User login
Clinical Challenges - February 2017: So-called carcinosarcoma of the esophagus
What's Your Diagnosis?
The Diagnosis
Carcinosarcoma is a rare malignant entity, representing less than 2% of all esophageal neoplasms. It usually shows a bulky appearance of an intraluminal polypoid lesion owing to predominant sarcomatous development with little stromal proliferation. 
References
1. Hung J.J., Li A.F., Liu J.S., et al. Esophageal carcinosarcoma with basaloid squamous cell carcinoma and osteosarcoma. Ann Thorac Surg. 2008;85[3]:1102-4.
2. Madan A.K., Long A.E., Weldon C.B., et al. Esophageal carcinosarcoma. J Gastrointest Surg. 2001;5[4]:414-7.
The Diagnosis
Carcinosarcoma is a rare malignant entity, representing less than 2% of all esophageal neoplasms. It usually shows a bulky appearance of an intraluminal polypoid lesion owing to predominant sarcomatous development with little stromal proliferation.
References
1. Hung J.J., Li A.F., Liu J.S., et al. Esophageal carcinosarcoma with basaloid squamous cell carcinoma and osteosarcoma. Ann Thorac Surg. 2008;85[3]:1102-4.
2. Madan A.K., Long A.E., Weldon C.B., et al. Esophageal carcinosarcoma. J Gastrointest Surg. 2001;5[4]:414-7.
The Diagnosis
Carcinosarcoma is a rare malignant entity, representing less than 2% of all esophageal neoplasms. It usually shows a bulky appearance of an intraluminal polypoid lesion owing to predominant sarcomatous development with little stromal proliferation.
References
1. Hung J.J., Li A.F., Liu J.S., et al. Esophageal carcinosarcoma with basaloid squamous cell carcinoma and osteosarcoma. Ann Thorac Surg. 2008;85[3]:1102-4.
2. Madan A.K., Long A.E., Weldon C.B., et al. Esophageal carcinosarcoma. J Gastrointest Surg. 2001;5[4]:414-7.
What's Your Diagnosis?
What's Your Diagnosis?
By Kensuke Adachi, MD, PhD, and Kazuaki Enatsu, MD.
Published previously in Gastroenterology (2013;144[1]:32, 251).
Researchers find ‘feedback loop’ key to reducing high blood pressure
Research with mice and rats in Germany may have found a new way to treat high blood pressure.
Using epifluorescence intravital video microscopy imaging, researchers examined mice to whom they had given angiotensin II hormones to induce arterial hypertension.
They determined that the mice with low levels of thrombin-driven factor XI (FXI) – either naturally or inhibited by antisense oligonucleotides – had healthier endothelium.
“Specificity of the effects of FXI depletion was confirmed by continuous in vivo supplementation with human FXI,” wrote Sabine Kossmann, PhD, of the Center for Thrombosis and Hemostasis, University Medical Center, Mainz (Germany), and her coauthors (Sci Transl Med. 2017 Feb 1. doi: 10.1126/scitranslmed.aah4923).
Targeting the “feedback loop” between the FXI and a receptor that helps thrombin propagate on platelets reduced both vascular inflammation and blood pressure.
“Our findings suggest that inhibiting the ... thrombin-FXI–amplifying loop may provide added cardiovascular benefits that are synergistic with those of established platelet inhibitors,” the authors wrote.
This work was supported by grants from the Stiftung Pathobiochemie und Molekulare Diagnostik and the Federal Ministry of Education and Research. The authors disclosed funding and grants from the German Research Society, the European Research Council, NIH, and other sources. One of the researchers is inventor of five patents related to the FXI inhibitor and equity holder in Aronora, and may have financial interest in the findings of the research.
Research with mice and rats in Germany may have found a new way to treat high blood pressure.
Using epifluorescence intravital video microscopy imaging, researchers examined mice to whom they had given angiotensin II hormones to induce arterial hypertension.
They determined that the mice with low levels of thrombin-driven factor XI (FXI) – either naturally or inhibited by antisense oligonucleotides – had healthier endothelium.
“Specificity of the effects of FXI depletion was confirmed by continuous in vivo supplementation with human FXI,” wrote Sabine Kossmann, PhD, of the Center for Thrombosis and Hemostasis, University Medical Center, Mainz (Germany), and her coauthors (Sci Transl Med. 2017 Feb 1. doi: 10.1126/scitranslmed.aah4923).
Targeting the “feedback loop” between the FXI and a receptor that helps thrombin propagate on platelets reduced both vascular inflammation and blood pressure.
“Our findings suggest that inhibiting the ... thrombin-FXI–amplifying loop may provide added cardiovascular benefits that are synergistic with those of established platelet inhibitors,” the authors wrote.
This work was supported by grants from the Stiftung Pathobiochemie und Molekulare Diagnostik and the Federal Ministry of Education and Research. The authors disclosed funding and grants from the German Research Society, the European Research Council, NIH, and other sources. One of the researchers is inventor of five patents related to the FXI inhibitor and equity holder in Aronora, and may have financial interest in the findings of the research.
Research with mice and rats in Germany may have found a new way to treat high blood pressure.
Using epifluorescence intravital video microscopy imaging, researchers examined mice to whom they had given angiotensin II hormones to induce arterial hypertension.
They determined that the mice with low levels of thrombin-driven factor XI (FXI) – either naturally or inhibited by antisense oligonucleotides – had healthier endothelium.
“Specificity of the effects of FXI depletion was confirmed by continuous in vivo supplementation with human FXI,” wrote Sabine Kossmann, PhD, of the Center for Thrombosis and Hemostasis, University Medical Center, Mainz (Germany), and her coauthors (Sci Transl Med. 2017 Feb 1. doi: 10.1126/scitranslmed.aah4923).
Targeting the “feedback loop” between the FXI and a receptor that helps thrombin propagate on platelets reduced both vascular inflammation and blood pressure.
“Our findings suggest that inhibiting the ... thrombin-FXI–amplifying loop may provide added cardiovascular benefits that are synergistic with those of established platelet inhibitors,” the authors wrote.
This work was supported by grants from the Stiftung Pathobiochemie und Molekulare Diagnostik and the Federal Ministry of Education and Research. The authors disclosed funding and grants from the German Research Society, the European Research Council, NIH, and other sources. One of the researchers is inventor of five patents related to the FXI inhibitor and equity holder in Aronora, and may have financial interest in the findings of the research.
FROM SCIENCE TRANSLATIONAL MEDICINE
Unpublished study on Bendectin prompts questions on hidden data
Doubt is being cast on the efficacy of Diclegis – the only prescription drug approved in the United States for treating nausea and vomiting in pregnancy – after researchers exposed flaws in previously unpublished data that served as the basis for the drug’s approval.
But the larger point, according to the researcher who brought the unpublished study to light, is the danger of relying too heavily on hidden data.
“It’s not like there’s some special concern over the safety of Diclegis. It’s that there is this commonly prescribed medication that hasn’t been proven to be effective,” Navindra Persaud, MD, a family physician and researcher at St. Michael’s Hospital in Toronto, said in an interview.
The 8-Way Bendectin Study was a double-blind, multicentered, randomized, placebo-controlled study of 2,359 women with morning sickness in the first trimester, conducted in the United States across multiple sites in 1976 by the now-defunct Wm. S. Merrell Co. The aim was to find a replacement formulation of a three-agent formula (Bendectin) for morning sickness, after one of the ingredients – dicyclomine hydrochloride – was determined ineffective for pregnancy-related nausea and vomiting.
Participants in the study, which had seven treatment arms and one control group, were asked to keep diaries for a week, detailing their bouts of nausea and vomiting. Clinicians then evaluated and rated the diary entries. In all, data for 1,599 of the women were analyzed, with all seven treatment arms besting placebo. Doxylamine-pyridoxine was rated “moderate or excellent” with a 21% absolute difference, compared with placebo (95% confidence interval, 11-30). The most commonly reported side effect across the study was drowsiness.
Dr. Persaud said he thinks the study was never published because of multiple flaws. For instance, there was not a clear baseline for symptoms, or clear parameters for how the clinicians rated those symptoms; outcome data for more than a third of controls were missing, as were completed reports about potential adverse outcomes; and P values were one sided and not adjusted to account for all eight study arms, he said.
“While the analyzed data indicate differences from placebo for several combinations, the questionable data integrity, high dropout rate, and other methodological concerns mean that the prescribing of this medication should not be based on this trial,” wrote Dr. Persaud and Dr. Zhang in their analysis.
The newly published analysis brings back the rocky history of morning sickness treatments in the United States, notably the withdrawal of Bendectin in 1983 following a barrage of teratogenicity claims against the drug maker that made it unprofitable to continue marketing.
This is all beside the point, according to Dr. Persaud. “For every medication, you’re going to find some of these associations. They might be real; they might be not. So you have to weigh potential harm against the benefit. The real problem here is that there is no demonstrated benefit even though the claim seems to be that there is,” he said.
Duchesnay defended the efficacy of the drug.
“The conclusions expressed in the report published in PLOS ONE are highly inconsistent with the large and comprehensive body of evidence regarding this combination drug,” Michael Gallo, Duchesnay vice president for regulatory and medical affairs, said in a statement posted on the company’s website. In its response to Dr. Persaud and Dr. Zhang’s analysis, the company also said that doxylamine succinate and pyridoxine hydrochloride – the two agents in the treatment – are “ the most studied drug combination used in pregnancy. The safety and efficacy of [Diclegis] have been proven in 16 cohort studies, two meta-analyses, an ecological study, a neurological development study, and numerous others.”
“It’s unclear if the [unpublished] study was carefully reassessed in the lead-up to the recent approval of Diclegis,” he said. “The available FDA review documents for the recent approval of Diclectin [pyridoxine/doxylamine] do not mention the problems with the study.”
One factor in the treatment’s place in standard of care might be anecdotal influences from some of the more than 35 million women around the world thought to have used the treatment, according to Dr. Persaud. “Lots of women have taken this medication and felt better shortly after, so they feel strongly that the medication is effective,” he said, but because nausea and vomiting in pregnancy is common in more than three-quarters of women, and typically does not last more than several weeks, most likely the patients would have gotten better over time anyway.
“Some women suffer greatly and do seem to get relief from medication,” Dr. Chambers said, but noted that Diclegis is not the only option available for women.
When Bendectin was pulled from the U.S. market, for example, Dr. Chambers said women turned to combinations of vitamin B6 and over-the-counter medications that contain the antihistamine doxylamine.
Dr. Persaud said his interest in the review started after a patient expressed her concerns over the medication. “She was reluctant to take it, and asked me if I was sure about it. I reassured her, but then after she left, I did wonder if I was correct,” he recalled. He said he checked all the guidelines, but could not find anything to justify its use other than the manufacturer’s monograph.
He said he suspects this is not the only prescription medication that would not withstand such scrutiny, but that uncovering the necessary data would be very difficult. “I was shocked it was very difficult to get access to this information as a clinician,” he said, adding that it also is impractical to expect physicians to spend 5 years to track the information down.
In their analysis of the study, Dr. Persaud and Dr. Zhang stated that their objective is to contribute to a movement across all of medicine to end the risks of data secrecy, and instead “restore invisible and abandoned trials” (RIAT). The U.S. Department of Health & Human Services has been pushing to make more clinical trials data public through ClinicalTrials.gov, including issuing federal regulations requiring information to be made public for certain trials involving drugs and devices regulated by the FDA.
As for how his own practice has been impacted by this research, Dr. Persaud said he no longer prescribes Diclegis.
Dr. Persaud, Dr. Zhang, and Dr. Chambers had no relevant financial disclosures.
[email protected]
On Twitter @whitneymcknight
Between 1956 and 1983, the primary treatment for nausea/vomiting of pregnancy (NVP) was Bendectin, a combination of doxylamine and pyridoxine. In 1983, it was removed from the market by the manufacturer because of litigation expense. Following this, there was a marked increase in the incidence of hyperemesis gravidarum, the most severe form of NVP, which was probably due to ineffective treatment of the condition.
Several organizations have stated that the combination of doxylamine/pyridoxine is safe and effective for use in pregnancy. In 2002, the Society of Obstetricians and Gynaecologists of Canada concluded that the doxylamine/pyridoxine combination should be the standard of care because it had the greatest evidence to support its efficacy and safety. In 2004, the American College of Obstetricians and Gynecologists stated that the combination was safe and effective and was the first-line treatment for NVP.
