hepatology.

If this finding from a single-center cohort study is validated in other patient populations, the B-cell signature may become a useful, minimally invasive tool for diagnosing celiac disease. Eventually, if biomarkers are developed from the peripheral B-cell signature, a simple blood test could be used for monitoring changes in gut inflammation over time as well as treatment response, said Mitchell E. Garber, PhD, of Alvine Pharmaceuticals, San Carlos, Calif., and the department of chemistry at Stanford University, and his associates.

However, it would be “premature but intriguing” to speculate about using this discovery to devise new, B cell–centered treatments for celiac disease, they added.

Noting that an inflammatory, gluten-induced immune response in the gut can be reflected in the peripheral blood, the investigators assessed whether a 6-week gluten challenge would induce damage to the small intestine that would show up in B-cell gene expression detected in blood samples. They assigned 73 patients at a single medical center in Finland to follow their usual gluten-free diets but to ingest an additional 6 g (20 patients), 3 g (26 patients), or 1.5 g (27 patients) of wheat gluten with a meal once per day for the study period.

The study participants (median age, 59 years; range, 23-74 years) underwent small-bowel biopsies obtained from the descending duodenum at baseline and after the gluten challenge. Damage to the intestinal mucosa was assessed by measuring the ratio of the height of the intestinal villi to the depth of the proliferative crypts at the base of the villi (villi height to crypt depth, or Vh:Cd). In celiac disease, gluten blunts the projection of the villi and causes hypertrophy or elongation of the crypts, resulting in flattened mucosa and a Vh:Cd approaching zero.

The study participants showed a wide variation in mucosal damage from the gluten exposure, with some patients showing no change and relatively healthy mucosa, and others showing extensive change and nearly flattened mucosa. The mucosal damage did not differ by gluten dose.

The largest change in Vh:Cd occurred in three patients who transitioned from relatively healthy intestinal mucosa (Vh:Cd 3.1) at baseline to nearly flat mucosa (Vh:Cd 0.2) after gluten exposure.

Patients with undamaged gut mucosa showed a relative increase in B-cell gene expression during the study period, while those who had increasing damage showed a relative decrease in B-cell expression. “The peripheral B cell therefore tracked with oral tolerance across the full spectrum of intestinal damage, from no change to a nearly flat mucosa,” Dr. Garber and his associates said (Cell Molec Gastroenterol Hepatol. 2017. doi: 10.1016/j.jcmgh.2017.01.011).

“The net increase in B-cell gene expression from baseline to 6 weeks in patients with little to no intestinal damage [suggests] that these individuals may have mounted a B-cell immune response to maintain mucosal homeostasis and circumvent inflammation,” they added.

Further study is needed to determine whether peripheral B cells are a marker that indicates tolerance to gluten but doesn’t play a functional role in the inflammatory process, or whether B cells may actually promote immune tolerance, the investigators said.

This study was funded by Alvine Pharmaceuticals, the American Recovery and Reinvestment Act, Tampere (Finland) University Hospital, the Academy of Finland Research Council for Health, and the U.S. National Institutes of Health. Dr. Garber reported ties to Alvine Pharmaceuticals, and his associates reported ties to ImmusanT, Celimmune, and ImmunogenX.

B-cell gene expression in the peripheral blood strongly correlates with the extent of gluten-induced damage to the intestinal mucosa in patients with celiac disease, according to a report in Cellular and Molecular Gastroenterology and Hepatology.

If this finding from a single-center cohort study is validated in other patient populations, the B-cell signature may become a useful, minimally invasive tool for diagnosing celiac disease. Eventually, if biomarkers are developed from the peripheral B-cell signature, a simple blood test could be used for monitoring changes in gut inflammation over time as well as treatment response, said Mitchell E. Garber, PhD, of Alvine Pharmaceuticals, San Carlos, Calif., and the department of chemistry at Stanford University, and his associates.

However, it would be “premature but intriguing” to speculate about using this discovery to devise new, B cell–centered treatments for celiac disease, they added.

Noting that an inflammatory, gluten-induced immune response in the gut can be reflected in the peripheral blood, the investigators assessed whether a 6-week gluten challenge would induce damage to the small intestine that would show up in B-cell gene expression detected in blood samples. They assigned 73 patients at a single medical center in Finland to follow their usual gluten-free diets but to ingest an additional 6 g (20 patients), 3 g (26 patients), or 1.5 g (27 patients) of wheat gluten with a meal once per day for the study period.

The study participants (median age, 59 years; range, 23-74 years) underwent small-bowel biopsies obtained from the descending duodenum at baseline and after the gluten challenge. Damage to the intestinal mucosa was assessed by measuring the ratio of the height of the intestinal villi to the depth of the proliferative crypts at the base of the villi (villi height to crypt depth, or Vh:Cd). In celiac disease, gluten blunts the projection of the villi and causes hypertrophy or elongation of the crypts, resulting in flattened mucosa and a Vh:Cd approaching zero.

The study participants showed a wide variation in mucosal damage from the gluten exposure, with some patients showing no change and relatively healthy mucosa, and others showing extensive change and nearly flattened mucosa. The mucosal damage did not differ by gluten dose.

The largest change in Vh:Cd occurred in three patients who transitioned from relatively healthy intestinal mucosa (Vh:Cd 3.1) at baseline to nearly flat mucosa (Vh:Cd 0.2) after gluten exposure.

Patients with undamaged gut mucosa showed a relative increase in B-cell gene expression during the study period, while those who had increasing damage showed a relative decrease in B-cell expression. “The peripheral B cell therefore tracked with oral tolerance across the full spectrum of intestinal damage, from no change to a nearly flat mucosa,” Dr. Garber and his associates said (Cell Molec Gastroenterol Hepatol. 2017. doi: 10.1016/j.jcmgh.2017.01.011).

“The net increase in B-cell gene expression from baseline to 6 weeks in patients with little to no intestinal damage [suggests] that these individuals may have mounted a B-cell immune response to maintain mucosal homeostasis and circumvent inflammation,” they added.

Further study is needed to determine whether peripheral B cells are a marker that indicates tolerance to gluten but doesn’t play a functional role in the inflammatory process, or whether B cells may actually promote immune tolerance, the investigators said.

This study was funded by Alvine Pharmaceuticals, the American Recovery and Reinvestment Act, Tampere (Finland) University Hospital, the Academy of Finland Research Council for Health, and the U.S. National Institutes of Health. Dr. Garber reported ties to Alvine Pharmaceuticals, and his associates reported ties to ImmusanT, Celimmune, and ImmunogenX.

HOUSTON – Most nongrafted, moderately stenosed coronary arteries progress to severe stenosis or occlusion in the long term, results from a large, long-term study have shown.

“Not uncommonly, patients referred for coronary surgery have one or more coronary arteries with only moderate stenosis,” Joseph F. Sabik III, MD, said at the annual meeting of the Society of Thoracic Surgeons.

