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Study links RA flares after joint replacement to disease activity, not medications
Patients with the most severe cases of rheumatoid arthritis are more likely to suffer flares after knee or hip replacement surgery, a new study finds, and it doesn’t seem to matter whether they stop taking biologics before their operation.
“We found that the majority of patients had active disease at the time of surgery, contrary to prior statements that RA patients have inactive disease at the time they go for hip or knee replacement. In fact, the majority – 65% of the patients – reported a flare of RA within 6 weeks of surgery,” lead author Susan M. Goodman, MD, of Cornell University and the Hospital for Special Surgery, New York, said in an interview. “Surprisingly, although more of the flaring patients were taking potent biologics that had been withheld preoperatively, the major risk factor for flares was their baseline disease activity.”
According to Dr. Goodman, the researchers launched the study to better understand how medical decisions prior to joint replacement surgery affect the progress of RA afterward.
In terms of continuing RA drug treatment, she said, “the decision really hinges on the risk of infection versus the risk of flare, and we didn’t know the usual course of events for these patients.”
In addition, she said, “many doctors incorrectly think that the majority of patients with RA have ‘burnt-out’ or inactive disease at the time of hip or knee replacement surgery.”
For the study, the researchers prospectively followed 120 patients who were to undergo joint replacement surgery. (The researchers initially approached 354 patients, of whom 169 declined to participate. Another 65 were dropped from the study for various reasons, including 42 who did not sufficiently fill out questionnaires and were deleted from the final analysis.)
The researchers tracked the patients before surgery and for 6 weeks after surgery. A majority of the patients were female (83%) and white (81%), with a mean age of 62 and a median RA symptom duration of 15 years. A total of 44% underwent hip replacement surgery while the rest underwent knee replacement surgery. Just over half of the patients were taking biologics, which were stopped prior to surgery, while glucocorticoids and methotrexate were usually continued.
Just under two-thirds of the patients flared within the first 6 weeks after surgery. The researchers didn’t find any connection between the flares and stopping biologics or using methotrexate. They did, however, link higher baseline RA activity to postsurgery flaring (odds ratio, 2.11; P = .015).
Dr. Goodman said that she and her colleagues continue to collect data to better understand flares and the link to disease severity. “The long-term implications of this are not yet known. We would like to know the effect on long-term functional outcome and complication rate.”
The National Institutes of Health, the Weill Cornell Clinical Translational Science Center, and the Block Family Foundation supported the study. Dr. Goodman disclosed receiving research funding from Novartis and Roche.
SOURCE: Goodman S et al. J Rheumatol. 2018 Mar 15. doi: 10.3899/jrheum.170366
Patients with the most severe cases of rheumatoid arthritis are more likely to suffer flares after knee or hip replacement surgery, a new study finds, and it doesn’t seem to matter whether they stop taking biologics before their operation.
“We found that the majority of patients had active disease at the time of surgery, contrary to prior statements that RA patients have inactive disease at the time they go for hip or knee replacement. In fact, the majority – 65% of the patients – reported a flare of RA within 6 weeks of surgery,” lead author Susan M. Goodman, MD, of Cornell University and the Hospital for Special Surgery, New York, said in an interview. “Surprisingly, although more of the flaring patients were taking potent biologics that had been withheld preoperatively, the major risk factor for flares was their baseline disease activity.”
According to Dr. Goodman, the researchers launched the study to better understand how medical decisions prior to joint replacement surgery affect the progress of RA afterward.
In terms of continuing RA drug treatment, she said, “the decision really hinges on the risk of infection versus the risk of flare, and we didn’t know the usual course of events for these patients.”
In addition, she said, “many doctors incorrectly think that the majority of patients with RA have ‘burnt-out’ or inactive disease at the time of hip or knee replacement surgery.”
For the study, the researchers prospectively followed 120 patients who were to undergo joint replacement surgery. (The researchers initially approached 354 patients, of whom 169 declined to participate. Another 65 were dropped from the study for various reasons, including 42 who did not sufficiently fill out questionnaires and were deleted from the final analysis.)
The researchers tracked the patients before surgery and for 6 weeks after surgery. A majority of the patients were female (83%) and white (81%), with a mean age of 62 and a median RA symptom duration of 15 years. A total of 44% underwent hip replacement surgery while the rest underwent knee replacement surgery. Just over half of the patients were taking biologics, which were stopped prior to surgery, while glucocorticoids and methotrexate were usually continued.
Just under two-thirds of the patients flared within the first 6 weeks after surgery. The researchers didn’t find any connection between the flares and stopping biologics or using methotrexate. They did, however, link higher baseline RA activity to postsurgery flaring (odds ratio, 2.11; P = .015).
Dr. Goodman said that she and her colleagues continue to collect data to better understand flares and the link to disease severity. “The long-term implications of this are not yet known. We would like to know the effect on long-term functional outcome and complication rate.”
The National Institutes of Health, the Weill Cornell Clinical Translational Science Center, and the Block Family Foundation supported the study. Dr. Goodman disclosed receiving research funding from Novartis and Roche.
SOURCE: Goodman S et al. J Rheumatol. 2018 Mar 15. doi: 10.3899/jrheum.170366
Patients with the most severe cases of rheumatoid arthritis are more likely to suffer flares after knee or hip replacement surgery, a new study finds, and it doesn’t seem to matter whether they stop taking biologics before their operation.
“We found that the majority of patients had active disease at the time of surgery, contrary to prior statements that RA patients have inactive disease at the time they go for hip or knee replacement. In fact, the majority – 65% of the patients – reported a flare of RA within 6 weeks of surgery,” lead author Susan M. Goodman, MD, of Cornell University and the Hospital for Special Surgery, New York, said in an interview. “Surprisingly, although more of the flaring patients were taking potent biologics that had been withheld preoperatively, the major risk factor for flares was their baseline disease activity.”
According to Dr. Goodman, the researchers launched the study to better understand how medical decisions prior to joint replacement surgery affect the progress of RA afterward.
In terms of continuing RA drug treatment, she said, “the decision really hinges on the risk of infection versus the risk of flare, and we didn’t know the usual course of events for these patients.”
In addition, she said, “many doctors incorrectly think that the majority of patients with RA have ‘burnt-out’ or inactive disease at the time of hip or knee replacement surgery.”
For the study, the researchers prospectively followed 120 patients who were to undergo joint replacement surgery. (The researchers initially approached 354 patients, of whom 169 declined to participate. Another 65 were dropped from the study for various reasons, including 42 who did not sufficiently fill out questionnaires and were deleted from the final analysis.)
The researchers tracked the patients before surgery and for 6 weeks after surgery. A majority of the patients were female (83%) and white (81%), with a mean age of 62 and a median RA symptom duration of 15 years. A total of 44% underwent hip replacement surgery while the rest underwent knee replacement surgery. Just over half of the patients were taking biologics, which were stopped prior to surgery, while glucocorticoids and methotrexate were usually continued.
Just under two-thirds of the patients flared within the first 6 weeks after surgery. The researchers didn’t find any connection between the flares and stopping biologics or using methotrexate. They did, however, link higher baseline RA activity to postsurgery flaring (odds ratio, 2.11; P = .015).
Dr. Goodman said that she and her colleagues continue to collect data to better understand flares and the link to disease severity. “The long-term implications of this are not yet known. We would like to know the effect on long-term functional outcome and complication rate.”
The National Institutes of Health, the Weill Cornell Clinical Translational Science Center, and the Block Family Foundation supported the study. Dr. Goodman disclosed receiving research funding from Novartis and Roche.
SOURCE: Goodman S et al. J Rheumatol. 2018 Mar 15. doi: 10.3899/jrheum.170366
FROM JOURNAL OF RHEUMATOLOGY
Key clinical point:
Major finding: Sixty-five percent of RA patients developed flares after joint replacement surgery, and it was more common in those with higher baseline RA activity (odds ratio, 2.11; P = .015).
Study details: Prospective study of 120 patients with RA who underwent hip replacement (44%) or knee replacement (56%).
Disclosures: The National Institutes of Health, the Weill Cornell Clinical Translational Science Center, and the Block Family Foundation supported the study. The lead author disclosed receiving research funding from Novartis and Roche.
Source: Goodman S et al. J Rheumatol. 2018 Mar 15. doi: 10.3899/jrheum.170366.
Low microbiota diversity linked to poor survival after transplant
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: High microbiota diversity post transplant was associated with better overall survival at two sites (P = .006 and P = .015).
Study details: Multicenter study of 5,310 fecal samples obtained from 1,034 hematopoietic cell transplant recipients.
Disclosures: The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics.
Source: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
Chemotherapy, metabolic pathway may affect CAR T-cell potential
Two critical factors – prior exposure to chemotherapy and a glycolytic metabolism – appear to degrade the potential of T cells to become chimeric antigen receptor–T cells.
Chemotherapy, especially with cyclophosphamide and doxorubicin, seems particularly toxic to T cells, damaging the mitochondria and decreasing the cells’ spare respiratory capacity – a measure of mitochondrial health, David Barrett, MD, said during a press briefing held in advance of the annual meeting of the American Association for Cancer Research.
These new findings may help explain why children with acute lymphoblastic leukemia (ALL) tend to respond so vigorously to CAR T treatment, and why T cells from patients with solid tumors simply don’t grow, or die soon after patient infusion, he said in an interview. They also suggest a benefit of harvesting T cells before any chemotherapy, a procedure Dr. Barrett and his colleagues have advocated.
“Based on these data we have altered our practice for T-cell therapy in high-risk leukemia patients. If we have a patient who may have a poor prognosis, we try to collect the cells early and store them before proceeding, because we know chemotherapy will progressively degrade them.”
There still is no successful CAR T-cell protocol for solid tumors, but Dr. Barrett said these findings eventually may help such patients, particularly if more advanced experiments in manipulating the cells’ metabolism prove successful.
He and his colleagues investigated why T cells from some patients result in a poor clinical product that either fails manufacture or does not proliferate in the patient. They examined T cells from 157 pediatric patients with a variety of cancers, including ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, Hodgkin disease, chronic myelogenous leukemia, and Ewing sarcoma. The team obtained cells at diagnosis and after each cycle of chemotherapy.
They examined how well the cells grew in the transformation and expansion process. A “pass” was considered a fivefold expansion in response to CD3/CD28 exposure for 7 days. Normal donor cells typically expand 20- to 30-fold in this time.
Only T cells taken from ALL and Wilms tumor patients before chemotherapy achieved a pass, Dr. Barrett said. Most of the ALL expansions (80%) and half of the Wilms tumor expansions passed. “We noted very poor CAR T-cell potential in all the other tumor types – less than a 30% pass. We noted a decline in potential with cumulative chemotherapy in all cases, though this was particularly significant in children less than 3 years old.”
The team also used RNA profiling to look at the cells’ metabolic pathways. Dr. Barrett noted that T cells are highly metabolically adaptable, capable of using several different fuel types and switching from one to another. Glucose and fatty acids are frequent fuels. Most of the cells from patients with solid tumors exhibited a glycolytic metabolism, while cells from patients with ALL and Wilms tumor appeared to rely more on fatty acids.
“One is not inherently worse than the other,” he said. “But glycolysis appears to be a bad thing when we’re trying to turn them into CAR T cells. Those T cells were too exhausted to do anything.”
However, Dr. Barrett encouraged the cells to switch fuels by treating them in vitro with palmitic acid, the most common fatty acid in plants and animals.