If NVP is not controlled with 2 tablets at bedtime, the Diclegis dose can be increased up to 4 tablets per day – 1 in the morning, 1 in midafternoon, and 2 at bedtime.
Gerald G. Briggs, BPharm, FCCP, is a clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.
Between 1956 and 1983, the primary treatment for nausea/vomiting of pregnancy (NVP) was Bendectin, a combination of doxylamine and pyridoxine. In 1983, it was removed from the market by the manufacturer because of litigation expense. Following this, there was a marked increase in the incidence of hyperemesis gravidarum, the most severe form of NVP, which was probably due to ineffective treatment of the condition.
Several organizations have stated that the combination of doxylamine/pyridoxine is safe and effective for use in pregnancy. In 2002, the Society of Obstetricians and Gynaecologists of Canada concluded that the doxylamine/pyridoxine combination should be the standard of care because it had the greatest evidence to support its efficacy and safety. In 2004, the American College of Obstetricians and Gynecologists stated that the combination was safe and effective and was the first-line treatment for NVP.
If NVP is not controlled with 2 tablets at bedtime, the Diclegis dose can be increased up to 4 tablets per day – 1 in the morning, 1 in midafternoon, and 2 at bedtime.
Gerald G. Briggs, BPharm, FCCP, is a clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.
Between 1956 and 1983, the primary treatment for nausea/vomiting of pregnancy (NVP) was Bendectin, a combination of doxylamine and pyridoxine. In 1983, it was removed from the market by the manufacturer because of litigation expense. Following this, there was a marked increase in the incidence of hyperemesis gravidarum, the most severe form of NVP, which was probably due to ineffective treatment of the condition.
Several organizations have stated that the combination of doxylamine/pyridoxine is safe and effective for use in pregnancy. In 2002, the Society of Obstetricians and Gynaecologists of Canada concluded that the doxylamine/pyridoxine combination should be the standard of care because it had the greatest evidence to support its efficacy and safety. In 2004, the American College of Obstetricians and Gynecologists stated that the combination was safe and effective and was the first-line treatment for NVP.
If NVP is not controlled with 2 tablets at bedtime, the Diclegis dose can be increased up to 4 tablets per day – 1 in the morning, 1 in midafternoon, and 2 at bedtime.
Gerald G. Briggs, BPharm, FCCP, is a clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.
Doubt is being cast on the efficacy of Diclegis – the only prescription drug approved in the United States for treating nausea and vomiting in pregnancy – after researchers exposed flaws in previously unpublished data that served as the basis for the drug’s approval.
But the larger point, according to the researcher who brought the unpublished study to light, is the danger of relying too heavily on hidden data.
“It’s not like there’s some special concern over the safety of Diclegis. It’s that there is this commonly prescribed medication that hasn’t been proven to be effective,” Navindra Persaud, MD, a family physician and researcher at St. Michael’s Hospital in Toronto, said in an interview.
The 8-Way Bendectin Study was a double-blind, multicentered, randomized, placebo-controlled study of 2,359 women with morning sickness in the first trimester, conducted in the United States across multiple sites in 1976 by the now-defunct Wm. S. Merrell Co. The aim was to find a replacement formulation of a three-agent formula (Bendectin) for morning sickness, after one of the ingredients – dicyclomine hydrochloride – was determined ineffective for pregnancy-related nausea and vomiting.
Participants in the study, which had seven treatment arms and one control group, were asked to keep diaries for a week, detailing their bouts of nausea and vomiting. Clinicians then evaluated and rated the diary entries. In all, data for 1,599 of the women were analyzed, with all seven treatment arms besting placebo. Doxylamine-pyridoxine was rated “moderate or excellent” with a 21% absolute difference, compared with placebo (95% confidence interval, 11-30). The most commonly reported side effect across the study was drowsiness.
Dr. Persaud said he thinks the study was never published because of multiple flaws. For instance, there was not a clear baseline for symptoms, or clear parameters for how the clinicians rated those symptoms; outcome data for more than a third of controls were missing, as were completed reports about potential adverse outcomes; and P values were one sided and not adjusted to account for all eight study arms, he said.
“While the analyzed data indicate differences from placebo for several combinations, the questionable data integrity, high dropout rate, and other methodological concerns mean that the prescribing of this medication should not be based on this trial,” wrote Dr. Persaud and Dr. Zhang in their analysis.
The newly published analysis brings back the rocky history of morning sickness treatments in the United States, notably the withdrawal of Bendectin in 1983 following a barrage of teratogenicity claims against the drug maker that made it unprofitable to continue marketing.
This is all beside the point, according to Dr. Persaud. “For every medication, you’re going to find some of these associations. They might be real; they might be not. So you have to weigh potential harm against the benefit. The real problem here is that there is no demonstrated benefit even though the claim seems to be that there is,” he said.
Duchesnay defended the efficacy of the drug.
“The conclusions expressed in the report published in PLOS ONE are highly inconsistent with the large and comprehensive body of evidence regarding this combination drug,” Michael Gallo, Duchesnay vice president for regulatory and medical affairs, said in a statement posted on the company’s website. In its response to Dr. Persaud and Dr. Zhang’s analysis, the company also said that doxylamine succinate and pyridoxine hydrochloride – the two agents in the treatment – are “ the most studied drug combination used in pregnancy. The safety and efficacy of [Diclegis] have been proven in 16 cohort studies, two meta-analyses, an ecological study, a neurological development study, and numerous others.”
“It’s unclear if the [unpublished] study was carefully reassessed in the lead-up to the recent approval of Diclegis,” he said. “The available FDA review documents for the recent approval of Diclectin [pyridoxine/doxylamine] do not mention the problems with the study.”
One factor in the treatment’s place in standard of care might be anecdotal influences from some of the more than 35 million women around the world thought to have used the treatment, according to Dr. Persaud. “Lots of women have taken this medication and felt better shortly after, so they feel strongly that the medication is effective,” he said, but because nausea and vomiting in pregnancy is common in more than three-quarters of women, and typically does not last more than several weeks, most likely the patients would have gotten better over time anyway.
“Some women suffer greatly and do seem to get relief from medication,” Dr. Chambers said, but noted that Diclegis is not the only option available for women.
When Bendectin was pulled from the U.S. market, for example, Dr. Chambers said women turned to combinations of vitamin B6 and over-the-counter medications that contain the antihistamine doxylamine.
Dr. Persaud said his interest in the review started after a patient expressed her concerns over the medication. “She was reluctant to take it, and asked me if I was sure about it. I reassured her, but then after she left, I did wonder if I was correct,” he recalled. He said he checked all the guidelines, but could not find anything to justify its use other than the manufacturer’s monograph.
He said he suspects this is not the only prescription medication that would not withstand such scrutiny, but that uncovering the necessary data would be very difficult. “I was shocked it was very difficult to get access to this information as a clinician,” he said, adding that it also is impractical to expect physicians to spend 5 years to track the information down.
In their analysis of the study, Dr. Persaud and Dr. Zhang stated that their objective is to contribute to a movement across all of medicine to end the risks of data secrecy, and instead “restore invisible and abandoned trials” (RIAT). The U.S. Department of Health & Human Services has been pushing to make more clinical trials data public through ClinicalTrials.gov, including issuing federal regulations requiring information to be made public for certain trials involving drugs and devices regulated by the FDA.
As for how his own practice has been impacted by this research, Dr. Persaud said he no longer prescribes Diclegis.
Dr. Persaud, Dr. Zhang, and Dr. Chambers had no relevant financial disclosures.
[email protected]
On Twitter @whitneymcknight
Doubt is being cast on the efficacy of Diclegis – the only prescription drug approved in the United States for treating nausea and vomiting in pregnancy – after researchers exposed flaws in previously unpublished data that served as the basis for the drug’s approval.
But the larger point, according to the researcher who brought the unpublished study to light, is the danger of relying too heavily on hidden data.
“It’s not like there’s some special concern over the safety of Diclegis. It’s that there is this commonly prescribed medication that hasn’t been proven to be effective,” Navindra Persaud, MD, a family physician and researcher at St. Michael’s Hospital in Toronto, said in an interview.
The 8-Way Bendectin Study was a double-blind, multicentered, randomized, placebo-controlled study of 2,359 women with morning sickness in the first trimester, conducted in the United States across multiple sites in 1976 by the now-defunct Wm. S. Merrell Co. The aim was to find a replacement formulation of a three-agent formula (Bendectin) for morning sickness, after one of the ingredients – dicyclomine hydrochloride – was determined ineffective for pregnancy-related nausea and vomiting.
Participants in the study, which had seven treatment arms and one control group, were asked to keep diaries for a week, detailing their bouts of nausea and vomiting. Clinicians then evaluated and rated the diary entries. In all, data for 1,599 of the women were analyzed, with all seven treatment arms besting placebo. Doxylamine-pyridoxine was rated “moderate or excellent” with a 21% absolute difference, compared with placebo (95% confidence interval, 11-30). The most commonly reported side effect across the study was drowsiness.
Dr. Persaud said he thinks the study was never published because of multiple flaws. For instance, there was not a clear baseline for symptoms, or clear parameters for how the clinicians rated those symptoms; outcome data for more than a third of controls were missing, as were completed reports about potential adverse outcomes; and P values were one sided and not adjusted to account for all eight study arms, he said.
“While the analyzed data indicate differences from placebo for several combinations, the questionable data integrity, high dropout rate, and other methodological concerns mean that the prescribing of this medication should not be based on this trial,” wrote Dr. Persaud and Dr. Zhang in their analysis.
The newly published analysis brings back the rocky history of morning sickness treatments in the United States, notably the withdrawal of Bendectin in 1983 following a barrage of teratogenicity claims against the drug maker that made it unprofitable to continue marketing.
This is all beside the point, according to Dr. Persaud. “For every medication, you’re going to find some of these associations. They might be real; they might be not. So you have to weigh potential harm against the benefit. The real problem here is that there is no demonstrated benefit even though the claim seems to be that there is,” he said.
Duchesnay defended the efficacy of the drug.
“The conclusions expressed in the report published in PLOS ONE are highly inconsistent with the large and comprehensive body of evidence regarding this combination drug,” Michael Gallo, Duchesnay vice president for regulatory and medical affairs, said in a statement posted on the company’s website. In its response to Dr. Persaud and Dr. Zhang’s analysis, the company also said that doxylamine succinate and pyridoxine hydrochloride – the two agents in the treatment – are “ the most studied drug combination used in pregnancy. The safety and efficacy of [Diclegis] have been proven in 16 cohort studies, two meta-analyses, an ecological study, a neurological development study, and numerous others.”
“It’s unclear if the [unpublished] study was carefully reassessed in the lead-up to the recent approval of Diclegis,” he said. “The available FDA review documents for the recent approval of Diclectin [pyridoxine/doxylamine] do not mention the problems with the study.”
One factor in the treatment’s place in standard of care might be anecdotal influences from some of the more than 35 million women around the world thought to have used the treatment, according to Dr. Persaud. “Lots of women have taken this medication and felt better shortly after, so they feel strongly that the medication is effective,” he said, but because nausea and vomiting in pregnancy is common in more than three-quarters of women, and typically does not last more than several weeks, most likely the patients would have gotten better over time anyway.
“Some women suffer greatly and do seem to get relief from medication,” Dr. Chambers said, but noted that Diclegis is not the only option available for women.
When Bendectin was pulled from the U.S. market, for example, Dr. Chambers said women turned to combinations of vitamin B6 and over-the-counter medications that contain the antihistamine doxylamine.
Dr. Persaud said his interest in the review started after a patient expressed her concerns over the medication. “She was reluctant to take it, and asked me if I was sure about it. I reassured her, but then after she left, I did wonder if I was correct,” he recalled. He said he checked all the guidelines, but could not find anything to justify its use other than the manufacturer’s monograph.
He said he suspects this is not the only prescription medication that would not withstand such scrutiny, but that uncovering the necessary data would be very difficult. “I was shocked it was very difficult to get access to this information as a clinician,” he said, adding that it also is impractical to expect physicians to spend 5 years to track the information down.
