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Moderate stenosis in coronary arteries grows severe over time
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%.
The researchers found that at 1, 5, 10, and 15 years, native-vessel disease progressed from moderate to severe stenosis/occlusion in 32%, 52%, 66%, and 72% of nongrafted MSCAs, respectively; in 55%, 73%, 84%, and 87% of ITA-grafted MSCAs, and in 67%, 82%, 90%, and 92% of SV-grafted MSCAs. After Dr. Sabik and his associates adjusted for patient characteristics, disease progression in MSCAs was significantly higher with ITA and SV grafting, compared with nongrafting (odds ratios, 3.6 and 9.9, respectively). At 1, 5, 10, and 15 years, occlusion in grafts to MSCAs was 8%, 9%, 11%, and 15%, respectively, for ITA grafts and 13%, 32%, 46%, and 56% for SV grafts. At these same time points, protection from myocardial ischemia in ITA-grafted vs. nongrafted MSCAs was 29%, 47%, 59%, and 61%.
“Our opinion is you that shouldn’t ignore moderate lesions,” Dr. Sabik, surgeon-in-chief and vice president for surgical operations for the University Hospitals system, said in an interview at the meeting. “Although it may not help that patient over the next short period of time, over their lifespan it will. What works for intervention doesn’t necessarily mean it’s right for bypass surgery. If you have a vessel that’s only moderately stenosed you should at least consider grafting it, because moderate lesions progress over time. Bypassing it helps people live longer when you use an internal thoracic artery graft, because they are likely to remain patent. You always have to individualize the therapy, but the key is to use your grafts in the best way possible.”
Dr. Sabik disclosed that he has received research grants from Medtronic, Abbott Vascular, and Edwards Lifesciences.
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%.
The researchers found that at 1, 5, 10, and 15 years, native-vessel disease progressed from moderate to severe stenosis/occlusion in 32%, 52%, 66%, and 72% of nongrafted MSCAs, respectively; in 55%, 73%, 84%, and 87% of ITA-grafted MSCAs, and in 67%, 82%, 90%, and 92% of SV-grafted MSCAs. After Dr. Sabik and his associates adjusted for patient characteristics, disease progression in MSCAs was significantly higher with ITA and SV grafting, compared with nongrafting (odds ratios, 3.6 and 9.9, respectively). At 1, 5, 10, and 15 years, occlusion in grafts to MSCAs was 8%, 9%, 11%, and 15%, respectively, for ITA grafts and 13%, 32%, 46%, and 56% for SV grafts. At these same time points, protection from myocardial ischemia in ITA-grafted vs. nongrafted MSCAs was 29%, 47%, 59%, and 61%.
“Our opinion is you that shouldn’t ignore moderate lesions,” Dr. Sabik, surgeon-in-chief and vice president for surgical operations for the University Hospitals system, said in an interview at the meeting. “Although it may not help that patient over the next short period of time, over their lifespan it will. What works for intervention doesn’t necessarily mean it’s right for bypass surgery. If you have a vessel that’s only moderately stenosed you should at least consider grafting it, because moderate lesions progress over time. Bypassing it helps people live longer when you use an internal thoracic artery graft, because they are likely to remain patent. You always have to individualize the therapy, but the key is to use your grafts in the best way possible.”
Dr. Sabik disclosed that he has received research grants from Medtronic, Abbott Vascular, and Edwards Lifesciences.
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%.
The researchers found that at 1, 5, 10, and 15 years, native-vessel disease progressed from moderate to severe stenosis/occlusion in 32%, 52%, 66%, and 72% of nongrafted MSCAs, respectively; in 55%, 73%, 84%, and 87% of ITA-grafted MSCAs, and in 67%, 82%, 90%, and 92% of SV-grafted MSCAs. After Dr. Sabik and his associates adjusted for patient characteristics, disease progression in MSCAs was significantly higher with ITA and SV grafting, compared with nongrafting (odds ratios, 3.6 and 9.9, respectively). At 1, 5, 10, and 15 years, occlusion in grafts to MSCAs was 8%, 9%, 11%, and 15%, respectively, for ITA grafts and 13%, 32%, 46%, and 56% for SV grafts. At these same time points, protection from myocardial ischemia in ITA-grafted vs. nongrafted MSCAs was 29%, 47%, 59%, and 61%.
