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Tolerability doesn’t explain why kids do better than adults on ALL regimens
The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney
It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.
To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).
Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).
About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.
The investigators also found that a body mass index at or above 30 kg/m2 and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.
They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”
Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.
The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.
The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney
It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.
To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).
Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).
About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.
The investigators also found that a body mass index at or above 30 kg/m2 and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.
They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”
Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.
The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.
The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney
It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.
To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).
Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).
About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.
The investigators also found that a body mass index at or above 30 kg/m2 and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.
They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”
Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.
The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.
FROM BLOOD ADVANCES
More than half of people living with HIV have coronary plaque
More than half of people living with HIV and suppressed viral loads nonetheless had imaging-confirmed coronary artery disease – and despite longtime use of HIV drugs that have been associated with cardiovascular trouble, none of those drugs were implicated in disease risk in this study.
“Traditional risk factors and duration of HIV infection were associated with severe coronary artery disease,” said Andreas Knudsen, MD, PhD, an infectious disease provider at Copenhagen University Hospital, Hvidovre, Denmark, during his presentation at the 18th European AIDS Conference. “When we adjusted for time since diagnosis of HIV, none of the drugs remained associated with the severity of coronary artery disease.”
Notably, that included abacavir, which was found in another EACS presentation and in past research to be associated with increased rates of heart attacks. Abacavir is sold individually as a generic as well as a component of Epzicom (abacavir/lamivudine) and the single-drug regimen Triumeq (dolutegravir/abacavir/lamivudine).
The Copenhagen Comorbidity in HIV Infection (COCOMO) study enrolled 1,099 people living with HIV in the Danish capital beginning in 2015, and 705 of them had angiographies via CT available to include in the results. The participants were almost all male (89%), at a healthy weight (BMI of 25), and 96% had undetectable viral loads.
Large minorities of participants also had traditional risk factors for coronary artery disease. More than one in four smoked, one in five had high cholesterol, and 42% had high blood pressure. In addition, many had used drugs that have been associated with cardiovascular trouble, including abacavir, which 26% of participants had used; indinavir, used by 17% of participants; zidovudine/AZT, used by 47%; and didanosine, which 14% used. (While abacavir is still in use, the other three drugs are considered legacy drugs and are not in current use.)
In addition, nearly one in three (29%) were currently using a protease inhibitor, which has been associated with heart failure.
When the investigators looked at participants’ CTs, they found that, by the Coronary Artery Disease-Reporting and Data Systems (CAD-RAMS) scoring system, close to half (46%) had clear arteries with no signs of coronary artery disease. But that also meant that 54% had some blockage or stiffening of the arteries. The good news is that 27% of those people had minimal or mild coronary artery disease.
But a full 17% had confirmed obstructive coronary artery disease, and another 1 in 10 participants had the highest level of blockages. When they broke the data down by traditional and HIV medication–related risk factors for coronary artery disease, they found something interesting. Although obesity was associated with the presence of atherosclerosis, it wasn’t associated with severe disease. But diabetes was the reverse of that: It wasn’t associated with the presence of the disease, but it was associated with more severe disease.
And when they looked at abacavir, they found no relationship between the drug and atherosclerosis. “Abacavir was not associated with the presence of atherosclerosis and was also not associated with severity of disease,” said Dr. Knudsen.
Although past use of AZT, indinavir, and didanosine were associated with severity of atherosclerosis, that association went away when Dr. Knudsen and team adjusted the findings for time since diagnosis. What was associated atherosclerosis was length of time living with HIV itself. For every 5 years a person lived with HIV, the study found the risk of having any atherosclerosis increased 20% and severity increased 23%. In addition, being a man was associated with a nearly 2.5-times increased risk of having any atherosclerosis and a 96% increased chance of having more severe atherosclerosis. Having diabetes was associated with a nearly threefold increased risk of atherosclerosis, as was every additional decade of life for a person who was living with HIV.
The findings confirm the baseline data of the REPRIEVE trial, which recently released data showing similarly high rates of atherosclerotic plaque in people living with HIV who didn’t register as “at risk” for cardiovascular disease using traditional scoring methods.
“It’s important in that it’s a huge study that’s confirmatory [of] what we know, which is that there are high levels of subclinical coronary artery disease in people living with HIV,” said Steven Grinspoon, MD, professor at Harvard Medical School in Boston, Massachusetts, and principal investigator of REPRIEVE.
As for the lack of association between abacavir and cardiovascular risk, he said he’s taking the findings with a grain of salt.
“It’s hard to make a lot out of that,” he said. “It’s hard to know in a cross-sectional study. People put people on different things.”
In Spain, where Jose Ignacio Bernardino, MD, treats people living with HIV at La Paz University Hospital in Madrid, abacavir is mostly a moot point, as clinicians have long since moved away from maintaining people living with HIV on any abacavir-containing regimens. What’s more important in the study, he told this news organization, is that “worrisome” high level of risk. REPRIEVE will test whether statins can reduce heart disease events in people living with HIV. But in the meantime, he said the take-away for clinicians from the study is the primary importance of traditional cardiovascular risk factors.
“We have to acknowledge that the major cardiovascular risk factor is age,” he said. “When patients are approaching their 50s, I usually try to stress a lot about cardiovascular risk factors in general. I stress healthy lifestyle – get physical exercise, hypertension, glucose, lipids – in every single patient.”
Dr. Knudsen and Dr. Bernardino have disclosed no relevant financial relationships. Dr. Grinspoon reports receiving personal and consulting fees from Theratechnologies and ViiV Healthcare.
A version of this article first appeared on Medscape.com.
More than half of people living with HIV and suppressed viral loads nonetheless had imaging-confirmed coronary artery disease – and despite longtime use of HIV drugs that have been associated with cardiovascular trouble, none of those drugs were implicated in disease risk in this study.
“Traditional risk factors and duration of HIV infection were associated with severe coronary artery disease,” said Andreas Knudsen, MD, PhD, an infectious disease provider at Copenhagen University Hospital, Hvidovre, Denmark, during his presentation at the 18th European AIDS Conference. “When we adjusted for time since diagnosis of HIV, none of the drugs remained associated with the severity of coronary artery disease.”
Notably, that included abacavir, which was found in another EACS presentation and in past research to be associated with increased rates of heart attacks. Abacavir is sold individually as a generic as well as a component of Epzicom (abacavir/lamivudine) and the single-drug regimen Triumeq (dolutegravir/abacavir/lamivudine).
The Copenhagen Comorbidity in HIV Infection (COCOMO) study enrolled 1,099 people living with HIV in the Danish capital beginning in 2015, and 705 of them had angiographies via CT available to include in the results. The participants were almost all male (89%), at a healthy weight (BMI of 25), and 96% had undetectable viral loads.
Large minorities of participants also had traditional risk factors for coronary artery disease. More than one in four smoked, one in five had high cholesterol, and 42% had high blood pressure. In addition, many had used drugs that have been associated with cardiovascular trouble, including abacavir, which 26% of participants had used; indinavir, used by 17% of participants; zidovudine/AZT, used by 47%; and didanosine, which 14% used. (While abacavir is still in use, the other three drugs are considered legacy drugs and are not in current use.)