In their analysis of the study, Dr. Persaud and Dr. Zhang stated that their objective is to contribute to a movement across all of medicine to end the risks of data secrecy, and instead “restore invisible and abandoned trials” (RIAT). The U.S. Department of Health & Human Services has been pushing to make more clinical trials data public through ClinicalTrials.gov, including issuing federal regulations requiring information to be made public for certain trials involving drugs and devices regulated by the FDA.
As for how his own practice has been impacted by this research, Dr. Persaud said he no longer prescribes Diclegis.
Dr. Persaud, Dr. Zhang, and Dr. Chambers had no relevant financial disclosures.
[email protected]
On Twitter @whitneymcknight
Pairing vascular reconstruction, pancreatic cancer resection
CHICAGO – More than 53,000 people will develop pancreatic ductal adenocarcinoma in the United States this year, and upwards of 41,000 will die from the disease, many of them with tumors considered unresectable because they involve adjacent vessels. However, researchers at the University of California, Irvine, have found that careful removal of the tumor around involved veins and arteries, even in borderline cases, can improve outcomes for these patients.
Roy M. Fujitani, MD, updated previously published data on a single-center study he coauthored in 2015 of 270 patients who had undergone a Whipple operation, 183 for pancreatic adenocarcinoma (J Vasc Surg. 2015;61:475-80) at a symposium on vascular surgery sponsored by Northwestern University.
Resection of pancreatic tumors without vascular involvement is fairly straightforward for surgical oncologists to perform, Dr. Fujitani said, but pancreatic tumors enter the borderline resectable category when preoperative CT scan shows portal vein abutment, for which vascular surgery should provide counsel and assist. However, even in some cases when preoperative CT scan shows unresectable, locally advanced pancreatic tumor with celiac artery encasement, neoadjuvant therapy may downstage the disease into the borderline category, he said.
“Patients with borderline resectable or stage II disease are those one should consider for reconstruction,” Dr. Fujitani said. Resectable findings of borderline disease include encasement of the portal vein, superior mesenteric vein and the confluence of the portal venous system (with suitable proximal and distal targets for reconstruction); and less-than-circumferential involvement of the common hepatic artery or right hepatic artery – but without involvement of the superior mesenteric artery or the celiac axis and “certainly not” the aorta. “This would account for about one-fourth of patients in high-volume centers as being able to receive concomitant vascular reconstruction,” Dr. Fujitani said.
In the UCI series, 60 patients with borderline lesions underwent vascular reconstruction. “As it turned out, there was no significant difference in survival between the reconstruction group and the nonreconstruction group,” Dr. Fujitani said, “but it’s important to note that these patients who had the reconstruction would never have been operated on if we were not able to do the reconstruction.” Thirty-day mortality was around 5% and 1-year survival around 70% in both groups, he said. However, at about 1.5 years the Kaplan-Meier survival curves between the two groups diverged, which Dr. Fujitani attributed to more advanced disease in the reconstruction group.
“We found lymph node status and tumor margins were most important in determining survival of these patients,” he said. “Gaining an R0 resection is the most important thing that determines favorable survivability.”
Dr. Fujitani also reviewed different techniques for vascular reconstruction, and while differences in complication rates or 1-, 2-, or 3-year survival were not statistically significant, he did note that mean survival with lateral venorrhaphy exceeded that of primary anastomosis and interposition graft – 21 months vs. 13 months vs. 4 months, suggesting the merits of a more aggressive approach to vascular resection and reconstruction.
“Improvement of survival outcomes may be achieved with concomitant advanced vascular reconstruction in carefully selected patients,” Dr. Fujitani said. “There are multiple options for vascular reconstruction for mesenteric portal venous and visceral arterial involvement using standard vascular surgical techniques.” He added that a dedicated team of experienced surgical oncologists and vascular surgeons for these reconstructions “is essential for successful outcomes.”
Dr. Fujitani had no relevant financial relationships to disclose.
CHICAGO – More than 53,000 people will develop pancreatic ductal adenocarcinoma in the United States this year, and upwards of 41,000 will die from the disease, many of them with tumors considered unresectable because they involve adjacent vessels. However, researchers at the University of California, Irvine, have found that careful removal of the tumor around involved veins and arteries, even in borderline cases, can improve outcomes for these patients.
Roy M. Fujitani, MD, updated previously published data on a single-center study he coauthored in 2015 of 270 patients who had undergone a Whipple operation, 183 for pancreatic adenocarcinoma (J Vasc Surg. 2015;61:475-80) at a symposium on vascular surgery sponsored by Northwestern University.
Resection of pancreatic tumors without vascular involvement is fairly straightforward for surgical oncologists to perform, Dr. Fujitani said, but pancreatic tumors enter the borderline resectable category when preoperative CT scan shows portal vein abutment, for which vascular surgery should provide counsel and assist. However, even in some cases when preoperative CT scan shows unresectable, locally advanced pancreatic tumor with celiac artery encasement, neoadjuvant therapy may downstage the disease into the borderline category, he said.
“Patients with borderline resectable or stage II disease are those one should consider for reconstruction,” Dr. Fujitani said. Resectable findings of borderline disease include encasement of the portal vein, superior mesenteric vein and the confluence of the portal venous system (with suitable proximal and distal targets for reconstruction); and less-than-circumferential involvement of the common hepatic artery or right hepatic artery – but without involvement of the superior mesenteric artery or the celiac axis and “certainly not” the aorta. “This would account for about one-fourth of patients in high-volume centers as being able to receive concomitant vascular reconstruction,” Dr. Fujitani said.
In the UCI series, 60 patients with borderline lesions underwent vascular reconstruction. “As it turned out, there was no significant difference in survival between the reconstruction group and the nonreconstruction group,” Dr. Fujitani said, “but it’s important to note that these patients who had the reconstruction would never have been operated on if we were not able to do the reconstruction.” Thirty-day mortality was around 5% and 1-year survival around 70% in both groups, he said. However, at about 1.5 years the Kaplan-Meier survival curves between the two groups diverged, which Dr. Fujitani attributed to more advanced disease in the reconstruction group.
“We found lymph node status and tumor margins were most important in determining survival of these patients,” he said. “Gaining an R0 resection is the most important thing that determines favorable survivability.”
Dr. Fujitani also reviewed different techniques for vascular reconstruction, and while differences in complication rates or 1-, 2-, or 3-year survival were not statistically significant, he did note that mean survival with lateral venorrhaphy exceeded that of primary anastomosis and interposition graft – 21 months vs. 13 months vs. 4 months, suggesting the merits of a more aggressive approach to vascular resection and reconstruction.
“Improvement of survival outcomes may be achieved with concomitant advanced vascular reconstruction in carefully selected patients,” Dr. Fujitani said. “There are multiple options for vascular reconstruction for mesenteric portal venous and visceral arterial involvement using standard vascular surgical techniques.” He added that a dedicated team of experienced surgical oncologists and vascular surgeons for these reconstructions “is essential for successful outcomes.”
Dr. Fujitani had no relevant financial relationships to disclose.
CHICAGO – More than 53,000 people will develop pancreatic ductal adenocarcinoma in the United States this year, and upwards of 41,000 will die from the disease, many of them with tumors considered unresectable because they involve adjacent vessels. However, researchers at the University of California, Irvine, have found that careful removal of the tumor around involved veins and arteries, even in borderline cases, can improve outcomes for these patients.
Roy M. Fujitani, MD, updated previously published data on a single-center study he coauthored in 2015 of 270 patients who had undergone a Whipple operation, 183 for pancreatic adenocarcinoma (J Vasc Surg. 2015;61:475-80) at a symposium on vascular surgery sponsored by Northwestern University.
Resection of pancreatic tumors without vascular involvement is fairly straightforward for surgical oncologists to perform, Dr. Fujitani said, but pancreatic tumors enter the borderline resectable category when preoperative CT scan shows portal vein abutment, for which vascular surgery should provide counsel and assist. However, even in some cases when preoperative CT scan shows unresectable, locally advanced pancreatic tumor with celiac artery encasement, neoadjuvant therapy may downstage the disease into the borderline category, he said.
“Patients with borderline resectable or stage II disease are those one should consider for reconstruction,” Dr. Fujitani said. Resectable findings of borderline disease include encasement of the portal vein, superior mesenteric vein and the confluence of the portal venous system (with suitable proximal and distal targets for reconstruction); and less-than-circumferential involvement of the common hepatic artery or right hepatic artery – but without involvement of the superior mesenteric artery or the celiac axis and “certainly not” the aorta. “This would account for about one-fourth of patients in high-volume centers as being able to receive concomitant vascular reconstruction,” Dr. Fujitani said.
In the UCI series, 60 patients with borderline lesions underwent vascular reconstruction. “As it turned out, there was no significant difference in survival between the reconstruction group and the nonreconstruction group,” Dr. Fujitani said, “but it’s important to note that these patients who had the reconstruction would never have been operated on if we were not able to do the reconstruction.” Thirty-day mortality was around 5% and 1-year survival around 70% in both groups, he said. However, at about 1.5 years the Kaplan-Meier survival curves between the two groups diverged, which Dr. Fujitani attributed to more advanced disease in the reconstruction group.
“We found lymph node status and tumor margins were most important in determining survival of these patients,” he said. “Gaining an R0 resection is the most important thing that determines favorable survivability.”
Dr. Fujitani also reviewed different techniques for vascular reconstruction, and while differences in complication rates or 1-, 2-, or 3-year survival were not statistically significant, he did note that mean survival with lateral venorrhaphy exceeded that of primary anastomosis and interposition graft – 21 months vs. 13 months vs. 4 months, suggesting the merits of a more aggressive approach to vascular resection and reconstruction.
“Improvement of survival outcomes may be achieved with concomitant advanced vascular reconstruction in carefully selected patients,” Dr. Fujitani said. “There are multiple options for vascular reconstruction for mesenteric portal venous and visceral arterial involvement using standard vascular surgical techniques.” He added that a dedicated team of experienced surgical oncologists and vascular surgeons for these reconstructions “is essential for successful outcomes.”
Dr. Fujitani had no relevant financial relationships to disclose.
AT THE NORTHWESTERN VASCULAR SYMPOSIUM
Key clinical point: A more aggressive vascular resection and reconstruction in pancreatic cancer may improve outcomes and palliation in these patients.
Major finding: Mean survival with lateral venorrhaphy exceeded primary anastomosis and interposition graft (21 months vs. 13 months vs. 4 months).
Data source: Updated data of previously published single-center retrospective review of 183 patients who had Whipple procedure for pancreatic adenocarcinoma.
Disclosures: Dr. Fujitani reported having no financial disclosures.
Effect of PCSK9 Inhibitors on Coronary Artery Disease Progression
Study Overview
Objective. To determine if evolocumab, a PCSK9 inhibitor, affects the progression of coronary artery disease in patients treated with statins.
Design. Multicenter, international, double-blind, placebo-controlled, randomized clinical trial.
Setting and participants. 197 community and academic hospitals worldwide enrolled 978 participants who underwent serial intravascular ultrasounds (IVUS) to measure their burden of coronary atherosclerosis. A total of 2628 patients were screened. Patients were considered for inclusion if they were 18 years of age or older and had at least 1 coronary artery stenosis of at least 20% on a clinically indicated catheterization. Additionally, the target vessel had to meet IVUS imaging quality and visibility standards. Participants were required to have been on stable statin therapy for at least 4 weeks with an LDL level of > 80 mg/dL or between 60–80 mg/dL with either 1 major or 3 minor cardiovascular risk factors. Major risk factors were noncoronary atherosclerotic disease, myocardial infarction (MI) or hospitalization for unstable angina within the past 2 years, or type 2 diabetes. Minor risk factors included current tobacco use, hypertension, low HDL-C levels, family history of early coronary disease, hsCRP level of 2 mg/L or greater, and age older than 50 years for men and 55 years for women. Patients with uncontrolled hypertension, uncontrolled diabetes, heart failure, renal insufficiency, or liver disease were excluded.
Intervention. Patients were randomized to either treatment with monthly subcutaneous injections of 420 mg evolocumab or placebo injections for 76 weeks. Participants attended 7 follow-up visits during the study period and then underwent repeat IVUS imaging at the 78th week. Research staff, who were blinded to both treatment status and imaging sequence, collected and assessed target vessel measurements, including the vessel lumen and external elastic membrane dimensions. IVUS imaging has been used in numerous clinical studies and has been shown to be accurate and reliable [1].