“Our opinion is you that shouldn’t ignore moderate lesions,” Dr. Sabik, surgeon-in-chief and vice president for surgical operations for the University Hospitals system, said in an interview at the meeting. “Although it may not help that patient over the next short period of time, over their lifespan it will. What works for intervention doesn’t necessarily mean it’s right for bypass surgery. If you have a vessel that’s only moderately stenosed you should at least consider grafting it, because moderate lesions progress over time. Bypassing it helps people live longer when you use an internal thoracic artery graft, because they are likely to remain patent. You always have to individualize the therapy, but the key is to use your grafts in the best way possible.”
Dr. Sabik disclosed that he has received research grants from Medtronic, Abbott Vascular, and Edwards Lifesciences.
AT THE STS ANNUAL MEETING
Key clinical point:
Major finding: At 15 years, native-vessel disease progressed from moderate to severe stenosis/occlusion in 72% of nongrafted coronary arteries, in 87% of internal thoracic artery–grafted arteries, and in 92% of saphenous vein–grafted moderately stenosed coronary arteries.
Data source: An analysis of medical records from 55,567 patients who underwent primary isolated CABG at the Cleveland Clinic from 1972 to 2011.
Disclosures: Dr. Sabik disclosed that he has received research grants from Medtronic, Abbott Vascular, and Edwards Lifesciences.
Cabozantinib versus everolimus in advanced RCC with bone mets
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.
AT ECCO2017
Key clinical point: Survival among patients with advanced renal cell carcinoma metastatic to bone was better with cabozantinib than everolimus.
Major finding: Median overall survival for the cabozantinib group was 20.1 months compared with 12.1 months for everolimus.
Data source: Subanalysis of 142 patients with bone metastases in the randomized phase III METEOR trial.
Disclosures: Dr. Bracarda has served as a consultant to Exelixis, which supported the trial and subanalysis. Two coauthors are employees of the company.
Computer predicts remission, relapse in AML
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.” 
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.”
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.”
Genetic profiling can guide HSCT in MDS, team says
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.”
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.”
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.”
Algorithm predicts NRM, GVHD after HSCT
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.”
Study shows no increased risk of mutations with 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.”
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.”
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.”
Anticoagulants: more harm than good in isolated calf DVT
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).
The primary efficacy outcome (a composite endpoint of extension of calf DVT to proximal veins, contralateral proximal DVT and symptomatic pulmonary embolism) was not statistically significant between the two groups (3% in the nadroparin group and 5% in the placebo group, P = .54). The primary safety outcome (the number of patients with major or clinically relevant non-major bleeding) was significantly higher in the nadroparin group (4% in nadroparin group, 0 patients in the placebo group, P = .0255).
The study was limited by the relative low number of patients (goal was 286 patients). The results of the study do not apply to inpatients and to cancer patients as patients with high risk for extension or recurrence of their DVT were excluded.
Bottom line: Therapeutic anticoagulation in low-risk outpatients with isolated calf DVT will likely cause more harm from bleeding than benefit.
Citation: Righini M, Galanaud J, Guenneguez H, et al. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): A randomised, double-blind, placebo-controlled trial. The Lancet Haematology. 2016;3(12):e556-e562. doi: 10.1016/S2352-3026(16)30131-4.
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).
The primary efficacy outcome (a composite endpoint of extension of calf DVT to proximal veins, contralateral proximal DVT and symptomatic pulmonary embolism) was not statistically significant between the two groups (3% in the nadroparin group and 5% in the placebo group, P = .54). The primary safety outcome (the number of patients with major or clinically relevant non-major bleeding) was significantly higher in the nadroparin group (4% in nadroparin group, 0 patients in the placebo group, P = .0255).
The study was limited by the relative low number of patients (goal was 286 patients). The results of the study do not apply to inpatients and to cancer patients as patients with high risk for extension or recurrence of their DVT were excluded.
Bottom line: Therapeutic anticoagulation in low-risk outpatients with isolated calf DVT will likely cause more harm from bleeding than benefit.
Citation: Righini M, Galanaud J, Guenneguez H, et al. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): A randomised, double-blind, placebo-controlled trial. The Lancet Haematology. 2016;3(12):e556-e562. doi: 10.1016/S2352-3026(16)30131-4.
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).