“There is controversy as to whether arteries with only moderate stenosis should be grafted during coronary surgery, and if it should be grafted, with what conduit?” For example, the Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease study, known as FAME, suggests not intervening on moderate stenosis, since stenting non–ischemia-producing lesions led to worse outcomes (N Engl J Med. 2012 Sep 13;367:991-1001). However, Dr. Sabik, who chairs the department of surgery at University Hospitals Cleveland Medical Center, and his associates recently reported that grafting moderately stenosed coronary arteries during surgical revascularization is not harmful and can be beneficial by improving survival if an internal thoracic artery graft is used (J. Thoracic Cardiovasc Surg. 2016 Mar;151[3]:806-11).

In an effort to determine how grafting moderately stenosed coronary arteries influences native-vessel disease progression, and whether grafting may be protective from late ischemia, Dr. Sabik and his associates evaluated the medical records of 55,567 patients who underwent primary isolated coronary artery bypass graft (CABG) surgery at the Cleveland Clinic from 1972 to 2011. Of the 55,567 patients, 1,902 had a single coronary artery with angiographically moderate stenosis (defined as a narrowing of 50%-69%) and results of at least one postoperative angiogram available. Of these moderately stenosed coronary arteries (MSCAs), 488 were not grafted, 385 were internal thoracic artery (ITA)–grafted, and 1,028 were saphenous vein (SV)–grafted. At follow-up angiograms, information about disease progression was available for 488 nongrafted, 371 ITA-grafted, and 957 SV-grafted MSCAs, and patency information was available for 376 ITA and 1,016 SV grafts to these MSCAs. Grafts were considered patent if they were not occluded. Severe occlusion was defined as a narrowing of more than 70%.

[email protected]

HOUSTON – Most nongrafted, moderately stenosed coronary arteries progress to severe stenosis or occlusion in the long term, results from a large, long-term study have shown.

“Not uncommonly, patients referred for coronary surgery have one or more coronary arteries with only moderate stenosis,” Joseph F. Sabik III, MD, said at the annual meeting of the Society of Thoracic Surgeons.

“There is controversy as to whether arteries with only moderate stenosis should be grafted during coronary surgery, and if it should be grafted, with what conduit?” For example, the Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease study, known as FAME, suggests not intervening on moderate stenosis, since stenting non–ischemia-producing lesions led to worse outcomes (N Engl J Med. 2012 Sep 13;367:991-1001). However, Dr. Sabik, who chairs the department of surgery at University Hospitals Cleveland Medical Center, and his associates recently reported that grafting moderately stenosed coronary arteries during surgical revascularization is not harmful and can be beneficial by improving survival if an internal thoracic artery graft is used (J. Thoracic Cardiovasc Surg. 2016 Mar;151[3]:806-11).

In an effort to determine how grafting moderately stenosed coronary arteries influences native-vessel disease progression, and whether grafting may be protective from late ischemia, Dr. Sabik and his associates evaluated the medical records of 55,567 patients who underwent primary isolated coronary artery bypass graft (CABG) surgery at the Cleveland Clinic from 1972 to 2011. Of the 55,567 patients, 1,902 had a single coronary artery with angiographically moderate stenosis (defined as a narrowing of 50%-69%) and results of at least one postoperative angiogram available. Of these moderately stenosed coronary arteries (MSCAs), 488 were not grafted, 385 were internal thoracic artery (ITA)–grafted, and 1,028 were saphenous vein (SV)–grafted. At follow-up angiograms, information about disease progression was available for 488 nongrafted, 371 ITA-grafted, and 957 SV-grafted MSCAs, and patency information was available for 376 ITA and 1,016 SV grafts to these MSCAs. Grafts were considered patent if they were not occluded. Severe occlusion was defined as a narrowing of more than 70%.

[email protected]

HOUSTON – Most nongrafted, moderately stenosed coronary arteries progress to severe stenosis or occlusion in the long term, results from a large, long-term study have shown.

“Not uncommonly, patients referred for coronary surgery have one or more coronary arteries with only moderate stenosis,” Joseph F. Sabik III, MD, said at the annual meeting of the Society of Thoracic Surgeons.

“There is controversy as to whether arteries with only moderate stenosis should be grafted during coronary surgery, and if it should be grafted, with what conduit?” For example, the Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease study, known as FAME, suggests not intervening on moderate stenosis, since stenting non–ischemia-producing lesions led to worse outcomes (N Engl J Med. 2012 Sep 13;367:991-1001). However, Dr. Sabik, who chairs the department of surgery at University Hospitals Cleveland Medical Center, and his associates recently reported that grafting moderately stenosed coronary arteries during surgical revascularization is not harmful and can be beneficial by improving survival if an internal thoracic artery graft is used (J. Thoracic Cardiovasc Surg. 2016 Mar;151[3]:806-11).

In an effort to determine how grafting moderately stenosed coronary arteries influences native-vessel disease progression, and whether grafting may be protective from late ischemia, Dr. Sabik and his associates evaluated the medical records of 55,567 patients who underwent primary isolated coronary artery bypass graft (CABG) surgery at the Cleveland Clinic from 1972 to 2011. Of the 55,567 patients, 1,902 had a single coronary artery with angiographically moderate stenosis (defined as a narrowing of 50%-69%) and results of at least one postoperative angiogram available. Of these moderately stenosed coronary arteries (MSCAs), 488 were not grafted, 385 were internal thoracic artery (ITA)–grafted, and 1,028 were saphenous vein (SV)–grafted. At follow-up angiograms, information about disease progression was available for 488 nongrafted, 371 ITA-grafted, and 957 SV-grafted MSCAs, and patency information was available for 376 ITA and 1,016 SV grafts to these MSCAs. Grafts were considered patent if they were not occluded. Severe occlusion was defined as a narrowing of more than 70%.

[email protected]

AMSTERDAM – Among patients with advanced renal cell carcinoma (RCC) with metastases to bone, cabozantinib (Cabometyx) was associated with better survival compared with everolimus (Afinitor), according to a subanalysis of data from the METEOR trial.

After 2 years of follow-up, median progression-free survival (PFS), overall survival (OS), and objective response rates (ORR) were significantly better for patients with bone metastases who received cabozantinib compared with those who received everolimus, reported Sergio Bracarda, MD, of Presidio Ospedaliero San Donato, Italy, and his colleagues.

“Cabozantinib is a new treatment option for previously-treated patients with advanced RCC with benefits that are maintained in patients with bone metastases,” they wrote in a poster presented at an annual congress sponsored by the European Cancer Organisation.

Previous studies have shown that patients with advanced RCC with bone metastases have generally poor prognosis compared with patients without bone metastases, the authors noted.

As previously reported, the METEOR trial, a randomized phase III study of 658 patients with advanced RCC, showed a significant survival advantage for patients treated with cabozantinib, with a median OS of 21.4 months compared with 16.5 months for patients treated with everolimus, with a hazard ratio (HR) of 0.66 (P = .0003).

In the current sub-analysis, the investigators looked at a subgroup of 142 patients with bone metastases at baseline as seen on CT or MRI. They conducted an exploratory analysis of bone scan response among 162 patients evaluated for bone lesions at baseline by technetium bone scans, and compared the incidence of skeletal-related events (SREs) for 181 patients with a history of SREs, and 477 with no prior SREs. SREs included pathological fractures, spinal cord compression, surgery to bone, and external radiation therapy to bone.