“We were growing the cells in a media containing sugar, fatty acids, and amino acids,” he explained. “We just started overloading them with palmitic acid, which has a natural transporter on the T-cell surface, so it already had a good pathway to get into the cell. It helped restore some of the performance of these T cells in some assays, although it wasn’t a complete reversal. But it was encouraging that something as simple as providing an alternate fuel was enough to get some positive effect. Whether or not we would also have to block glucose use to get it to really work is something we continue to study.”
T cells that had been exposed to chemotherapy also did poorly. Cyclophosphamide and doxorubicin seemed particularly toxic. Cells with exposure to these two agents had severely depleted CAR T cell potential with very poor spare respiratory capacity. This is a marker of mitochondrial injury, Dr. Barrett said. “That wasn’t a huge surprise. We already knew that cyclophosphamide is very toxic to T cells.”
But the finding did suggest the simple intervention of harvesting T cells before chemotherapy, which is what Dr. Barrett and his colleagues now do in their high-risk ALL patients. Whether or not this would improve response in patients with solid tumors is still unknown.
He had no financial disclosures. This study was supported by the AACR, the Doris Duke Charitable Foundation Clinical Science Development Award, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award.
SOURCE: Barrett DM et al. AACR 2018, Abstract 1631.
Two critical factors – prior exposure to chemotherapy and a glycolytic metabolism – appear to degrade the potential of T cells to become chimeric antigen receptor–T cells.
Chemotherapy, especially with cyclophosphamide and doxorubicin, seems particularly toxic to T cells, damaging the mitochondria and decreasing the cells’ spare respiratory capacity – a measure of mitochondrial health, David Barrett, MD, said during a press briefing held in advance of the annual meeting of the American Association for Cancer Research.
These new findings may help explain why children with acute lymphoblastic leukemia (ALL) tend to respond so vigorously to CAR T treatment, and why T cells from patients with solid tumors simply don’t grow, or die soon after patient infusion, he said in an interview. They also suggest a benefit of harvesting T cells before any chemotherapy, a procedure Dr. Barrett and his colleagues have advocated.
“Based on these data we have altered our practice for T-cell therapy in high-risk leukemia patients. If we have a patient who may have a poor prognosis, we try to collect the cells early and store them before proceeding, because we know chemotherapy will progressively degrade them.”
There still is no successful CAR T-cell protocol for solid tumors, but Dr. Barrett said these findings eventually may help such patients, particularly if more advanced experiments in manipulating the cells’ metabolism prove successful.
He and his colleagues investigated why T cells from some patients result in a poor clinical product that either fails manufacture or does not proliferate in the patient. They examined T cells from 157 pediatric patients with a variety of cancers, including ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, Hodgkin disease, chronic myelogenous leukemia, and Ewing sarcoma. The team obtained cells at diagnosis and after each cycle of chemotherapy.
They examined how well the cells grew in the transformation and expansion process. A “pass” was considered a fivefold expansion in response to CD3/CD28 exposure for 7 days. Normal donor cells typically expand 20- to 30-fold in this time.
Only T cells taken from ALL and Wilms tumor patients before chemotherapy achieved a pass, Dr. Barrett said. Most of the ALL expansions (80%) and half of the Wilms tumor expansions passed. “We noted very poor CAR T-cell potential in all the other tumor types – less than a 30% pass. We noted a decline in potential with cumulative chemotherapy in all cases, though this was particularly significant in children less than 3 years old.”
The team also used RNA profiling to look at the cells’ metabolic pathways. Dr. Barrett noted that T cells are highly metabolically adaptable, capable of using several different fuel types and switching from one to another. Glucose and fatty acids are frequent fuels. Most of the cells from patients with solid tumors exhibited a glycolytic metabolism, while cells from patients with ALL and Wilms tumor appeared to rely more on fatty acids.
“One is not inherently worse than the other,” he said. “But glycolysis appears to be a bad thing when we’re trying to turn them into CAR T cells. Those T cells were too exhausted to do anything.”
However, Dr. Barrett encouraged the cells to switch fuels by treating them in vitro with palmitic acid, the most common fatty acid in plants and animals.
“We were growing the cells in a media containing sugar, fatty acids, and amino acids,” he explained. “We just started overloading them with palmitic acid, which has a natural transporter on the T-cell surface, so it already had a good pathway to get into the cell. It helped restore some of the performance of these T cells in some assays, although it wasn’t a complete reversal. But it was encouraging that something as simple as providing an alternate fuel was enough to get some positive effect. Whether or not we would also have to block glucose use to get it to really work is something we continue to study.”
T cells that had been exposed to chemotherapy also did poorly. Cyclophosphamide and doxorubicin seemed particularly toxic. Cells with exposure to these two agents had severely depleted CAR T cell potential with very poor spare respiratory capacity. This is a marker of mitochondrial injury, Dr. Barrett said. “That wasn’t a huge surprise. We already knew that cyclophosphamide is very toxic to T cells.”
But the finding did suggest the simple intervention of harvesting T cells before chemotherapy, which is what Dr. Barrett and his colleagues now do in their high-risk ALL patients. Whether or not this would improve response in patients with solid tumors is still unknown.
He had no financial disclosures. This study was supported by the AACR, the Doris Duke Charitable Foundation Clinical Science Development Award, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award.
SOURCE: Barrett DM et al. AACR 2018, Abstract 1631.
Two critical factors – prior exposure to chemotherapy and a glycolytic metabolism – appear to degrade the potential of T cells to become chimeric antigen receptor–T cells.
Chemotherapy, especially with cyclophosphamide and doxorubicin, seems particularly toxic to T cells, damaging the mitochondria and decreasing the cells’ spare respiratory capacity – a measure of mitochondrial health, David Barrett, MD, said during a press briefing held in advance of the annual meeting of the American Association for Cancer Research.
These new findings may help explain why children with acute lymphoblastic leukemia (ALL) tend to respond so vigorously to CAR T treatment, and why T cells from patients with solid tumors simply don’t grow, or die soon after patient infusion, he said in an interview. They also suggest a benefit of harvesting T cells before any chemotherapy, a procedure Dr. Barrett and his colleagues have advocated.
“Based on these data we have altered our practice for T-cell therapy in high-risk leukemia patients. If we have a patient who may have a poor prognosis, we try to collect the cells early and store them before proceeding, because we know chemotherapy will progressively degrade them.”
There still is no successful CAR T-cell protocol for solid tumors, but Dr. Barrett said these findings eventually may help such patients, particularly if more advanced experiments in manipulating the cells’ metabolism prove successful.
He and his colleagues investigated why T cells from some patients result in a poor clinical product that either fails manufacture or does not proliferate in the patient. They examined T cells from 157 pediatric patients with a variety of cancers, including ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, Hodgkin disease, chronic myelogenous leukemia, and Ewing sarcoma. The team obtained cells at diagnosis and after each cycle of chemotherapy.
They examined how well the cells grew in the transformation and expansion process. A “pass” was considered a fivefold expansion in response to CD3/CD28 exposure for 7 days. Normal donor cells typically expand 20- to 30-fold in this time.
Only T cells taken from ALL and Wilms tumor patients before chemotherapy achieved a pass, Dr. Barrett said. Most of the ALL expansions (80%) and half of the Wilms tumor expansions passed. “We noted very poor CAR T-cell potential in all the other tumor types – less than a 30% pass. We noted a decline in potential with cumulative chemotherapy in all cases, though this was particularly significant in children less than 3 years old.”
The team also used RNA profiling to look at the cells’ metabolic pathways. Dr. Barrett noted that T cells are highly metabolically adaptable, capable of using several different fuel types and switching from one to another. Glucose and fatty acids are frequent fuels. Most of the cells from patients with solid tumors exhibited a glycolytic metabolism, while cells from patients with ALL and Wilms tumor appeared to rely more on fatty acids.
“One is not inherently worse than the other,” he said. “But glycolysis appears to be a bad thing when we’re trying to turn them into CAR T cells. Those T cells were too exhausted to do anything.”
However, Dr. Barrett encouraged the cells to switch fuels by treating them in vitro with palmitic acid, the most common fatty acid in plants and animals.
“We were growing the cells in a media containing sugar, fatty acids, and amino acids,” he explained. “We just started overloading them with palmitic acid, which has a natural transporter on the T-cell surface, so it already had a good pathway to get into the cell. It helped restore some of the performance of these T cells in some assays, although it wasn’t a complete reversal. But it was encouraging that something as simple as providing an alternate fuel was enough to get some positive effect. Whether or not we would also have to block glucose use to get it to really work is something we continue to study.”
T cells that had been exposed to chemotherapy also did poorly. Cyclophosphamide and doxorubicin seemed particularly toxic. Cells with exposure to these two agents had severely depleted CAR T cell potential with very poor spare respiratory capacity. This is a marker of mitochondrial injury, Dr. Barrett said. “That wasn’t a huge surprise. We already knew that cyclophosphamide is very toxic to T cells.”
But the finding did suggest the simple intervention of harvesting T cells before chemotherapy, which is what Dr. Barrett and his colleagues now do in their high-risk ALL patients. Whether or not this would improve response in patients with solid tumors is still unknown.
He had no financial disclosures. This study was supported by the AACR, the Doris Duke Charitable Foundation Clinical Science Development Award, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award.
SOURCE: Barrett DM et al. AACR 2018, Abstract 1631.
FROM AACR 2018
Key clinical point: Prior exposure to chemotherapy may degrade the potential of T cells to become CAR T cells, suggesting a benefit of harvesting T cells before any chemotherapy.
Major finding: Only T cells taken from ALL and Wilm’s tumor patients before chemotherapy achieved a fivefold expansion in response to CD3/CD28 exposure for 7 days.
Study details: An examination of T cells from 157 pediatric patients with a variety of cancers at diagnosis and after each cycle of chemotherapy.
Disclosures: The study was supported by the American Association of Cancer Research, the Doris Duke Charitable Foundation Clinical Science Development Award, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award. Dr. Barrett and his coauthors had no financial disclosures.
Source: Barrett DM et al. AACR 2018, Abstract 1631.
Maternal biologic therapy does not affect infant vaccine responses
MAUI, HAWAII – The infants of inflammatory bowel disease patients on biologic therapy during pregnancy and breastfeeding do not have a diminished response rate to the inactivated vaccines routinely given during the first 6 months of life, Uma Mahadevan, MD, said at the 2018 Rheumatology Winter Clinical Symposium.
“Those babies are going to have detectable levels of drug on board, but they respond to vaccines just as well as infants born to mothers with IBD who were not on biologic therapy. The rates are the same, albeit lower than in the general population,” according to Dr. Mahadevan, professor of medicine and medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.
Previous reports from the national registry have established that continuation of biologics in IBD patients throughout pregnancy and breastfeeding to maintain disease control poses no increased risks to the fetus in terms of rates of congenital anomalies, spontaneous abortion, intrauterine growth restriction, low birth weight, or longer-term developmental delay, compared with unexposed babies whose mothers have IBD.
Dr. Ananthakrishnan’s analysis focused on response rates to tetanus and Haemophilus influenzae B vaccines in the infants of 179 PIANO patients. Sixty-five percent of the IBD patients were on various biologic agents during pregnancy, 8% were on a thiopurine, 21% were on combination therapy, and 6% weren’t exposed to any IBD medications. Serologic studies showed that there was no difference across the four groups in terms of infant rates of protective titers in response to the vaccines. However, the 69%-84% rates of protective titers in the four groups fell short of the 90%-plus rate expected in the general population.
