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Genetic markers may predict response to biologics in rheumatoid arthritis
WASHINGTON – Three gene expression markers appear to predict response to some of the most common and powerful rheumatoid arthritis drugs employed in clinical practice.
In the largest gene-expression study of these drugs to date, researchers from Glasgow found 23 genes that predicted response to TNF inhibitors, and 23 more that predicted response to rituximab. They also found eight genes that predicted positive response to both types of drugs.
Just as important, the team found that 10% of patients in the study had none of the markers, Duncan Porter, MD, said during a press briefing at the annual meeting of the American College of Rheumatology.
If confirmed in independent validation cohorts, the findings could revolutionize medical therapy for rheumatoid arthritis, Dr. Porter said in an interview.
“Right now, the choice of treatment is mostly a flip of the coin,” said Dr. Porter, a rheumatologist at Queen Elizabeth University Hospital in Glasgow. “We don’t have a lot of comparative data to support one drug over the other, and most head-to-head studies show noninferiority.
“So, it would be ideal to be able to identify patients who will respond to one class or the other, and give them the right medicine the first time,” he noted. “If we can do that, we have the beginnings of really meaningful personalized therapy in RA.”
Dr. Porter reported a transcriptome-wide association study of 250 patients with RA who were enrolled in the ORBIT trial (Lancet. 2016 Jul 16;388[10041]:239-47). Dr. Porter was the study’s primary investigator.
ORBIT comprised 295 patients with active, seropositive rheumatoid arthritis who had failed disease-modifying antirheumatic therapy. They were randomized to B-cell depletion with rituximab or to the TNF inhibitors adalimumab or etanercept. ORBIT concluded that clinical response was similar with all three drugs. However, while most patients did well on their assigned drug, no matter which class, 20% failed their initial assignment.
The genetic study examined RNA transcripts in whole blood samples among a subset of the ORBIT patients. Most of the samples (70%) were used to identify markers and created a prediction model; that was then verified in the remaining 30% of samples. Markers were correlated to clinical response associated with rituximab and TNF inhibition. Clinical response was defined as a 1.2-point decline in the Disease Activity Score from baseline to 3 months of therapy.
At least 1 of the 54 genetic response markers was present in 90% of the population; 50% would have responded well to either drug, or 40% to just one of them.
But 10% of the population lacked either of the response markers – a very important finding, Dr. Porter noted, because if identified early, these patients could potentially avoid ineffective medication trials.
The markers’ predictive values were uniformly high, with a sensitivity of 93% and specificity of 91%. The positive predictive value was 96%, and the negative predictive value was 86%. Patients predicted to respond at 3 months were also more likely to have a good response (43% vs. 23%) or remission (23% vs. 10%), as measured by the Disease Activity Score 28 at 12 months.
While Dr. Porter was excited about the findings, he eyed them cautiously.
“The landscape is littered with biomarkers that had great early promise but failed in later validation studies,” he said. “We must be very careful in interpreting this. However, the other response studies have been small, and have not compared two drugs. This study was large with robust results, so we are encouraged.”
Dr Porter is now designing the protocol for a large external validation cohort study, which he hopes to launch in 2017.
Roche funded aspects of the ORBIT trial and the genetic substudy. Dr. Porter has been a consultant for Roche, as well as for AbbVie and Pfizer.
msullivan@frontlinemedcom.comOn Twitter @alz_gal
WASHINGTON – Three gene expression markers appear to predict response to some of the most common and powerful rheumatoid arthritis drugs employed in clinical practice.
In the largest gene-expression study of these drugs to date, researchers from Glasgow found 23 genes that predicted response to TNF inhibitors, and 23 more that predicted response to rituximab. They also found eight genes that predicted positive response to both types of drugs.
Just as important, the team found that 10% of patients in the study had none of the markers, Duncan Porter, MD, said during a press briefing at the annual meeting of the American College of Rheumatology.
If confirmed in independent validation cohorts, the findings could revolutionize medical therapy for rheumatoid arthritis, Dr. Porter said in an interview.
“Right now, the choice of treatment is mostly a flip of the coin,” said Dr. Porter, a rheumatologist at Queen Elizabeth University Hospital in Glasgow. “We don’t have a lot of comparative data to support one drug over the other, and most head-to-head studies show noninferiority.
“So, it would be ideal to be able to identify patients who will respond to one class or the other, and give them the right medicine the first time,” he noted. “If we can do that, we have the beginnings of really meaningful personalized therapy in RA.”
Dr. Porter reported a transcriptome-wide association study of 250 patients with RA who were enrolled in the ORBIT trial (Lancet. 2016 Jul 16;388[10041]:239-47). Dr. Porter was the study’s primary investigator.
ORBIT comprised 295 patients with active, seropositive rheumatoid arthritis who had failed disease-modifying antirheumatic therapy. They were randomized to B-cell depletion with rituximab or to the TNF inhibitors adalimumab or etanercept. ORBIT concluded that clinical response was similar with all three drugs. However, while most patients did well on their assigned drug, no matter which class, 20% failed their initial assignment.
The genetic study examined RNA transcripts in whole blood samples among a subset of the ORBIT patients. Most of the samples (70%) were used to identify markers and created a prediction model; that was then verified in the remaining 30% of samples. Markers were correlated to clinical response associated with rituximab and TNF inhibition. Clinical response was defined as a 1.2-point decline in the Disease Activity Score from baseline to 3 months of therapy.
At least 1 of the 54 genetic response markers was present in 90% of the population; 50% would have responded well to either drug, or 40% to just one of them.
But 10% of the population lacked either of the response markers – a very important finding, Dr. Porter noted, because if identified early, these patients could potentially avoid ineffective medication trials.
The markers’ predictive values were uniformly high, with a sensitivity of 93% and specificity of 91%. The positive predictive value was 96%, and the negative predictive value was 86%. Patients predicted to respond at 3 months were also more likely to have a good response (43% vs. 23%) or remission (23% vs. 10%), as measured by the Disease Activity Score 28 at 12 months.
While Dr. Porter was excited about the findings, he eyed them cautiously.
“The landscape is littered with biomarkers that had great early promise but failed in later validation studies,” he said. “We must be very careful in interpreting this. However, the other response studies have been small, and have not compared two drugs. This study was large with robust results, so we are encouraged.”
Dr Porter is now designing the protocol for a large external validation cohort study, which he hopes to launch in 2017.
Roche funded aspects of the ORBIT trial and the genetic substudy. Dr. Porter has been a consultant for Roche, as well as for AbbVie and Pfizer.
msullivan@frontlinemedcom.comOn Twitter @alz_gal
WASHINGTON – Three gene expression markers appear to predict response to some of the most common and powerful rheumatoid arthritis drugs employed in clinical practice.
In the largest gene-expression study of these drugs to date, researchers from Glasgow found 23 genes that predicted response to TNF inhibitors, and 23 more that predicted response to rituximab. They also found eight genes that predicted positive response to both types of drugs.
Just as important, the team found that 10% of patients in the study had none of the markers, Duncan Porter, MD, said during a press briefing at the annual meeting of the American College of Rheumatology.
If confirmed in independent validation cohorts, the findings could revolutionize medical therapy for rheumatoid arthritis, Dr. Porter said in an interview.
“Right now, the choice of treatment is mostly a flip of the coin,” said Dr. Porter, a rheumatologist at Queen Elizabeth University Hospital in Glasgow. “We don’t have a lot of comparative data to support one drug over the other, and most head-to-head studies show noninferiority.
“So, it would be ideal to be able to identify patients who will respond to one class or the other, and give them the right medicine the first time,” he noted. “If we can do that, we have the beginnings of really meaningful personalized therapy in RA.”
Dr. Porter reported a transcriptome-wide association study of 250 patients with RA who were enrolled in the ORBIT trial (Lancet. 2016 Jul 16;388[10041]:239-47). Dr. Porter was the study’s primary investigator.
ORBIT comprised 295 patients with active, seropositive rheumatoid arthritis who had failed disease-modifying antirheumatic therapy. They were randomized to B-cell depletion with rituximab or to the TNF inhibitors adalimumab or etanercept. ORBIT concluded that clinical response was similar with all three drugs. However, while most patients did well on their assigned drug, no matter which class, 20% failed their initial assignment.
The genetic study examined RNA transcripts in whole blood samples among a subset of the ORBIT patients. Most of the samples (70%) were used to identify markers and created a prediction model; that was then verified in the remaining 30% of samples. Markers were correlated to clinical response associated with rituximab and TNF inhibition. Clinical response was defined as a 1.2-point decline in the Disease Activity Score from baseline to 3 months of therapy.
At least 1 of the 54 genetic response markers was present in 90% of the population; 50% would have responded well to either drug, or 40% to just one of them.
But 10% of the population lacked either of the response markers – a very important finding, Dr. Porter noted, because if identified early, these patients could potentially avoid ineffective medication trials.
The markers’ predictive values were uniformly high, with a sensitivity of 93% and specificity of 91%. The positive predictive value was 96%, and the negative predictive value was 86%. Patients predicted to respond at 3 months were also more likely to have a good response (43% vs. 23%) or remission (23% vs. 10%), as measured by the Disease Activity Score 28 at 12 months.
While Dr. Porter was excited about the findings, he eyed them cautiously.
“The landscape is littered with biomarkers that had great early promise but failed in later validation studies,” he said. “We must be very careful in interpreting this. However, the other response studies have been small, and have not compared two drugs. This study was large with robust results, so we are encouraged.”
Dr Porter is now designing the protocol for a large external validation cohort study, which he hopes to launch in 2017.
Roche funded aspects of the ORBIT trial and the genetic substudy. Dr. Porter has been a consultant for Roche, as well as for AbbVie and Pfizer.
msullivan@frontlinemedcom.comOn Twitter @alz_gal
Key clinical point:
Major finding: The markers’ sensitivity and specificity for clinical response exceeded 90%.
Data source: The genetic-association study comprised 250 patients.
Disclosures: Roche funded aspects of the ORBIT trial and the genetic substudy. Dr. Porter has been a consultant for Roche, as well as for AbbVie and Pfizer.
In era of infliximab, ulcerative colitis surgical outcomes worsen
WASHINGTON – The era of powerful biologics has led to unforeseen surgical outcomes in patients with ulcerative colitis.
Patients undergoing surgery for ulcerative colitis now are 38% more likely to die in the hospital than they were 15 years ago, before infliximab and other biologics were adopted as medical therapy for the disease. A database review covering 18 years found that other surgical outcomes are worse, too, Jonathan Abelson, MD, said at the annual clinical congress of the American College of Surgeons.
“These very powerful agents could be completely eliminating the need for surgery in patients with mild disease, leaving surgery for those who have very advanced disease and didn’t respond well to medical therapy,” said Dr. Abelson, a clinical research fellow at New York–Presbyterian Hospital, N.Y. “We are operating now only on patients with very severe disease, not the wider range of patients we had 15 years ago, when there weren’t as effective medical options.”
He and his colleagues used the New York Statewide Planning and Research Cooperative System (SPARCS) database to identify 7,070 patients who had undergone bowel resection for ulcerative colitis during two epochs: prebiologics (1995-2005) and postbiologics (2006-2013). The cohorts were about evenly split in numbers.
There were some statistically significant differences in baseline characteristics. Patients in epoch 2 were about a year older (51 vs. 50 years). Significantly more of them had at least two major comorbidities (28% vs. 18%). Minimally invasive surgery was significantly more common in epoch 2 (28% vs. 3%).
Significantly more surgeries in epoch 2 were staged into three or more procedures (14% vs. 9%). This finding probably reflects the level of disease severity in those presenting for surgery or the fact that they underwent surgery after recently receiving biologics, Dr. Abelson said.
“One of the limits of this study is that we don’t know exactly the reasons for these one-, two-, or three-stage surgeries. The theory is that patients who were more ill at presentation are more likely to have a multistaged surgery. Another reason could be that if they are on these powerful immunosuppressive regimens, the surgeon might be concerned about not healing well from a definitive one- or two-stage surgery.”
He then conducted a multivariate analysis that controlled for baseline factors, including a variety of individual comorbid conditions. In this analysis, patients in epoch 2 were 38% more likely to die in the hospital and 51% more likely to experience a major postoperative event, like shock, pulmonary embolism, stroke, or heart attack. The chance of a surgical complication was increased by 39%, and these patients were 25% more likely to need a transfusion during surgery than those from epoch 1.
The poorer outcomes held for an at least an entire year after surgery, Dr. Abelson said. At 1 year, patients in epoch 2 were 36% more likely to have a readmission than those in epoch 1. Major events and procedural complications were both 46% more likely. Patients were also 36% more likely to require an additional procedure.
“These are not the outcomes we want to see, especially in this era when our surgical techniques have improved so much,” Dr. Abelson said. “If what this represents, though, is that we are now operating on a higher-risk population, we can’t just say, ‘Well, that’s how it’s going to be.’ We need to figure out how to minimize morbidity and mortality in this high-risk patient population.”
One goal, he suggested, would be to assess response to a biologic regimen earlier in the hopes of determining who will respond well, and moving ahead with surgery in those who don’t.
This is a tough sell for patients, he said.
“There is a big fear of this surgery. It usually requires a temporary ileostomy and a stoma bag, and patients are terrified of that. There have been a few studies demonstrating that earlier referral to surgery improves quality of life; living with advanced ulcerative colitis can be extremely difficult and patients often feel a lot better after we remove their diseased colon. But getting there is a challenge.”
Dr. Abelson had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
WASHINGTON – The era of powerful biologics has led to unforeseen surgical outcomes in patients with ulcerative colitis.
Patients undergoing surgery for ulcerative colitis now are 38% more likely to die in the hospital than they were 15 years ago, before infliximab and other biologics were adopted as medical therapy for the disease. A database review covering 18 years found that other surgical outcomes are worse, too, Jonathan Abelson, MD, said at the annual clinical congress of the American College of Surgeons.
“These very powerful agents could be completely eliminating the need for surgery in patients with mild disease, leaving surgery for those who have very advanced disease and didn’t respond well to medical therapy,” said Dr. Abelson, a clinical research fellow at New York–Presbyterian Hospital, N.Y. “We are operating now only on patients with very severe disease, not the wider range of patients we had 15 years ago, when there weren’t as effective medical options.”
He and his colleagues used the New York Statewide Planning and Research Cooperative System (SPARCS) database to identify 7,070 patients who had undergone bowel resection for ulcerative colitis during two epochs: prebiologics (1995-2005) and postbiologics (2006-2013). The cohorts were about evenly split in numbers.
There were some statistically significant differences in baseline characteristics. Patients in epoch 2 were about a year older (51 vs. 50 years). Significantly more of them had at least two major comorbidities (28% vs. 18%). Minimally invasive surgery was significantly more common in epoch 2 (28% vs. 3%).
Significantly more surgeries in epoch 2 were staged into three or more procedures (14% vs. 9%). This finding probably reflects the level of disease severity in those presenting for surgery or the fact that they underwent surgery after recently receiving biologics, Dr. Abelson said.
“One of the limits of this study is that we don’t know exactly the reasons for these one-, two-, or three-stage surgeries. The theory is that patients who were more ill at presentation are more likely to have a multistaged surgery. Another reason could be that if they are on these powerful immunosuppressive regimens, the surgeon might be concerned about not healing well from a definitive one- or two-stage surgery.”
He then conducted a multivariate analysis that controlled for baseline factors, including a variety of individual comorbid conditions. In this analysis, patients in epoch 2 were 38% more likely to die in the hospital and 51% more likely to experience a major postoperative event, like shock, pulmonary embolism, stroke, or heart attack. The chance of a surgical complication was increased by 39%, and these patients were 25% more likely to need a transfusion during surgery than those from epoch 1.
The poorer outcomes held for an at least an entire year after surgery, Dr. Abelson said. At 1 year, patients in epoch 2 were 36% more likely to have a readmission than those in epoch 1. Major events and procedural complications were both 46% more likely. Patients were also 36% more likely to require an additional procedure.
“These are not the outcomes we want to see, especially in this era when our surgical techniques have improved so much,” Dr. Abelson said. “If what this represents, though, is that we are now operating on a higher-risk population, we can’t just say, ‘Well, that’s how it’s going to be.’ We need to figure out how to minimize morbidity and mortality in this high-risk patient population.”
One goal, he suggested, would be to assess response to a biologic regimen earlier in the hopes of determining who will respond well, and moving ahead with surgery in those who don’t.
This is a tough sell for patients, he said.
“There is a big fear of this surgery. It usually requires a temporary ileostomy and a stoma bag, and patients are terrified of that. There have been a few studies demonstrating that earlier referral to surgery improves quality of life; living with advanced ulcerative colitis can be extremely difficult and patients often feel a lot better after we remove their diseased colon. But getting there is a challenge.”