Patients underwent CT or MRI screening every 8 weeks for the first 12 months post randomization, then every 12 weeks thereafter. All patients were screened with technetium bone scans every 18 weeks for the first years, and those patients with bone lesions at baseline were followed with additional scans every 24 weeks.

The authors also looked at serum bone biomarkers, including bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type 1 collagen (P1NP), and C-terminal cross-linked telopeptides of type I collagen.

The median PFS for patients with bone metastases treated with cabozantinib was 7.4 months, compared with 2.7 months for everolimus (HR 0.33, 95% confidence interval [CI] 0.21-0.51). For patients with both bone and visceral metastasis, median PFS was 5.6 months vs. 1.9 months, respectively (HR 0.26, 95% CI, 0.16-0.43).

Median OS for the cabozantinib group was 20.1 months compared with 12.1 months for everolimus (HR 0.54, 95% CI, 0.34-0.84) for patients with bone metastases alone. For patients with both bone and visceral metastases, median OS was 20.1 months with cabozantinib, and 10.7 months with everolimus (HR 0.45, 95% CI, 0.28-0.72).

The ORR with cabozantinib as rated by an independent radiology committee was 17% for patients with bone metastases alone, and 20% for patients with bone and visceral metastases. In contrast, there were no objective responses seen in patients treated with everolimus.

Bone scan responses, defined as a 30% or greater decrease from baseline in bone scan lesion area, were seen in 18% of patients on cabozantinib vs. 10% with everolimus (significance not shown).

Among patients with a history of SREs, 22% had an SRE on cabozantinib, compared with 31% on everolimus. Respective rates among patients without a prior history of SREs were 27% and 15%. At least one SRE occurred in 12% (cabo) and 14% (eve) of patients, including four (cabo) and eight (eve) cases of spinal cord compression. For patients with a history of SREs at randomization, the incidence of postrandomization SREs was 16% (cabo) and 34% (eve) and included zero (cabo) and five (eve) cases of spinal cord compression. Reductions in the bone markers P1NP and CTx were greater with cabo vs. eve. The most common adverse events in patients with bone metastases were consistent with those observed in the overall study population.

The investigators noted that “the safety profile of cabozantinib in the bone metastases subgroup was consistent with the safety profile in the overall population.”

Dr. Bracarda has served as a consultant to Exelixis, which supported the trial and subanalysis. Two coauthors are employees of the company.

AMSTERDAM – Among patients with advanced renal cell carcinoma (RCC) with metastases to bone, cabozantinib (Cabometyx) was associated with better survival compared with everolimus (Afinitor), according to a subanalysis of data from the METEOR trial.

After 2 years of follow-up, median progression-free survival (PFS), overall survival (OS), and objective response rates (ORR) were significantly better for patients with bone metastases who received cabozantinib compared with those who received everolimus, reported Sergio Bracarda, MD, of Presidio Ospedaliero San Donato, Italy, and his colleagues.

“Cabozantinib is a new treatment option for previously-treated patients with advanced RCC with benefits that are maintained in patients with bone metastases,” they wrote in a poster presented at an annual congress sponsored by the European Cancer Organisation.

Previous studies have shown that patients with advanced RCC with bone metastases have generally poor prognosis compared with patients without bone metastases, the authors noted.

As previously reported, the METEOR trial, a randomized phase III study of 658 patients with advanced RCC, showed a significant survival advantage for patients treated with cabozantinib, with a median OS of 21.4 months compared with 16.5 months for patients treated with everolimus, with a hazard ratio (HR) of 0.66 (P = .0003).

In the current sub-analysis, the investigators looked at a subgroup of 142 patients with bone metastases at baseline as seen on CT or MRI. They conducted an exploratory analysis of bone scan response among 162 patients evaluated for bone lesions at baseline by technetium bone scans, and compared the incidence of skeletal-related events (SREs) for 181 patients with a history of SREs, and 477 with no prior SREs. SREs included pathological fractures, spinal cord compression, surgery to bone, and external radiation therapy to bone.

Patients underwent CT or MRI screening every 8 weeks for the first 12 months post randomization, then every 12 weeks thereafter. All patients were screened with technetium bone scans every 18 weeks for the first years, and those patients with bone lesions at baseline were followed with additional scans every 24 weeks.

The authors also looked at serum bone biomarkers, including bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type 1 collagen (P1NP), and C-terminal cross-linked telopeptides of type I collagen.

The median PFS for patients with bone metastases treated with cabozantinib was 7.4 months, compared with 2.7 months for everolimus (HR 0.33, 95% confidence interval [CI] 0.21-0.51). For patients with both bone and visceral metastasis, median PFS was 5.6 months vs. 1.9 months, respectively (HR 0.26, 95% CI, 0.16-0.43).

Median OS for the cabozantinib group was 20.1 months compared with 12.1 months for everolimus (HR 0.54, 95% CI, 0.34-0.84) for patients with bone metastases alone. For patients with both bone and visceral metastases, median OS was 20.1 months with cabozantinib, and 10.7 months with everolimus (HR 0.45, 95% CI, 0.28-0.72).

The ORR with cabozantinib as rated by an independent radiology committee was 17% for patients with bone metastases alone, and 20% for patients with bone and visceral metastases. In contrast, there were no objective responses seen in patients treated with everolimus.

Bone scan responses, defined as a 30% or greater decrease from baseline in bone scan lesion area, were seen in 18% of patients on cabozantinib vs. 10% with everolimus (significance not shown).

Among patients with a history of SREs, 22% had an SRE on cabozantinib, compared with 31% on everolimus. Respective rates among patients without a prior history of SREs were 27% and 15%. At least one SRE occurred in 12% (cabo) and 14% (eve) of patients, including four (cabo) and eight (eve) cases of spinal cord compression. For patients with a history of SREs at randomization, the incidence of postrandomization SREs was 16% (cabo) and 34% (eve) and included zero (cabo) and five (eve) cases of spinal cord compression. Reductions in the bone markers P1NP and CTx were greater with cabo vs. eve. The most common adverse events in patients with bone metastases were consistent with those observed in the overall study population.

The investigators noted that “the safety profile of cabozantinib in the bone metastases subgroup was consistent with the safety profile in the overall population.”

Dr. Bracarda has served as a consultant to Exelixis, which supported the trial and subanalysis. Two coauthors are employees of the company.

AMSTERDAM – Among patients with advanced renal cell carcinoma (RCC) with metastases to bone, cabozantinib (Cabometyx) was associated with better survival compared with everolimus (Afinitor), according to a subanalysis of data from the METEOR trial.

After 2 years of follow-up, median progression-free survival (PFS), overall survival (OS), and objective response rates (ORR) were significantly better for patients with bone metastases who received cabozantinib compared with those who received everolimus, reported Sergio Bracarda, MD, of Presidio Ospedaliero San Donato, Italy, and his colleagues.

“Cabozantinib is a new treatment option for previously-treated patients with advanced RCC with benefits that are maintained in patients with bone metastases,” they wrote in a poster presented at an annual congress sponsored by the European Cancer Organisation.

