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Air pollution – second leading cause of lung cancer
The new data show that the rate of lung cancer deaths attributable to air pollution varies widely between countries. Serbia, Poland, China, Mongolia, and Turkey are among the worst affected. The analysis shows an association between deaths from lung cancer and the proportion of national energy that is produced from coal.
“Both smoking and air pollution are important causes of lung cancer,” said study presenter Christine D. Berg, MD, former codirector of the National Lung Screening Trial, and “both need to be eliminated to help prevent lung cancer and save lives.
“As lung cancer professionals, we can mitigate the effects of air pollution on causing lung cancer by speaking out for clean energy standards,” she said.
Dr. Berg presented the new analysis on Sept. 9 at the 2021 World Conference on Lung Cancer, which was organized by the International Association for the Study of Lung Cancer.
She welcomed the recent statement issued by the IASLC in support of the International Day of Clean Air for Blue Skies, which took place on Sept. 7. It was a call for action that emphasized the need for further efforts to improve air quality to protect human health.
The findings from the new analysis are “depressing,” commented Joachim G. J. V. Aerts, MD. PhD, department of pulmonary diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.
It is now clear that air pollution has an impact not only on the incidence of lung cancer but also on its outcome, he added.
Indeed, previous research showed that each 10 mcg/m3 increase in particular matter of 2.5 mcg in size was associated with a 15%-27% increase in lung cancer mortality. There was no difference in rates between women and men.
A key question, Dr. Aerts said, is whether reducing air pollution would be beneficial.
Efforts to reduce air pollution over recent decades in the United Kingdom have not led to a reduction in lung cancer deaths. This is because of the increase in life expectancy – individuals have been exposed to pollution for longer, albeit at lower levels, he pointed out.
Because of lockdowns during the COVID pandemic, travel has been greatly reduced. This has resulted in a dramatic reduction in air pollution, “and this led to a decrease in the number of children born with low birth weight,” said Dr. Aerts.
Hopefully, that benefit will also be seen regarding other diseases, he added.
The call to action to reduce air pollution is of the “utmost importance,” he said. He noted that the focus should be on global, national, local, and personal preventive measures.
“It is time to join forces,” he added, “to ‘clean the air.’ ”
Dr. Berg’s presentation was warmly received on social media.
It was “fabulous,” commented Eric H. Bernicker, MD, director of medical thoracic oncology at Houston Methodist Cancer Center.
“Thoracic oncologists need to add air pollution to things they advocate about; we have an important voice here,” he added.
It is “so important to understand that air pollution is a human carcinogen,” commented Ivy Elkins, a lung cancer survivor and advocate and cofounder of the EGFR Resisters Lung Cancer Patient Group. “All you need are lungs to get lung cancer!”
Contribution of air pollution to lung cancer
In her presentation, Dr. Berg emphasized that lung cancer is the leading cause of cancer death worldwide, although the distribution between countries “depends on historical and current smoking patterns and the demographics of the population.”
Overall, data from GLOBOCAN 2018 indicate that annually there are approximately 2.1 million incident cases of lung cancer and almost 1.8 million lung cancer deaths around the globe.
A recent study estimated that, worldwide, 14.1% of all lung cancer deaths, including in never-smokers, are directly linked to air pollution.
Dr. Berg said that this makes it the “second-leading cause of lung cancer” behind smoking.
The figure is somewhat lower for the United States, where around 4.7% of lung cancer deaths each year are directly attributable to pollution. However, with “the wildfires out West, we’re going to be seeing more of a toll from air pollution,” she predicted.
She pointed out that the International Agency for Research on Cancer classifies outdoor air pollution, especially particulate matter, as a human carcinogen on the basis of evidence of an association with lung cancer.
It is thought that direct deposits and local effects of particulate matter lead to oxidative damage and low-grade chronic inflammation. These in turn result in molecular changes that affect DNA and gene transcription and inhibit apoptosis, all of which lead to the development of cancerous lesions, she explained.
Synthesizing various estimates on global burden of disease, Dr. Berg and colleagues calculated that in 2019 the rate of lung cancer deaths attributable to particular matter in people aged 50-69 years was highest in Serbia, at 36.88 attributable deaths per 100,000.
Next was Poland, with a rate of 27.97 per 100,000, followed by China at 24.63 per 100,000, Mongolia at 19.71 per 100,000, and Turkey at 19.2 per 100,000.
The major sources of air pollution in the most affected countries were transportation, indoor cooking, and energy sources, she said.
In Serbia, 70% of energy production was from coal. It was 74% in Poland, 65% in China, 80% in Mongolia, 35% in Turkey, and 19% in the United States.
At the time of the analysis, only 17.3% of U.S. adults were smokers, and the air concentration of particular matter of 2.5 mcm was 9.6% mcg/m3. Both of these rates are far below those seen in more severely affected countries.
“But 40% of our energy now comes from natural gas,” noted Dr. Berg, “which is still a pollutant and a source of methane. It’s a very potent greenhouse gas.”
No funding for the study has been reported. Dr. Berg has relationships with GRAIL and Mercy BioAnalytics. Dr. Aerts has relationships with Amphera, AstraZeneca, Bayer, BIOCAD, Bristol-Myers Squibb, Eli Lilly, and Roche.
A version of this article first appeared on Medscape.com.
The new data show that the rate of lung cancer deaths attributable to air pollution varies widely between countries. Serbia, Poland, China, Mongolia, and Turkey are among the worst affected. The analysis shows an association between deaths from lung cancer and the proportion of national energy that is produced from coal.
“Both smoking and air pollution are important causes of lung cancer,” said study presenter Christine D. Berg, MD, former codirector of the National Lung Screening Trial, and “both need to be eliminated to help prevent lung cancer and save lives.
“As lung cancer professionals, we can mitigate the effects of air pollution on causing lung cancer by speaking out for clean energy standards,” she said.
Dr. Berg presented the new analysis on Sept. 9 at the 2021 World Conference on Lung Cancer, which was organized by the International Association for the Study of Lung Cancer.
She welcomed the recent statement issued by the IASLC in support of the International Day of Clean Air for Blue Skies, which took place on Sept. 7. It was a call for action that emphasized the need for further efforts to improve air quality to protect human health.
The findings from the new analysis are “depressing,” commented Joachim G. J. V. Aerts, MD. PhD, department of pulmonary diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.
It is now clear that air pollution has an impact not only on the incidence of lung cancer but also on its outcome, he added.
Indeed, previous research showed that each 10 mcg/m3 increase in particular matter of 2.5 mcg in size was associated with a 15%-27% increase in lung cancer mortality. There was no difference in rates between women and men.
A key question, Dr. Aerts said, is whether reducing air pollution would be beneficial.
Efforts to reduce air pollution over recent decades in the United Kingdom have not led to a reduction in lung cancer deaths. This is because of the increase in life expectancy – individuals have been exposed to pollution for longer, albeit at lower levels, he pointed out.
Because of lockdowns during the COVID pandemic, travel has been greatly reduced. This has resulted in a dramatic reduction in air pollution, “and this led to a decrease in the number of children born with low birth weight,” said Dr. Aerts.
Hopefully, that benefit will also be seen regarding other diseases, he added.
The call to action to reduce air pollution is of the “utmost importance,” he said. He noted that the focus should be on global, national, local, and personal preventive measures.
“It is time to join forces,” he added, “to ‘clean the air.’ ”
Dr. Berg’s presentation was warmly received on social media.
It was “fabulous,” commented Eric H. Bernicker, MD, director of medical thoracic oncology at Houston Methodist Cancer Center.
“Thoracic oncologists need to add air pollution to things they advocate about; we have an important voice here,” he added.
It is “so important to understand that air pollution is a human carcinogen,” commented Ivy Elkins, a lung cancer survivor and advocate and cofounder of the EGFR Resisters Lung Cancer Patient Group. “All you need are lungs to get lung cancer!”
Contribution of air pollution to lung cancer
In her presentation, Dr. Berg emphasized that lung cancer is the leading cause of cancer death worldwide, although the distribution between countries “depends on historical and current smoking patterns and the demographics of the population.”
Overall, data from GLOBOCAN 2018 indicate that annually there are approximately 2.1 million incident cases of lung cancer and almost 1.8 million lung cancer deaths around the globe.
A recent study estimated that, worldwide, 14.1% of all lung cancer deaths, including in never-smokers, are directly linked to air pollution.
Dr. Berg said that this makes it the “second-leading cause of lung cancer” behind smoking.
The figure is somewhat lower for the United States, where around 4.7% of lung cancer deaths each year are directly attributable to pollution. However, with “the wildfires out West, we’re going to be seeing more of a toll from air pollution,” she predicted.
She pointed out that the International Agency for Research on Cancer classifies outdoor air pollution, especially particulate matter, as a human carcinogen on the basis of evidence of an association with lung cancer.
It is thought that direct deposits and local effects of particulate matter lead to oxidative damage and low-grade chronic inflammation. These in turn result in molecular changes that affect DNA and gene transcription and inhibit apoptosis, all of which lead to the development of cancerous lesions, she explained.
Synthesizing various estimates on global burden of disease, Dr. Berg and colleagues calculated that in 2019 the rate of lung cancer deaths attributable to particular matter in people aged 50-69 years was highest in Serbia, at 36.88 attributable deaths per 100,000.
Next was Poland, with a rate of 27.97 per 100,000, followed by China at 24.63 per 100,000, Mongolia at 19.71 per 100,000, and Turkey at 19.2 per 100,000.
The major sources of air pollution in the most affected countries were transportation, indoor cooking, and energy sources, she said.
In Serbia, 70% of energy production was from coal. It was 74% in Poland, 65% in China, 80% in Mongolia, 35% in Turkey, and 19% in the United States.
At the time of the analysis, only 17.3% of U.S. adults were smokers, and the air concentration of particular matter of 2.5 mcm was 9.6% mcg/m3. Both of these rates are far below those seen in more severely affected countries.
“But 40% of our energy now comes from natural gas,” noted Dr. Berg, “which is still a pollutant and a source of methane. It’s a very potent greenhouse gas.”
No funding for the study has been reported. Dr. Berg has relationships with GRAIL and Mercy BioAnalytics. Dr. Aerts has relationships with Amphera, AstraZeneca, Bayer, BIOCAD, Bristol-Myers Squibb, Eli Lilly, and Roche.
A version of this article first appeared on Medscape.com.
The new data show that the rate of lung cancer deaths attributable to air pollution varies widely between countries. Serbia, Poland, China, Mongolia, and Turkey are among the worst affected. The analysis shows an association between deaths from lung cancer and the proportion of national energy that is produced from coal.
“Both smoking and air pollution are important causes of lung cancer,” said study presenter Christine D. Berg, MD, former codirector of the National Lung Screening Trial, and “both need to be eliminated to help prevent lung cancer and save lives.
“As lung cancer professionals, we can mitigate the effects of air pollution on causing lung cancer by speaking out for clean energy standards,” she said.
Dr. Berg presented the new analysis on Sept. 9 at the 2021 World Conference on Lung Cancer, which was organized by the International Association for the Study of Lung Cancer.
She welcomed the recent statement issued by the IASLC in support of the International Day of Clean Air for Blue Skies, which took place on Sept. 7. It was a call for action that emphasized the need for further efforts to improve air quality to protect human health.
The findings from the new analysis are “depressing,” commented Joachim G. J. V. Aerts, MD. PhD, department of pulmonary diseases, Erasmus University Medical Center, Rotterdam, the Netherlands.
It is now clear that air pollution has an impact not only on the incidence of lung cancer but also on its outcome, he added.
Indeed, previous research showed that each 10 mcg/m3 increase in particular matter of 2.5 mcg in size was associated with a 15%-27% increase in lung cancer mortality. There was no difference in rates between women and men.
A key question, Dr. Aerts said, is whether reducing air pollution would be beneficial.
Efforts to reduce air pollution over recent decades in the United Kingdom have not led to a reduction in lung cancer deaths. This is because of the increase in life expectancy – individuals have been exposed to pollution for longer, albeit at lower levels, he pointed out.
Because of lockdowns during the COVID pandemic, travel has been greatly reduced. This has resulted in a dramatic reduction in air pollution, “and this led to a decrease in the number of children born with low birth weight,” said Dr. Aerts.
Hopefully, that benefit will also be seen regarding other diseases, he added.
The call to action to reduce air pollution is of the “utmost importance,” he said. He noted that the focus should be on global, national, local, and personal preventive measures.
“It is time to join forces,” he added, “to ‘clean the air.’ ”
Dr. Berg’s presentation was warmly received on social media.
It was “fabulous,” commented Eric H. Bernicker, MD, director of medical thoracic oncology at Houston Methodist Cancer Center.
“Thoracic oncologists need to add air pollution to things they advocate about; we have an important voice here,” he added.
It is “so important to understand that air pollution is a human carcinogen,” commented Ivy Elkins, a lung cancer survivor and advocate and cofounder of the EGFR Resisters Lung Cancer Patient Group. “All you need are lungs to get lung cancer!”
Contribution of air pollution to lung cancer
In her presentation, Dr. Berg emphasized that lung cancer is the leading cause of cancer death worldwide, although the distribution between countries “depends on historical and current smoking patterns and the demographics of the population.”
Overall, data from GLOBOCAN 2018 indicate that annually there are approximately 2.1 million incident cases of lung cancer and almost 1.8 million lung cancer deaths around the globe.
A recent study estimated that, worldwide, 14.1% of all lung cancer deaths, including in never-smokers, are directly linked to air pollution.
Dr. Berg said that this makes it the “second-leading cause of lung cancer” behind smoking.
The figure is somewhat lower for the United States, where around 4.7% of lung cancer deaths each year are directly attributable to pollution. However, with “the wildfires out West, we’re going to be seeing more of a toll from air pollution,” she predicted.
She pointed out that the International Agency for Research on Cancer classifies outdoor air pollution, especially particulate matter, as a human carcinogen on the basis of evidence of an association with lung cancer.
It is thought that direct deposits and local effects of particulate matter lead to oxidative damage and low-grade chronic inflammation. These in turn result in molecular changes that affect DNA and gene transcription and inhibit apoptosis, all of which lead to the development of cancerous lesions, she explained.
Synthesizing various estimates on global burden of disease, Dr. Berg and colleagues calculated that in 2019 the rate of lung cancer deaths attributable to particular matter in people aged 50-69 years was highest in Serbia, at 36.88 attributable deaths per 100,000.
Next was Poland, with a rate of 27.97 per 100,000, followed by China at 24.63 per 100,000, Mongolia at 19.71 per 100,000, and Turkey at 19.2 per 100,000.
The major sources of air pollution in the most affected countries were transportation, indoor cooking, and energy sources, she said.
In Serbia, 70% of energy production was from coal. It was 74% in Poland, 65% in China, 80% in Mongolia, 35% in Turkey, and 19% in the United States.
At the time of the analysis, only 17.3% of U.S. adults were smokers, and the air concentration of particular matter of 2.5 mcm was 9.6% mcg/m3. Both of these rates are far below those seen in more severely affected countries.
“But 40% of our energy now comes from natural gas,” noted Dr. Berg, “which is still a pollutant and a source of methane. It’s a very potent greenhouse gas.”
No funding for the study has been reported. Dr. Berg has relationships with GRAIL and Mercy BioAnalytics. Dr. Aerts has relationships with Amphera, AstraZeneca, Bayer, BIOCAD, Bristol-Myers Squibb, Eli Lilly, and Roche.
A version of this article first appeared on Medscape.com.
Microwave ablation an alternative therapy in lung malignancy
Lung cancer patients with relatively small nodules who cannot or will not undergo surgery or radiotherapy can be successfully treated with targeted transbronchial microwave ablation, indicate results from a U.K.-led preliminary trial.
The NAVABLATE study included 30 patients from the U.K. and Hong Kong who had malignant lung nodules no more than 30 mm in diameter, who underwent transbronchial microwave ablation and were followed up one month later.
On the day, the technique was performed successfully in all 30 patients, while follow-up imaging at one month suggested that the ablation had been satisfactory in every case, with no repeat procedures necessary.
It was also associated with a “low rate of device-related adverse events and no serious adverse events,” said lead author Kevin Lau, Barts Thorax Centre, St. Bartholomew’s Hospital, Barts Health NHS Trust, London.
Consequently, transbronchial microwave ablation can be considered “an alternative treatment modality for patients with primary and metastatic malignant lung nodules … who decline or are ineligible” for surgery and radiotherapy.
The research was presented at the European Respiratory Society International Congress (ERS) 2021 on September 5.
‘Encouraging’ results
Professor Stefano Elia, head of the European Respiratory Society’s Assembly on Thoracic Surgery and Transplantation, told this news organization that the results “are encouraging.”
However, the patient numbers are “very low, so it is difficult to draw value conclusions,” and he would like to have seen more detailed characterization of the patients’ tumors.
Prof. Elia, from the University of Rome Tor Vergata, added that transbronchial microwave ablation should, in line with the study’s inclusion criteria, “probably be reserved” for lung cancer patients “who are unfit for or refuse surgery or alternative treatment strategies.”
He added that “prospective, randomized trials are warranted to see if the technique is feasible, safe and indicated” in these patients, and the potential cost of performing it needs to be specified.
Study details
Presenting the study, Mr. Lau explained that NAVABLATE was a prospective, multicenter study that enrolled patients with a confirmed malignant lung nodule ≤30 mm that did not abut the pleura, fissure, or critical structures.
In addition, the patients had declined or were not eligible for both surgery and stereotactic body radiotherapy.
They underwent transbronchial microwave ablation with the Emprint ablation catheter (Medtronic) in a hybrid theatre while undergoing cone-beam computed tomography. Only one nodule was ablated if the patients had more than one.
The team recruited 30 patients at two centres in the U.K. and Hong Kong, who had a mean age of 68.4 years and of whom 40% were female. The majority (66.7%) were prior or current tobacco users.
Primary lung cancer was the diagnosis in 20 patients, while 10 had oligometastatic disease, and the median nodule size was 12.5 mm. Thirty percent of patients had previously undergone lobectomy and 16.7% wedge resection.
Thirty-nine ablations were performed in the 30 patients, with 22 having a single ablation. Two ablations were performed in seven patients, while one had three ablations.
The most common ablation times were 10 minutes, in 21 procedures, and 7 minutes, in eight procedures, and the average total bronchoscopy time was 127 minutes.
Technical success
The procedure was deemed a technical success, defined as the nodule being reached and ablated according to the study protocol, in all patients.
The average ablation margin was 9.9 mm, and 1-month follow-up imaging was performed in all patients. This revealed a satisfactory ablation in 100% of cases. No patients required retreatment.
One patient had an adverse event relating to the ablation itself over the one-month follow-up, consisting of grade 1 mild haemoptysis on day 5, which self-resolved.
Adverse events relating to any aspect of the bronchoscopy were seen in 70% of patients, while 13.3% had grade ≥3 events, These included post-procedure pleuritic chest pain in two patients, pleural effusion in two patients, post-ablation syndrome in one patient, and ablation site infection in one patient, all grade 3.
The researchers found that the patients reported only mild pain immediately post-procedure, at an average score of 1.5 on a 10-point scale, falling to 1.4 one week later. At one month, the average pain score was 0.5.
Quality of life, as measured on the EQ-5D-3L was unaffected by the procedure, with scores rising slightly from 74.6 at baseline to 77.4 at the one-month follow-up.
The study was sponsored and funded by Medtronic.
Mr. Lau declares relationships with Medtronic, Philips, and Johnson & Johnson.
A version of this article first appeared on Medscape.com.
Lung cancer patients with relatively small nodules who cannot or will not undergo surgery or radiotherapy can be successfully treated with targeted transbronchial microwave ablation, indicate results from a U.K.-led preliminary trial.