Live virus vaccines are contraindicated in the first 6 months of life in infants exposed to maternal biologics in utero. The only live virus vaccine given during that time frame in the United States is rotavirus, administered at months 2 and 3. Dr. Mahadevan and others recommend skipping that vaccine in babies exposed in utero to any IBD biologic other than certolizumab pegol (Cimzia), which uniquely doesn’t cross the placenta.
“That being said, infants born to 71 of our PIANO participants on anti-TNF therapy in pregnancy inadvertently got the rotavirus vaccine, and they were all just fine, even with very high drug levels,” the gastroenterologist said.
The live virus varicella and MMR vaccines can safely be given as scheduled at 1 year of age. By that time the biologics are long gone from the child.
Dr. Mahadevan reported receiving research funding from the Crohn’s and Colitis Foundation of America, which sponsors the PIANO registry. She also has financial relationships with several pharmaceutical companies.
MAUI, HAWAII – The infants of inflammatory bowel disease patients on biologic therapy during pregnancy and breastfeeding do not have a diminished response rate to the inactivated vaccines routinely given during the first 6 months of life, Uma Mahadevan, MD, said at the 2018 Rheumatology Winter Clinical Symposium.
“Those babies are going to have detectable levels of drug on board, but they respond to vaccines just as well as infants born to mothers with IBD who were not on biologic therapy. The rates are the same, albeit lower than in the general population,” according to Dr. Mahadevan, professor of medicine and medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.
Previous reports from the national registry have established that continuation of biologics in IBD patients throughout pregnancy and breastfeeding to maintain disease control poses no increased risks to the fetus in terms of rates of congenital anomalies, spontaneous abortion, intrauterine growth restriction, low birth weight, or longer-term developmental delay, compared with unexposed babies whose mothers have IBD.
Dr. Ananthakrishnan’s analysis focused on response rates to tetanus and Haemophilus influenzae B vaccines in the infants of 179 PIANO patients. Sixty-five percent of the IBD patients were on various biologic agents during pregnancy, 8% were on a thiopurine, 21% were on combination therapy, and 6% weren’t exposed to any IBD medications. Serologic studies showed that there was no difference across the four groups in terms of infant rates of protective titers in response to the vaccines. However, the 69%-84% rates of protective titers in the four groups fell short of the 90%-plus rate expected in the general population.
Live virus vaccines are contraindicated in the first 6 months of life in infants exposed to maternal biologics in utero. The only live virus vaccine given during that time frame in the United States is rotavirus, administered at months 2 and 3. Dr. Mahadevan and others recommend skipping that vaccine in babies exposed in utero to any IBD biologic other than certolizumab pegol (Cimzia), which uniquely doesn’t cross the placenta.
“That being said, infants born to 71 of our PIANO participants on anti-TNF therapy in pregnancy inadvertently got the rotavirus vaccine, and they were all just fine, even with very high drug levels,” the gastroenterologist said.
The live virus varicella and MMR vaccines can safely be given as scheduled at 1 year of age. By that time the biologics are long gone from the child.
Dr. Mahadevan reported receiving research funding from the Crohn’s and Colitis Foundation of America, which sponsors the PIANO registry. She also has financial relationships with several pharmaceutical companies.
MAUI, HAWAII – The infants of inflammatory bowel disease patients on biologic therapy during pregnancy and breastfeeding do not have a diminished response rate to the inactivated vaccines routinely given during the first 6 months of life, Uma Mahadevan, MD, said at the 2018 Rheumatology Winter Clinical Symposium.
“Those babies are going to have detectable levels of drug on board, but they respond to vaccines just as well as infants born to mothers with IBD who were not on biologic therapy. The rates are the same, albeit lower than in the general population,” according to Dr. Mahadevan, professor of medicine and medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.
Previous reports from the national registry have established that continuation of biologics in IBD patients throughout pregnancy and breastfeeding to maintain disease control poses no increased risks to the fetus in terms of rates of congenital anomalies, spontaneous abortion, intrauterine growth restriction, low birth weight, or longer-term developmental delay, compared with unexposed babies whose mothers have IBD.
Dr. Ananthakrishnan’s analysis focused on response rates to tetanus and Haemophilus influenzae B vaccines in the infants of 179 PIANO patients. Sixty-five percent of the IBD patients were on various biologic agents during pregnancy, 8% were on a thiopurine, 21% were on combination therapy, and 6% weren’t exposed to any IBD medications. Serologic studies showed that there was no difference across the four groups in terms of infant rates of protective titers in response to the vaccines. However, the 69%-84% rates of protective titers in the four groups fell short of the 90%-plus rate expected in the general population.
Live virus vaccines are contraindicated in the first 6 months of life in infants exposed to maternal biologics in utero. The only live virus vaccine given during that time frame in the United States is rotavirus, administered at months 2 and 3. Dr. Mahadevan and others recommend skipping that vaccine in babies exposed in utero to any IBD biologic other than certolizumab pegol (Cimzia), which uniquely doesn’t cross the placenta.
“That being said, infants born to 71 of our PIANO participants on anti-TNF therapy in pregnancy inadvertently got the rotavirus vaccine, and they were all just fine, even with very high drug levels,” the gastroenterologist said.
The live virus varicella and MMR vaccines can safely be given as scheduled at 1 year of age. By that time the biologics are long gone from the child.
Dr. Mahadevan reported receiving research funding from the Crohn’s and Colitis Foundation of America, which sponsors the PIANO registry. She also has financial relationships with several pharmaceutical companies.
EXPERT ANALYSIS FROM RWCS 2018
Protons linked to lower urinary AEs, higher costs than with IMRT for prostate cancer
Among men younger than 65 with prostate cancer, proton beam radiotherapy (PBT) was associated with significantly lower rates of urinary toxicities than was intensity-modulated radiotherapy (IMRT), but this safety advantage came at the cost of nearly $60,000 extra per patient, results of an insurance claims study show.
The rate of a composite of urinary toxicities at 2 years among 693 men treated with PBT was 33%, compared with 42% for 3,465 men matched by propensity score who were treated with IMRT. Respective rates of erectile dysfunction were 21% vs. 28%. The mean cost for PBT, however, was nearly double that for IMRT, reported Benjamin D. Smith, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
Although PBT was better at sparing patients from urinary toxicities, it was associated with increased bowel toxicities, and a second comparison of IMRT with stereotactic body radiotherapy (SBRT) showed that SBRT, while slightly cheaper than IMRT, was associated with modest increases in some urinary toxicities, the researchers reported in a study published online in the Journal of Clinical Oncology.
“These key findings, coupled with the real-world private insurance cost reported herein, will be useful for patients selecting the most appropriate treatment and for researchers designing cost-effectiveness models to guide treatment decisions in prostate cancer,” they wrote.
The investigators combed through the MarketScan Commercial Claims and Encounters database to identify men who underwent radiation therapy for prostate cancer between 2008 and 2015. They used propensity-score matching, a technique designed to even out potential confounding factors, to compare those treated with IMRT with others treated with PBT or SBRT.
As noted, PBT was associated with significantly lower urinary toxicities and erectile dysfunction compared with IMRT (P less than .001 for each comparison), but with a higher rate of bowel toxicities at 2 years (20% vs. 15%, P = .02).
The mean cost per patient in 2015 dollars for PBT was $115,501, compared with $59,012 for IMRT.
In a comparison of outcomes and costs for 310 patients who underwent SBRT matched with 3,100 who underwent IMRT, the investigators found no significant differences in composite urinary, erectile dysfunction, or bowel toxicities. However, the risk of urinary fistula, while low, was significantly higher with SBRT compared with IMRT, with rates of 1% vs. 0.1%, respectively (P = .009).
The mean cost of SBRT in this analysis was $49,504, compared with $57,244 for IMRT (P less than .001).
The investigators acknowledged that by using claims data they were unable to plug information about potential confounding factors such as Gleason score, prostate-specific antigen level, clinical stage, or radiation field and dose into their propensity-score models. They also noted that follow-up was relatively short because of the vicissitudes of the U.S. insurance market, which causes many patients to change insurers frequently.
The study was supported by grants from the National Cancer Institute and by Varian Medical Systems. Dr. Smith, lead author Hubert Y. Pan, MD, and others disclosed research support, consulting, and/or travel support from Varian.
SOURCE: Smith BD et al. J Clin Oncol. 2018 Mar 21. doi: 10.1200/JCO.2017.75.5371.
Among men younger than 65 with prostate cancer, proton beam radiotherapy (PBT) was associated with significantly lower rates of urinary toxicities than was intensity-modulated radiotherapy (IMRT), but this safety advantage came at the cost of nearly $60,000 extra per patient, results of an insurance claims study show.
The rate of a composite of urinary toxicities at 2 years among 693 men treated with PBT was 33%, compared with 42% for 3,465 men matched by propensity score who were treated with IMRT. Respective rates of erectile dysfunction were 21% vs. 28%. The mean cost for PBT, however, was nearly double that for IMRT, reported Benjamin D. Smith, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
Although PBT was better at sparing patients from urinary toxicities, it was associated with increased bowel toxicities, and a second comparison of IMRT with stereotactic body radiotherapy (SBRT) showed that SBRT, while slightly cheaper than IMRT, was associated with modest increases in some urinary toxicities, the researchers reported in a study published online in the Journal of Clinical Oncology.
“These key findings, coupled with the real-world private insurance cost reported herein, will be useful for patients selecting the most appropriate treatment and for researchers designing cost-effectiveness models to guide treatment decisions in prostate cancer,” they wrote.
The investigators combed through the MarketScan Commercial Claims and Encounters database to identify men who underwent radiation therapy for prostate cancer between 2008 and 2015. They used propensity-score matching, a technique designed to even out potential confounding factors, to compare those treated with IMRT with others treated with PBT or SBRT.
As noted, PBT was associated with significantly lower urinary toxicities and erectile dysfunction compared with IMRT (P less than .001 for each comparison), but with a higher rate of bowel toxicities at 2 years (20% vs. 15%, P = .02).
The mean cost per patient in 2015 dollars for PBT was $115,501, compared with $59,012 for IMRT.
In a comparison of outcomes and costs for 310 patients who underwent SBRT matched with 3,100 who underwent IMRT, the investigators found no significant differences in composite urinary, erectile dysfunction, or bowel toxicities. However, the risk of urinary fistula, while low, was significantly higher with SBRT compared with IMRT, with rates of 1% vs. 0.1%, respectively (P = .009).
The mean cost of SBRT in this analysis was $49,504, compared with $57,244 for IMRT (P less than .001).
The investigators acknowledged that by using claims data they were unable to plug information about potential confounding factors such as Gleason score, prostate-specific antigen level, clinical stage, or radiation field and dose into their propensity-score models. They also noted that follow-up was relatively short because of the vicissitudes of the U.S. insurance market, which causes many patients to change insurers frequently.
The study was supported by grants from the National Cancer Institute and by Varian Medical Systems. Dr. Smith, lead author Hubert Y. Pan, MD, and others disclosed research support, consulting, and/or travel support from Varian.
SOURCE: Smith BD et al. J Clin Oncol. 2018 Mar 21. doi: 10.1200/JCO.2017.75.5371.
Among men younger than 65 with prostate cancer, proton beam radiotherapy (PBT) was associated with significantly lower rates of urinary toxicities than was intensity-modulated radiotherapy (IMRT), but this safety advantage came at the cost of nearly $60,000 extra per patient, results of an insurance claims study show.