Previous studies have shown that patients with advanced RCC with bone metastases have generally poor prognosis compared with patients without bone metastases, the authors noted.

As previously reported, the METEOR trial, a randomized phase III study of 658 patients with advanced RCC, showed a significant survival advantage for patients treated with cabozantinib, with a median OS of 21.4 months compared with 16.5 months for patients treated with everolimus, with a hazard ratio (HR) of 0.66 (P = .0003).

In the current sub-analysis, the investigators looked at a subgroup of 142 patients with bone metastases at baseline as seen on CT or MRI. They conducted an exploratory analysis of bone scan response among 162 patients evaluated for bone lesions at baseline by technetium bone scans, and compared the incidence of skeletal-related events (SREs) for 181 patients with a history of SREs, and 477 with no prior SREs. SREs included pathological fractures, spinal cord compression, surgery to bone, and external radiation therapy to bone.

Patients underwent CT or MRI screening every 8 weeks for the first 12 months post randomization, then every 12 weeks thereafter. All patients were screened with technetium bone scans every 18 weeks for the first years, and those patients with bone lesions at baseline were followed with additional scans every 24 weeks.

The authors also looked at serum bone biomarkers, including bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type 1 collagen (P1NP), and C-terminal cross-linked telopeptides of type I collagen.

The median PFS for patients with bone metastases treated with cabozantinib was 7.4 months, compared with 2.7 months for everolimus (HR 0.33, 95% confidence interval [CI] 0.21-0.51). For patients with both bone and visceral metastasis, median PFS was 5.6 months vs. 1.9 months, respectively (HR 0.26, 95% CI, 0.16-0.43).

Median OS for the cabozantinib group was 20.1 months compared with 12.1 months for everolimus (HR 0.54, 95% CI, 0.34-0.84) for patients with bone metastases alone. For patients with both bone and visceral metastases, median OS was 20.1 months with cabozantinib, and 10.7 months with everolimus (HR 0.45, 95% CI, 0.28-0.72).

The ORR with cabozantinib as rated by an independent radiology committee was 17% for patients with bone metastases alone, and 20% for patients with bone and visceral metastases. In contrast, there were no objective responses seen in patients treated with everolimus.

Bone scan responses, defined as a 30% or greater decrease from baseline in bone scan lesion area, were seen in 18% of patients on cabozantinib vs. 10% with everolimus (significance not shown).

Among patients with a history of SREs, 22% had an SRE on cabozantinib, compared with 31% on everolimus. Respective rates among patients without a prior history of SREs were 27% and 15%. At least one SRE occurred in 12% (cabo) and 14% (eve) of patients, including four (cabo) and eight (eve) cases of spinal cord compression. For patients with a history of SREs at randomization, the incidence of postrandomization SREs was 16% (cabo) and 34% (eve) and included zero (cabo) and five (eve) cases of spinal cord compression. Reductions in the bone markers P1NP and CTx were greater with cabo vs. eve. The most common adverse events in patients with bone metastases were consistent with those observed in the overall study population.

The investigators noted that “the safety profile of cabozantinib in the bone metastases subgroup was consistent with the safety profile in the overall population.”

Dr. Bracarda has served as a consultant to Exelixis, which supported the trial and subanalysis. Two coauthors are employees of the company.

Scientist at a computer
Photo by Darren Baker

Researchers say they have developed the first computer machine-learning model to accurately predict which patients diagnosed with acute

myeloid leukemia (AML) will go into remission after treatment and which will relapse.

“It’s pretty straightforward to teach a computer to recognize AML, once you develop a robust algorithm, and, in previous work, we did it with almost 100% accuracy,” said study author Murat Dundar, PhD of Indiana University-Purdue University Indianapolis.

“What was challenging was to go beyond that work and teach the computer to accurately predict the direction of change in disease progression in AML patients, interpreting new data to predict the unknown: which new AML patients will go into remission and which will relapse.”

Dr Dundar and his colleagues described this work in IEEE Transactions on Biomedical Engineering.

The researchers said they modeled data from multiple flow cytometry samples to identify functionally distinct cell populations and their local realizations. Each sample was characterized by the proportions of recovered cell populations, which were used to predict the direction of change in disease progression for each AML patient.

“As the input, our computational system employs data from flow cytometry, a widely utilized technology that can rapidly provide detailed characteristics of single cells in samples such as blood or bone marrow,” explained study author Bartek Rajwa, PhD, of Purdue University in Lafayette, Indiana.

“Traditionally, the results of flow cytometry analyses are evaluated by highly trained human experts rather than by machine-learning algorithms. But computers are often better at extracting knowledge from complex data than humans are.”

The researchers used 200 diseased and non-diseased immunophenotypic panels for training and tested
the computational system with samples collected at multiple time points from 36 additional AML patients.

The system was able to predict remission with 100% accuracy (26 of 26 cases) and relapse with 90% accuracy (9 of 10 cases).

“Machine learning is not about modeling data,” Dr Dundar noted. “It’s about extracting knowledge from the data you have so you can build a powerful, intuitive tool that can make predictions about future data that the computer has not previously seen. The machine is learning, not memorizing, and that’s what we did.”

Scientist at a computer
Photo by Darren Baker

Researchers say they have developed the first computer machine-learning model to accurately predict which patients diagnosed with acute

myeloid leukemia (AML) will go into remission after treatment and which will relapse.

“It’s pretty straightforward to teach a computer to recognize AML, once you develop a robust algorithm, and, in previous work, we did it with almost 100% accuracy,” said study author Murat Dundar, PhD of Indiana University-Purdue University Indianapolis.

“What was challenging was to go beyond that work and teach the computer to accurately predict the direction of change in disease progression in AML patients, interpreting new data to predict the unknown: which new AML patients will go into remission and which will relapse.”

Dr Dundar and his colleagues described this work in IEEE Transactions on Biomedical Engineering.

The researchers said they modeled data from multiple flow cytometry samples to identify functionally distinct cell populations and their local realizations. Each sample was characterized by the proportions of recovered cell populations, which were used to predict the direction of change in disease progression for each AML patient.

“As the input, our computational system employs data from flow cytometry, a widely utilized technology that can rapidly provide detailed characteristics of single cells in samples such as blood or bone marrow,” explained study author Bartek Rajwa, PhD, of Purdue University in Lafayette, Indiana.

“Traditionally, the results of flow cytometry analyses are evaluated by highly trained human experts rather than by machine-learning algorithms. But computers are often better at extracting knowledge from complex data than humans are.”

The researchers used 200 diseased and non-diseased immunophenotypic panels for training and tested
the computational system with samples collected at multiple time points from 36 additional AML patients.

The system was able to predict remission with 100% accuracy (26 of 26 cases) and relapse with 90% accuracy (9 of 10 cases).

“Machine learning is not about modeling data,” Dr Dundar noted. “It’s about extracting knowledge from the data you have so you can build a powerful, intuitive tool that can make predictions about future data that the computer has not previously seen. The machine is learning, not memorizing, and that’s what we did.”

Scientist at a computer
Photo by Darren Baker

Researchers say they have developed the first computer machine-learning model to accurately predict which patients diagnosed with acute

myeloid leukemia (AML) will go into remission after treatment and which will relapse.