The NAVABLATE study included 30 patients from the U.K. and Hong Kong who had malignant lung nodules no more than 30 mm in diameter, who underwent transbronchial microwave ablation and were followed up one month later.
On the day, the technique was performed successfully in all 30 patients, while follow-up imaging at one month suggested that the ablation had been satisfactory in every case, with no repeat procedures necessary.
It was also associated with a “low rate of device-related adverse events and no serious adverse events,” said lead author Kevin Lau, Barts Thorax Centre, St. Bartholomew’s Hospital, Barts Health NHS Trust, London.
Consequently, transbronchial microwave ablation can be considered “an alternative treatment modality for patients with primary and metastatic malignant lung nodules … who decline or are ineligible” for surgery and radiotherapy.
The research was presented at the European Respiratory Society International Congress (ERS) 2021 on September 5.
‘Encouraging’ results
Professor Stefano Elia, head of the European Respiratory Society’s Assembly on Thoracic Surgery and Transplantation, told this news organization that the results “are encouraging.”
However, the patient numbers are “very low, so it is difficult to draw value conclusions,” and he would like to have seen more detailed characterization of the patients’ tumors.
Prof. Elia, from the University of Rome Tor Vergata, added that transbronchial microwave ablation should, in line with the study’s inclusion criteria, “probably be reserved” for lung cancer patients “who are unfit for or refuse surgery or alternative treatment strategies.”
He added that “prospective, randomized trials are warranted to see if the technique is feasible, safe and indicated” in these patients, and the potential cost of performing it needs to be specified.
Study details
Presenting the study, Mr. Lau explained that NAVABLATE was a prospective, multicenter study that enrolled patients with a confirmed malignant lung nodule ≤30 mm that did not abut the pleura, fissure, or critical structures.
In addition, the patients had declined or were not eligible for both surgery and stereotactic body radiotherapy.
They underwent transbronchial microwave ablation with the Emprint ablation catheter (Medtronic) in a hybrid theatre while undergoing cone-beam computed tomography. Only one nodule was ablated if the patients had more than one.
The team recruited 30 patients at two centres in the U.K. and Hong Kong, who had a mean age of 68.4 years and of whom 40% were female. The majority (66.7%) were prior or current tobacco users.
Primary lung cancer was the diagnosis in 20 patients, while 10 had oligometastatic disease, and the median nodule size was 12.5 mm. Thirty percent of patients had previously undergone lobectomy and 16.7% wedge resection.
Thirty-nine ablations were performed in the 30 patients, with 22 having a single ablation. Two ablations were performed in seven patients, while one had three ablations.
The most common ablation times were 10 minutes, in 21 procedures, and 7 minutes, in eight procedures, and the average total bronchoscopy time was 127 minutes.
Technical success
The procedure was deemed a technical success, defined as the nodule being reached and ablated according to the study protocol, in all patients.
The average ablation margin was 9.9 mm, and 1-month follow-up imaging was performed in all patients. This revealed a satisfactory ablation in 100% of cases. No patients required retreatment.
One patient had an adverse event relating to the ablation itself over the one-month follow-up, consisting of grade 1 mild haemoptysis on day 5, which self-resolved.
Adverse events relating to any aspect of the bronchoscopy were seen in 70% of patients, while 13.3% had grade ≥3 events, These included post-procedure pleuritic chest pain in two patients, pleural effusion in two patients, post-ablation syndrome in one patient, and ablation site infection in one patient, all grade 3.
The researchers found that the patients reported only mild pain immediately post-procedure, at an average score of 1.5 on a 10-point scale, falling to 1.4 one week later. At one month, the average pain score was 0.5.
Quality of life, as measured on the EQ-5D-3L was unaffected by the procedure, with scores rising slightly from 74.6 at baseline to 77.4 at the one-month follow-up.
The study was sponsored and funded by Medtronic.
Mr. Lau declares relationships with Medtronic, Philips, and Johnson & Johnson.
A version of this article first appeared on Medscape.com.
Lung cancer patients with relatively small nodules who cannot or will not undergo surgery or radiotherapy can be successfully treated with targeted transbronchial microwave ablation, indicate results from a U.K.-led preliminary trial.
The NAVABLATE study included 30 patients from the U.K. and Hong Kong who had malignant lung nodules no more than 30 mm in diameter, who underwent transbronchial microwave ablation and were followed up one month later.
On the day, the technique was performed successfully in all 30 patients, while follow-up imaging at one month suggested that the ablation had been satisfactory in every case, with no repeat procedures necessary.
It was also associated with a “low rate of device-related adverse events and no serious adverse events,” said lead author Kevin Lau, Barts Thorax Centre, St. Bartholomew’s Hospital, Barts Health NHS Trust, London.
Consequently, transbronchial microwave ablation can be considered “an alternative treatment modality for patients with primary and metastatic malignant lung nodules … who decline or are ineligible” for surgery and radiotherapy.
The research was presented at the European Respiratory Society International Congress (ERS) 2021 on September 5.
‘Encouraging’ results
Professor Stefano Elia, head of the European Respiratory Society’s Assembly on Thoracic Surgery and Transplantation, told this news organization that the results “are encouraging.”
However, the patient numbers are “very low, so it is difficult to draw value conclusions,” and he would like to have seen more detailed characterization of the patients’ tumors.
Prof. Elia, from the University of Rome Tor Vergata, added that transbronchial microwave ablation should, in line with the study’s inclusion criteria, “probably be reserved” for lung cancer patients “who are unfit for or refuse surgery or alternative treatment strategies.”
He added that “prospective, randomized trials are warranted to see if the technique is feasible, safe and indicated” in these patients, and the potential cost of performing it needs to be specified.
Study details
Presenting the study, Mr. Lau explained that NAVABLATE was a prospective, multicenter study that enrolled patients with a confirmed malignant lung nodule ≤30 mm that did not abut the pleura, fissure, or critical structures.
In addition, the patients had declined or were not eligible for both surgery and stereotactic body radiotherapy.
They underwent transbronchial microwave ablation with the Emprint ablation catheter (Medtronic) in a hybrid theatre while undergoing cone-beam computed tomography. Only one nodule was ablated if the patients had more than one.
The team recruited 30 patients at two centres in the U.K. and Hong Kong, who had a mean age of 68.4 years and of whom 40% were female. The majority (66.7%) were prior or current tobacco users.
Primary lung cancer was the diagnosis in 20 patients, while 10 had oligometastatic disease, and the median nodule size was 12.5 mm. Thirty percent of patients had previously undergone lobectomy and 16.7% wedge resection.
Thirty-nine ablations were performed in the 30 patients, with 22 having a single ablation. Two ablations were performed in seven patients, while one had three ablations.
The most common ablation times were 10 minutes, in 21 procedures, and 7 minutes, in eight procedures, and the average total bronchoscopy time was 127 minutes.
Technical success
The procedure was deemed a technical success, defined as the nodule being reached and ablated according to the study protocol, in all patients.
The average ablation margin was 9.9 mm, and 1-month follow-up imaging was performed in all patients. This revealed a satisfactory ablation in 100% of cases. No patients required retreatment.
One patient had an adverse event relating to the ablation itself over the one-month follow-up, consisting of grade 1 mild haemoptysis on day 5, which self-resolved.
Adverse events relating to any aspect of the bronchoscopy were seen in 70% of patients, while 13.3% had grade ≥3 events, These included post-procedure pleuritic chest pain in two patients, pleural effusion in two patients, post-ablation syndrome in one patient, and ablation site infection in one patient, all grade 3.
The researchers found that the patients reported only mild pain immediately post-procedure, at an average score of 1.5 on a 10-point scale, falling to 1.4 one week later. At one month, the average pain score was 0.5.
Quality of life, as measured on the EQ-5D-3L was unaffected by the procedure, with scores rising slightly from 74.6 at baseline to 77.4 at the one-month follow-up.
The study was sponsored and funded by Medtronic.
Mr. Lau declares relationships with Medtronic, Philips, and Johnson & Johnson.
A version of this article first appeared on Medscape.com.
Metformin disappoints in two phase 2 lung cancer trials
Although well tolerated, metformin does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and may even make survival worse, suggest results from two recent phase 2 trials.
Epidemiologic studies have suggested that metformin is associated with a reduced incidence of cancer, while retrospective case studies have indicated that patients taking the drug have improved outcomes.
Moreover, preclinical data indicated that metformin has antineoplastic effects, with the drug showing both cytostatic and cytotoxic effects.
The current results cast doubt, however, over whether these benefits can be replicated in randomized controlled trials and thence brought to the clinic.
Despite this, “I don’t think metformin is dead,” commented Heath D. Skinner, MD, PhD, first author on one of the trials, published in JAMA Oncology.
He said in an interview there are “a few key areas where I think metformin could be of benefit” in lung cancer, such as in combination with tyrosine kinase inhibitors, or with immunotherapy.
Dr. Skinner also highlighted the unexpectedly good performance of standard chemoradiation, showing the “progress” that has been made in recent years in treatment delivery and quality.
No survival benefit
In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin.
Among the 167 patients eligible for analysis, 1-year progression-free survival (PFS) was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months.
The only clinical factor associated with progression-free survival on multivariate analysis was clinical stage, at a hazard ratio of 1.79 (P = .05), reports Dr. Skinner, from the University of Pittsburgh Hillman Cancer Center, and colleagues.
With 1-year overall survival at 80.2% in the control group and 80.8% in the metformin arm, and no significant differences in rates of locoregional recurrence or distant metastasis, the team concluded that adding metformin to chemoradiation may have been “well tolerated but did not improve survival.”
Not recommended
The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes.
They were treated with platinum-based chemoradiotherapy, with chest radiotherapy with or without consolidation chemotherapy. They were randomized to metformin or no additional treatment for up to 12 months.
The trial had to be stopped early because of slow accrual, with only 54 patients randomized between 2014 and 2019, wrote the authors who were led by Theodoros Tsakiridis, MD, PhD, Juravinski Cancer Center, McMaster University, Hamilton, Ont.
The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.
The 1-year progression survival was markedly worse with metformin, at 34.8% versus 63.0% in the control arm and an HR for progression of 2.42, while overall survival was 47.4% versus 85.2% and an HR for death of 3.80.
With more than twice as many metformin than control patients reporting at least one grade 3 or higher adverse event, the researchers conclude the drug is “not recommended in patients with locally advanced non–small cell lung cancer who are candidates for chemoradiotherapy.”
Future research directions
Do these results sound the death knell for metformin in the treatment of lung cancer, or could lessons be learned from both studies that leave the door open for future research?
Chukwuka Eze, MD, of the University Hospital LMU Munich (Germany), thinks there may well be.
In an editorial accompanying the two studies, he and colleagues wrote: “Despite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted.”
For example, “there might yet be a role for metformin in selected patients with non–small cell lung cancer patients,” they continued, such as those with KRAS/LKB1-mutated tumors, or with tumors that have elevated fluorodeoxyglucose metabolism.
They also suggested that future studies should include continuous assessment of metabolic parameters and “comprehensive” analysis of responses on imaging, as well as biomarker analysis.
Moreover, in the era of immuno-oncology, “special attention to the immunomodulatory effects of metformin in the host and tumor are pertinent.”
Better-than-expected outcomes
Beyond that, both studies were hampered by limitations that make drawing conclusions difficult.
In the OCOG-ALMERA trial, the lack of double-blinding or placebo control, and limited accrual are identified by the authors as “weaknesses.”
The “much slower than anticipated” accrual may have been caused not only by exclusion of patients with diabetes, but also bias against the trial among physicians, who may have looked instead to immunotherapy trials for their patients.
On the other hand, the issue for NRG-LU001 was the “better-than-expected” performance of control arm, the researchers noted.
They make the comparison with the PACIFIC trial, which showed that giving durvalumab (Imfinzi, AstraZeneca) after platinum-based doublet chemotherapy and concurrent radiotherapy was associated with a doubling of progression-free survival over chemoradiation alone.
However, Dr. Skinner and colleagues pointed out that the 1-year progression-free survival achieved in PACIFIC with durvalumab after chemoradiotherapy was, at 55.9%, lower than that seen in the control arm of NRG-LU001.
“The PFS in NRG-LU001 remains striking, particularly as PACIFIC trial patients were randomized only when progression was not detected after concurrent chemoradiation,” the researchers wrote.
Dr. Skinner said in an interview they expected the control arm in their study “to do far worse than it actually did.”
He continued that they did not follow up chemoradiation with adjuvant immunotherapy, as would be the case nowadays, because it was “not the standard when we started the trial,” and did not become so “until the very end of accrual.”
Dr. Skinner warned that there are “many caveats” to comparing two different trials, but looking at the current results alongside those from PACIFIC, he said that, “for me, it seems like we have been making progress in the delivery of concurrent chemoradiation. I think that good quality concurrent chemoradiation and improvement in delivery really is one of the take-homes from this trial.”
NRG-LU001 was supported by grants from NRG Oncology and the National Cancer Institute. OCOG-ALMERA was funded by a grant from the Canadian Institutes of Health Research to Dr Tsakiridis. The Ontario Clinical Oncology Group assumed the role of the sponsor of this trial. Dr. Skinner reported receiving research funding from the National Cancer Institute and National Institute of Dental and Craniofacial Research outside the submitted work and has previously received a grant from the National Cancer Institute for a separate metformin-related clinical trial. Dr. Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Dr. Eze declares no relevant relationships.
Although well tolerated, metformin does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and may even make survival worse, suggest results from two recent phase 2 trials.
Epidemiologic studies have suggested that metformin is associated with a reduced incidence of cancer, while retrospective case studies have indicated that patients taking the drug have improved outcomes.
Moreover, preclinical data indicated that metformin has antineoplastic effects, with the drug showing both cytostatic and cytotoxic effects.
The current results cast doubt, however, over whether these benefits can be replicated in randomized controlled trials and thence brought to the clinic.
Despite this, “I don’t think metformin is dead,” commented Heath D. Skinner, MD, PhD, first author on one of the trials, published in JAMA Oncology.
He said in an interview there are “a few key areas where I think metformin could be of benefit” in lung cancer, such as in combination with tyrosine kinase inhibitors, or with immunotherapy.
Dr. Skinner also highlighted the unexpectedly good performance of standard chemoradiation, showing the “progress” that has been made in recent years in treatment delivery and quality.
No survival benefit
In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin.
Among the 167 patients eligible for analysis, 1-year progression-free survival (PFS) was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months.
The only clinical factor associated with progression-free survival on multivariate analysis was clinical stage, at a hazard ratio of 1.79 (P = .05), reports Dr. Skinner, from the University of Pittsburgh Hillman Cancer Center, and colleagues.
With 1-year overall survival at 80.2% in the control group and 80.8% in the metformin arm, and no significant differences in rates of locoregional recurrence or distant metastasis, the team concluded that adding metformin to chemoradiation may have been “well tolerated but did not improve survival.”
Not recommended
The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes.
They were treated with platinum-based chemoradiotherapy, with chest radiotherapy with or without consolidation chemotherapy. They were randomized to metformin or no additional treatment for up to 12 months.
The trial had to be stopped early because of slow accrual, with only 54 patients randomized between 2014 and 2019, wrote the authors who were led by Theodoros Tsakiridis, MD, PhD, Juravinski Cancer Center, McMaster University, Hamilton, Ont.
The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.
The 1-year progression survival was markedly worse with metformin, at 34.8% versus 63.0% in the control arm and an HR for progression of 2.42, while overall survival was 47.4% versus 85.2% and an HR for death of 3.80.
With more than twice as many metformin than control patients reporting at least one grade 3 or higher adverse event, the researchers conclude the drug is “not recommended in patients with locally advanced non–small cell lung cancer who are candidates for chemoradiotherapy.”
Future research directions
Do these results sound the death knell for metformin in the treatment of lung cancer, or could lessons be learned from both studies that leave the door open for future research?
Chukwuka Eze, MD, of the University Hospital LMU Munich (Germany), thinks there may well be.
In an editorial accompanying the two studies, he and colleagues wrote: “Despite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted.”
For example, “there might yet be a role for metformin in selected patients with non–small cell lung cancer patients,” they continued, such as those with KRAS/LKB1-mutated tumors, or with tumors that have elevated fluorodeoxyglucose metabolism.
They also suggested that future studies should include continuous assessment of metabolic parameters and “comprehensive” analysis of responses on imaging, as well as biomarker analysis.
Moreover, in the era of immuno-oncology, “special attention to the immunomodulatory effects of metformin in the host and tumor are pertinent.”
Better-than-expected outcomes
Beyond that, both studies were hampered by limitations that make drawing conclusions difficult.
In the OCOG-ALMERA trial, the lack of double-blinding or placebo control, and limited accrual are identified by the authors as “weaknesses.”
The “much slower than anticipated” accrual may have been caused not only by exclusion of patients with diabetes, but also bias against the trial among physicians, who may have looked instead to immunotherapy trials for their patients.
On the other hand, the issue for NRG-LU001 was the “better-than-expected” performance of control arm, the researchers noted.
They make the comparison with the PACIFIC trial, which showed that giving durvalumab (Imfinzi, AstraZeneca) after platinum-based doublet chemotherapy and concurrent radiotherapy was associated with a doubling of progression-free survival over chemoradiation alone.
However, Dr. Skinner and colleagues pointed out that the 1-year progression-free survival achieved in PACIFIC with durvalumab after chemoradiotherapy was, at 55.9%, lower than that seen in the control arm of NRG-LU001.
“The PFS in NRG-LU001 remains striking, particularly as PACIFIC trial patients were randomized only when progression was not detected after concurrent chemoradiation,” the researchers wrote.
Dr. Skinner said in an interview they expected the control arm in their study “to do far worse than it actually did.”
He continued that they did not follow up chemoradiation with adjuvant immunotherapy, as would be the case nowadays, because it was “not the standard when we started the trial,” and did not become so “until the very end of accrual.”
Dr. Skinner warned that there are “many caveats” to comparing two different trials, but looking at the current results alongside those from PACIFIC, he said that, “for me, it seems like we have been making progress in the delivery of concurrent chemoradiation. I think that good quality concurrent chemoradiation and improvement in delivery really is one of the take-homes from this trial.”
NRG-LU001 was supported by grants from NRG Oncology and the National Cancer Institute. OCOG-ALMERA was funded by a grant from the Canadian Institutes of Health Research to Dr Tsakiridis. The Ontario Clinical Oncology Group assumed the role of the sponsor of this trial. Dr. Skinner reported receiving research funding from the National Cancer Institute and National Institute of Dental and Craniofacial Research outside the submitted work and has previously received a grant from the National Cancer Institute for a separate metformin-related clinical trial. Dr. Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Dr. Eze declares no relevant relationships.
Although well tolerated, metformin does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and may even make survival worse, suggest results from two recent phase 2 trials.
Epidemiologic studies have suggested that metformin is associated with a reduced incidence of cancer, while retrospective case studies have indicated that patients taking the drug have improved outcomes.
Moreover, preclinical data indicated that metformin has antineoplastic effects, with the drug showing both cytostatic and cytotoxic effects.
The current results cast doubt, however, over whether these benefits can be replicated in randomized controlled trials and thence brought to the clinic.
Despite this, “I don’t think metformin is dead,” commented Heath D. Skinner, MD, PhD, first author on one of the trials, published in JAMA Oncology.
He said in an interview there are “a few key areas where I think metformin could be of benefit” in lung cancer, such as in combination with tyrosine kinase inhibitors, or with immunotherapy.
Dr. Skinner also highlighted the unexpectedly good performance of standard chemoradiation, showing the “progress” that has been made in recent years in treatment delivery and quality.
