Ideally, Americans receiving their Pfizer/BioNTech or Moderna COVID-19 vaccines will get both doses from the same manufacturer, said Gregory Poland, MD, a vaccinologist at the Mayo Clinic in Rochester, Minn.

After all, that’s how they were tested for efficacy and safety, and it was results from those studies that led to emergency use authorization (EUA) being granted by the Food and Drug Administration.

But states and countries have struggled to keep up with the demand for vaccine, and more flexible vaccination schedules could help.

So researchers are exploring whether it is safe and effective to get the first and second doses from different manufacturers. And they are even wondering whether mixing doses from different manufacturers could increase effectiveness, particularly in light of emerging variants.

It’s called the “interchangeability issue,” said Dr. Poland, who has gotten a steady stream of questions about it.

For example, a patient recently asked about options for his father, who had gotten his first dose of the AstraZeneca vaccine in Ecuador, but had since moved to the United States, where that product has not been approved for use.

Dr. Poland said in an interview that he prefaces each answer with: “I’ve got no science for what I’m about to tell you.”

In this particular case, he recommended that the man’s father talk with his doctor about his level of COVID-19 risk and consider whether he should gamble on the AstraZeneca vaccine getting approved in the United States soon, or whether he should ask for a second dose from one of the three vaccines currently approved.

On March 22, 2021, AstraZeneca released positive results from its phase 3 trial, which will likely speed its path toward use in the United States.

Although clinical trials have started to test combinations and boosters, there’s currently no definitive evidence from human trials on mixing COVID vaccines, Dr. Poland pointed out.

But a study of a mixed-vaccine regimen is currently underway in the United Kingdom.

Participants in that 13-month trial will be given the Oxford/AstraZeneca and Pfizer/BioNTech vaccines in different combinations and at different intervals. The first results from that trial are expected this summer.

And interim results from a trial combining Russia’s Sputnik V and the AstraZeneca vaccines are expected in 2 months, according to a Reuters report.
 

Mix only in ‘exceptional situations’

The Centers for Disease Control and Prevention has been hesitant to open the door to mixing Pfizer and Moderna vaccinations, noting that the two “are not interchangeable.” But CDC guidance has changed slightly. Now, instead of saying the two vaccines should not be mixed, CDC guidance says they can be mixed in “exceptional situations,” and that the second dose can be administered up to 6 weeks after the first dose.

It is reasonable to assume that mixing COVID-19 vaccines that use the same platform – such as the mRNA platform used by both the Pfizer and Moderna vaccines – will be acceptable, Dr. Poland said, although human trials have not proven that.

However, it is unclear whether vaccines that use different platforms can be mixed. Can the first dose of an mRNA vaccine be followed by an adenovirus-based vaccine, like the Johnson & Johnson product or Novavax, if that vaccine is granted an EUA?

Ross Kedl, PhD, a vaccine researcher and professor of immunology at the University of Colorado at Denver, Aurora, said matching vaccine platforms might not be the preferred vaccination strategy.

He disagreed that there’s a lack of science surrounding the issue, and said all signs point to mixing as not only a good option, but probably a better one.
 

Researcher says science backs mixing

A mix of two different vaccine platforms likely enhances immunity, Dr. Kedl said. The heterologous prime-boost strategy has been used in animal studies for decades, “and it is well known that this promotes a much better immune response than when immunizing with the same vaccine twice.

“If you think about it in a Venn diagram sort of way, it makes sense,” he said in an interview. “Each vaccine has a number of components in it that influence immunity in various ways, but between the two of them, they only have one component that is similar. In the case of the coronavirus vaccines, the one thing both have in common is the spike protein from SARS-CoV-2. In essence, this gives you two shots at generating immunity against the one thing in each vaccine you care most about, but only one shot for the other vaccine components in each platform, resulting in an amplified response against the common target.”

In fact, the heterologous prime-boost vaccination strategy has proven to be effective in humans in early studies.

For example, an Ebola regimen that consisted of an adenovirus vector, similar to the AstraZeneca COVID vaccine, and a modified vaccinia virus vector showed promise in a phase 1 study. And an HIV regimen that consisted of the combination of a DNA vaccine, similar to the Pfizer and Moderna mRNA vaccines, and another viral vector showed encouraging results in a proof-of-concept study.

In both these cases, the heterologous prime-boost strategy was far better than single-vaccine prime-boost regimens, Dr. Kedl pointed out. And neither study reported any safety issues with the combinations.

For now, it’s best to stick with the same manufacturer for both shots, as the CDC guidance suggests, he said, agreeing with Dr. Poland.

But “I would be very surprised if we didn’t move to a mixing of vaccine platforms for the population,” Dr. Kedl said.

A version of this article first appeared on Medscape.com.

Ideally, Americans receiving their Pfizer/BioNTech or Moderna COVID-19 vaccines will get both doses from the same manufacturer, said Gregory Poland, MD, a vaccinologist at the Mayo Clinic in Rochester, Minn.

After all, that’s how they were tested for efficacy and safety, and it was results from those studies that led to emergency use authorization (EUA) being granted by the Food and Drug Administration.

But states and countries have struggled to keep up with the demand for vaccine, and more flexible vaccination schedules could help.

So researchers are exploring whether it is safe and effective to get the first and second doses from different manufacturers. And they are even wondering whether mixing doses from different manufacturers could increase effectiveness, particularly in light of emerging variants.

It’s called the “interchangeability issue,” said Dr. Poland, who has gotten a steady stream of questions about it.

For example, a patient recently asked about options for his father, who had gotten his first dose of the AstraZeneca vaccine in Ecuador, but had since moved to the United States, where that product has not been approved for use.

Dr. Poland said in an interview that he prefaces each answer with: “I’ve got no science for what I’m about to tell you.”

In this particular case, he recommended that the man’s father talk with his doctor about his level of COVID-19 risk and consider whether he should gamble on the AstraZeneca vaccine getting approved in the United States soon, or whether he should ask for a second dose from one of the three vaccines currently approved.

On March 22, 2021, AstraZeneca released positive results from its phase 3 trial, which will likely speed its path toward use in the United States.

Although clinical trials have started to test combinations and boosters, there’s currently no definitive evidence from human trials on mixing COVID vaccines, Dr. Poland pointed out.

But a study of a mixed-vaccine regimen is currently underway in the United Kingdom.

Participants in that 13-month trial will be given the Oxford/AstraZeneca and Pfizer/BioNTech vaccines in different combinations and at different intervals. The first results from that trial are expected this summer.

And interim results from a trial combining Russia’s Sputnik V and the AstraZeneca vaccines are expected in 2 months, according to a Reuters report.
 

Mix only in ‘exceptional situations’

The Centers for Disease Control and Prevention has been hesitant to open the door to mixing Pfizer and Moderna vaccinations, noting that the two “are not interchangeable.” But CDC guidance has changed slightly. Now, instead of saying the two vaccines should not be mixed, CDC guidance says they can be mixed in “exceptional situations,” and that the second dose can be administered up to 6 weeks after the first dose.

It is reasonable to assume that mixing COVID-19 vaccines that use the same platform – such as the mRNA platform used by both the Pfizer and Moderna vaccines – will be acceptable, Dr. Poland said, although human trials have not proven that.

However, it is unclear whether vaccines that use different platforms can be mixed. Can the first dose of an mRNA vaccine be followed by an adenovirus-based vaccine, like the Johnson & Johnson product or Novavax, if that vaccine is granted an EUA?

Ross Kedl, PhD, a vaccine researcher and professor of immunology at the University of Colorado at Denver, Aurora, said matching vaccine platforms might not be the preferred vaccination strategy.

He disagreed that there’s a lack of science surrounding the issue, and said all signs point to mixing as not only a good option, but probably a better one.
 

Researcher says science backs mixing

A mix of two different vaccine platforms likely enhances immunity, Dr. Kedl said. The heterologous prime-boost strategy has been used in animal studies for decades, “and it is well known that this promotes a much better immune response than when immunizing with the same vaccine twice.