In addition, nearly one in three (29%) were currently using a protease inhibitor, which has been associated with heart failure.
When the investigators looked at participants’ CTs, they found that, by the Coronary Artery Disease-Reporting and Data Systems (CAD-RAMS) scoring system, close to half (46%) had clear arteries with no signs of coronary artery disease. But that also meant that 54% had some blockage or stiffening of the arteries. The good news is that 27% of those people had minimal or mild coronary artery disease.
But a full 17% had confirmed obstructive coronary artery disease, and another 1 in 10 participants had the highest level of blockages. When they broke the data down by traditional and HIV medication–related risk factors for coronary artery disease, they found something interesting. Although obesity was associated with the presence of atherosclerosis, it wasn’t associated with severe disease. But diabetes was the reverse of that: It wasn’t associated with the presence of the disease, but it was associated with more severe disease.
And when they looked at abacavir, they found no relationship between the drug and atherosclerosis. “Abacavir was not associated with the presence of atherosclerosis and was also not associated with severity of disease,” said Dr. Knudsen.
Although past use of AZT, indinavir, and didanosine were associated with severity of atherosclerosis, that association went away when Dr. Knudsen and team adjusted the findings for time since diagnosis. What was associated atherosclerosis was length of time living with HIV itself. For every 5 years a person lived with HIV, the study found the risk of having any atherosclerosis increased 20% and severity increased 23%. In addition, being a man was associated with a nearly 2.5-times increased risk of having any atherosclerosis and a 96% increased chance of having more severe atherosclerosis. Having diabetes was associated with a nearly threefold increased risk of atherosclerosis, as was every additional decade of life for a person who was living with HIV.
The findings confirm the baseline data of the REPRIEVE trial, which recently released data showing similarly high rates of atherosclerotic plaque in people living with HIV who didn’t register as “at risk” for cardiovascular disease using traditional scoring methods.
“It’s important in that it’s a huge study that’s confirmatory [of] what we know, which is that there are high levels of subclinical coronary artery disease in people living with HIV,” said Steven Grinspoon, MD, professor at Harvard Medical School in Boston, Massachusetts, and principal investigator of REPRIEVE.
As for the lack of association between abacavir and cardiovascular risk, he said he’s taking the findings with a grain of salt.
“It’s hard to make a lot out of that,” he said. “It’s hard to know in a cross-sectional study. People put people on different things.”
In Spain, where Jose Ignacio Bernardino, MD, treats people living with HIV at La Paz University Hospital in Madrid, abacavir is mostly a moot point, as clinicians have long since moved away from maintaining people living with HIV on any abacavir-containing regimens. What’s more important in the study, he told this news organization, is that “worrisome” high level of risk. REPRIEVE will test whether statins can reduce heart disease events in people living with HIV. But in the meantime, he said the take-away for clinicians from the study is the primary importance of traditional cardiovascular risk factors.
“We have to acknowledge that the major cardiovascular risk factor is age,” he said. “When patients are approaching their 50s, I usually try to stress a lot about cardiovascular risk factors in general. I stress healthy lifestyle – get physical exercise, hypertension, glucose, lipids – in every single patient.”
Dr. Knudsen and Dr. Bernardino have disclosed no relevant financial relationships. Dr. Grinspoon reports receiving personal and consulting fees from Theratechnologies and ViiV Healthcare.
A version of this article first appeared on Medscape.com.
More than half of people living with HIV and suppressed viral loads nonetheless had imaging-confirmed coronary artery disease – and despite longtime use of HIV drugs that have been associated with cardiovascular trouble, none of those drugs were implicated in disease risk in this study.
“Traditional risk factors and duration of HIV infection were associated with severe coronary artery disease,” said Andreas Knudsen, MD, PhD, an infectious disease provider at Copenhagen University Hospital, Hvidovre, Denmark, during his presentation at the 18th European AIDS Conference. “When we adjusted for time since diagnosis of HIV, none of the drugs remained associated with the severity of coronary artery disease.”
Notably, that included abacavir, which was found in another EACS presentation and in past research to be associated with increased rates of heart attacks. Abacavir is sold individually as a generic as well as a component of Epzicom (abacavir/lamivudine) and the single-drug regimen Triumeq (dolutegravir/abacavir/lamivudine).
The Copenhagen Comorbidity in HIV Infection (COCOMO) study enrolled 1,099 people living with HIV in the Danish capital beginning in 2015, and 705 of them had angiographies via CT available to include in the results. The participants were almost all male (89%), at a healthy weight (BMI of 25), and 96% had undetectable viral loads.
Large minorities of participants also had traditional risk factors for coronary artery disease. More than one in four smoked, one in five had high cholesterol, and 42% had high blood pressure. In addition, many had used drugs that have been associated with cardiovascular trouble, including abacavir, which 26% of participants had used; indinavir, used by 17% of participants; zidovudine/AZT, used by 47%; and didanosine, which 14% used. (While abacavir is still in use, the other three drugs are considered legacy drugs and are not in current use.)
In addition, nearly one in three (29%) were currently using a protease inhibitor, which has been associated with heart failure.
When the investigators looked at participants’ CTs, they found that, by the Coronary Artery Disease-Reporting and Data Systems (CAD-RAMS) scoring system, close to half (46%) had clear arteries with no signs of coronary artery disease. But that also meant that 54% had some blockage or stiffening of the arteries. The good news is that 27% of those people had minimal or mild coronary artery disease.
But a full 17% had confirmed obstructive coronary artery disease, and another 1 in 10 participants had the highest level of blockages. When they broke the data down by traditional and HIV medication–related risk factors for coronary artery disease, they found something interesting. Although obesity was associated with the presence of atherosclerosis, it wasn’t associated with severe disease. But diabetes was the reverse of that: It wasn’t associated with the presence of the disease, but it was associated with more severe disease.
And when they looked at abacavir, they found no relationship between the drug and atherosclerosis. “Abacavir was not associated with the presence of atherosclerosis and was also not associated with severity of disease,” said Dr. Knudsen.
Although past use of AZT, indinavir, and didanosine were associated with severity of atherosclerosis, that association went away when Dr. Knudsen and team adjusted the findings for time since diagnosis. What was associated atherosclerosis was length of time living with HIV itself. For every 5 years a person lived with HIV, the study found the risk of having any atherosclerosis increased 20% and severity increased 23%. In addition, being a man was associated with a nearly 2.5-times increased risk of having any atherosclerosis and a 96% increased chance of having more severe atherosclerosis. Having diabetes was associated with a nearly threefold increased risk of atherosclerosis, as was every additional decade of life for a person who was living with HIV.
The findings confirm the baseline data of the REPRIEVE trial, which recently released data showing similarly high rates of atherosclerotic plaque in people living with HIV who didn’t register as “at risk” for cardiovascular disease using traditional scoring methods.