No survival benefit
In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin.
Among the 167 patients eligible for analysis, 1-year progression-free survival (PFS) was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months.
The only clinical factor associated with progression-free survival on multivariate analysis was clinical stage, at a hazard ratio of 1.79 (P = .05), reports Dr. Skinner, from the University of Pittsburgh Hillman Cancer Center, and colleagues.
With 1-year overall survival at 80.2% in the control group and 80.8% in the metformin arm, and no significant differences in rates of locoregional recurrence or distant metastasis, the team concluded that adding metformin to chemoradiation may have been “well tolerated but did not improve survival.”
Not recommended
The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes.
They were treated with platinum-based chemoradiotherapy, with chest radiotherapy with or without consolidation chemotherapy. They were randomized to metformin or no additional treatment for up to 12 months.
The trial had to be stopped early because of slow accrual, with only 54 patients randomized between 2014 and 2019, wrote the authors who were led by Theodoros Tsakiridis, MD, PhD, Juravinski Cancer Center, McMaster University, Hamilton, Ont.
The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.
The 1-year progression survival was markedly worse with metformin, at 34.8% versus 63.0% in the control arm and an HR for progression of 2.42, while overall survival was 47.4% versus 85.2% and an HR for death of 3.80.
With more than twice as many metformin than control patients reporting at least one grade 3 or higher adverse event, the researchers conclude the drug is “not recommended in patients with locally advanced non–small cell lung cancer who are candidates for chemoradiotherapy.”
Future research directions
Do these results sound the death knell for metformin in the treatment of lung cancer, or could lessons be learned from both studies that leave the door open for future research?
Chukwuka Eze, MD, of the University Hospital LMU Munich (Germany), thinks there may well be.
In an editorial accompanying the two studies, he and colleagues wrote: “Despite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted.”
For example, “there might yet be a role for metformin in selected patients with non–small cell lung cancer patients,” they continued, such as those with KRAS/LKB1-mutated tumors, or with tumors that have elevated fluorodeoxyglucose metabolism.
They also suggested that future studies should include continuous assessment of metabolic parameters and “comprehensive” analysis of responses on imaging, as well as biomarker analysis.
Moreover, in the era of immuno-oncology, “special attention to the immunomodulatory effects of metformin in the host and tumor are pertinent.”
Better-than-expected outcomes
Beyond that, both studies were hampered by limitations that make drawing conclusions difficult.
In the OCOG-ALMERA trial, the lack of double-blinding or placebo control, and limited accrual are identified by the authors as “weaknesses.”
The “much slower than anticipated” accrual may have been caused not only by exclusion of patients with diabetes, but also bias against the trial among physicians, who may have looked instead to immunotherapy trials for their patients.
On the other hand, the issue for NRG-LU001 was the “better-than-expected” performance of control arm, the researchers noted.
They make the comparison with the PACIFIC trial, which showed that giving durvalumab (Imfinzi, AstraZeneca) after platinum-based doublet chemotherapy and concurrent radiotherapy was associated with a doubling of progression-free survival over chemoradiation alone.
However, Dr. Skinner and colleagues pointed out that the 1-year progression-free survival achieved in PACIFIC with durvalumab after chemoradiotherapy was, at 55.9%, lower than that seen in the control arm of NRG-LU001.
“The PFS in NRG-LU001 remains striking, particularly as PACIFIC trial patients were randomized only when progression was not detected after concurrent chemoradiation,” the researchers wrote.
Dr. Skinner said in an interview they expected the control arm in their study “to do far worse than it actually did.”
He continued that they did not follow up chemoradiation with adjuvant immunotherapy, as would be the case nowadays, because it was “not the standard when we started the trial,” and did not become so “until the very end of accrual.”
Dr. Skinner warned that there are “many caveats” to comparing two different trials, but looking at the current results alongside those from PACIFIC, he said that, “for me, it seems like we have been making progress in the delivery of concurrent chemoradiation. I think that good quality concurrent chemoradiation and improvement in delivery really is one of the take-homes from this trial.”
NRG-LU001 was supported by grants from NRG Oncology and the National Cancer Institute. OCOG-ALMERA was funded by a grant from the Canadian Institutes of Health Research to Dr Tsakiridis. The Ontario Clinical Oncology Group assumed the role of the sponsor of this trial. Dr. Skinner reported receiving research funding from the National Cancer Institute and National Institute of Dental and Craniofacial Research outside the submitted work and has previously received a grant from the National Cancer Institute for a separate metformin-related clinical trial. Dr. Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Dr. Eze declares no relevant relationships.
FROM JAMA ONCOLOGY
Patients with diabetes more likely to be hospitalized, especially with foot infection
People with diabetes are at increased risk of hospitalization for infection, as well as infection-related mortality, shows a large U.S. study that suggests the risk is even higher in younger and Black individuals.
Michael Fang, PhD, Johns Hopkins University, Baltimore, and colleagues studied more than 12,000 participants in a community cohort study who were followed for an average of 24 years, between 1987-1989 and 2019.
Participants with diabetes faced a 67% increase risk of infection-related hospitalization, compared with those without diabetes.
Of particular note, the risk of hospitalization with foot infection was almost sixfold higher for people with diabetes than those without.
The research, published in Diabetologia on August 4, also suggests that diabetes may be associated with a 72% increased risk of infection-related mortality, although the absolute numbers were small.
Dr. Fang explained to this news organization that they focused on infection-related hospitalization and mortality “because these are comprehensively tracked in administrative data and ... are the most severe types of outcomes.”
However, this is probably just the tip of the iceberg, as people with diabetes are “likely at increased risk for milder infection too,” which can have a “significant adverse impact on people’s well-being and quality of life.”
As a result of their findings, the authors call for “broader guidance on infection prevention and management” in people with diabetes. To achieve this, Dr. Fang said, “we need to better understand why diabetes is associated with an increased risk of infection-related complications.”
“One likely factor is glycemic control: Emerging research suggests patients with diabetes with better glycemic control may be at significantly lower risk of infection-related complications.”
He continued that, in younger patients, a factor for worse outcomes could be that “diabetes tends to be more aggressive when it emerges early in life,” while in Black patients “there is research highlighting Black-White differences in glycemic control, access to care, and beliefs around vaccines.”
Overall, their findings – coupled with recent data showing that diabetes is an important risk factor for adverse outcomes with COVID-19 infection – paint “a common picture,” Dr. Fang said.
“People with diabetes are much more susceptible to infection-related complications, including COVID-related hospitalization and mortality,” which suggests people with diabetes “may need to be especially cautious.”
Adds to existing literature; amputations begin with infections
Robert A. Gabbay, MD, PhD, chief scientific and medical officer for the American Diabetes Association (ADA), said the study “does add to the existing literature by having followed a larger number of people over time and linking them to serious complications from infections.”
“Sadly, we have seen this play out in real-time during the COVID-19 pandemic.”
“One of the sobering bits of data is the significant health disparities that exist in Black Americans and the fact that foot infections remain a significant problem,” he said in an interview.
“Given that amputation rates for [Black Americans] are three times higher than White Americans, amputations begin with infections,” Dr. Gabbay added, noting the ADA “has been taking a strong stand to prevent amputations and address the inequities in health that exist.”
Jamie Hartmann-Boyce, PhD, from the University of Oxford, U.K., who was not involved in the study, commented that diabetes is a “well-known risk factor for worse outcomes from all kinds of infection,” which is why they “are prioritized for flu vaccination every year.”
She told this news organization that the current study “further confirms that people with diabetes are more likely to be hospitalized for infection of any type and most markedly for foot infection.”
“These new data further highlight the need for public health interventions to prevent type 2 diabetes, and for preventive health care in people with diabetes, including access to diabetes medications and support and to vaccinations to prevent infection,” added Dr. Hartmann-Boyce, who is a senior research fellow in health behaviors.
Diabetes is thought to be associated with susceptibility to infection via mechanisms such as impaired neutrophil functioning and humoral immune responses, and studies have shown a link with both common and rare infections.
However, the authors point out that “most” of those included “small clinical populations and were cross-sectional or had short follow-up.”
Guidelines for diabetes management, they note, also “pay less attention” to infectious diseases than they do to the prevention of micro- and macrovascular complications.
ARIC data mined for infections in those with diabetes
The team analyzed data from the ongoing U.S. community-based Atherosclerosis Risk in Communities (ARIC) study.
The National Heart, Lung, and Blood Institute–sponsored cohort was comprised of adults aged 45-64 years from four U.S. communities, recruited between 1987 and 1989 for clinical examinations, medical interviews, and laboratory tests, repeated over five more visits up to 2018-2019.
For the current analysis, the team included 12,739 individuals with a mean age of 54.5 years, of whom 54.3% were female and 24.7% were Black.
Patients were defined as having diabetes if their baseline fasting blood glucose was greater than or equal to 7 mmol/L, or nonfasting glucose was greater than or equal to 11.1 mmol/l, they self-reported a diagnosis of diabetes by a physician, or they were taking glucose-lowering medication at the first study visit. The researchers weren’t able to distinguish between type 1 and type 2 diabetes.
In total, 1,485 individuals had diabetes at baseline. They were more likely to be older, Black, have a low socioeconomic status, and have worse cardiometabolic health than participants without diabetes.
Over an average follow-up of 23.8 years, there were 4,229 incident hospitalizations for infection, at an overall rate of 15.9 per 1,000 person-years.
Individuals with diabetes at baseline had a higher rate of hospitalizations than those without, at 25.4 per 1,000 person-years versus 15.2 per 1,000 person-years.
After taking into account sociodemographic characteristics, socioeconomic status, and cardiometabolic risk factors, this equated to a hazard ratio for hospitalization with any infection of 1.67 (P < .001).
The risk of hospitalization for any infection was significantly higher for younger patients with diabetes, defined as aged less than 55 years (P = .005), and for Black patients (P < .001).
While the increased risk was generally consistent across infection types, it was markedly increased for foot infection, at a hazard ratio of 5.99 (P < .001).
Overall, there were few deaths due to infection in the study, at just 362. The risk of infection mortality was nevertheless significantly increased in people with diabetes, at an adjusted hazard ratio of 1.72 (P < .001).
Dr. Fang has reported being supported by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute. Dr. Selvin has reported being supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Selvin is an associate editor for Diabetologia and had no role in the peer review of the manuscript.
A version of this article first appeared on Medscape.com.
People with diabetes are at increased risk of hospitalization for infection, as well as infection-related mortality, shows a large U.S. study that suggests the risk is even higher in younger and Black individuals.
Michael Fang, PhD, Johns Hopkins University, Baltimore, and colleagues studied more than 12,000 participants in a community cohort study who were followed for an average of 24 years, between 1987-1989 and 2019.
Participants with diabetes faced a 67% increase risk of infection-related hospitalization, compared with those without diabetes.
Of particular note, the risk of hospitalization with foot infection was almost sixfold higher for people with diabetes than those without.
The research, published in Diabetologia on August 4, also suggests that diabetes may be associated with a 72% increased risk of infection-related mortality, although the absolute numbers were small.
Dr. Fang explained to this news organization that they focused on infection-related hospitalization and mortality “because these are comprehensively tracked in administrative data and ... are the most severe types of outcomes.”
However, this is probably just the tip of the iceberg, as people with diabetes are “likely at increased risk for milder infection too,” which can have a “significant adverse impact on people’s well-being and quality of life.”
As a result of their findings, the authors call for “broader guidance on infection prevention and management” in people with diabetes. To achieve this, Dr. Fang said, “we need to better understand why diabetes is associated with an increased risk of infection-related complications.”
“One likely factor is glycemic control: Emerging research suggests patients with diabetes with better glycemic control may be at significantly lower risk of infection-related complications.”
He continued that, in younger patients, a factor for worse outcomes could be that “diabetes tends to be more aggressive when it emerges early in life,” while in Black patients “there is research highlighting Black-White differences in glycemic control, access to care, and beliefs around vaccines.”
Overall, their findings – coupled with recent data showing that diabetes is an important risk factor for adverse outcomes with COVID-19 infection – paint “a common picture,” Dr. Fang said.
“People with diabetes are much more susceptible to infection-related complications, including COVID-related hospitalization and mortality,” which suggests people with diabetes “may need to be especially cautious.”
Adds to existing literature; amputations begin with infections
Robert A. Gabbay, MD, PhD, chief scientific and medical officer for the American Diabetes Association (ADA), said the study “does add to the existing literature by having followed a larger number of people over time and linking them to serious complications from infections.”
“Sadly, we have seen this play out in real-time during the COVID-19 pandemic.”
“One of the sobering bits of data is the significant health disparities that exist in Black Americans and the fact that foot infections remain a significant problem,” he said in an interview.
“Given that amputation rates for [Black Americans] are three times higher than White Americans, amputations begin with infections,” Dr. Gabbay added, noting the ADA “has been taking a strong stand to prevent amputations and address the inequities in health that exist.”
Jamie Hartmann-Boyce, PhD, from the University of Oxford, U.K., who was not involved in the study, commented that diabetes is a “well-known risk factor for worse outcomes from all kinds of infection,” which is why they “are prioritized for flu vaccination every year.”
She told this news organization that the current study “further confirms that people with diabetes are more likely to be hospitalized for infection of any type and most markedly for foot infection.”
“These new data further highlight the need for public health interventions to prevent type 2 diabetes, and for preventive health care in people with diabetes, including access to diabetes medications and support and to vaccinations to prevent infection,” added Dr. Hartmann-Boyce, who is a senior research fellow in health behaviors.
Diabetes is thought to be associated with susceptibility to infection via mechanisms such as impaired neutrophil functioning and humoral immune responses, and studies have shown a link with both common and rare infections.
However, the authors point out that “most” of those included “small clinical populations and were cross-sectional or had short follow-up.”
Guidelines for diabetes management, they note, also “pay less attention” to infectious diseases than they do to the prevention of micro- and macrovascular complications.
ARIC data mined for infections in those with diabetes
The team analyzed data from the ongoing U.S. community-based Atherosclerosis Risk in Communities (ARIC) study.
The National Heart, Lung, and Blood Institute–sponsored cohort was comprised of adults aged 45-64 years from four U.S. communities, recruited between 1987 and 1989 for clinical examinations, medical interviews, and laboratory tests, repeated over five more visits up to 2018-2019.
For the current analysis, the team included 12,739 individuals with a mean age of 54.5 years, of whom 54.3% were female and 24.7% were Black.
Patients were defined as having diabetes if their baseline fasting blood glucose was greater than or equal to 7 mmol/L, or nonfasting glucose was greater than or equal to 11.1 mmol/l, they self-reported a diagnosis of diabetes by a physician, or they were taking glucose-lowering medication at the first study visit. The researchers weren’t able to distinguish between type 1 and type 2 diabetes.
In total, 1,485 individuals had diabetes at baseline. They were more likely to be older, Black, have a low socioeconomic status, and have worse cardiometabolic health than participants without diabetes.
Over an average follow-up of 23.8 years, there were 4,229 incident hospitalizations for infection, at an overall rate of 15.9 per 1,000 person-years.
Individuals with diabetes at baseline had a higher rate of hospitalizations than those without, at 25.4 per 1,000 person-years versus 15.2 per 1,000 person-years.
After taking into account sociodemographic characteristics, socioeconomic status, and cardiometabolic risk factors, this equated to a hazard ratio for hospitalization with any infection of 1.67 (P < .001).
The risk of hospitalization for any infection was significantly higher for younger patients with diabetes, defined as aged less than 55 years (P = .005), and for Black patients (P < .001).
While the increased risk was generally consistent across infection types, it was markedly increased for foot infection, at a hazard ratio of 5.99 (P < .001).
Overall, there were few deaths due to infection in the study, at just 362. The risk of infection mortality was nevertheless significantly increased in people with diabetes, at an adjusted hazard ratio of 1.72 (P < .001).
Dr. Fang has reported being supported by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute. Dr. Selvin has reported being supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Selvin is an associate editor for Diabetologia and had no role in the peer review of the manuscript.
A version of this article first appeared on Medscape.com.
People with diabetes are at increased risk of hospitalization for infection, as well as infection-related mortality, shows a large U.S. study that suggests the risk is even higher in younger and Black individuals.
Michael Fang, PhD, Johns Hopkins University, Baltimore, and colleagues studied more than 12,000 participants in a community cohort study who were followed for an average of 24 years, between 1987-1989 and 2019.
Participants with diabetes faced a 67% increase risk of infection-related hospitalization, compared with those without diabetes.
Of particular note, the risk of hospitalization with foot infection was almost sixfold higher for people with diabetes than those without.
The research, published in Diabetologia on August 4, also suggests that diabetes may be associated with a 72% increased risk of infection-related mortality, although the absolute numbers were small.
Dr. Fang explained to this news organization that they focused on infection-related hospitalization and mortality “because these are comprehensively tracked in administrative data and ... are the most severe types of outcomes.”
However, this is probably just the tip of the iceberg, as people with diabetes are “likely at increased risk for milder infection too,” which can have a “significant adverse impact on people’s well-being and quality of life.”
As a result of their findings, the authors call for “broader guidance on infection prevention and management” in people with diabetes. To achieve this, Dr. Fang said, “we need to better understand why diabetes is associated with an increased risk of infection-related complications.”
“One likely factor is glycemic control: Emerging research suggests patients with diabetes with better glycemic control may be at significantly lower risk of infection-related complications.”
He continued that, in younger patients, a factor for worse outcomes could be that “diabetes tends to be more aggressive when it emerges early in life,” while in Black patients “there is research highlighting Black-White differences in glycemic control, access to care, and beliefs around vaccines.”
Overall, their findings – coupled with recent data showing that diabetes is an important risk factor for adverse outcomes with COVID-19 infection – paint “a common picture,” Dr. Fang said.
“People with diabetes are much more susceptible to infection-related complications, including COVID-related hospitalization and mortality,” which suggests people with diabetes “may need to be especially cautious.”
Adds to existing literature; amputations begin with infections
Robert A. Gabbay, MD, PhD, chief scientific and medical officer for the American Diabetes Association (ADA), said the study “does add to the existing literature by having followed a larger number of people over time and linking them to serious complications from infections.”
“Sadly, we have seen this play out in real-time during the COVID-19 pandemic.”
“One of the sobering bits of data is the significant health disparities that exist in Black Americans and the fact that foot infections remain a significant problem,” he said in an interview.
“Given that amputation rates for [Black Americans] are three times higher than White Americans, amputations begin with infections,” Dr. Gabbay added, noting the ADA “has been taking a strong stand to prevent amputations and address the inequities in health that exist.”
Jamie Hartmann-Boyce, PhD, from the University of Oxford, U.K., who was not involved in the study, commented that diabetes is a “well-known risk factor for worse outcomes from all kinds of infection,” which is why they “are prioritized for flu vaccination every year.”
She told this news organization that the current study “further confirms that people with diabetes are more likely to be hospitalized for infection of any type and most markedly for foot infection.”
“These new data further highlight the need for public health interventions to prevent type 2 diabetes, and for preventive health care in people with diabetes, including access to diabetes medications and support and to vaccinations to prevent infection,” added Dr. Hartmann-Boyce, who is a senior research fellow in health behaviors.
Diabetes is thought to be associated with susceptibility to infection via mechanisms such as impaired neutrophil functioning and humoral immune responses, and studies have shown a link with both common and rare infections.
However, the authors point out that “most” of those included “small clinical populations and were cross-sectional or had short follow-up.”
Guidelines for diabetes management, they note, also “pay less attention” to infectious diseases than they do to the prevention of micro- and macrovascular complications.
ARIC data mined for infections in those with diabetes
The team analyzed data from the ongoing U.S. community-based Atherosclerosis Risk in Communities (ARIC) study.