Dr. Abelson had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
WASHINGTON – The era of powerful biologics has led to unforeseen surgical outcomes in patients with ulcerative colitis.
Patients undergoing surgery for ulcerative colitis now are 38% more likely to die in the hospital than they were 15 years ago, before infliximab and other biologics were adopted as medical therapy for the disease. A database review covering 18 years found that other surgical outcomes are worse, too, Jonathan Abelson, MD, said at the annual clinical congress of the American College of Surgeons.
“These very powerful agents could be completely eliminating the need for surgery in patients with mild disease, leaving surgery for those who have very advanced disease and didn’t respond well to medical therapy,” said Dr. Abelson, a clinical research fellow at New York–Presbyterian Hospital, N.Y. “We are operating now only on patients with very severe disease, not the wider range of patients we had 15 years ago, when there weren’t as effective medical options.”
He and his colleagues used the New York Statewide Planning and Research Cooperative System (SPARCS) database to identify 7,070 patients who had undergone bowel resection for ulcerative colitis during two epochs: prebiologics (1995-2005) and postbiologics (2006-2013). The cohorts were about evenly split in numbers.
There were some statistically significant differences in baseline characteristics. Patients in epoch 2 were about a year older (51 vs. 50 years). Significantly more of them had at least two major comorbidities (28% vs. 18%). Minimally invasive surgery was significantly more common in epoch 2 (28% vs. 3%).
Significantly more surgeries in epoch 2 were staged into three or more procedures (14% vs. 9%). This finding probably reflects the level of disease severity in those presenting for surgery or the fact that they underwent surgery after recently receiving biologics, Dr. Abelson said.
“One of the limits of this study is that we don’t know exactly the reasons for these one-, two-, or three-stage surgeries. The theory is that patients who were more ill at presentation are more likely to have a multistaged surgery. Another reason could be that if they are on these powerful immunosuppressive regimens, the surgeon might be concerned about not healing well from a definitive one- or two-stage surgery.”
He then conducted a multivariate analysis that controlled for baseline factors, including a variety of individual comorbid conditions. In this analysis, patients in epoch 2 were 38% more likely to die in the hospital and 51% more likely to experience a major postoperative event, like shock, pulmonary embolism, stroke, or heart attack. The chance of a surgical complication was increased by 39%, and these patients were 25% more likely to need a transfusion during surgery than those from epoch 1.
The poorer outcomes held for an at least an entire year after surgery, Dr. Abelson said. At 1 year, patients in epoch 2 were 36% more likely to have a readmission than those in epoch 1. Major events and procedural complications were both 46% more likely. Patients were also 36% more likely to require an additional procedure.
“These are not the outcomes we want to see, especially in this era when our surgical techniques have improved so much,” Dr. Abelson said. “If what this represents, though, is that we are now operating on a higher-risk population, we can’t just say, ‘Well, that’s how it’s going to be.’ We need to figure out how to minimize morbidity and mortality in this high-risk patient population.”
One goal, he suggested, would be to assess response to a biologic regimen earlier in the hopes of determining who will respond well, and moving ahead with surgery in those who don’t.
This is a tough sell for patients, he said.
“There is a big fear of this surgery. It usually requires a temporary ileostomy and a stoma bag, and patients are terrified of that. There have been a few studies demonstrating that earlier referral to surgery improves quality of life; living with advanced ulcerative colitis can be extremely difficult and patients often feel a lot better after we remove their diseased colon. But getting there is a challenge.”
Dr. Abelson had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
AT THE ACS CLINICAL CONGRESS
Key clinical point:
Major finding: Patients are 38% more likely to die in the hospital than they were 15 years ago.
Data source: The 18-year database review comprised more than 7,000 surgeries.
Disclosures: Dr. Abelson had no financial disclosures.
ACR annual meeting pediatric track highlights gene sequencing, brain disease
Will gene sequencing be one of the keys to unlocking previously mysterious inflammatory disorders in children?
Yes, according to new research to be presented at the annual meeting of the American College of Rheumatology in Washington. Gene and whole-exome sequencing will change the way these disorders are categorized, diagnosed, and managed, bringing new hope to the children who suffer from these rare, and devastating illnesses.
Program cochairs Anne M. Stevens, MD, and Anthony French, MD, PhD, agree: Gene sequencing is one of the most exciting and potentially practice-changing topics that ACR’s pediatric track will explore.
A session at 11:00 a.m. on Sunday, Nov. 13, is particularly intriguing, said Dr. Stevens of Seattle Children’s Hospital. “Early-Onset Monogenic Inflammatory Diseases” features two speakers.
Hal Hoffman, MD, chief of allergy, immunology and rheumatology in the department of pediatrics at the University of California, San Diego, will speak on inflammasome-associated disorders. He’ll present a case-based lecture, “so pediatric rheumatologists will be able to recognize these diseases, identify the genes underlying them, and make a clear genetic diagnosis,” Dr. Stevens said.
“These two speakers have been successful in identifying specific genes for these illnesses that have led to very specific treatments and, in some cases, complete resolution of symptoms,” Dr. Stevens noted.
“Advances in Clinical Care through Whole Exome Sequencing,” set for 11:00 a.m. on Tuesday, Nov. 15, will explore the practical impact of gene sequencing studies. Alexei A. Grom, MD, of Cincinnati Children’s Hospital, will discuss the practicalities of whole-exome sequencing: when to order it, how to interpret the findings, and how to use the results to help patients.
Jordan S. Orange, MD, PhD, of Baylor College of Medicine, Houston, will discuss his lab’s recent project: whole-exome sequencing of hundreds of pediatric rheumatology patients. “This study hasn’t focused on a specific disease or a specific gene but looked at the entire exome in an unbiased way,” Dr. Stevens said. “So far, they have identified genes associated with inflammatory disease in about 25% of this population.”
The session is meant to be practical as well as academic, Dr. French noted. “In the last few years, these tests have become much more accessible and easier to do in the clinic, not just in a research setting, and we’re going to focus on how to use them to individualize care.”
Dr. Stevens and Dr. French are also excited about the pediatric nephrology track, which kicks off with “What a Pediatric Rheumatologist May Want to Know About the Kidneys” at 8:30 a.m. on Monday, Nov. 14.
Mark M. Mitsnefes, MD, director of clinical and translational research at Cincinnati Children’s Hospital, will focus on treating hypertension in pediatric rheumatology patients. Bradley P. Dixon, MD, director of the nephrology clinical laboratory at Cincinnati Children’s, will review the thrombotic microangiopathies and discuss new treatment options. Stephen Marks, MD, a kidney transplant expert from London, will finish the session with a detailed discussion of lupus nephritis in children, focusing on early diagnosis.
Pediatric autoimmune brain disorders are on tap for a morning session on Tuesday, Nov. 14. Dr. Stevens is particularly looking forward to this session, which begins at 8:30 a.m.
“As pediatric rheumatologists, we are more and more often being asked to consult on new-onset seizures, psychoses, hallucinations, and stroke. It’s quite a challenge to figure out whether these are related to autoimmune disorders.”
The first lecture of the series focuses on the pathogenesis of autoimmune brain disease, and how to make the diagnosis. Russell Dale, MD, of the University of Sydney will talk about therapeutic decision making in these illnesses.
Josep Obrador Dalmau, MD, of the University of Pennsylvania, Philadelphia, will discuss anti–NMDA receptor encephalitis. Hermine I. Brunner, MD, director of rheumatology at Cincinnati Children’s, will close with a diagnostic and therapeutic update of neuropsychiatric systemic lupus erythematosus.
“This is a huge challenge for us,” Dr. Stevens said. “Children with lupus can have obvious central nervous system involvement, but also not-so-obvious involvement, including depression, anxiety, and cognitive difficulties.”
Will gene sequencing be one of the keys to unlocking previously mysterious inflammatory disorders in children?
Yes, according to new research to be presented at the annual meeting of the American College of Rheumatology in Washington. Gene and whole-exome sequencing will change the way these disorders are categorized, diagnosed, and managed, bringing new hope to the children who suffer from these rare, and devastating illnesses.
Program cochairs Anne M. Stevens, MD, and Anthony French, MD, PhD, agree: Gene sequencing is one of the most exciting and potentially practice-changing topics that ACR’s pediatric track will explore.
A session at 11:00 a.m. on Sunday, Nov. 13, is particularly intriguing, said Dr. Stevens of Seattle Children’s Hospital. “Early-Onset Monogenic Inflammatory Diseases” features two speakers.
Hal Hoffman, MD, chief of allergy, immunology and rheumatology in the department of pediatrics at the University of California, San Diego, will speak on inflammasome-associated disorders. He’ll present a case-based lecture, “so pediatric rheumatologists will be able to recognize these diseases, identify the genes underlying them, and make a clear genetic diagnosis,” Dr. Stevens said.
“These two speakers have been successful in identifying specific genes for these illnesses that have led to very specific treatments and, in some cases, complete resolution of symptoms,” Dr. Stevens noted.
“Advances in Clinical Care through Whole Exome Sequencing,” set for 11:00 a.m. on Tuesday, Nov. 15, will explore the practical impact of gene sequencing studies. Alexei A. Grom, MD, of Cincinnati Children’s Hospital, will discuss the practicalities of whole-exome sequencing: when to order it, how to interpret the findings, and how to use the results to help patients.
Jordan S. Orange, MD, PhD, of Baylor College of Medicine, Houston, will discuss his lab’s recent project: whole-exome sequencing of hundreds of pediatric rheumatology patients. “This study hasn’t focused on a specific disease or a specific gene but looked at the entire exome in an unbiased way,” Dr. Stevens said. “So far, they have identified genes associated with inflammatory disease in about 25% of this population.”
The session is meant to be practical as well as academic, Dr. French noted. “In the last few years, these tests have become much more accessible and easier to do in the clinic, not just in a research setting, and we’re going to focus on how to use them to individualize care.”
Dr. Stevens and Dr. French are also excited about the pediatric nephrology track, which kicks off with “What a Pediatric Rheumatologist May Want to Know About the Kidneys” at 8:30 a.m. on Monday, Nov. 14.
Mark M. Mitsnefes, MD, director of clinical and translational research at Cincinnati Children’s Hospital, will focus on treating hypertension in pediatric rheumatology patients. Bradley P. Dixon, MD, director of the nephrology clinical laboratory at Cincinnati Children’s, will review the thrombotic microangiopathies and discuss new treatment options. Stephen Marks, MD, a kidney transplant expert from London, will finish the session with a detailed discussion of lupus nephritis in children, focusing on early diagnosis.
Pediatric autoimmune brain disorders are on tap for a morning session on Tuesday, Nov. 14. Dr. Stevens is particularly looking forward to this session, which begins at 8:30 a.m.
“As pediatric rheumatologists, we are more and more often being asked to consult on new-onset seizures, psychoses, hallucinations, and stroke. It’s quite a challenge to figure out whether these are related to autoimmune disorders.”
The first lecture of the series focuses on the pathogenesis of autoimmune brain disease, and how to make the diagnosis. Russell Dale, MD, of the University of Sydney will talk about therapeutic decision making in these illnesses.
Josep Obrador Dalmau, MD, of the University of Pennsylvania, Philadelphia, will discuss anti–NMDA receptor encephalitis. Hermine I. Brunner, MD, director of rheumatology at Cincinnati Children’s, will close with a diagnostic and therapeutic update of neuropsychiatric systemic lupus erythematosus.
“This is a huge challenge for us,” Dr. Stevens said. “Children with lupus can have obvious central nervous system involvement, but also not-so-obvious involvement, including depression, anxiety, and cognitive difficulties.”
Will gene sequencing be one of the keys to unlocking previously mysterious inflammatory disorders in children?
Yes, according to new research to be presented at the annual meeting of the American College of Rheumatology in Washington. Gene and whole-exome sequencing will change the way these disorders are categorized, diagnosed, and managed, bringing new hope to the children who suffer from these rare, and devastating illnesses.
Program cochairs Anne M. Stevens, MD, and Anthony French, MD, PhD, agree: Gene sequencing is one of the most exciting and potentially practice-changing topics that ACR’s pediatric track will explore.
A session at 11:00 a.m. on Sunday, Nov. 13, is particularly intriguing, said Dr. Stevens of Seattle Children’s Hospital. “Early-Onset Monogenic Inflammatory Diseases” features two speakers.
Hal Hoffman, MD, chief of allergy, immunology and rheumatology in the department of pediatrics at the University of California, San Diego, will speak on inflammasome-associated disorders. He’ll present a case-based lecture, “so pediatric rheumatologists will be able to recognize these diseases, identify the genes underlying them, and make a clear genetic diagnosis,” Dr. Stevens said.
“These two speakers have been successful in identifying specific genes for these illnesses that have led to very specific treatments and, in some cases, complete resolution of symptoms,” Dr. Stevens noted.
“Advances in Clinical Care through Whole Exome Sequencing,” set for 11:00 a.m. on Tuesday, Nov. 15, will explore the practical impact of gene sequencing studies. Alexei A. Grom, MD, of Cincinnati Children’s Hospital, will discuss the practicalities of whole-exome sequencing: when to order it, how to interpret the findings, and how to use the results to help patients.
Jordan S. Orange, MD, PhD, of Baylor College of Medicine, Houston, will discuss his lab’s recent project: whole-exome sequencing of hundreds of pediatric rheumatology patients. “This study hasn’t focused on a specific disease or a specific gene but looked at the entire exome in an unbiased way,” Dr. Stevens said. “So far, they have identified genes associated with inflammatory disease in about 25% of this population.”
The session is meant to be practical as well as academic, Dr. French noted. “In the last few years, these tests have become much more accessible and easier to do in the clinic, not just in a research setting, and we’re going to focus on how to use them to individualize care.”
Dr. Stevens and Dr. French are also excited about the pediatric nephrology track, which kicks off with “What a Pediatric Rheumatologist May Want to Know About the Kidneys” at 8:30 a.m. on Monday, Nov. 14.
Mark M. Mitsnefes, MD, director of clinical and translational research at Cincinnati Children’s Hospital, will focus on treating hypertension in pediatric rheumatology patients. Bradley P. Dixon, MD, director of the nephrology clinical laboratory at Cincinnati Children’s, will review the thrombotic microangiopathies and discuss new treatment options. Stephen Marks, MD, a kidney transplant expert from London, will finish the session with a detailed discussion of lupus nephritis in children, focusing on early diagnosis.
Pediatric autoimmune brain disorders are on tap for a morning session on Tuesday, Nov. 14. Dr. Stevens is particularly looking forward to this session, which begins at 8:30 a.m.
“As pediatric rheumatologists, we are more and more often being asked to consult on new-onset seizures, psychoses, hallucinations, and stroke. It’s quite a challenge to figure out whether these are related to autoimmune disorders.”
The first lecture of the series focuses on the pathogenesis of autoimmune brain disease, and how to make the diagnosis. Russell Dale, MD, of the University of Sydney will talk about therapeutic decision making in these illnesses.
Josep Obrador Dalmau, MD, of the University of Pennsylvania, Philadelphia, will discuss anti–NMDA receptor encephalitis. Hermine I. Brunner, MD, director of rheumatology at Cincinnati Children’s, will close with a diagnostic and therapeutic update of neuropsychiatric systemic lupus erythematosus.
“This is a huge challenge for us,” Dr. Stevens said. “Children with lupus can have obvious central nervous system involvement, but also not-so-obvious involvement, including depression, anxiety, and cognitive difficulties.”
FROM THE ACR ANNUAL MEETING
Staple line reinforcement linked to increased leak risk in bariatric surgery
Laparoscopic sleeve gastrectomy is safe and effective overall, but staple line reinforcement appears to increase the rate of postsurgical leaks – which were associated with readmissions and, in some cases, reoperations.
A large review of quality improvement data found that staple line reinforcement – an extremely common technique – was associated with a 60% increased risk of leak, compared with closures without staple line reinforcement, Elizabeth R. Berger, MD, and her colleagues reported in the October issue of the Annals of Surgery (2016;264:464-73).
“This study also demonstrates that leaks were significantly more morbid than bleeding with higher readmission and reoperation rates in patients with a leak vs. a bleed,” wrote Dr. Berger of Loyola University, Chicago, and her coauthors. “Therefore, a surgeon should consider the benefits, risks, and costs of each surgical technique in performing a laparoscopic sleeve gastrectomy and selectively utilize those that, in their hands, minimize morbidity while maximizing clinical effectiveness.”
The team examined outcomes in 189,477 laparoscopic sleeve gastrectomies performed by 1,634 surgeons at 720 centers from 2012 to 2014. All of the data were extracted from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, created in 2012 by the American College of Surgeons and the American Society for Metabolic and Bariatric Surgery.