Main outcome measures. The primary outcome was the target artery change in percent atheroma volume (PAV) from baseline to week 78. PAV was calculated from IVUS measurements. Nominal change in PAV was then determined by calculating the difference of the PAV at baseline and at week 78.
The secondary measure was the normalized total atheroma volume (TAV). TAV addresses variability in the length of vessel segments and the number of images collected during IVUS catheter pullback. The nominal change in TAV was then determined by the difference at baseline and at week 78.
Additional secondary efficacy endpoints included number of patients with regression of plaque and change in lipid parameters. Safety outcomes were investigated through evaluation of the incidence of adjudicated clinical events, including all-cause mortality, cardiovascular death, MI, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and heart failure requiring hospitalization. Post-hoc analysis compared baseline LDL-C level and change in PAV and regression of PAV. The association between LDL lowering and plaque progression was also assessed post hoc.
IVUS measurements were evaluated as least squares means. Comparison of treatment groups was conducted using analysis of covariance on rank transformed data that accounted for baseline value and geographic location. Investigators used a step-down statistical procedure to evaluate primary and secondary endpoints. The statistical model accounted for confounders such as baseline LDL-C, baseline PAV, intensity of statin therapy, geographic region, age, and sex.
Main results. 484 participants were randomized to the evolocumab group and 484 to the placebo group, and 423 participants in both groups completed both baseline and follow-up IVUS imaging. Treatment and control groups contained participants matched for age, gender, ethnicity, cardiovascular risk factors, and baseline medication use, including lipid-lowering agents, ACE inhibitors, ARBs, beta-blockers, and antiplatelet therapies. Both groups consisted of a majority of white (93.4% in placebo and 94.2% in treatment) males (72.3% in placebo and 72.1% in treatment). Approximately 80% of participants had hypertension (83.7% in placebo and 82.2% in treatment), about 35% had prior MIs (35.3% in placebo and 34.9% in treatment), and roughly a fifth of participants had diabetes (21.5% in placebo and 20.2% in treatment). At baseline 98.6% of participants were treated with statins, with 58.9% on high-intensity therapy and 39.4% on moderate-intensity. Mean LDL-C level at baseline was 92.5 (SD, 27.2) mg/dL.
After 76 weeks of treatment, mean LDL-C level in the placebo group was 93.0 mg/dL and 36.6 mg/dL in the treatment group, which corresponds to a 0.2 mg/dL increase in the placebo group and a 56.3 mg/dL reduction in the treatment group. The change in LDL-C level was statistically significant (P < 0.001).
Placebo group participants had no significant change in PAV (0.05%, P = 0.78), but the evolocumab group experienced a 0.95% decrease from baseline (P < 0.001). Similarly, the placebo group had no change in TAV from baseline (–0.9 mm3, P = 0.45), but the treatment group had a 5.8 mm3 reduction in TAV from baseline (P < 0.001). The treatment group had a greater proportion of patients who experienced PAV regression (64.3% vs. 47.3%, P < 0.001) and TAV regression (61.5% vs. 48.9%, P < 0.001).
Subgroup analysis did not demonstrate a significant association between change in PAV and specific study participant characteristics (eg, age, gender, ethnicity).
Post-hoc analysis using local regression (LOESS) curve revealed a linear relationship between achieved LDL-C level and change in PAV for LDL-C levels from 110 mg/dL to 20 mg/dL.
The treatment group did not exhibit a significant increase in adverse drug events, which included injection site reactions, myalgias, neurocognitive events, and incidence of diabetes. There was no significant difference in adverse cardiovascular outcomes between groups; however, there were numerically fewer nonfatal MIs and coronary revascularizations in the treatment group.
Conclusion. The use of evolocumab in statin-treated patients resulted in greater reduction of PAV than use of statins alone.
Commentary
Evolocumab is a monoclonal antibody that inhibits pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is involved in LDL-C receptor recycling. By reducing removal of LDL-C receptors, evolocumab amplifies LDL-C clearance and has been shown to reduce LDL-C levels by approximately 61% from baseline with 12 weeks oftreatment [2]. Studies have shown that the lipid-lowering potential of evolocumab is superior to statins alone and to combination therapy with statins and ezetimibe [2]. Furthermore, PCSK9 inhibitors have been effective at LDL-lowering in patients who failed or could not tolerate standard of care therapy with statins and ezetimibe [3,4]. PCSK9 inhibitors hold great promise for reducing morbidity and mortality of cardiovascular disease; however, LDL-lowering is not equivalent to improved clinical outcomes.
The GLAGOV study moves toward demonstration of the clinical benefit of evolocumab. The study shows that combined therapy with statins and evolocumab, versus statins alone, not only achieves better stability of atherosclerotic plaque dimensions but actually results in regression of plaque size. In the study, plaque burden is extrapolated from vessel measurements obtained through IVUS, and nominal changes in PAV and TAV serve as markers for atherosclerosis, but these surrogates cannot be equated to a reduction in cardiovascular events. The GLAGOV trial does explore clinical outcomes such as MI, stroke, unstable angina, coronary revascularization, and death; however, the study is not powered to evaluate the statistical significance of these events. We await sufficiently powered phase 3 clinical trials to determine the clinical benefits of PCSK9 inhibitors on cardiovascular disease.
The GLAGOV trial has several strengths, including its design as an international, double-blind, placebo-controlled, randomized clinical trial. The intervention is simple and the outcomes are clearly defined. The statistical assessment yields significant results. Nonetheless, there are multiple limitations to the study. The lead author has received research support from Amgen, the maker of evolocumab. Amgen also participated in study design and maintenance of trial databases; however, data analysis was conducted by an independent statistician. Additionally, the majority of study participants were white males with very few minority patients despite inclusion of study sites around the globe. The homogeneity of the study cohort makes the data difficult to generalize to a larger population. Similarly, patients who lacked a clinical indication for coronary catheterization and those with uncontrolled diabetes, hypertension, and heart failure were excluded, which further limits application of this study to many patients with atherosclerosis. Another limitation is study attrition; only 87% of participants completed the 78-week IVUS and were included in the data analysis, and results may have differed if those lost to follow-up had completed the trial. Furthermore, study duration was limited to 76 weeks and the magnitude and durability of study outcomes after this time point remain unknown.
Applications for Clinical Practice
Reduction in PAV and TAV are surrogate endpoints and are not indicative of a clinical benefit. Nonetheless, the GLAGOV study demonstrates that evolocumab, when used in conjunction with statins, can promote regression of atherosclerosis greater than treatment with statins alone. More studies are needed to evaluate a clinical benefit of adding evolocumab to the regularly used arsenal of lipid-lowering therapies for the treatment of atherosclerosis. Furthermore, cost-effectiveness of evolocumab has not been shown. In 2015 the yearly wholesale price of evolcumab was $14,350. A cost-effectiveness analysis based on this price estimates that treatment of atherosclerotic coronary vascular disease with evolocumab has a cost of $414,000 per quality-adjusted life year [5]. Evolocumab is well tolerated, but additional studies for cardiovascular and mortality outcomes are needed before it can be considered part of the standard of treatment for coronary artery disease.
—Lauren Brooks, MD, University of Maryland School of Medicine, Baltimore, MD
1. Nicholls SJ, Hsu A, Wolski K, et al. Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol 2010;55:2399–407.
2. Sabatine MS, Giugliano RP, Wiviolt SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500–9.
3. Giugliano RP, Sabatine MS. Are PCSK9 inhibitors the next breakthrough in the cardiovascular field. J Am Coll Cardiol 2015;65:2639–51.
4. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541–8.
5. Dhruv KS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic coronary artery disease. JAMA 2016;316:743–53.
Study Overview
Objective. To determine if evolocumab, a PCSK9 inhibitor, affects the progression of coronary artery disease in patients treated with statins.
Design. Multicenter, international, double-blind, placebo-controlled, randomized clinical trial.
Setting and participants. 197 community and academic hospitals worldwide enrolled 978 participants who underwent serial intravascular ultrasounds (IVUS) to measure their burden of coronary atherosclerosis. A total of 2628 patients were screened. Patients were considered for inclusion if they were 18 years of age or older and had at least 1 coronary artery stenosis of at least 20% on a clinically indicated catheterization. Additionally, the target vessel had to meet IVUS imaging quality and visibility standards. Participants were required to have been on stable statin therapy for at least 4 weeks with an LDL level of > 80 mg/dL or between 60–80 mg/dL with either 1 major or 3 minor cardiovascular risk factors. Major risk factors were noncoronary atherosclerotic disease, myocardial infarction (MI) or hospitalization for unstable angina within the past 2 years, or type 2 diabetes. Minor risk factors included current tobacco use, hypertension, low HDL-C levels, family history of early coronary disease, hsCRP level of 2 mg/L or greater, and age older than 50 years for men and 55 years for women. Patients with uncontrolled hypertension, uncontrolled diabetes, heart failure, renal insufficiency, or liver disease were excluded.
Intervention. Patients were randomized to either treatment with monthly subcutaneous injections of 420 mg evolocumab or placebo injections for 76 weeks. Participants attended 7 follow-up visits during the study period and then underwent repeat IVUS imaging at the 78th week. Research staff, who were blinded to both treatment status and imaging sequence, collected and assessed target vessel measurements, including the vessel lumen and external elastic membrane dimensions. IVUS imaging has been used in numerous clinical studies and has been shown to be accurate and reliable [1].
Main outcome measures. The primary outcome was the target artery change in percent atheroma volume (PAV) from baseline to week 78. PAV was calculated from IVUS measurements. Nominal change in PAV was then determined by calculating the difference of the PAV at baseline and at week 78.
The secondary measure was the normalized total atheroma volume (TAV). TAV addresses variability in the length of vessel segments and the number of images collected during IVUS catheter pullback. The nominal change in TAV was then determined by the difference at baseline and at week 78.
Additional secondary efficacy endpoints included number of patients with regression of plaque and change in lipid parameters. Safety outcomes were investigated through evaluation of the incidence of adjudicated clinical events, including all-cause mortality, cardiovascular death, MI, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and heart failure requiring hospitalization. Post-hoc analysis compared baseline LDL-C level and change in PAV and regression of PAV. The association between LDL lowering and plaque progression was also assessed post hoc.
IVUS measurements were evaluated as least squares means. Comparison of treatment groups was conducted using analysis of covariance on rank transformed data that accounted for baseline value and geographic location. Investigators used a step-down statistical procedure to evaluate primary and secondary endpoints. The statistical model accounted for confounders such as baseline LDL-C, baseline PAV, intensity of statin therapy, geographic region, age, and sex.
Main results. 484 participants were randomized to the evolocumab group and 484 to the placebo group, and 423 participants in both groups completed both baseline and follow-up IVUS imaging. Treatment and control groups contained participants matched for age, gender, ethnicity, cardiovascular risk factors, and baseline medication use, including lipid-lowering agents, ACE inhibitors, ARBs, beta-blockers, and antiplatelet therapies. Both groups consisted of a majority of white (93.4% in placebo and 94.2% in treatment) males (72.3% in placebo and 72.1% in treatment). Approximately 80% of participants had hypertension (83.7% in placebo and 82.2% in treatment), about 35% had prior MIs (35.3% in placebo and 34.9% in treatment), and roughly a fifth of participants had diabetes (21.5% in placebo and 20.2% in treatment). At baseline 98.6% of participants were treated with statins, with 58.9% on high-intensity therapy and 39.4% on moderate-intensity. Mean LDL-C level at baseline was 92.5 (SD, 27.2) mg/dL.
After 76 weeks of treatment, mean LDL-C level in the placebo group was 93.0 mg/dL and 36.6 mg/dL in the treatment group, which corresponds to a 0.2 mg/dL increase in the placebo group and a 56.3 mg/dL reduction in the treatment group. The change in LDL-C level was statistically significant (P < 0.001).
Placebo group participants had no significant change in PAV (0.05%, P = 0.78), but the evolocumab group experienced a 0.95% decrease from baseline (P < 0.001). Similarly, the placebo group had no change in TAV from baseline (–0.9 mm3, P = 0.45), but the treatment group had a 5.8 mm3 reduction in TAV from baseline (P < 0.001). The treatment group had a greater proportion of patients who experienced PAV regression (64.3% vs. 47.3%, P < 0.001) and TAV regression (61.5% vs. 48.9%, P < 0.001).