The National Heart, Lung, and Blood Institute–sponsored cohort was comprised of adults aged 45-64 years from four U.S. communities, recruited between 1987 and 1989 for clinical examinations, medical interviews, and laboratory tests, repeated over five more visits up to 2018-2019.
For the current analysis, the team included 12,739 individuals with a mean age of 54.5 years, of whom 54.3% were female and 24.7% were Black.
Patients were defined as having diabetes if their baseline fasting blood glucose was greater than or equal to 7 mmol/L, or nonfasting glucose was greater than or equal to 11.1 mmol/l, they self-reported a diagnosis of diabetes by a physician, or they were taking glucose-lowering medication at the first study visit. The researchers weren’t able to distinguish between type 1 and type 2 diabetes.
In total, 1,485 individuals had diabetes at baseline. They were more likely to be older, Black, have a low socioeconomic status, and have worse cardiometabolic health than participants without diabetes.
Over an average follow-up of 23.8 years, there were 4,229 incident hospitalizations for infection, at an overall rate of 15.9 per 1,000 person-years.
Individuals with diabetes at baseline had a higher rate of hospitalizations than those without, at 25.4 per 1,000 person-years versus 15.2 per 1,000 person-years.
After taking into account sociodemographic characteristics, socioeconomic status, and cardiometabolic risk factors, this equated to a hazard ratio for hospitalization with any infection of 1.67 (P < .001).
The risk of hospitalization for any infection was significantly higher for younger patients with diabetes, defined as aged less than 55 years (P = .005), and for Black patients (P < .001).
While the increased risk was generally consistent across infection types, it was markedly increased for foot infection, at a hazard ratio of 5.99 (P < .001).
Overall, there were few deaths due to infection in the study, at just 362. The risk of infection mortality was nevertheless significantly increased in people with diabetes, at an adjusted hazard ratio of 1.72 (P < .001).
Dr. Fang has reported being supported by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute. Dr. Selvin has reported being supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Selvin is an associate editor for Diabetologia and had no role in the peer review of the manuscript.
A version of this article first appeared on Medscape.com.
Antibiotic linked to rise in early onset colon cancer?
Exposure to antibiotics appears to be associated with the development of colon cancer, particularly in younger people, and could be contributing to the increase in early-onset colorectal cancer (CRC) that is being documented, say U.K. researchers.
The team conducted a nested case-control study using data from primary care in Scotland, which involved almost 8,000 cases of CRC and over 30,000 healthy controls.
The analysis suggests that a history of antibiotic use among individuals younger than 50 appeared to increase the risk of developing colon cancer (but not rectal) by 49%.
“To our knowledge, this is the first study to link antibiotic use with the growing risk of early onset colon cancer, a disease which has been increasing at a rate of at least 3% per year over the last two decades,” said study presenter Sarah Perrott, a medical student at the University of Aberdeen, Scotland.
“Junk food, sugary drinks, obesity, and alcohol are likely to have played a part in that rise, but our data stress the importance of avoiding unnecessary antibiotics, especially in children and young adults,” Ms. Perrott said in a statement.
“We now want to find out if there is a link between antibiotic use and changes in the microbiome which can make the colon more susceptible to cancer, especially in younger people,” added senior author Leslie Samuel, MD, consultant oncologist at Aberdeen Royal Infirmary.
“It’s a complex situation, as we know that the microbiome can quickly revert to its previous state, even when the bowel has been cleared out for a diagnostic procedure,” Dr. Samuel continued.
The research was presented on July 2 at the European Society for Medical Oncology Congress 2021.
Commenting for ESMO, Alberto Sobrero, MD, PhD, Medical Oncology Unit, Ospedale San Martino, Genoa, Italy, said that younger patients with colon cancer typically have a worse prognosis than older people because they are generally diagnosed later.
“Physicians are less likely to investigate a patient with abdominal discomfort for colon cancer if they are in their 30s than if they are in their 70s, and younger patients are not eligible for bowel cancer screening,” he explained.
However, Dr. Sobrero believes it is “too early to say if excessive use of antibiotics could be a causative factor, and we need to understand more about the possible role of the microbiome in bowel cancer before we consider the impact of antibiotics on the intestinal flora.”
The results, nevertheless, “remind us that antibiotics should not be given unless they are really needed, and we cannot exclude the possibility that unnecessary use of antibiotics may be exposing people to an increased risk of cancer,” he concluded.
Similar comments were made by Thomas Seufferlein, MD, department of internal medicine, Ulm University, Germany, who discussed the findings.
He agreed with the authors “that careful use of antibiotics is sensible and paramount” but added that more studies are needed on this suggestion of a link between antibiotic use and the observed increase in early CRC.
Study details
Previous studies have demonstrated that, in older adults, significant alterations in the structure and diversity of the gut microbiome induced by antibiotic therapy influence the development of colorectal cancer.
However, Ms. Perrott said that the impact of antibiotic use on early onset colorectal cancer has not been investigated.
The researchers therefore conducted a nested case-control study of primary care records to identify colorectal cancer cases diagnosed in Scotland between 1999 and 2011.
Patients were divided into those diagnosed before 50 years of age and those diagnosed at 50 years and older and matched with up to five healthy controls.
The study included 7,903 CRC cases, of which 5,281 were colon cancer and 2,622 rectal cancer, alongside 30,418 controls.
Among the CRC patients, 445 (5.6%) were under 50 years of age at diagnosis.
The team also analyzed antibiotic use history. Prescriptions for oral antibiotics, stratified by drug class and by anaerobic/nonanaerobic effect, were extracted, and the total antibiotic exposure period was calculated and categorized as 0, 1-15, 16-60, and >60 days.
Overall, 45% of the patients were prescribed antibiotics. Any antibiotic use was associated with a significantly increased risk of colon cancer, but this was most pronounced in patients aged less than 50 years at diagnosis.
Specifically, any antibiotic use was associated with an adjusted odds ratio of colon cancer of 1.49 (P = .018) in patients aged less than 50 years versus 1.09 (P = .029) in those aged 50 years and over.
In younger patients, the largest association between antibiotic use and colon cancer was seen in patients with a total antibiotic exposure of 1-15 days (at an adjusted odds ratio of 1.55), falling to 1.46 with 16-60 days of exposure, and no association for >60 days exposure.
No such relationship was seen in patients with colon cancer aged 50 years and over at diagnosis.
There was also no significant relationship between any antibiotic use and the occurrence of rectal cancer, at an adjusted odds ratio of 1.17 (P = .493) in those aged under 50 years at diagnosis and 1.07 (P = .698) in older patients.
The study was supported by Cancer Research UK. Ms. Perrott, Dr. Sobrero, and Dr. Samuels declared having no conflicts of interest. Dr. Seufferlien has reported relationships with Amgen, Bayer, Merck, Sanofi, Celgene, Shire, Roche, Falk Foundation, AstraZeneca, Lilly, Merck-Serono, Servier, Pierre Fabre, Cantargia, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
Exposure to antibiotics appears to be associated with the development of colon cancer, particularly in younger people, and could be contributing to the increase in early-onset colorectal cancer (CRC) that is being documented, say U.K. researchers.
The team conducted a nested case-control study using data from primary care in Scotland, which involved almost 8,000 cases of CRC and over 30,000 healthy controls.
The analysis suggests that a history of antibiotic use among individuals younger than 50 appeared to increase the risk of developing colon cancer (but not rectal) by 49%.
“To our knowledge, this is the first study to link antibiotic use with the growing risk of early onset colon cancer, a disease which has been increasing at a rate of at least 3% per year over the last two decades,” said study presenter Sarah Perrott, a medical student at the University of Aberdeen, Scotland.
“Junk food, sugary drinks, obesity, and alcohol are likely to have played a part in that rise, but our data stress the importance of avoiding unnecessary antibiotics, especially in children and young adults,” Ms. Perrott said in a statement.
“We now want to find out if there is a link between antibiotic use and changes in the microbiome which can make the colon more susceptible to cancer, especially in younger people,” added senior author Leslie Samuel, MD, consultant oncologist at Aberdeen Royal Infirmary.
“It’s a complex situation, as we know that the microbiome can quickly revert to its previous state, even when the bowel has been cleared out for a diagnostic procedure,” Dr. Samuel continued.
The research was presented on July 2 at the European Society for Medical Oncology Congress 2021.
Commenting for ESMO, Alberto Sobrero, MD, PhD, Medical Oncology Unit, Ospedale San Martino, Genoa, Italy, said that younger patients with colon cancer typically have a worse prognosis than older people because they are generally diagnosed later.
“Physicians are less likely to investigate a patient with abdominal discomfort for colon cancer if they are in their 30s than if they are in their 70s, and younger patients are not eligible for bowel cancer screening,” he explained.
However, Dr. Sobrero believes it is “too early to say if excessive use of antibiotics could be a causative factor, and we need to understand more about the possible role of the microbiome in bowel cancer before we consider the impact of antibiotics on the intestinal flora.”
The results, nevertheless, “remind us that antibiotics should not be given unless they are really needed, and we cannot exclude the possibility that unnecessary use of antibiotics may be exposing people to an increased risk of cancer,” he concluded.
Similar comments were made by Thomas Seufferlein, MD, department of internal medicine, Ulm University, Germany, who discussed the findings.
He agreed with the authors “that careful use of antibiotics is sensible and paramount” but added that more studies are needed on this suggestion of a link between antibiotic use and the observed increase in early CRC.
Study details
Previous studies have demonstrated that, in older adults, significant alterations in the structure and diversity of the gut microbiome induced by antibiotic therapy influence the development of colorectal cancer.
However, Ms. Perrott said that the impact of antibiotic use on early onset colorectal cancer has not been investigated.
The researchers therefore conducted a nested case-control study of primary care records to identify colorectal cancer cases diagnosed in Scotland between 1999 and 2011.
Patients were divided into those diagnosed before 50 years of age and those diagnosed at 50 years and older and matched with up to five healthy controls.
The study included 7,903 CRC cases, of which 5,281 were colon cancer and 2,622 rectal cancer, alongside 30,418 controls.
Among the CRC patients, 445 (5.6%) were under 50 years of age at diagnosis.
The team also analyzed antibiotic use history. Prescriptions for oral antibiotics, stratified by drug class and by anaerobic/nonanaerobic effect, were extracted, and the total antibiotic exposure period was calculated and categorized as 0, 1-15, 16-60, and >60 days.
Overall, 45% of the patients were prescribed antibiotics. Any antibiotic use was associated with a significantly increased risk of colon cancer, but this was most pronounced in patients aged less than 50 years at diagnosis.
Specifically, any antibiotic use was associated with an adjusted odds ratio of colon cancer of 1.49 (P = .018) in patients aged less than 50 years versus 1.09 (P = .029) in those aged 50 years and over.
In younger patients, the largest association between antibiotic use and colon cancer was seen in patients with a total antibiotic exposure of 1-15 days (at an adjusted odds ratio of 1.55), falling to 1.46 with 16-60 days of exposure, and no association for >60 days exposure.
No such relationship was seen in patients with colon cancer aged 50 years and over at diagnosis.
There was also no significant relationship between any antibiotic use and the occurrence of rectal cancer, at an adjusted odds ratio of 1.17 (P = .493) in those aged under 50 years at diagnosis and 1.07 (P = .698) in older patients.
The study was supported by Cancer Research UK. Ms. Perrott, Dr. Sobrero, and Dr. Samuels declared having no conflicts of interest. Dr. Seufferlien has reported relationships with Amgen, Bayer, Merck, Sanofi, Celgene, Shire, Roche, Falk Foundation, AstraZeneca, Lilly, Merck-Serono, Servier, Pierre Fabre, Cantargia, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
Exposure to antibiotics appears to be associated with the development of colon cancer, particularly in younger people, and could be contributing to the increase in early-onset colorectal cancer (CRC) that is being documented, say U.K. researchers.
The team conducted a nested case-control study using data from primary care in Scotland, which involved almost 8,000 cases of CRC and over 30,000 healthy controls.
The analysis suggests that a history of antibiotic use among individuals younger than 50 appeared to increase the risk of developing colon cancer (but not rectal) by 49%.
“To our knowledge, this is the first study to link antibiotic use with the growing risk of early onset colon cancer, a disease which has been increasing at a rate of at least 3% per year over the last two decades,” said study presenter Sarah Perrott, a medical student at the University of Aberdeen, Scotland.
“Junk food, sugary drinks, obesity, and alcohol are likely to have played a part in that rise, but our data stress the importance of avoiding unnecessary antibiotics, especially in children and young adults,” Ms. Perrott said in a statement.
“We now want to find out if there is a link between antibiotic use and changes in the microbiome which can make the colon more susceptible to cancer, especially in younger people,” added senior author Leslie Samuel, MD, consultant oncologist at Aberdeen Royal Infirmary.
“It’s a complex situation, as we know that the microbiome can quickly revert to its previous state, even when the bowel has been cleared out for a diagnostic procedure,” Dr. Samuel continued.
The research was presented on July 2 at the European Society for Medical Oncology Congress 2021.
Commenting for ESMO, Alberto Sobrero, MD, PhD, Medical Oncology Unit, Ospedale San Martino, Genoa, Italy, said that younger patients with colon cancer typically have a worse prognosis than older people because they are generally diagnosed later.
“Physicians are less likely to investigate a patient with abdominal discomfort for colon cancer if they are in their 30s than if they are in their 70s, and younger patients are not eligible for bowel cancer screening,” he explained.
However, Dr. Sobrero believes it is “too early to say if excessive use of antibiotics could be a causative factor, and we need to understand more about the possible role of the microbiome in bowel cancer before we consider the impact of antibiotics on the intestinal flora.”
The results, nevertheless, “remind us that antibiotics should not be given unless they are really needed, and we cannot exclude the possibility that unnecessary use of antibiotics may be exposing people to an increased risk of cancer,” he concluded.
Similar comments were made by Thomas Seufferlein, MD, department of internal medicine, Ulm University, Germany, who discussed the findings.
He agreed with the authors “that careful use of antibiotics is sensible and paramount” but added that more studies are needed on this suggestion of a link between antibiotic use and the observed increase in early CRC.
Study details
Previous studies have demonstrated that, in older adults, significant alterations in the structure and diversity of the gut microbiome induced by antibiotic therapy influence the development of colorectal cancer.
However, Ms. Perrott said that the impact of antibiotic use on early onset colorectal cancer has not been investigated.
The researchers therefore conducted a nested case-control study of primary care records to identify colorectal cancer cases diagnosed in Scotland between 1999 and 2011.
Patients were divided into those diagnosed before 50 years of age and those diagnosed at 50 years and older and matched with up to five healthy controls.
The study included 7,903 CRC cases, of which 5,281 were colon cancer and 2,622 rectal cancer, alongside 30,418 controls.
Among the CRC patients, 445 (5.6%) were under 50 years of age at diagnosis.
The team also analyzed antibiotic use history. Prescriptions for oral antibiotics, stratified by drug class and by anaerobic/nonanaerobic effect, were extracted, and the total antibiotic exposure period was calculated and categorized as 0, 1-15, 16-60, and >60 days.
Overall, 45% of the patients were prescribed antibiotics. Any antibiotic use was associated with a significantly increased risk of colon cancer, but this was most pronounced in patients aged less than 50 years at diagnosis.
Specifically, any antibiotic use was associated with an adjusted odds ratio of colon cancer of 1.49 (P = .018) in patients aged less than 50 years versus 1.09 (P = .029) in those aged 50 years and over.
In younger patients, the largest association between antibiotic use and colon cancer was seen in patients with a total antibiotic exposure of 1-15 days (at an adjusted odds ratio of 1.55), falling to 1.46 with 16-60 days of exposure, and no association for >60 days exposure.
No such relationship was seen in patients with colon cancer aged 50 years and over at diagnosis.
There was also no significant relationship between any antibiotic use and the occurrence of rectal cancer, at an adjusted odds ratio of 1.17 (P = .493) in those aged under 50 years at diagnosis and 1.07 (P = .698) in older patients.
The study was supported by Cancer Research UK. Ms. Perrott, Dr. Sobrero, and Dr. Samuels declared having no conflicts of interest. Dr. Seufferlien has reported relationships with Amgen, Bayer, Merck, Sanofi, Celgene, Shire, Roche, Falk Foundation, AstraZeneca, Lilly, Merck-Serono, Servier, Pierre Fabre, Cantargia, and Boehringer Ingelheim.
A version of this article first appeared on Medscape.com.
EAS lipid guidance: Start high-risk patients on combo drug
Very-high-risk dyslipidemia patients unlikely to reach goal with a statin should be given combination statin–ezetimibe (Nustendi) therapy upfront, rather than wasting time and resources on trialing a statin alone, suggests a practical guidance document.
The document points out that, even with high-intensity statin therapy, patients achieve a reduction in low-density-lipoprotein (LDL) cholesterol levels of around 50%, which for many is not enough for them to achieve the stringent new guideline targets deemed necessary for risk reduction.
Instead, clinicians should determine at the first visit whether their patient, if they are not already on a statin, is likely to reach their goal with that drug alone, and if not, should immediately start them on the combination.
The guidance, which aims to offer a practical way to implement the 2019 European Society of Cardiology/EAS guidelines for the management of dyslipidemias, was published April 12 in Atherosclerosis .
Lead author Alberico L. Catapano, MD, PhD, discussed the new practical guidance at the recent European Atherosclerosis Society (EAS) 2021 Virtual Congress.
He explained that the motivation for creating the practical guidance was “very simple” and concerns something already embedded in the ESC/EAS guidelines; it’s just that “people didn’t notice” it.
Dr. Catapano, professor of pharmacology at the University of Milan and past president of the EAS, said the guidelines set out the average reduction in LDL-cholesterol levels “you can get by starting with high-intensity therapy and/or starting with a combination therapy.”
The guidelines, he said, suggest steps for achieving lipid control: Begin with a statin, add ezetimibe if the patient is still not at goal, and proceed to a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor if the patient is still not at target levels.
Dr. Catapano added that, “having said that, at the beginning, you can guess by knowing how far you are from the goal as to whether a statin by itself with help you get [there].”
If clinicians follow the new practical guidance of giving upfront combination statin–ezetimibe therapy in very-high-risk patients with high LDL-cholesterol levels, it will “save a lot of time, a lot of clinic visits, and will you get you to goal earlier.”
He gave the example of a patient who has an LDL-cholesterol level of 190 mg/dL, who would be classified as being at very high risk. With the target goal of 55 mg/dL, “you would never be able to get them to goal [with only] a high-intensity statin.”
The addition of ezetimibe to the regimen of this patient would have two advantages, Dr. Catapano said. The first is that “you get to goal more easily,” and the second is that, with the drugs available as a single-pill combination, it “makes it easier for the patient to be compliant.”
Consequently, there will be no “unnecessary back and forth,” he said. “Some of these are young people. They go to work; one less visit is less time lost at work.
“This is a practical issue,” he added. “It doesn’t contradict the guidelines,” it’s about “everyday clinical practice.”
Useful between updates
Responding to the guidance, Donald Lloyd-Jones, MD, president-elect of the American Heart Association (AHA), told this news organization that “this kind of document can be useful in periods between updates of the formal guidelines.”
New evidence comes out in between guidelines, and they “don’t often provide us with all of the practical solutions needed for everyday guidance when we’re dealing with individual patients with real-world problems.”
Dr. Lloyd-Jones, who is chair of the Department of Preventive Medicine at Northwestern University, Chicago, said the 2019 ESC/EAS guidelines set “quite aggressive targets, particularly for LDL cholesterol … but didn’t really provide much practical advice on how clinicians could get there for their patients.”