The primary efficacy outcome (a composite endpoint of extension of calf DVT to proximal veins, contralateral proximal DVT and symptomatic pulmonary embolism) was not statistically significant between the two groups (3% in the nadroparin group and 5% in the placebo group, P = .54). The primary safety outcome (the number of patients with major or clinically relevant non-major bleeding) was significantly higher in the nadroparin group (4% in nadroparin group, 0 patients in the placebo group, P = .0255).
The study was limited by the relative low number of patients (goal was 286 patients). The results of the study do not apply to inpatients and to cancer patients as patients with high risk for extension or recurrence of their DVT were excluded.
Bottom line: Therapeutic anticoagulation in low-risk outpatients with isolated calf DVT will likely cause more harm from bleeding than benefit.
Citation: Righini M, Galanaud J, Guenneguez H, et al. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): A randomised, double-blind, placebo-controlled trial. The Lancet Haematology. 2016;3(12):e556-e562. doi: 10.1016/S2352-3026(16)30131-4.
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.
The cost of misdiagnosing cellulitis
Clinical question: What are the national health care costs of misdiagnosing cellulitis?
Background: Lower extremity cellulitis is primarily a clinical diagnosis but many mimickers such as venous stasis, lymphedema, gout, deep venous thrombosis, and contact dermatitis can lead to a misdiagnosis rate of 30%-90%. Between 14% and 17% of emergency department patients with cellulitis are admitted, accounting for 10% of all infectious disease-related hospitalizations. Overdiagnosis leads to antibiotic misuse and increased hospital utilization.
Study design: Retrospective cross-sectional study.
Setting: Emergency department of Massachusetts General Hospital.
Synopsis: Among 259 ED patients identified from all screened (840 patients total) from June 2010 to December 2012, 79 (30.5%) were incorrectly diagnosed with lower extremity cellulitis and 52 of these misdiagnosed patients were admitted primarily for their cellulitis, resulting in 92.3% of this group receiving unnecessary antibiotics and 84.6% unnecessarily hospitalized.
The authors used cost estimates and previously published data from the Medical Expenditure Panel Survey (MEPS) provided by the Agency for Healthcare Research and Quality (AHRQ) 2010 to project that cellulitis misdiagnosis leads to 50,000-130,000 unnecessary hospitalizations and $195-$515 million in avoidable health care expense annually. The estimates include over 44,000 pseudocellulitis patients being exposed to antibiotics annually with an associated 13% readmission rate and medication complications such as rash and gastrointestinal side effects and implications for resistance selection and antimicrobial stewardship efforts. Nationally, the unnecessary antibiotics and hospitalization associated with misdiagnosis were estimated to cause more than 9,000 nosocomial infections, 1,000 to 5,000 Clostridium difficile infections, and two to six cases of anaphylaxis annually.
Bottom line: Misdiagnosis of lower extremity cellulitis is common and leads to unnecessary patient exposures (antibiotics, hospitalization) and excessive health care spending.
Citations: Weng QY, Raff AB, Cohen JM, et al. Costs and consequences associated with misdiagnosed lower extremity cellulitis. JAMA Dermatol. 2016; doi: 10.1001/jamadermatol.2016.3816.
Dr. Cerceo is an assistant professor in the Division of Hospital Medicine, and associate director of the internal medicine residency program at Cooper Medical School of Rowan University, Camden, N.J.
Clinical question: What are the national health care costs of misdiagnosing cellulitis?
Background: Lower extremity cellulitis is primarily a clinical diagnosis but many mimickers such as venous stasis, lymphedema, gout, deep venous thrombosis, and contact dermatitis can lead to a misdiagnosis rate of 30%-90%. Between 14% and 17% of emergency department patients with cellulitis are admitted, accounting for 10% of all infectious disease-related hospitalizations. Overdiagnosis leads to antibiotic misuse and increased hospital utilization.
Study design: Retrospective cross-sectional study.
Setting: Emergency department of Massachusetts General Hospital.
Synopsis: Among 259 ED patients identified from all screened (840 patients total) from June 2010 to December 2012, 79 (30.5%) were incorrectly diagnosed with lower extremity cellulitis and 52 of these misdiagnosed patients were admitted primarily for their cellulitis, resulting in 92.3% of this group receiving unnecessary antibiotics and 84.6% unnecessarily hospitalized.