“It’s pretty straightforward to teach a computer to recognize AML, once you develop a robust algorithm, and, in previous work, we did it with almost 100% accuracy,” said study author Murat Dundar, PhD of Indiana University-Purdue University Indianapolis.

“What was challenging was to go beyond that work and teach the computer to accurately predict the direction of change in disease progression in AML patients, interpreting new data to predict the unknown: which new AML patients will go into remission and which will relapse.”

Dr Dundar and his colleagues described this work in IEEE Transactions on Biomedical Engineering.

The researchers said they modeled data from multiple flow cytometry samples to identify functionally distinct cell populations and their local realizations. Each sample was characterized by the proportions of recovered cell populations, which were used to predict the direction of change in disease progression for each AML patient.

“As the input, our computational system employs data from flow cytometry, a widely utilized technology that can rapidly provide detailed characteristics of single cells in samples such as blood or bone marrow,” explained study author Bartek Rajwa, PhD, of Purdue University in Lafayette, Indiana.

“Traditionally, the results of flow cytometry analyses are evaluated by highly trained human experts rather than by machine-learning algorithms. But computers are often better at extracting knowledge from complex data than humans are.”

The researchers used 200 diseased and non-diseased immunophenotypic panels for training and tested
the computational system with samples collected at multiple time points from 36 additional AML patients.

The system was able to predict remission with 100% accuracy (26 of 26 cases) and relapse with 90% accuracy (9 of 10 cases).

“Machine learning is not about modeling data,” Dr Dundar noted. “It’s about extracting knowledge from the data you have so you can build a powerful, intuitive tool that can make predictions about future data that the computer has not previously seen. The machine is learning, not memorizing, and that’s what we did.”

Micrograph showing MDS

Genetic profiling can be used to determine which patients with myelodysplastic syndrome (MDS) are likely to benefit from allogeneic hematopoietic stem cell transplant (HSCT), according to research published in NEJM.

Targeted sequencing of 129 genes revealed mutations that, after adjustment for clinical variables, were associated with shorter survival and/or relapse after HSCT.

Patients with mutations in TP53, JAK2, and the RAS pathway tended to have worse outcomes after HSCT than patients without such mutations.

“Although donor stem cell transplantation is the only curative therapy for MDS, many patients die after transplantation, largely due to relapse of the disease or complications relating to the transplant itself,” said study author R. Coleman Lindsley, MD, PhD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“As physicians, one of our major challenges is to be able to predict which patients are most likely to benefit from a transplant. Improving our ability to identify patients who are most likely to have a relapse or to experience life-threatening complications from a transplant could lead to better pre-transplant therapies and strategies for preventing relapse.”

Researchers have long known that specific genetic mutations are closely related to the course MDS takes. With this study, Dr Lindsley and his colleagues sought to discover whether mutations can be used to predict how patients will fare following allogeneic HSCT.

The team analyzed blood samples from 1514 MDS patients, performing targeted sequencing of 129 genes. The genes were selected based on their known or suspected involvement in the pathogenesis of myeloid cancers or bone marrow failure syndromes.

Dr Lindsley and his colleagues then evaluated the association between mutations and HSCT outcomes, including overall survival, relapse, and death without relapse.

After adjusting for significant clinical variables, the researchers found that having mutated TP53 was significantly associated with shorter survival and shorter time to relapse after HSCT (P<0.001 for both comparisons). This was true whether patients received standard conditioning or reduced-intensity conditioning.

In patients age 40 and older who did not have TP53 mutations, mutations in RAS pathway genes (P=0.004) or JAK2 (P=0.001) were significantly associated with shorter survival.

The shorter survival in patients with mutated RAS pathway genes was due to a higher risk of relapse, while the shorter survival in patients with JAK2 mutations was due to a higher risk of death without relapse.

In contrast to TP53 mutations, the adverse effect of RAS mutations on survival and risk of relapse was evident only in patients who received reduced-intensity conditioning (P<0.001). This suggests these patients may benefit from higher intensity conditioning regimens, the researchers said.

This study also yielded insights about the biology of MDS in specific groups of patients.

For example, the researchers found that 4% of MDS patients between the ages of 18 and 40 had mutations associated with Shwachman-Diamond syndrome (in the SBDS gene), but most of them had not previously been diagnosed with the syndrome.

In each case, the patients had acquired a TP53 mutation, suggesting not only how MDS develops in patients with Schwachman-Diamond syndrome but also what underlies their poor prognosis after HSCT.

The researchers also analyzed patients with therapy-related MDS. The team found that TP53 mutations and mutations in PPM1D, a gene that regulates TP53 function, were far more common in these patients than in those with primary MDS (15% and 3%, respectively, P<0.001).

“In deciding whether a stem cell transplant is appropriate for a patient with MDS, it’s always necessary to balance the potential benefit with the risk of complications,” Dr Lindsley noted.

“Our findings offer physicians a guide—based on the genetic profile of the disease and certain clinical factors—to identifying patients for whom a transplant is appropriate, and the intensity of treatment most likely to be effective.”

Micrograph showing MDS

Genetic profiling can be used to determine which patients with myelodysplastic syndrome (MDS) are likely to benefit from allogeneic hematopoietic stem cell transplant (HSCT), according to research published in NEJM.

Targeted sequencing of 129 genes revealed mutations that, after adjustment for clinical variables, were associated with shorter survival and/or relapse after HSCT.

Patients with mutations in TP53, JAK2, and the RAS pathway tended to have worse outcomes after HSCT than patients without such mutations.

“Although donor stem cell transplantation is the only curative therapy for MDS, many patients die after transplantation, largely due to relapse of the disease or complications relating to the transplant itself,” said study author R. Coleman Lindsley, MD, PhD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“As physicians, one of our major challenges is to be able to predict which patients are most likely to benefit from a transplant. Improving our ability to identify patients who are most likely to have a relapse or to experience life-threatening complications from a transplant could lead to better pre-transplant therapies and strategies for preventing relapse.”

Researchers have long known that specific genetic mutations are closely related to the course MDS takes. With this study, Dr Lindsley and his colleagues sought to discover whether mutations can be used to predict how patients will fare following allogeneic HSCT.

The team analyzed blood samples from 1514 MDS patients, performing targeted sequencing of 129 genes. The genes were selected based on their known or suspected involvement in the pathogenesis of myeloid cancers or bone marrow failure syndromes.

Dr Lindsley and his colleagues then evaluated the association between mutations and HSCT outcomes, including overall survival, relapse, and death without relapse.

After adjusting for significant clinical variables, the researchers found that having mutated TP53 was significantly associated with shorter survival and shorter time to relapse after HSCT (P<0.001 for both comparisons). This was true whether patients received standard conditioning or reduced-intensity conditioning.

In patients age 40 and older who did not have TP53 mutations, mutations in RAS pathway genes (P=0.004) or JAK2 (P=0.001) were significantly associated with shorter survival.

The shorter survival in patients with mutated RAS pathway genes was due to a higher risk of relapse, while the shorter survival in patients with JAK2 mutations was due to a higher risk of death without relapse.