The rate of a composite of urinary toxicities at 2 years among 693 men treated with PBT was 33%, compared with 42% for 3,465 men matched by propensity score who were treated with IMRT. Respective rates of erectile dysfunction were 21% vs. 28%. The mean cost for PBT, however, was nearly double that for IMRT, reported Benjamin D. Smith, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
Although PBT was better at sparing patients from urinary toxicities, it was associated with increased bowel toxicities, and a second comparison of IMRT with stereotactic body radiotherapy (SBRT) showed that SBRT, while slightly cheaper than IMRT, was associated with modest increases in some urinary toxicities, the researchers reported in a study published online in the Journal of Clinical Oncology.
“These key findings, coupled with the real-world private insurance cost reported herein, will be useful for patients selecting the most appropriate treatment and for researchers designing cost-effectiveness models to guide treatment decisions in prostate cancer,” they wrote.
The investigators combed through the MarketScan Commercial Claims and Encounters database to identify men who underwent radiation therapy for prostate cancer between 2008 and 2015. They used propensity-score matching, a technique designed to even out potential confounding factors, to compare those treated with IMRT with others treated with PBT or SBRT.
As noted, PBT was associated with significantly lower urinary toxicities and erectile dysfunction compared with IMRT (P less than .001 for each comparison), but with a higher rate of bowel toxicities at 2 years (20% vs. 15%, P = .02).
The mean cost per patient in 2015 dollars for PBT was $115,501, compared with $59,012 for IMRT.
In a comparison of outcomes and costs for 310 patients who underwent SBRT matched with 3,100 who underwent IMRT, the investigators found no significant differences in composite urinary, erectile dysfunction, or bowel toxicities. However, the risk of urinary fistula, while low, was significantly higher with SBRT compared with IMRT, with rates of 1% vs. 0.1%, respectively (P = .009).
The mean cost of SBRT in this analysis was $49,504, compared with $57,244 for IMRT (P less than .001).
The investigators acknowledged that by using claims data they were unable to plug information about potential confounding factors such as Gleason score, prostate-specific antigen level, clinical stage, or radiation field and dose into their propensity-score models. They also noted that follow-up was relatively short because of the vicissitudes of the U.S. insurance market, which causes many patients to change insurers frequently.
The study was supported by grants from the National Cancer Institute and by Varian Medical Systems. Dr. Smith, lead author Hubert Y. Pan, MD, and others disclosed research support, consulting, and/or travel support from Varian.
SOURCE: Smith BD et al. J Clin Oncol. 2018 Mar 21. doi: 10.1200/JCO.2017.75.5371.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Proton beam therapy is nearly twice as costly as intensity-modulated radiation for prostate cancer.
Major finding: Proton therapy was associated with a 9% lower incidence of urinary toxicities, but at a significantly greater cost than IMRT.
Study details: Retrospective claims data study of 693 men treated with protons compared with 3,465 propensity-matched men treated with IMRT, and 310 men treated with SBRT vs. 3,100 matched men treated with IMRT.
Disclosures: The study was supported by grants from the National Cancer Institute and by Varian Medical Systems. Dr. Smith, lead author Hubert Y. Pan, MD, and others disclosed research support, consulting, and/or travel support from Varian.
Source: Smith BD et al. J Clin Oncol. 2018 Mar 21. doi: 10.1200/JCO.2017.75.5371.
Putting IBD medication risks into perspective
MAUI, HAWAII – Prolonged corticosteroid therapy for inflammatory bowel disease (IBD) was associated with a significantly increased mortality risk compared with anti–tumor necrosis factor therapy in a landmark study spotlighted by Edward V. Loftus Jr., MD, at the Gastroenterology Updates, IBD, Liver Disease meeting.
This was one of several key studies on safety issues involving IBD medications published in the past year. Others highlighted by Dr. Loftus and copanelist William J. Sandborn, MD, included a study that provided persuasive evidence that TNF inhibitors modestly increase lymphoma risk in IBD patients to a degree similar to that of thiopurines, and several reports addressing the question of whether preoperative use of vedolizumab in patients undergoing major abdominal operations for IBD boosts postoperative infection risk.
Mortality impact of prolonged steroids vs. anti-TNF therapy
That will come as an unpleasant surprise to many physicians. There is a widespread reluctance to turn to continuous chronic immunosuppression via anti-TNF therapy in patients with challenging IBD, particularly in elderly individuals with multiple comorbid conditions. Many physicians have heard and read so much about the biologics’ risks of serious adverse events that they opt instead for multiple courses of corticosteroids for disease control. This is a serious mistake, emphasized Dr. Loftus, professor of medicine and director of the IBD Interest Group at the Mayo Clinic in Rochester, Minn.
“When you say, ‘Oh, I’ll just give that patient another prednisone taper, he doesn’t want to start taking a TNF inhibitor,’ you’re actually doing the patient harm. You’re actually affecting the patient’s life expectancy when you do that,” he declared. “The message is, yes, steroids are cheap, steroids are easy, nobody’s afraid of steroids, but you should be afraid of steroids.”
The 1,879 Crohn’s disease patients who entered the cohort as new users of anti-TNF therapy had a subsequent mortality incidence rate of 21.4 per 1,000 person-years, compared with a rate of 30.1 per 1,000 person-years in the 7,694 who entered the study period as prolonged steroid users. In a multivariate analysis accounting for 57 potential confounding factors, this translated to a highly significant 22% relative risk reduction in mortality in the patients who went with anti-TNF therapy (Am J Gastroenterol. 2018 Jan 16. doi: 10.1038/ajg.2017.479).
A similar trend was seen in the ulcerative colitis cohort. The 459 ulcerative colitis patients who entered the cohort as new anti-TNF therapy users had a mortality incidence rate of 23.0 per 1,000 person-years, compared with a rate of 30.9 in the 3,224 who received more than 3,000 mg of prednisone in the next 12 months. This represented a 14% relative risk reduction, although this favorable trend did not achieve statistical significance, perhaps because of the smaller size of the ulcerative colitis cohort.
In addition to demonstrably greater life expectancy, anti-TNF therapy offered additional benefits: a 32% reduction in the risk of major adverse cardiovascular events and a 46% lower incidence of hip fracture.
Dr. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California, San Diego, spun the study data another way: “It shows the number needed to kill is 33. So for every 33 patients you put on prolonged corticosteroids, you’re killing one extra patient by doing that. Of course, you probably blame it on their age and comorbidities, but this is it. This is the data.”
TNF blockers, thiopurines, and lymphoma
The use of thiopurines for treatment of IBD is widely recognized to be associated with a small but real increased risk of lymphoma. Now a large French national study has demonstrated for the first time that anti-TNF therapy for IBD is also associated with an increased risk that needs to be discussed with patients. And in IBD patients on combination therapy with both classes of medication, that risk jumps to 6.1-fold greater than in unexposed IBD patients (JAMA 2017 Nov 7;318[17]:1679-86).
Dr. Loftus and Dr. Sandborn urged their colleagues to keep this increased risk in perspective in counseling patients by focusing on the modest absolute increase in risk rather than the scarier-sounding relative risk. Notably, two-thirds of lymphomas in the French study occurred in patients not on thiopurines or anti-TNF agents.
“The most interesting thing to me is that we worry and worry about lymphoma, and guess what? In this study and in multiple other studies, the majority of lymphomas occurring in IBD patients have nothing to do with their medications. They’re due to the usual risk factors for lymphoma, which include age and male gender,” Dr. Loftus observed.
The French study included more than 189,000 IBD patients followed for a median of 6.7 years, during which 336 cases of lymphoma occurred. The incidence rate was 0.26 cases per 1,000 person-years in unexposed patients. The rate was significantly higher at 0.54 per 1,000 person-years in those on thiopurine monotherapy, increased to a similar extent at 0.41 cases per 1,000 person-years in patients on anti-TNF monotherapy, and 0.95 per 1,000 person-years in those on combination therapy.
In a multivariate analysis, the lymphoma risk was an adjusted 2.6-fold greater in patients exposed to thiopurine monotherapy than in unexposed patients, 2.41-fold greater in patients exposed to anti-TNF monotherapy, and 6.1-fold greater in those exposed to combination therapy.
“The point I want to make is the lymphoma rates in the thiopurine monotherapy and anti-TNF monotherapy groups are not significantly different. So the claim that’s been out there that the increased lymphoma risk in IBD patients can be completely explained by thiopurines is wrong. This study is showing us that with anti-TNF monotherapy there is still a low-level risk of lymphoma,” Dr. Loftus said.
“It is somewhat eyebrow-raising when you see that relative risk of 6.1, and that’s what patients are going to focus on, but when you counsel patients you have to redirect them to the absolute risk. You can say, ‘Even on combination therapy, your risk is 1 in 1,000,’ ” the gastroenterologist said.
Dr. Sandborn said the lymphoma signal hadn’t been spotted previously because the individual registries of IBD patients on anti-TNF agents are too small to allow for identification of a small increase in risk. The French investigators overcame that limitation by tapping into the country’s national health care system.
“This is a huge dataset and I think the message is unequivocal,” Dr. Sandborn said.
He noted that strongly risk-averse patients may find ustekinumab (Stelara) and vedolizumab (Entyvio) to be attractive treatment options. Neither has any link to lymphoma.
Preoperative vedolizumab and postoperative infection risk
“The overall safety profile of vedolizumab is pretty good,” Dr. Loftus observed. “The one unanswered question is its safety when used within 8-12 weeks of a major abdominal operation.”
It’s a clinically relevant question because vedolizumab selectively inhibits leukocyte migration into the intestinal tract, which could provide a mechanism for impaired postoperative wound healing in patients undergoing major abdominal surgery. And sooner or later a high proportion of IBD patients have a major abdominal operation.
Dr. Loftus and his coinvestigators kicked off a controversy by reporting a 37% incidence of surgical site infections in IBD patients who received vedolizumab within 30 days of a major abdominal operation in a retrospective chart review of the Mayo Clinic experience, a postoperative infection rate strikingly higher than in their patients on anti-TNF or nonbiologic therapy (J Crohns Colitis. 2017 Feb;11[2]:185-90).
This prompted investigators at the University of Chicago to look retrospectively at their institutional experience. They reported no increased risk in IBD patients on vedolizumab (Am J Gastroenterol. 2017 Sep;112[9]:1423-9). Neither did Belgian gastroenterologists at the Catholic University of Leuven (J Crohns Colitis. 2017 Oct 27;11[11]:1353-61).
Most recently, the Mayo Clinic group along with gastroenterologists at three other U.S. centers collaborated in a multicenter retrospective review of 146 adult IBD patients who received vedolizumab within 12 weeks before major abdominal surgery and 289 who received anti-TNF therapy. In a multivariate analysis, perioperative use of vedolizumab was independently associated with a 5.8-fold increased risk of developing a surgical site infection (J Inflamm Bowel Dis. 2018 Mar 19. doi: 10.1093/ibd/izx076).
Dr. Sandborn, who like Dr. Loftus was a coauthor of the multicenter study, drew back to look at the big picture.
“Is vedolizumab really causal? I doubt it, although it’s remotely possible. But I bet vedolizumab therapy is a really good marker for sick patients, and sick patients have worse operative outcomes, so we ought to be conservative with their surgery. My read of this is this [postoperative infection risk] isn’t unique to vedolizumab. Just be careful with sick patients when you’re operating and do more conservative surgeries,” he said.
Both gastroenterologists reported serving as consultants to and receiving research grants from numerous pharmaceutical companies.