The authors used cost estimates and previously published data from the Medical Expenditure Panel Survey (MEPS) provided by the Agency for Healthcare Research and Quality (AHRQ) 2010 to project that cellulitis misdiagnosis leads to 50,000-130,000 unnecessary hospitalizations and $195-$515 million in avoidable health care expense annually. The estimates include over 44,000 pseudocellulitis patients being exposed to antibiotics annually with an associated 13% readmission rate and medication complications such as rash and gastrointestinal side effects and implications for resistance selection and antimicrobial stewardship efforts. Nationally, the unnecessary antibiotics and hospitalization associated with misdiagnosis were estimated to cause more than 9,000 nosocomial infections, 1,000 to 5,000 Clostridium difficile infections, and two to six cases of anaphylaxis annually.
Bottom line: Misdiagnosis of lower extremity cellulitis is common and leads to unnecessary patient exposures (antibiotics, hospitalization) and excessive health care spending.
Citations: Weng QY, Raff AB, Cohen JM, et al. Costs and consequences associated with misdiagnosed lower extremity cellulitis. JAMA Dermatol. 2016; doi: 10.1001/jamadermatol.2016.3816.
Dr. Cerceo is an assistant professor in the Division of Hospital Medicine, and associate director of the internal medicine residency program at Cooper Medical School of Rowan University, Camden, N.J.
Clinical question: What are the national health care costs of misdiagnosing cellulitis?
Background: Lower extremity cellulitis is primarily a clinical diagnosis but many mimickers such as venous stasis, lymphedema, gout, deep venous thrombosis, and contact dermatitis can lead to a misdiagnosis rate of 30%-90%. Between 14% and 17% of emergency department patients with cellulitis are admitted, accounting for 10% of all infectious disease-related hospitalizations. Overdiagnosis leads to antibiotic misuse and increased hospital utilization.
Study design: Retrospective cross-sectional study.
Setting: Emergency department of Massachusetts General Hospital.
Synopsis: Among 259 ED patients identified from all screened (840 patients total) from June 2010 to December 2012, 79 (30.5%) were incorrectly diagnosed with lower extremity cellulitis and 52 of these misdiagnosed patients were admitted primarily for their cellulitis, resulting in 92.3% of this group receiving unnecessary antibiotics and 84.6% unnecessarily hospitalized.
The authors used cost estimates and previously published data from the Medical Expenditure Panel Survey (MEPS) provided by the Agency for Healthcare Research and Quality (AHRQ) 2010 to project that cellulitis misdiagnosis leads to 50,000-130,000 unnecessary hospitalizations and $195-$515 million in avoidable health care expense annually. The estimates include over 44,000 pseudocellulitis patients being exposed to antibiotics annually with an associated 13% readmission rate and medication complications such as rash and gastrointestinal side effects and implications for resistance selection and antimicrobial stewardship efforts. Nationally, the unnecessary antibiotics and hospitalization associated with misdiagnosis were estimated to cause more than 9,000 nosocomial infections, 1,000 to 5,000 Clostridium difficile infections, and two to six cases of anaphylaxis annually.
Bottom line: Misdiagnosis of lower extremity cellulitis is common and leads to unnecessary patient exposures (antibiotics, hospitalization) and excessive health care spending.
Citations: Weng QY, Raff AB, Cohen JM, et al. Costs and consequences associated with misdiagnosed lower extremity cellulitis. JAMA Dermatol. 2016; doi: 10.1001/jamadermatol.2016.3816.
Dr. Cerceo is an assistant professor in the Division of Hospital Medicine, and associate director of the internal medicine residency program at Cooper Medical School of Rowan University, Camden, N.J.
FDA approves Emflaza for Duchenne muscular dystrophy
Emflaza, a tablet and oral suspension corticosteroid, has been approved by the Food and Drug Administration for the treatment of Duchenne muscular dystrophy in patients aged 5 years and older.
The agency’s Feb. 9 announcement notes that similar corticosteroids have been used around the world to treat Duchenne muscular dystrophy (DMD), but this is the first to gain approval in the United States. Emflaza (deflazacort) works by decreasing inflammation and immune system activity.