“It’s important in that it’s a huge study that’s confirmatory [of] what we know, which is that there are high levels of subclinical coronary artery disease in people living with HIV,” said Steven Grinspoon, MD, professor at Harvard Medical School in Boston, Massachusetts, and principal investigator of REPRIEVE.
As for the lack of association between abacavir and cardiovascular risk, he said he’s taking the findings with a grain of salt.
“It’s hard to make a lot out of that,” he said. “It’s hard to know in a cross-sectional study. People put people on different things.”
In Spain, where Jose Ignacio Bernardino, MD, treats people living with HIV at La Paz University Hospital in Madrid, abacavir is mostly a moot point, as clinicians have long since moved away from maintaining people living with HIV on any abacavir-containing regimens. What’s more important in the study, he told this news organization, is that “worrisome” high level of risk. REPRIEVE will test whether statins can reduce heart disease events in people living with HIV. But in the meantime, he said the take-away for clinicians from the study is the primary importance of traditional cardiovascular risk factors.
“We have to acknowledge that the major cardiovascular risk factor is age,” he said. “When patients are approaching their 50s, I usually try to stress a lot about cardiovascular risk factors in general. I stress healthy lifestyle – get physical exercise, hypertension, glucose, lipids – in every single patient.”
Dr. Knudsen and Dr. Bernardino have disclosed no relevant financial relationships. Dr. Grinspoon reports receiving personal and consulting fees from Theratechnologies and ViiV Healthcare.
A version of this article first appeared on Medscape.com.
SBRT on oligoprogressive lesions: Benefit in lung cancer
Patients treated with SBRT had a median PFS of 44 weeks, compared with 9 weeks for those who received standard care.
However, no benefit was observed in patients with metastatic breast cancer. There was no significant difference in PFS between the two groups (18 weeks with SBRT vs. 19 weeks with standard care).
“In this preplanned interim analysis, we demonstrated the benefit of SBRT to sites of oligoprogression on overall progression-free survival, which was the primary endpoint,” said lead author C. Jillian Tsai, MD, PhD, a radiation oncologist and director of metastatic disease radiation oncology research at Memorial Sloan Kettering Cancer Center in New York. “The difference was driven by the substantial response in [this] NSCLC cohort.”
There was no benefit of SBRT seen in the breast cohort, she noted, and most breast patients developed new lesions upon further progression.
Dr. Tsai and colleagues are planning to close the trial early, after the interim analysis established the benefit of SBRT. They are now investigating why SBRT was beneficial in NSCLC but not in breast cancer.
The findings were presented at the American Society for Radiation Oncology (ASTRO) annual meeting.
Dr. Tsai explained that the current standard of care for patients with oligoprogressive metastatic NSCLC is to switch to a different targeted therapy or chemotherapy following progression, but options may be limited. Efficacy for second-line therapy can be poor, with PFS ranging from about 4 months to 10 months for NSCLC, “and after second line, efficacy for third and fourth lines is even poorer,” she said.
Similarly, for breast cancer, PFS ranges from about 9 months to 20 months for estrogen-receptor positive patients. “But for triple negative patients, there really is no standard of care and PFS is poor,” Dr. Tsai said.
SBRT superior to standard of care
The authors hypothesized that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved by applying local therapy to progressive lesions only.
The cohort included 102 patients with metastatic NSCLC or breast cancer who had received one or more lines of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of nonprogressive lesions.
Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤5 individual lesions.
Patients were randomly assigned to receive either SBRT to all progressive sites plus palliative standard of care or systemic SOC only. Systemic therapy was per physician’s discretion.
There were 58 patients with NSCLC (30 in the SBRT group) and 44 patients with breast cancer (22 in each group).
Most patients (75%) had more than one site of oligoprogression and 47% had more than 5 total metastatic lesions. About half of patients (54%) had received immunotherapy and the majority of those with NSCLC (86%) did not harbor an actionable driver mutation. About one-third (32%) of the breast cancer cohort were triple negative.
Patients were followed for a median of 45 weeks (58 weeks for living patients), by which time 78 (74%) had experienced further tumor progression and 39 (37%) had died.
Median progression-free survival for the entire cohort was 31 weeks for SBRT and 11 weeks for palliative SOC (P = .002).
In multivariable analysis that stratified for factors including age, sex, lines of systemic therapy, and change of systemic therapy, the progression-free survival benefit of SBRT continued to remain substantial in the NSCLC cohort (hazard ratio: 0.38; P = .007).
Adverse events were higher in the SBRT group. Grade 2 or higher adverse events occurred in 23 (61%) of SBRT patients, and 15 (40%) of SOC patients (P = .13).
Hoped-for results, with a few caveats
Approached for comment on the new findings, Clifford Robinson, MD, professor of radiation oncology, chief of SBRT service, and director of clinical trials and informatics at Washington University, St. Louis, said the results tie in with previous findings.
There are multiple published or presented prospective randomized phase 2 and 3 trials in various disease sites that have explored the role of local therapy, including SBRT, for patients who present with oligometastatic disease.
“These studies have nearly uniformly shown improvements in progression-free and/or overall survival with the inclusion of local therapy,” he told this news organization. Dr. Robinson was not involved with the study.
He explained that relatively few patients present with oligometastatic disease. However, many patients present with more advanced disease, but after an initial course of systemic therapy, develop oligoprogression.
“There is tremendous appeal to using local therapy at the time of oligoprogression in lieu of switching systemic therapy,” said Dr. Robinson. “It allows patients to stay on systemic therapy that is otherwise effective for the remainder of their disease.”
First-line systemic therapies are the most effective and the most tolerable, he continued, and switching systemic therapy introduces the potential for more toxicity and less efficacy. Therefore, it has become increasingly popular to offer SBRT to one or a few sites of oligoprogressive disease based on the results of oligometastatic disease.
“However, there is no established prospective data to guide this practice,” he said. “This trial is the first to examine this carefully in lung and breast cancer patients, and this trial shows what we hoped to see – that use of SBRT after oligoprogression results in improved progression-free survival as compared with standard of care alone. And this was accomplished with limited toxicity.”
There are a few caveats, though, he pointed out. “Progression-free survival is defined as time to first progression or death,” he said. “Since we don’t know what the overall survival is in this abstract, it’s entirely possible that patients live for the same length of time, but just take longer to progress.”
Another caveat is that this was a planned interim analysis. “Typically, planned interim analyses occur to see if the trial should be stopped or to adjust the study based on results,” he said. “It’s unclear what the investigators will do with this information.”
“But overall, these are very exciting data and lend support to the increasingly common practice of treating oligoprogressive disease,” Dr. Robinson added. “Since most of the serious adverse events of SBRT occur later, longer follow-up is needed, although the median survival of patients may not reach that timepoint.”
“For now, practice should not be altered based on these interim results,” he added.
Dr. Tsai reported acting as a consultant/advisor for Varian and Galera and also receiving research funding from Varian. Dr. Robinson reports stock/ownership in Radialogica, acting as a consultant/advisor for Varian, AstraZeneca, EMD Serono, Quantitative Radiology Solutions, research funding from Varian and Merck, and owning patents on systems for cardiac arrhythmias and ablation.