They examined the impact of staple line reinforcement, oversewing the staple line, bougie size, and distance of the staple line from the pylorus on 30-day outcomes, and their effect on weight loss and weight-related comorbidities at 1 year. Outcomes included morbidity, leak rates, and bleeding, which were examined at both the patient and surgeon levels.
Most patients (126,904; 67%) patients had some type of staple line reinforcement (SLR); the rest had only oversewn staple lines (OSL) or no reinforcement. Leaks occurred in 1,703 patients and bleeds in 1,436 patients. Leaks were more serious than bleeds: Patients with a leak were almost 28% more likely to readmitted and 11% more likely to need a reoperation than were patients who had only a bleed.
At the patient level, those with SLR with or without OSL were 20%-46% more likely to experience a leak than were those who had neither. Bleeding rates were about 70% lower in the SLR groups.
Most surgeons in the analysis (80%) used some type of SLR; almost 20% routinely used only OSL, and 30% routinely used only SLR. At the surgeon level, SLR was associated with a 60% increased risk of a postoperative leak, compared with no reinforcement. There was no association between SLR and bleeding risk, however.
Oversewing had an effect on 1-year weight loss. Patients with oversewn staple lines lost an additional 1.3 points on the body mass index (BMI) scale, compared with patients with no type of reinforcement.
“The reason for increased leaks from SLR is relatively unclear,” the authors wrote. “The two layers of material that are placed within the staple line could increase ischemia or decrease the relative staple heights. At the notches, where one staple firing ends and the next one begins, there is sandwiching of the two layers of staples and a combined four layers of SLR. This bulk may predispose to leaks.”
Larger bougie sizes (BS) seemed more beneficial than did smaller ones, in both the surgeon- and patient-level analyses. A BS of at least 38 French was associated with a 28% decreased risk of a leak (odds ratio 0.72) at the patient level and a 10% decreased risk at the surgeon level (OR 0.90). There were no associations with bleeding.
“Our findings support literature that describes narrower BSs leads to increased ischemia secondary to increased intraluminal pressure, causing more leaks,” the authors wrote.
A BS of at least 40 French had a significant impact on weight loss. At 1 year, patients with the larger BS had lost 2.45 points more on the BMI scale than did those with smaller sizes.
This finding is in accord with other studies, including one that found the best weight-loss outcomes associated with a BS of more than 60 French. “Perhaps the sleeve works because of more rapid emptying, which is favored by a relatively larger BS, rather than because of restriction,” they said.
The distance to the pylorus (DP) from the staple line initiation point was divided into four sections: less than 4 cm; 4-5 cm; 5-6 cm; and 6 cm or more.
On a patient level, there was no association between DP and leak rates. There was, however, an association with bleeding. A DP of 4-4.99 cm had the highest rate, 90%, while a DP of 5-5.99 cm had the lowest (71%). DP was also associated with weight loss on this level, with a distance of more than 6 cm being associated with the biggest BMI decrease (3.7 points).
“Our data show significantly increased excess weight loss in a stepwise fashion as the DP increases,” the authors said. “Our data suggest that as DP increased, there was an increased excess weight loss, possibly explained by preserving the ‘antral mill.’ Stapling further from the pylorus perhaps keeps the antrum’s functional component intact and allows food to enter the distal gut more quickly, leading to earlier satiety and increased weight loss.”
Only 114 surgeons (8%) used a DP of less than 4 cm. There were no significant associations with any 30-day outcomes and DP after adjustment.
The authors had no financial disclosures.
Before drawing overarching conclusions and implementing recommendations based on this study, there are several limitations that must be borne in mind when considering data-mining exercises such as this one:
• It should be taken into account that there was significant intraoperative variation in technique and experience among the surgeons that was not captured through the data acquisition.
• Similarly, the true distance between the stapler and the selected bougie is also variable, adding an inherent lack of accuracy of the true real diameter of the completed gastric tube.
• There is a lack of granular information, including the type of SLR or staplers used, thereby also limiting any reliable conclusions that could be drawn.
• There are additional techniques, such as omental buttressing, and the use of clips, sutures, or hemostatic agents that are not reported, yet may have an impact on leak and bleeding rates.
• The reported follow-up rate of 39.4% at 1 year is typically considered to be suboptimal.
• SLR techniques may also include oversewing, and these are also subject to wide variation, including the type of suture material used, and the actual suturing technique that was implemented.
• Only those patients whose bleeding was severe enough to warrant transfusions were included, such that lower level bleeding would have not been represented in this report.
• There were also deficiencies in correlating leaks or bleeding rates with staple height selection, or the experience and learning curve of the surgeon.
Samer Mattar, MD, is a bariatric surgeon and professor of surgery at Oregon Health and Science University, Portland. Dr. Mattar has no disclosures.
Before drawing overarching conclusions and implementing recommendations based on this study, there are several limitations that must be borne in mind when considering data-mining exercises such as this one:
• It should be taken into account that there was significant intraoperative variation in technique and experience among the surgeons that was not captured through the data acquisition.
• Similarly, the true distance between the stapler and the selected bougie is also variable, adding an inherent lack of accuracy of the true real diameter of the completed gastric tube.
• There is a lack of granular information, including the type of SLR or staplers used, thereby also limiting any reliable conclusions that could be drawn.
• There are additional techniques, such as omental buttressing, and the use of clips, sutures, or hemostatic agents that are not reported, yet may have an impact on leak and bleeding rates.
• The reported follow-up rate of 39.4% at 1 year is typically considered to be suboptimal.
• SLR techniques may also include oversewing, and these are also subject to wide variation, including the type of suture material used, and the actual suturing technique that was implemented.
• Only those patients whose bleeding was severe enough to warrant transfusions were included, such that lower level bleeding would have not been represented in this report.
• There were also deficiencies in correlating leaks or bleeding rates with staple height selection, or the experience and learning curve of the surgeon.
Samer Mattar, MD, is a bariatric surgeon and professor of surgery at Oregon Health and Science University, Portland. Dr. Mattar has no disclosures.
Before drawing overarching conclusions and implementing recommendations based on this study, there are several limitations that must be borne in mind when considering data-mining exercises such as this one:
• It should be taken into account that there was significant intraoperative variation in technique and experience among the surgeons that was not captured through the data acquisition.
• Similarly, the true distance between the stapler and the selected bougie is also variable, adding an inherent lack of accuracy of the true real diameter of the completed gastric tube.
• There is a lack of granular information, including the type of SLR or staplers used, thereby also limiting any reliable conclusions that could be drawn.
• There are additional techniques, such as omental buttressing, and the use of clips, sutures, or hemostatic agents that are not reported, yet may have an impact on leak and bleeding rates.
• The reported follow-up rate of 39.4% at 1 year is typically considered to be suboptimal.
• SLR techniques may also include oversewing, and these are also subject to wide variation, including the type of suture material used, and the actual suturing technique that was implemented.
• Only those patients whose bleeding was severe enough to warrant transfusions were included, such that lower level bleeding would have not been represented in this report.
• There were also deficiencies in correlating leaks or bleeding rates with staple height selection, or the experience and learning curve of the surgeon.
Samer Mattar, MD, is a bariatric surgeon and professor of surgery at Oregon Health and Science University, Portland. Dr. Mattar has no disclosures.
Laparoscopic sleeve gastrectomy is safe and effective overall, but staple line reinforcement appears to increase the rate of postsurgical leaks – which were associated with readmissions and, in some cases, reoperations.
A large review of quality improvement data found that staple line reinforcement – an extremely common technique – was associated with a 60% increased risk of leak, compared with closures without staple line reinforcement, Elizabeth R. Berger, MD, and her colleagues reported in the October issue of the Annals of Surgery (2016;264:464-73).
“This study also demonstrates that leaks were significantly more morbid than bleeding with higher readmission and reoperation rates in patients with a leak vs. a bleed,” wrote Dr. Berger of Loyola University, Chicago, and her coauthors. “Therefore, a surgeon should consider the benefits, risks, and costs of each surgical technique in performing a laparoscopic sleeve gastrectomy and selectively utilize those that, in their hands, minimize morbidity while maximizing clinical effectiveness.”
The team examined outcomes in 189,477 laparoscopic sleeve gastrectomies performed by 1,634 surgeons at 720 centers from 2012 to 2014. All of the data were extracted from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, created in 2012 by the American College of Surgeons and the American Society for Metabolic and Bariatric Surgery.
They examined the impact of staple line reinforcement, oversewing the staple line, bougie size, and distance of the staple line from the pylorus on 30-day outcomes, and their effect on weight loss and weight-related comorbidities at 1 year. Outcomes included morbidity, leak rates, and bleeding, which were examined at both the patient and surgeon levels.
Most patients (126,904; 67%) patients had some type of staple line reinforcement (SLR); the rest had only oversewn staple lines (OSL) or no reinforcement. Leaks occurred in 1,703 patients and bleeds in 1,436 patients. Leaks were more serious than bleeds: Patients with a leak were almost 28% more likely to readmitted and 11% more likely to need a reoperation than were patients who had only a bleed.
At the patient level, those with SLR with or without OSL were 20%-46% more likely to experience a leak than were those who had neither. Bleeding rates were about 70% lower in the SLR groups.
Most surgeons in the analysis (80%) used some type of SLR; almost 20% routinely used only OSL, and 30% routinely used only SLR. At the surgeon level, SLR was associated with a 60% increased risk of a postoperative leak, compared with no reinforcement. There was no association between SLR and bleeding risk, however.
Oversewing had an effect on 1-year weight loss. Patients with oversewn staple lines lost an additional 1.3 points on the body mass index (BMI) scale, compared with patients with no type of reinforcement.
“The reason for increased leaks from SLR is relatively unclear,” the authors wrote. “The two layers of material that are placed within the staple line could increase ischemia or decrease the relative staple heights. At the notches, where one staple firing ends and the next one begins, there is sandwiching of the two layers of staples and a combined four layers of SLR. This bulk may predispose to leaks.”
Larger bougie sizes (BS) seemed more beneficial than did smaller ones, in both the surgeon- and patient-level analyses. A BS of at least 38 French was associated with a 28% decreased risk of a leak (odds ratio 0.72) at the patient level and a 10% decreased risk at the surgeon level (OR 0.90). There were no associations with bleeding.
“Our findings support literature that describes narrower BSs leads to increased ischemia secondary to increased intraluminal pressure, causing more leaks,” the authors wrote.
A BS of at least 40 French had a significant impact on weight loss. At 1 year, patients with the larger BS had lost 2.45 points more on the BMI scale than did those with smaller sizes.
This finding is in accord with other studies, including one that found the best weight-loss outcomes associated with a BS of more than 60 French. “Perhaps the sleeve works because of more rapid emptying, which is favored by a relatively larger BS, rather than because of restriction,” they said.
The distance to the pylorus (DP) from the staple line initiation point was divided into four sections: less than 4 cm; 4-5 cm; 5-6 cm; and 6 cm or more.
On a patient level, there was no association between DP and leak rates. There was, however, an association with bleeding. A DP of 4-4.99 cm had the highest rate, 90%, while a DP of 5-5.99 cm had the lowest (71%). DP was also associated with weight loss on this level, with a distance of more than 6 cm being associated with the biggest BMI decrease (3.7 points).
“Our data show significantly increased excess weight loss in a stepwise fashion as the DP increases,” the authors said. “Our data suggest that as DP increased, there was an increased excess weight loss, possibly explained by preserving the ‘antral mill.’ Stapling further from the pylorus perhaps keeps the antrum’s functional component intact and allows food to enter the distal gut more quickly, leading to earlier satiety and increased weight loss.”
Only 114 surgeons (8%) used a DP of less than 4 cm. There were no significant associations with any 30-day outcomes and DP after adjustment.
The authors had no financial disclosures.
Laparoscopic sleeve gastrectomy is safe and effective overall, but staple line reinforcement appears to increase the rate of postsurgical leaks – which were associated with readmissions and, in some cases, reoperations.
A large review of quality improvement data found that staple line reinforcement – an extremely common technique – was associated with a 60% increased risk of leak, compared with closures without staple line reinforcement, Elizabeth R. Berger, MD, and her colleagues reported in the October issue of the Annals of Surgery (2016;264:464-73).
“This study also demonstrates that leaks were significantly more morbid than bleeding with higher readmission and reoperation rates in patients with a leak vs. a bleed,” wrote Dr. Berger of Loyola University, Chicago, and her coauthors. “Therefore, a surgeon should consider the benefits, risks, and costs of each surgical technique in performing a laparoscopic sleeve gastrectomy and selectively utilize those that, in their hands, minimize morbidity while maximizing clinical effectiveness.”
The team examined outcomes in 189,477 laparoscopic sleeve gastrectomies performed by 1,634 surgeons at 720 centers from 2012 to 2014. All of the data were extracted from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program, created in 2012 by the American College of Surgeons and the American Society for Metabolic and Bariatric Surgery.
They examined the impact of staple line reinforcement, oversewing the staple line, bougie size, and distance of the staple line from the pylorus on 30-day outcomes, and their effect on weight loss and weight-related comorbidities at 1 year. Outcomes included morbidity, leak rates, and bleeding, which were examined at both the patient and surgeon levels.
Most patients (126,904; 67%) patients had some type of staple line reinforcement (SLR); the rest had only oversewn staple lines (OSL) or no reinforcement. Leaks occurred in 1,703 patients and bleeds in 1,436 patients. Leaks were more serious than bleeds: Patients with a leak were almost 28% more likely to readmitted and 11% more likely to need a reoperation than were patients who had only a bleed.
At the patient level, those with SLR with or without OSL were 20%-46% more likely to experience a leak than were those who had neither. Bleeding rates were about 70% lower in the SLR groups.
Most surgeons in the analysis (80%) used some type of SLR; almost 20% routinely used only OSL, and 30% routinely used only SLR. At the surgeon level, SLR was associated with a 60% increased risk of a postoperative leak, compared with no reinforcement. There was no association between SLR and bleeding risk, however.
Oversewing had an effect on 1-year weight loss. Patients with oversewn staple lines lost an additional 1.3 points on the body mass index (BMI) scale, compared with patients with no type of reinforcement.
“The reason for increased leaks from SLR is relatively unclear,” the authors wrote. “The two layers of material that are placed within the staple line could increase ischemia or decrease the relative staple heights. At the notches, where one staple firing ends and the next one begins, there is sandwiching of the two layers of staples and a combined four layers of SLR. This bulk may predispose to leaks.”
Larger bougie sizes (BS) seemed more beneficial than did smaller ones, in both the surgeon- and patient-level analyses. A BS of at least 38 French was associated with a 28% decreased risk of a leak (odds ratio 0.72) at the patient level and a 10% decreased risk at the surgeon level (OR 0.90). There were no associations with bleeding.
“Our findings support literature that describes narrower BSs leads to increased ischemia secondary to increased intraluminal pressure, causing more leaks,” the authors wrote.
A BS of at least 40 French had a significant impact on weight loss. At 1 year, patients with the larger BS had lost 2.45 points more on the BMI scale than did those with smaller sizes.
This finding is in accord with other studies, including one that found the best weight-loss outcomes associated with a BS of more than 60 French. “Perhaps the sleeve works because of more rapid emptying, which is favored by a relatively larger BS, rather than because of restriction,” they said.
The distance to the pylorus (DP) from the staple line initiation point was divided into four sections: less than 4 cm; 4-5 cm; 5-6 cm; and 6 cm or more.
On a patient level, there was no association between DP and leak rates. There was, however, an association with bleeding. A DP of 4-4.99 cm had the highest rate, 90%, while a DP of 5-5.99 cm had the lowest (71%). DP was also associated with weight loss on this level, with a distance of more than 6 cm being associated with the biggest BMI decrease (3.7 points).
“Our data show significantly increased excess weight loss in a stepwise fashion as the DP increases,” the authors said. “Our data suggest that as DP increased, there was an increased excess weight loss, possibly explained by preserving the ‘antral mill.’ Stapling further from the pylorus perhaps keeps the antrum’s functional component intact and allows food to enter the distal gut more quickly, leading to earlier satiety and increased weight loss.”
Only 114 surgeons (8%) used a DP of less than 4 cm. There were no significant associations with any 30-day outcomes and DP after adjustment.
The authors had no financial disclosures.
FROM THE ANNALS OF SURGERY
Key clinical point:
Major finding: Compared to not reinforcing the staple line, doing sow as associated with up to a 60% increase in the risk of a postsurgical leak.
Data source: The database review contained outcomes on 189,477 laparoscopic sleeve gastrectomies.
Disclosures: None of the study authors had any financial disclosures.
ACP on gout: Treat to symptoms, not to urate targets
New gout treatment guidelines support the use of urate-lowering therapy, but find no place for treating patients to achieve any specific serum urate target – a dichotomy that has some rheumatologists scratching their heads.