DMD is the most common form of muscular dystrophy but is still rare, occurring in about 1 in 3,600 male infants worldwide. One study found that patients taking deflazacort had some improvements in muscle strength at 12 weeks, compared with those taking placebo, and maintained muscle strength stability through 52 weeks. A longer-term study showed that patients who took deflazacort had better average muscle strength than did those taking placebo and suggested that deflazacort helped prolong patients’ ability to walk.
Side effects experienced by patients taking Emflaza are similar to those associated with other corticosteroids, such as facial puffiness (cushingoid appearance), weight gain, increased appetite, upper respiratory tract infection, cough, extraordinary daytime urinary frequency (pollakiuria), unwanted hair growth (hirsutism), and excessive fat around the stomach (central obesity).
In the FDA’s announcement, Billy Dunn, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, said, “We hope that this treatment option will benefit many patients with DMD.”
Emflaza, a tablet and oral suspension corticosteroid, has been approved by the Food and Drug Administration for the treatment of Duchenne muscular dystrophy in patients aged 5 years and older.
The agency’s Feb. 9 announcement notes that similar corticosteroids have been used around the world to treat Duchenne muscular dystrophy (DMD), but this is the first to gain approval in the United States. Emflaza (deflazacort) works by decreasing inflammation and immune system activity.
DMD is the most common form of muscular dystrophy but is still rare, occurring in about 1 in 3,600 male infants worldwide. One study found that patients taking deflazacort had some improvements in muscle strength at 12 weeks, compared with those taking placebo, and maintained muscle strength stability through 52 weeks. A longer-term study showed that patients who took deflazacort had better average muscle strength than did those taking placebo and suggested that deflazacort helped prolong patients’ ability to walk.
Side effects experienced by patients taking Emflaza are similar to those associated with other corticosteroids, such as facial puffiness (cushingoid appearance), weight gain, increased appetite, upper respiratory tract infection, cough, extraordinary daytime urinary frequency (pollakiuria), unwanted hair growth (hirsutism), and excessive fat around the stomach (central obesity).
In the FDA’s announcement, Billy Dunn, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, said, “We hope that this treatment option will benefit many patients with DMD.”
Emflaza, a tablet and oral suspension corticosteroid, has been approved by the Food and Drug Administration for the treatment of Duchenne muscular dystrophy in patients aged 5 years and older.
The agency’s Feb. 9 announcement notes that similar corticosteroids have been used around the world to treat Duchenne muscular dystrophy (DMD), but this is the first to gain approval in the United States. Emflaza (deflazacort) works by decreasing inflammation and immune system activity.
DMD is the most common form of muscular dystrophy but is still rare, occurring in about 1 in 3,600 male infants worldwide. One study found that patients taking deflazacort had some improvements in muscle strength at 12 weeks, compared with those taking placebo, and maintained muscle strength stability through 52 weeks. A longer-term study showed that patients who took deflazacort had better average muscle strength than did those taking placebo and suggested that deflazacort helped prolong patients’ ability to walk.
Side effects experienced by patients taking Emflaza are similar to those associated with other corticosteroids, such as facial puffiness (cushingoid appearance), weight gain, increased appetite, upper respiratory tract infection, cough, extraordinary daytime urinary frequency (pollakiuria), unwanted hair growth (hirsutism), and excessive fat around the stomach (central obesity).
In the FDA’s announcement, Billy Dunn, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, said, “We hope that this treatment option will benefit many patients with DMD.”
IgG4-related disease can strike any organ system
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
SNOWMASS, COLO. – Progress in the understanding and treatment of immunoglobulin G4–related disease is occurring “at lightning speed,” John H. Stone, MD, said at the Winter Rheumatology Symposium sponsored by the American College of Rheumatology.
Eight or nine years ago no one had heard of immunoglobulin G4–related disease (IgG4-RD). Today, because of the broad swathe the disease cuts, it’s a hot research topic in every subspecialty of medicine as well as surgery, pathology, and radiology.
This new understanding of IgG4-RD, he added, is opening the door to novel treatments.
“This is not a new disease. It was there when we were all in medical school, and for hundreds of years before that. But it’s really only in the last decade that we have come to understand that the disease can affect literally every organ system in the body with syndromes that we once thought were isolated organ-specific syndromes but we now recognize are part of a multiorgan disease currently called IgG4-related disease,” the rheumatologist said.