MAUI, HAWAII – Prolonged corticosteroid therapy for inflammatory bowel disease (IBD) was associated with a significantly increased mortality risk compared with anti–tumor necrosis factor therapy in a landmark study spotlighted by Edward V. Loftus Jr., MD, at the Gastroenterology Updates, IBD, Liver Disease meeting.
This was one of several key studies on safety issues involving IBD medications published in the past year. Others highlighted by Dr. Loftus and copanelist William J. Sandborn, MD, included a study that provided persuasive evidence that TNF inhibitors modestly increase lymphoma risk in IBD patients to a degree similar to that of thiopurines, and several reports addressing the question of whether preoperative use of vedolizumab in patients undergoing major abdominal operations for IBD boosts postoperative infection risk.
Mortality impact of prolonged steroids vs. anti-TNF therapy
That will come as an unpleasant surprise to many physicians. There is a widespread reluctance to turn to continuous chronic immunosuppression via anti-TNF therapy in patients with challenging IBD, particularly in elderly individuals with multiple comorbid conditions. Many physicians have heard and read so much about the biologics’ risks of serious adverse events that they opt instead for multiple courses of corticosteroids for disease control. This is a serious mistake, emphasized Dr. Loftus, professor of medicine and director of the IBD Interest Group at the Mayo Clinic in Rochester, Minn.
“When you say, ‘Oh, I’ll just give that patient another prednisone taper, he doesn’t want to start taking a TNF inhibitor,’ you’re actually doing the patient harm. You’re actually affecting the patient’s life expectancy when you do that,” he declared. “The message is, yes, steroids are cheap, steroids are easy, nobody’s afraid of steroids, but you should be afraid of steroids.”
The 1,879 Crohn’s disease patients who entered the cohort as new users of anti-TNF therapy had a subsequent mortality incidence rate of 21.4 per 1,000 person-years, compared with a rate of 30.1 per 1,000 person-years in the 7,694 who entered the study period as prolonged steroid users. In a multivariate analysis accounting for 57 potential confounding factors, this translated to a highly significant 22% relative risk reduction in mortality in the patients who went with anti-TNF therapy (Am J Gastroenterol. 2018 Jan 16. doi: 10.1038/ajg.2017.479).
A similar trend was seen in the ulcerative colitis cohort. The 459 ulcerative colitis patients who entered the cohort as new anti-TNF therapy users had a mortality incidence rate of 23.0 per 1,000 person-years, compared with a rate of 30.9 in the 3,224 who received more than 3,000 mg of prednisone in the next 12 months. This represented a 14% relative risk reduction, although this favorable trend did not achieve statistical significance, perhaps because of the smaller size of the ulcerative colitis cohort.
In addition to demonstrably greater life expectancy, anti-TNF therapy offered additional benefits: a 32% reduction in the risk of major adverse cardiovascular events and a 46% lower incidence of hip fracture.
Dr. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California, San Diego, spun the study data another way: “It shows the number needed to kill is 33. So for every 33 patients you put on prolonged corticosteroids, you’re killing one extra patient by doing that. Of course, you probably blame it on their age and comorbidities, but this is it. This is the data.”
TNF blockers, thiopurines, and lymphoma
The use of thiopurines for treatment of IBD is widely recognized to be associated with a small but real increased risk of lymphoma. Now a large French national study has demonstrated for the first time that anti-TNF therapy for IBD is also associated with an increased risk that needs to be discussed with patients. And in IBD patients on combination therapy with both classes of medication, that risk jumps to 6.1-fold greater than in unexposed IBD patients (JAMA 2017 Nov 7;318[17]:1679-86).
Dr. Loftus and Dr. Sandborn urged their colleagues to keep this increased risk in perspective in counseling patients by focusing on the modest absolute increase in risk rather than the scarier-sounding relative risk. Notably, two-thirds of lymphomas in the French study occurred in patients not on thiopurines or anti-TNF agents.
“The most interesting thing to me is that we worry and worry about lymphoma, and guess what? In this study and in multiple other studies, the majority of lymphomas occurring in IBD patients have nothing to do with their medications. They’re due to the usual risk factors for lymphoma, which include age and male gender,” Dr. Loftus observed.
The French study included more than 189,000 IBD patients followed for a median of 6.7 years, during which 336 cases of lymphoma occurred. The incidence rate was 0.26 cases per 1,000 person-years in unexposed patients. The rate was significantly higher at 0.54 per 1,000 person-years in those on thiopurine monotherapy, increased to a similar extent at 0.41 cases per 1,000 person-years in patients on anti-TNF monotherapy, and 0.95 per 1,000 person-years in those on combination therapy.
In a multivariate analysis, the lymphoma risk was an adjusted 2.6-fold greater in patients exposed to thiopurine monotherapy than in unexposed patients, 2.41-fold greater in patients exposed to anti-TNF monotherapy, and 6.1-fold greater in those exposed to combination therapy.
“The point I want to make is the lymphoma rates in the thiopurine monotherapy and anti-TNF monotherapy groups are not significantly different. So the claim that’s been out there that the increased lymphoma risk in IBD patients can be completely explained by thiopurines is wrong. This study is showing us that with anti-TNF monotherapy there is still a low-level risk of lymphoma,” Dr. Loftus said.
“It is somewhat eyebrow-raising when you see that relative risk of 6.1, and that’s what patients are going to focus on, but when you counsel patients you have to redirect them to the absolute risk. You can say, ‘Even on combination therapy, your risk is 1 in 1,000,’ ” the gastroenterologist said.
Dr. Sandborn said the lymphoma signal hadn’t been spotted previously because the individual registries of IBD patients on anti-TNF agents are too small to allow for identification of a small increase in risk. The French investigators overcame that limitation by tapping into the country’s national health care system.
“This is a huge dataset and I think the message is unequivocal,” Dr. Sandborn said.
He noted that strongly risk-averse patients may find ustekinumab (Stelara) and vedolizumab (Entyvio) to be attractive treatment options. Neither has any link to lymphoma.
Preoperative vedolizumab and postoperative infection risk
“The overall safety profile of vedolizumab is pretty good,” Dr. Loftus observed. “The one unanswered question is its safety when used within 8-12 weeks of a major abdominal operation.”
It’s a clinically relevant question because vedolizumab selectively inhibits leukocyte migration into the intestinal tract, which could provide a mechanism for impaired postoperative wound healing in patients undergoing major abdominal surgery. And sooner or later a high proportion of IBD patients have a major abdominal operation.
Dr. Loftus and his coinvestigators kicked off a controversy by reporting a 37% incidence of surgical site infections in IBD patients who received vedolizumab within 30 days of a major abdominal operation in a retrospective chart review of the Mayo Clinic experience, a postoperative infection rate strikingly higher than in their patients on anti-TNF or nonbiologic therapy (J Crohns Colitis. 2017 Feb;11[2]:185-90).
This prompted investigators at the University of Chicago to look retrospectively at their institutional experience. They reported no increased risk in IBD patients on vedolizumab (Am J Gastroenterol. 2017 Sep;112[9]:1423-9). Neither did Belgian gastroenterologists at the Catholic University of Leuven (J Crohns Colitis. 2017 Oct 27;11[11]:1353-61).
Most recently, the Mayo Clinic group along with gastroenterologists at three other U.S. centers collaborated in a multicenter retrospective review of 146 adult IBD patients who received vedolizumab within 12 weeks before major abdominal surgery and 289 who received anti-TNF therapy. In a multivariate analysis, perioperative use of vedolizumab was independently associated with a 5.8-fold increased risk of developing a surgical site infection (J Inflamm Bowel Dis. 2018 Mar 19. doi: 10.1093/ibd/izx076).
Dr. Sandborn, who like Dr. Loftus was a coauthor of the multicenter study, drew back to look at the big picture.
“Is vedolizumab really causal? I doubt it, although it’s remotely possible. But I bet vedolizumab therapy is a really good marker for sick patients, and sick patients have worse operative outcomes, so we ought to be conservative with their surgery. My read of this is this [postoperative infection risk] isn’t unique to vedolizumab. Just be careful with sick patients when you’re operating and do more conservative surgeries,” he said.
Both gastroenterologists reported serving as consultants to and receiving research grants from numerous pharmaceutical companies.
MAUI, HAWAII – Prolonged corticosteroid therapy for inflammatory bowel disease (IBD) was associated with a significantly increased mortality risk compared with anti–tumor necrosis factor therapy in a landmark study spotlighted by Edward V. Loftus Jr., MD, at the Gastroenterology Updates, IBD, Liver Disease meeting.
This was one of several key studies on safety issues involving IBD medications published in the past year. Others highlighted by Dr. Loftus and copanelist William J. Sandborn, MD, included a study that provided persuasive evidence that TNF inhibitors modestly increase lymphoma risk in IBD patients to a degree similar to that of thiopurines, and several reports addressing the question of whether preoperative use of vedolizumab in patients undergoing major abdominal operations for IBD boosts postoperative infection risk.
Mortality impact of prolonged steroids vs. anti-TNF therapy
That will come as an unpleasant surprise to many physicians. There is a widespread reluctance to turn to continuous chronic immunosuppression via anti-TNF therapy in patients with challenging IBD, particularly in elderly individuals with multiple comorbid conditions. Many physicians have heard and read so much about the biologics’ risks of serious adverse events that they opt instead for multiple courses of corticosteroids for disease control. This is a serious mistake, emphasized Dr. Loftus, professor of medicine and director of the IBD Interest Group at the Mayo Clinic in Rochester, Minn.
“When you say, ‘Oh, I’ll just give that patient another prednisone taper, he doesn’t want to start taking a TNF inhibitor,’ you’re actually doing the patient harm. You’re actually affecting the patient’s life expectancy when you do that,” he declared. “The message is, yes, steroids are cheap, steroids are easy, nobody’s afraid of steroids, but you should be afraid of steroids.”
The 1,879 Crohn’s disease patients who entered the cohort as new users of anti-TNF therapy had a subsequent mortality incidence rate of 21.4 per 1,000 person-years, compared with a rate of 30.1 per 1,000 person-years in the 7,694 who entered the study period as prolonged steroid users. In a multivariate analysis accounting for 57 potential confounding factors, this translated to a highly significant 22% relative risk reduction in mortality in the patients who went with anti-TNF therapy (Am J Gastroenterol. 2018 Jan 16. doi: 10.1038/ajg.2017.479).
A similar trend was seen in the ulcerative colitis cohort. The 459 ulcerative colitis patients who entered the cohort as new anti-TNF therapy users had a mortality incidence rate of 23.0 per 1,000 person-years, compared with a rate of 30.9 in the 3,224 who received more than 3,000 mg of prednisone in the next 12 months. This represented a 14% relative risk reduction, although this favorable trend did not achieve statistical significance, perhaps because of the smaller size of the ulcerative colitis cohort.
In addition to demonstrably greater life expectancy, anti-TNF therapy offered additional benefits: a 32% reduction in the risk of major adverse cardiovascular events and a 46% lower incidence of hip fracture.
Dr. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California, San Diego, spun the study data another way: “It shows the number needed to kill is 33. So for every 33 patients you put on prolonged corticosteroids, you’re killing one extra patient by doing that. Of course, you probably blame it on their age and comorbidities, but this is it. This is the data.”
TNF blockers, thiopurines, and lymphoma
The use of thiopurines for treatment of IBD is widely recognized to be associated with a small but real increased risk of lymphoma. Now a large French national study has demonstrated for the first time that anti-TNF therapy for IBD is also associated with an increased risk that needs to be discussed with patients. And in IBD patients on combination therapy with both classes of medication, that risk jumps to 6.1-fold greater than in unexposed IBD patients (JAMA 2017 Nov 7;318[17]:1679-86).