A version of this article first appeared on Medscape.com.
Patients treated with SBRT had a median PFS of 44 weeks, compared with 9 weeks for those who received standard care.
However, no benefit was observed in patients with metastatic breast cancer. There was no significant difference in PFS between the two groups (18 weeks with SBRT vs. 19 weeks with standard care).
“In this preplanned interim analysis, we demonstrated the benefit of SBRT to sites of oligoprogression on overall progression-free survival, which was the primary endpoint,” said lead author C. Jillian Tsai, MD, PhD, a radiation oncologist and director of metastatic disease radiation oncology research at Memorial Sloan Kettering Cancer Center in New York. “The difference was driven by the substantial response in [this] NSCLC cohort.”
There was no benefit of SBRT seen in the breast cohort, she noted, and most breast patients developed new lesions upon further progression.
Dr. Tsai and colleagues are planning to close the trial early, after the interim analysis established the benefit of SBRT. They are now investigating why SBRT was beneficial in NSCLC but not in breast cancer.
The findings were presented at the American Society for Radiation Oncology (ASTRO) annual meeting.
Dr. Tsai explained that the current standard of care for patients with oligoprogressive metastatic NSCLC is to switch to a different targeted therapy or chemotherapy following progression, but options may be limited. Efficacy for second-line therapy can be poor, with PFS ranging from about 4 months to 10 months for NSCLC, “and after second line, efficacy for third and fourth lines is even poorer,” she said.
Similarly, for breast cancer, PFS ranges from about 9 months to 20 months for estrogen-receptor positive patients. “But for triple negative patients, there really is no standard of care and PFS is poor,” Dr. Tsai said.
SBRT superior to standard of care
The authors hypothesized that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved by applying local therapy to progressive lesions only.
The cohort included 102 patients with metastatic NSCLC or breast cancer who had received one or more lines of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of nonprogressive lesions.
Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤5 individual lesions.
Patients were randomly assigned to receive either SBRT to all progressive sites plus palliative standard of care or systemic SOC only. Systemic therapy was per physician’s discretion.
There were 58 patients with NSCLC (30 in the SBRT group) and 44 patients with breast cancer (22 in each group).
Most patients (75%) had more than one site of oligoprogression and 47% had more than 5 total metastatic lesions. About half of patients (54%) had received immunotherapy and the majority of those with NSCLC (86%) did not harbor an actionable driver mutation. About one-third (32%) of the breast cancer cohort were triple negative.
Patients were followed for a median of 45 weeks (58 weeks for living patients), by which time 78 (74%) had experienced further tumor progression and 39 (37%) had died.
Median progression-free survival for the entire cohort was 31 weeks for SBRT and 11 weeks for palliative SOC (P = .002).
In multivariable analysis that stratified for factors including age, sex, lines of systemic therapy, and change of systemic therapy, the progression-free survival benefit of SBRT continued to remain substantial in the NSCLC cohort (hazard ratio: 0.38; P = .007).
Adverse events were higher in the SBRT group. Grade 2 or higher adverse events occurred in 23 (61%) of SBRT patients, and 15 (40%) of SOC patients (P = .13).
Hoped-for results, with a few caveats
Approached for comment on the new findings, Clifford Robinson, MD, professor of radiation oncology, chief of SBRT service, and director of clinical trials and informatics at Washington University, St. Louis, said the results tie in with previous findings.
There are multiple published or presented prospective randomized phase 2 and 3 trials in various disease sites that have explored the role of local therapy, including SBRT, for patients who present with oligometastatic disease.
“These studies have nearly uniformly shown improvements in progression-free and/or overall survival with the inclusion of local therapy,” he told this news organization. Dr. Robinson was not involved with the study.
He explained that relatively few patients present with oligometastatic disease. However, many patients present with more advanced disease, but after an initial course of systemic therapy, develop oligoprogression.
“There is tremendous appeal to using local therapy at the time of oligoprogression in lieu of switching systemic therapy,” said Dr. Robinson. “It allows patients to stay on systemic therapy that is otherwise effective for the remainder of their disease.”
First-line systemic therapies are the most effective and the most tolerable, he continued, and switching systemic therapy introduces the potential for more toxicity and less efficacy. Therefore, it has become increasingly popular to offer SBRT to one or a few sites of oligoprogressive disease based on the results of oligometastatic disease.
“However, there is no established prospective data to guide this practice,” he said. “This trial is the first to examine this carefully in lung and breast cancer patients, and this trial shows what we hoped to see – that use of SBRT after oligoprogression results in improved progression-free survival as compared with standard of care alone. And this was accomplished with limited toxicity.”
There are a few caveats, though, he pointed out. “Progression-free survival is defined as time to first progression or death,” he said. “Since we don’t know what the overall survival is in this abstract, it’s entirely possible that patients live for the same length of time, but just take longer to progress.”
Another caveat is that this was a planned interim analysis. “Typically, planned interim analyses occur to see if the trial should be stopped or to adjust the study based on results,” he said. “It’s unclear what the investigators will do with this information.”
“But overall, these are very exciting data and lend support to the increasingly common practice of treating oligoprogressive disease,” Dr. Robinson added. “Since most of the serious adverse events of SBRT occur later, longer follow-up is needed, although the median survival of patients may not reach that timepoint.”
“For now, practice should not be altered based on these interim results,” he added.
Dr. Tsai reported acting as a consultant/advisor for Varian and Galera and also receiving research funding from Varian. Dr. Robinson reports stock/ownership in Radialogica, acting as a consultant/advisor for Varian, AstraZeneca, EMD Serono, Quantitative Radiology Solutions, research funding from Varian and Merck, and owning patents on systems for cardiac arrhythmias and ablation.
A version of this article first appeared on Medscape.com.
Patients treated with SBRT had a median PFS of 44 weeks, compared with 9 weeks for those who received standard care.
However, no benefit was observed in patients with metastatic breast cancer. There was no significant difference in PFS between the two groups (18 weeks with SBRT vs. 19 weeks with standard care).
“In this preplanned interim analysis, we demonstrated the benefit of SBRT to sites of oligoprogression on overall progression-free survival, which was the primary endpoint,” said lead author C. Jillian Tsai, MD, PhD, a radiation oncologist and director of metastatic disease radiation oncology research at Memorial Sloan Kettering Cancer Center in New York. “The difference was driven by the substantial response in [this] NSCLC cohort.”
There was no benefit of SBRT seen in the breast cohort, she noted, and most breast patients developed new lesions upon further progression.
Dr. Tsai and colleagues are planning to close the trial early, after the interim analysis established the benefit of SBRT. They are now investigating why SBRT was beneficial in NSCLC but not in breast cancer.
The findings were presented at the American Society for Radiation Oncology (ASTRO) annual meeting.
Dr. Tsai explained that the current standard of care for patients with oligoprogressive metastatic NSCLC is to switch to a different targeted therapy or chemotherapy following progression, but options may be limited. Efficacy for second-line therapy can be poor, with PFS ranging from about 4 months to 10 months for NSCLC, “and after second line, efficacy for third and fourth lines is even poorer,” she said.