“If you think about it in a Venn diagram sort of way, it makes sense,” he said in an interview. “Each vaccine has a number of components in it that influence immunity in various ways, but between the two of them, they only have one component that is similar. In the case of the coronavirus vaccines, the one thing both have in common is the spike protein from SARS-CoV-2. In essence, this gives you two shots at generating immunity against the one thing in each vaccine you care most about, but only one shot for the other vaccine components in each platform, resulting in an amplified response against the common target.”

In fact, the heterologous prime-boost vaccination strategy has proven to be effective in humans in early studies.

For example, an Ebola regimen that consisted of an adenovirus vector, similar to the AstraZeneca COVID vaccine, and a modified vaccinia virus vector showed promise in a phase 1 study. And an HIV regimen that consisted of the combination of a DNA vaccine, similar to the Pfizer and Moderna mRNA vaccines, and another viral vector showed encouraging results in a proof-of-concept study.

In both these cases, the heterologous prime-boost strategy was far better than single-vaccine prime-boost regimens, Dr. Kedl pointed out. And neither study reported any safety issues with the combinations.

For now, it’s best to stick with the same manufacturer for both shots, as the CDC guidance suggests, he said, agreeing with Dr. Poland.

But “I would be very surprised if we didn’t move to a mixing of vaccine platforms for the population,” Dr. Kedl said.

A version of this article first appeared on Medscape.com.

Ideally, Americans receiving their Pfizer/BioNTech or Moderna COVID-19 vaccines will get both doses from the same manufacturer, said Gregory Poland, MD, a vaccinologist at the Mayo Clinic in Rochester, Minn.

After all, that’s how they were tested for efficacy and safety, and it was results from those studies that led to emergency use authorization (EUA) being granted by the Food and Drug Administration.

But states and countries have struggled to keep up with the demand for vaccine, and more flexible vaccination schedules could help.

So researchers are exploring whether it is safe and effective to get the first and second doses from different manufacturers. And they are even wondering whether mixing doses from different manufacturers could increase effectiveness, particularly in light of emerging variants.

It’s called the “interchangeability issue,” said Dr. Poland, who has gotten a steady stream of questions about it.

For example, a patient recently asked about options for his father, who had gotten his first dose of the AstraZeneca vaccine in Ecuador, but had since moved to the United States, where that product has not been approved for use.

Dr. Poland said in an interview that he prefaces each answer with: “I’ve got no science for what I’m about to tell you.”

In this particular case, he recommended that the man’s father talk with his doctor about his level of COVID-19 risk and consider whether he should gamble on the AstraZeneca vaccine getting approved in the United States soon, or whether he should ask for a second dose from one of the three vaccines currently approved.

On March 22, 2021, AstraZeneca released positive results from its phase 3 trial, which will likely speed its path toward use in the United States.

Although clinical trials have started to test combinations and boosters, there’s currently no definitive evidence from human trials on mixing COVID vaccines, Dr. Poland pointed out.

But a study of a mixed-vaccine regimen is currently underway in the United Kingdom.

Participants in that 13-month trial will be given the Oxford/AstraZeneca and Pfizer/BioNTech vaccines in different combinations and at different intervals. The first results from that trial are expected this summer.

And interim results from a trial combining Russia’s Sputnik V and the AstraZeneca vaccines are expected in 2 months, according to a Reuters report.
 

Mix only in ‘exceptional situations’

The Centers for Disease Control and Prevention has been hesitant to open the door to mixing Pfizer and Moderna vaccinations, noting that the two “are not interchangeable.” But CDC guidance has changed slightly. Now, instead of saying the two vaccines should not be mixed, CDC guidance says they can be mixed in “exceptional situations,” and that the second dose can be administered up to 6 weeks after the first dose.

It is reasonable to assume that mixing COVID-19 vaccines that use the same platform – such as the mRNA platform used by both the Pfizer and Moderna vaccines – will be acceptable, Dr. Poland said, although human trials have not proven that.

However, it is unclear whether vaccines that use different platforms can be mixed. Can the first dose of an mRNA vaccine be followed by an adenovirus-based vaccine, like the Johnson & Johnson product or Novavax, if that vaccine is granted an EUA?

Ross Kedl, PhD, a vaccine researcher and professor of immunology at the University of Colorado at Denver, Aurora, said matching vaccine platforms might not be the preferred vaccination strategy.

He disagreed that there’s a lack of science surrounding the issue, and said all signs point to mixing as not only a good option, but probably a better one.
 

Researcher says science backs mixing

A mix of two different vaccine platforms likely enhances immunity, Dr. Kedl said. The heterologous prime-boost strategy has been used in animal studies for decades, “and it is well known that this promotes a much better immune response than when immunizing with the same vaccine twice.

“If you think about it in a Venn diagram sort of way, it makes sense,” he said in an interview. “Each vaccine has a number of components in it that influence immunity in various ways, but between the two of them, they only have one component that is similar. In the case of the coronavirus vaccines, the one thing both have in common is the spike protein from SARS-CoV-2. In essence, this gives you two shots at generating immunity against the one thing in each vaccine you care most about, but only one shot for the other vaccine components in each platform, resulting in an amplified response against the common target.”

In fact, the heterologous prime-boost vaccination strategy has proven to be effective in humans in early studies.

For example, an Ebola regimen that consisted of an adenovirus vector, similar to the AstraZeneca COVID vaccine, and a modified vaccinia virus vector showed promise in a phase 1 study. And an HIV regimen that consisted of the combination of a DNA vaccine, similar to the Pfizer and Moderna mRNA vaccines, and another viral vector showed encouraging results in a proof-of-concept study.

In both these cases, the heterologous prime-boost strategy was far better than single-vaccine prime-boost regimens, Dr. Kedl pointed out. And neither study reported any safety issues with the combinations.

For now, it’s best to stick with the same manufacturer for both shots, as the CDC guidance suggests, he said, agreeing with Dr. Poland.

But “I would be very surprised if we didn’t move to a mixing of vaccine platforms for the population,” Dr. Kedl said.

A version of this article first appeared on Medscape.com.

Adding oxaliplatin to fluoropyrimidine improves survival outcomes in patients with stage 3 N1 colon cancer whose tumors show microsatellite instability (MSI), according to a pooled analysis of individual patient data from 12 adjuvant trials.

The findings suggest the treatment combination should be the standard of care adjuvant treatment in this setting, and that N stage “should at least be a stratification parameter” in future trials in the MSI population, the investigators said.

Overall survival (OS) in 185 patients with MSI, which is associated with a deficient DNA mismatch repair system (dMMR), and 1,440 patients with microsatellite stability (MSS), which is associated with a proficient mismatch repair (pMMR), was better with the combination therapy versus fluoropyrimidine alone (adjusted hazard ratios, 0.52 and 0.89 for the groups, respectively), Romain Cohen, MD, PhD, of Saint-Antoine Hospital, medical oncology department, Sorbonne Universite, both in Paris, and colleagues reported online in the Journal of Clinical Oncology.
 

Encouraging results

Disease-free survival (DFS) was similarly improved with the combination therapy in the MSI and MSS groups (aHRs, 0.47 and 0.82, respectively).

Further, in 461 MSI/dMMR and 3,789 MSS/pMMR patients treated with the combination therapy, MSI status had different prognostic effects depending on N stage category.

“Compared with MSS/pMMR, MSI/dMMR was associated with better OS in the N1 population (HR, 0.66) but a similar OS in the N2 population (HR, 1.13),” they wrote.

Multivariate analysis showed that prognosticators for OS were N stage (HR for OS in N2 vs. N1, 3.10), T stage (HR for OS with T4 vs. T1-3, 2.39), and sex (HR for OS in men vs. women, HR, 1.71).

The 3-year DFS estimates for N2 vs. N1 disease in the MSI/dMMR group were 65% versus 87%, for T4 versus T1-3 they were 60.4% versus 82.1%, and for high- versus low-risk MSI/dMMR colorectal cancer patients they were 64.5% versus 90.1%.

“MSI/dMMR has become a major theranostic biomarker, harboring a high discrimination capacity for the efficacy of immune checkpoint inhibitors among patients with colorectal cancer,” the authors noted. “Given their impressive activity in the metastatic setting, this justifies evaluating these antibodies in the adjuvant setting.”

To date, the efficacy of the adding oxaliplatin to fluoropyrimidine inpatients with stage 3 colon cancer and MSI has not been clearly demonstrated, they added.