Created by the American College of Physicians, the gout diagnosis and treatment guideline doesn’t recommend monitoring physiologic response to urate-lowering therapy or treating to specific serum urate target (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-0570). Instead, it says patients should be treated according to their symptomatic response – a recommendation that flies in the face of accepted clinical practice.
“When we step back and ask the question, ‘Has a randomized, controlled trial looked at this approach?’ The answer is simply no. And we are not willing to take that leap of faith without data.”
Reliance on lower-grade clinical evidence is simply no longer a strong-enough basis for a clinical practice recommendation, Dr. McLean said in an interview. In 2011, the Institute of Medicine raised the bar for guidelines evidence in its report, “Finding What Works in Health Care: Standards for Systematic Reviews.”
That report explicitly states that a clinical guideline cannot be driven by low-grade evidence, including meta-analysis and expert opinion, Dr. McLean said. The Agency for Healthcare Research and Quality National Guideline Clearinghouse incorporated this into its 2013 revision of guidelines acceptance policy: A review must be based on the highest level of evidence – randomized, controlled studies – and not be driven by expert opinion or review articles. Additionally, the literature reviews upon which guidelines are based must be published in a peer-reviewed journal. Guidelines that don’t meet these criteria will no longer be accepted into the clearinghouse.
“The 2012 ACR guidelines didn’t meet that criteria,” he said. “The authors clearly point out in their methodology section where the evidence is weak and admit that 80% of it is low grade. How can you make a guideline that is 80% based on weak evidence? The ACP doesn’t allow us to do that.”
The argument about whether or not to treat to a specific urate target is not simply philosophical, said Dr. McLean, who authored an accompanying editorial (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-2401). In it, he argued that treating to a prespecified target would certainly help some patients but would probably hurt others.
“Treating to a target necessarily means increasing doses of medication in patients who may be asymptomatic,” he wrote. “Examples exist from other studies using intermediary biomarkers (such as elevated blood pressure or blood glucose level or low hemoglobin level), in which treating to a target resulted in more adverse effects than benefits. Thus, despite the strong biologic appeal of such a strategy and its advocacy by major specialty society guidelines, we judged the strength of evidence for monitoring to be low.”
“This paradigm also has not been formally tested in a randomized clinical trial, and there’s no scientific evidence to support that strategy and a lot of evidence to show its harm,” she said in an interview. “We have a large clinical experience about the ineffectiveness of that strategy. Patients eventually develop tophi, joint damage, and functional limitations when their physicians only treat their gout flares using anti-inflammatory therapy without addressing their underlying cause of gout – high uric acid. They are often dismayed and upset when they realize their physician had let their gout get to that point by just treating their gout flares.”
In other important ways, the two documents are complementary. Both put NSAIDs, corticosteroids, and colchicine at the heart of treating acute gout attacks.
According to the ACP guideline, these treatment strategies are all supported by high-level evidence, which was drawn from a review of 28 studies.
• Corticosteroids, NSAIDs, and colchicine are effective treatments to reduce pain in patients with acute gout.
• Lower doses of colchicine (1.2 mg, followed by 0.6 mg 1 hour later) are as effective as higher doses (1.2 mg, followed by 0.6 mg/hour for 6 hours) at reducing pain and are associated with fewer gastrointestinal adverse effects.
• Do not initiate long-term uric acid–lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.
• Although evidence supports the benefits of using uric acid–lowering therapy for shorter durations to reduce gout flares, the benefits of long-term use in patients with a single or infrequent gout attacks have not been studied.
• Clinicians should discuss benefits, harms, costs, and individual preferences with patients before initiating uric acid–lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence).
• Febuxostat (40 mg/day) and allopurinol (300 mg/day) are equally effective at decreasing serum urate levels, and prophylactic therapy with low-dose colchicine or low-dose NSAIDs reduces the risk for acute gout attacks in patients initiating urate-lowering therapy.
Allopurinol dosage, however, is one key point upon which the ACP and ACR guidelines are sharply divided. The ACR guideline calls for starting at low doses – 100 mg/day, and even lower in patients with kidney disease – with very slow upward titration, only if necessary, to 300 mg/day or more. Allopurinol is not without risk and should be used with caution, Dr. Neogi wrote in her commentary.
“Continuing a management strategy of starting allopurinol at an inappropriately high dose will perpetuate the problem of unnecessarily increasing flare risk, because this risk in the early treatment phase is directly proportional to the potency of the urate-lowering therapy used.”
However, allopurinol doses of 300 mg/day or less leave more than half of all patients undertreated, she said. This dilemma points up the difficulty with symptomatic treatment. Without checking urate levels, clinicians may be shooting blind when trying to dose appropriately.
She refuted any suggestion that the ACR guidelines were based on a lesser degree of evidence than the ACP document.
“The ACR uses a rigorous evidence-based method to develop treatment guidelines. It is inaccurate to say that ACR relies on lower-class evidence or expert opinion ‘to a large extent.’ In the absence of randomized controlled data, other peer-reviewed, available published data are used to formulate guidance, supported by the known biology.”
Current practices outlined in the ACR document are based on a thorough understanding of the biology of gout and how it progresses. Hard data on uric acid targets would greatly impact current therapeutic thinking. But in the meantime, there are patients to be treated, Dr. Neogi said.
“Of course, it would be ideal if we had randomized trial data to definitively provide insights, but we don’t have that right now. So does that mean that patients should suffer unnecessarily because we can’t use the remaining existing body of scientific knowledge to guide rational treatment decisions? What if funding agencies never fund such a study – should gout patients remain poorly managed? Should we abandon all scientific knowledge that isn’t randomized trial data and just not treat at all while waiting to see if a randomized trial will ever be funded and conducted?”
Dr. McLean sees the flip side of that coin.
“I think the effect of our guideline will be to help push the need for more explicit evidence in treat to target being the right way to go. But right now there is not enough evidence now to endorse that approach.”
Dr. McLean reports personal fees from Takeda Pharmaceuticals speakers’ bureau before 2015. Dr. Neogi had no financial disclosures.
New gout treatment guidelines support the use of urate-lowering therapy, but find no place for treating patients to achieve any specific serum urate target – a dichotomy that has some rheumatologists scratching their heads.
Created by the American College of Physicians, the gout diagnosis and treatment guideline doesn’t recommend monitoring physiologic response to urate-lowering therapy or treating to specific serum urate target (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-0570). Instead, it says patients should be treated according to their symptomatic response – a recommendation that flies in the face of accepted clinical practice.
“When we step back and ask the question, ‘Has a randomized, controlled trial looked at this approach?’ The answer is simply no. And we are not willing to take that leap of faith without data.”
Reliance on lower-grade clinical evidence is simply no longer a strong-enough basis for a clinical practice recommendation, Dr. McLean said in an interview. In 2011, the Institute of Medicine raised the bar for guidelines evidence in its report, “Finding What Works in Health Care: Standards for Systematic Reviews.”
That report explicitly states that a clinical guideline cannot be driven by low-grade evidence, including meta-analysis and expert opinion, Dr. McLean said. The Agency for Healthcare Research and Quality National Guideline Clearinghouse incorporated this into its 2013 revision of guidelines acceptance policy: A review must be based on the highest level of evidence – randomized, controlled studies – and not be driven by expert opinion or review articles. Additionally, the literature reviews upon which guidelines are based must be published in a peer-reviewed journal. Guidelines that don’t meet these criteria will no longer be accepted into the clearinghouse.
“The 2012 ACR guidelines didn’t meet that criteria,” he said. “The authors clearly point out in their methodology section where the evidence is weak and admit that 80% of it is low grade. How can you make a guideline that is 80% based on weak evidence? The ACP doesn’t allow us to do that.”
The argument about whether or not to treat to a specific urate target is not simply philosophical, said Dr. McLean, who authored an accompanying editorial (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-2401). In it, he argued that treating to a prespecified target would certainly help some patients but would probably hurt others.
“Treating to a target necessarily means increasing doses of medication in patients who may be asymptomatic,” he wrote. “Examples exist from other studies using intermediary biomarkers (such as elevated blood pressure or blood glucose level or low hemoglobin level), in which treating to a target resulted in more adverse effects than benefits. Thus, despite the strong biologic appeal of such a strategy and its advocacy by major specialty society guidelines, we judged the strength of evidence for monitoring to be low.”
“This paradigm also has not been formally tested in a randomized clinical trial, and there’s no scientific evidence to support that strategy and a lot of evidence to show its harm,” she said in an interview. “We have a large clinical experience about the ineffectiveness of that strategy. Patients eventually develop tophi, joint damage, and functional limitations when their physicians only treat their gout flares using anti-inflammatory therapy without addressing their underlying cause of gout – high uric acid. They are often dismayed and upset when they realize their physician had let their gout get to that point by just treating their gout flares.”
In other important ways, the two documents are complementary. Both put NSAIDs, corticosteroids, and colchicine at the heart of treating acute gout attacks.
According to the ACP guideline, these treatment strategies are all supported by high-level evidence, which was drawn from a review of 28 studies.
• Corticosteroids, NSAIDs, and colchicine are effective treatments to reduce pain in patients with acute gout.
• Lower doses of colchicine (1.2 mg, followed by 0.6 mg 1 hour later) are as effective as higher doses (1.2 mg, followed by 0.6 mg/hour for 6 hours) at reducing pain and are associated with fewer gastrointestinal adverse effects.
• Do not initiate long-term uric acid–lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.
• Although evidence supports the benefits of using uric acid–lowering therapy for shorter durations to reduce gout flares, the benefits of long-term use in patients with a single or infrequent gout attacks have not been studied.
• Clinicians should discuss benefits, harms, costs, and individual preferences with patients before initiating uric acid–lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence).
• Febuxostat (40 mg/day) and allopurinol (300 mg/day) are equally effective at decreasing serum urate levels, and prophylactic therapy with low-dose colchicine or low-dose NSAIDs reduces the risk for acute gout attacks in patients initiating urate-lowering therapy.
Allopurinol dosage, however, is one key point upon which the ACP and ACR guidelines are sharply divided. The ACR guideline calls for starting at low doses – 100 mg/day, and even lower in patients with kidney disease – with very slow upward titration, only if necessary, to 300 mg/day or more. Allopurinol is not without risk and should be used with caution, Dr. Neogi wrote in her commentary.
“Continuing a management strategy of starting allopurinol at an inappropriately high dose will perpetuate the problem of unnecessarily increasing flare risk, because this risk in the early treatment phase is directly proportional to the potency of the urate-lowering therapy used.”
However, allopurinol doses of 300 mg/day or less leave more than half of all patients undertreated, she said. This dilemma points up the difficulty with symptomatic treatment. Without checking urate levels, clinicians may be shooting blind when trying to dose appropriately.
She refuted any suggestion that the ACR guidelines were based on a lesser degree of evidence than the ACP document.
“The ACR uses a rigorous evidence-based method to develop treatment guidelines. It is inaccurate to say that ACR relies on lower-class evidence or expert opinion ‘to a large extent.’ In the absence of randomized controlled data, other peer-reviewed, available published data are used to formulate guidance, supported by the known biology.”
Current practices outlined in the ACR document are based on a thorough understanding of the biology of gout and how it progresses. Hard data on uric acid targets would greatly impact current therapeutic thinking. But in the meantime, there are patients to be treated, Dr. Neogi said.
“Of course, it would be ideal if we had randomized trial data to definitively provide insights, but we don’t have that right now. So does that mean that patients should suffer unnecessarily because we can’t use the remaining existing body of scientific knowledge to guide rational treatment decisions? What if funding agencies never fund such a study – should gout patients remain poorly managed? Should we abandon all scientific knowledge that isn’t randomized trial data and just not treat at all while waiting to see if a randomized trial will ever be funded and conducted?”
Dr. McLean sees the flip side of that coin.
“I think the effect of our guideline will be to help push the need for more explicit evidence in treat to target being the right way to go. But right now there is not enough evidence now to endorse that approach.”
Dr. McLean reports personal fees from Takeda Pharmaceuticals speakers’ bureau before 2015. Dr. Neogi had no financial disclosures.
New gout treatment guidelines support the use of urate-lowering therapy, but find no place for treating patients to achieve any specific serum urate target – a dichotomy that has some rheumatologists scratching their heads.
Created by the American College of Physicians, the gout diagnosis and treatment guideline doesn’t recommend monitoring physiologic response to urate-lowering therapy or treating to specific serum urate target (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-0570). Instead, it says patients should be treated according to their symptomatic response – a recommendation that flies in the face of accepted clinical practice.
“When we step back and ask the question, ‘Has a randomized, controlled trial looked at this approach?’ The answer is simply no. And we are not willing to take that leap of faith without data.”
Reliance on lower-grade clinical evidence is simply no longer a strong-enough basis for a clinical practice recommendation, Dr. McLean said in an interview. In 2011, the Institute of Medicine raised the bar for guidelines evidence in its report, “Finding What Works in Health Care: Standards for Systematic Reviews.”
That report explicitly states that a clinical guideline cannot be driven by low-grade evidence, including meta-analysis and expert opinion, Dr. McLean said. The Agency for Healthcare Research and Quality National Guideline Clearinghouse incorporated this into its 2013 revision of guidelines acceptance policy: A review must be based on the highest level of evidence – randomized, controlled studies – and not be driven by expert opinion or review articles. Additionally, the literature reviews upon which guidelines are based must be published in a peer-reviewed journal. Guidelines that don’t meet these criteria will no longer be accepted into the clearinghouse.
“The 2012 ACR guidelines didn’t meet that criteria,” he said. “The authors clearly point out in their methodology section where the evidence is weak and admit that 80% of it is low grade. How can you make a guideline that is 80% based on weak evidence? The ACP doesn’t allow us to do that.”
The argument about whether or not to treat to a specific urate target is not simply philosophical, said Dr. McLean, who authored an accompanying editorial (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-2401). In it, he argued that treating to a prespecified target would certainly help some patients but would probably hurt others.
“Treating to a target necessarily means increasing doses of medication in patients who may be asymptomatic,” he wrote. “Examples exist from other studies using intermediary biomarkers (such as elevated blood pressure or blood glucose level or low hemoglobin level), in which treating to a target resulted in more adverse effects than benefits. Thus, despite the strong biologic appeal of such a strategy and its advocacy by major specialty society guidelines, we judged the strength of evidence for monitoring to be low.”
“This paradigm also has not been formally tested in a randomized clinical trial, and there’s no scientific evidence to support that strategy and a lot of evidence to show its harm,” she said in an interview. “We have a large clinical experience about the ineffectiveness of that strategy. Patients eventually develop tophi, joint damage, and functional limitations when their physicians only treat their gout flares using anti-inflammatory therapy without addressing their underlying cause of gout – high uric acid. They are often dismayed and upset when they realize their physician had let their gout get to that point by just treating their gout flares.”
In other important ways, the two documents are complementary. Both put NSAIDs, corticosteroids, and colchicine at the heart of treating acute gout attacks.
According to the ACP guideline, these treatment strategies are all supported by high-level evidence, which was drawn from a review of 28 studies.
• Corticosteroids, NSAIDs, and colchicine are effective treatments to reduce pain in patients with acute gout.
• Lower doses of colchicine (1.2 mg, followed by 0.6 mg 1 hour later) are as effective as higher doses (1.2 mg, followed by 0.6 mg/hour for 6 hours) at reducing pain and are associated with fewer gastrointestinal adverse effects.
• Do not initiate long-term uric acid–lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.
• Although evidence supports the benefits of using uric acid–lowering therapy for shorter durations to reduce gout flares, the benefits of long-term use in patients with a single or infrequent gout attacks have not been studied.
• Clinicians should discuss benefits, harms, costs, and individual preferences with patients before initiating uric acid–lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence).
• Febuxostat (40 mg/day) and allopurinol (300 mg/day) are equally effective at decreasing serum urate levels, and prophylactic therapy with low-dose colchicine or low-dose NSAIDs reduces the risk for acute gout attacks in patients initiating urate-lowering therapy.
Allopurinol dosage, however, is one key point upon which the ACP and ACR guidelines are sharply divided. The ACR guideline calls for starting at low doses – 100 mg/day, and even lower in patients with kidney disease – with very slow upward titration, only if necessary, to 300 mg/day or more. Allopurinol is not without risk and should be used with caution, Dr. Neogi wrote in her commentary.
“Continuing a management strategy of starting allopurinol at an inappropriately high dose will perpetuate the problem of unnecessarily increasing flare risk, because this risk in the early treatment phase is directly proportional to the potency of the urate-lowering therapy used.”