IgG4-RD is an immune-mediated fibroinflammatory condition characterized histopathologically by three hallmark features in involved tissue: obliterative phlebitis, storiform fibrosis, and a dense lymphoplasmacytic infiltrate.
Clinically, IgG4-RD often presents as a mass lesion that can affect any organ.
“I have many patients who’ve undergone modified Whipple procedures because they were thought to have adenocarcinoma of the pancreas,” according to Dr. Stone.
Other common presentations include Riedel’s thyroiditis, autoimmune pancreatitis, sclerosing cholangitis, sialadenitis, dacryoadenitis, periaortitis, an eosinophilic rash, and pseudotumor of the lung, lymph nodes, or orbits.
“Retroperitoneal fibrosis is a common and underappreciated manifestation. It may be the most common subsyndrome associated with IgG4-related disease,” he observed.
Another common presentation involves atopic disease – asthma, allergic rhinitis, eczema, eosinophilia, nasal polyps – developing out of the blue in middle age or later life. This observation led some other investigators to posit that IgG4-RD is a T-helper type 2–driven disease, an assertion debunked by Dr. Stone and coworkers (Allergy. 2014 Feb;69[2]:269-72).
Dr. Stone and his coinvestigators have published the largest series of patients with biopsy-proven IgG4-RD reported to date (Arthritis Rheumatol. 2015 Sep; 67[9]:2466-75). The average age at disease onset was 50 years. Of note, multiorgan involvement was the norm: 24% of patients had two organs involved, and 38% had three or more.
Analysis of this large patient series has led Dr. Stone to a surprising conclusion about the nature of IgG4-RD: “We have greatly overemphasized the importance of IgG4 in this condition,” he asserted.
Indeed, a mere 51% of the patients with clinically active untreated IgG4-RD in his series had an elevated serum IgG level. Dr. Stone characterized IgG4 as “kind of a wimpy antibody” incapable of driving the disease process because it is a noninflammatory immunoglobulin. This has led to speculation that IgG4 functions as what he termed an “antigen sink,” attempting to bind antigen at sites of inflammation.
But while an elevated serum IgG4 is of limited utility for diagnostic purposes, Dr. Stone and coworkers have demonstrated that it is of value as a predictor of relapse. Among patients with a treatment-induced remission, those in the top quartile in terms of baseline pretreatment serum IgG4 were 6.2-fold more likely to relapse (Rheumatology [Oxford]. 2016 Jun;55[6]:1000-8).
“This is a very useful marker for patients who are going to need chronic ongoing therapy. The notion of putting such patients on steroids for months and years is not appealing,” he said.
Levels of circulating plasmablasts as measured by peripheral blood flow cytometry, especially IgG4-positive plasmablasts, have proven much more helpful than serum IgG4 levels as a diagnostic tool, a reliable biomarker of disease activity, and a therapeutic target. Levels of these short-lived CD19+CD38+CD27+ plasmablasts are enormously elevated independent of serum IgG4 in patients with active IgG4-RD.
“One of the questions I’m most often asked is whether IgG4-related disease is a premalignant condition. My answer is no. The plasmablast expansion is oligoclonal, not polyclonal,” Dr. Stone continued.
He described IgG4-RD as “a continuous dance between T cells and B cells.” The latest thinking regarding pathogenesis is that type 2 T follicular helper cells activate B cells, which become memory B cells or plasmablasts. These activated B cells and plasmablasts present antigen to CD4+ cytotoxic T cells at sites of disease. Dr. Stone and his coinvestigators recently identified these CD4+ cytotoxic T cells as a novel population of clonally expanded T cells with SLAMF7 as a surface marker. The cells secrete interferon-gamma, interleukin-1, and transforming growth factor-beta, all of which are capable of driving the intense fibrosis characteristic of IgG4-RD. In addition, these CD4+ cytotoxic T cells secrete granzyme B and perforin, previously thought to be released mainly by natural killer T cells.
Joint American College of Rheumatology/European League Against Rheumatism classification criteria for the disease are expected to be finalized this winter at the Third International Symposium on IgG4-Related Diseases.
Dr. Stone reported receiving IgG4-RD–related research funding from and serving as a consultant to Genentech and Xencor.
EXPERT ANALYSIS FROM THE WINTER RHEUMATOLOGY SYMPOSIUM