Therefore, they analyzed individual patient data from 12 randomized, controlled, phase 3 trials in the ACCENT database and adjusted for demographic and clinicopathologic factors.

“Here, in the T4 and/or N2 MSI/dMMR groups, we were able to identify populations of patients with MSI/dMMR [stage 3 colorectal cancer] with a high risk of disease recurrence. Indeed, the estimated 3-year DFS rates of patients with MSI/dMMR T4 stage III and N2 patients were, respectively, 60.4% and 64.9%, the latter experiencing poorer survival than the MSS/pMMR N2 population,” they wrote, concluding that, “with one-third of T4 and/or N2 high-risk ... patients experiencing disease recurrence or death within 2 years after curative tumor resection, therapeutic innovations should be sought for this patient population.”

This study was supported by the National Cancer Institute, the ARCAD foundation, and research grants from Nuovo-Soldati Foundation, ARC Foundation for Cancer Research, and Servier Institute. Dr. Cohen reported research funding and/or honoraria from Servier and MSD Oncology.

[email protected]

Adding oxaliplatin to fluoropyrimidine improves survival outcomes in patients with stage 3 N1 colon cancer whose tumors show microsatellite instability (MSI), according to a pooled analysis of individual patient data from 12 adjuvant trials.

The findings suggest the treatment combination should be the standard of care adjuvant treatment in this setting, and that N stage “should at least be a stratification parameter” in future trials in the MSI population, the investigators said.

Overall survival (OS) in 185 patients with MSI, which is associated with a deficient DNA mismatch repair system (dMMR), and 1,440 patients with microsatellite stability (MSS), which is associated with a proficient mismatch repair (pMMR), was better with the combination therapy versus fluoropyrimidine alone (adjusted hazard ratios, 0.52 and 0.89 for the groups, respectively), Romain Cohen, MD, PhD, of Saint-Antoine Hospital, medical oncology department, Sorbonne Universite, both in Paris, and colleagues reported online in the Journal of Clinical Oncology.
 

Encouraging results

Disease-free survival (DFS) was similarly improved with the combination therapy in the MSI and MSS groups (aHRs, 0.47 and 0.82, respectively).

Further, in 461 MSI/dMMR and 3,789 MSS/pMMR patients treated with the combination therapy, MSI status had different prognostic effects depending on N stage category.

“Compared with MSS/pMMR, MSI/dMMR was associated with better OS in the N1 population (HR, 0.66) but a similar OS in the N2 population (HR, 1.13),” they wrote.

Multivariate analysis showed that prognosticators for OS were N stage (HR for OS in N2 vs. N1, 3.10), T stage (HR for OS with T4 vs. T1-3, 2.39), and sex (HR for OS in men vs. women, HR, 1.71).

The 3-year DFS estimates for N2 vs. N1 disease in the MSI/dMMR group were 65% versus 87%, for T4 versus T1-3 they were 60.4% versus 82.1%, and for high- versus low-risk MSI/dMMR colorectal cancer patients they were 64.5% versus 90.1%.

“MSI/dMMR has become a major theranostic biomarker, harboring a high discrimination capacity for the efficacy of immune checkpoint inhibitors among patients with colorectal cancer,” the authors noted. “Given their impressive activity in the metastatic setting, this justifies evaluating these antibodies in the adjuvant setting.”

To date, the efficacy of the adding oxaliplatin to fluoropyrimidine inpatients with stage 3 colon cancer and MSI has not been clearly demonstrated, they added.

Therefore, they analyzed individual patient data from 12 randomized, controlled, phase 3 trials in the ACCENT database and adjusted for demographic and clinicopathologic factors.

“Here, in the T4 and/or N2 MSI/dMMR groups, we were able to identify populations of patients with MSI/dMMR [stage 3 colorectal cancer] with a high risk of disease recurrence. Indeed, the estimated 3-year DFS rates of patients with MSI/dMMR T4 stage III and N2 patients were, respectively, 60.4% and 64.9%, the latter experiencing poorer survival than the MSS/pMMR N2 population,” they wrote, concluding that, “with one-third of T4 and/or N2 high-risk ... patients experiencing disease recurrence or death within 2 years after curative tumor resection, therapeutic innovations should be sought for this patient population.”

This study was supported by the National Cancer Institute, the ARCAD foundation, and research grants from Nuovo-Soldati Foundation, ARC Foundation for Cancer Research, and Servier Institute. Dr. Cohen reported research funding and/or honoraria from Servier and MSD Oncology.

[email protected]

Adding oxaliplatin to fluoropyrimidine improves survival outcomes in patients with stage 3 N1 colon cancer whose tumors show microsatellite instability (MSI), according to a pooled analysis of individual patient data from 12 adjuvant trials.

The findings suggest the treatment combination should be the standard of care adjuvant treatment in this setting, and that N stage “should at least be a stratification parameter” in future trials in the MSI population, the investigators said.

Overall survival (OS) in 185 patients with MSI, which is associated with a deficient DNA mismatch repair system (dMMR), and 1,440 patients with microsatellite stability (MSS), which is associated with a proficient mismatch repair (pMMR), was better with the combination therapy versus fluoropyrimidine alone (adjusted hazard ratios, 0.52 and 0.89 for the groups, respectively), Romain Cohen, MD, PhD, of Saint-Antoine Hospital, medical oncology department, Sorbonne Universite, both in Paris, and colleagues reported online in the Journal of Clinical Oncology.
 

Encouraging results

Disease-free survival (DFS) was similarly improved with the combination therapy in the MSI and MSS groups (aHRs, 0.47 and 0.82, respectively).

Further, in 461 MSI/dMMR and 3,789 MSS/pMMR patients treated with the combination therapy, MSI status had different prognostic effects depending on N stage category.

“Compared with MSS/pMMR, MSI/dMMR was associated with better OS in the N1 population (HR, 0.66) but a similar OS in the N2 population (HR, 1.13),” they wrote.

Multivariate analysis showed that prognosticators for OS were N stage (HR for OS in N2 vs. N1, 3.10), T stage (HR for OS with T4 vs. T1-3, 2.39), and sex (HR for OS in men vs. women, HR, 1.71).

The 3-year DFS estimates for N2 vs. N1 disease in the MSI/dMMR group were 65% versus 87%, for T4 versus T1-3 they were 60.4% versus 82.1%, and for high- versus low-risk MSI/dMMR colorectal cancer patients they were 64.5% versus 90.1%.

“MSI/dMMR has become a major theranostic biomarker, harboring a high discrimination capacity for the efficacy of immune checkpoint inhibitors among patients with colorectal cancer,” the authors noted. “Given their impressive activity in the metastatic setting, this justifies evaluating these antibodies in the adjuvant setting.”

To date, the efficacy of the adding oxaliplatin to fluoropyrimidine inpatients with stage 3 colon cancer and MSI has not been clearly demonstrated, they added.

Therefore, they analyzed individual patient data from 12 randomized, controlled, phase 3 trials in the ACCENT database and adjusted for demographic and clinicopathologic factors.

“Here, in the T4 and/or N2 MSI/dMMR groups, we were able to identify populations of patients with MSI/dMMR [stage 3 colorectal cancer] with a high risk of disease recurrence. Indeed, the estimated 3-year DFS rates of patients with MSI/dMMR T4 stage III and N2 patients were, respectively, 60.4% and 64.9%, the latter experiencing poorer survival than the MSS/pMMR N2 population,” they wrote, concluding that, “with one-third of T4 and/or N2 high-risk ... patients experiencing disease recurrence or death within 2 years after curative tumor resection, therapeutic innovations should be sought for this patient population.”

This study was supported by the National Cancer Institute, the ARCAD foundation, and research grants from Nuovo-Soldati Foundation, ARC Foundation for Cancer Research, and Servier Institute. Dr. Cohen reported research funding and/or honoraria from Servier and MSD Oncology.

[email protected]

Upfront resection of an asymptomatic primary tumor does not improve survival over chemotherapy alone in stage IV colorectal cancer with unresectable synchronous metastases, according to a randomized trial in Japan with 165 patients.

Median overall survival was slightly more than 2 years with or without primary resection, plus upfront surgery delayed systemic treatment and had a 4% risk of fatal complications. The trial was terminated early because of futility.