Subgroup analysis did not demonstrate a significant association between change in PAV and specific study participant characteristics (eg, age, gender, ethnicity).
Post-hoc analysis using local regression (LOESS) curve revealed a linear relationship between achieved LDL-C level and change in PAV for LDL-C levels from 110 mg/dL to 20 mg/dL.
The treatment group did not exhibit a significant increase in adverse drug events, which included injection site reactions, myalgias, neurocognitive events, and incidence of diabetes. There was no significant difference in adverse cardiovascular outcomes between groups; however, there were numerically fewer nonfatal MIs and coronary revascularizations in the treatment group.
Conclusion. The use of evolocumab in statin-treated patients resulted in greater reduction of PAV than use of statins alone.
Commentary
Evolocumab is a monoclonal antibody that inhibits pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is involved in LDL-C receptor recycling. By reducing removal of LDL-C receptors, evolocumab amplifies LDL-C clearance and has been shown to reduce LDL-C levels by approximately 61% from baseline with 12 weeks oftreatment [2]. Studies have shown that the lipid-lowering potential of evolocumab is superior to statins alone and to combination therapy with statins and ezetimibe [2]. Furthermore, PCSK9 inhibitors have been effective at LDL-lowering in patients who failed or could not tolerate standard of care therapy with statins and ezetimibe [3,4]. PCSK9 inhibitors hold great promise for reducing morbidity and mortality of cardiovascular disease; however, LDL-lowering is not equivalent to improved clinical outcomes.
The GLAGOV study moves toward demonstration of the clinical benefit of evolocumab. The study shows that combined therapy with statins and evolocumab, versus statins alone, not only achieves better stability of atherosclerotic plaque dimensions but actually results in regression of plaque size. In the study, plaque burden is extrapolated from vessel measurements obtained through IVUS, and nominal changes in PAV and TAV serve as markers for atherosclerosis, but these surrogates cannot be equated to a reduction in cardiovascular events. The GLAGOV trial does explore clinical outcomes such as MI, stroke, unstable angina, coronary revascularization, and death; however, the study is not powered to evaluate the statistical significance of these events. We await sufficiently powered phase 3 clinical trials to determine the clinical benefits of PCSK9 inhibitors on cardiovascular disease.
The GLAGOV trial has several strengths, including its design as an international, double-blind, placebo-controlled, randomized clinical trial. The intervention is simple and the outcomes are clearly defined. The statistical assessment yields significant results. Nonetheless, there are multiple limitations to the study. The lead author has received research support from Amgen, the maker of evolocumab. Amgen also participated in study design and maintenance of trial databases; however, data analysis was conducted by an independent statistician. Additionally, the majority of study participants were white males with very few minority patients despite inclusion of study sites around the globe. The homogeneity of the study cohort makes the data difficult to generalize to a larger population. Similarly, patients who lacked a clinical indication for coronary catheterization and those with uncontrolled diabetes, hypertension, and heart failure were excluded, which further limits application of this study to many patients with atherosclerosis. Another limitation is study attrition; only 87% of participants completed the 78-week IVUS and were included in the data analysis, and results may have differed if those lost to follow-up had completed the trial. Furthermore, study duration was limited to 76 weeks and the magnitude and durability of study outcomes after this time point remain unknown.
Applications for Clinical Practice
Reduction in PAV and TAV are surrogate endpoints and are not indicative of a clinical benefit. Nonetheless, the GLAGOV study demonstrates that evolocumab, when used in conjunction with statins, can promote regression of atherosclerosis greater than treatment with statins alone. More studies are needed to evaluate a clinical benefit of adding evolocumab to the regularly used arsenal of lipid-lowering therapies for the treatment of atherosclerosis. Furthermore, cost-effectiveness of evolocumab has not been shown. In 2015 the yearly wholesale price of evolcumab was $14,350. A cost-effectiveness analysis based on this price estimates that treatment of atherosclerotic coronary vascular disease with evolocumab has a cost of $414,000 per quality-adjusted life year [5]. Evolocumab is well tolerated, but additional studies for cardiovascular and mortality outcomes are needed before it can be considered part of the standard of treatment for coronary artery disease.
—Lauren Brooks, MD, University of Maryland School of Medicine, Baltimore, MD
Study Overview
Objective. To determine if evolocumab, a PCSK9 inhibitor, affects the progression of coronary artery disease in patients treated with statins.
Design. Multicenter, international, double-blind, placebo-controlled, randomized clinical trial.
Setting and participants. 197 community and academic hospitals worldwide enrolled 978 participants who underwent serial intravascular ultrasounds (IVUS) to measure their burden of coronary atherosclerosis. A total of 2628 patients were screened. Patients were considered for inclusion if they were 18 years of age or older and had at least 1 coronary artery stenosis of at least 20% on a clinically indicated catheterization. Additionally, the target vessel had to meet IVUS imaging quality and visibility standards. Participants were required to have been on stable statin therapy for at least 4 weeks with an LDL level of > 80 mg/dL or between 60–80 mg/dL with either 1 major or 3 minor cardiovascular risk factors. Major risk factors were noncoronary atherosclerotic disease, myocardial infarction (MI) or hospitalization for unstable angina within the past 2 years, or type 2 diabetes. Minor risk factors included current tobacco use, hypertension, low HDL-C levels, family history of early coronary disease, hsCRP level of 2 mg/L or greater, and age older than 50 years for men and 55 years for women. Patients with uncontrolled hypertension, uncontrolled diabetes, heart failure, renal insufficiency, or liver disease were excluded.
Intervention. Patients were randomized to either treatment with monthly subcutaneous injections of 420 mg evolocumab or placebo injections for 76 weeks. Participants attended 7 follow-up visits during the study period and then underwent repeat IVUS imaging at the 78th week. Research staff, who were blinded to both treatment status and imaging sequence, collected and assessed target vessel measurements, including the vessel lumen and external elastic membrane dimensions. IVUS imaging has been used in numerous clinical studies and has been shown to be accurate and reliable [1].
Main outcome measures. The primary outcome was the target artery change in percent atheroma volume (PAV) from baseline to week 78. PAV was calculated from IVUS measurements. Nominal change in PAV was then determined by calculating the difference of the PAV at baseline and at week 78.
The secondary measure was the normalized total atheroma volume (TAV). TAV addresses variability in the length of vessel segments and the number of images collected during IVUS catheter pullback. The nominal change in TAV was then determined by the difference at baseline and at week 78.
Additional secondary efficacy endpoints included number of patients with regression of plaque and change in lipid parameters. Safety outcomes were investigated through evaluation of the incidence of adjudicated clinical events, including all-cause mortality, cardiovascular death, MI, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and heart failure requiring hospitalization. Post-hoc analysis compared baseline LDL-C level and change in PAV and regression of PAV. The association between LDL lowering and plaque progression was also assessed post hoc.
IVUS measurements were evaluated as least squares means. Comparison of treatment groups was conducted using analysis of covariance on rank transformed data that accounted for baseline value and geographic location. Investigators used a step-down statistical procedure to evaluate primary and secondary endpoints. The statistical model accounted for confounders such as baseline LDL-C, baseline PAV, intensity of statin therapy, geographic region, age, and sex.
Main results. 484 participants were randomized to the evolocumab group and 484 to the placebo group, and 423 participants in both groups completed both baseline and follow-up IVUS imaging. Treatment and control groups contained participants matched for age, gender, ethnicity, cardiovascular risk factors, and baseline medication use, including lipid-lowering agents, ACE inhibitors, ARBs, beta-blockers, and antiplatelet therapies. Both groups consisted of a majority of white (93.4% in placebo and 94.2% in treatment) males (72.3% in placebo and 72.1% in treatment). Approximately 80% of participants had hypertension (83.7% in placebo and 82.2% in treatment), about 35% had prior MIs (35.3% in placebo and 34.9% in treatment), and roughly a fifth of participants had diabetes (21.5% in placebo and 20.2% in treatment). At baseline 98.6% of participants were treated with statins, with 58.9% on high-intensity therapy and 39.4% on moderate-intensity. Mean LDL-C level at baseline was 92.5 (SD, 27.2) mg/dL.
After 76 weeks of treatment, mean LDL-C level in the placebo group was 93.0 mg/dL and 36.6 mg/dL in the treatment group, which corresponds to a 0.2 mg/dL increase in the placebo group and a 56.3 mg/dL reduction in the treatment group. The change in LDL-C level was statistically significant (P < 0.001).
Placebo group participants had no significant change in PAV (0.05%, P = 0.78), but the evolocumab group experienced a 0.95% decrease from baseline (P < 0.001). Similarly, the placebo group had no change in TAV from baseline (–0.9 mm3, P = 0.45), but the treatment group had a 5.8 mm3 reduction in TAV from baseline (P < 0.001). The treatment group had a greater proportion of patients who experienced PAV regression (64.3% vs. 47.3%, P < 0.001) and TAV regression (61.5% vs. 48.9%, P < 0.001).
Subgroup analysis did not demonstrate a significant association between change in PAV and specific study participant characteristics (eg, age, gender, ethnicity).
Post-hoc analysis using local regression (LOESS) curve revealed a linear relationship between achieved LDL-C level and change in PAV for LDL-C levels from 110 mg/dL to 20 mg/dL.
The treatment group did not exhibit a significant increase in adverse drug events, which included injection site reactions, myalgias, neurocognitive events, and incidence of diabetes. There was no significant difference in adverse cardiovascular outcomes between groups; however, there were numerically fewer nonfatal MIs and coronary revascularizations in the treatment group.
Conclusion. The use of evolocumab in statin-treated patients resulted in greater reduction of PAV than use of statins alone.
Commentary
Evolocumab is a monoclonal antibody that inhibits pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is involved in LDL-C receptor recycling. By reducing removal of LDL-C receptors, evolocumab amplifies LDL-C clearance and has been shown to reduce LDL-C levels by approximately 61% from baseline with 12 weeks oftreatment [2]. Studies have shown that the lipid-lowering potential of evolocumab is superior to statins alone and to combination therapy with statins and ezetimibe [2]. Furthermore, PCSK9 inhibitors have been effective at LDL-lowering in patients who failed or could not tolerate standard of care therapy with statins and ezetimibe [3,4]. PCSK9 inhibitors hold great promise for reducing morbidity and mortality of cardiovascular disease; however, LDL-lowering is not equivalent to improved clinical outcomes.
The GLAGOV study moves toward demonstration of the clinical benefit of evolocumab. The study shows that combined therapy with statins and evolocumab, versus statins alone, not only achieves better stability of atherosclerotic plaque dimensions but actually results in regression of plaque size. In the study, plaque burden is extrapolated from vessel measurements obtained through IVUS, and nominal changes in PAV and TAV serve as markers for atherosclerosis, but these surrogates cannot be equated to a reduction in cardiovascular events. The GLAGOV trial does explore clinical outcomes such as MI, stroke, unstable angina, coronary revascularization, and death; however, the study is not powered to evaluate the statistical significance of these events. We await sufficiently powered phase 3 clinical trials to determine the clinical benefits of PCSK9 inhibitors on cardiovascular disease.
The GLAGOV trial has several strengths, including its design as an international, double-blind, placebo-controlled, randomized clinical trial. The intervention is simple and the outcomes are clearly defined. The statistical assessment yields significant results. Nonetheless, there are multiple limitations to the study. The lead author has received research support from Amgen, the maker of evolocumab. Amgen also participated in study design and maintenance of trial databases; however, data analysis was conducted by an independent statistician. Additionally, the majority of study participants were white males with very few minority patients despite inclusion of study sites around the globe. The homogeneity of the study cohort makes the data difficult to generalize to a larger population. Similarly, patients who lacked a clinical indication for coronary catheterization and those with uncontrolled diabetes, hypertension, and heart failure were excluded, which further limits application of this study to many patients with atherosclerosis. Another limitation is study attrition; only 87% of participants completed the 78-week IVUS and were included in the data analysis, and results may have differed if those lost to follow-up had completed the trial. Furthermore, study duration was limited to 76 weeks and the magnitude and durability of study outcomes after this time point remain unknown.