In contrast to TP53 mutations, the adverse effect of RAS mutations on survival and risk of relapse was evident only in patients who received reduced-intensity conditioning (P<0.001). This suggests these patients may benefit from higher intensity conditioning regimens, the researchers said.

This study also yielded insights about the biology of MDS in specific groups of patients.

For example, the researchers found that 4% of MDS patients between the ages of 18 and 40 had mutations associated with Shwachman-Diamond syndrome (in the SBDS gene), but most of them had not previously been diagnosed with the syndrome.

In each case, the patients had acquired a TP53 mutation, suggesting not only how MDS develops in patients with Schwachman-Diamond syndrome but also what underlies their poor prognosis after HSCT.

The researchers also analyzed patients with therapy-related MDS. The team found that TP53 mutations and mutations in PPM1D, a gene that regulates TP53 function, were far more common in these patients than in those with primary MDS (15% and 3%, respectively, P<0.001).

“In deciding whether a stem cell transplant is appropriate for a patient with MDS, it’s always necessary to balance the potential benefit with the risk of complications,” Dr Lindsley noted.

“Our findings offer physicians a guide—based on the genetic profile of the disease and certain clinical factors—to identifying patients for whom a transplant is appropriate, and the intensity of treatment most likely to be effective.”

Micrograph showing MDS

Genetic profiling can be used to determine which patients with myelodysplastic syndrome (MDS) are likely to benefit from allogeneic hematopoietic stem cell transplant (HSCT), according to research published in NEJM.

Targeted sequencing of 129 genes revealed mutations that, after adjustment for clinical variables, were associated with shorter survival and/or relapse after HSCT.

Patients with mutations in TP53, JAK2, and the RAS pathway tended to have worse outcomes after HSCT than patients without such mutations.

“Although donor stem cell transplantation is the only curative therapy for MDS, many patients die after transplantation, largely due to relapse of the disease or complications relating to the transplant itself,” said study author R. Coleman Lindsley, MD, PhD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“As physicians, one of our major challenges is to be able to predict which patients are most likely to benefit from a transplant. Improving our ability to identify patients who are most likely to have a relapse or to experience life-threatening complications from a transplant could lead to better pre-transplant therapies and strategies for preventing relapse.”

Researchers have long known that specific genetic mutations are closely related to the course MDS takes. With this study, Dr Lindsley and his colleagues sought to discover whether mutations can be used to predict how patients will fare following allogeneic HSCT.

The team analyzed blood samples from 1514 MDS patients, performing targeted sequencing of 129 genes. The genes were selected based on their known or suspected involvement in the pathogenesis of myeloid cancers or bone marrow failure syndromes.

Dr Lindsley and his colleagues then evaluated the association between mutations and HSCT outcomes, including overall survival, relapse, and death without relapse.

After adjusting for significant clinical variables, the researchers found that having mutated TP53 was significantly associated with shorter survival and shorter time to relapse after HSCT (P<0.001 for both comparisons). This was true whether patients received standard conditioning or reduced-intensity conditioning.

In patients age 40 and older who did not have TP53 mutations, mutations in RAS pathway genes (P=0.004) or JAK2 (P=0.001) were significantly associated with shorter survival.

The shorter survival in patients with mutated RAS pathway genes was due to a higher risk of relapse, while the shorter survival in patients with JAK2 mutations was due to a higher risk of death without relapse.

In contrast to TP53 mutations, the adverse effect of RAS mutations on survival and risk of relapse was evident only in patients who received reduced-intensity conditioning (P<0.001). This suggests these patients may benefit from higher intensity conditioning regimens, the researchers said.

This study also yielded insights about the biology of MDS in specific groups of patients.

For example, the researchers found that 4% of MDS patients between the ages of 18 and 40 had mutations associated with Shwachman-Diamond syndrome (in the SBDS gene), but most of them had not previously been diagnosed with the syndrome.

In each case, the patients had acquired a TP53 mutation, suggesting not only how MDS develops in patients with Schwachman-Diamond syndrome but also what underlies their poor prognosis after HSCT.

The researchers also analyzed patients with therapy-related MDS. The team found that TP53 mutations and mutations in PPM1D, a gene that regulates TP53 function, were far more common in these patients than in those with primary MDS (15% and 3%, respectively, P<0.001).

“In deciding whether a stem cell transplant is appropriate for a patient with MDS, it’s always necessary to balance the potential benefit with the risk of complications,” Dr Lindsley noted.

“Our findings offer physicians a guide—based on the genetic profile of the disease and certain clinical factors—to identifying patients for whom a transplant is appropriate, and the intensity of treatment most likely to be effective.”

A biomarker algorithm can identify patients with a high risk of graft-vs-host disease (GVHD) and non-relapse mortality (NRM) after hematopoietic stem cell transplant (HSCT), according to researchers.

The team found evidence to suggest that 2 proteins—ST2 and REG3α—present in blood drawn a week after HSCT can predict the likelihood of GVHD, including lethal GVHD, and NRM in patients with hematologic disorders.

James L.M. Ferrara, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues reported these findings in JCI Insight.

The researchers analyzed blood samples collected on day 7 after HSCT from 1287 patients. Of these, 620 samples were designated the training set.

The team measured the concentrations of 4 GVHD biomarkers—ST2, REG3α, TNFR1, and IL-2Rα—in the training set and used them to model 6-month NRM in an attempt to identify the best algorithm that defined 2 distinct risk groups.

The researchers applied the resulting algorithm to the test set of samples (n=309) and the validation set of samples (n=358).

The final algorithm used ST2 and REG3α concentrations to identify patients with a high and low risk of NRM at 6 months. Sixteen percent of patients in the training set belonged to the high-risk group, as did 17% of the test set and 20% of the validation set.

In the training set, the cumulative incidence of NRM at 6 months was 28% in the high-risk group and 7% in the low-risk group (P<0.001). The incidence was 33% and 7%, respectively (P<0.001), in the test set and 26% and 10%, respectively (P<0.001), in the validation set.

The high-risk patients were 3 times more likely to die from GVHD than low-risk patients in the overall cohort. The incidence of lethal GVHD was 19% and 6%, respectively (P<0.001).

GVHD-related mortality in the high-risk and low-risk groups, respectively, was 18% and 5% (P<0.001) in the training set, 24% and 4% (P<0.001) in the test set, and 14% and 5% (P<0.001) in the validation set.

The researchers said their algorithm can also be adapted to define 3 distinct risk groups at GVHD onset—Ann Arbor scores 1, 2, and 3.

The team dubbed their algorithm the “MAGIC algorithm,” after the Mount Sinai Acute GVHD International Consortium (MAGIC).

“The MAGIC algorithm gives doctors a roadmap to save many lives in the future,” Dr Ferrara said. “This simple blood test can determine which bone marrow transplant patients are at high risk for a lethal complication before it occurs. It will allow early intervention and potentially save many lives.”

Doctors at Mount Sinai are now designing clinical trials to determine whether immunotherapy drugs would benefit patients if the MAGIC algorithm determines they are at high risk for severe GVHD.