“PTR [primary tumor resection] should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases,” said investigators led by Yukihide Kanemitsu, MD, a colorectal surgeon at National Cancer Center Hospital in Tokyo.

“This paper is important for establishing solid evidence-based decisions. Why perform an invasive procedure on a patient that introduces additional risks if it won’t change their disease course?” said colorectal surgeon Deborah Keller, MD, clinical assistant professor of surgery at the University of California at Davis Medical Center, when asked for comment.

She explained that, in general, when the primary tumor is not obstructing, the standard of care is upfront chemotherapy, as supported by National Comprehensive Cancer Network guidelines.

“However, there was a change in practice over the last few years” after several retrospective studies reported better overall survival with surgery before chemotherapy, but “the studies were not the highest quality of evidence,” she said.

To bring better data to bear, the Japanese team randomized 84 patients to chemotherapy alone and 81 to PTR followed by chemotherapy. Primary tumors were asymptomatic, and patients had no more than three unresectable metastases in the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy was either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab at investigator discretion.

The trial was halted at interim analysis in September 2019. With a median follow-up of 22 months, median overall survival – the primary endpoint – was 25.9 months in the surgery-first arm and 26.7 months in the chemotherapy-alone group (P = .69). Subgroup analysis found no populations that benefited from PTR. Median progression free survival was 10.4 months with PTR first and 12.1 months with chemotherapy alone (P = .48)

Twenty-seven patients in the PTR arm had grade 3 or worse surgery-related adverse events, including anastomotic leakage in 3 and increased aspartate aminotransferase in 13. Three patients (4%) died within 30 days of surgery. Chemotherapy-related grade 3 or worse adverse events were more frequent and severe in the PTR arm (48% PTR versus 34% chemotherapy alone).

“For those who had been performing resections, this could push the paradigm back to chemotherapy alone,” Dr. Keller said.

Eleven patients (13%) in the chemotherapy-alone arm required surgery for intestinal obstruction or other primary tumor symptoms that developed after randomization, which means that 87% avoided surgery entirely, the investigators noted.

In the PTR group, surgery was performed within 21 days of enrollment, and chemotherapy started a median of 34 days after PTR. Chemotherapy was started within 14 days of enrollment in the chemotherapy-alone arm.

The groups were well balanced, including colon and rectosigmoid tumor locations in 93% of both arms and liver metastases in 73% of both. A bit over half the subjects were men and the median age was 65 years.

The team noted that early termination meant that the planned sample size was not achieved, which in turn limited the statistical power of the conclusions. “It is hoped that the comprehensive results of [ongoing trials] will clearly demonstrate the role of PTR for these patients,” they said.

The study was conducted by the Japan Clinical Oncology Group at 38 cancer centers in Japan. The work was funded by the Ministry of Health of Japan. The investigators had numerous industry ties, including Dr. Kanemitsu, who reported honoraria from Chugai Pharma, Ethicon, Covidien, and Intuitive Surgical, and being a Covidien adviser.

[email protected]

Upfront resection of an asymptomatic primary tumor does not improve survival over chemotherapy alone in stage IV colorectal cancer with unresectable synchronous metastases, according to a randomized trial in Japan with 165 patients.

Median overall survival was slightly more than 2 years with or without primary resection, plus upfront surgery delayed systemic treatment and had a 4% risk of fatal complications. The trial was terminated early because of futility.

“PTR [primary tumor resection] should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases,” said investigators led by Yukihide Kanemitsu, MD, a colorectal surgeon at National Cancer Center Hospital in Tokyo.

“This paper is important for establishing solid evidence-based decisions. Why perform an invasive procedure on a patient that introduces additional risks if it won’t change their disease course?” said colorectal surgeon Deborah Keller, MD, clinical assistant professor of surgery at the University of California at Davis Medical Center, when asked for comment.

She explained that, in general, when the primary tumor is not obstructing, the standard of care is upfront chemotherapy, as supported by National Comprehensive Cancer Network guidelines.

“However, there was a change in practice over the last few years” after several retrospective studies reported better overall survival with surgery before chemotherapy, but “the studies were not the highest quality of evidence,” she said.

To bring better data to bear, the Japanese team randomized 84 patients to chemotherapy alone and 81 to PTR followed by chemotherapy. Primary tumors were asymptomatic, and patients had no more than three unresectable metastases in the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy was either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab at investigator discretion.

The trial was halted at interim analysis in September 2019. With a median follow-up of 22 months, median overall survival – the primary endpoint – was 25.9 months in the surgery-first arm and 26.7 months in the chemotherapy-alone group (P = .69). Subgroup analysis found no populations that benefited from PTR. Median progression free survival was 10.4 months with PTR first and 12.1 months with chemotherapy alone (P = .48)

Twenty-seven patients in the PTR arm had grade 3 or worse surgery-related adverse events, including anastomotic leakage in 3 and increased aspartate aminotransferase in 13. Three patients (4%) died within 30 days of surgery. Chemotherapy-related grade 3 or worse adverse events were more frequent and severe in the PTR arm (48% PTR versus 34% chemotherapy alone).

“For those who had been performing resections, this could push the paradigm back to chemotherapy alone,” Dr. Keller said.

Eleven patients (13%) in the chemotherapy-alone arm required surgery for intestinal obstruction or other primary tumor symptoms that developed after randomization, which means that 87% avoided surgery entirely, the investigators noted.

In the PTR group, surgery was performed within 21 days of enrollment, and chemotherapy started a median of 34 days after PTR. Chemotherapy was started within 14 days of enrollment in the chemotherapy-alone arm.

The groups were well balanced, including colon and rectosigmoid tumor locations in 93% of both arms and liver metastases in 73% of both. A bit over half the subjects were men and the median age was 65 years.

The team noted that early termination meant that the planned sample size was not achieved, which in turn limited the statistical power of the conclusions. “It is hoped that the comprehensive results of [ongoing trials] will clearly demonstrate the role of PTR for these patients,” they said.

The study was conducted by the Japan Clinical Oncology Group at 38 cancer centers in Japan. The work was funded by the Ministry of Health of Japan. The investigators had numerous industry ties, including Dr. Kanemitsu, who reported honoraria from Chugai Pharma, Ethicon, Covidien, and Intuitive Surgical, and being a Covidien adviser.

[email protected]

Upfront resection of an asymptomatic primary tumor does not improve survival over chemotherapy alone in stage IV colorectal cancer with unresectable synchronous metastases, according to a randomized trial in Japan with 165 patients.

Median overall survival was slightly more than 2 years with or without primary resection, plus upfront surgery delayed systemic treatment and had a 4% risk of fatal complications. The trial was terminated early because of futility.

“PTR [primary tumor resection] should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases,” said investigators led by Yukihide Kanemitsu, MD, a colorectal surgeon at National Cancer Center Hospital in Tokyo.

“This paper is important for establishing solid evidence-based decisions. Why perform an invasive procedure on a patient that introduces additional risks if it won’t change their disease course?” said colorectal surgeon Deborah Keller, MD, clinical assistant professor of surgery at the University of California at Davis Medical Center, when asked for comment.

She explained that, in general, when the primary tumor is not obstructing, the standard of care is upfront chemotherapy, as supported by National Comprehensive Cancer Network guidelines.

“However, there was a change in practice over the last few years” after several retrospective studies reported better overall survival with surgery before chemotherapy, but “the studies were not the highest quality of evidence,” she said.

To bring better data to bear, the Japanese team randomized 84 patients to chemotherapy alone and 81 to PTR followed by chemotherapy. Primary tumors were asymptomatic, and patients had no more than three unresectable metastases in the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy was either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab at investigator discretion.

The trial was halted at interim analysis in September 2019. With a median follow-up of 22 months, median overall survival – the primary endpoint – was 25.9 months in the surgery-first arm and 26.7 months in the chemotherapy-alone group (P = .69). Subgroup analysis found no populations that benefited from PTR. Median progression free survival was 10.4 months with PTR first and 12.1 months with chemotherapy alone (P = .48)

Twenty-seven patients in the PTR arm had grade 3 or worse surgery-related adverse events, including anastomotic leakage in 3 and increased aspartate aminotransferase in 13. Three patients (4%) died within 30 days of surgery. Chemotherapy-related grade 3 or worse adverse events were more frequent and severe in the PTR arm (48% PTR versus 34% chemotherapy alone).