Dr. Loftus and Dr. Sandborn urged their colleagues to keep this increased risk in perspective in counseling patients by focusing on the modest absolute increase in risk rather than the scarier-sounding relative risk. Notably, two-thirds of lymphomas in the French study occurred in patients not on thiopurines or anti-TNF agents.
“The most interesting thing to me is that we worry and worry about lymphoma, and guess what? In this study and in multiple other studies, the majority of lymphomas occurring in IBD patients have nothing to do with their medications. They’re due to the usual risk factors for lymphoma, which include age and male gender,” Dr. Loftus observed.
The French study included more than 189,000 IBD patients followed for a median of 6.7 years, during which 336 cases of lymphoma occurred. The incidence rate was 0.26 cases per 1,000 person-years in unexposed patients. The rate was significantly higher at 0.54 per 1,000 person-years in those on thiopurine monotherapy, increased to a similar extent at 0.41 cases per 1,000 person-years in patients on anti-TNF monotherapy, and 0.95 per 1,000 person-years in those on combination therapy.
In a multivariate analysis, the lymphoma risk was an adjusted 2.6-fold greater in patients exposed to thiopurine monotherapy than in unexposed patients, 2.41-fold greater in patients exposed to anti-TNF monotherapy, and 6.1-fold greater in those exposed to combination therapy.
“The point I want to make is the lymphoma rates in the thiopurine monotherapy and anti-TNF monotherapy groups are not significantly different. So the claim that’s been out there that the increased lymphoma risk in IBD patients can be completely explained by thiopurines is wrong. This study is showing us that with anti-TNF monotherapy there is still a low-level risk of lymphoma,” Dr. Loftus said.
“It is somewhat eyebrow-raising when you see that relative risk of 6.1, and that’s what patients are going to focus on, but when you counsel patients you have to redirect them to the absolute risk. You can say, ‘Even on combination therapy, your risk is 1 in 1,000,’ ” the gastroenterologist said.
Dr. Sandborn said the lymphoma signal hadn’t been spotted previously because the individual registries of IBD patients on anti-TNF agents are too small to allow for identification of a small increase in risk. The French investigators overcame that limitation by tapping into the country’s national health care system.
“This is a huge dataset and I think the message is unequivocal,” Dr. Sandborn said.
He noted that strongly risk-averse patients may find ustekinumab (Stelara) and vedolizumab (Entyvio) to be attractive treatment options. Neither has any link to lymphoma.
Preoperative vedolizumab and postoperative infection risk
“The overall safety profile of vedolizumab is pretty good,” Dr. Loftus observed. “The one unanswered question is its safety when used within 8-12 weeks of a major abdominal operation.”
It’s a clinically relevant question because vedolizumab selectively inhibits leukocyte migration into the intestinal tract, which could provide a mechanism for impaired postoperative wound healing in patients undergoing major abdominal surgery. And sooner or later a high proportion of IBD patients have a major abdominal operation.
Dr. Loftus and his coinvestigators kicked off a controversy by reporting a 37% incidence of surgical site infections in IBD patients who received vedolizumab within 30 days of a major abdominal operation in a retrospective chart review of the Mayo Clinic experience, a postoperative infection rate strikingly higher than in their patients on anti-TNF or nonbiologic therapy (J Crohns Colitis. 2017 Feb;11[2]:185-90).
This prompted investigators at the University of Chicago to look retrospectively at their institutional experience. They reported no increased risk in IBD patients on vedolizumab (Am J Gastroenterol. 2017 Sep;112[9]:1423-9). Neither did Belgian gastroenterologists at the Catholic University of Leuven (J Crohns Colitis. 2017 Oct 27;11[11]:1353-61).
Most recently, the Mayo Clinic group along with gastroenterologists at three other U.S. centers collaborated in a multicenter retrospective review of 146 adult IBD patients who received vedolizumab within 12 weeks before major abdominal surgery and 289 who received anti-TNF therapy. In a multivariate analysis, perioperative use of vedolizumab was independently associated with a 5.8-fold increased risk of developing a surgical site infection (J Inflamm Bowel Dis. 2018 Mar 19. doi: 10.1093/ibd/izx076).
Dr. Sandborn, who like Dr. Loftus was a coauthor of the multicenter study, drew back to look at the big picture.
“Is vedolizumab really causal? I doubt it, although it’s remotely possible. But I bet vedolizumab therapy is a really good marker for sick patients, and sick patients have worse operative outcomes, so we ought to be conservative with their surgery. My read of this is this [postoperative infection risk] isn’t unique to vedolizumab. Just be careful with sick patients when you’re operating and do more conservative surgeries,” he said.
Both gastroenterologists reported serving as consultants to and receiving research grants from numerous pharmaceutical companies.
EXPERT ANALYSIS FROM GUILD 2018
Xenon imaging could detect lung involvement after HSCT
SALT LAKE CITY – Hyperpolarized xenon-129 magnetic resonance imaging, or 129Xe MRI, showed strong promise for revealing early lung ventilation deficits in pediatric hematopoietic stem cell transplant (HSCT) patients in a proof-of-concept study.
The use of hyperpolarized xenon gas in this setting remains investigational, but is emerging as a safe non-ionizing approach for mapping and quantifying regional airway obstruction in the pediatric population. It has been shown to be more sensitive to early disease than the current clinical gold standard of measuring forced expiratory volume in 1 second (FEV1) by spirometry, Laura L. Walkup, PhD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The 129Xe MRI provides regional information that spirometry cannot, allowing for a targeted approach to planned procedures such as bronchoscopy, said Dr. Walkup of Cincinnati Children’s Hospital Medical Center.
“We hypothesized that hyperpolarized 129Xe MRI would be sensitive to lung abnormalities in the pediatric HSCT population,” she said.
Of 13 patients aged 6-13 years (mean, 10 years) who were enrolled in the study and underwent 129XeMRI, 9 also completed spirometry successfully, and the average FEV1 in those patients was 83% of the predicted value.
Ventilation deficits were apparent on the 129Xe MRI imaging in 8 of the 13 subjects and varied in regional distribution. The whole-lung 129Xe ventilation defect percentage for the HSCT group was 14%, which was significantly greater than the approximately 6% ventilation defect percentage in a cohort of age-matched controls, Dr. Walkup said, noting that ventilation deficits were seen in three of four subjects who were unable to complete reliable spirometry.
“So those are lung abnormalities that may have otherwise gone undetected,” she said, adding that hyperpolarized xenon gas also highlighted the wide individual variation in ventilation, even among cases with similar FEV1 percentages.
The findings are notable, because pulmonary complications such as bronchiolitis obliterans are a major source of morbidity and mortality in the pediatric HSCT population, and an accurate and early diagnostic tool identifying the location and severity of suspected obstructive lung pathology following HSCT is desperately needed, she said.
The HSCT patients in the current study included four boys and nine girls. Isotopically-enriched xenon gas (86% 129Xe) was hyperpolarized using a commercial polarizer and images were acquired during a breath hold of up to 16 seconds and up to 1 L of xenon gas. Conventional anatomic MR images also were acquired.
The 129Xe ventilation was quantified using a less than 60% mean whole-lung 129Xe signal threshold, and was compared to FEV1 percentage predicted as measured via spirometry.
The procedure was well tolerated by all patients, Dr. Walkup said, noting that no patients withdrew from the study, and all were able to maintain the required breath hold.
Drops in blood oxygen saturation level did occur, but were transient and resolved within 10-30 seconds of normal breathing. Further, there were no changes in heart rate during imaging, and any side effects related to xenon, such as tingling in extremities, dizziness, or euphoria, were also quickly resolved with normal breathing, she said.
“There were no serious adverse events related to the study ... these results are in good agreement with previously published safety assessments of xenon in kids and in adults, and at our institution we routinely perform xenon imaging in children as young as age 6,” she added.
The findings, which are consistent with those seen in studies of other conditions such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease, suggest that 129Xe MRI is an emerging modality with strong translational potential for detecting early pulmonary involvement following HSCT, she said.
“The real power of the xenon MRI is the spatial information that it provides; we can use that information to plan targeted procedures like bronchoscopy and biopsies ... and since it is non-ionizing, it may be used serially to assess disease progression or response to an intervention,” Dr. Walkup said.
She noted, however, that because it is not yet approved by the Food and Drug Administration, and because it requires specialized expertise and hardware, it is available at only a handful of centers worldwide.
There is a long way to go before the technology will be widely clinically implemented, but work is ongoing at Cincinnati Children’s Hospital to determine how xenon MRI may play a role in pulmonary screening of patients, she said.
Dr. Walkup reported having no financial disclosures.
SOURCE: Walkup L et al. 2018 BMT Tandem Meetings Abstract 56.
SALT LAKE CITY – Hyperpolarized xenon-129 magnetic resonance imaging, or 129Xe MRI, showed strong promise for revealing early lung ventilation deficits in pediatric hematopoietic stem cell transplant (HSCT) patients in a proof-of-concept study.
The use of hyperpolarized xenon gas in this setting remains investigational, but is emerging as a safe non-ionizing approach for mapping and quantifying regional airway obstruction in the pediatric population. It has been shown to be more sensitive to early disease than the current clinical gold standard of measuring forced expiratory volume in 1 second (FEV1) by spirometry, Laura L. Walkup, PhD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The 129Xe MRI provides regional information that spirometry cannot, allowing for a targeted approach to planned procedures such as bronchoscopy, said Dr. Walkup of Cincinnati Children’s Hospital Medical Center.
“We hypothesized that hyperpolarized 129Xe MRI would be sensitive to lung abnormalities in the pediatric HSCT population,” she said.
Of 13 patients aged 6-13 years (mean, 10 years) who were enrolled in the study and underwent 129XeMRI, 9 also completed spirometry successfully, and the average FEV1 in those patients was 83% of the predicted value.
Ventilation deficits were apparent on the 129Xe MRI imaging in 8 of the 13 subjects and varied in regional distribution. The whole-lung 129Xe ventilation defect percentage for the HSCT group was 14%, which was significantly greater than the approximately 6% ventilation defect percentage in a cohort of age-matched controls, Dr. Walkup said, noting that ventilation deficits were seen in three of four subjects who were unable to complete reliable spirometry.
“So those are lung abnormalities that may have otherwise gone undetected,” she said, adding that hyperpolarized xenon gas also highlighted the wide individual variation in ventilation, even among cases with similar FEV1 percentages.
The findings are notable, because pulmonary complications such as bronchiolitis obliterans are a major source of morbidity and mortality in the pediatric HSCT population, and an accurate and early diagnostic tool identifying the location and severity of suspected obstructive lung pathology following HSCT is desperately needed, she said.
The HSCT patients in the current study included four boys and nine girls. Isotopically-enriched xenon gas (86% 129Xe) was hyperpolarized using a commercial polarizer and images were acquired during a breath hold of up to 16 seconds and up to 1 L of xenon gas. Conventional anatomic MR images also were acquired.
The 129Xe ventilation was quantified using a less than 60% mean whole-lung 129Xe signal threshold, and was compared to FEV1 percentage predicted as measured via spirometry.
The procedure was well tolerated by all patients, Dr. Walkup said, noting that no patients withdrew from the study, and all were able to maintain the required breath hold.
Drops in blood oxygen saturation level did occur, but were transient and resolved within 10-30 seconds of normal breathing. Further, there were no changes in heart rate during imaging, and any side effects related to xenon, such as tingling in extremities, dizziness, or euphoria, were also quickly resolved with normal breathing, she said.