The researchers believe that if patients receive the drugs once the blood test is administered, which is well before symptoms develop, they would be spared the full force of GVHD, and fewer of them would die. 

“This test will make bone marrow transplant safer and more effective for patients because it will guide adjustment of medications to protect against graft-vs-host disease,” said study author John Levine, MD, of the Icahn School of Medicine at Mount Sinai.

“If successful, the early use of the drugs would become a standard of care for bone marrow transplant patients.”

A biomarker algorithm can identify patients with a high risk of graft-vs-host disease (GVHD) and non-relapse mortality (NRM) after hematopoietic stem cell transplant (HSCT), according to researchers.

The team found evidence to suggest that 2 proteins—ST2 and REG3α—present in blood drawn a week after HSCT can predict the likelihood of GVHD, including lethal GVHD, and NRM in patients with hematologic disorders.

James L.M. Ferrara, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues reported these findings in JCI Insight.

The researchers analyzed blood samples collected on day 7 after HSCT from 1287 patients. Of these, 620 samples were designated the training set.

The team measured the concentrations of 4 GVHD biomarkers—ST2, REG3α, TNFR1, and IL-2Rα—in the training set and used them to model 6-month NRM in an attempt to identify the best algorithm that defined 2 distinct risk groups.

The researchers applied the resulting algorithm to the test set of samples (n=309) and the validation set of samples (n=358).

The final algorithm used ST2 and REG3α concentrations to identify patients with a high and low risk of NRM at 6 months. Sixteen percent of patients in the training set belonged to the high-risk group, as did 17% of the test set and 20% of the validation set.

In the training set, the cumulative incidence of NRM at 6 months was 28% in the high-risk group and 7% in the low-risk group (P<0.001). The incidence was 33% and 7%, respectively (P<0.001), in the test set and 26% and 10%, respectively (P<0.001), in the validation set.

The high-risk patients were 3 times more likely to die from GVHD than low-risk patients in the overall cohort. The incidence of lethal GVHD was 19% and 6%, respectively (P<0.001).

GVHD-related mortality in the high-risk and low-risk groups, respectively, was 18% and 5% (P<0.001) in the training set, 24% and 4% (P<0.001) in the test set, and 14% and 5% (P<0.001) in the validation set.

The researchers said their algorithm can also be adapted to define 3 distinct risk groups at GVHD onset—Ann Arbor scores 1, 2, and 3.

The team dubbed their algorithm the “MAGIC algorithm,” after the Mount Sinai Acute GVHD International Consortium (MAGIC).

“The MAGIC algorithm gives doctors a roadmap to save many lives in the future,” Dr Ferrara said. “This simple blood test can determine which bone marrow transplant patients are at high risk for a lethal complication before it occurs. It will allow early intervention and potentially save many lives.”

Doctors at Mount Sinai are now designing clinical trials to determine whether immunotherapy drugs would benefit patients if the MAGIC algorithm determines they are at high risk for severe GVHD.

The researchers believe that if patients receive the drugs once the blood test is administered, which is well before symptoms develop, they would be spared the full force of GVHD, and fewer of them would die. 

“This test will make bone marrow transplant safer and more effective for patients because it will guide adjustment of medications to protect against graft-vs-host disease,” said study author John Levine, MD, of the Icahn School of Medicine at Mount Sinai.

“If successful, the early use of the drugs would become a standard of care for bone marrow transplant patients.”

A biomarker algorithm can identify patients with a high risk of graft-vs-host disease (GVHD) and non-relapse mortality (NRM) after hematopoietic stem cell transplant (HSCT), according to researchers.

The team found evidence to suggest that 2 proteins—ST2 and REG3α—present in blood drawn a week after HSCT can predict the likelihood of GVHD, including lethal GVHD, and NRM in patients with hematologic disorders.

James L.M. Ferrara, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues reported these findings in JCI Insight.

The researchers analyzed blood samples collected on day 7 after HSCT from 1287 patients. Of these, 620 samples were designated the training set.

The team measured the concentrations of 4 GVHD biomarkers—ST2, REG3α, TNFR1, and IL-2Rα—in the training set and used them to model 6-month NRM in an attempt to identify the best algorithm that defined 2 distinct risk groups.

The researchers applied the resulting algorithm to the test set of samples (n=309) and the validation set of samples (n=358).

The final algorithm used ST2 and REG3α concentrations to identify patients with a high and low risk of NRM at 6 months. Sixteen percent of patients in the training set belonged to the high-risk group, as did 17% of the test set and 20% of the validation set.

In the training set, the cumulative incidence of NRM at 6 months was 28% in the high-risk group and 7% in the low-risk group (P<0.001). The incidence was 33% and 7%, respectively (P<0.001), in the test set and 26% and 10%, respectively (P<0.001), in the validation set.

The high-risk patients were 3 times more likely to die from GVHD than low-risk patients in the overall cohort. The incidence of lethal GVHD was 19% and 6%, respectively (P<0.001).

GVHD-related mortality in the high-risk and low-risk groups, respectively, was 18% and 5% (P<0.001) in the training set, 24% and 4% (P<0.001) in the test set, and 14% and 5% (P<0.001) in the validation set.

The researchers said their algorithm can also be adapted to define 3 distinct risk groups at GVHD onset—Ann Arbor scores 1, 2, and 3.

The team dubbed their algorithm the “MAGIC algorithm,” after the Mount Sinai Acute GVHD International Consortium (MAGIC).

“The MAGIC algorithm gives doctors a roadmap to save many lives in the future,” Dr Ferrara said. “This simple blood test can determine which bone marrow transplant patients are at high risk for a lethal complication before it occurs. It will allow early intervention and potentially save many lives.”

Doctors at Mount Sinai are now designing clinical trials to determine whether immunotherapy drugs would benefit patients if the MAGIC algorithm determines they are at high risk for severe GVHD.

The researchers believe that if patients receive the drugs once the blood test is administered, which is well before symptoms develop, they would be spared the full force of GVHD, and fewer of them would die. 

“This test will make bone marrow transplant safer and more effective for patients because it will guide adjustment of medications to protect against graft-vs-host disease,” said study author John Levine, MD, of the Icahn School of Medicine at Mount Sinai.

“If successful, the early use of the drugs would become a standard of care for bone marrow transplant patients.”

Colony of iPSCs
Image from Salk Institute

The use of induced pluripotent stem cells (iPSCs) in biomedical research and medicine has been slowed by concerns that these cells are prone to increased numbers of genetic mutations.

However, a new study suggests iPSCs do not develop more mutations than cells that are duplicated by subcloning, a technique where single cells are cultured individually and then grown into a cell line.

Subcloning is similar to the technique used to create iPSCs, except the subcloned cells are not treated with the reprogramming factors that have been thought to cause mutations in iPSCs.

“These findings suggest that the question of safety shouldn’t impede research using iPSCs,” said study author Paul Liu, MD, PhD, of the National Human Genome Research Institute, part of the National Institutes of Health, in Bethesda, Maryland.

Dr Liu and his colleagues reported the findings in PNAS.

For this study, the researchers examined 2 sets of donated cells. One set came from a healthy individual, and the second came from a person with familial platelet disorder.