“For those who had been performing resections, this could push the paradigm back to chemotherapy alone,” Dr. Keller said.

Eleven patients (13%) in the chemotherapy-alone arm required surgery for intestinal obstruction or other primary tumor symptoms that developed after randomization, which means that 87% avoided surgery entirely, the investigators noted.

In the PTR group, surgery was performed within 21 days of enrollment, and chemotherapy started a median of 34 days after PTR. Chemotherapy was started within 14 days of enrollment in the chemotherapy-alone arm.

The groups were well balanced, including colon and rectosigmoid tumor locations in 93% of both arms and liver metastases in 73% of both. A bit over half the subjects were men and the median age was 65 years.

The team noted that early termination meant that the planned sample size was not achieved, which in turn limited the statistical power of the conclusions. “It is hoped that the comprehensive results of [ongoing trials] will clearly demonstrate the role of PTR for these patients,” they said.

The study was conducted by the Japan Clinical Oncology Group at 38 cancer centers in Japan. The work was funded by the Ministry of Health of Japan. The investigators had numerous industry ties, including Dr. Kanemitsu, who reported honoraria from Chugai Pharma, Ethicon, Covidien, and Intuitive Surgical, and being a Covidien adviser.

[email protected]

The following two studies are related to additional at-risk patient populations for exocrine pancreatic insufficiency. In a single-center cross-sectional study out of Italy, researchers demonstrated that EPI is a feature of type 1 diabetes—compared with healthy individuals, fecal elastase-1 levels were significantly lower in participants with new-onset and long-standing T1D (P = .0070 and .0010, respectively). Notably the study showed correlation between progressive exocrine and endocrine function throughout the natural history of disease. Certainly, further research is needed to clarify the pathogenesis and role of EPI in type 1 diabetes.

Lastly the final selection comes from AIIMS in India, where they assessed endocrine and exocrine function in patients following pancreatic trauma. Notably, of the 20 patients studied with trauma, 11 of them (55%) had evidence of pancreatic exocrine insufficiency by fecal elastase measurement. 4 patients had severe pancreatic insufficiency, 3 of which had partial pancreatectomy (with mean pancreatic volume of 48.65cm3 following surgery). Classic teaching is that EPI develops when exocrine function is impaired by ~90%, however in the resection groups, they have demonstrated severe EPI in patients with roughly 50% retained pancreatic volume.   

The following two studies are related to additional at-risk patient populations for exocrine pancreatic insufficiency. In a single-center cross-sectional study out of Italy, researchers demonstrated that EPI is a feature of type 1 diabetes—compared with healthy individuals, fecal elastase-1 levels were significantly lower in participants with new-onset and long-standing T1D (P = .0070 and .0010, respectively). Notably the study showed correlation between progressive exocrine and endocrine function throughout the natural history of disease. Certainly, further research is needed to clarify the pathogenesis and role of EPI in type 1 diabetes.

Lastly the final selection comes from AIIMS in India, where they assessed endocrine and exocrine function in patients following pancreatic trauma. Notably, of the 20 patients studied with trauma, 11 of them (55%) had evidence of pancreatic exocrine insufficiency by fecal elastase measurement. 4 patients had severe pancreatic insufficiency, 3 of which had partial pancreatectomy (with mean pancreatic volume of 48.65cm3 following surgery). Classic teaching is that EPI develops when exocrine function is impaired by ~90%, however in the resection groups, they have demonstrated severe EPI in patients with roughly 50% retained pancreatic volume.   

The following two studies are related to additional at-risk patient populations for exocrine pancreatic insufficiency. In a single-center cross-sectional study out of Italy, researchers demonstrated that EPI is a feature of type 1 diabetes—compared with healthy individuals, fecal elastase-1 levels were significantly lower in participants with new-onset and long-standing T1D (P = .0070 and .0010, respectively). Notably the study showed correlation between progressive exocrine and endocrine function throughout the natural history of disease. Certainly, further research is needed to clarify the pathogenesis and role of EPI in type 1 diabetes.

Lastly the final selection comes from AIIMS in India, where they assessed endocrine and exocrine function in patients following pancreatic trauma. Notably, of the 20 patients studied with trauma, 11 of them (55%) had evidence of pancreatic exocrine insufficiency by fecal elastase measurement. 4 patients had severe pancreatic insufficiency, 3 of which had partial pancreatectomy (with mean pancreatic volume of 48.65cm3 following surgery). Classic teaching is that EPI develops when exocrine function is impaired by ~90%, however in the resection groups, they have demonstrated severe EPI in patients with roughly 50% retained pancreatic volume.   

Key clinical point: The sphere size is not an essential parameter for selecting effective pancreatin preparations for patients with exocrine pancreatic insufficiency (EPI).

Major finding: One study reported faster emptying of 2 mm pellets than a pancake meal in patients with pancreatic disease. Another study reported parallel emptying of liver pate and 1.5 mm pellets (range, 1.0-1.5 mm). One study reported no clear pattern in stomach emptying for pancreatin pellets of less than 1.2 mm. Emptying of pancreatin preparations with a particle size of up to 7 mm is also documented in the postprandial phase in healthy individuals.

Study details: Meta-analysis of 26 studies that evaluated gastric emptying of indigestible particles of different sizes in healthy volunteers or patients with EPI under fed conditions.

Disclosures: This meta-analysis was supported by Nordmark. The authors received consulting fees outside of this work.

Citation: Peterson K-U. J Gastrointestin Liver Dis. 2021 Mar 12. doi: 10.15403/jgld-2985.

Key clinical point: The sphere size is not an essential parameter for selecting effective pancreatin preparations for patients with exocrine pancreatic insufficiency (EPI).

Major finding: One study reported faster emptying of 2 mm pellets than a pancake meal in patients with pancreatic disease. Another study reported parallel emptying of liver pate and 1.5 mm pellets (range, 1.0-1.5 mm). One study reported no clear pattern in stomach emptying for pancreatin pellets of less than 1.2 mm. Emptying of pancreatin preparations with a particle size of up to 7 mm is also documented in the postprandial phase in healthy individuals.

Study details: Meta-analysis of 26 studies that evaluated gastric emptying of indigestible particles of different sizes in healthy volunteers or patients with EPI under fed conditions.

Disclosures: This meta-analysis was supported by Nordmark. The authors received consulting fees outside of this work.

Citation: Peterson K-U. J Gastrointestin Liver Dis. 2021 Mar 12. doi: 10.15403/jgld-2985.

Key clinical point: The sphere size is not an essential parameter for selecting effective pancreatin preparations for patients with exocrine pancreatic insufficiency (EPI).

Major finding: One study reported faster emptying of 2 mm pellets than a pancake meal in patients with pancreatic disease. Another study reported parallel emptying of liver pate and 1.5 mm pellets (range, 1.0-1.5 mm). One study reported no clear pattern in stomach emptying for pancreatin pellets of less than 1.2 mm. Emptying of pancreatin preparations with a particle size of up to 7 mm is also documented in the postprandial phase in healthy individuals.

Study details: Meta-analysis of 26 studies that evaluated gastric emptying of indigestible particles of different sizes in healthy volunteers or patients with EPI under fed conditions.

Disclosures: This meta-analysis was supported by Nordmark. The authors received consulting fees outside of this work.

Citation: Peterson K-U. J Gastrointestin Liver Dis. 2021 Mar 12. doi: 10.15403/jgld-2985.

Depression might be a disorder of the brain, but its harms aren’t confined to the cranium. Prolonged depression has been linked with a slew of health problems, from impaired immune function to gastrointestinal dysfunction. It’s also been linked with cardiovascular disease (CVD), even increasing the risk for heart attack and a disrupted heart rate. Now, researchers are exploring whether heart function could be a valuable biomarker in informing depression diagnosis and treatment.

Major depressive disorder has proved difficult to diagnose and treat, and biomarkers that indicate a depressive episode or suggest specific interventions would be an attractive solution to its clinically nebulous nature.