Applications for Clinical Practice
Reduction in PAV and TAV are surrogate endpoints and are not indicative of a clinical benefit. Nonetheless, the GLAGOV study demonstrates that evolocumab, when used in conjunction with statins, can promote regression of atherosclerosis greater than treatment with statins alone. More studies are needed to evaluate a clinical benefit of adding evolocumab to the regularly used arsenal of lipid-lowering therapies for the treatment of atherosclerosis. Furthermore, cost-effectiveness of evolocumab has not been shown. In 2015 the yearly wholesale price of evolcumab was $14,350. A cost-effectiveness analysis based on this price estimates that treatment of atherosclerotic coronary vascular disease with evolocumab has a cost of $414,000 per quality-adjusted life year [5]. Evolocumab is well tolerated, but additional studies for cardiovascular and mortality outcomes are needed before it can be considered part of the standard of treatment for coronary artery disease.
—Lauren Brooks, MD, University of Maryland School of Medicine, Baltimore, MD
1. Nicholls SJ, Hsu A, Wolski K, et al. Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol 2010;55:2399–407.
2. Sabatine MS, Giugliano RP, Wiviolt SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500–9.
3. Giugliano RP, Sabatine MS. Are PCSK9 inhibitors the next breakthrough in the cardiovascular field. J Am Coll Cardiol 2015;65:2639–51.
4. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541–8.
5. Dhruv KS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic coronary artery disease. JAMA 2016;316:743–53.
1. Nicholls SJ, Hsu A, Wolski K, et al. Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol 2010;55:2399–407.
2. Sabatine MS, Giugliano RP, Wiviolt SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500–9.
3. Giugliano RP, Sabatine MS. Are PCSK9 inhibitors the next breakthrough in the cardiovascular field. J Am Coll Cardiol 2015;65:2639–51.
4. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541–8.
5. Dhruv KS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic coronary artery disease. JAMA 2016;316:743–53.
Adjuvant GEMOX disappoints for localized biliary tract cancer
SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.
Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.
Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.
Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.
In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.
The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.
The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.
“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”
Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.
“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.
“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.
Dr. Edeline reported having no disclosures.
SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.
Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.
Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.
Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.
In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.
The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.
The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.
“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”
Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.
“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.
“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.
Dr. Edeline reported having no disclosures.
SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.
Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.
No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.
Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.
Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.
In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.
The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.
The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.
“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”
Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.
“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.
“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.
Dr. Edeline reported having no disclosures.
AT THE 2017 GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point:
Major finding: Relapse-free survival at 4 years was 39.3% and 33.2% with GEMOX and surveillance, respectively.
Data source: The randomized, phase III PRODIGE 12-ACCORD 18 trial.
Disclosures: Dr. Edeline reported having no disclosures.
SSRI activation in children, adolescents often misdiagnosed as bipolar
SAN FRANCISCO – It’s not uncommon for children to arrive at the Western Psychiatric Institute and Clinic in Pittsburgh with selective serotonin reuptake inhibitor activation that was misdiagnosed as bipolar disorder, according to Boris Birmaher, MD.
“We get many kids into our clinic with a diagnosis of bipolar because of this, and they are not bipolar. You have to be careful,” he said during a talk about pediatric depression at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.
SSRIs activate about 5%-10% of children. There might be sleep problems, fast speech, hyperactivity, agitation, aggression, and even suicidality, he said.
Younger children and those with autism or developmental disabilities are particularly at risk. Occasionally, a child might be a slow metabolizer so that even low SSRI doses cause problems. “Once in a blue moon,” Dr. Birmaher said he will screen for genetic cytochrome P450 deficiency, especially if a child doesn’t seem able to tolerate medications in general, not just psychiatric ones. He’s found a few slow metabolizers over the years.
Psychiatrists also have to be careful when children and adolescents are tagged as “treatment resistant.” It’s important to teach parents what treatment resistance would actually look like for their child, so they don’t jump to conclusions and misdirect therapy, he said.
For example, when a child has been prescribed an SSRI for anxiety, parents might come in and say it’s not helping, when in fact they’re concerned about homework not getting done and restlessness in class. “There’s no treatment resistance. You teach the parent how to measure improvement of anxiety” and tackle the ADHD if it’s truly a problem, said Dr. Birmaher, also professor of psychiatry at the University of Pittsburgh.
If there really is SSRI treatment resistance, he said he first ensures that a maximum dose of the drug has been tried, so long as it’s tolerated. If it doesn’t work after 4-6 weeks, he’ll switch to another SSRI or selective norepinephrine reuptake inhibitor, or combination treatment with, for instance, bupropion (Wellbutrin) or an atypical antipsychotic, which are particularly helpful for irritability, even in small doses. Atypicals seem to take the edge off, he said.
It’s trial and error, since there aren’t much data in children to guide treatment. “The only thing I highly recommend is to make one change at a time. Sometimes we see kids who’ve had two or three changes at the same time.” In those cases, he said, it’s impossible to know what to blame if there are side effects or what to credit if depression improves.
Dr. Birmaher said he had no pharmaceutical industry ties.
SAN FRANCISCO – It’s not uncommon for children to arrive at the Western Psychiatric Institute and Clinic in Pittsburgh with selective serotonin reuptake inhibitor activation that was misdiagnosed as bipolar disorder, according to Boris Birmaher, MD.
“We get many kids into our clinic with a diagnosis of bipolar because of this, and they are not bipolar. You have to be careful,” he said during a talk about pediatric depression at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.
SSRIs activate about 5%-10% of children. There might be sleep problems, fast speech, hyperactivity, agitation, aggression, and even suicidality, he said.
Younger children and those with autism or developmental disabilities are particularly at risk. Occasionally, a child might be a slow metabolizer so that even low SSRI doses cause problems. “Once in a blue moon,” Dr. Birmaher said he will screen for genetic cytochrome P450 deficiency, especially if a child doesn’t seem able to tolerate medications in general, not just psychiatric ones. He’s found a few slow metabolizers over the years.
Psychiatrists also have to be careful when children and adolescents are tagged as “treatment resistant.” It’s important to teach parents what treatment resistance would actually look like for their child, so they don’t jump to conclusions and misdirect therapy, he said.
For example, when a child has been prescribed an SSRI for anxiety, parents might come in and say it’s not helping, when in fact they’re concerned about homework not getting done and restlessness in class. “There’s no treatment resistance. You teach the parent how to measure improvement of anxiety” and tackle the ADHD if it’s truly a problem, said Dr. Birmaher, also professor of psychiatry at the University of Pittsburgh.
If there really is SSRI treatment resistance, he said he first ensures that a maximum dose of the drug has been tried, so long as it’s tolerated. If it doesn’t work after 4-6 weeks, he’ll switch to another SSRI or selective norepinephrine reuptake inhibitor, or combination treatment with, for instance, bupropion (Wellbutrin) or an atypical antipsychotic, which are particularly helpful for irritability, even in small doses. Atypicals seem to take the edge off, he said.
It’s trial and error, since there aren’t much data in children to guide treatment. “The only thing I highly recommend is to make one change at a time. Sometimes we see kids who’ve had two or three changes at the same time.” In those cases, he said, it’s impossible to know what to blame if there are side effects or what to credit if depression improves.
Dr. Birmaher said he had no pharmaceutical industry ties.
SAN FRANCISCO – It’s not uncommon for children to arrive at the Western Psychiatric Institute and Clinic in Pittsburgh with selective serotonin reuptake inhibitor activation that was misdiagnosed as bipolar disorder, according to Boris Birmaher, MD.
“We get many kids into our clinic with a diagnosis of bipolar because of this, and they are not bipolar. You have to be careful,” he said during a talk about pediatric depression at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.
SSRIs activate about 5%-10% of children. There might be sleep problems, fast speech, hyperactivity, agitation, aggression, and even suicidality, he said.
Younger children and those with autism or developmental disabilities are particularly at risk. Occasionally, a child might be a slow metabolizer so that even low SSRI doses cause problems. “Once in a blue moon,” Dr. Birmaher said he will screen for genetic cytochrome P450 deficiency, especially if a child doesn’t seem able to tolerate medications in general, not just psychiatric ones. He’s found a few slow metabolizers over the years.
Psychiatrists also have to be careful when children and adolescents are tagged as “treatment resistant.” It’s important to teach parents what treatment resistance would actually look like for their child, so they don’t jump to conclusions and misdirect therapy, he said.
For example, when a child has been prescribed an SSRI for anxiety, parents might come in and say it’s not helping, when in fact they’re concerned about homework not getting done and restlessness in class. “There’s no treatment resistance. You teach the parent how to measure improvement of anxiety” and tackle the ADHD if it’s truly a problem, said Dr. Birmaher, also professor of psychiatry at the University of Pittsburgh.
If there really is SSRI treatment resistance, he said he first ensures that a maximum dose of the drug has been tried, so long as it’s tolerated. If it doesn’t work after 4-6 weeks, he’ll switch to another SSRI or selective norepinephrine reuptake inhibitor, or combination treatment with, for instance, bupropion (Wellbutrin) or an atypical antipsychotic, which are particularly helpful for irritability, even in small doses. Atypicals seem to take the edge off, he said.
It’s trial and error, since there aren’t much data in children to guide treatment. “The only thing I highly recommend is to make one change at a time. Sometimes we see kids who’ve had two or three changes at the same time.” In those cases, he said, it’s impossible to know what to blame if there are side effects or what to credit if depression improves.
Dr. Birmaher said he had no pharmaceutical industry ties.
EXPERT ANALYSIS AT THE PSYCHOPHARMACOLOGY UPDATE INSTITUTE
Medical organizations respond to Trump’s immigration order
Organizations representing physicians and medical students have expressed their concern regarding President Trump’s executive order of Jan. 27 that curtails entry into the United States by travelers from seven Muslim-majority countries. The order also suspends for 120 days entry into the United States for all persons seeking refugee status, and it bars refugees from Syria indefinitely.
Following are direct excerpts from statements issued by medical organizations.
American Academy of Family Physicians
“We are deeply concerned that steps your Administration has taken will have a chilling effect on our nation’s physician workforce, biomedical research, and global health. It is often America’s physicians who answer the call to assist people around the world when a public health crisis occurs. Imagine a world where physicians fail to answer the call of the needy because they fear they may not be able to return to their home and families in the United States.
Many family physicians are international medical graduates (IMG), who have completed all or part of their education and training in the United States. They are professionals who dedicate their careers to the service of their patients in communities large and small, urban and rural. In fact, 20% of our membership and over 25% of family medicine residents [comprise] IMGs. The AAFP applauds and supports wholly the contributions of these individual family physicians to their patients and communities and we celebrate their diversity.
We recognize that one of your primary responsibilities as President is to ensure the safety and security of the country and its citizens. This is, without question, a daunting responsibility. But we strongly urge that the methods of doing so be examined carefully, so that the many people who can add so much to our country through immigration have the opportunity to do so, and those who are doing so already are treated with the respect and dignity they deserve.”
American Academy of Pediatrics
“The executive orders signed today are harmful to immigrant children and families throughout our country. Many of the children who will be most affected are the victims of unspeakable violence and have been exposed to trauma. Children do not immigrate, they flee. They are coming to the United States seeking safe haven in our country and they need our compassion and assistance. Broad scale expansion of family detention only exacerbates their suffering ... The AAP is non-partisan and pro-children. We urge President Trump and his administration to ensure that children and families who are fleeing violence and adversity can continue to seek refuge in our country. Immigrant children and families are an integral part of our communities and our nation, and they deserve to be cared for, treated with compassion, and celebrated. Most of all, they deserve to be healthy and safe. Pediatricians stand with the immigrant families we care for and will continue to advocate that their needs are met and prioritized.”
American Association of Medical Colleges
“The United States is facing a serious shortage of physicians. IMGs play an important role in U.S. health care, representing roughly 25% of the workforce. Current immigration pathways – including student, exchange-visitor, and employment visas – provide a balanced solution that improves health care access across the country through programs like the National Interest Waiver and the Conrad 30 J-1 Visa Waiver. In the last decade, Conrad 30 alone has directed nearly 10,000 physicians into rural and urban underserved communities. Impeding these U.S. immigration pathways jeopardizes critical access to high-quality physician care for our nation’s most vulnerable populations.