However, allopurinol doses of 300 mg/day or less leave more than half of all patients undertreated, she said. This dilemma points up the difficulty with symptomatic treatment. Without checking urate levels, clinicians may be shooting blind when trying to dose appropriately.
She refuted any suggestion that the ACR guidelines were based on a lesser degree of evidence than the ACP document.
“The ACR uses a rigorous evidence-based method to develop treatment guidelines. It is inaccurate to say that ACR relies on lower-class evidence or expert opinion ‘to a large extent.’ In the absence of randomized controlled data, other peer-reviewed, available published data are used to formulate guidance, supported by the known biology.”
Current practices outlined in the ACR document are based on a thorough understanding of the biology of gout and how it progresses. Hard data on uric acid targets would greatly impact current therapeutic thinking. But in the meantime, there are patients to be treated, Dr. Neogi said.
“Of course, it would be ideal if we had randomized trial data to definitively provide insights, but we don’t have that right now. So does that mean that patients should suffer unnecessarily because we can’t use the remaining existing body of scientific knowledge to guide rational treatment decisions? What if funding agencies never fund such a study – should gout patients remain poorly managed? Should we abandon all scientific knowledge that isn’t randomized trial data and just not treat at all while waiting to see if a randomized trial will ever be funded and conducted?”
Dr. McLean sees the flip side of that coin.
“I think the effect of our guideline will be to help push the need for more explicit evidence in treat to target being the right way to go. But right now there is not enough evidence now to endorse that approach.”
Dr. McLean reports personal fees from Takeda Pharmaceuticals speakers’ bureau before 2015. Dr. Neogi had no financial disclosures.
Surgical infections, early discharge hike readmissions in extrahepatic cholangiocarcinoma
WASHINGTON – Hospital readmissions are common after resection of extrahepatic cholangiocarcinoma, with about 20% of patients returning in the first 90 days after surgery.
Two factors – surgical site infections and an abbreviated length of stay – both quadrupled the risk of readmission, Michail Mavros, MD, said at the American College of Surgeons Clinical Congress.
“Surgeons are scrutinized over length of stay and, as a result, these fast-track recovery pathways are increasingly important. Readmission rates are being used as a quality metric and performance indicator, and tied to reimbursement. But our data suggest that we should be somewhat cautious in implementing those with this surgery. The patient may look great with good pain control, and be eating and ambulating by day 4 or 5, but it may be premature to discharge at that point, and safer to wait a little longer. The financial penalty for readmission is probably not worth that small bonus we get for early discharge.”
The study comprised 422 patients who underwent resection with curative intent for extrahepatic cholangiocarcinoma. This is a rare tumor with about 5,000 cases presenting each year. Dr. Mavros and his colleagues extracted their data from the U.S. Extrahepatic Cholangiocarcinoma Collaborative. The primary outcomes were 30- and 90-day readmission rates.
The patients’ median age was 67 years. About a third had mild comorbidities with an American Society of Anesthesiologist (ASA) comorbidity class of 1-2. The rest had moderate to severe comorbidities (ASA class 3-4). Hypertension was common (48%); 18% had diabetes.
Tumor location was split almost equally between distal and hilar; the median tumor size was 2.3 cm.
Final margins were positive in 28% and half of the cohort had positive regional lymph nodes.
The procedures were quite varied, and included common bile duct resection (18%); hepatectomy plus common bile duct resection (40%); and Whipple procedure (42%). The median estimated blood loss was 500 cc; 28% of the cohort required transfusion with packed red blood cells and 8% with fresh frozen plasma.
Postoperative complications were common (63%), with half of those being classed as serious. Infectious complications were most common, including superficial (11%), deep (7%), and organ space infections (16%).
Bile leaks occurred in 4% of cases. Reoperations were necessary in 7%. The 30-day mortality was 4.5% and 90-day mortality, 8%.The median length of stay was 8 days but this ranged from 7 to 18 days.
The 30-day readmission rate was 19% and the 90-day readmission rate was 23%. Most readmissions occurred fairly quickly – the median time to readmission was 12 days, with a range of 6-24 days.
The investigators conducted a multivariate analysis to determine independent predictors of readmission. The strongest predictors were any surgical complications (odds ratio, 8.4); organ-space infection (OR, 4.5); and length of stay of 8 days or less (OR, 4.3). Other predictors were advancing age (OR, 1.5 for each 10 years) and having had a liver resection (OR, 2.0).
“It’s clear from these results that avoidance of complications, especially infectious complications, may improve readmission rates dramatically,” Dr. Mavros said. “We would advise caution in implementing any fast-track protocols with these patients, given the finding that early discharge was associated with a higher rate of readmission.”
Dr. Mavros had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
WASHINGTON – Hospital readmissions are common after resection of extrahepatic cholangiocarcinoma, with about 20% of patients returning in the first 90 days after surgery.
Two factors – surgical site infections and an abbreviated length of stay – both quadrupled the risk of readmission, Michail Mavros, MD, said at the American College of Surgeons Clinical Congress.
“Surgeons are scrutinized over length of stay and, as a result, these fast-track recovery pathways are increasingly important. Readmission rates are being used as a quality metric and performance indicator, and tied to reimbursement. But our data suggest that we should be somewhat cautious in implementing those with this surgery. The patient may look great with good pain control, and be eating and ambulating by day 4 or 5, but it may be premature to discharge at that point, and safer to wait a little longer. The financial penalty for readmission is probably not worth that small bonus we get for early discharge.”
The study comprised 422 patients who underwent resection with curative intent for extrahepatic cholangiocarcinoma. This is a rare tumor with about 5,000 cases presenting each year. Dr. Mavros and his colleagues extracted their data from the U.S. Extrahepatic Cholangiocarcinoma Collaborative. The primary outcomes were 30- and 90-day readmission rates.
The patients’ median age was 67 years. About a third had mild comorbidities with an American Society of Anesthesiologist (ASA) comorbidity class of 1-2. The rest had moderate to severe comorbidities (ASA class 3-4). Hypertension was common (48%); 18% had diabetes.
Tumor location was split almost equally between distal and hilar; the median tumor size was 2.3 cm.
Final margins were positive in 28% and half of the cohort had positive regional lymph nodes.
The procedures were quite varied, and included common bile duct resection (18%); hepatectomy plus common bile duct resection (40%); and Whipple procedure (42%). The median estimated blood loss was 500 cc; 28% of the cohort required transfusion with packed red blood cells and 8% with fresh frozen plasma.
Postoperative complications were common (63%), with half of those being classed as serious. Infectious complications were most common, including superficial (11%), deep (7%), and organ space infections (16%).
Bile leaks occurred in 4% of cases. Reoperations were necessary in 7%. The 30-day mortality was 4.5% and 90-day mortality, 8%.The median length of stay was 8 days but this ranged from 7 to 18 days.
The 30-day readmission rate was 19% and the 90-day readmission rate was 23%. Most readmissions occurred fairly quickly – the median time to readmission was 12 days, with a range of 6-24 days.
The investigators conducted a multivariate analysis to determine independent predictors of readmission. The strongest predictors were any surgical complications (odds ratio, 8.4); organ-space infection (OR, 4.5); and length of stay of 8 days or less (OR, 4.3). Other predictors were advancing age (OR, 1.5 for each 10 years) and having had a liver resection (OR, 2.0).
“It’s clear from these results that avoidance of complications, especially infectious complications, may improve readmission rates dramatically,” Dr. Mavros said. “We would advise caution in implementing any fast-track protocols with these patients, given the finding that early discharge was associated with a higher rate of readmission.”
Dr. Mavros had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
WASHINGTON – Hospital readmissions are common after resection of extrahepatic cholangiocarcinoma, with about 20% of patients returning in the first 90 days after surgery.
Two factors – surgical site infections and an abbreviated length of stay – both quadrupled the risk of readmission, Michail Mavros, MD, said at the American College of Surgeons Clinical Congress.
“Surgeons are scrutinized over length of stay and, as a result, these fast-track recovery pathways are increasingly important. Readmission rates are being used as a quality metric and performance indicator, and tied to reimbursement. But our data suggest that we should be somewhat cautious in implementing those with this surgery. The patient may look great with good pain control, and be eating and ambulating by day 4 or 5, but it may be premature to discharge at that point, and safer to wait a little longer. The financial penalty for readmission is probably not worth that small bonus we get for early discharge.”
The study comprised 422 patients who underwent resection with curative intent for extrahepatic cholangiocarcinoma. This is a rare tumor with about 5,000 cases presenting each year. Dr. Mavros and his colleagues extracted their data from the U.S. Extrahepatic Cholangiocarcinoma Collaborative. The primary outcomes were 30- and 90-day readmission rates.
The patients’ median age was 67 years. About a third had mild comorbidities with an American Society of Anesthesiologist (ASA) comorbidity class of 1-2. The rest had moderate to severe comorbidities (ASA class 3-4). Hypertension was common (48%); 18% had diabetes.
Tumor location was split almost equally between distal and hilar; the median tumor size was 2.3 cm.
Final margins were positive in 28% and half of the cohort had positive regional lymph nodes.
The procedures were quite varied, and included common bile duct resection (18%); hepatectomy plus common bile duct resection (40%); and Whipple procedure (42%). The median estimated blood loss was 500 cc; 28% of the cohort required transfusion with packed red blood cells and 8% with fresh frozen plasma.
Postoperative complications were common (63%), with half of those being classed as serious. Infectious complications were most common, including superficial (11%), deep (7%), and organ space infections (16%).
Bile leaks occurred in 4% of cases. Reoperations were necessary in 7%. The 30-day mortality was 4.5% and 90-day mortality, 8%.The median length of stay was 8 days but this ranged from 7 to 18 days.
The 30-day readmission rate was 19% and the 90-day readmission rate was 23%. Most readmissions occurred fairly quickly – the median time to readmission was 12 days, with a range of 6-24 days.
The investigators conducted a multivariate analysis to determine independent predictors of readmission. The strongest predictors were any surgical complications (odds ratio, 8.4); organ-space infection (OR, 4.5); and length of stay of 8 days or less (OR, 4.3). Other predictors were advancing age (OR, 1.5 for each 10 years) and having had a liver resection (OR, 2.0).
“It’s clear from these results that avoidance of complications, especially infectious complications, may improve readmission rates dramatically,” Dr. Mavros said. “We would advise caution in implementing any fast-track protocols with these patients, given the finding that early discharge was associated with a higher rate of readmission.”
Dr. Mavros had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
Key clinical point:
Major finding: Organ space infections and a shorter length of stay both quadrupled the risk of a readmission.
Data source: The database review comprised 422 patients.
Disclosures: Dr. Mavros had no financial disclosures.
TBI scoring system predicts outcomes with only initial head CT findings
WASHINGTON – A simple 8-point scoring system based on head CT accurately predicts mortality, morbidity, and even discharge disposition among patients with a traumatic brain injury (TBI).
In its first clinical study, the Cranial CT Scoring Tool (CCTST) predictive power rivaled both the Glasgow Coma Score (GCS) and the Abbreviated Injury Scale (AIS), Ronnie Mubang, MD, said at the American College of Surgeons’ Clinical Congress.
In addition to adding valuable prognostic information, the CCTST is quick, easy, and completely objective, said Dr. Mubang, of St. Luke’s University Health Network, Bethlehem, Pa.
“The near-universal head CT makes this tool valuable in immediate prognostication and clinical risk assessment for physicians, patients and families. It can serve as a potential adjunct to the Glasgow score and Abbreviated Injury Score for risk assessment,” he said. Of note, the final AIS-Head may not be available until relatively late in the patient’s clinical course, and the GCS has important limitations in terms of outcome prognostication.
The CCTST is an 8-point assessment with one point assigned to each individual cranial CT finding: epidural hematoma, subdural hematoma, subarachnoid hemorrhage, intraventricular hemorrhage, cerebral contusion/ intraparenchymal hemorrhage, skull fracture, brain edema/herniation, and midline shift. The ninth factor is the presence of an external injury to the head.
Dr. Mubang, a fourth-year surgical resident, and his colleagues retrospectively examined the CCTST in 620 patients included in an administrative database at the three-hospital St. Luke’s Regional Trauma Network. Patients were older than 45 years. Half of them underwent neurosurgical intervention within 24 hours of admission and were matched with 310 patients who did not require neurosurgery. The primary clinical endpoint was mortality from head injury. Secondary endpoints included morbidity, hospital and intensive care unit length of stay, and post-discharge destination.
The mean age of the cohort was 73 years. Almost all injuries (99%) were due to blunt force trauma. The mean GCS was 11; the mean Injury Severity Score (ISS) was 24; and the mean AIS – Head score was 4.6, indicating severe to critical level of TBI. Midline shift was significantly greater in the surgical group (0.74 cm vs. 0.29 cm).
Several CT findings were significantly more common in the surgical group, including subdural hematoma (96% vs. 7%); midline shift (74% vs. 29%); brain edema (39% vs. 23%); and epidural hematoma (10% vs. 3%).
As the total CCTST score increased, outcomes worsened accordingly, Dr. Mubang said. Patients with a score of 1-2 had a 20%-30% chance of complications and an approximately 10% chance of injury-related mortality. Patients with higher scores (7-8) had a 60%-75% chance of morbidity and a 55% chance of mortality.
Rising scores correlated well with both hospital and ICU length of stay, with a score of 1-2 associated with a 3-day average stay, and a score of 8 associated with stays exceeding 10 days. The same pattern occurred with overall hospital length of stay: the lowest scores were associated with a stay of about a week, while the highest scores with a stay exceeding 2 weeks.
CCTST was highly associated with discharge disposition. With every additional point, the chance of discharge to home fell. While the majority of patients with scores below 2 were discharged home, no patients with a score of 8 were discharged home.
Finally, the investigators performed a multivariate analysis that controlled for sex; GCS, ISS, and AIS-head scores; time in the trauma bay; and preinjury anticoagulation treatment. The CCTST score was strongly associated with patient mortality (OR 1.31), rivaling both GCS (OR, 1.14) and AIS-Head (OR, 2.68). Neither ISS nor pre-injury anticoagulation predicted mortality. CCTST was also the only variable independently associated with the need for neurosurgical intervention.
The team is planning a multicenter retrospective validation, followed by a prospective observational study in the next 2 years, according to Dr. Stan Stawicki, the senior investigator, also with St. Luke’s. “CCTST offers potential promise to add much needed granularity to our existing TBI clinical assessment paradigm that continues to rely heavily on AIS-Head and GCS,” he said.
Neither Dr. Mubang nor Dr. Stawicki had any financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
WASHINGTON – A simple 8-point scoring system based on head CT accurately predicts mortality, morbidity, and even discharge disposition among patients with a traumatic brain injury (TBI).
In its first clinical study, the Cranial CT Scoring Tool (CCTST) predictive power rivaled both the Glasgow Coma Score (GCS) and the Abbreviated Injury Scale (AIS), Ronnie Mubang, MD, said at the American College of Surgeons’ Clinical Congress.
In addition to adding valuable prognostic information, the CCTST is quick, easy, and completely objective, said Dr. Mubang, of St. Luke’s University Health Network, Bethlehem, Pa.
“The near-universal head CT makes this tool valuable in immediate prognostication and clinical risk assessment for physicians, patients and families. It can serve as a potential adjunct to the Glasgow score and Abbreviated Injury Score for risk assessment,” he said. Of note, the final AIS-Head may not be available until relatively late in the patient’s clinical course, and the GCS has important limitations in terms of outcome prognostication.
The CCTST is an 8-point assessment with one point assigned to each individual cranial CT finding: epidural hematoma, subdural hematoma, subarachnoid hemorrhage, intraventricular hemorrhage, cerebral contusion/ intraparenchymal hemorrhage, skull fracture, brain edema/herniation, and midline shift. The ninth factor is the presence of an external injury to the head.
Dr. Mubang, a fourth-year surgical resident, and his colleagues retrospectively examined the CCTST in 620 patients included in an administrative database at the three-hospital St. Luke’s Regional Trauma Network. Patients were older than 45 years. Half of them underwent neurosurgical intervention within 24 hours of admission and were matched with 310 patients who did not require neurosurgery. The primary clinical endpoint was mortality from head injury. Secondary endpoints included morbidity, hospital and intensive care unit length of stay, and post-discharge destination.
The mean age of the cohort was 73 years. Almost all injuries (99%) were due to blunt force trauma. The mean GCS was 11; the mean Injury Severity Score (ISS) was 24; and the mean AIS – Head score was 4.6, indicating severe to critical level of TBI. Midline shift was significantly greater in the surgical group (0.74 cm vs. 0.29 cm).
Several CT findings were significantly more common in the surgical group, including subdural hematoma (96% vs. 7%); midline shift (74% vs. 29%); brain edema (39% vs. 23%); and epidural hematoma (10% vs. 3%).