Currently, diagnosing depression relies on the patients effectively communicating their symptoms. If the patient does receive a diagnosis, treating it remains a matter of trial and error. It takes weeks to know whether a treatment is working, and in only one-third of cases does the condition go into remission after the patient is initially prescribed an antidepressant. Even after successful treatment, it’s challenging to identify who might be at risk for relapse, and when. Research now shows that cardiac biomarkers may be a way improve this picture. Clinicians could use changes in heart rate to both inform depression diagnosis and gauge a patient’s predicted response to treatment.

Given the increased risk for CVD among people with depression and the link between heart rate changes and CVD risk, these biomarkers could have implications for heart health, too. “We need more than just the current toolkit,” said Amit Shah, MD, a cardiologist and assistant professor of epidemiology at Emory University, Atlanta. “Ultimately, what we’re trying to do is develop interventions not only for depression but also for the associated physical health problems related to depression, in particular, cardiovascular disease,” he said. These overlapping interests – and the prospect of clinically considering both conditions in tandem – mean this research is “really worth its weight in gold,” added Dr. Shah.
 

The data on heart rate biomarkers

Patients with depression are often found to have lower heart rate variability (HRV) and higher heart rates. Scientists don’t know the mechanisms underpinning this relationship but think changes in the autonomic nervous system during depression, as well as stress generally, have a role.

Rébecca Robillard, PhD, is the head scientist of the Clinical Sleep Research Platform at the Royal’s Institute of Mental Health Research, Ottawa, Ont. In a 2019 study published in BMC Psychiatry, Dr. Robillard’s team used electrocardiogram recordings from sleep studies to see whether heart rate abnormalities were associated with depression. Using a profiling algorithm to analyze heart rate and HRV data, the team identified persons with depression with 80% accuracy among 174 people with sleep complaints.

“It’s still early days, but our work certainly suggests that [HRV and heart rate] could serve as potential biomarkers,” Dr. Robillard said.

In another study, Stephan Claes, MD, PhD, psychiatrist and professor of psychiatry at Katholieke Universiteit Leuven, Belgium, and his group tested the biomarker potential of heart rate and HRV data that were continuously recorded over several days. They too used an algorithm to distinguish 16 people with treatment-resistant depression from 16 without depression. Within the depression group, they used the algorithm to distinguish patients who had received ketamine treatment from those who had not.

The algorithm could differentiate between the depressed and nondepressed groups with 90% accuracy. Those with depression had higher overall heart rates, particularly at night, and lower HRV. Dr. Claes noted that, unlike in other studies, “the most reliable parameter that we had for this prediction was the heart rate, not the HRV.” After treatment, heart rates improved, but HRV remained the same.

Although their study has not yet been peer reviewed and more research is needed, Dr. Claes said that increased heart rate, especially during the night, could eventually serve as a warning sign of depression relapse. “That would allow a quicker referral to care and better care because of earlier intervention,” he said.
 

Finding a signal amid the noise

But heart rate and HRV aren’t foolproof biomarkers. Some studies have found that antidepressant use lowers HRV and that HRV changes aren’t unique to depression. There’s the added complication that depression often overlaps with other mental disorders.

“I think we’ve been very disappointed about the success of using particular biomarkers for particular disorders, because the majority of mental disorders are very heterogeneous,” said Andrew Kemp, PhD, psychology professor at Swansea University, Swansea, Wales. “A particular biomarker will, at the end of the day, be just one particular aspect of the overall profile that clinicians will have on particular individuals.”

The clinical utility of a heart rate–depression connection may go both ways.

For instance, depression could serve as a warning sign for atrial fibrillation, according to research from Parveen K. Garg, MD, associate professor of clinical medicine at the University of Southern California, Los Angeles. In a study involving more than 6,000 people, Dr. Garg showed that higher scores on depression scales correlated with a higher risk for the occurrence of atrial fibrillation over a follow-up period of about 13 years.

Depression is associated with other heart conditions as well. “A lot of data seem to suggest that just the presence of depression can increase risk for a whole range of cardiovascular problems,” said Dr. Garg. Epidemiologic studies have found associations between depression and the development of coronary heart disease and a modest increased risk for stroke.

“Things going on in your brain also have effects on the rest of your body,” said Dr. Garg. “Just recognizing this link, that maybe mental illness has an effect on other illnesses or diseases that can affect other parts of your body – I think that’s something we can share now.”

A version of this article first appeared on Medscape.com.

Depression might be a disorder of the brain, but its harms aren’t confined to the cranium. Prolonged depression has been linked with a slew of health problems, from impaired immune function to gastrointestinal dysfunction. It’s also been linked with cardiovascular disease (CVD), even increasing the risk for heart attack and a disrupted heart rate. Now, researchers are exploring whether heart function could be a valuable biomarker in informing depression diagnosis and treatment.

Major depressive disorder has proved difficult to diagnose and treat, and biomarkers that indicate a depressive episode or suggest specific interventions would be an attractive solution to its clinically nebulous nature.

Currently, diagnosing depression relies on the patients effectively communicating their symptoms. If the patient does receive a diagnosis, treating it remains a matter of trial and error. It takes weeks to know whether a treatment is working, and in only one-third of cases does the condition go into remission after the patient is initially prescribed an antidepressant. Even after successful treatment, it’s challenging to identify who might be at risk for relapse, and when. Research now shows that cardiac biomarkers may be a way improve this picture. Clinicians could use changes in heart rate to both inform depression diagnosis and gauge a patient’s predicted response to treatment.

Given the increased risk for CVD among people with depression and the link between heart rate changes and CVD risk, these biomarkers could have implications for heart health, too. “We need more than just the current toolkit,” said Amit Shah, MD, a cardiologist and assistant professor of epidemiology at Emory University, Atlanta. “Ultimately, what we’re trying to do is develop interventions not only for depression but also for the associated physical health problems related to depression, in particular, cardiovascular disease,” he said. These overlapping interests – and the prospect of clinically considering both conditions in tandem – mean this research is “really worth its weight in gold,” added Dr. Shah.
 

The data on heart rate biomarkers

Patients with depression are often found to have lower heart rate variability (HRV) and higher heart rates. Scientists don’t know the mechanisms underpinning this relationship but think changes in the autonomic nervous system during depression, as well as stress generally, have a role.

Rébecca Robillard, PhD, is the head scientist of the Clinical Sleep Research Platform at the Royal’s Institute of Mental Health Research, Ottawa, Ont. In a 2019 study published in BMC Psychiatry, Dr. Robillard’s team used electrocardiogram recordings from sleep studies to see whether heart rate abnormalities were associated with depression. Using a profiling algorithm to analyze heart rate and HRV data, the team identified persons with depression with 80% accuracy among 174 people with sleep complaints.

“It’s still early days, but our work certainly suggests that [HRV and heart rate] could serve as potential biomarkers,” Dr. Robillard said.

In another study, Stephan Claes, MD, PhD, psychiatrist and professor of psychiatry at Katholieke Universiteit Leuven, Belgium, and his group tested the biomarker potential of heart rate and HRV data that were continuously recorded over several days. They too used an algorithm to distinguish 16 people with treatment-resistant depression from 16 without depression. Within the depression group, they used the algorithm to distinguish patients who had received ketamine treatment from those who had not.

The algorithm could differentiate between the depressed and nondepressed groups with 90% accuracy. Those with depression had higher overall heart rates, particularly at night, and lower HRV. Dr. Claes noted that, unlike in other studies, “the most reliable parameter that we had for this prediction was the heart rate, not the HRV.” After treatment, heart rates improved, but HRV remained the same.

Although their study has not yet been peer reviewed and more research is needed, Dr. Claes said that increased heart rate, especially during the night, could eventually serve as a warning sign of depression relapse. “That would allow a quicker referral to care and better care because of earlier intervention,” he said.
 

Finding a signal amid the noise

But heart rate and HRV aren’t foolproof biomarkers. Some studies have found that antidepressant use lowers HRV and that HRV changes aren’t unique to depression. There’s the added complication that depression often overlaps with other mental disorders.

“I think we’ve been very disappointed about the success of using particular biomarkers for particular disorders, because the majority of mental disorders are very heterogeneous,” said Andrew Kemp, PhD, psychology professor at Swansea University, Swansea, Wales. “A particular biomarker will, at the end of the day, be just one particular aspect of the overall profile that clinicians will have on particular individuals.”