Our ability to attract top talent from around the world also enriches the research laboratories at medical schools and teaching hospitals that are working toward cures and has helped position the United States as a global leader in medical research, strengthening our economy and bolstering the public’s health. Because disease knows no geographic boundaries, it is essential to ensure that we continue to foster, rather than impede, scientific cooperation with physicians and researchers of all nationalities, as we strive to keep our country healthy.”
American College of Cardiology
“The ability to share ideas and knowledge necessary to address [the global epidemic of cardiovascular disease] is imperative. Policies that impede this free-flow of ideas will have a detrimental impact on scientific discovery, as well as the lives of patients around the world. If we are to realize a future where cardiovascular disease is no longer the number one killer of men and women worldwide we must ensure that our system of scientific exchange allows for health care professionals to learn from each other regardless of their nationality.
Additionally, IMGs, naturalized citizens, and legal residents make up a significant portion of the health care workforce in hospitals and practices across the country. More than 25% of current practicing physicians are IMGs, with cardiology ranking among the top when broken down by medical specialty. Policies that bring the immigration status of those already here into question, while also limiting the ability of others to legally train in the United States going forward, will only serve to exacerbate the already existing cardiovascular workforce shortage, especially in rural America. Such policies also threaten the care continuum of patients who rely on these providers for their medical care.”
American College of Physicians
“The executive order could deny entry or reentry to tens of thousands more persons, including medical students and physicians who are being trained in the United States and/or are delivering direct patient care. ... It also creates a precedent for barring entry of IMGs based on their religion and country of origin. ... Approximately 30% of ACP members are IMGs.”
American Gastroenterological Association
Science and illness ignore borders and political divides. That is why AGA is concerned that the recent U.S. executive order on immigration could limit scientific exchange, delay patient care and impair medical training.
AGA is committed to diversity, which we define as inclusive of race, ethnicity and national origin. Diversity within training programs and laboratories in the United States built today’s practice of gastroenterology. Scientists from around the world publish in our journals, work in our laboratories, train in our programs and present data at Digestive Disease Week. This exchange leads to better patient care, and very sick patients travel to the United States from around the world for the best digestive health care.
AGA adds our support to a growing number of medical institutions urging the administration to consider the devastating impact of the executive order on the health of the nation that will result from turning away patients, health professionals, and researchers. The recent immigration policy is clearly detrimental to America’s leadership role in advancing health care, and to the standing of the United States within the international community.
American Society of Clinical Oncology
ASCO is deeply concerned about the potential impact of the recent executive order on cancer research, patient care, and international scientific collaboration.
Our more than 40,000 members in 148 countries lead the charge to conquer cancer in all its forms and in every nation. Tens of thousands of people from more than 100 countries participate in our scientific meetings to exchange advances and ideas to improve patient care. Millions of cancer survivors are alive today because of the progress made possible by scientific collaboration. Progress against this disease will falter if the close-knit global community of cancer care providers is divided by policies that bar members of certain nationalities from entering the United States to conduct research, care for people with cancer, or participate in scientific and medical conferences.
American Society of Hematology
We express our deep concern about the Administration’s executive order that has denied U.S. entry to people who bring unique expertise to the practice of medicine and the conduct of cancer and biomedical research. Our nation depends on the contributions of the greatest minds from around the world to maintain the high quality of our biomedical research enterprise and health care services.
The benefits of scientific collaborations are amplified by our diversity. Limiting the exchange of ideas, practices, and data across cultures has the potential to significantly retard scientific progress and adversely affect public health. Any loss of researchers and physicians will render the United States less competitive over time, and our traditionally strong research institutions and the patients they serve will be negatively affected.
We remain deeply concerned that restricting travel will prohibit participation in scientific meetings, where cutting-edge science and treatment methods are often first introduced. These in-person meetings and other global exchanges are vitally important because they provide unparalleled opportunities for collaborations and information-sharing. Such scientific and medical meetings are absolutely essential to the conquest of cancer and blood diseases.
(Statement issued on behalf of ASH, American Association for Cancer Research, Association of American Cancer Institutes, American Society for Radiation Oncology, The American Society for Pediatric Hematology/Oncology, and LUNGevity Foundation.)
The text of the executive order can be found on the White House website.
Updated 2/2/17 to include the position of the American Gastroenterological Association.
[email protected]
On Twitter @denisefulton
Organizations representing physicians and medical students have expressed their concern regarding President Trump’s executive order of Jan. 27 that curtails entry into the United States by travelers from seven Muslim-majority countries. The order also suspends for 120 days entry into the United States for all persons seeking refugee status, and it bars refugees from Syria indefinitely.
Following are direct excerpts from statements issued by medical organizations.
American Academy of Family Physicians
“We are deeply concerned that steps your Administration has taken will have a chilling effect on our nation’s physician workforce, biomedical research, and global health. It is often America’s physicians who answer the call to assist people around the world when a public health crisis occurs. Imagine a world where physicians fail to answer the call of the needy because they fear they may not be able to return to their home and families in the United States.
Many family physicians are international medical graduates (IMG), who have completed all or part of their education and training in the United States. They are professionals who dedicate their careers to the service of their patients in communities large and small, urban and rural. In fact, 20% of our membership and over 25% of family medicine residents [comprise] IMGs. The AAFP applauds and supports wholly the contributions of these individual family physicians to their patients and communities and we celebrate their diversity.
We recognize that one of your primary responsibilities as President is to ensure the safety and security of the country and its citizens. This is, without question, a daunting responsibility. But we strongly urge that the methods of doing so be examined carefully, so that the many people who can add so much to our country through immigration have the opportunity to do so, and those who are doing so already are treated with the respect and dignity they deserve.”
American Academy of Pediatrics
“The executive orders signed today are harmful to immigrant children and families throughout our country. Many of the children who will be most affected are the victims of unspeakable violence and have been exposed to trauma. Children do not immigrate, they flee. They are coming to the United States seeking safe haven in our country and they need our compassion and assistance. Broad scale expansion of family detention only exacerbates their suffering ... The AAP is non-partisan and pro-children. We urge President Trump and his administration to ensure that children and families who are fleeing violence and adversity can continue to seek refuge in our country. Immigrant children and families are an integral part of our communities and our nation, and they deserve to be cared for, treated with compassion, and celebrated. Most of all, they deserve to be healthy and safe. Pediatricians stand with the immigrant families we care for and will continue to advocate that their needs are met and prioritized.”
American Association of Medical Colleges
“The United States is facing a serious shortage of physicians. IMGs play an important role in U.S. health care, representing roughly 25% of the workforce. Current immigration pathways – including student, exchange-visitor, and employment visas – provide a balanced solution that improves health care access across the country through programs like the National Interest Waiver and the Conrad 30 J-1 Visa Waiver. In the last decade, Conrad 30 alone has directed nearly 10,000 physicians into rural and urban underserved communities. Impeding these U.S. immigration pathways jeopardizes critical access to high-quality physician care for our nation’s most vulnerable populations.
Our ability to attract top talent from around the world also enriches the research laboratories at medical schools and teaching hospitals that are working toward cures and has helped position the United States as a global leader in medical research, strengthening our economy and bolstering the public’s health. Because disease knows no geographic boundaries, it is essential to ensure that we continue to foster, rather than impede, scientific cooperation with physicians and researchers of all nationalities, as we strive to keep our country healthy.”
American College of Cardiology
“The ability to share ideas and knowledge necessary to address [the global epidemic of cardiovascular disease] is imperative. Policies that impede this free-flow of ideas will have a detrimental impact on scientific discovery, as well as the lives of patients around the world. If we are to realize a future where cardiovascular disease is no longer the number one killer of men and women worldwide we must ensure that our system of scientific exchange allows for health care professionals to learn from each other regardless of their nationality.
Additionally, IMGs, naturalized citizens, and legal residents make up a significant portion of the health care workforce in hospitals and practices across the country. More than 25% of current practicing physicians are IMGs, with cardiology ranking among the top when broken down by medical specialty. Policies that bring the immigration status of those already here into question, while also limiting the ability of others to legally train in the United States going forward, will only serve to exacerbate the already existing cardiovascular workforce shortage, especially in rural America. Such policies also threaten the care continuum of patients who rely on these providers for their medical care.”
American College of Physicians
“The executive order could deny entry or reentry to tens of thousands more persons, including medical students and physicians who are being trained in the United States and/or are delivering direct patient care. ... It also creates a precedent for barring entry of IMGs based on their religion and country of origin. ... Approximately 30% of ACP members are IMGs.”
American Gastroenterological Association
Science and illness ignore borders and political divides. That is why AGA is concerned that the recent U.S. executive order on immigration could limit scientific exchange, delay patient care and impair medical training.
AGA is committed to diversity, which we define as inclusive of race, ethnicity and national origin. Diversity within training programs and laboratories in the United States built today’s practice of gastroenterology. Scientists from around the world publish in our journals, work in our laboratories, train in our programs and present data at Digestive Disease Week. This exchange leads to better patient care, and very sick patients travel to the United States from around the world for the best digestive health care.
AGA adds our support to a growing number of medical institutions urging the administration to consider the devastating impact of the executive order on the health of the nation that will result from turning away patients, health professionals, and researchers. The recent immigration policy is clearly detrimental to America’s leadership role in advancing health care, and to the standing of the United States within the international community.
American Society of Clinical Oncology
ASCO is deeply concerned about the potential impact of the recent executive order on cancer research, patient care, and international scientific collaboration.
Our more than 40,000 members in 148 countries lead the charge to conquer cancer in all its forms and in every nation. Tens of thousands of people from more than 100 countries participate in our scientific meetings to exchange advances and ideas to improve patient care. Millions of cancer survivors are alive today because of the progress made possible by scientific collaboration. Progress against this disease will falter if the close-knit global community of cancer care providers is divided by policies that bar members of certain nationalities from entering the United States to conduct research, care for people with cancer, or participate in scientific and medical conferences.
American Society of Hematology
We express our deep concern about the Administration’s executive order that has denied U.S. entry to people who bring unique expertise to the practice of medicine and the conduct of cancer and biomedical research. Our nation depends on the contributions of the greatest minds from around the world to maintain the high quality of our biomedical research enterprise and health care services.
The benefits of scientific collaborations are amplified by our diversity. Limiting the exchange of ideas, practices, and data across cultures has the potential to significantly retard scientific progress and adversely affect public health. Any loss of researchers and physicians will render the United States less competitive over time, and our traditionally strong research institutions and the patients they serve will be negatively affected.
We remain deeply concerned that restricting travel will prohibit participation in scientific meetings, where cutting-edge science and treatment methods are often first introduced. These in-person meetings and other global exchanges are vitally important because they provide unparalleled opportunities for collaborations and information-sharing. Such scientific and medical meetings are absolutely essential to the conquest of cancer and blood diseases.
(Statement issued on behalf of ASH, American Association for Cancer Research, Association of American Cancer Institutes, American Society for Radiation Oncology, The American Society for Pediatric Hematology/Oncology, and LUNGevity Foundation.)
The text of the executive order can be found on the White House website.
Updated 2/2/17 to include the position of the American Gastroenterological Association.
[email protected]
On Twitter @denisefulton
Organizations representing physicians and medical students have expressed their concern regarding President Trump’s executive order of Jan. 27 that curtails entry into the United States by travelers from seven Muslim-majority countries. The order also suspends for 120 days entry into the United States for all persons seeking refugee status, and it bars refugees from Syria indefinitely.
Following are direct excerpts from statements issued by medical organizations.
American Academy of Family Physicians
“We are deeply concerned that steps your Administration has taken will have a chilling effect on our nation’s physician workforce, biomedical research, and global health. It is often America’s physicians who answer the call to assist people around the world when a public health crisis occurs. Imagine a world where physicians fail to answer the call of the needy because they fear they may not be able to return to their home and families in the United States.
Many family physicians are international medical graduates (IMG), who have completed all or part of their education and training in the United States. They are professionals who dedicate their careers to the service of their patients in communities large and small, urban and rural. In fact, 20% of our membership and over 25% of family medicine residents [comprise] IMGs. The AAFP applauds and supports wholly the contributions of these individual family physicians to their patients and communities and we celebrate their diversity.