Similarly, for breast cancer, PFS ranges from about 9 months to 20 months for estrogen-receptor positive patients. “But for triple negative patients, there really is no standard of care and PFS is poor,” Dr. Tsai said.
SBRT superior to standard of care
The authors hypothesized that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved by applying local therapy to progressive lesions only.
The cohort included 102 patients with metastatic NSCLC or breast cancer who had received one or more lines of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of nonprogressive lesions.
Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤5 individual lesions.
Patients were randomly assigned to receive either SBRT to all progressive sites plus palliative standard of care or systemic SOC only. Systemic therapy was per physician’s discretion.
There were 58 patients with NSCLC (30 in the SBRT group) and 44 patients with breast cancer (22 in each group).
Most patients (75%) had more than one site of oligoprogression and 47% had more than 5 total metastatic lesions. About half of patients (54%) had received immunotherapy and the majority of those with NSCLC (86%) did not harbor an actionable driver mutation. About one-third (32%) of the breast cancer cohort were triple negative.
Patients were followed for a median of 45 weeks (58 weeks for living patients), by which time 78 (74%) had experienced further tumor progression and 39 (37%) had died.
Median progression-free survival for the entire cohort was 31 weeks for SBRT and 11 weeks for palliative SOC (P = .002).
In multivariable analysis that stratified for factors including age, sex, lines of systemic therapy, and change of systemic therapy, the progression-free survival benefit of SBRT continued to remain substantial in the NSCLC cohort (hazard ratio: 0.38; P = .007).
Adverse events were higher in the SBRT group. Grade 2 or higher adverse events occurred in 23 (61%) of SBRT patients, and 15 (40%) of SOC patients (P = .13).
Hoped-for results, with a few caveats
Approached for comment on the new findings, Clifford Robinson, MD, professor of radiation oncology, chief of SBRT service, and director of clinical trials and informatics at Washington University, St. Louis, said the results tie in with previous findings.
There are multiple published or presented prospective randomized phase 2 and 3 trials in various disease sites that have explored the role of local therapy, including SBRT, for patients who present with oligometastatic disease.
“These studies have nearly uniformly shown improvements in progression-free and/or overall survival with the inclusion of local therapy,” he told this news organization. Dr. Robinson was not involved with the study.
He explained that relatively few patients present with oligometastatic disease. However, many patients present with more advanced disease, but after an initial course of systemic therapy, develop oligoprogression.
“There is tremendous appeal to using local therapy at the time of oligoprogression in lieu of switching systemic therapy,” said Dr. Robinson. “It allows patients to stay on systemic therapy that is otherwise effective for the remainder of their disease.”
First-line systemic therapies are the most effective and the most tolerable, he continued, and switching systemic therapy introduces the potential for more toxicity and less efficacy. Therefore, it has become increasingly popular to offer SBRT to one or a few sites of oligoprogressive disease based on the results of oligometastatic disease.
“However, there is no established prospective data to guide this practice,” he said. “This trial is the first to examine this carefully in lung and breast cancer patients, and this trial shows what we hoped to see – that use of SBRT after oligoprogression results in improved progression-free survival as compared with standard of care alone. And this was accomplished with limited toxicity.”
There are a few caveats, though, he pointed out. “Progression-free survival is defined as time to first progression or death,” he said. “Since we don’t know what the overall survival is in this abstract, it’s entirely possible that patients live for the same length of time, but just take longer to progress.”
Another caveat is that this was a planned interim analysis. “Typically, planned interim analyses occur to see if the trial should be stopped or to adjust the study based on results,” he said. “It’s unclear what the investigators will do with this information.”
“But overall, these are very exciting data and lend support to the increasingly common practice of treating oligoprogressive disease,” Dr. Robinson added. “Since most of the serious adverse events of SBRT occur later, longer follow-up is needed, although the median survival of patients may not reach that timepoint.”
“For now, practice should not be altered based on these interim results,” he added.
Dr. Tsai reported acting as a consultant/advisor for Varian and Galera and also receiving research funding from Varian. Dr. Robinson reports stock/ownership in Radialogica, acting as a consultant/advisor for Varian, AstraZeneca, EMD Serono, Quantitative Radiology Solutions, research funding from Varian and Merck, and owning patents on systems for cardiac arrhythmias and ablation.
A version of this article first appeared on Medscape.com.
NCI mammography trial mostly a ‘waste,’ says expert
Funding for this trial is largely misspent money, it may produce misleading results, and it should be abandoned, he says.
Dr. Kopans has been an outspoken critic of the trial, describing it as a “huge waste of money” in comments made last year. Now he has set out his criticisms of the trial in an essay published in the October issue of Clinical Imaging, which outlines his objections and concerns for the first time in a peer-reviewed journal.
The Tomosynthesis Mammographic Imaging Screening Trial (TMIST) is comparing digital breast tomosynthesis (DBT), also known as 3-D mammography, with the older 2-D technology or full-field digital mammography (FFDM).
Dr. Kopans coined the term DBT and formerly held a now-expired patent on the first version of this technology.
“It could be argued that the imaging part of TMIST is a waste of valuable resources,” he writes in the essay.
The “imaging part” of the trial refers to the primary outcome measure and driving purpose of the trial, which is designed to learn which technology is better at finding – and reducing the rate of – potentially lethal “advanced” cancers.
These cancers include larger HER2-positive and triple-negative malignancies; those associated with positive nodes; and metastatic disease. These malignancies correlate with breast cancer mortality, TMIST’s principal investigator Etta Pisano, MD, of the American College of Radiology, has said in the past.
However, Dr. Kopans says that this surrogate endpoint is problematic. “TMIST will only investigate whether or not digital breast tomography results in a decline in advanced cancers, ignoring the fact that many women still die from cancers that are not advanced at the time of diagnosis,” he writes.
“Clearly reducing the rate of advanced cancers is not the only way that early detection saves lives. Lives are also saved by finding cancers at a smaller size within stages,” Dr. Kopans writes. He adds that DBT has been proven in observational cohort studies to find more smaller breast cancers than FFDM.
Dr. Kopans’ opinion that TMIST is largely a waste of resources is not shared by the National Cancer Institute. “We feel strongly that TMIST is a critical study,” an NCI spokesperson told this news organization.
Study power concerns
Another concern is that TMIST “may be underpowered,” Dr. Kopans writes. That concern arises in part from a recent review of TMIST by an advisory committee (that was prompted by low patient accrual rates), which proposed reducing the size of the trial. Dr. Kopans says this would result in “a reduction of the planned power of the trial.”
The NCI says that reducing the study size has been discussed but has not yet been implemented. “Any reduction in size would, of course, have appropriate statistical considerations in mind,” according to the NCI spokesperson.
Dr. Kopans’ concern about statistical power extends beyond downsizing the trial. An advanced cancer in TMIST is counted “if it occurs at any time while the participant is on study,” according to the NCI. Dr. Kopans says that is a problem.