The clinical utility of a heart rate–depression connection may go both ways.

For instance, depression could serve as a warning sign for atrial fibrillation, according to research from Parveen K. Garg, MD, associate professor of clinical medicine at the University of Southern California, Los Angeles. In a study involving more than 6,000 people, Dr. Garg showed that higher scores on depression scales correlated with a higher risk for the occurrence of atrial fibrillation over a follow-up period of about 13 years.

Depression is associated with other heart conditions as well. “A lot of data seem to suggest that just the presence of depression can increase risk for a whole range of cardiovascular problems,” said Dr. Garg. Epidemiologic studies have found associations between depression and the development of coronary heart disease and a modest increased risk for stroke.

“Things going on in your brain also have effects on the rest of your body,” said Dr. Garg. “Just recognizing this link, that maybe mental illness has an effect on other illnesses or diseases that can affect other parts of your body – I think that’s something we can share now.”

A version of this article first appeared on Medscape.com.

Depression might be a disorder of the brain, but its harms aren’t confined to the cranium. Prolonged depression has been linked with a slew of health problems, from impaired immune function to gastrointestinal dysfunction. It’s also been linked with cardiovascular disease (CVD), even increasing the risk for heart attack and a disrupted heart rate. Now, researchers are exploring whether heart function could be a valuable biomarker in informing depression diagnosis and treatment.

Major depressive disorder has proved difficult to diagnose and treat, and biomarkers that indicate a depressive episode or suggest specific interventions would be an attractive solution to its clinically nebulous nature.

Currently, diagnosing depression relies on the patients effectively communicating their symptoms. If the patient does receive a diagnosis, treating it remains a matter of trial and error. It takes weeks to know whether a treatment is working, and in only one-third of cases does the condition go into remission after the patient is initially prescribed an antidepressant. Even after successful treatment, it’s challenging to identify who might be at risk for relapse, and when. Research now shows that cardiac biomarkers may be a way improve this picture. Clinicians could use changes in heart rate to both inform depression diagnosis and gauge a patient’s predicted response to treatment.

Given the increased risk for CVD among people with depression and the link between heart rate changes and CVD risk, these biomarkers could have implications for heart health, too. “We need more than just the current toolkit,” said Amit Shah, MD, a cardiologist and assistant professor of epidemiology at Emory University, Atlanta. “Ultimately, what we’re trying to do is develop interventions not only for depression but also for the associated physical health problems related to depression, in particular, cardiovascular disease,” he said. These overlapping interests – and the prospect of clinically considering both conditions in tandem – mean this research is “really worth its weight in gold,” added Dr. Shah.
 

The data on heart rate biomarkers

Patients with depression are often found to have lower heart rate variability (HRV) and higher heart rates. Scientists don’t know the mechanisms underpinning this relationship but think changes in the autonomic nervous system during depression, as well as stress generally, have a role.

Rébecca Robillard, PhD, is the head scientist of the Clinical Sleep Research Platform at the Royal’s Institute of Mental Health Research, Ottawa, Ont. In a 2019 study published in BMC Psychiatry, Dr. Robillard’s team used electrocardiogram recordings from sleep studies to see whether heart rate abnormalities were associated with depression. Using a profiling algorithm to analyze heart rate and HRV data, the team identified persons with depression with 80% accuracy among 174 people with sleep complaints.

“It’s still early days, but our work certainly suggests that [HRV and heart rate] could serve as potential biomarkers,” Dr. Robillard said.

In another study, Stephan Claes, MD, PhD, psychiatrist and professor of psychiatry at Katholieke Universiteit Leuven, Belgium, and his group tested the biomarker potential of heart rate and HRV data that were continuously recorded over several days. They too used an algorithm to distinguish 16 people with treatment-resistant depression from 16 without depression. Within the depression group, they used the algorithm to distinguish patients who had received ketamine treatment from those who had not.

The algorithm could differentiate between the depressed and nondepressed groups with 90% accuracy. Those with depression had higher overall heart rates, particularly at night, and lower HRV. Dr. Claes noted that, unlike in other studies, “the most reliable parameter that we had for this prediction was the heart rate, not the HRV.” After treatment, heart rates improved, but HRV remained the same.

Although their study has not yet been peer reviewed and more research is needed, Dr. Claes said that increased heart rate, especially during the night, could eventually serve as a warning sign of depression relapse. “That would allow a quicker referral to care and better care because of earlier intervention,” he said.
 

Finding a signal amid the noise

But heart rate and HRV aren’t foolproof biomarkers. Some studies have found that antidepressant use lowers HRV and that HRV changes aren’t unique to depression. There’s the added complication that depression often overlaps with other mental disorders.

“I think we’ve been very disappointed about the success of using particular biomarkers for particular disorders, because the majority of mental disorders are very heterogeneous,” said Andrew Kemp, PhD, psychology professor at Swansea University, Swansea, Wales. “A particular biomarker will, at the end of the day, be just one particular aspect of the overall profile that clinicians will have on particular individuals.”

The clinical utility of a heart rate–depression connection may go both ways.

For instance, depression could serve as a warning sign for atrial fibrillation, according to research from Parveen K. Garg, MD, associate professor of clinical medicine at the University of Southern California, Los Angeles. In a study involving more than 6,000 people, Dr. Garg showed that higher scores on depression scales correlated with a higher risk for the occurrence of atrial fibrillation over a follow-up period of about 13 years.

Depression is associated with other heart conditions as well. “A lot of data seem to suggest that just the presence of depression can increase risk for a whole range of cardiovascular problems,” said Dr. Garg. Epidemiologic studies have found associations between depression and the development of coronary heart disease and a modest increased risk for stroke.

“Things going on in your brain also have effects on the rest of your body,” said Dr. Garg. “Just recognizing this link, that maybe mental illness has an effect on other illnesses or diseases that can affect other parts of your body – I think that’s something we can share now.”

A version of this article first appeared on Medscape.com.

Key clinical point: In patients with advanced pancreatic cancer, pancreatic enzyme replacement therapy (PERT) for exocrine pancreatic insufficiency (EPI) does not affect survival.

Major finding: There was no significant difference in the overall survival in patients who received PERT vs. those who did not (weighted estimate, 9.5 months vs. 8.1 months; P = .464). No PERT-related adverse events were reported.

Study details: A meta-analysis of 4 randomized controlled trials including 194 patients with pancreatic cancer. The patients with EPI received PERT.

Disclosures: No specific sponsor was identified. One reviewer received personal fees from Abbott Pharmaceuticals and Mylan.

Citation: Ammar K. Expert Rev Gastroenterol Hepatol. 2021 Feb 15. doi: 10.1080/17474124.2021.1884544.

Key clinical point: In patients with advanced pancreatic cancer, pancreatic enzyme replacement therapy (PERT) for exocrine pancreatic insufficiency (EPI) does not affect survival.

Major finding: There was no significant difference in the overall survival in patients who received PERT vs. those who did not (weighted estimate, 9.5 months vs. 8.1 months; P = .464). No PERT-related adverse events were reported.

Study details: A meta-analysis of 4 randomized controlled trials including 194 patients with pancreatic cancer. The patients with EPI received PERT.

Disclosures: No specific sponsor was identified. One reviewer received personal fees from Abbott Pharmaceuticals and Mylan.

Citation: Ammar K. Expert Rev Gastroenterol Hepatol. 2021 Feb 15. doi: 10.1080/17474124.2021.1884544.

Key clinical point: In patients with advanced pancreatic cancer, pancreatic enzyme replacement therapy (PERT) for exocrine pancreatic insufficiency (EPI) does not affect survival.

Major finding: There was no significant difference in the overall survival in patients who received PERT vs. those who did not (weighted estimate, 9.5 months vs. 8.1 months; P = .464). No PERT-related adverse events were reported.

Study details: A meta-analysis of 4 randomized controlled trials including 194 patients with pancreatic cancer. The patients with EPI received PERT.

Disclosures: No specific sponsor was identified. One reviewer received personal fees from Abbott Pharmaceuticals and Mylan.

Citation: Ammar K. Expert Rev Gastroenterol Hepatol. 2021 Feb 15. doi: 10.1080/17474124.2021.1884544.