“There were no serious adverse events related to the study ... these results are in good agreement with previously published safety assessments of xenon in kids and in adults, and at our institution we routinely perform xenon imaging in children as young as age 6,” she added.
The findings, which are consistent with those seen in studies of other conditions such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease, suggest that 129Xe MRI is an emerging modality with strong translational potential for detecting early pulmonary involvement following HSCT, she said.
“The real power of the xenon MRI is the spatial information that it provides; we can use that information to plan targeted procedures like bronchoscopy and biopsies ... and since it is non-ionizing, it may be used serially to assess disease progression or response to an intervention,” Dr. Walkup said.
She noted, however, that because it is not yet approved by the Food and Drug Administration, and because it requires specialized expertise and hardware, it is available at only a handful of centers worldwide.
There is a long way to go before the technology will be widely clinically implemented, but work is ongoing at Cincinnati Children’s Hospital to determine how xenon MRI may play a role in pulmonary screening of patients, she said.
Dr. Walkup reported having no financial disclosures.
SOURCE: Walkup L et al. 2018 BMT Tandem Meetings Abstract 56.
SALT LAKE CITY – Hyperpolarized xenon-129 magnetic resonance imaging, or 129Xe MRI, showed strong promise for revealing early lung ventilation deficits in pediatric hematopoietic stem cell transplant (HSCT) patients in a proof-of-concept study.
The use of hyperpolarized xenon gas in this setting remains investigational, but is emerging as a safe non-ionizing approach for mapping and quantifying regional airway obstruction in the pediatric population. It has been shown to be more sensitive to early disease than the current clinical gold standard of measuring forced expiratory volume in 1 second (FEV1) by spirometry, Laura L. Walkup, PhD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The 129Xe MRI provides regional information that spirometry cannot, allowing for a targeted approach to planned procedures such as bronchoscopy, said Dr. Walkup of Cincinnati Children’s Hospital Medical Center.
“We hypothesized that hyperpolarized 129Xe MRI would be sensitive to lung abnormalities in the pediatric HSCT population,” she said.
Of 13 patients aged 6-13 years (mean, 10 years) who were enrolled in the study and underwent 129XeMRI, 9 also completed spirometry successfully, and the average FEV1 in those patients was 83% of the predicted value.
Ventilation deficits were apparent on the 129Xe MRI imaging in 8 of the 13 subjects and varied in regional distribution. The whole-lung 129Xe ventilation defect percentage for the HSCT group was 14%, which was significantly greater than the approximately 6% ventilation defect percentage in a cohort of age-matched controls, Dr. Walkup said, noting that ventilation deficits were seen in three of four subjects who were unable to complete reliable spirometry.
“So those are lung abnormalities that may have otherwise gone undetected,” she said, adding that hyperpolarized xenon gas also highlighted the wide individual variation in ventilation, even among cases with similar FEV1 percentages.
The findings are notable, because pulmonary complications such as bronchiolitis obliterans are a major source of morbidity and mortality in the pediatric HSCT population, and an accurate and early diagnostic tool identifying the location and severity of suspected obstructive lung pathology following HSCT is desperately needed, she said.
The HSCT patients in the current study included four boys and nine girls. Isotopically-enriched xenon gas (86% 129Xe) was hyperpolarized using a commercial polarizer and images were acquired during a breath hold of up to 16 seconds and up to 1 L of xenon gas. Conventional anatomic MR images also were acquired.
The 129Xe ventilation was quantified using a less than 60% mean whole-lung 129Xe signal threshold, and was compared to FEV1 percentage predicted as measured via spirometry.
The procedure was well tolerated by all patients, Dr. Walkup said, noting that no patients withdrew from the study, and all were able to maintain the required breath hold.
Drops in blood oxygen saturation level did occur, but were transient and resolved within 10-30 seconds of normal breathing. Further, there were no changes in heart rate during imaging, and any side effects related to xenon, such as tingling in extremities, dizziness, or euphoria, were also quickly resolved with normal breathing, she said.
“There were no serious adverse events related to the study ... these results are in good agreement with previously published safety assessments of xenon in kids and in adults, and at our institution we routinely perform xenon imaging in children as young as age 6,” she added.
The findings, which are consistent with those seen in studies of other conditions such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease, suggest that 129Xe MRI is an emerging modality with strong translational potential for detecting early pulmonary involvement following HSCT, she said.
“The real power of the xenon MRI is the spatial information that it provides; we can use that information to plan targeted procedures like bronchoscopy and biopsies ... and since it is non-ionizing, it may be used serially to assess disease progression or response to an intervention,” Dr. Walkup said.
She noted, however, that because it is not yet approved by the Food and Drug Administration, and because it requires specialized expertise and hardware, it is available at only a handful of centers worldwide.
There is a long way to go before the technology will be widely clinically implemented, but work is ongoing at Cincinnati Children’s Hospital to determine how xenon MRI may play a role in pulmonary screening of patients, she said.
Dr. Walkup reported having no financial disclosures.
SOURCE: Walkup L et al. 2018 BMT Tandem Meetings Abstract 56.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point: Hyperpolarized 129Xe MRI shows promise for revealing lung ventilation deficits in pediatric HSCT patients.
Major finding: The whole-lung 129Xe ventilation defect percentage was 14% for HSCT group versus 6% for controls; deficits were seen in three of four subjects who were who were unable to complete reliable spirometry.
Study details: A proof-of-concept study involving 13 children.
Disclosures: Dr. Walkup reported having no financial disclosures.
Source: Walkup L et al. 2018 BMT Tandem Meetings. Abstract 56.
Podcasts
you need no effort to enjoy them. Indeed, you can be actively engaged elsewhere: running, cycling, commuting, or simply loafing. The detail and richness of the sound also creates an intimate connection with the host in a way other mediums cannot. It feels like they are talking only to you.
Yet, there is a problem with podcasts: There are too many of them. If I listened continuously to the episodes in my queue it would take 6 months. I suppose I could see patients and listen at the same time. (Yes, I have a problem.) I also own far more books than I’ll ever read. Aspirational, I call it.
If, like me, you’re unable to dedicate your life to consuming podcasts, you might appreciate a few recommendations. Here’s a charcuterie board of tasty bits, carefully curated to avoid political allergies and Dunning-Kruger references.
1. Physicians Practice. It’s one of the oldest podcasts running and addresses a wide range of issues affecting health care professionals and the industry at large. Episodes are short (typically under 10 minutes) and address a range of issues relevant to both young and seasoned physicians With scores of podcasts from which to choose, I suggest just selecting one and jumping in. With episode titles such as “The Patient Empathy Problem Physicians Must Face” and “EHRs Not Designed with Real People in Mind, Expert Opines,” it’s easy to do.
2. UpToDate. If you’re looking for straight clinical talk buttressed with scientific evidence, then download UpToDate. Episodes typically feature interviews with one or two respected physician leaders who share their clinical findings. You can select episode topics based upon clinical specialty or simply start listening. Here is a sampling of topics: sentinel lymph node metastasis in melanoma; dexamethasone and acute pharyngitis pain in adults; management of anticoagulation for patients with nonvalvular atrial fibrillation. UpToDate states that it is entirely funded by user subscriptions and does not accept advertising or funding unrelated to subscriptions.
3. Bedside Rounds. The tagline for the podcast Bedside Rounds is “Because medicine is awesome.” This is not meant to be ironic. Creator and host, Adam Rodman, MD, a global health hospitalist who divides his time between Boston (at the Beth Israel Deaconess Medical Center) and Botswana, is that eager kid in the classroom who sits in the front row just because he’s so excited to be there. Unlike UpToDate, which focuses on current advances in clinical medicine, Bedside Rounds explores both the science and art of medicine through captivating stories heavily rooted in the history of medicine. Instead of brushing the dust off of your old medical books, tune in to Bedside Rounds to hear stories such as “Bone Portraits,” which explores the history of radiation, and “Curse of the Ninth,” which explores whether or not composer Gustav Mahler, worked his heart murmur into his famous Ninth Symphony.
4. The Adventures of Memento Mori. Creator and host, D.S. Moss, has created a podcast about death, or, to be more upbeat, the quest for the meaning of life. A screenwriter/producer, Mr. Moss deep dives into all things death. But it’s not as depressing as it sounds. “Memento mori,” he explains, is Latin for being mindful that you will die. As a result, Mr. Moss has created his podcast with the goal of encouraging listeners to live a more engaged, mindful, and meaningful life. We can apply many of these lessons to our own professional and personal lives and perhaps learn some ways to help our patients cope with terminal illness and mortality. Topics range from the emotional (“Thoughts in Passing,” which features several hospice patients) to the technological (“Digital Afterlife,” which explores what our digital legacies say about us), to the scientific (“The Science of Immortality,” which explores venture capital’s movement in the science of living forever).
5. Invisibilia. Invisibilia – Latin for invisible things – is an exploration of the “unseeable forces” that shape human behavior – our beliefs, thoughts, and assumptions. Hosts Alix Spiegel and Hanna Rosin, both of National Public Radio, seamlessly weave storytelling, interviewing, and scientific data to tackle a wide range of topics such as prejudice and implicit bias in “The Culture Inside” to people’s desire for radical change in “Bubble Hopping.” Part behavioral economics, part neuroscience, part sociology, part pop culture, fully fascinating.
6. Jocko Podcast. Jocko Willink, a retired Navy SEAL and motivational author and speaker, along with Echo Charles, conduct compelling interviews with leaders from various fields including the military, sports, medicine, and the arts. Mr. Willink’s style of motivation is refreshingly honest and direct. I have taken tips from his podcasts that have helped me become a more efficient and energetic physician and leader. Two fundamental themes that run through his podcast are the value of treating people well and of living your life with discipline. It gets you a long way as a Navy SEAL, as well as a doctor. One of my personal favorites is Episode 69: “The Real Top Gun. Battlefield, Work, and Life are Identical” with Elite Marine Fighter Pilot, David Berke. If that doesn’t pique your interest, no worries; there are over 100 episodes from which to choose.
There are many, many more podcasts I’d like to recommend, but I’ll show some discipline (thanks, Jocko) and save them for next time.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@frontlinemedcom.com.
you need no effort to enjoy them. Indeed, you can be actively engaged elsewhere: running, cycling, commuting, or simply loafing. The detail and richness of the sound also creates an intimate connection with the host in a way other mediums cannot. It feels like they are talking only to you.
Yet, there is a problem with podcasts: There are too many of them. If I listened continuously to the episodes in my queue it would take 6 months. I suppose I could see patients and listen at the same time. (Yes, I have a problem.) I also own far more books than I’ll ever read. Aspirational, I call it.
If, like me, you’re unable to dedicate your life to consuming podcasts, you might appreciate a few recommendations. Here’s a charcuterie board of tasty bits, carefully curated to avoid political allergies and Dunning-Kruger references.
1. Physicians Practice. It’s one of the oldest podcasts running and addresses a wide range of issues affecting health care professionals and the industry at large. Episodes are short (typically under 10 minutes) and address a range of issues relevant to both young and seasoned physicians With scores of podcasts from which to choose, I suggest just selecting one and jumping in. With episode titles such as “The Patient Empathy Problem Physicians Must Face” and “EHRs Not Designed with Real People in Mind, Expert Opines,” it’s easy to do.