“Since DBT cannot have any effect on advanced cancers in the prevalence year (they are already there), data from the first year (prevalence cancers are likely the largest number) will be unusable, and if used will, inappropriately, dilute the results,” he writes.
Dr. Kopans hopes that the investigators address the statistical power issues with the trial because, if not, “its results may be grossly misleading.”
American radiology practice
Dr. Kopans praises one aspect of TMIST – the trial’s effort to create a repository of blood and oral swab specimens, along with participant genetic data. The goal, say TMIST investigators, is to individualize or optimize screening strategies by tying molecular data to clinical outcomes in the trial.
However, apart from that one aspect, Dr. Kopans is highly critical of the trial.
It is now too late to compare the two technologies, he suggests, as DBT is already replacing FFDM for breast cancer screening in the U.S.
He notes that 76% of mammography facilities in the United States have 3-D devices (as of April 2021). That percentage has climbed steadily in recent years. “By the time the TMIST study is completed, DBT will, almost certainly, have become the ‘standard of care,’” he asserts, echoing others who have commented on the trial, including some participating physicians.
The money being spent on TMIST “should not be used for looking backwards,” says Dr. Kopans.
The NCI responded to that criticism. “TMIST is looking to clarify the best screening for women based on the science and is not solely about access. We are seeking to determine which technology is better and [are] providing access to the trial across the country in diverse practices and populations,” the NCI said in an email.
In his essay, Dr. Kopans says it is time to stop TMIST and put the money into other pressing breast cancer issues and questions. “... it makes no sense to continue this flawed trial whose results will be obsolete by the time they become available,” he writes.
Dr. Kopans reports consulting with DART Imaging in China, which is developing a digital breast tomosynthesis machine.
A version of this article first appeared on Medscape.com.
Funding for this trial is largely misspent money, it may produce misleading results, and it should be abandoned, he says.
Dr. Kopans has been an outspoken critic of the trial, describing it as a “huge waste of money” in comments made last year. Now he has set out his criticisms of the trial in an essay published in the October issue of Clinical Imaging, which outlines his objections and concerns for the first time in a peer-reviewed journal.
The Tomosynthesis Mammographic Imaging Screening Trial (TMIST) is comparing digital breast tomosynthesis (DBT), also known as 3-D mammography, with the older 2-D technology or full-field digital mammography (FFDM).
Dr. Kopans coined the term DBT and formerly held a now-expired patent on the first version of this technology.
“It could be argued that the imaging part of TMIST is a waste of valuable resources,” he writes in the essay.
The “imaging part” of the trial refers to the primary outcome measure and driving purpose of the trial, which is designed to learn which technology is better at finding – and reducing the rate of – potentially lethal “advanced” cancers.
These cancers include larger HER2-positive and triple-negative malignancies; those associated with positive nodes; and metastatic disease. These malignancies correlate with breast cancer mortality, TMIST’s principal investigator Etta Pisano, MD, of the American College of Radiology, has said in the past.
However, Dr. Kopans says that this surrogate endpoint is problematic. “TMIST will only investigate whether or not digital breast tomography results in a decline in advanced cancers, ignoring the fact that many women still die from cancers that are not advanced at the time of diagnosis,” he writes.
“Clearly reducing the rate of advanced cancers is not the only way that early detection saves lives. Lives are also saved by finding cancers at a smaller size within stages,” Dr. Kopans writes. He adds that DBT has been proven in observational cohort studies to find more smaller breast cancers than FFDM.
Dr. Kopans’ opinion that TMIST is largely a waste of resources is not shared by the National Cancer Institute. “We feel strongly that TMIST is a critical study,” an NCI spokesperson told this news organization.
Study power concerns
Another concern is that TMIST “may be underpowered,” Dr. Kopans writes. That concern arises in part from a recent review of TMIST by an advisory committee (that was prompted by low patient accrual rates), which proposed reducing the size of the trial. Dr. Kopans says this would result in “a reduction of the planned power of the trial.”
The NCI says that reducing the study size has been discussed but has not yet been implemented. “Any reduction in size would, of course, have appropriate statistical considerations in mind,” according to the NCI spokesperson.
Dr. Kopans’ concern about statistical power extends beyond downsizing the trial. An advanced cancer in TMIST is counted “if it occurs at any time while the participant is on study,” according to the NCI. Dr. Kopans says that is a problem.
“Since DBT cannot have any effect on advanced cancers in the prevalence year (they are already there), data from the first year (prevalence cancers are likely the largest number) will be unusable, and if used will, inappropriately, dilute the results,” he writes.
Dr. Kopans hopes that the investigators address the statistical power issues with the trial because, if not, “its results may be grossly misleading.”
American radiology practice
Dr. Kopans praises one aspect of TMIST – the trial’s effort to create a repository of blood and oral swab specimens, along with participant genetic data. The goal, say TMIST investigators, is to individualize or optimize screening strategies by tying molecular data to clinical outcomes in the trial.
However, apart from that one aspect, Dr. Kopans is highly critical of the trial.
It is now too late to compare the two technologies, he suggests, as DBT is already replacing FFDM for breast cancer screening in the U.S.
He notes that 76% of mammography facilities in the United States have 3-D devices (as of April 2021). That percentage has climbed steadily in recent years. “By the time the TMIST study is completed, DBT will, almost certainly, have become the ‘standard of care,’” he asserts, echoing others who have commented on the trial, including some participating physicians.
The money being spent on TMIST “should not be used for looking backwards,” says Dr. Kopans.
The NCI responded to that criticism. “TMIST is looking to clarify the best screening for women based on the science and is not solely about access. We are seeking to determine which technology is better and [are] providing access to the trial across the country in diverse practices and populations,” the NCI said in an email.
In his essay, Dr. Kopans says it is time to stop TMIST and put the money into other pressing breast cancer issues and questions. “... it makes no sense to continue this flawed trial whose results will be obsolete by the time they become available,” he writes.
Dr. Kopans reports consulting with DART Imaging in China, which is developing a digital breast tomosynthesis machine.
A version of this article first appeared on Medscape.com.
Funding for this trial is largely misspent money, it may produce misleading results, and it should be abandoned, he says.
Dr. Kopans has been an outspoken critic of the trial, describing it as a “huge waste of money” in comments made last year. Now he has set out his criticisms of the trial in an essay published in the October issue of Clinical Imaging, which outlines his objections and concerns for the first time in a peer-reviewed journal.
The Tomosynthesis Mammographic Imaging Screening Trial (TMIST) is comparing digital breast tomosynthesis (DBT), also known as 3-D mammography, with the older 2-D technology or full-field digital mammography (FFDM).
Dr. Kopans coined the term DBT and formerly held a now-expired patent on the first version of this technology.
“It could be argued that the imaging part of TMIST is a waste of valuable resources,” he writes in the essay.
The “imaging part” of the trial refers to the primary outcome measure and driving purpose of the trial, which is designed to learn which technology is better at finding – and reducing the rate of – potentially lethal “advanced” cancers.