“While this document doesn’t completely address all patient groups, it does provide some good practical advice,” recognizing that “if you need to get to a certain LDL target, it’s unlikely you’re going to get there with just a statin in certain types of patients,” and “if you need a certain amount of LDL lowering, it’s certainly reasonable to start upfront with a statin and ezetimibe and see how you do.”
Crucially, Dr. Lloyd-Jones believes that the practical guidance does “flesh out some of the details the guidelines didn’t address.”
In terms of the aggressive LDL-cholesterol targets set out in the original guidelines, he said that “everyone agrees that lower is always better … and we’ve not get yet found a level that is too low.”
Further, “we’re certainly pushing patients lower and lower, especially with the use of PCSK9 inhibitors, so I think the general philosophy is consistent and correct,” although “it’s difficult to point to great evidence from clinical trials that specially says that 55 mg/dL or 40 mg/dL is the right target for a given group of patients.”
“There’s really very limited evidence for those specific numbers,” Dr. Lloyd-Jones added, “but I think everyone agrees, especially for patients at higher risk, the lower we can get them the better. What really matters, and what this document starts to address, is how we achieve as low as possible, and I think there are some important considerations that they take into account.”
Aside from how far patients need their LDL cholesterol lowered from baseline, there are issues like cost and patient preference for different types of medication, and these “weren’t particularly well addressed in the guidelines,” he added.
Scott D. Isaacs, MD, Secretary of the American Association of Clinical Endocrinologists (AACE), commented that the ESC/EAS recommendations echo the 2017 AACE/American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease.
He said that both guidelines “call for the need to lower LDL cholesterol as much as possible to prevent cardiovascular disease.”
He agreed, however, that high- or very-high-risk patients “have aggressive LDL targets that are often lower than what can be accomplished with high-dose, high-intensity statin monotherapy. Therefore, starting with combination therapy … will get more patients to goal more quickly and will prevent more cardiovascular events.”
Isaacs added: “It just makes sense that if you know a drug will not be strong enough, then you should start with two drugs.”
He noted that this approach is commonly used for conditions such as diabetes and hypertension, “when monotherapy is not expected to achieve the desired results.”
Dr. Isaacs also underlined that the combination of a statin plus ezetimibe “is appealing because of the price and ease of use.”
Although PCSK9 inhibitors are more potent and achieve even lower LDL levels, “the higher price and need to take an injection has limited their use,” he noted.
“One would expect that as the prices of PCSK9 inhibitors come down, their place in care pathways will move up since they are more effective and have proven cardiovascular benefit, but for now, statin plus ezetimibe is a potent and cost-effective way to achieve LDL targets in high- and very-high-risk patients,” Dr. Isaacs concluded.
One issue Dr. Lloyd-Jones raised with the ESC/EAS guidelines is that they seem to have put a lot of weight Mendelian randomization analysis.
“Those are useful in understanding whether having low LDL-cholesterol levels or triglycerides naturally are better for you – of course they are – but they actually provide no evidence about treatment effects, so I think what we need from that is actual data from the clinical trials to understand the treatment effects, both positive and negative.”
He added that that “really then helps us to drive to how and in whom we want to achieve the lowest levels possible.”
Dr. Lloyd-Jones said that Mendelian randomization analyses “continue to crop in a lot of these ESC and EAS documents,” and although they are “elegant and interesting,” they “don’t really inform treatment at all.”
No funding declared. Catapano declares relationships with Pfizer, Sanofi, Regeneron, Merck, Mediolanum, SigmaTau, Menarini, Kowa, Recordati, Eli Lilly, AstraZeneca, Merck, Aegerion and Amgen.
A version of this article first appeared on Medscape.com.
Very-high-risk dyslipidemia patients unlikely to reach goal with a statin should be given combination statin–ezetimibe (Nustendi) therapy upfront, rather than wasting time and resources on trialing a statin alone, suggests a practical guidance document.
The document points out that, even with high-intensity statin therapy, patients achieve a reduction in low-density-lipoprotein (LDL) cholesterol levels of around 50%, which for many is not enough for them to achieve the stringent new guideline targets deemed necessary for risk reduction.
Instead, clinicians should determine at the first visit whether their patient, if they are not already on a statin, is likely to reach their goal with that drug alone, and if not, should immediately start them on the combination.
The guidance, which aims to offer a practical way to implement the 2019 European Society of Cardiology/EAS guidelines for the management of dyslipidemias, was published April 12 in Atherosclerosis .
Lead author Alberico L. Catapano, MD, PhD, discussed the new practical guidance at the recent European Atherosclerosis Society (EAS) 2021 Virtual Congress.
He explained that the motivation for creating the practical guidance was “very simple” and concerns something already embedded in the ESC/EAS guidelines; it’s just that “people didn’t notice” it.
Dr. Catapano, professor of pharmacology at the University of Milan and past president of the EAS, said the guidelines set out the average reduction in LDL-cholesterol levels “you can get by starting with high-intensity therapy and/or starting with a combination therapy.”
The guidelines, he said, suggest steps for achieving lipid control: Begin with a statin, add ezetimibe if the patient is still not at goal, and proceed to a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor if the patient is still not at target levels.
Dr. Catapano added that, “having said that, at the beginning, you can guess by knowing how far you are from the goal as to whether a statin by itself with help you get [there].”
If clinicians follow the new practical guidance of giving upfront combination statin–ezetimibe therapy in very-high-risk patients with high LDL-cholesterol levels, it will “save a lot of time, a lot of clinic visits, and will you get you to goal earlier.”
He gave the example of a patient who has an LDL-cholesterol level of 190 mg/dL, who would be classified as being at very high risk. With the target goal of 55 mg/dL, “you would never be able to get them to goal [with only] a high-intensity statin.”
The addition of ezetimibe to the regimen of this patient would have two advantages, Dr. Catapano said. The first is that “you get to goal more easily,” and the second is that, with the drugs available as a single-pill combination, it “makes it easier for the patient to be compliant.”
Consequently, there will be no “unnecessary back and forth,” he said. “Some of these are young people. They go to work; one less visit is less time lost at work.
“This is a practical issue,” he added. “It doesn’t contradict the guidelines,” it’s about “everyday clinical practice.”
Useful between updates
Responding to the guidance, Donald Lloyd-Jones, MD, president-elect of the American Heart Association (AHA), told this news organization that “this kind of document can be useful in periods between updates of the formal guidelines.”
New evidence comes out in between guidelines, and they “don’t often provide us with all of the practical solutions needed for everyday guidance when we’re dealing with individual patients with real-world problems.”
Dr. Lloyd-Jones, who is chair of the Department of Preventive Medicine at Northwestern University, Chicago, said the 2019 ESC/EAS guidelines set “quite aggressive targets, particularly for LDL cholesterol … but didn’t really provide much practical advice on how clinicians could get there for their patients.”
“While this document doesn’t completely address all patient groups, it does provide some good practical advice,” recognizing that “if you need to get to a certain LDL target, it’s unlikely you’re going to get there with just a statin in certain types of patients,” and “if you need a certain amount of LDL lowering, it’s certainly reasonable to start upfront with a statin and ezetimibe and see how you do.”
Crucially, Dr. Lloyd-Jones believes that the practical guidance does “flesh out some of the details the guidelines didn’t address.”
In terms of the aggressive LDL-cholesterol targets set out in the original guidelines, he said that “everyone agrees that lower is always better … and we’ve not get yet found a level that is too low.”
Further, “we’re certainly pushing patients lower and lower, especially with the use of PCSK9 inhibitors, so I think the general philosophy is consistent and correct,” although “it’s difficult to point to great evidence from clinical trials that specially says that 55 mg/dL or 40 mg/dL is the right target for a given group of patients.”
“There’s really very limited evidence for those specific numbers,” Dr. Lloyd-Jones added, “but I think everyone agrees, especially for patients at higher risk, the lower we can get them the better. What really matters, and what this document starts to address, is how we achieve as low as possible, and I think there are some important considerations that they take into account.”
Aside from how far patients need their LDL cholesterol lowered from baseline, there are issues like cost and patient preference for different types of medication, and these “weren’t particularly well addressed in the guidelines,” he added.
Scott D. Isaacs, MD, Secretary of the American Association of Clinical Endocrinologists (AACE), commented that the ESC/EAS recommendations echo the 2017 AACE/American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease.
He said that both guidelines “call for the need to lower LDL cholesterol as much as possible to prevent cardiovascular disease.”
He agreed, however, that high- or very-high-risk patients “have aggressive LDL targets that are often lower than what can be accomplished with high-dose, high-intensity statin monotherapy. Therefore, starting with combination therapy … will get more patients to goal more quickly and will prevent more cardiovascular events.”
Isaacs added: “It just makes sense that if you know a drug will not be strong enough, then you should start with two drugs.”
He noted that this approach is commonly used for conditions such as diabetes and hypertension, “when monotherapy is not expected to achieve the desired results.”
Dr. Isaacs also underlined that the combination of a statin plus ezetimibe “is appealing because of the price and ease of use.”
Although PCSK9 inhibitors are more potent and achieve even lower LDL levels, “the higher price and need to take an injection has limited their use,” he noted.
“One would expect that as the prices of PCSK9 inhibitors come down, their place in care pathways will move up since they are more effective and have proven cardiovascular benefit, but for now, statin plus ezetimibe is a potent and cost-effective way to achieve LDL targets in high- and very-high-risk patients,” Dr. Isaacs concluded.
One issue Dr. Lloyd-Jones raised with the ESC/EAS guidelines is that they seem to have put a lot of weight Mendelian randomization analysis.
“Those are useful in understanding whether having low LDL-cholesterol levels or triglycerides naturally are better for you – of course they are – but they actually provide no evidence about treatment effects, so I think what we need from that is actual data from the clinical trials to understand the treatment effects, both positive and negative.”
He added that that “really then helps us to drive to how and in whom we want to achieve the lowest levels possible.”
Dr. Lloyd-Jones said that Mendelian randomization analyses “continue to crop in a lot of these ESC and EAS documents,” and although they are “elegant and interesting,” they “don’t really inform treatment at all.”
No funding declared. Catapano declares relationships with Pfizer, Sanofi, Regeneron, Merck, Mediolanum, SigmaTau, Menarini, Kowa, Recordati, Eli Lilly, AstraZeneca, Merck, Aegerion and Amgen.
A version of this article first appeared on Medscape.com.
Very-high-risk dyslipidemia patients unlikely to reach goal with a statin should be given combination statin–ezetimibe (Nustendi) therapy upfront, rather than wasting time and resources on trialing a statin alone, suggests a practical guidance document.
The document points out that, even with high-intensity statin therapy, patients achieve a reduction in low-density-lipoprotein (LDL) cholesterol levels of around 50%, which for many is not enough for them to achieve the stringent new guideline targets deemed necessary for risk reduction.
Instead, clinicians should determine at the first visit whether their patient, if they are not already on a statin, is likely to reach their goal with that drug alone, and if not, should immediately start them on the combination.
The guidance, which aims to offer a practical way to implement the 2019 European Society of Cardiology/EAS guidelines for the management of dyslipidemias, was published April 12 in Atherosclerosis .
Lead author Alberico L. Catapano, MD, PhD, discussed the new practical guidance at the recent European Atherosclerosis Society (EAS) 2021 Virtual Congress.
He explained that the motivation for creating the practical guidance was “very simple” and concerns something already embedded in the ESC/EAS guidelines; it’s just that “people didn’t notice” it.
Dr. Catapano, professor of pharmacology at the University of Milan and past president of the EAS, said the guidelines set out the average reduction in LDL-cholesterol levels “you can get by starting with high-intensity therapy and/or starting with a combination therapy.”
The guidelines, he said, suggest steps for achieving lipid control: Begin with a statin, add ezetimibe if the patient is still not at goal, and proceed to a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor if the patient is still not at target levels.
Dr. Catapano added that, “having said that, at the beginning, you can guess by knowing how far you are from the goal as to whether a statin by itself with help you get [there].”
If clinicians follow the new practical guidance of giving upfront combination statin–ezetimibe therapy in very-high-risk patients with high LDL-cholesterol levels, it will “save a lot of time, a lot of clinic visits, and will you get you to goal earlier.”
He gave the example of a patient who has an LDL-cholesterol level of 190 mg/dL, who would be classified as being at very high risk. With the target goal of 55 mg/dL, “you would never be able to get them to goal [with only] a high-intensity statin.”
The addition of ezetimibe to the regimen of this patient would have two advantages, Dr. Catapano said. The first is that “you get to goal more easily,” and the second is that, with the drugs available as a single-pill combination, it “makes it easier for the patient to be compliant.”
Consequently, there will be no “unnecessary back and forth,” he said. “Some of these are young people. They go to work; one less visit is less time lost at work.
“This is a practical issue,” he added. “It doesn’t contradict the guidelines,” it’s about “everyday clinical practice.”
Useful between updates
Responding to the guidance, Donald Lloyd-Jones, MD, president-elect of the American Heart Association (AHA), told this news organization that “this kind of document can be useful in periods between updates of the formal guidelines.”
New evidence comes out in between guidelines, and they “don’t often provide us with all of the practical solutions needed for everyday guidance when we’re dealing with individual patients with real-world problems.”
Dr. Lloyd-Jones, who is chair of the Department of Preventive Medicine at Northwestern University, Chicago, said the 2019 ESC/EAS guidelines set “quite aggressive targets, particularly for LDL cholesterol … but didn’t really provide much practical advice on how clinicians could get there for their patients.”
“While this document doesn’t completely address all patient groups, it does provide some good practical advice,” recognizing that “if you need to get to a certain LDL target, it’s unlikely you’re going to get there with just a statin in certain types of patients,” and “if you need a certain amount of LDL lowering, it’s certainly reasonable to start upfront with a statin and ezetimibe and see how you do.”
Crucially, Dr. Lloyd-Jones believes that the practical guidance does “flesh out some of the details the guidelines didn’t address.”
In terms of the aggressive LDL-cholesterol targets set out in the original guidelines, he said that “everyone agrees that lower is always better … and we’ve not get yet found a level that is too low.”
Further, “we’re certainly pushing patients lower and lower, especially with the use of PCSK9 inhibitors, so I think the general philosophy is consistent and correct,” although “it’s difficult to point to great evidence from clinical trials that specially says that 55 mg/dL or 40 mg/dL is the right target for a given group of patients.”
“There’s really very limited evidence for those specific numbers,” Dr. Lloyd-Jones added, “but I think everyone agrees, especially for patients at higher risk, the lower we can get them the better. What really matters, and what this document starts to address, is how we achieve as low as possible, and I think there are some important considerations that they take into account.”
Aside from how far patients need their LDL cholesterol lowered from baseline, there are issues like cost and patient preference for different types of medication, and these “weren’t particularly well addressed in the guidelines,” he added.
Scott D. Isaacs, MD, Secretary of the American Association of Clinical Endocrinologists (AACE), commented that the ESC/EAS recommendations echo the 2017 AACE/American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease.
He said that both guidelines “call for the need to lower LDL cholesterol as much as possible to prevent cardiovascular disease.”
He agreed, however, that high- or very-high-risk patients “have aggressive LDL targets that are often lower than what can be accomplished with high-dose, high-intensity statin monotherapy. Therefore, starting with combination therapy … will get more patients to goal more quickly and will prevent more cardiovascular events.”
Isaacs added: “It just makes sense that if you know a drug will not be strong enough, then you should start with two drugs.”
He noted that this approach is commonly used for conditions such as diabetes and hypertension, “when monotherapy is not expected to achieve the desired results.”
Dr. Isaacs also underlined that the combination of a statin plus ezetimibe “is appealing because of the price and ease of use.”
Although PCSK9 inhibitors are more potent and achieve even lower LDL levels, “the higher price and need to take an injection has limited their use,” he noted.
“One would expect that as the prices of PCSK9 inhibitors come down, their place in care pathways will move up since they are more effective and have proven cardiovascular benefit, but for now, statin plus ezetimibe is a potent and cost-effective way to achieve LDL targets in high- and very-high-risk patients,” Dr. Isaacs concluded.
One issue Dr. Lloyd-Jones raised with the ESC/EAS guidelines is that they seem to have put a lot of weight Mendelian randomization analysis.
“Those are useful in understanding whether having low LDL-cholesterol levels or triglycerides naturally are better for you – of course they are – but they actually provide no evidence about treatment effects, so I think what we need from that is actual data from the clinical trials to understand the treatment effects, both positive and negative.”
He added that that “really then helps us to drive to how and in whom we want to achieve the lowest levels possible.”
Dr. Lloyd-Jones said that Mendelian randomization analyses “continue to crop in a lot of these ESC and EAS documents,” and although they are “elegant and interesting,” they “don’t really inform treatment at all.”
No funding declared. Catapano declares relationships with Pfizer, Sanofi, Regeneron, Merck, Mediolanum, SigmaTau, Menarini, Kowa, Recordati, Eli Lilly, AstraZeneca, Merck, Aegerion and Amgen.
A version of this article first appeared on Medscape.com.
Simple risk assessment predicts post-PCI ischemic events
A patient’s risk for ischemic events, but not bleeding, after percutaneous coronary intervention (PCI) can be predicted simply based on whether they have one or more guideline-based standardized risk criteria, a large-scale real-world analysis suggests.
Haoyu Wang, MD, and colleagues showed that having at least one high-risk feature, as outlined in the 2018 European Society of Cardiology and European Association for Cardiothoracic Surgery (ESC/EACTS) Guidelines on Myocardial Revascularization, was associated with an increased risk for target vessel failure by 48% and for a patient-oriented composite outcome by 44%.
Moreover, they showed that implantation of at least three stents and the presence of diabetes and diffuse multivessel disease were the only high-risk features from the guidelines that were independent predictors of the two outcomes.
The study of more than 10,000 PCI patients also showed that determining whether patients were at high bleeding risk (HBR) did not modify their ischemic risk.
This, said Dr. Wang, from the National Center for Cardiovascular Diseases, Fuwai Hospital, Beijing, underscores the importance of applying the high ischemic risk (HIR) criteria from the ESC/EACTS guidelines when tailoring dual antiplatelet therapy (DAPT).
The research was presented at the European Atherosclerosis Society 2021 Virtual Congress on June 2, and published online in the Journal of Atherosclerosis and Thrombosis.
Dr. Wang told theheart.org | Medscape Cardiology that they conducted the study to determine which – HIR or HBR – is “most important to balance when treating patients undergoing PCI and then having dual antiplatelet therapy.”
The results showed that when patients have both a HIR and HBR, it is the ESC/EACTS guideline HIR criteria that have “a higher impact” than the bleeding risk, and that this can be “used to guide our choice of the duration of dual anti-platelet therapy.”
“Maybe we can extend, or use more potent, P2Y12 inhibitors” in those situations, he said.
S. Lale Tokgözoglu, MD, PhD, professor of cardiology, Hacettepe University, Ankara, Turkey, who was not involved in the study, said the HIR assessment “performed well,” adding that the HBR score might have been expected to attenuate its “prognostic advantage.”
She told this news organization that the results “are interesting since previous observations have suggested that Asian patients may be more prone to medication side effects and bleeding.”
These findings emphasize the importance of assessing HIR in daily PCI practice and confirm that it “performs well in different populations in real life,” added Dr. Tokgözoglu, a former president of the EAS.
The ESC/EACTS guidelines aimed to standardize the definition of HIR, Dr. Wang said during the presentation.
They set out 10 high-risk features for ischemic events for patients undergoing revascularization, which included patient medical history, comorbid conditions, and the characteristics of the PCI procedure.
Although the goals of the criteria are to inform decision-making and stimulate research, Dr. Wang said that their “prevalence and prognostic association with clinical outcomes are yet to be established in real-world PCI practice.”