2. UpToDate. If you’re looking for straight clinical talk buttressed with scientific evidence, then download UpToDate. Episodes typically feature interviews with one or two respected physician leaders who share their clinical findings. You can select episode topics based upon clinical specialty or simply start listening. Here is a sampling of topics: sentinel lymph node metastasis in melanoma; dexamethasone and acute pharyngitis pain in adults; management of anticoagulation for patients with nonvalvular atrial fibrillation. UpToDate states that it is entirely funded by user subscriptions and does not accept advertising or funding unrelated to subscriptions.
3. Bedside Rounds. The tagline for the podcast Bedside Rounds is “Because medicine is awesome.” This is not meant to be ironic. Creator and host, Adam Rodman, MD, a global health hospitalist who divides his time between Boston (at the Beth Israel Deaconess Medical Center) and Botswana, is that eager kid in the classroom who sits in the front row just because he’s so excited to be there. Unlike UpToDate, which focuses on current advances in clinical medicine, Bedside Rounds explores both the science and art of medicine through captivating stories heavily rooted in the history of medicine. Instead of brushing the dust off of your old medical books, tune in to Bedside Rounds to hear stories such as “Bone Portraits,” which explores the history of radiation, and “Curse of the Ninth,” which explores whether or not composer Gustav Mahler, worked his heart murmur into his famous Ninth Symphony.
4. The Adventures of Memento Mori. Creator and host, D.S. Moss, has created a podcast about death, or, to be more upbeat, the quest for the meaning of life. A screenwriter/producer, Mr. Moss deep dives into all things death. But it’s not as depressing as it sounds. “Memento mori,” he explains, is Latin for being mindful that you will die. As a result, Mr. Moss has created his podcast with the goal of encouraging listeners to live a more engaged, mindful, and meaningful life. We can apply many of these lessons to our own professional and personal lives and perhaps learn some ways to help our patients cope with terminal illness and mortality. Topics range from the emotional (“Thoughts in Passing,” which features several hospice patients) to the technological (“Digital Afterlife,” which explores what our digital legacies say about us), to the scientific (“The Science of Immortality,” which explores venture capital’s movement in the science of living forever).
5. Invisibilia. Invisibilia – Latin for invisible things – is an exploration of the “unseeable forces” that shape human behavior – our beliefs, thoughts, and assumptions. Hosts Alix Spiegel and Hanna Rosin, both of National Public Radio, seamlessly weave storytelling, interviewing, and scientific data to tackle a wide range of topics such as prejudice and implicit bias in “The Culture Inside” to people’s desire for radical change in “Bubble Hopping.” Part behavioral economics, part neuroscience, part sociology, part pop culture, fully fascinating.
6. Jocko Podcast. Jocko Willink, a retired Navy SEAL and motivational author and speaker, along with Echo Charles, conduct compelling interviews with leaders from various fields including the military, sports, medicine, and the arts. Mr. Willink’s style of motivation is refreshingly honest and direct. I have taken tips from his podcasts that have helped me become a more efficient and energetic physician and leader. Two fundamental themes that run through his podcast are the value of treating people well and of living your life with discipline. It gets you a long way as a Navy SEAL, as well as a doctor. One of my personal favorites is Episode 69: “The Real Top Gun. Battlefield, Work, and Life are Identical” with Elite Marine Fighter Pilot, David Berke. If that doesn’t pique your interest, no worries; there are over 100 episodes from which to choose.
There are many, many more podcasts I’d like to recommend, but I’ll show some discipline (thanks, Jocko) and save them for next time.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@frontlinemedcom.com.
you need no effort to enjoy them. Indeed, you can be actively engaged elsewhere: running, cycling, commuting, or simply loafing. The detail and richness of the sound also creates an intimate connection with the host in a way other mediums cannot. It feels like they are talking only to you.
Yet, there is a problem with podcasts: There are too many of them. If I listened continuously to the episodes in my queue it would take 6 months. I suppose I could see patients and listen at the same time. (Yes, I have a problem.) I also own far more books than I’ll ever read. Aspirational, I call it.
If, like me, you’re unable to dedicate your life to consuming podcasts, you might appreciate a few recommendations. Here’s a charcuterie board of tasty bits, carefully curated to avoid political allergies and Dunning-Kruger references.
1. Physicians Practice. It’s one of the oldest podcasts running and addresses a wide range of issues affecting health care professionals and the industry at large. Episodes are short (typically under 10 minutes) and address a range of issues relevant to both young and seasoned physicians With scores of podcasts from which to choose, I suggest just selecting one and jumping in. With episode titles such as “The Patient Empathy Problem Physicians Must Face” and “EHRs Not Designed with Real People in Mind, Expert Opines,” it’s easy to do.
2. UpToDate. If you’re looking for straight clinical talk buttressed with scientific evidence, then download UpToDate. Episodes typically feature interviews with one or two respected physician leaders who share their clinical findings. You can select episode topics based upon clinical specialty or simply start listening. Here is a sampling of topics: sentinel lymph node metastasis in melanoma; dexamethasone and acute pharyngitis pain in adults; management of anticoagulation for patients with nonvalvular atrial fibrillation. UpToDate states that it is entirely funded by user subscriptions and does not accept advertising or funding unrelated to subscriptions.
3. Bedside Rounds. The tagline for the podcast Bedside Rounds is “Because medicine is awesome.” This is not meant to be ironic. Creator and host, Adam Rodman, MD, a global health hospitalist who divides his time between Boston (at the Beth Israel Deaconess Medical Center) and Botswana, is that eager kid in the classroom who sits in the front row just because he’s so excited to be there. Unlike UpToDate, which focuses on current advances in clinical medicine, Bedside Rounds explores both the science and art of medicine through captivating stories heavily rooted in the history of medicine. Instead of brushing the dust off of your old medical books, tune in to Bedside Rounds to hear stories such as “Bone Portraits,” which explores the history of radiation, and “Curse of the Ninth,” which explores whether or not composer Gustav Mahler, worked his heart murmur into his famous Ninth Symphony.
4. The Adventures of Memento Mori. Creator and host, D.S. Moss, has created a podcast about death, or, to be more upbeat, the quest for the meaning of life. A screenwriter/producer, Mr. Moss deep dives into all things death. But it’s not as depressing as it sounds. “Memento mori,” he explains, is Latin for being mindful that you will die. As a result, Mr. Moss has created his podcast with the goal of encouraging listeners to live a more engaged, mindful, and meaningful life. We can apply many of these lessons to our own professional and personal lives and perhaps learn some ways to help our patients cope with terminal illness and mortality. Topics range from the emotional (“Thoughts in Passing,” which features several hospice patients) to the technological (“Digital Afterlife,” which explores what our digital legacies say about us), to the scientific (“The Science of Immortality,” which explores venture capital’s movement in the science of living forever).
5. Invisibilia. Invisibilia – Latin for invisible things – is an exploration of the “unseeable forces” that shape human behavior – our beliefs, thoughts, and assumptions. Hosts Alix Spiegel and Hanna Rosin, both of National Public Radio, seamlessly weave storytelling, interviewing, and scientific data to tackle a wide range of topics such as prejudice and implicit bias in “The Culture Inside” to people’s desire for radical change in “Bubble Hopping.” Part behavioral economics, part neuroscience, part sociology, part pop culture, fully fascinating.
6. Jocko Podcast. Jocko Willink, a retired Navy SEAL and motivational author and speaker, along with Echo Charles, conduct compelling interviews with leaders from various fields including the military, sports, medicine, and the arts. Mr. Willink’s style of motivation is refreshingly honest and direct. I have taken tips from his podcasts that have helped me become a more efficient and energetic physician and leader. Two fundamental themes that run through his podcast are the value of treating people well and of living your life with discipline. It gets you a long way as a Navy SEAL, as well as a doctor. One of my personal favorites is Episode 69: “The Real Top Gun. Battlefield, Work, and Life are Identical” with Elite Marine Fighter Pilot, David Berke. If that doesn’t pique your interest, no worries; there are over 100 episodes from which to choose.
There are many, many more podcasts I’d like to recommend, but I’ll show some discipline (thanks, Jocko) and save them for next time.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@frontlinemedcom.com.
MDedge Daily News: Avoid warfarin’s polypharmacy perils
Which non-AIDS conditions hint at HIV infection? How San Francisco delivers faster HIV treatment. And red meat may fuel the rise of fatty livers.
Listen to the MDedge Daily News podcast for all the details on today’s top news.
Which non-AIDS conditions hint at HIV infection? How San Francisco delivers faster HIV treatment. And red meat may fuel the rise of fatty livers.
Listen to the MDedge Daily News podcast for all the details on today’s top news.
Which non-AIDS conditions hint at HIV infection? How San Francisco delivers faster HIV treatment. And red meat may fuel the rise of fatty livers.
Listen to the MDedge Daily News podcast for all the details on today’s top news.
Unprecedented Study Gathers Data on Adolescent Development
An “unparalleled dataset” is providing high-quality information on the many factors that influence brain, cognitive, social, and emotional development in children.
The Adolescent Brain Cognitive Development (ABCD) study, involving > 7,500 children aged between 9 and 10 years and their families, is the largest long-term study of brain development and child health in the US. Interim results on about 30 terabytes of data (3 times the size of the Library of Congress collection) obtained from the first 4,500 participants will allow scientists to begin analyzing and publishing novel research, according to Nora Volkow, MD, director of the National Institute on Drug Abuse.
Researchers will be able to examine many aspects of growth and development, such as the impact of sports injuries on developmental outcomes, the relationship between screen time and brain and social development, and which brain pathways are associated with the onset and progression of mental health disorders.
The study aims to enroll 11,500 children by the end of 2018. Participants will be followed for 10 years, with data collected every 6 months through interviews and behavioral testing. Neuroimaging data, including high resolution MRI, are collected every 2 years.
An “unparalleled dataset” is providing high-quality information on the many factors that influence brain, cognitive, social, and emotional development in children.
The Adolescent Brain Cognitive Development (ABCD) study, involving > 7,500 children aged between 9 and 10 years and their families, is the largest long-term study of brain development and child health in the US. Interim results on about 30 terabytes of data (3 times the size of the Library of Congress collection) obtained from the first 4,500 participants will allow scientists to begin analyzing and publishing novel research, according to Nora Volkow, MD, director of the National Institute on Drug Abuse.
Researchers will be able to examine many aspects of growth and development, such as the impact of sports injuries on developmental outcomes, the relationship between screen time and brain and social development, and which brain pathways are associated with the onset and progression of mental health disorders.
The study aims to enroll 11,500 children by the end of 2018. Participants will be followed for 10 years, with data collected every 6 months through interviews and behavioral testing. Neuroimaging data, including high resolution MRI, are collected every 2 years.
An “unparalleled dataset” is providing high-quality information on the many factors that influence brain, cognitive, social, and emotional development in children.
The Adolescent Brain Cognitive Development (ABCD) study, involving > 7,500 children aged between 9 and 10 years and their families, is the largest long-term study of brain development and child health in the US. Interim results on about 30 terabytes of data (3 times the size of the Library of Congress collection) obtained from the first 4,500 participants will allow scientists to begin analyzing and publishing novel research, according to Nora Volkow, MD, director of the National Institute on Drug Abuse.
Researchers will be able to examine many aspects of growth and development, such as the impact of sports injuries on developmental outcomes, the relationship between screen time and brain and social development, and which brain pathways are associated with the onset and progression of mental health disorders.
The study aims to enroll 11,500 children by the end of 2018. Participants will be followed for 10 years, with data collected every 6 months through interviews and behavioral testing. Neuroimaging data, including high resolution MRI, are collected every 2 years.