These cancers include larger HER2-positive and triple-negative malignancies; those associated with positive nodes; and metastatic disease. These malignancies correlate with breast cancer mortality, TMIST’s principal investigator Etta Pisano, MD, of the American College of Radiology, has said in the past.
However, Dr. Kopans says that this surrogate endpoint is problematic. “TMIST will only investigate whether or not digital breast tomography results in a decline in advanced cancers, ignoring the fact that many women still die from cancers that are not advanced at the time of diagnosis,” he writes.
“Clearly reducing the rate of advanced cancers is not the only way that early detection saves lives. Lives are also saved by finding cancers at a smaller size within stages,” Dr. Kopans writes. He adds that DBT has been proven in observational cohort studies to find more smaller breast cancers than FFDM.
Dr. Kopans’ opinion that TMIST is largely a waste of resources is not shared by the National Cancer Institute. “We feel strongly that TMIST is a critical study,” an NCI spokesperson told this news organization.
Study power concerns
Another concern is that TMIST “may be underpowered,” Dr. Kopans writes. That concern arises in part from a recent review of TMIST by an advisory committee (that was prompted by low patient accrual rates), which proposed reducing the size of the trial. Dr. Kopans says this would result in “a reduction of the planned power of the trial.”
The NCI says that reducing the study size has been discussed but has not yet been implemented. “Any reduction in size would, of course, have appropriate statistical considerations in mind,” according to the NCI spokesperson.
Dr. Kopans’ concern about statistical power extends beyond downsizing the trial. An advanced cancer in TMIST is counted “if it occurs at any time while the participant is on study,” according to the NCI. Dr. Kopans says that is a problem.
“Since DBT cannot have any effect on advanced cancers in the prevalence year (they are already there), data from the first year (prevalence cancers are likely the largest number) will be unusable, and if used will, inappropriately, dilute the results,” he writes.
Dr. Kopans hopes that the investigators address the statistical power issues with the trial because, if not, “its results may be grossly misleading.”
American radiology practice
Dr. Kopans praises one aspect of TMIST – the trial’s effort to create a repository of blood and oral swab specimens, along with participant genetic data. The goal, say TMIST investigators, is to individualize or optimize screening strategies by tying molecular data to clinical outcomes in the trial.
However, apart from that one aspect, Dr. Kopans is highly critical of the trial.
It is now too late to compare the two technologies, he suggests, as DBT is already replacing FFDM for breast cancer screening in the U.S.
He notes that 76% of mammography facilities in the United States have 3-D devices (as of April 2021). That percentage has climbed steadily in recent years. “By the time the TMIST study is completed, DBT will, almost certainly, have become the ‘standard of care,’” he asserts, echoing others who have commented on the trial, including some participating physicians.
The money being spent on TMIST “should not be used for looking backwards,” says Dr. Kopans.
The NCI responded to that criticism. “TMIST is looking to clarify the best screening for women based on the science and is not solely about access. We are seeking to determine which technology is better and [are] providing access to the trial across the country in diverse practices and populations,” the NCI said in an email.
In his essay, Dr. Kopans says it is time to stop TMIST and put the money into other pressing breast cancer issues and questions. “... it makes no sense to continue this flawed trial whose results will be obsolete by the time they become available,” he writes.
Dr. Kopans reports consulting with DART Imaging in China, which is developing a digital breast tomosynthesis machine.
A version of this article first appeared on Medscape.com.
Prostate cancer risk higher with Lynch syndrome variants
Men who carry certain pathogenic variants in mismatch repair genes that characterize Lynch syndrome may have a higher risk of prostate cancer, shows a new study. However, for men who carry MSH2 and MSH6 variants, the risk of contracting cancer rises significantly.
Called IMPACT, the study, which was published online in The Lancet Oncology, is an international, prospective study of 828 men aged between 40 and 69 years who were prostate cancer free, but they carried germline pathogenic variants in one of the mismatch repair genes MLH1, MSH2, or MSH6.
The researchers, who were led by Rosalind A. Eeles, PhD, a specialist in oncogenetics with the Institute of Cancer Research, London, found that after one screening “a higher incidence of prostate cancer was detected in men with MSH2 and MHS6 pathogenic variants, compared with age-matched noncarrier controls.”
She and her team also found that MSH2 carriers “were diagnosed at a nonsignificantly younger age and had more clinically significant disease at diagnosis, compared with noncarriers. These data add evidence that prostate screening in this higher-risk context has potential to detect tumors that are highly likely to need treatment.”
The findings suggest that targeted prostate-specific antigen (PSA) screening in men with mismatch repair gene pathogenic variants is justifiable. “Testing for mismatch repair variants will likely become routine practice at diagnosis over the coming years,” the authors wrote.
Lynch syndrome can increase the risk of prostate cancer by 2-10 times, yet there is no international consensus for screening. The 2019 National Comprehensive Cancer Network guidelines recommend considering tumor testing for deficient mismatch repair in men with regional or metastatic prostate cancer. The NCCN also recommends germline testing for all newly diagnosed men with high-risk, very-high-risk, regional, or metastatic prostate cancer.
Currently, the PSA test is the most commonly used test, however, it is not recommended as a routine screening tool because of the negative consequences of overdetection. The American Cancer Society and European Association of Urology recommend PSA screening for men with a strong family history of prostate cancer. The EAU also supports annual PSA screening for men with BRCA2 variants.
“From a treatment perspective, knowledge of mismatch repair pathogenic variant status is increasingly important because of the evidence that mismatch repair-deficient prostate tumors can be sensitive to immune checkpoint inhibitors,” the investigators wrote.
NCCN guidelines support the use of the progressive death–1 inhibitor pembrolizumab (Keytruda, Merck) in these patients, among others.
Although immune checkpoint inhibitors are predominantly used to treat metastatic disease, “this field is rapidly evolving and we will likely see these treatments move earlier in the treatment pathway,” the authors predicted.
The findings in detail
The IMPACT study was established in 2005 to assess targeted PSA screening in men with BRCA1 or BRCA2 pathogenic variants. It was extended in 2012 to include men from families with MLH1, MSH2, and MSH6 pathogenic variants.
In this new report, within the first round of screening, 6% of the cohort had a PSA concentration higher than 3.0 ng/mL and the overall incidence of prostate cancer was 1.9%, the investigators noted.
MSH2 carriers were diagnosed at 58 years old on average, compared with 66 years old for the control group. MSH2-positive men had more clinically significant disease, compared with noncarriers. The incidence of prostate cancer was higher at 4.3% in MSH2 carriers than in controls at 0.5%. In MSH6 carriers, the incidence of prostate cancer was 3.0%, compared with 0% for controls.
Only 4% of men underwent a biopsy and only one cancer was found among the MSH2 noncarriers while no cancers were found in MLH1 carriers, MLH1 noncarriers, or MSH6 noncarriers.
The overall positive predictive value of using a PSA threshold of 3.0 ng/mL was 51.4%; separated by genetic status, the PPV in MSH2 carriers was higher at 72.2% and in MSH6 carriers, the PPV was 80%, the researchers noted.