Alongside, the Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score was developed to predict out-of-hospital bleeding in patients receiving DAPT after stent implantation.
Although a PRECISE-DAPT score of at least 25 constitutes a patient at high bleeding risk, Dr. Wang pointed out that such patients are typically also at risk for ischemic events after PCI, and it is “unclear” whether being at HBR modifies this risk.
To investigate further, they used the prospective, real-world Fuwai PCI registry to collate an all-comer patient population with unselected use of drug-eluting stents at the National Center for Cardiovascular Diseases at Fuwai Hospital.
They excluded individuals who were treated with balloon angioplasty alone, bioresorbable scaffolds, or bare metal stents, leaving a total population of 10,167 patients who were treated in 2013.
In that cohort, 5,149 patients (50.6%) met at least one risk criterion from the ESC/EACTS guidelines (HIR patients) and 5,018 (49.4%) met none of the risk criteria (non-HIR patients).
The most common criteria were implantation of at least three stents (23.5%); total stent length greater than 60 mm (20.2%); diffuse multivessel disease, especially in diabetic patients (18.5%); and a history of ST-segment elevation myocardial infarction (13.9%).
HIR patients were significantly older than non-HIR patients (average age, 58.86 vs. 57.77 years; P < .001), were more likely to have diabetes mellitus (42.6% vs. 16.9%; P < .001); and were more likely to have already had a myocardial infarction (32.2% vs. 5.2%; P < .001).
HIR patients also had higher average PRECISE-ADAPT scores than those without HIR (11.22 vs. 9.94; P < .001), and were conversely less likely to have the left anterior descending artery as the target vessel than non-HIR patients (86.0% vs. 94.6%; P < .001).
Cox regression analysis taking into account a range of patient and clinical factors revealed that HIR patients were significantly more likely than their non-HIR counterparts to experience target vessel failure (hazard ratio, 1.48; 95% confidence interval, 1.25-1.74; P < .001).
They were also significantly more likely to have a patient-oriented composite outcome, defined as all-cause death, any myocardial infarction, or any revascularization (HR, 1.44; 95% CI, 1.28-1.63; P < .001).
There was also a significantly higher risk for cardiac death in HIR than in non-HIR patients (HR, 1.95; 95% CI, 1.16-3.29; P = .012).
However, there was no significant association between HIR status and clinically relevant bleeding (HR, 0.84; 95% CI, 0.66-1.06; P = .143).
When the researchers looked at individual ischemic risk features, they found that, on fully adjusted analyses, only two were independent predictors of target vessel failure and the patient-oriented composite outcome.
Having at least three stents implanted was significantly associated with target vessel failure (HR, 1.36; 95% CI, 1.02-1.80; P = .038), and borderline significantly associated with the patient oriented composite outcome (HR, 1.23; 95% CI, 1.00-1.53; P = .056).
Diffuse multivessel disease, especially in diabetic patients, was significantly associated with both target vessel failure (HR, 1.24; 95% CI, 1.02-1.51; P = .035) and with the patient-oriented composite outcome (HR, 1.20; 95% CI, 1.04-1.39; P = .012).
Neither risk feature was significantly associated with clinically relevant bleeding, Dr. Wang noted.
Stratifying the patients by HBR status, the team found that rates of target vessel failure, the patient-oriented composite outcome, cardiac death, myocardial infarction, and definite/probable stent thrombosis were higher in patients with both HIR and HBR than those with neither HIR nor HBR (P < .001).
Further stratifying patients by PRECISE-ADAPT scores – 10 or less indicating very low risk, 11-17 indicating low risk, 18-24 indicating moderate risk, and at least 25 indicating high risk – showed that HIR features had a consistent effect on ischemic and bleeding outcomes, regardless of bleeding risk.
No funding declared. No relevant financial relationships declared.
A version of this article first appeared on Medscape.com.
A patient’s risk for ischemic events, but not bleeding, after percutaneous coronary intervention (PCI) can be predicted simply based on whether they have one or more guideline-based standardized risk criteria, a large-scale real-world analysis suggests.
Haoyu Wang, MD, and colleagues showed that having at least one high-risk feature, as outlined in the 2018 European Society of Cardiology and European Association for Cardiothoracic Surgery (ESC/EACTS) Guidelines on Myocardial Revascularization, was associated with an increased risk for target vessel failure by 48% and for a patient-oriented composite outcome by 44%.
Moreover, they showed that implantation of at least three stents and the presence of diabetes and diffuse multivessel disease were the only high-risk features from the guidelines that were independent predictors of the two outcomes.
The study of more than 10,000 PCI patients also showed that determining whether patients were at high bleeding risk (HBR) did not modify their ischemic risk.
This, said Dr. Wang, from the National Center for Cardiovascular Diseases, Fuwai Hospital, Beijing, underscores the importance of applying the high ischemic risk (HIR) criteria from the ESC/EACTS guidelines when tailoring dual antiplatelet therapy (DAPT).
The research was presented at the European Atherosclerosis Society 2021 Virtual Congress on June 2, and published online in the Journal of Atherosclerosis and Thrombosis.
Dr. Wang told theheart.org | Medscape Cardiology that they conducted the study to determine which – HIR or HBR – is “most important to balance when treating patients undergoing PCI and then having dual antiplatelet therapy.”
The results showed that when patients have both a HIR and HBR, it is the ESC/EACTS guideline HIR criteria that have “a higher impact” than the bleeding risk, and that this can be “used to guide our choice of the duration of dual anti-platelet therapy.”
“Maybe we can extend, or use more potent, P2Y12 inhibitors” in those situations, he said.
S. Lale Tokgözoglu, MD, PhD, professor of cardiology, Hacettepe University, Ankara, Turkey, who was not involved in the study, said the HIR assessment “performed well,” adding that the HBR score might have been expected to attenuate its “prognostic advantage.”
She told this news organization that the results “are interesting since previous observations have suggested that Asian patients may be more prone to medication side effects and bleeding.”
These findings emphasize the importance of assessing HIR in daily PCI practice and confirm that it “performs well in different populations in real life,” added Dr. Tokgözoglu, a former president of the EAS.
The ESC/EACTS guidelines aimed to standardize the definition of HIR, Dr. Wang said during the presentation.
They set out 10 high-risk features for ischemic events for patients undergoing revascularization, which included patient medical history, comorbid conditions, and the characteristics of the PCI procedure.
Although the goals of the criteria are to inform decision-making and stimulate research, Dr. Wang said that their “prevalence and prognostic association with clinical outcomes are yet to be established in real-world PCI practice.”
Alongside, the Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score was developed to predict out-of-hospital bleeding in patients receiving DAPT after stent implantation.
Although a PRECISE-DAPT score of at least 25 constitutes a patient at high bleeding risk, Dr. Wang pointed out that such patients are typically also at risk for ischemic events after PCI, and it is “unclear” whether being at HBR modifies this risk.
To investigate further, they used the prospective, real-world Fuwai PCI registry to collate an all-comer patient population with unselected use of drug-eluting stents at the National Center for Cardiovascular Diseases at Fuwai Hospital.
They excluded individuals who were treated with balloon angioplasty alone, bioresorbable scaffolds, or bare metal stents, leaving a total population of 10,167 patients who were treated in 2013.
In that cohort, 5,149 patients (50.6%) met at least one risk criterion from the ESC/EACTS guidelines (HIR patients) and 5,018 (49.4%) met none of the risk criteria (non-HIR patients).
The most common criteria were implantation of at least three stents (23.5%); total stent length greater than 60 mm (20.2%); diffuse multivessel disease, especially in diabetic patients (18.5%); and a history of ST-segment elevation myocardial infarction (13.9%).
HIR patients were significantly older than non-HIR patients (average age, 58.86 vs. 57.77 years; P < .001), were more likely to have diabetes mellitus (42.6% vs. 16.9%; P < .001); and were more likely to have already had a myocardial infarction (32.2% vs. 5.2%; P < .001).
HIR patients also had higher average PRECISE-ADAPT scores than those without HIR (11.22 vs. 9.94; P < .001), and were conversely less likely to have the left anterior descending artery as the target vessel than non-HIR patients (86.0% vs. 94.6%; P < .001).
Cox regression analysis taking into account a range of patient and clinical factors revealed that HIR patients were significantly more likely than their non-HIR counterparts to experience target vessel failure (hazard ratio, 1.48; 95% confidence interval, 1.25-1.74; P < .001).
They were also significantly more likely to have a patient-oriented composite outcome, defined as all-cause death, any myocardial infarction, or any revascularization (HR, 1.44; 95% CI, 1.28-1.63; P < .001).
There was also a significantly higher risk for cardiac death in HIR than in non-HIR patients (HR, 1.95; 95% CI, 1.16-3.29; P = .012).
However, there was no significant association between HIR status and clinically relevant bleeding (HR, 0.84; 95% CI, 0.66-1.06; P = .143).
When the researchers looked at individual ischemic risk features, they found that, on fully adjusted analyses, only two were independent predictors of target vessel failure and the patient-oriented composite outcome.
Having at least three stents implanted was significantly associated with target vessel failure (HR, 1.36; 95% CI, 1.02-1.80; P = .038), and borderline significantly associated with the patient oriented composite outcome (HR, 1.23; 95% CI, 1.00-1.53; P = .056).
Diffuse multivessel disease, especially in diabetic patients, was significantly associated with both target vessel failure (HR, 1.24; 95% CI, 1.02-1.51; P = .035) and with the patient-oriented composite outcome (HR, 1.20; 95% CI, 1.04-1.39; P = .012).
Neither risk feature was significantly associated with clinically relevant bleeding, Dr. Wang noted.
Stratifying the patients by HBR status, the team found that rates of target vessel failure, the patient-oriented composite outcome, cardiac death, myocardial infarction, and definite/probable stent thrombosis were higher in patients with both HIR and HBR than those with neither HIR nor HBR (P < .001).
Further stratifying patients by PRECISE-ADAPT scores – 10 or less indicating very low risk, 11-17 indicating low risk, 18-24 indicating moderate risk, and at least 25 indicating high risk – showed that HIR features had a consistent effect on ischemic and bleeding outcomes, regardless of bleeding risk.
No funding declared. No relevant financial relationships declared.
A version of this article first appeared on Medscape.com.
A patient’s risk for ischemic events, but not bleeding, after percutaneous coronary intervention (PCI) can be predicted simply based on whether they have one or more guideline-based standardized risk criteria, a large-scale real-world analysis suggests.
Haoyu Wang, MD, and colleagues showed that having at least one high-risk feature, as outlined in the 2018 European Society of Cardiology and European Association for Cardiothoracic Surgery (ESC/EACTS) Guidelines on Myocardial Revascularization, was associated with an increased risk for target vessel failure by 48% and for a patient-oriented composite outcome by 44%.
Moreover, they showed that implantation of at least three stents and the presence of diabetes and diffuse multivessel disease were the only high-risk features from the guidelines that were independent predictors of the two outcomes.
The study of more than 10,000 PCI patients also showed that determining whether patients were at high bleeding risk (HBR) did not modify their ischemic risk.
This, said Dr. Wang, from the National Center for Cardiovascular Diseases, Fuwai Hospital, Beijing, underscores the importance of applying the high ischemic risk (HIR) criteria from the ESC/EACTS guidelines when tailoring dual antiplatelet therapy (DAPT).
The research was presented at the European Atherosclerosis Society 2021 Virtual Congress on June 2, and published online in the Journal of Atherosclerosis and Thrombosis.
Dr. Wang told theheart.org | Medscape Cardiology that they conducted the study to determine which – HIR or HBR – is “most important to balance when treating patients undergoing PCI and then having dual antiplatelet therapy.”
The results showed that when patients have both a HIR and HBR, it is the ESC/EACTS guideline HIR criteria that have “a higher impact” than the bleeding risk, and that this can be “used to guide our choice of the duration of dual anti-platelet therapy.”
“Maybe we can extend, or use more potent, P2Y12 inhibitors” in those situations, he said.
S. Lale Tokgözoglu, MD, PhD, professor of cardiology, Hacettepe University, Ankara, Turkey, who was not involved in the study, said the HIR assessment “performed well,” adding that the HBR score might have been expected to attenuate its “prognostic advantage.”
She told this news organization that the results “are interesting since previous observations have suggested that Asian patients may be more prone to medication side effects and bleeding.”
These findings emphasize the importance of assessing HIR in daily PCI practice and confirm that it “performs well in different populations in real life,” added Dr. Tokgözoglu, a former president of the EAS.
The ESC/EACTS guidelines aimed to standardize the definition of HIR, Dr. Wang said during the presentation.
They set out 10 high-risk features for ischemic events for patients undergoing revascularization, which included patient medical history, comorbid conditions, and the characteristics of the PCI procedure.
Although the goals of the criteria are to inform decision-making and stimulate research, Dr. Wang said that their “prevalence and prognostic association with clinical outcomes are yet to be established in real-world PCI practice.”
Alongside, the Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score was developed to predict out-of-hospital bleeding in patients receiving DAPT after stent implantation.
Although a PRECISE-DAPT score of at least 25 constitutes a patient at high bleeding risk, Dr. Wang pointed out that such patients are typically also at risk for ischemic events after PCI, and it is “unclear” whether being at HBR modifies this risk.
To investigate further, they used the prospective, real-world Fuwai PCI registry to collate an all-comer patient population with unselected use of drug-eluting stents at the National Center for Cardiovascular Diseases at Fuwai Hospital.
They excluded individuals who were treated with balloon angioplasty alone, bioresorbable scaffolds, or bare metal stents, leaving a total population of 10,167 patients who were treated in 2013.
In that cohort, 5,149 patients (50.6%) met at least one risk criterion from the ESC/EACTS guidelines (HIR patients) and 5,018 (49.4%) met none of the risk criteria (non-HIR patients).
The most common criteria were implantation of at least three stents (23.5%); total stent length greater than 60 mm (20.2%); diffuse multivessel disease, especially in diabetic patients (18.5%); and a history of ST-segment elevation myocardial infarction (13.9%).
HIR patients were significantly older than non-HIR patients (average age, 58.86 vs. 57.77 years; P < .001), were more likely to have diabetes mellitus (42.6% vs. 16.9%; P < .001); and were more likely to have already had a myocardial infarction (32.2% vs. 5.2%; P < .001).
HIR patients also had higher average PRECISE-ADAPT scores than those without HIR (11.22 vs. 9.94; P < .001), and were conversely less likely to have the left anterior descending artery as the target vessel than non-HIR patients (86.0% vs. 94.6%; P < .001).
Cox regression analysis taking into account a range of patient and clinical factors revealed that HIR patients were significantly more likely than their non-HIR counterparts to experience target vessel failure (hazard ratio, 1.48; 95% confidence interval, 1.25-1.74; P < .001).
They were also significantly more likely to have a patient-oriented composite outcome, defined as all-cause death, any myocardial infarction, or any revascularization (HR, 1.44; 95% CI, 1.28-1.63; P < .001).
There was also a significantly higher risk for cardiac death in HIR than in non-HIR patients (HR, 1.95; 95% CI, 1.16-3.29; P = .012).
However, there was no significant association between HIR status and clinically relevant bleeding (HR, 0.84; 95% CI, 0.66-1.06; P = .143).
When the researchers looked at individual ischemic risk features, they found that, on fully adjusted analyses, only two were independent predictors of target vessel failure and the patient-oriented composite outcome.
Having at least three stents implanted was significantly associated with target vessel failure (HR, 1.36; 95% CI, 1.02-1.80; P = .038), and borderline significantly associated with the patient oriented composite outcome (HR, 1.23; 95% CI, 1.00-1.53; P = .056).
Diffuse multivessel disease, especially in diabetic patients, was significantly associated with both target vessel failure (HR, 1.24; 95% CI, 1.02-1.51; P = .035) and with the patient-oriented composite outcome (HR, 1.20; 95% CI, 1.04-1.39; P = .012).
Neither risk feature was significantly associated with clinically relevant bleeding, Dr. Wang noted.
Stratifying the patients by HBR status, the team found that rates of target vessel failure, the patient-oriented composite outcome, cardiac death, myocardial infarction, and definite/probable stent thrombosis were higher in patients with both HIR and HBR than those with neither HIR nor HBR (P < .001).
Further stratifying patients by PRECISE-ADAPT scores – 10 or less indicating very low risk, 11-17 indicating low risk, 18-24 indicating moderate risk, and at least 25 indicating high risk – showed that HIR features had a consistent effect on ischemic and bleeding outcomes, regardless of bleeding risk.
No funding declared. No relevant financial relationships declared.
A version of this article first appeared on Medscape.com.
Urine metabolites could predict end of life in lung cancer
Lung cancer patients could soon have their risk of dying over the following 3 months accurately predicted by analyzing their urine samples, allowing them to better prepare for their end of life, say U.K. researchers.
Dr. Seamus Coyle, consultant in palliative medicine, the Clatterbridge Cancer Centre, Liverpool, and colleagues studied urine samples from more than 100 lung cancer patients, deriving a model based on their metabolite profile.
This allowed patients to be divided into high- and low-risk groups for dying over the following 3 months, with an accuracy of 88%.
The model “predicts dying … for every single day for the last 3 months of life,” Dr. Coyle said.
“That’s an outstanding prediction,” Dr. Coyle added, “based on the fact that people actively die over 2 to 3 days on average,” while “some die over a day.”
He continued: “It’s the only test that predicts dying within the last 2 weeks of life, and that’s what I’m passionate about: The earlier recognition of dying.”
The research was presented at the 2021 American Society of Clinical Oncology Annual Meeting on June 4.
‘Promising and important pilot study’
Dr. Nathan Pennell, an ASCO expert, told this news organization that “predicting the actual ‘time’ someone has left is more of an art than a science.”
“For people who may be closer to death, this would potentially allow more focus on supportive care and allow families and patients to plan more accurately for supporting their loved one through the dying process.”
He continued that “while this is a promising and important pilot study, there is more work to be done before this could be used in practice.”
For example, the treatment status of the patients was not clear.
“Were these patients all in hospice, or were some undergoing treatment which, if effective, could ‘rescue’ them from their poor prognostic state?”
Dr. Pennell continued: “Would measuring kidney function be just as good? Is this something that could be intervened upon?
“For example, if someone has a high-risk score for dying, could medical intervention to treat an infection or some other modifiable action change that ‘fate’?”
Death ‘difficult to predict’
Dr. Coyle began by saying that, while for him recognizing that a patient is dying is the start of good end of life care, “recognizing dying accurately, when someone is in the last days of life, is difficult.”
He noted that the 2019 National Audit of Care at the End of Life found that people were recognized to be dying at median of 34 hours before death, with 20% recognized in the last 8 hours.
Moreover, 50% of people who are dying “are unconscious and unable to be involved in any conversation that [is] pertinent to them.”
In an attempt to better predict the onset of dying, the researchers conducted a prospective, longitudinal study in which 424 urine samples were collected from 162 lung cancer patients from six centers.
Of those, 63 patients gave a sample within the last 28 days of life, and 29 within the last week of life.
Urine samples were analyzed using a liquid chromatography quadrupole time-of-flight mass spectrometer for 112 patients, who had a median age of 71 years and a range of 47-89 years, and 40.2% were female. The most common diagnosis was non–small cell lung cancer, in 55.4%, while 19.6% had small cell lung cancer.
Performing Cox Lasso regression analysis on the “hundreds of metabolites” identified in the urine samples, the team developed an End of Life Metabolome (ELM) that predicted an individual’s risk of dying over the following 3 months.
Kaplan-Meier analysis allowed the patients to be divided into five risk groups based on their ELM (P < .001 for trend), which showed that all patients in the lowest-risk group were still alive after more than 2 months following the urine sample.