Key clinical point: Presence of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis is associated with lower levels of phytosterol and cholesterol. Pancreatic enzyme supplement improves cholesterol levels in these patients.

Major finding: Total fat and cholesterol intake were higher in patients with cystic fibrosis. Total cholesterol, low-density lipoprotein cholesterol, campesterol, and β-sitosterol levels were significantly lower in cystic fibrosis patients with EPI vs. those without (all P less than .05). The rate of hypocholesterolemia was lower in patients with EPI receiving a supplementation dose of greater than 2500 U of lipase/g of fat (P = .0026).

Study details: The study included 55 patients with cystic fibrosis and 45 healthy adults. Forty-eight patients with cystic fibrosis had EPI (fecal elastase-1 concentrations less than 100 µg/g) and received pancreatic enzymes.

Disclosures: The study was supported by the Polish National Science Centre. The authors declared no conflicts of interest.

Citation: Drzymała-Czyż S et al. Biomolecules. 2021 Feb 19. doi: 10.3390/biom11020313.

Key clinical point: Presence of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis is associated with lower levels of phytosterol and cholesterol. Pancreatic enzyme supplement improves cholesterol levels in these patients.

Major finding: Total fat and cholesterol intake were higher in patients with cystic fibrosis. Total cholesterol, low-density lipoprotein cholesterol, campesterol, and β-sitosterol levels were significantly lower in cystic fibrosis patients with EPI vs. those without (all P less than .05). The rate of hypocholesterolemia was lower in patients with EPI receiving a supplementation dose of greater than 2500 U of lipase/g of fat (P = .0026).

Study details: The study included 55 patients with cystic fibrosis and 45 healthy adults. Forty-eight patients with cystic fibrosis had EPI (fecal elastase-1 concentrations less than 100 µg/g) and received pancreatic enzymes.

Disclosures: The study was supported by the Polish National Science Centre. The authors declared no conflicts of interest.

Citation: Drzymała-Czyż S et al. Biomolecules. 2021 Feb 19. doi: 10.3390/biom11020313.

Key clinical point: Presence of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis is associated with lower levels of phytosterol and cholesterol. Pancreatic enzyme supplement improves cholesterol levels in these patients.

Major finding: Total fat and cholesterol intake were higher in patients with cystic fibrosis. Total cholesterol, low-density lipoprotein cholesterol, campesterol, and β-sitosterol levels were significantly lower in cystic fibrosis patients with EPI vs. those without (all P less than .05). The rate of hypocholesterolemia was lower in patients with EPI receiving a supplementation dose of greater than 2500 U of lipase/g of fat (P = .0026).

Study details: The study included 55 patients with cystic fibrosis and 45 healthy adults. Forty-eight patients with cystic fibrosis had EPI (fecal elastase-1 concentrations less than 100 µg/g) and received pancreatic enzymes.

Disclosures: The study was supported by the Polish National Science Centre. The authors declared no conflicts of interest.

Citation: Drzymała-Czyż S et al. Biomolecules. 2021 Feb 19. doi: 10.3390/biom11020313.

Key clinical point: Impaired exocrine pancreatic function is reported in a subgroup of patients undergoing esophagectomy, and pancreatic enzyme replacement therapy can improve symptoms and body weight in these patients.

Major finding: Fecal elastase-1 levels of less than 200 µg/g were reported in 16%-18% of patients at 4-6 months following esophagectomy. Pancreatic enzyme replacement therapy (25,000-50,000 units lipase per meal) improved gastrointestinal symptoms, body weight, and normalized stool in patients with steatorrhea.

Study details: Systematic review of 3 prospective cohort studies reporting exocrine pancreatic insufficiency (EPI) in 107 patients undergoing esophagectomy.

Disclosures: No sponsor was identified for this review.

Citation: Blonk L et al. Dis Esophagus. 2021 Feb 9. doi: 10.1093/dote/doab003.

Key clinical point: Impaired exocrine pancreatic function is reported in a subgroup of patients undergoing esophagectomy, and pancreatic enzyme replacement therapy can improve symptoms and body weight in these patients.

Major finding: Fecal elastase-1 levels of less than 200 µg/g were reported in 16%-18% of patients at 4-6 months following esophagectomy. Pancreatic enzyme replacement therapy (25,000-50,000 units lipase per meal) improved gastrointestinal symptoms, body weight, and normalized stool in patients with steatorrhea.

Study details: Systematic review of 3 prospective cohort studies reporting exocrine pancreatic insufficiency (EPI) in 107 patients undergoing esophagectomy.

Disclosures: No sponsor was identified for this review.

Citation: Blonk L et al. Dis Esophagus. 2021 Feb 9. doi: 10.1093/dote/doab003.

Key clinical point: Impaired exocrine pancreatic function is reported in a subgroup of patients undergoing esophagectomy, and pancreatic enzyme replacement therapy can improve symptoms and body weight in these patients.

Major finding: Fecal elastase-1 levels of less than 200 µg/g were reported in 16%-18% of patients at 4-6 months following esophagectomy. Pancreatic enzyme replacement therapy (25,000-50,000 units lipase per meal) improved gastrointestinal symptoms, body weight, and normalized stool in patients with steatorrhea.

Study details: Systematic review of 3 prospective cohort studies reporting exocrine pancreatic insufficiency (EPI) in 107 patients undergoing esophagectomy.

Disclosures: No sponsor was identified for this review.

Citation: Blonk L et al. Dis Esophagus. 2021 Feb 9. doi: 10.1093/dote/doab003.

Key clinical point: Asymptomatic patients with pancreatic trauma may have exocrine insufficiency when evaluated with specific investigations.

Major finding: Patients who underwent pancreatic resection had a lower fecal elastase value vs. those who did not, but the difference was not statistically significant (113 vs. 162.5 μg/g; P = .7). One patient in the resection group reported steatorrhea. Three patients in the pancreatic resection and 1 in the nonresection group had severe pancreatic exocrine insufficiency (P = .7). No patient required pancreatic enzyme supplements.

Study details: A study of 20 patients (mean age, 25 years) with pancreatic trauma between June 2016 and December 2017. Partial pancreatic resection was performed in 12 patients. Exocrine functions were evaluated with the fecal elastase test at 6 months.

Disclosures: No study sponsor was identified.

Citation: Colney L et al. Eur J Trauma Emerg Surg. 2021 Mar 14. doi: 10.1007/s00068-021-01638-8.

Key clinical point: Asymptomatic patients with pancreatic trauma may have exocrine insufficiency when evaluated with specific investigations.

Major finding: Patients who underwent pancreatic resection had a lower fecal elastase value vs. those who did not, but the difference was not statistically significant (113 vs. 162.5 μg/g; P = .7). One patient in the resection group reported steatorrhea. Three patients in the pancreatic resection and 1 in the nonresection group had severe pancreatic exocrine insufficiency (P = .7). No patient required pancreatic enzyme supplements.

Study details: A study of 20 patients (mean age, 25 years) with pancreatic trauma between June 2016 and December 2017. Partial pancreatic resection was performed in 12 patients. Exocrine functions were evaluated with the fecal elastase test at 6 months.

Disclosures: No study sponsor was identified.

Citation: Colney L et al. Eur J Trauma Emerg Surg. 2021 Mar 14. doi: 10.1007/s00068-021-01638-8.

Key clinical point: Asymptomatic patients with pancreatic trauma may have exocrine insufficiency when evaluated with specific investigations.

Major finding: Patients who underwent pancreatic resection had a lower fecal elastase value vs. those who did not, but the difference was not statistically significant (113 vs. 162.5 μg/g; P = .7). One patient in the resection group reported steatorrhea. Three patients in the pancreatic resection and 1 in the nonresection group had severe pancreatic exocrine insufficiency (P = .7). No patient required pancreatic enzyme supplements.

Study details: A study of 20 patients (mean age, 25 years) with pancreatic trauma between June 2016 and December 2017. Partial pancreatic resection was performed in 12 patients. Exocrine functions were evaluated with the fecal elastase test at 6 months.

Disclosures: No study sponsor was identified.

Citation: Colney L et al. Eur J Trauma Emerg Surg. 2021 Mar 14. doi: 10.1007/s00068-021-01638-8.