As the total CCTST score increased, outcomes worsened accordingly, Dr. Mubang said. Patients with a score of 1-2 had a 20%-30% chance of complications and an approximately 10% chance of injury-related mortality. Patients with higher scores (7-8) had a 60%-75% chance of morbidity and a 55% chance of mortality.
Rising scores correlated well with both hospital and ICU length of stay, with a score of 1-2 associated with a 3-day average stay, and a score of 8 associated with stays exceeding 10 days. The same pattern occurred with overall hospital length of stay: the lowest scores were associated with a stay of about a week, while the highest scores with a stay exceeding 2 weeks.
CCTST was highly associated with discharge disposition. With every additional point, the chance of discharge to home fell. While the majority of patients with scores below 2 were discharged home, no patients with a score of 8 were discharged home.
Finally, the investigators performed a multivariate analysis that controlled for sex; GCS, ISS, and AIS-head scores; time in the trauma bay; and preinjury anticoagulation treatment. The CCTST score was strongly associated with patient mortality (OR 1.31), rivaling both GCS (OR, 1.14) and AIS-Head (OR, 2.68). Neither ISS nor pre-injury anticoagulation predicted mortality. CCTST was also the only variable independently associated with the need for neurosurgical intervention.
The team is planning a multicenter retrospective validation, followed by a prospective observational study in the next 2 years, according to Dr. Stan Stawicki, the senior investigator, also with St. Luke’s. “CCTST offers potential promise to add much needed granularity to our existing TBI clinical assessment paradigm that continues to rely heavily on AIS-Head and GCS,” he said.
Neither Dr. Mubang nor Dr. Stawicki had any financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
WASHINGTON – A simple 8-point scoring system based on head CT accurately predicts mortality, morbidity, and even discharge disposition among patients with a traumatic brain injury (TBI).
In its first clinical study, the Cranial CT Scoring Tool (CCTST) predictive power rivaled both the Glasgow Coma Score (GCS) and the Abbreviated Injury Scale (AIS), Ronnie Mubang, MD, said at the American College of Surgeons’ Clinical Congress.
In addition to adding valuable prognostic information, the CCTST is quick, easy, and completely objective, said Dr. Mubang, of St. Luke’s University Health Network, Bethlehem, Pa.
“The near-universal head CT makes this tool valuable in immediate prognostication and clinical risk assessment for physicians, patients and families. It can serve as a potential adjunct to the Glasgow score and Abbreviated Injury Score for risk assessment,” he said. Of note, the final AIS-Head may not be available until relatively late in the patient’s clinical course, and the GCS has important limitations in terms of outcome prognostication.
The CCTST is an 8-point assessment with one point assigned to each individual cranial CT finding: epidural hematoma, subdural hematoma, subarachnoid hemorrhage, intraventricular hemorrhage, cerebral contusion/ intraparenchymal hemorrhage, skull fracture, brain edema/herniation, and midline shift. The ninth factor is the presence of an external injury to the head.
Dr. Mubang, a fourth-year surgical resident, and his colleagues retrospectively examined the CCTST in 620 patients included in an administrative database at the three-hospital St. Luke’s Regional Trauma Network. Patients were older than 45 years. Half of them underwent neurosurgical intervention within 24 hours of admission and were matched with 310 patients who did not require neurosurgery. The primary clinical endpoint was mortality from head injury. Secondary endpoints included morbidity, hospital and intensive care unit length of stay, and post-discharge destination.
The mean age of the cohort was 73 years. Almost all injuries (99%) were due to blunt force trauma. The mean GCS was 11; the mean Injury Severity Score (ISS) was 24; and the mean AIS – Head score was 4.6, indicating severe to critical level of TBI. Midline shift was significantly greater in the surgical group (0.74 cm vs. 0.29 cm).
Several CT findings were significantly more common in the surgical group, including subdural hematoma (96% vs. 7%); midline shift (74% vs. 29%); brain edema (39% vs. 23%); and epidural hematoma (10% vs. 3%).
As the total CCTST score increased, outcomes worsened accordingly, Dr. Mubang said. Patients with a score of 1-2 had a 20%-30% chance of complications and an approximately 10% chance of injury-related mortality. Patients with higher scores (7-8) had a 60%-75% chance of morbidity and a 55% chance of mortality.
Rising scores correlated well with both hospital and ICU length of stay, with a score of 1-2 associated with a 3-day average stay, and a score of 8 associated with stays exceeding 10 days. The same pattern occurred with overall hospital length of stay: the lowest scores were associated with a stay of about a week, while the highest scores with a stay exceeding 2 weeks.
CCTST was highly associated with discharge disposition. With every additional point, the chance of discharge to home fell. While the majority of patients with scores below 2 were discharged home, no patients with a score of 8 were discharged home.
Finally, the investigators performed a multivariate analysis that controlled for sex; GCS, ISS, and AIS-head scores; time in the trauma bay; and preinjury anticoagulation treatment. The CCTST score was strongly associated with patient mortality (OR 1.31), rivaling both GCS (OR, 1.14) and AIS-Head (OR, 2.68). Neither ISS nor pre-injury anticoagulation predicted mortality. CCTST was also the only variable independently associated with the need for neurosurgical intervention.
The team is planning a multicenter retrospective validation, followed by a prospective observational study in the next 2 years, according to Dr. Stan Stawicki, the senior investigator, also with St. Luke’s. “CCTST offers potential promise to add much needed granularity to our existing TBI clinical assessment paradigm that continues to rely heavily on AIS-Head and GCS,” he said.
Neither Dr. Mubang nor Dr. Stawicki had any financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
AT ACS 2016
Key clinical point:
Major finding: CCTST score was strongly associated with patient mortality (Odds ratio, 1.31), rivaling both the Glasgow Coma Score (OR, 1.14) and the Abbreviated Injury Score – Head (OR, 2.68)Data source: The retrospective database study comprised 620 head trauma patients.
Disclosures: Neither Ronnie Mubang, MD, or Stan Stawicki, MD, had financial disclosures.
VIDEO: Pre–gastric bypass antibiotics alter gut microbiome
WASHINGTON – Antibiotics given in advance of gastric bypass surgery preferentially alter the microbiome, nudging it toward a more “lean” physiologic profile.
Given before a sleeve gastrectomy, vancomycin, which has little gut penetration, barely shifted the high ratio of Firmicutes to Bacteroidetes, a profile typically associated with obesity and insulin resistance. But cefazolin, which has much higher gut penetration, suppressed the presence of Firmicutes, which metabolize fat, and allowed the expansion of carbohydrate-loving Bacteroidetes – a profile generally seen in lean people.
Cyrus Jahansouz, MD, of the University of Minnesota, Minneapolis, and his colleagues wanted to examine whether a shift in preoperative antibiotics might affect the way the microbiome re-establishes itself in the wake of vertical sleeve gastrectomy. They enrolled 32 patients who were candidates for the procedure. None had undergone prior gastrointestinal surgery, and none had been exposed to antibiotics in the 3 months prior to bariatric surgery. They were similar in age, weight, body mass index, and fasting glucose. The mean HbA1c was about 6%.
Patients were randomized to three groups: maximal diet therapy (800 calories per day) without surgery; vertical sleeve gastrectomy with the usual preoperative antibiotic cefazolin and the postsurgical diet; and vertical sleeve gastrectomy with preoperative vancomycin and the postsurgical diet. All patients gave a fecal sample immediately before surgery and another one 6 days after surgery.
Preoperative cluster analysis of bacterial DNA showed that all of the samples had a similar composition, predominated by Firmicutes species (60%-70%). Bacteroidetes species made up about 20%-30%, with Proteobacteriae, Actinobacteriae, Verrucomicrobia, and other phyla comprising the remainder of the microbiome.
At the second sampling, the diet-only group showed no microbiome changes at all. The vancomycin group showed a very small but not significant expansion of Bacteroidetes and reduction of Firmicutes.
Patients in the cefazolin group showed a significant shift in the ratio – and it was quite striking, Dr. Jahansouz said. Among these patients, Firmicutes had decreased from 70% to 40% of the community. Bacteroidetes showed a corresponding shift, increasing from 20% of the community to 45%. The findings are quite surprising, he noted, considering that only one dose of antibiotic was associated with the changes and that they were evident within just a few days.
Although “a little hard to interpret” because of its small size and short follow-up, the study suggests that antibiotic choice might contribute to the success of weight-loss surgery, Dr. Jahansouz said at the annual clinical congress of the American College of Surgeons.
“There are still several factors in the perioperative period that we have to study to be able to identify what other things might have also influenced the shift,” he said in an interview. “But I do think that, in the future, these changes can be manipulated to benefit metabolic outcomes.”
Two phyla – Bacteroidetes and Firmicutes – dominate the human gut microbiome in a dynamic ratio that is highly associated with the way energy is extracted from food. Bacteroidetes species specialize in carbohydrate digestion and Firmicutes in fat digestion. “In a lean, insulin-sensitive state, Bacteroidetes dominates the human gut microbiome,” Dr. Jahansouz said. “With the progression of obesity and insulin resistance, there is a subsequent shift in the microbiome phenotype, favoring the growth of Firmicutes at the expense and reduction of Bacteroidetes. This is a significant change, because this obesity-associated phenotype has an increased capacity to harvest energy. It’s not the same for a lean person to consume 1,000 calories as it is for an obese person to consume them.”
Bariatric surgery has been shown to alter the gut microbiome, shifting it toward this more “lean” profile (Cell Metab. 2015 Aug 4;22[2]:228-38). This shift may be an important component of the still not fully elucidated mechanisms by which bariatric surgery causes weight loss and normalizes insulin signaling, Dr. Jahansouz said.
Dr. Jahansouz is following this group of patients to explore whether there are differences in weight loss and insulin signaling. He also will track whether the microbiome stabilizes at its early postsurgical profile, or continues to shift, either toward an even higher Bacteroidetes to Firmicutes ratio, or back to a more “obese” profile.
He and his colleagues are also investigating the effect of antibiotics and gastric bypass surgery in mouse models. “I can say that antibiotics seem to have a remarkable impact on the effect of mouse sleeve gastrectomy. We’re not quite there yet with humans,” but the data are compelling.
Dr. Jahansouz said that he had no financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
WASHINGTON – Antibiotics given in advance of gastric bypass surgery preferentially alter the microbiome, nudging it toward a more “lean” physiologic profile.
Given before a sleeve gastrectomy, vancomycin, which has little gut penetration, barely shifted the high ratio of Firmicutes to Bacteroidetes, a profile typically associated with obesity and insulin resistance. But cefazolin, which has much higher gut penetration, suppressed the presence of Firmicutes, which metabolize fat, and allowed the expansion of carbohydrate-loving Bacteroidetes – a profile generally seen in lean people.
Cyrus Jahansouz, MD, of the University of Minnesota, Minneapolis, and his colleagues wanted to examine whether a shift in preoperative antibiotics might affect the way the microbiome re-establishes itself in the wake of vertical sleeve gastrectomy. They enrolled 32 patients who were candidates for the procedure. None had undergone prior gastrointestinal surgery, and none had been exposed to antibiotics in the 3 months prior to bariatric surgery. They were similar in age, weight, body mass index, and fasting glucose. The mean HbA1c was about 6%.
Patients were randomized to three groups: maximal diet therapy (800 calories per day) without surgery; vertical sleeve gastrectomy with the usual preoperative antibiotic cefazolin and the postsurgical diet; and vertical sleeve gastrectomy with preoperative vancomycin and the postsurgical diet. All patients gave a fecal sample immediately before surgery and another one 6 days after surgery.
Preoperative cluster analysis of bacterial DNA showed that all of the samples had a similar composition, predominated by Firmicutes species (60%-70%). Bacteroidetes species made up about 20%-30%, with Proteobacteriae, Actinobacteriae, Verrucomicrobia, and other phyla comprising the remainder of the microbiome.
At the second sampling, the diet-only group showed no microbiome changes at all. The vancomycin group showed a very small but not significant expansion of Bacteroidetes and reduction of Firmicutes.
Patients in the cefazolin group showed a significant shift in the ratio – and it was quite striking, Dr. Jahansouz said. Among these patients, Firmicutes had decreased from 70% to 40% of the community. Bacteroidetes showed a corresponding shift, increasing from 20% of the community to 45%. The findings are quite surprising, he noted, considering that only one dose of antibiotic was associated with the changes and that they were evident within just a few days.
Although “a little hard to interpret” because of its small size and short follow-up, the study suggests that antibiotic choice might contribute to the success of weight-loss surgery, Dr. Jahansouz said at the annual clinical congress of the American College of Surgeons.
“There are still several factors in the perioperative period that we have to study to be able to identify what other things might have also influenced the shift,” he said in an interview. “But I do think that, in the future, these changes can be manipulated to benefit metabolic outcomes.”
Two phyla – Bacteroidetes and Firmicutes – dominate the human gut microbiome in a dynamic ratio that is highly associated with the way energy is extracted from food. Bacteroidetes species specialize in carbohydrate digestion and Firmicutes in fat digestion. “In a lean, insulin-sensitive state, Bacteroidetes dominates the human gut microbiome,” Dr. Jahansouz said. “With the progression of obesity and insulin resistance, there is a subsequent shift in the microbiome phenotype, favoring the growth of Firmicutes at the expense and reduction of Bacteroidetes. This is a significant change, because this obesity-associated phenotype has an increased capacity to harvest energy. It’s not the same for a lean person to consume 1,000 calories as it is for an obese person to consume them.”
Bariatric surgery has been shown to alter the gut microbiome, shifting it toward this more “lean” profile (Cell Metab. 2015 Aug 4;22[2]:228-38). This shift may be an important component of the still not fully elucidated mechanisms by which bariatric surgery causes weight loss and normalizes insulin signaling, Dr. Jahansouz said.
Dr. Jahansouz is following this group of patients to explore whether there are differences in weight loss and insulin signaling. He also will track whether the microbiome stabilizes at its early postsurgical profile, or continues to shift, either toward an even higher Bacteroidetes to Firmicutes ratio, or back to a more “obese” profile.
He and his colleagues are also investigating the effect of antibiotics and gastric bypass surgery in mouse models. “I can say that antibiotics seem to have a remarkable impact on the effect of mouse sleeve gastrectomy. We’re not quite there yet with humans,” but the data are compelling.
Dr. Jahansouz said that he had no financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
WASHINGTON – Antibiotics given in advance of gastric bypass surgery preferentially alter the microbiome, nudging it toward a more “lean” physiologic profile.
Given before a sleeve gastrectomy, vancomycin, which has little gut penetration, barely shifted the high ratio of Firmicutes to Bacteroidetes, a profile typically associated with obesity and insulin resistance. But cefazolin, which has much higher gut penetration, suppressed the presence of Firmicutes, which metabolize fat, and allowed the expansion of carbohydrate-loving Bacteroidetes – a profile generally seen in lean people.
Cyrus Jahansouz, MD, of the University of Minnesota, Minneapolis, and his colleagues wanted to examine whether a shift in preoperative antibiotics might affect the way the microbiome re-establishes itself in the wake of vertical sleeve gastrectomy. They enrolled 32 patients who were candidates for the procedure. None had undergone prior gastrointestinal surgery, and none had been exposed to antibiotics in the 3 months prior to bariatric surgery. They were similar in age, weight, body mass index, and fasting glucose. The mean HbA1c was about 6%.
Patients were randomized to three groups: maximal diet therapy (800 calories per day) without surgery; vertical sleeve gastrectomy with the usual preoperative antibiotic cefazolin and the postsurgical diet; and vertical sleeve gastrectomy with preoperative vancomycin and the postsurgical diet. All patients gave a fecal sample immediately before surgery and another one 6 days after surgery.
Preoperative cluster analysis of bacterial DNA showed that all of the samples had a similar composition, predominated by Firmicutes species (60%-70%). Bacteroidetes species made up about 20%-30%, with Proteobacteriae, Actinobacteriae, Verrucomicrobia, and other phyla comprising the remainder of the microbiome.
At the second sampling, the diet-only group showed no microbiome changes at all. The vancomycin group showed a very small but not significant expansion of Bacteroidetes and reduction of Firmicutes.
Patients in the cefazolin group showed a significant shift in the ratio – and it was quite striking, Dr. Jahansouz said. Among these patients, Firmicutes had decreased from 70% to 40% of the community. Bacteroidetes showed a corresponding shift, increasing from 20% of the community to 45%. The findings are quite surprising, he noted, considering that only one dose of antibiotic was associated with the changes and that they were evident within just a few days.
Although “a little hard to interpret” because of its small size and short follow-up, the study suggests that antibiotic choice might contribute to the success of weight-loss surgery, Dr. Jahansouz said at the annual clinical congress of the American College of Surgeons.