In contrast, more than 50% of patients in the highest-risk group died within 1 week of their urine sample being taken, and 100% had died within 3 weeks.
Calculating the area under the receiver operating characteristic curve revealed that the ELM was able to predict the risk of dying for every day for the last 3 months of life with an accuracy of 88%.
ELM is being validated in a new cohort of lung cancer patients and it is being assessed in multiple cancers.
The study was funded by the Wellcome Trust UK and North West Cancer Research UK.
No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
Lung cancer patients could soon have their risk of dying over the following 3 months accurately predicted by analyzing their urine samples, allowing them to better prepare for their end of life, say U.K. researchers.
Dr. Seamus Coyle, consultant in palliative medicine, the Clatterbridge Cancer Centre, Liverpool, and colleagues studied urine samples from more than 100 lung cancer patients, deriving a model based on their metabolite profile.
This allowed patients to be divided into high- and low-risk groups for dying over the following 3 months, with an accuracy of 88%.
The model “predicts dying … for every single day for the last 3 months of life,” Dr. Coyle said.
“That’s an outstanding prediction,” Dr. Coyle added, “based on the fact that people actively die over 2 to 3 days on average,” while “some die over a day.”
He continued: “It’s the only test that predicts dying within the last 2 weeks of life, and that’s what I’m passionate about: The earlier recognition of dying.”
The research was presented at the 2021 American Society of Clinical Oncology Annual Meeting on June 4.
‘Promising and important pilot study’
Dr. Nathan Pennell, an ASCO expert, told this news organization that “predicting the actual ‘time’ someone has left is more of an art than a science.”
“For people who may be closer to death, this would potentially allow more focus on supportive care and allow families and patients to plan more accurately for supporting their loved one through the dying process.”
He continued that “while this is a promising and important pilot study, there is more work to be done before this could be used in practice.”
For example, the treatment status of the patients was not clear.
“Were these patients all in hospice, or were some undergoing treatment which, if effective, could ‘rescue’ them from their poor prognostic state?”
Dr. Pennell continued: “Would measuring kidney function be just as good? Is this something that could be intervened upon?
“For example, if someone has a high-risk score for dying, could medical intervention to treat an infection or some other modifiable action change that ‘fate’?”
Death ‘difficult to predict’
Dr. Coyle began by saying that, while for him recognizing that a patient is dying is the start of good end of life care, “recognizing dying accurately, when someone is in the last days of life, is difficult.”
He noted that the 2019 National Audit of Care at the End of Life found that people were recognized to be dying at median of 34 hours before death, with 20% recognized in the last 8 hours.
Moreover, 50% of people who are dying “are unconscious and unable to be involved in any conversation that [is] pertinent to them.”
In an attempt to better predict the onset of dying, the researchers conducted a prospective, longitudinal study in which 424 urine samples were collected from 162 lung cancer patients from six centers.
Of those, 63 patients gave a sample within the last 28 days of life, and 29 within the last week of life.
Urine samples were analyzed using a liquid chromatography quadrupole time-of-flight mass spectrometer for 112 patients, who had a median age of 71 years and a range of 47-89 years, and 40.2% were female. The most common diagnosis was non–small cell lung cancer, in 55.4%, while 19.6% had small cell lung cancer.
Performing Cox Lasso regression analysis on the “hundreds of metabolites” identified in the urine samples, the team developed an End of Life Metabolome (ELM) that predicted an individual’s risk of dying over the following 3 months.
Kaplan-Meier analysis allowed the patients to be divided into five risk groups based on their ELM (P < .001 for trend), which showed that all patients in the lowest-risk group were still alive after more than 2 months following the urine sample.
In contrast, more than 50% of patients in the highest-risk group died within 1 week of their urine sample being taken, and 100% had died within 3 weeks.
Calculating the area under the receiver operating characteristic curve revealed that the ELM was able to predict the risk of dying for every day for the last 3 months of life with an accuracy of 88%.
ELM is being validated in a new cohort of lung cancer patients and it is being assessed in multiple cancers.
The study was funded by the Wellcome Trust UK and North West Cancer Research UK.
No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
Lung cancer patients could soon have their risk of dying over the following 3 months accurately predicted by analyzing their urine samples, allowing them to better prepare for their end of life, say U.K. researchers.
Dr. Seamus Coyle, consultant in palliative medicine, the Clatterbridge Cancer Centre, Liverpool, and colleagues studied urine samples from more than 100 lung cancer patients, deriving a model based on their metabolite profile.
This allowed patients to be divided into high- and low-risk groups for dying over the following 3 months, with an accuracy of 88%.
The model “predicts dying … for every single day for the last 3 months of life,” Dr. Coyle said.
“That’s an outstanding prediction,” Dr. Coyle added, “based on the fact that people actively die over 2 to 3 days on average,” while “some die over a day.”
He continued: “It’s the only test that predicts dying within the last 2 weeks of life, and that’s what I’m passionate about: The earlier recognition of dying.”
The research was presented at the 2021 American Society of Clinical Oncology Annual Meeting on June 4.
‘Promising and important pilot study’
Dr. Nathan Pennell, an ASCO expert, told this news organization that “predicting the actual ‘time’ someone has left is more of an art than a science.”
“For people who may be closer to death, this would potentially allow more focus on supportive care and allow families and patients to plan more accurately for supporting their loved one through the dying process.”
He continued that “while this is a promising and important pilot study, there is more work to be done before this could be used in practice.”
For example, the treatment status of the patients was not clear.
“Were these patients all in hospice, or were some undergoing treatment which, if effective, could ‘rescue’ them from their poor prognostic state?”
Dr. Pennell continued: “Would measuring kidney function be just as good? Is this something that could be intervened upon?
“For example, if someone has a high-risk score for dying, could medical intervention to treat an infection or some other modifiable action change that ‘fate’?”
Death ‘difficult to predict’
Dr. Coyle began by saying that, while for him recognizing that a patient is dying is the start of good end of life care, “recognizing dying accurately, when someone is in the last days of life, is difficult.”
He noted that the 2019 National Audit of Care at the End of Life found that people were recognized to be dying at median of 34 hours before death, with 20% recognized in the last 8 hours.
Moreover, 50% of people who are dying “are unconscious and unable to be involved in any conversation that [is] pertinent to them.”
In an attempt to better predict the onset of dying, the researchers conducted a prospective, longitudinal study in which 424 urine samples were collected from 162 lung cancer patients from six centers.
Of those, 63 patients gave a sample within the last 28 days of life, and 29 within the last week of life.
Urine samples were analyzed using a liquid chromatography quadrupole time-of-flight mass spectrometer for 112 patients, who had a median age of 71 years and a range of 47-89 years, and 40.2% were female. The most common diagnosis was non–small cell lung cancer, in 55.4%, while 19.6% had small cell lung cancer.
Performing Cox Lasso regression analysis on the “hundreds of metabolites” identified in the urine samples, the team developed an End of Life Metabolome (ELM) that predicted an individual’s risk of dying over the following 3 months.
Kaplan-Meier analysis allowed the patients to be divided into five risk groups based on their ELM (P < .001 for trend), which showed that all patients in the lowest-risk group were still alive after more than 2 months following the urine sample.
In contrast, more than 50% of patients in the highest-risk group died within 1 week of their urine sample being taken, and 100% had died within 3 weeks.
Calculating the area under the receiver operating characteristic curve revealed that the ELM was able to predict the risk of dying for every day for the last 3 months of life with an accuracy of 88%.
ELM is being validated in a new cohort of lung cancer patients and it is being assessed in multiple cancers.
The study was funded by the Wellcome Trust UK and North West Cancer Research UK.
No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
Free U.K. tool could help guide COVID-19 care for cancer patients
An online support tool for health care professionals that recommends whether to admit or discharge a cancer patient with COVID-19, based on their risk of a severe complication, has been developed by researchers from Manchester.
The team used machine learning on data from more than 900 cancer patients with COVID-19, conducting multiple analyses to arrive at a set of features that could accurately predict the need for admission or oxygen therapy, as well as the risk of death.
Dr. Rebecca Lee, The Christie NHS Foundation Trust, Manchester, and colleagues then developed thresholds to derive a score that recommended admission in 95% of patients who went on to need oxygen and an even greater proportion of those who later died.
The research was presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting on June 4.
CORONET
The resulting COVID-19 Risk in Oncology Evaluation Tool (CORONET) model “performs very well at predicting admission and severity of COVID-19 in patients with cancer,” Dr. Lee said. “We have set pragmatic and clinically relevant thresholds that focus on the safety regarding an admission versus discharge decision.”
To help health care professionals, the researchers have built a free online support tool that allows them to enter data and receive a recommendation “as to whether their patient should be considered for discharge, considered for admission, or is at high risk of having a severe outcome of coronavirus,” Dr. Lee explained.
“The health care professional can then explore the recommendation by seeing how their patient … compares with the rest of the cohort.”
The tool also includes a “diagram showing which features are most important to recommend a discharge decision versus an admission decision for each individual patient.”
Clinically intuitive
Dr. Alexi Wright, associate professor, Dana-Faber Cancer Institute, Boston, who was not involved in the study, commented that there were many things that were “really nice about the study.”
“First and foremost that they were establishing a tool to efficiently triage [patients] presenting with COVID,” she said, adding that it was “clinically intuitive” that the team made “pragmatic choices,” and the use of a random forest algorithm means the results are “very interpretable.”
However, Dr. Wright wondered whether the results can be replicated.
Alongside a lack of information on the deaths in the cohort, she pointed out that “ideally you have three data sets, with a training set, a testing set, and a validation set.”
The CORONET model was, however, trained and evaluated on the same dataset, “so it really needs external validation before it would be ready for direct clinical application.”
She continued that there is a “critical need to establish that studies can both be reproduced and replicated,” noting that a recent review showed that 85% of machine-learning studies that were used to detect COVID-19 using chest radiographs “failed fundamental reproducibility and quality checks.”
Risk factors
Dr. Lee began her presentation by reminding the audience that cancer patients are at increased risk of severe COVID-19 and death, with older age, male sex, nosocomial infection, higher ECOG performance status, and active cancer among the risk factors for mortality.
“However, outcomes are very heterogeneous, ranging from patients without symptoms at all to cases with multi-organ failure and death,” she said.
It is consequently “very important for the treating clinician to determine which patients could be safely discharged to the community versus those who need additional support in being admitted to hospital.”
To develop a tool that could distinguish between those two groups of patients, the researchers collected data on 1,743 cancer patients, which was reduced down to 920 patients after excluding those without laboratory confirmed COVID-19 and those with missing data.
Using recursive feature elimination, they selected 10 key patient features associated with prognosis, then compared a lasso regression model with a random forest model, with the latter performing the best.
The team then divided their patients into four cohorts, with the model trained on three cohorts and tested on the fourth. This resulted in the CORONET score, with the final model determined by testing it against the entire patient population.
Next, thresholds were determined for assessing patients for admission versus discharge, as well as for severity of illness, giving the final CORONET model, from which the online tool was developed.
Checking performance
The results showed that the model was able to predict admission with an area under the receiver operating characteristics curve (AUROC) of 0.82 for admission, 0.85 for oxygen requirement, and 0.79 for death.
Further analysis revealed that the most important feature at the time of presentation for determining outcome was the National Early Warning Score 2 (NEWS2), “which is a composite score of heart rate, respiratory rate, saturations and confusion level,” Dr. Lee said.
In addition, C-reactive protein levels, albumin, age, and platelet counts “were also very important features,” she continued, “and these have also been shown in a number of different studies to be important at determining the outcome from coronavirus.”
To examine the performance of the CORONET score further, they applied it to a European hospital dataset, ESMO-CoCARE registry data, and a U.S. cohort, the COVID-19 and Cancer Consortium Registry (CCC19). They found that the score discriminated between patients, but it did so with some degree of heterogeneity.
This was largely driven by higher patient age among the U.S. patients, a higher NEWS2 score, and lower albumin levels, Dr. Lee said.
To ensure the score’s applicability to clinical practice, the team set pragmatic thresholds to determine whether or not a patient required admission or whether they were at risk of dying.
For admission, they set a sensitivity of 85% and a specificity of 56%, while for mortality they set a sensitivity of 43% and a specificity of 92%.
When this was converted into a decision support tool, the model recommended hospital admission for 95% of patients who eventually required oxygen and 97% of patients who died.
The study was funded by The Christie Charitable Foundation. Dr. Lee declares relationships with AstraZeneca and Bristol-Myers Squibb (Inst). Dr. Wright declares relationships with NCCN/AstraZeneca (Inst).
A version of this article first appeared on Medscape.com.
An online support tool for health care professionals that recommends whether to admit or discharge a cancer patient with COVID-19, based on their risk of a severe complication, has been developed by researchers from Manchester.
The team used machine learning on data from more than 900 cancer patients with COVID-19, conducting multiple analyses to arrive at a set of features that could accurately predict the need for admission or oxygen therapy, as well as the risk of death.
Dr. Rebecca Lee, The Christie NHS Foundation Trust, Manchester, and colleagues then developed thresholds to derive a score that recommended admission in 95% of patients who went on to need oxygen and an even greater proportion of those who later died.
The research was presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting on June 4.
CORONET
The resulting COVID-19 Risk in Oncology Evaluation Tool (CORONET) model “performs very well at predicting admission and severity of COVID-19 in patients with cancer,” Dr. Lee said. “We have set pragmatic and clinically relevant thresholds that focus on the safety regarding an admission versus discharge decision.”
To help health care professionals, the researchers have built a free online support tool that allows them to enter data and receive a recommendation “as to whether their patient should be considered for discharge, considered for admission, or is at high risk of having a severe outcome of coronavirus,” Dr. Lee explained.
“The health care professional can then explore the recommendation by seeing how their patient … compares with the rest of the cohort.”
The tool also includes a “diagram showing which features are most important to recommend a discharge decision versus an admission decision for each individual patient.”
Clinically intuitive
Dr. Alexi Wright, associate professor, Dana-Faber Cancer Institute, Boston, who was not involved in the study, commented that there were many things that were “really nice about the study.”
“First and foremost that they were establishing a tool to efficiently triage [patients] presenting with COVID,” she said, adding that it was “clinically intuitive” that the team made “pragmatic choices,” and the use of a random forest algorithm means the results are “very interpretable.”
However, Dr. Wright wondered whether the results can be replicated.
Alongside a lack of information on the deaths in the cohort, she pointed out that “ideally you have three data sets, with a training set, a testing set, and a validation set.”
The CORONET model was, however, trained and evaluated on the same dataset, “so it really needs external validation before it would be ready for direct clinical application.”
She continued that there is a “critical need to establish that studies can both be reproduced and replicated,” noting that a recent review showed that 85% of machine-learning studies that were used to detect COVID-19 using chest radiographs “failed fundamental reproducibility and quality checks.”
Risk factors
Dr. Lee began her presentation by reminding the audience that cancer patients are at increased risk of severe COVID-19 and death, with older age, male sex, nosocomial infection, higher ECOG performance status, and active cancer among the risk factors for mortality.
“However, outcomes are very heterogeneous, ranging from patients without symptoms at all to cases with multi-organ failure and death,” she said.
It is consequently “very important for the treating clinician to determine which patients could be safely discharged to the community versus those who need additional support in being admitted to hospital.”
To develop a tool that could distinguish between those two groups of patients, the researchers collected data on 1,743 cancer patients, which was reduced down to 920 patients after excluding those without laboratory confirmed COVID-19 and those with missing data.
Using recursive feature elimination, they selected 10 key patient features associated with prognosis, then compared a lasso regression model with a random forest model, with the latter performing the best.
The team then divided their patients into four cohorts, with the model trained on three cohorts and tested on the fourth. This resulted in the CORONET score, with the final model determined by testing it against the entire patient population.
Next, thresholds were determined for assessing patients for admission versus discharge, as well as for severity of illness, giving the final CORONET model, from which the online tool was developed.
Checking performance
The results showed that the model was able to predict admission with an area under the receiver operating characteristics curve (AUROC) of 0.82 for admission, 0.85 for oxygen requirement, and 0.79 for death.
Further analysis revealed that the most important feature at the time of presentation for determining outcome was the National Early Warning Score 2 (NEWS2), “which is a composite score of heart rate, respiratory rate, saturations and confusion level,” Dr. Lee said.
In addition, C-reactive protein levels, albumin, age, and platelet counts “were also very important features,” she continued, “and these have also been shown in a number of different studies to be important at determining the outcome from coronavirus.”
To examine the performance of the CORONET score further, they applied it to a European hospital dataset, ESMO-CoCARE registry data, and a U.S. cohort, the COVID-19 and Cancer Consortium Registry (CCC19). They found that the score discriminated between patients, but it did so with some degree of heterogeneity.
This was largely driven by higher patient age among the U.S. patients, a higher NEWS2 score, and lower albumin levels, Dr. Lee said.
To ensure the score’s applicability to clinical practice, the team set pragmatic thresholds to determine whether or not a patient required admission or whether they were at risk of dying.
For admission, they set a sensitivity of 85% and a specificity of 56%, while for mortality they set a sensitivity of 43% and a specificity of 92%.
When this was converted into a decision support tool, the model recommended hospital admission for 95% of patients who eventually required oxygen and 97% of patients who died.
The study was funded by The Christie Charitable Foundation. Dr. Lee declares relationships with AstraZeneca and Bristol-Myers Squibb (Inst). Dr. Wright declares relationships with NCCN/AstraZeneca (Inst).
A version of this article first appeared on Medscape.com.
An online support tool for health care professionals that recommends whether to admit or discharge a cancer patient with COVID-19, based on their risk of a severe complication, has been developed by researchers from Manchester.
The team used machine learning on data from more than 900 cancer patients with COVID-19, conducting multiple analyses to arrive at a set of features that could accurately predict the need for admission or oxygen therapy, as well as the risk of death.
Dr. Rebecca Lee, The Christie NHS Foundation Trust, Manchester, and colleagues then developed thresholds to derive a score that recommended admission in 95% of patients who went on to need oxygen and an even greater proportion of those who later died.
The research was presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting on June 4.
CORONET
The resulting COVID-19 Risk in Oncology Evaluation Tool (CORONET) model “performs very well at predicting admission and severity of COVID-19 in patients with cancer,” Dr. Lee said. “We have set pragmatic and clinically relevant thresholds that focus on the safety regarding an admission versus discharge decision.”
To help health care professionals, the researchers have built a free online support tool that allows them to enter data and receive a recommendation “as to whether their patient should be considered for discharge, considered for admission, or is at high risk of having a severe outcome of coronavirus,” Dr. Lee explained.
“The health care professional can then explore the recommendation by seeing how their patient … compares with the rest of the cohort.”
The tool also includes a “diagram showing which features are most important to recommend a discharge decision versus an admission decision for each individual patient.”
Clinically intuitive
Dr. Alexi Wright, associate professor, Dana-Faber Cancer Institute, Boston, who was not involved in the study, commented that there were many things that were “really nice about the study.”
“First and foremost that they were establishing a tool to efficiently triage [patients] presenting with COVID,” she said, adding that it was “clinically intuitive” that the team made “pragmatic choices,” and the use of a random forest algorithm means the results are “very interpretable.”
However, Dr. Wright wondered whether the results can be replicated.
Alongside a lack of information on the deaths in the cohort, she pointed out that “ideally you have three data sets, with a training set, a testing set, and a validation set.”
The CORONET model was, however, trained and evaluated on the same dataset, “so it really needs external validation before it would be ready for direct clinical application.”
She continued that there is a “critical need to establish that studies can both be reproduced and replicated,” noting that a recent review showed that 85% of machine-learning studies that were used to detect COVID-19 using chest radiographs “failed fundamental reproducibility and quality checks.”