We recognize that one of your primary responsibilities as President is to ensure the safety and security of the country and its citizens. This is, without question, a daunting responsibility. But we strongly urge that the methods of doing so be examined carefully, so that the many people who can add so much to our country through immigration have the opportunity to do so, and those who are doing so already are treated with the respect and dignity they deserve.”
American Academy of Pediatrics
“The executive orders signed today are harmful to immigrant children and families throughout our country. Many of the children who will be most affected are the victims of unspeakable violence and have been exposed to trauma. Children do not immigrate, they flee. They are coming to the United States seeking safe haven in our country and they need our compassion and assistance. Broad scale expansion of family detention only exacerbates their suffering ... The AAP is non-partisan and pro-children. We urge President Trump and his administration to ensure that children and families who are fleeing violence and adversity can continue to seek refuge in our country. Immigrant children and families are an integral part of our communities and our nation, and they deserve to be cared for, treated with compassion, and celebrated. Most of all, they deserve to be healthy and safe. Pediatricians stand with the immigrant families we care for and will continue to advocate that their needs are met and prioritized.”
American Association of Medical Colleges
“The United States is facing a serious shortage of physicians. IMGs play an important role in U.S. health care, representing roughly 25% of the workforce. Current immigration pathways – including student, exchange-visitor, and employment visas – provide a balanced solution that improves health care access across the country through programs like the National Interest Waiver and the Conrad 30 J-1 Visa Waiver. In the last decade, Conrad 30 alone has directed nearly 10,000 physicians into rural and urban underserved communities. Impeding these U.S. immigration pathways jeopardizes critical access to high-quality physician care for our nation’s most vulnerable populations.
Our ability to attract top talent from around the world also enriches the research laboratories at medical schools and teaching hospitals that are working toward cures and has helped position the United States as a global leader in medical research, strengthening our economy and bolstering the public’s health. Because disease knows no geographic boundaries, it is essential to ensure that we continue to foster, rather than impede, scientific cooperation with physicians and researchers of all nationalities, as we strive to keep our country healthy.”
American College of Cardiology
“The ability to share ideas and knowledge necessary to address [the global epidemic of cardiovascular disease] is imperative. Policies that impede this free-flow of ideas will have a detrimental impact on scientific discovery, as well as the lives of patients around the world. If we are to realize a future where cardiovascular disease is no longer the number one killer of men and women worldwide we must ensure that our system of scientific exchange allows for health care professionals to learn from each other regardless of their nationality.
Additionally, IMGs, naturalized citizens, and legal residents make up a significant portion of the health care workforce in hospitals and practices across the country. More than 25% of current practicing physicians are IMGs, with cardiology ranking among the top when broken down by medical specialty. Policies that bring the immigration status of those already here into question, while also limiting the ability of others to legally train in the United States going forward, will only serve to exacerbate the already existing cardiovascular workforce shortage, especially in rural America. Such policies also threaten the care continuum of patients who rely on these providers for their medical care.”
American College of Physicians
“The executive order could deny entry or reentry to tens of thousands more persons, including medical students and physicians who are being trained in the United States and/or are delivering direct patient care. ... It also creates a precedent for barring entry of IMGs based on their religion and country of origin. ... Approximately 30% of ACP members are IMGs.”
American Gastroenterological Association
Science and illness ignore borders and political divides. That is why AGA is concerned that the recent U.S. executive order on immigration could limit scientific exchange, delay patient care and impair medical training.
AGA is committed to diversity, which we define as inclusive of race, ethnicity and national origin. Diversity within training programs and laboratories in the United States built today’s practice of gastroenterology. Scientists from around the world publish in our journals, work in our laboratories, train in our programs and present data at Digestive Disease Week. This exchange leads to better patient care, and very sick patients travel to the United States from around the world for the best digestive health care.
AGA adds our support to a growing number of medical institutions urging the administration to consider the devastating impact of the executive order on the health of the nation that will result from turning away patients, health professionals, and researchers. The recent immigration policy is clearly detrimental to America’s leadership role in advancing health care, and to the standing of the United States within the international community.
American Society of Clinical Oncology
ASCO is deeply concerned about the potential impact of the recent executive order on cancer research, patient care, and international scientific collaboration.
Our more than 40,000 members in 148 countries lead the charge to conquer cancer in all its forms and in every nation. Tens of thousands of people from more than 100 countries participate in our scientific meetings to exchange advances and ideas to improve patient care. Millions of cancer survivors are alive today because of the progress made possible by scientific collaboration. Progress against this disease will falter if the close-knit global community of cancer care providers is divided by policies that bar members of certain nationalities from entering the United States to conduct research, care for people with cancer, or participate in scientific and medical conferences.
American Society of Hematology
We express our deep concern about the Administration’s executive order that has denied U.S. entry to people who bring unique expertise to the practice of medicine and the conduct of cancer and biomedical research. Our nation depends on the contributions of the greatest minds from around the world to maintain the high quality of our biomedical research enterprise and health care services.
The benefits of scientific collaborations are amplified by our diversity. Limiting the exchange of ideas, practices, and data across cultures has the potential to significantly retard scientific progress and adversely affect public health. Any loss of researchers and physicians will render the United States less competitive over time, and our traditionally strong research institutions and the patients they serve will be negatively affected.
We remain deeply concerned that restricting travel will prohibit participation in scientific meetings, where cutting-edge science and treatment methods are often first introduced. These in-person meetings and other global exchanges are vitally important because they provide unparalleled opportunities for collaborations and information-sharing. Such scientific and medical meetings are absolutely essential to the conquest of cancer and blood diseases.
(Statement issued on behalf of ASH, American Association for Cancer Research, Association of American Cancer Institutes, American Society for Radiation Oncology, The American Society for Pediatric Hematology/Oncology, and LUNGevity Foundation.)
The text of the executive order can be found on the White House website.
Updated 2/2/17 to include the position of the American Gastroenterological Association.
[email protected]
On Twitter @denisefulton
February 2017 Quiz 2
Q2: Answer: B
Objective: Recognize the features of CVID-associated noninfectious gastrointestinal manifestations.
Explanation: This patient has gastrointestinal manifestations of common variable immune deficiency (CVID), which can present similarly to celiac disease or inflammatory bowel disease. Histologically, intestinal biopsies will reveal villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis similar to celiac disease. However, while plasma cells are increased in celiac disease, they are absent in CVID.
The initial treatment strategy for CVID typically includes oral corticosteroids, either prednisone or budesonide, with other immunosuppressants such as the thiopurines or anti–tumor necrosis factor agents reserved for steroid-dependent or refractory disease.
Gluten-free diet is ineffective for the treatment of CVID-associated enteropathy. Intravenous immunoglobulin therapy reduces the frequency of infections associated with CVID, but does not affect the noninfectious GI symptoms. While bacterial overgrowth can occur in CVID, it is typically the consequence of the luminal changes, not the cause.
Reference
1. Agarwal S., Mayer L. Gastrointestinal manifestations in primary immune disorders. Inflamm Bowel Dis. 2010;16:703-11.
Q2: Answer: B
Objective: Recognize the features of CVID-associated noninfectious gastrointestinal manifestations.
Explanation: This patient has gastrointestinal manifestations of common variable immune deficiency (CVID), which can present similarly to celiac disease or inflammatory bowel disease. Histologically, intestinal biopsies will reveal villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis similar to celiac disease. However, while plasma cells are increased in celiac disease, they are absent in CVID.
The initial treatment strategy for CVID typically includes oral corticosteroids, either prednisone or budesonide, with other immunosuppressants such as the thiopurines or anti–tumor necrosis factor agents reserved for steroid-dependent or refractory disease.
Gluten-free diet is ineffective for the treatment of CVID-associated enteropathy. Intravenous immunoglobulin therapy reduces the frequency of infections associated with CVID, but does not affect the noninfectious GI symptoms. While bacterial overgrowth can occur in CVID, it is typically the consequence of the luminal changes, not the cause.
Reference
1. Agarwal S., Mayer L. Gastrointestinal manifestations in primary immune disorders. Inflamm Bowel Dis. 2010;16:703-11.
Q2: Answer: B
Objective: Recognize the features of CVID-associated noninfectious gastrointestinal manifestations.
Explanation: This patient has gastrointestinal manifestations of common variable immune deficiency (CVID), which can present similarly to celiac disease or inflammatory bowel disease. Histologically, intestinal biopsies will reveal villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis similar to celiac disease. However, while plasma cells are increased in celiac disease, they are absent in CVID.
The initial treatment strategy for CVID typically includes oral corticosteroids, either prednisone or budesonide, with other immunosuppressants such as the thiopurines or anti–tumor necrosis factor agents reserved for steroid-dependent or refractory disease.
Gluten-free diet is ineffective for the treatment of CVID-associated enteropathy. Intravenous immunoglobulin therapy reduces the frequency of infections associated with CVID, but does not affect the noninfectious GI symptoms. While bacterial overgrowth can occur in CVID, it is typically the consequence of the luminal changes, not the cause.
Reference
1. Agarwal S., Mayer L. Gastrointestinal manifestations in primary immune disorders. Inflamm Bowel Dis. 2010;16:703-11.
Q2: A 34-year-old woman presents with a 3-year history of watery, nonbloody diarrhea with associated weight loss, and recurrent bacterial bronchitis and pneumonias. Laboratory studies show iron deficiency anemia, low 25-OH vitamin D, and a slightly elevated INR. Celiac serologies were negative, and small bowel biopsies revealed near total villous atrophy, increased intraepithelial lymphocytes, and crypt hyperplasia with absent plasma cells.
February 2017 Quiz 1
Q1: Answer: D
Current recommendations suggest H. pylori testing for patients with active or a documented history of peptic ulcer disease, gastric MALT lymphoma, or gastric carcinoma. The H. pylori test-and-treat strategy is also recommended for patients less than 55 years of age who present with dyspepsia symptoms without “alarm features.”
There is currently no recommendation for asymptomatic family members of patients diagnosed with H. pylori infection to be tested, unless there are known factors that may increase the patient’s risk for gastric malignancy (e.g., family history of gastric carcinoma, and ethnic background from areas with high prevalence of H. pylori and gastric cancer such as East Asia, Latin America, and Eastern Europe).
References
1. Chey W.D., Wong B.C. Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-25.
2. Talley N.J., Vakil N.B., Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756-80.
3. Suerbaum S., Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:1175-86.
4. Everhart J.E., Kruszon-Moran D., Perez-Perez G.I., et al. Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States. J Infect Dis. 2000;181:1359-63.
Q1: Answer: D
Current recommendations suggest H. pylori testing for patients with active or a documented history of peptic ulcer disease, gastric MALT lymphoma, or gastric carcinoma. The H. pylori test-and-treat strategy is also recommended for patients less than 55 years of age who present with dyspepsia symptoms without “alarm features.”
There is currently no recommendation for asymptomatic family members of patients diagnosed with H. pylori infection to be tested, unless there are known factors that may increase the patient’s risk for gastric malignancy (e.g., family history of gastric carcinoma, and ethnic background from areas with high prevalence of H. pylori and gastric cancer such as East Asia, Latin America, and Eastern Europe).
References
1. Chey W.D., Wong B.C. Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-25.
2. Talley N.J., Vakil N.B., Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756-80.
3. Suerbaum S., Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:1175-86.
4. Everhart J.E., Kruszon-Moran D., Perez-Perez G.I., et al. Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States. J Infect Dis. 2000;181:1359-63.
Q1: Answer: D
Current recommendations suggest H. pylori testing for patients with active or a documented history of peptic ulcer disease, gastric MALT lymphoma, or gastric carcinoma. The H. pylori test-and-treat strategy is also recommended for patients less than 55 years of age who present with dyspepsia symptoms without “alarm features.”
There is currently no recommendation for asymptomatic family members of patients diagnosed with H. pylori infection to be tested, unless there are known factors that may increase the patient’s risk for gastric malignancy (e.g., family history of gastric carcinoma, and ethnic background from areas with high prevalence of H. pylori and gastric cancer such as East Asia, Latin America, and Eastern Europe).
References
1. Chey W.D., Wong B.C. Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-25.
2. Talley N.J., Vakil N.B., Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756-80.
3. Suerbaum S., Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:1175-86.
4. Everhart J.E., Kruszon-Moran D., Perez-Perez G.I., et al. Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States. J Infect Dis. 2000;181:1359-63.