“There are still several factors in the perioperative period that we have to study to be able to identify what other things might have also influenced the shift,” he said in an interview. “But I do think that, in the future, these changes can be manipulated to benefit metabolic outcomes.”
Two phyla – Bacteroidetes and Firmicutes – dominate the human gut microbiome in a dynamic ratio that is highly associated with the way energy is extracted from food. Bacteroidetes species specialize in carbohydrate digestion and Firmicutes in fat digestion. “In a lean, insulin-sensitive state, Bacteroidetes dominates the human gut microbiome,” Dr. Jahansouz said. “With the progression of obesity and insulin resistance, there is a subsequent shift in the microbiome phenotype, favoring the growth of Firmicutes at the expense and reduction of Bacteroidetes. This is a significant change, because this obesity-associated phenotype has an increased capacity to harvest energy. It’s not the same for a lean person to consume 1,000 calories as it is for an obese person to consume them.”
Bariatric surgery has been shown to alter the gut microbiome, shifting it toward this more “lean” profile (Cell Metab. 2015 Aug 4;22[2]:228-38). This shift may be an important component of the still not fully elucidated mechanisms by which bariatric surgery causes weight loss and normalizes insulin signaling, Dr. Jahansouz said.
Dr. Jahansouz is following this group of patients to explore whether there are differences in weight loss and insulin signaling. He also will track whether the microbiome stabilizes at its early postsurgical profile, or continues to shift, either toward an even higher Bacteroidetes to Firmicutes ratio, or back to a more “obese” profile.
He and his colleagues are also investigating the effect of antibiotics and gastric bypass surgery in mouse models. “I can say that antibiotics seem to have a remarkable impact on the effect of mouse sleeve gastrectomy. We’re not quite there yet with humans,” but the data are compelling.
Dr. Jahansouz said that he had no financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
EXPERT ANALYSIS FROM THE ACS CLINICAL CONGRESS
VIDEO: Open, robotic, laparoscopic approaches equally effective in pancreatectomy
WASHINGTON – Minimally invasive surgery – whether robotic or laparoscopic – is just as effective as open surgery in pancreatectomy.
Both minimally invasive approaches had perioperative and oncologic outcomes that were similar to open approaches, as well as to each other, Katelin Mirkin, MD, reported at the annual clinical congress of the American College of Surgeons. And while minimally invasive surgery (MIS) techniques were associated with a slightly faster move to neoadjuvant chemotherapy, survival outcomes in all three surgical approaches were similar.
Dr. Mirkin, a surgery resident at Penn State Milton S. Hershey Medical Center, Hershey, Pa., plumbed the National Cancer Database for patients with stage I-III pancreatic cancer who were treated by surgical resection from 2010 to 2012. Her cohort comprised 9,047 patients; of these, 7,924 were treated with open surgery, 992 with laparoscopic surgery, and 131 with robotic surgery. She examined a number of factors including lymph node harvest and surgical margins, length of stay and time to adjuvant chemotherapy, and survival.
Patients who had MIS were older (67 vs. 66 years) and more often treated at an academic center, but otherwise there were no significant baseline differences.
Dr. Mirkin first compared the open surgeries with MIS. There were no significant associations with surgical approach and cancer stage. However, distal resections were significantly more likely to be dealt with by MIS, and Whipple procedures by open approaches. There were also more open than MIS total resections.
MIS was more likely to conclude with negative surgical margins (79% vs. 75%), and open surgery more likely to end with positive margins (22% vs. 19%).
Perioperative outcomes favored MIS approaches for all types of surgery, with a mean overall stay of 9.5 days vs. 11.3 days for open surgery. The mean length of stay for a distal resection was 7 days for MIS vs. 8 for open. For a Whipple procedure, the mean stay was 10.7 vs. 11.9 days. For a total resection, it was 10 vs. 11.8 days.
MIS was also associated with a significantly shorter time to the initiation of adjuvant chemotherapy overall (56 vs. 59 days). For a Whipple, time to chemotherapy was 58 vs. 60 days, respectively. For a distal resection, it was 52 vs. 56 days, and for a total resection, 52 vs. 58 days.
Neither approach offered a survival benefit over the other, Dr. Mirkin noted. For stage I cancers, less than 50% of MIS patients and less than 25% of open patients were alive by 50 months. For those with stage II tumors, less than 25% of each group was alive by 40 months. For stage III tumors, the 40-month survival rates were about 10% for MIS patients and 15% for open patients.
Dr. Mirkin then examined perioperative, oncologic, and survival outcomes among those who underwent laparoscopic and robotic surgeries. There were no demographic differences between these groups.
Oncologic outcomes were almost identical with regard to the number of positive regional nodes harvested (six), and surgical margins. Nodes were negative in 82% of robotic cases vs. 78% of laparoscopic cases and positive in 17.6% of robotic cases and 19.4% of laparoscopic cases.
Length of stay was significantly shorter for a laparoscopic approach overall (10 vs. 9.4 days) and particularly in distal resection (7 vs. 10 days). However, there were no differences in length of stay in any other surgery type. Nor was there any difference in the time to neoadjuvant chemotherapy.
Survival outcomes were similar as well. For stage I cancers, 40-month survival was about 40% in the laparoscopic group and 25% in the robotic group. For stage II cancers, 40-month survival was about 15% and 25%, respectively. For stage III tumors, 20-month survival in the robotic group was near 0 and 25% in the laparoscopic group. By 40 months almost all patients were deceased.
A multivariate survival analysis controlled for age, sex, race, comorbidities, facility type and location, surgery type, surgical margins, pathologic stage, and systemic therapy. It found only one significant association: Patients with 12 or more lymph nodes harvested were 19% more likely to die than those with fewer than 12 nodes harvested.
Time to chemotherapy (longer or shorter than 57 days) did not significantly impact survival, Dr. Mirkin said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @alz_gal
WASHINGTON – Minimally invasive surgery – whether robotic or laparoscopic – is just as effective as open surgery in pancreatectomy.
Both minimally invasive approaches had perioperative and oncologic outcomes that were similar to open approaches, as well as to each other, Katelin Mirkin, MD, reported at the annual clinical congress of the American College of Surgeons. And while minimally invasive surgery (MIS) techniques were associated with a slightly faster move to neoadjuvant chemotherapy, survival outcomes in all three surgical approaches were similar.
Dr. Mirkin, a surgery resident at Penn State Milton S. Hershey Medical Center, Hershey, Pa., plumbed the National Cancer Database for patients with stage I-III pancreatic cancer who were treated by surgical resection from 2010 to 2012. Her cohort comprised 9,047 patients; of these, 7,924 were treated with open surgery, 992 with laparoscopic surgery, and 131 with robotic surgery. She examined a number of factors including lymph node harvest and surgical margins, length of stay and time to adjuvant chemotherapy, and survival.
Patients who had MIS were older (67 vs. 66 years) and more often treated at an academic center, but otherwise there were no significant baseline differences.
Dr. Mirkin first compared the open surgeries with MIS. There were no significant associations with surgical approach and cancer stage. However, distal resections were significantly more likely to be dealt with by MIS, and Whipple procedures by open approaches. There were also more open than MIS total resections.
MIS was more likely to conclude with negative surgical margins (79% vs. 75%), and open surgery more likely to end with positive margins (22% vs. 19%).
Perioperative outcomes favored MIS approaches for all types of surgery, with a mean overall stay of 9.5 days vs. 11.3 days for open surgery. The mean length of stay for a distal resection was 7 days for MIS vs. 8 for open. For a Whipple procedure, the mean stay was 10.7 vs. 11.9 days. For a total resection, it was 10 vs. 11.8 days.
MIS was also associated with a significantly shorter time to the initiation of adjuvant chemotherapy overall (56 vs. 59 days). For a Whipple, time to chemotherapy was 58 vs. 60 days, respectively. For a distal resection, it was 52 vs. 56 days, and for a total resection, 52 vs. 58 days.
Neither approach offered a survival benefit over the other, Dr. Mirkin noted. For stage I cancers, less than 50% of MIS patients and less than 25% of open patients were alive by 50 months. For those with stage II tumors, less than 25% of each group was alive by 40 months. For stage III tumors, the 40-month survival rates were about 10% for MIS patients and 15% for open patients.
Dr. Mirkin then examined perioperative, oncologic, and survival outcomes among those who underwent laparoscopic and robotic surgeries. There were no demographic differences between these groups.
Oncologic outcomes were almost identical with regard to the number of positive regional nodes harvested (six), and surgical margins. Nodes were negative in 82% of robotic cases vs. 78% of laparoscopic cases and positive in 17.6% of robotic cases and 19.4% of laparoscopic cases.
Length of stay was significantly shorter for a laparoscopic approach overall (10 vs. 9.4 days) and particularly in distal resection (7 vs. 10 days). However, there were no differences in length of stay in any other surgery type. Nor was there any difference in the time to neoadjuvant chemotherapy.
Survival outcomes were similar as well. For stage I cancers, 40-month survival was about 40% in the laparoscopic group and 25% in the robotic group. For stage II cancers, 40-month survival was about 15% and 25%, respectively. For stage III tumors, 20-month survival in the robotic group was near 0 and 25% in the laparoscopic group. By 40 months almost all patients were deceased.
A multivariate survival analysis controlled for age, sex, race, comorbidities, facility type and location, surgery type, surgical margins, pathologic stage, and systemic therapy. It found only one significant association: Patients with 12 or more lymph nodes harvested were 19% more likely to die than those with fewer than 12 nodes harvested.
Time to chemotherapy (longer or shorter than 57 days) did not significantly impact survival, Dr. Mirkin said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @alz_gal
WASHINGTON – Minimally invasive surgery – whether robotic or laparoscopic – is just as effective as open surgery in pancreatectomy.
Both minimally invasive approaches had perioperative and oncologic outcomes that were similar to open approaches, as well as to each other, Katelin Mirkin, MD, reported at the annual clinical congress of the American College of Surgeons. And while minimally invasive surgery (MIS) techniques were associated with a slightly faster move to neoadjuvant chemotherapy, survival outcomes in all three surgical approaches were similar.
Dr. Mirkin, a surgery resident at Penn State Milton S. Hershey Medical Center, Hershey, Pa., plumbed the National Cancer Database for patients with stage I-III pancreatic cancer who were treated by surgical resection from 2010 to 2012. Her cohort comprised 9,047 patients; of these, 7,924 were treated with open surgery, 992 with laparoscopic surgery, and 131 with robotic surgery. She examined a number of factors including lymph node harvest and surgical margins, length of stay and time to adjuvant chemotherapy, and survival.
Patients who had MIS were older (67 vs. 66 years) and more often treated at an academic center, but otherwise there were no significant baseline differences.
Dr. Mirkin first compared the open surgeries with MIS. There were no significant associations with surgical approach and cancer stage. However, distal resections were significantly more likely to be dealt with by MIS, and Whipple procedures by open approaches. There were also more open than MIS total resections.
MIS was more likely to conclude with negative surgical margins (79% vs. 75%), and open surgery more likely to end with positive margins (22% vs. 19%).
Perioperative outcomes favored MIS approaches for all types of surgery, with a mean overall stay of 9.5 days vs. 11.3 days for open surgery. The mean length of stay for a distal resection was 7 days for MIS vs. 8 for open. For a Whipple procedure, the mean stay was 10.7 vs. 11.9 days. For a total resection, it was 10 vs. 11.8 days.
MIS was also associated with a significantly shorter time to the initiation of adjuvant chemotherapy overall (56 vs. 59 days). For a Whipple, time to chemotherapy was 58 vs. 60 days, respectively. For a distal resection, it was 52 vs. 56 days, and for a total resection, 52 vs. 58 days.
Neither approach offered a survival benefit over the other, Dr. Mirkin noted. For stage I cancers, less than 50% of MIS patients and less than 25% of open patients were alive by 50 months. For those with stage II tumors, less than 25% of each group was alive by 40 months. For stage III tumors, the 40-month survival rates were about 10% for MIS patients and 15% for open patients.
Dr. Mirkin then examined perioperative, oncologic, and survival outcomes among those who underwent laparoscopic and robotic surgeries. There were no demographic differences between these groups.
Oncologic outcomes were almost identical with regard to the number of positive regional nodes harvested (six), and surgical margins. Nodes were negative in 82% of robotic cases vs. 78% of laparoscopic cases and positive in 17.6% of robotic cases and 19.4% of laparoscopic cases.
Length of stay was significantly shorter for a laparoscopic approach overall (10 vs. 9.4 days) and particularly in distal resection (7 vs. 10 days). However, there were no differences in length of stay in any other surgery type. Nor was there any difference in the time to neoadjuvant chemotherapy.
Survival outcomes were similar as well. For stage I cancers, 40-month survival was about 40% in the laparoscopic group and 25% in the robotic group. For stage II cancers, 40-month survival was about 15% and 25%, respectively. For stage III tumors, 20-month survival in the robotic group was near 0 and 25% in the laparoscopic group. By 40 months almost all patients were deceased.
A multivariate survival analysis controlled for age, sex, race, comorbidities, facility type and location, surgery type, surgical margins, pathologic stage, and systemic therapy. It found only one significant association: Patients with 12 or more lymph nodes harvested were 19% more likely to die than those with fewer than 12 nodes harvested.
Time to chemotherapy (longer or shorter than 57 days) did not significantly impact survival, Dr. Mirkin said.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
msullivan@frontlinemedcom.com
On Twitter @alz_gal
AT THE ACS CLINICAL CONGRESS
Key clinical point:
Major finding: For stage I cancers, less than 50% of minimally invasive surgery patients and less than 25% of open surgery patients were alive by 50 months. For those with stage II tumors, less than 25% of each group was alive by 40 months.
Data source: The database review comprised 9,047 cases.
Disclosures: Dr. Mirkin had no financial disclosures.
Reslizumab performance tied to eosinophil count
Reslizumab was most effective in patients with high baseline eosinophil counts, two randomized, placebo-controlled studies have determined. The companion studies were simultaneously published in the October issue of Chest.
The drug reslizumab, an anti–interleukin-5 monoclonal antibody, is made by Teva Branded Pharmaceutical Products R&D, who sponsored both studies.
The larger study, comprising 492 patients, found no significant benefit of reslizumab over placebo, Jonathan Corren, MD, and his colleagues wrote (Chest. 2016;150:799-810). But this study didn’t stratify patients by baseline eosinophil levels; a post-hoc subanalysis found a significant benefit in forced expiratory volume in 69 of the patients who had at least 400 eosinophils/microliter (mcL) when treatment began.
In these patients, the drug significantly improved not only lung function, but asthma symptoms and asthma-related quality of life scores.
“These efficacy findings are consistent with results from other reslizumab trials and combined with the favorable safety profile observed, support the use of reslizumab in patients with asthma and elevated blood eosinophils, uncontrolled by an inhaled corticosteroid-based regimen,” Dr. Bjermer and his coauthors wrote.
The unstratified trial was conducted at 66 sites in the U.S. All of the patients had poorly controlled asthma despite using at least a medium-dosed inhaled corticosteroid. They were randomized to infusions of reslizumab 3.0 mg/kg or placebo given once every 4 weeks for 16 weeks.*
The primary endpoint was the change in forced expiratory volume in one second (FEV1); secondary endpoints included quality of life scores; the need for rescue medication; forced vital capacity; and eosinophil count.
Patients in the placebo and reslizumab groups were an average age of 45.1 years and 44.9 years, respectively. The mean disease duration of patients in both groups was 26 years.
At week 16, the mean change in FEV1 from baseline was 255 ml in the active group and 187 ml in the placebo group – not a significant difference.
The team performed a post-hoc subgroup analysis that dichotomized the cohort based on baseline eosinophil levels. For the 343 with counts of less than 400 cells/mcL, there was no difference in FEV1 at 16 weeks, between the patients who received treatment and the patients who received a placebo. The FEV1s of these two groups were separated by just 33 mL.
The story was different for the 82 patients with at least 400 cells/mcL, with 69 of such patients receiving the drug and 13 of such patients receiving the placebo. At 16 weeks, the difference in FEV1 change was 270 mL, in favor of the active group. The strength of these findings may be weakened by the large difference in size between the treatment and placebo groups and the “near complete lack of response in the small number of placebo-treated patients.”
“Interpretation of the results in the [400 or more cells/mcL] subgroup is limited as the study was not designed or statistically powered to specifically test this group of patients,” the team wrote. Nevertheless, they concluded that reslizumab is a reasonable treatment option for this group. “These findings support an acceptable benefit-risk profile for reslizumab in asthma patients with a blood eosinophil threshold” of at least 400 cells/mcL.