Risk factors
Dr. Lee began her presentation by reminding the audience that cancer patients are at increased risk of severe COVID-19 and death, with older age, male sex, nosocomial infection, higher ECOG performance status, and active cancer among the risk factors for mortality.
“However, outcomes are very heterogeneous, ranging from patients without symptoms at all to cases with multi-organ failure and death,” she said.
It is consequently “very important for the treating clinician to determine which patients could be safely discharged to the community versus those who need additional support in being admitted to hospital.”
To develop a tool that could distinguish between those two groups of patients, the researchers collected data on 1,743 cancer patients, which was reduced down to 920 patients after excluding those without laboratory confirmed COVID-19 and those with missing data.
Using recursive feature elimination, they selected 10 key patient features associated with prognosis, then compared a lasso regression model with a random forest model, with the latter performing the best.
The team then divided their patients into four cohorts, with the model trained on three cohorts and tested on the fourth. This resulted in the CORONET score, with the final model determined by testing it against the entire patient population.
Next, thresholds were determined for assessing patients for admission versus discharge, as well as for severity of illness, giving the final CORONET model, from which the online tool was developed.
Checking performance
The results showed that the model was able to predict admission with an area under the receiver operating characteristics curve (AUROC) of 0.82 for admission, 0.85 for oxygen requirement, and 0.79 for death.
Further analysis revealed that the most important feature at the time of presentation for determining outcome was the National Early Warning Score 2 (NEWS2), “which is a composite score of heart rate, respiratory rate, saturations and confusion level,” Dr. Lee said.
In addition, C-reactive protein levels, albumin, age, and platelet counts “were also very important features,” she continued, “and these have also been shown in a number of different studies to be important at determining the outcome from coronavirus.”
To examine the performance of the CORONET score further, they applied it to a European hospital dataset, ESMO-CoCARE registry data, and a U.S. cohort, the COVID-19 and Cancer Consortium Registry (CCC19). They found that the score discriminated between patients, but it did so with some degree of heterogeneity.
This was largely driven by higher patient age among the U.S. patients, a higher NEWS2 score, and lower albumin levels, Dr. Lee said.
To ensure the score’s applicability to clinical practice, the team set pragmatic thresholds to determine whether or not a patient required admission or whether they were at risk of dying.
For admission, they set a sensitivity of 85% and a specificity of 56%, while for mortality they set a sensitivity of 43% and a specificity of 92%.
When this was converted into a decision support tool, the model recommended hospital admission for 95% of patients who eventually required oxygen and 97% of patients who died.
The study was funded by The Christie Charitable Foundation. Dr. Lee declares relationships with AstraZeneca and Bristol-Myers Squibb (Inst). Dr. Wright declares relationships with NCCN/AstraZeneca (Inst).
A version of this article first appeared on Medscape.com.
Do anti–apo A-I antibodies link fatty liver disease and CVD?
Anti–apolipoprotein A-I (apo A-I) antibodies are common in nonalcoholic fatty liver disease and may not only drive its development but also underlie the link between NAFLD and cardiovascular disease, suggests a novel analysis.
Conducting a clinical analysis and a series of experiments, Sabrina Pagano, PhD, diagnostic department, Geneva University Hospital, and colleagues looked for anti–apo A-I antibodies in patients with NAFLD and then examined their impact on hepatic cells and inflammatory markers.
They found that nearly half of 137 patients with NAFLD were seropositive, and that the antibodies were associated with increased lipid accumulation in the liver, altered triglyceride metabolism, and proinflammatory effects on liver cells.
“We hypothesize that anti–apo A-I IgG may be a potential driver in the development of NAFLD, and further studies are needed to support anti–apo A-I IgG as a possible link between NAFLD and cardiovascular disease,” Dr. Pagano said.
The research was presented at the European Atherosclerosis Society 2021 Virtual Congress.
Asked whether anti–apo A-I antibodies could represent a potential treatment target for NAFLD, Dr. Pagano said in an interview that they have “already developed a peptide that is recognized by the antibodies in order to try to reverse the anti–apo A-I deleterious effect.”
While this was successful in vitro, “unfortunately we didn’t observe ... the peptide reverse of these anti–apo A-I effects in mice, so ... for the moment it’s a little early,” to say whether it represents a promising target.
Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, said that the results are “very interesting and encouraging.”
He said that his own global burden of disease analysis, which is set to be published soon, showed that the worldwide prevalence of NAFLD is 11%, “representing almost 900 million cases,” and a more than 33% increase in prevalence in the past 30 years.
Consequently, any “attempt to have effective, especially early, diagnosis and treatment,” is highly anticipated.
Dr. Banach said the findings from the experimental analyses are “very interesting and promising,” especially regarding the proinflammatory effects of anti–apo A-I antibodies.
However, he underlined that the clinical part, looking at antibody seropositivity in patients with NAFLD, was limited by the lack of a control group, and there was no indication as to what treatment the patients received, despite it being clear that many were obese.
Dr. Banach also believes that, taking into account the patient characteristics, it is likely that most of the patients had the more severe nonalcoholic steatohepatitis, and “it would be additionally useful to see the autoantibodies levels both in NASH and NAFLD.”
Nevertheless, the clinical utility of measuring anti–apo A-I antibodies is limited at this stage.
He said that the lack of “good, easy, and cheap diagnostic methods based on both laboratory and imaging data” for NAFLD means it would be difficult to determine whether assessing antibody seropositivity “might be indeed an added value.”
Independent predictors
Dr. Pagano explained that anti–apo A-I antibodies, which target the major protein fraction of HDL cholesterol, are independent predictors of cardiovascular events in high-risk populations.
They are also independently associated with cardiovascular disease in the general population, as well as atherosclerotic plaque vulnerability in both mice and humans.
She said that apo A-I antibodies have a metabolic role in vivo, and have been shown in vitro to disrupt cholesterol metabolism, promoting foam cell formation.
Studies have also indicated they play a role in hepatic fibrosis, predicting the development of cirrhosis in individuals with chronic hepatitis C infection.
The team therefore set out to determine the presence of anti–apo A-I antibodies in individuals with NAFLD, defined here as fatty acid levels greater than 5% of liver weight, as well as their effect on hepatic cells.
Working with colleagues at Magna Græcia University of Catanzaro (Italy), they obtained serum samples from 137 patients with NAFLD confirmed on ultrasound.
The patients had an average age of 49 years, and 48.9% were male. The median body mass index was 31.8 kg/m2. Cholesterol levels were typically in the intermediate range.
They found that 46% of the participants had anti–apo A-I IgG antibodies, “which is quite high when compared with the 15%-20% positivity that we retrieved from the general population,” Dr. Pagano said.
To explore the link between high anti–apo A-I antibodies and NAFLD, the team studied hepatic cells, treating them with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, for 24 hours.
This revealed that anti–apo A-I IgG antibodies were associated with a significant increase in liquid droplet content in hepatic cells, compared with both cells treated with control IgG (P = .0008), and untreated cells (P = .0002).
Next, the team immunized apo E knockout mice with anti–apo A-I or control IgG antibodies. After 16 weeks, they found there was a significant increase in liver lipid content in mice given anti–apo A-I antibodies versus those treated with controls (P = .03).
They then asked whether anti–apo A-I antibodies could affect triglyceride metabolism. They examined the expression of the transcription factor sterol regulatory element binding protein (SREBP) and regulation of the triglyceride and cholesterol pathways.
Treating hepatic cells again for 24 hours with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, showed that anti–apo A-I antibodies were associated with “dramatic” increases in the active form of SREBP.
They also found that expression of two key enzymes in the triglyceride pathway, fatty acid synthetase and glycerol phosphate acyltransferase, was substantially decreased in the presence anti–apo A-I antibodies.
In both experiments, the untreated hepatic cells and those exposed to control IgG antibodies showed no significant changes.
“These results suggest that negative feedback ... turns off these enzymes, probably due to the lipid overload that is found in the cells after 24 hours of anti–apo A-I treatment,” Dr. Pagano said.
Finally, the researchers observed that anti–apo A-I, but not control antibodies, were associated with increases in inflammatory markers in liver cells.
Specifically, exposure to the antibodies was linked to an approximately 10-fold increase in interleukin-6 levels, as well as an approximate 25-fold increase in IL-8, and around a 7-fold increase in tumor necrosis factor–alpha.
Dr. Pagano suggested that the inflammatory effects are “probably mediated by binding anti–apo A-I antibodies to toll-like receptor 2, which has been previously described in macrophages.”
No funding was declared. The study authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Anti–apolipoprotein A-I (apo A-I) antibodies are common in nonalcoholic fatty liver disease and may not only drive its development but also underlie the link between NAFLD and cardiovascular disease, suggests a novel analysis.
Conducting a clinical analysis and a series of experiments, Sabrina Pagano, PhD, diagnostic department, Geneva University Hospital, and colleagues looked for anti–apo A-I antibodies in patients with NAFLD and then examined their impact on hepatic cells and inflammatory markers.
They found that nearly half of 137 patients with NAFLD were seropositive, and that the antibodies were associated with increased lipid accumulation in the liver, altered triglyceride metabolism, and proinflammatory effects on liver cells.
“We hypothesize that anti–apo A-I IgG may be a potential driver in the development of NAFLD, and further studies are needed to support anti–apo A-I IgG as a possible link between NAFLD and cardiovascular disease,” Dr. Pagano said.
The research was presented at the European Atherosclerosis Society 2021 Virtual Congress.
Asked whether anti–apo A-I antibodies could represent a potential treatment target for NAFLD, Dr. Pagano said in an interview that they have “already developed a peptide that is recognized by the antibodies in order to try to reverse the anti–apo A-I deleterious effect.”
While this was successful in vitro, “unfortunately we didn’t observe ... the peptide reverse of these anti–apo A-I effects in mice, so ... for the moment it’s a little early,” to say whether it represents a promising target.
Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, said that the results are “very interesting and encouraging.”
He said that his own global burden of disease analysis, which is set to be published soon, showed that the worldwide prevalence of NAFLD is 11%, “representing almost 900 million cases,” and a more than 33% increase in prevalence in the past 30 years.
Consequently, any “attempt to have effective, especially early, diagnosis and treatment,” is highly anticipated.
Dr. Banach said the findings from the experimental analyses are “very interesting and promising,” especially regarding the proinflammatory effects of anti–apo A-I antibodies.
However, he underlined that the clinical part, looking at antibody seropositivity in patients with NAFLD, was limited by the lack of a control group, and there was no indication as to what treatment the patients received, despite it being clear that many were obese.
Dr. Banach also believes that, taking into account the patient characteristics, it is likely that most of the patients had the more severe nonalcoholic steatohepatitis, and “it would be additionally useful to see the autoantibodies levels both in NASH and NAFLD.”
Nevertheless, the clinical utility of measuring anti–apo A-I antibodies is limited at this stage.
He said that the lack of “good, easy, and cheap diagnostic methods based on both laboratory and imaging data” for NAFLD means it would be difficult to determine whether assessing antibody seropositivity “might be indeed an added value.”
Independent predictors
Dr. Pagano explained that anti–apo A-I antibodies, which target the major protein fraction of HDL cholesterol, are independent predictors of cardiovascular events in high-risk populations.
They are also independently associated with cardiovascular disease in the general population, as well as atherosclerotic plaque vulnerability in both mice and humans.
She said that apo A-I antibodies have a metabolic role in vivo, and have been shown in vitro to disrupt cholesterol metabolism, promoting foam cell formation.
Studies have also indicated they play a role in hepatic fibrosis, predicting the development of cirrhosis in individuals with chronic hepatitis C infection.
The team therefore set out to determine the presence of anti–apo A-I antibodies in individuals with NAFLD, defined here as fatty acid levels greater than 5% of liver weight, as well as their effect on hepatic cells.
Working with colleagues at Magna Græcia University of Catanzaro (Italy), they obtained serum samples from 137 patients with NAFLD confirmed on ultrasound.
The patients had an average age of 49 years, and 48.9% were male. The median body mass index was 31.8 kg/m2. Cholesterol levels were typically in the intermediate range.
They found that 46% of the participants had anti–apo A-I IgG antibodies, “which is quite high when compared with the 15%-20% positivity that we retrieved from the general population,” Dr. Pagano said.
To explore the link between high anti–apo A-I antibodies and NAFLD, the team studied hepatic cells, treating them with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, for 24 hours.
This revealed that anti–apo A-I IgG antibodies were associated with a significant increase in liquid droplet content in hepatic cells, compared with both cells treated with control IgG (P = .0008), and untreated cells (P = .0002).
Next, the team immunized apo E knockout mice with anti–apo A-I or control IgG antibodies. After 16 weeks, they found there was a significant increase in liver lipid content in mice given anti–apo A-I antibodies versus those treated with controls (P = .03).
They then asked whether anti–apo A-I antibodies could affect triglyceride metabolism. They examined the expression of the transcription factor sterol regulatory element binding protein (SREBP) and regulation of the triglyceride and cholesterol pathways.
Treating hepatic cells again for 24 hours with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, showed that anti–apo A-I antibodies were associated with “dramatic” increases in the active form of SREBP.
They also found that expression of two key enzymes in the triglyceride pathway, fatty acid synthetase and glycerol phosphate acyltransferase, was substantially decreased in the presence anti–apo A-I antibodies.
In both experiments, the untreated hepatic cells and those exposed to control IgG antibodies showed no significant changes.
“These results suggest that negative feedback ... turns off these enzymes, probably due to the lipid overload that is found in the cells after 24 hours of anti–apo A-I treatment,” Dr. Pagano said.
Finally, the researchers observed that anti–apo A-I, but not control antibodies, were associated with increases in inflammatory markers in liver cells.
Specifically, exposure to the antibodies was linked to an approximately 10-fold increase in interleukin-6 levels, as well as an approximate 25-fold increase in IL-8, and around a 7-fold increase in tumor necrosis factor–alpha.
Dr. Pagano suggested that the inflammatory effects are “probably mediated by binding anti–apo A-I antibodies to toll-like receptor 2, which has been previously described in macrophages.”
No funding was declared. The study authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Anti–apolipoprotein A-I (apo A-I) antibodies are common in nonalcoholic fatty liver disease and may not only drive its development but also underlie the link between NAFLD and cardiovascular disease, suggests a novel analysis.
Conducting a clinical analysis and a series of experiments, Sabrina Pagano, PhD, diagnostic department, Geneva University Hospital, and colleagues looked for anti–apo A-I antibodies in patients with NAFLD and then examined their impact on hepatic cells and inflammatory markers.
They found that nearly half of 137 patients with NAFLD were seropositive, and that the antibodies were associated with increased lipid accumulation in the liver, altered triglyceride metabolism, and proinflammatory effects on liver cells.
“We hypothesize that anti–apo A-I IgG may be a potential driver in the development of NAFLD, and further studies are needed to support anti–apo A-I IgG as a possible link between NAFLD and cardiovascular disease,” Dr. Pagano said.
The research was presented at the European Atherosclerosis Society 2021 Virtual Congress.
Asked whether anti–apo A-I antibodies could represent a potential treatment target for NAFLD, Dr. Pagano said in an interview that they have “already developed a peptide that is recognized by the antibodies in order to try to reverse the anti–apo A-I deleterious effect.”
While this was successful in vitro, “unfortunately we didn’t observe ... the peptide reverse of these anti–apo A-I effects in mice, so ... for the moment it’s a little early,” to say whether it represents a promising target.
Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, said that the results are “very interesting and encouraging.”
He said that his own global burden of disease analysis, which is set to be published soon, showed that the worldwide prevalence of NAFLD is 11%, “representing almost 900 million cases,” and a more than 33% increase in prevalence in the past 30 years.
Consequently, any “attempt to have effective, especially early, diagnosis and treatment,” is highly anticipated.
Dr. Banach said the findings from the experimental analyses are “very interesting and promising,” especially regarding the proinflammatory effects of anti–apo A-I antibodies.
However, he underlined that the clinical part, looking at antibody seropositivity in patients with NAFLD, was limited by the lack of a control group, and there was no indication as to what treatment the patients received, despite it being clear that many were obese.
Dr. Banach also believes that, taking into account the patient characteristics, it is likely that most of the patients had the more severe nonalcoholic steatohepatitis, and “it would be additionally useful to see the autoantibodies levels both in NASH and NAFLD.”
Nevertheless, the clinical utility of measuring anti–apo A-I antibodies is limited at this stage.
He said that the lack of “good, easy, and cheap diagnostic methods based on both laboratory and imaging data” for NAFLD means it would be difficult to determine whether assessing antibody seropositivity “might be indeed an added value.”
Independent predictors
Dr. Pagano explained that anti–apo A-I antibodies, which target the major protein fraction of HDL cholesterol, are independent predictors of cardiovascular events in high-risk populations.
They are also independently associated with cardiovascular disease in the general population, as well as atherosclerotic plaque vulnerability in both mice and humans.
She said that apo A-I antibodies have a metabolic role in vivo, and have been shown in vitro to disrupt cholesterol metabolism, promoting foam cell formation.
Studies have also indicated they play a role in hepatic fibrosis, predicting the development of cirrhosis in individuals with chronic hepatitis C infection.
The team therefore set out to determine the presence of anti–apo A-I antibodies in individuals with NAFLD, defined here as fatty acid levels greater than 5% of liver weight, as well as their effect on hepatic cells.
Working with colleagues at Magna Græcia University of Catanzaro (Italy), they obtained serum samples from 137 patients with NAFLD confirmed on ultrasound.
The patients had an average age of 49 years, and 48.9% were male. The median body mass index was 31.8 kg/m2. Cholesterol levels were typically in the intermediate range.
They found that 46% of the participants had anti–apo A-I IgG antibodies, “which is quite high when compared with the 15%-20% positivity that we retrieved from the general population,” Dr. Pagano said.
To explore the link between high anti–apo A-I antibodies and NAFLD, the team studied hepatic cells, treating them with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, for 24 hours.
This revealed that anti–apo A-I IgG antibodies were associated with a significant increase in liquid droplet content in hepatic cells, compared with both cells treated with control IgG (P = .0008), and untreated cells (P = .0002).
Next, the team immunized apo E knockout mice with anti–apo A-I or control IgG antibodies. After 16 weeks, they found there was a significant increase in liver lipid content in mice given anti–apo A-I antibodies versus those treated with controls (P = .03).
They then asked whether anti–apo A-I antibodies could affect triglyceride metabolism. They examined the expression of the transcription factor sterol regulatory element binding protein (SREBP) and regulation of the triglyceride and cholesterol pathways.
Treating hepatic cells again for 24 hours with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, showed that anti–apo A-I antibodies were associated with “dramatic” increases in the active form of SREBP.
They also found that expression of two key enzymes in the triglyceride pathway, fatty acid synthetase and glycerol phosphate acyltransferase, was substantially decreased in the presence anti–apo A-I antibodies.
In both experiments, the untreated hepatic cells and those exposed to control IgG antibodies showed no significant changes.
“These results suggest that negative feedback ... turns off these enzymes, probably due to the lipid overload that is found in the cells after 24 hours of anti–apo A-I treatment,” Dr. Pagano said.
Finally, the researchers observed that anti–apo A-I, but not control antibodies, were associated with increases in inflammatory markers in liver cells.
Specifically, exposure to the antibodies was linked to an approximately 10-fold increase in interleukin-6 levels, as well as an approximate 25-fold increase in IL-8, and around a 7-fold increase in tumor necrosis factor–alpha.
Dr. Pagano suggested that the inflammatory effects are “probably mediated by binding anti–apo A-I antibodies to toll-like receptor 2, which has been previously described in macrophages.”
No funding was declared. The study authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.