Using fibroblasts from each of the donors, the researchers created genetically identical copies of the cells using both the iPSC and subcloning techniques.

The team then sequenced the DNA of the fibroblasts as well as the iPSCs and the subcloned cells and determined that mutations occurred at the same rate in cells that were reprogrammed and cells that were subcloned.

More than 90% of the genetic variants detected in the iPSCs and subclones were rare variants inherited from the parent cells.

This suggests that most mutations in iPSCs are not generated during the reprogramming or iPSC production phase and provides evidence that iPSCs are stable and safe to use for both basic and clinical research, Dr Liu said.

“Based on this data, we plan to start using iPSCs to gain a deeper understanding of how diseases start and progress,” said study author Erika Mijin Kwon, PhD, also of the National Human Genome Research Institute.

“We eventually hope to develop new therapies to treat patients with leukemia using their own iPSCs. We encourage other researchers to embrace the use of iPSCs.”

Colony of iPSCs
Image from Salk Institute

The use of induced pluripotent stem cells (iPSCs) in biomedical research and medicine has been slowed by concerns that these cells are prone to increased numbers of genetic mutations.

However, a new study suggests iPSCs do not develop more mutations than cells that are duplicated by subcloning, a technique where single cells are cultured individually and then grown into a cell line.

Subcloning is similar to the technique used to create iPSCs, except the subcloned cells are not treated with the reprogramming factors that have been thought to cause mutations in iPSCs.

“These findings suggest that the question of safety shouldn’t impede research using iPSCs,” said study author Paul Liu, MD, PhD, of the National Human Genome Research Institute, part of the National Institutes of Health, in Bethesda, Maryland.

Dr Liu and his colleagues reported the findings in PNAS.

For this study, the researchers examined 2 sets of donated cells. One set came from a healthy individual, and the second came from a person with familial platelet disorder.

Using fibroblasts from each of the donors, the researchers created genetically identical copies of the cells using both the iPSC and subcloning techniques.

The team then sequenced the DNA of the fibroblasts as well as the iPSCs and the subcloned cells and determined that mutations occurred at the same rate in cells that were reprogrammed and cells that were subcloned.

More than 90% of the genetic variants detected in the iPSCs and subclones were rare variants inherited from the parent cells.

This suggests that most mutations in iPSCs are not generated during the reprogramming or iPSC production phase and provides evidence that iPSCs are stable and safe to use for both basic and clinical research, Dr Liu said.

“Based on this data, we plan to start using iPSCs to gain a deeper understanding of how diseases start and progress,” said study author Erika Mijin Kwon, PhD, also of the National Human Genome Research Institute.

“We eventually hope to develop new therapies to treat patients with leukemia using their own iPSCs. We encourage other researchers to embrace the use of iPSCs.”

Colony of iPSCs
Image from Salk Institute

The use of induced pluripotent stem cells (iPSCs) in biomedical research and medicine has been slowed by concerns that these cells are prone to increased numbers of genetic mutations.

However, a new study suggests iPSCs do not develop more mutations than cells that are duplicated by subcloning, a technique where single cells are cultured individually and then grown into a cell line.

Subcloning is similar to the technique used to create iPSCs, except the subcloned cells are not treated with the reprogramming factors that have been thought to cause mutations in iPSCs.

“These findings suggest that the question of safety shouldn’t impede research using iPSCs,” said study author Paul Liu, MD, PhD, of the National Human Genome Research Institute, part of the National Institutes of Health, in Bethesda, Maryland.

Dr Liu and his colleagues reported the findings in PNAS.

For this study, the researchers examined 2 sets of donated cells. One set came from a healthy individual, and the second came from a person with familial platelet disorder.

Using fibroblasts from each of the donors, the researchers created genetically identical copies of the cells using both the iPSC and subcloning techniques.

The team then sequenced the DNA of the fibroblasts as well as the iPSCs and the subcloned cells and determined that mutations occurred at the same rate in cells that were reprogrammed and cells that were subcloned.

More than 90% of the genetic variants detected in the iPSCs and subclones were rare variants inherited from the parent cells.

This suggests that most mutations in iPSCs are not generated during the reprogramming or iPSC production phase and provides evidence that iPSCs are stable and safe to use for both basic and clinical research, Dr Liu said.

“Based on this data, we plan to start using iPSCs to gain a deeper understanding of how diseases start and progress,” said study author Erika Mijin Kwon, PhD, also of the National Human Genome Research Institute.

“We eventually hope to develop new therapies to treat patients with leukemia using their own iPSCs. We encourage other researchers to embrace the use of iPSCs.”

Clinical question: Is therapeutic anticoagulation superior to placebo in patients with symptomatic acute calf deep venous thrombosis (DVT)?

Background: Medical evidence supporting the usage of therapeutic anticoagulation in symptomatic acute isolated calf DVT is lacking. This type of DVT has a low embolic potential. The bleeding risk of anticoagulation might therefore be higher than its benefit.

Study design: Double-blind, placebo-controlled trial.

Setting: Twenty-three centers in Canada, France and Switzerland.

Synopsis: A total of 259 outpatients with a first acute symptomatic objectively confirmed isolated calf DVT were enrolled to receive either a therapeutic dose of the low-molecular weight heparin nadroparin (122 patients), or a placebo (130 patients).

Dr. Badr is a hospitalist at Cooper University Hospital in Camden, N.J., and an assistant professor of clinical medicine at the Cooper Medical School of Rowan University.

Clinical question: Is therapeutic anticoagulation superior to placebo in patients with symptomatic acute calf deep venous thrombosis (DVT)?

Background: Medical evidence supporting the usage of therapeutic anticoagulation in symptomatic acute isolated calf DVT is lacking. This type of DVT has a low embolic potential. The bleeding risk of anticoagulation might therefore be higher than its benefit.

Study design: Double-blind, placebo-controlled trial.

Setting: Twenty-three centers in Canada, France and Switzerland.

Synopsis: A total of 259 outpatients with a first acute symptomatic objectively confirmed isolated calf DVT were enrolled to receive either a therapeutic dose of the low-molecular weight heparin nadroparin (122 patients), or a placebo (130 patients).

Dr. Badr is a hospitalist at Cooper University Hospital in Camden, N.J., and an assistant professor of clinical medicine at the Cooper Medical School of Rowan University.

Clinical question: Is therapeutic anticoagulation superior to placebo in patients with symptomatic acute calf deep venous thrombosis (DVT)?

Background: Medical evidence supporting the usage of therapeutic anticoagulation in symptomatic acute isolated calf DVT is lacking. This type of DVT has a low embolic potential. The bleeding risk of anticoagulation might therefore be higher than its benefit.

Study design: Double-blind, placebo-controlled trial.

Setting: Twenty-three centers in Canada, France and Switzerland.

Synopsis: A total of 259 outpatients with a first acute symptomatic objectively confirmed isolated calf DVT were enrolled to receive either a therapeutic dose of the low-molecular weight heparin nadroparin (122 patients), or a placebo (130 patients).

Dr. Badr is a hospitalist at Cooper University Hospital in Camden, N.J., and an assistant professor of clinical medicine at the Cooper Medical School of Rowan University.