The stratified study examined more endpoints: pre-bronchodilator spirometry (forced expiratory volume in one second FEV1, forced vital capacity, and forced expiratory flow), asthma symptoms, quality of life, rescue inhaler use, and blood eosinophil levels.
The 315 patients in this study all had a baseline eosinophil count of at least 400 cells/mcL. They were randomized to placebo or to 0.3 or 3.0 mg/kg reslizumab dose once every 4 weeks for 16 weeks. The mean ages for the patients taking the placebo, reslizumab 0.3 mg/kg, and reslizumab 3.0 mg/kg were 44.2, 44.5, and 43.0, respectively. The range of average disease durations for patients in the placebo group and two reslizumab groups was 20 to 20.7 years.
The final FEV1 was significantly improved over placebo in both active groups, although the change was much more pronounced in those taking 3.0 mg/kg, compared with those taking 0.3 mg/kg (160 mL and 115 mL, respectively, relative to placebo). Forced vital capacity also improved significantly in the 3.0 mg/kg dose group (130 mL relative to placebo).
Reslizumab was generally well tolerated in both studies. The most frequent adverse events in the stratified study were asthma worsening, headache, nasopharyngitis, upper respiratory infections, and sinusitis.
In the unstratified study, there were two anaphylactic reactions, but only one was related to the study drug. No deaths occurred in either treatment group of this study.
Both trials were sponsored by Teva. Dr. Bjermer has served on advisory boards or provided lectures for Aerocrine, Airsonett, ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Meda, Mundipharma, Nigaard, Novartis, Regeneron, Sanofi-Aventis, Takeda, and Teva. Dr. Corren has been involved in speaker bureau activities for Genentech and Merck; he has served on advisory boards for Genentech, Merck, Novartis, and Vectura.
*CORRECTION 12/9/16: An earlier version of this article misstated the infusion frequency.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
Persistent eosinophilic inflammation is present in about half of patients with severe asthma, and the studies by Corren and Bjermer represent important advances in learning how to target this inflammatory pathway, Richard Russell, MBBS, MRCP, and Christopher Brightling, PhD, FCCP, wrote in an accompanying editorial (Chest. 2016;150:766-8).
“The most advanced therapeutic target is IL-5, which is an attractive target because it is an obligate cytokine for eosinophil maturation and survival. Its inhibition is thus predicted to reduce bone marrow production of eosinophils and promote apoptosis,” wrote Dr. Russell, a clinical research fellow, and Dr. Brightling, a professor, both at the University of Leicester (England).
“These findings support the view that an elevated blood eosinophil count is associated with a good clinical response [to the antibody reslizumab] but [the studies] did not find a clear correlation between the intensity of the baseline eosinophil count and response,” the colleagues wrote. “Thus, the best cut-off for the blood eosinophil count to apply clinically remains uncertain.”
Clinicians and patients may find a different answer to this riddle than do payers.
“From a patient perspective there is an argument to select a low or no cut-off as there is some benefit even with low baseline eosinophil counts, whereas from a payer’s perspective the health economic benefit is better with a higher cut-off.”
As is often the case, more study will help clarify these new concerns.
“We are moving into a new era of Type-2 immunity-mediated therapies that will bring new opportunities for clinicians and our patients, but with this opportunity comes new challenges. Biomarkers will increase in importance to help drive precision medicine, but we need to understand how to use them, and, in particular, what cut-points to apply. For anti-IL-5 approaches, we probably need to look towards elevated blood eosinophil counts, as aiming for a high cut-off is most likely the best way we shall achieve success.”
Dr. Russell had no financial disclosures. Mr. Brightling reported financial relationships with several pharmaceutical companies, but not with Teva.
Persistent eosinophilic inflammation is present in about half of patients with severe asthma, and the studies by Corren and Bjermer represent important advances in learning how to target this inflammatory pathway, Richard Russell, MBBS, MRCP, and Christopher Brightling, PhD, FCCP, wrote in an accompanying editorial (Chest. 2016;150:766-8).
“The most advanced therapeutic target is IL-5, which is an attractive target because it is an obligate cytokine for eosinophil maturation and survival. Its inhibition is thus predicted to reduce bone marrow production of eosinophils and promote apoptosis,” wrote Dr. Russell, a clinical research fellow, and Dr. Brightling, a professor, both at the University of Leicester (England).
“These findings support the view that an elevated blood eosinophil count is associated with a good clinical response [to the antibody reslizumab] but [the studies] did not find a clear correlation between the intensity of the baseline eosinophil count and response,” the colleagues wrote. “Thus, the best cut-off for the blood eosinophil count to apply clinically remains uncertain.”
Clinicians and patients may find a different answer to this riddle than do payers.
“From a patient perspective there is an argument to select a low or no cut-off as there is some benefit even with low baseline eosinophil counts, whereas from a payer’s perspective the health economic benefit is better with a higher cut-off.”
As is often the case, more study will help clarify these new concerns.
“We are moving into a new era of Type-2 immunity-mediated therapies that will bring new opportunities for clinicians and our patients, but with this opportunity comes new challenges. Biomarkers will increase in importance to help drive precision medicine, but we need to understand how to use them, and, in particular, what cut-points to apply. For anti-IL-5 approaches, we probably need to look towards elevated blood eosinophil counts, as aiming for a high cut-off is most likely the best way we shall achieve success.”
Dr. Russell had no financial disclosures. Mr. Brightling reported financial relationships with several pharmaceutical companies, but not with Teva.
Persistent eosinophilic inflammation is present in about half of patients with severe asthma, and the studies by Corren and Bjermer represent important advances in learning how to target this inflammatory pathway, Richard Russell, MBBS, MRCP, and Christopher Brightling, PhD, FCCP, wrote in an accompanying editorial (Chest. 2016;150:766-8).
“The most advanced therapeutic target is IL-5, which is an attractive target because it is an obligate cytokine for eosinophil maturation and survival. Its inhibition is thus predicted to reduce bone marrow production of eosinophils and promote apoptosis,” wrote Dr. Russell, a clinical research fellow, and Dr. Brightling, a professor, both at the University of Leicester (England).
“These findings support the view that an elevated blood eosinophil count is associated with a good clinical response [to the antibody reslizumab] but [the studies] did not find a clear correlation between the intensity of the baseline eosinophil count and response,” the colleagues wrote. “Thus, the best cut-off for the blood eosinophil count to apply clinically remains uncertain.”
Clinicians and patients may find a different answer to this riddle than do payers.
“From a patient perspective there is an argument to select a low or no cut-off as there is some benefit even with low baseline eosinophil counts, whereas from a payer’s perspective the health economic benefit is better with a higher cut-off.”
As is often the case, more study will help clarify these new concerns.
“We are moving into a new era of Type-2 immunity-mediated therapies that will bring new opportunities for clinicians and our patients, but with this opportunity comes new challenges. Biomarkers will increase in importance to help drive precision medicine, but we need to understand how to use them, and, in particular, what cut-points to apply. For anti-IL-5 approaches, we probably need to look towards elevated blood eosinophil counts, as aiming for a high cut-off is most likely the best way we shall achieve success.”
Dr. Russell had no financial disclosures. Mr. Brightling reported financial relationships with several pharmaceutical companies, but not with Teva.
Reslizumab was most effective in patients with high baseline eosinophil counts, two randomized, placebo-controlled studies have determined. The companion studies were simultaneously published in the October issue of Chest.
The drug reslizumab, an anti–interleukin-5 monoclonal antibody, is made by Teva Branded Pharmaceutical Products R&D, who sponsored both studies.
The larger study, comprising 492 patients, found no significant benefit of reslizumab over placebo, Jonathan Corren, MD, and his colleagues wrote (Chest. 2016;150:799-810). But this study didn’t stratify patients by baseline eosinophil levels; a post-hoc subanalysis found a significant benefit in forced expiratory volume in 69 of the patients who had at least 400 eosinophils/microliter (mcL) when treatment began.
In these patients, the drug significantly improved not only lung function, but asthma symptoms and asthma-related quality of life scores.
“These efficacy findings are consistent with results from other reslizumab trials and combined with the favorable safety profile observed, support the use of reslizumab in patients with asthma and elevated blood eosinophils, uncontrolled by an inhaled corticosteroid-based regimen,” Dr. Bjermer and his coauthors wrote.
The unstratified trial was conducted at 66 sites in the U.S. All of the patients had poorly controlled asthma despite using at least a medium-dosed inhaled corticosteroid. They were randomized to infusions of reslizumab 3.0 mg/kg or placebo given once every 4 weeks for 16 weeks.*
The primary endpoint was the change in forced expiratory volume in one second (FEV1); secondary endpoints included quality of life scores; the need for rescue medication; forced vital capacity; and eosinophil count.
Patients in the placebo and reslizumab groups were an average age of 45.1 years and 44.9 years, respectively. The mean disease duration of patients in both groups was 26 years.
At week 16, the mean change in FEV1 from baseline was 255 ml in the active group and 187 ml in the placebo group – not a significant difference.
The team performed a post-hoc subgroup analysis that dichotomized the cohort based on baseline eosinophil levels. For the 343 with counts of less than 400 cells/mcL, there was no difference in FEV1 at 16 weeks, between the patients who received treatment and the patients who received a placebo. The FEV1s of these two groups were separated by just 33 mL.
The story was different for the 82 patients with at least 400 cells/mcL, with 69 of such patients receiving the drug and 13 of such patients receiving the placebo. At 16 weeks, the difference in FEV1 change was 270 mL, in favor of the active group. The strength of these findings may be weakened by the large difference in size between the treatment and placebo groups and the “near complete lack of response in the small number of placebo-treated patients.”
“Interpretation of the results in the [400 or more cells/mcL] subgroup is limited as the study was not designed or statistically powered to specifically test this group of patients,” the team wrote. Nevertheless, they concluded that reslizumab is a reasonable treatment option for this group. “These findings support an acceptable benefit-risk profile for reslizumab in asthma patients with a blood eosinophil threshold” of at least 400 cells/mcL.
The stratified study examined more endpoints: pre-bronchodilator spirometry (forced expiratory volume in one second FEV1, forced vital capacity, and forced expiratory flow), asthma symptoms, quality of life, rescue inhaler use, and blood eosinophil levels.
The 315 patients in this study all had a baseline eosinophil count of at least 400 cells/mcL. They were randomized to placebo or to 0.3 or 3.0 mg/kg reslizumab dose once every 4 weeks for 16 weeks. The mean ages for the patients taking the placebo, reslizumab 0.3 mg/kg, and reslizumab 3.0 mg/kg were 44.2, 44.5, and 43.0, respectively. The range of average disease durations for patients in the placebo group and two reslizumab groups was 20 to 20.7 years.
The final FEV1 was significantly improved over placebo in both active groups, although the change was much more pronounced in those taking 3.0 mg/kg, compared with those taking 0.3 mg/kg (160 mL and 115 mL, respectively, relative to placebo). Forced vital capacity also improved significantly in the 3.0 mg/kg dose group (130 mL relative to placebo).
Reslizumab was generally well tolerated in both studies. The most frequent adverse events in the stratified study were asthma worsening, headache, nasopharyngitis, upper respiratory infections, and sinusitis.
In the unstratified study, there were two anaphylactic reactions, but only one was related to the study drug. No deaths occurred in either treatment group of this study.
Both trials were sponsored by Teva. Dr. Bjermer has served on advisory boards or provided lectures for Aerocrine, Airsonett, ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Meda, Mundipharma, Nigaard, Novartis, Regeneron, Sanofi-Aventis, Takeda, and Teva. Dr. Corren has been involved in speaker bureau activities for Genentech and Merck; he has served on advisory boards for Genentech, Merck, Novartis, and Vectura.
*CORRECTION 12/9/16: An earlier version of this article misstated the infusion frequency.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
Reslizumab was most effective in patients with high baseline eosinophil counts, two randomized, placebo-controlled studies have determined. The companion studies were simultaneously published in the October issue of Chest.
The drug reslizumab, an anti–interleukin-5 monoclonal antibody, is made by Teva Branded Pharmaceutical Products R&D, who sponsored both studies.
The larger study, comprising 492 patients, found no significant benefit of reslizumab over placebo, Jonathan Corren, MD, and his colleagues wrote (Chest. 2016;150:799-810). But this study didn’t stratify patients by baseline eosinophil levels; a post-hoc subanalysis found a significant benefit in forced expiratory volume in 69 of the patients who had at least 400 eosinophils/microliter (mcL) when treatment began.
In these patients, the drug significantly improved not only lung function, but asthma symptoms and asthma-related quality of life scores.
“These efficacy findings are consistent with results from other reslizumab trials and combined with the favorable safety profile observed, support the use of reslizumab in patients with asthma and elevated blood eosinophils, uncontrolled by an inhaled corticosteroid-based regimen,” Dr. Bjermer and his coauthors wrote.
The unstratified trial was conducted at 66 sites in the U.S. All of the patients had poorly controlled asthma despite using at least a medium-dosed inhaled corticosteroid. They were randomized to infusions of reslizumab 3.0 mg/kg or placebo given once every 4 weeks for 16 weeks.*
The primary endpoint was the change in forced expiratory volume in one second (FEV1); secondary endpoints included quality of life scores; the need for rescue medication; forced vital capacity; and eosinophil count.
Patients in the placebo and reslizumab groups were an average age of 45.1 years and 44.9 years, respectively. The mean disease duration of patients in both groups was 26 years.
At week 16, the mean change in FEV1 from baseline was 255 ml in the active group and 187 ml in the placebo group – not a significant difference.
The team performed a post-hoc subgroup analysis that dichotomized the cohort based on baseline eosinophil levels. For the 343 with counts of less than 400 cells/mcL, there was no difference in FEV1 at 16 weeks, between the patients who received treatment and the patients who received a placebo. The FEV1s of these two groups were separated by just 33 mL.
The story was different for the 82 patients with at least 400 cells/mcL, with 69 of such patients receiving the drug and 13 of such patients receiving the placebo. At 16 weeks, the difference in FEV1 change was 270 mL, in favor of the active group. The strength of these findings may be weakened by the large difference in size between the treatment and placebo groups and the “near complete lack of response in the small number of placebo-treated patients.”
“Interpretation of the results in the [400 or more cells/mcL] subgroup is limited as the study was not designed or statistically powered to specifically test this group of patients,” the team wrote. Nevertheless, they concluded that reslizumab is a reasonable treatment option for this group. “These findings support an acceptable benefit-risk profile for reslizumab in asthma patients with a blood eosinophil threshold” of at least 400 cells/mcL.
The stratified study examined more endpoints: pre-bronchodilator spirometry (forced expiratory volume in one second FEV1, forced vital capacity, and forced expiratory flow), asthma symptoms, quality of life, rescue inhaler use, and blood eosinophil levels.
The 315 patients in this study all had a baseline eosinophil count of at least 400 cells/mcL. They were randomized to placebo or to 0.3 or 3.0 mg/kg reslizumab dose once every 4 weeks for 16 weeks. The mean ages for the patients taking the placebo, reslizumab 0.3 mg/kg, and reslizumab 3.0 mg/kg were 44.2, 44.5, and 43.0, respectively. The range of average disease durations for patients in the placebo group and two reslizumab groups was 20 to 20.7 years.
The final FEV1 was significantly improved over placebo in both active groups, although the change was much more pronounced in those taking 3.0 mg/kg, compared with those taking 0.3 mg/kg (160 mL and 115 mL, respectively, relative to placebo). Forced vital capacity also improved significantly in the 3.0 mg/kg dose group (130 mL relative to placebo).
Reslizumab was generally well tolerated in both studies. The most frequent adverse events in the stratified study were asthma worsening, headache, nasopharyngitis, upper respiratory infections, and sinusitis.
In the unstratified study, there were two anaphylactic reactions, but only one was related to the study drug. No deaths occurred in either treatment group of this study.
Both trials were sponsored by Teva. Dr. Bjermer has served on advisory boards or provided lectures for Aerocrine, Airsonett, ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Meda, Mundipharma, Nigaard, Novartis, Regeneron, Sanofi-Aventis, Takeda, and Teva. Dr. Corren has been involved in speaker bureau activities for Genentech and Merck; he has served on advisory boards for Genentech, Merck, Novartis, and Vectura.
*CORRECTION 12/9/16: An earlier version of this article misstated the infusion frequency.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
FROM CHEST
Key clinical point:
Major finding: Forced expiratory volume in 1 second (FEV1) improved by 160 mL with reslizumab 3.0 mg/kg relative to placebo.
Data source: The two randomized, placebo-controlled studies comprised about 800 patients.
Disclosures: Both trials were sponsored by Teva Branded Pharmaceutical Products R&D. Dr. Bjermer has served on an advisory board or provided lectures for Teva. Dr. Corren has served on advisory boards and has been involved in speaker bureau activities for various pharmaceutical companies.