Limitations of the study include the fact that the number of cancers detected in the study was relatively small, thus requiring further data from subsequent screening rounds.
One study coauthor disclosed a potential conflict of interest by holding a PSA test patent.
Men who carry certain pathogenic variants in mismatch repair genes that characterize Lynch syndrome may have a higher risk of prostate cancer, shows a new study. However, for men who carry MSH2 and MSH6 variants, the risk of contracting cancer rises significantly.
Called IMPACT, the study, which was published online in The Lancet Oncology, is an international, prospective study of 828 men aged between 40 and 69 years who were prostate cancer free, but they carried germline pathogenic variants in one of the mismatch repair genes MLH1, MSH2, or MSH6.
The researchers, who were led by Rosalind A. Eeles, PhD, a specialist in oncogenetics with the Institute of Cancer Research, London, found that after one screening “a higher incidence of prostate cancer was detected in men with MSH2 and MHS6 pathogenic variants, compared with age-matched noncarrier controls.”
She and her team also found that MSH2 carriers “were diagnosed at a nonsignificantly younger age and had more clinically significant disease at diagnosis, compared with noncarriers. These data add evidence that prostate screening in this higher-risk context has potential to detect tumors that are highly likely to need treatment.”
The findings suggest that targeted prostate-specific antigen (PSA) screening in men with mismatch repair gene pathogenic variants is justifiable. “Testing for mismatch repair variants will likely become routine practice at diagnosis over the coming years,” the authors wrote.
Lynch syndrome can increase the risk of prostate cancer by 2-10 times, yet there is no international consensus for screening. The 2019 National Comprehensive Cancer Network guidelines recommend considering tumor testing for deficient mismatch repair in men with regional or metastatic prostate cancer. The NCCN also recommends germline testing for all newly diagnosed men with high-risk, very-high-risk, regional, or metastatic prostate cancer.
Currently, the PSA test is the most commonly used test, however, it is not recommended as a routine screening tool because of the negative consequences of overdetection. The American Cancer Society and European Association of Urology recommend PSA screening for men with a strong family history of prostate cancer. The EAU also supports annual PSA screening for men with BRCA2 variants.
“From a treatment perspective, knowledge of mismatch repair pathogenic variant status is increasingly important because of the evidence that mismatch repair-deficient prostate tumors can be sensitive to immune checkpoint inhibitors,” the investigators wrote.
NCCN guidelines support the use of the progressive death–1 inhibitor pembrolizumab (Keytruda, Merck) in these patients, among others.
Although immune checkpoint inhibitors are predominantly used to treat metastatic disease, “this field is rapidly evolving and we will likely see these treatments move earlier in the treatment pathway,” the authors predicted.
The findings in detail
The IMPACT study was established in 2005 to assess targeted PSA screening in men with BRCA1 or BRCA2 pathogenic variants. It was extended in 2012 to include men from families with MLH1, MSH2, and MSH6 pathogenic variants.
In this new report, within the first round of screening, 6% of the cohort had a PSA concentration higher than 3.0 ng/mL and the overall incidence of prostate cancer was 1.9%, the investigators noted.
MSH2 carriers were diagnosed at 58 years old on average, compared with 66 years old for the control group. MSH2-positive men had more clinically significant disease, compared with noncarriers. The incidence of prostate cancer was higher at 4.3% in MSH2 carriers than in controls at 0.5%. In MSH6 carriers, the incidence of prostate cancer was 3.0%, compared with 0% for controls.
Only 4% of men underwent a biopsy and only one cancer was found among the MSH2 noncarriers while no cancers were found in MLH1 carriers, MLH1 noncarriers, or MSH6 noncarriers.
The overall positive predictive value of using a PSA threshold of 3.0 ng/mL was 51.4%; separated by genetic status, the PPV in MSH2 carriers was higher at 72.2% and in MSH6 carriers, the PPV was 80%, the researchers noted.
Limitations of the study include the fact that the number of cancers detected in the study was relatively small, thus requiring further data from subsequent screening rounds.
One study coauthor disclosed a potential conflict of interest by holding a PSA test patent.
Men who carry certain pathogenic variants in mismatch repair genes that characterize Lynch syndrome may have a higher risk of prostate cancer, shows a new study. However, for men who carry MSH2 and MSH6 variants, the risk of contracting cancer rises significantly.
Called IMPACT, the study, which was published online in The Lancet Oncology, is an international, prospective study of 828 men aged between 40 and 69 years who were prostate cancer free, but they carried germline pathogenic variants in one of the mismatch repair genes MLH1, MSH2, or MSH6.
The researchers, who were led by Rosalind A. Eeles, PhD, a specialist in oncogenetics with the Institute of Cancer Research, London, found that after one screening “a higher incidence of prostate cancer was detected in men with MSH2 and MHS6 pathogenic variants, compared with age-matched noncarrier controls.”
She and her team also found that MSH2 carriers “were diagnosed at a nonsignificantly younger age and had more clinically significant disease at diagnosis, compared with noncarriers. These data add evidence that prostate screening in this higher-risk context has potential to detect tumors that are highly likely to need treatment.”
The findings suggest that targeted prostate-specific antigen (PSA) screening in men with mismatch repair gene pathogenic variants is justifiable. “Testing for mismatch repair variants will likely become routine practice at diagnosis over the coming years,” the authors wrote.
Lynch syndrome can increase the risk of prostate cancer by 2-10 times, yet there is no international consensus for screening. The 2019 National Comprehensive Cancer Network guidelines recommend considering tumor testing for deficient mismatch repair in men with regional or metastatic prostate cancer. The NCCN also recommends germline testing for all newly diagnosed men with high-risk, very-high-risk, regional, or metastatic prostate cancer.
Currently, the PSA test is the most commonly used test, however, it is not recommended as a routine screening tool because of the negative consequences of overdetection. The American Cancer Society and European Association of Urology recommend PSA screening for men with a strong family history of prostate cancer. The EAU also supports annual PSA screening for men with BRCA2 variants.
“From a treatment perspective, knowledge of mismatch repair pathogenic variant status is increasingly important because of the evidence that mismatch repair-deficient prostate tumors can be sensitive to immune checkpoint inhibitors,” the investigators wrote.
NCCN guidelines support the use of the progressive death–1 inhibitor pembrolizumab (Keytruda, Merck) in these patients, among others.
Although immune checkpoint inhibitors are predominantly used to treat metastatic disease, “this field is rapidly evolving and we will likely see these treatments move earlier in the treatment pathway,” the authors predicted.
The findings in detail
The IMPACT study was established in 2005 to assess targeted PSA screening in men with BRCA1 or BRCA2 pathogenic variants. It was extended in 2012 to include men from families with MLH1, MSH2, and MSH6 pathogenic variants.
In this new report, within the first round of screening, 6% of the cohort had a PSA concentration higher than 3.0 ng/mL and the overall incidence of prostate cancer was 1.9%, the investigators noted.
MSH2 carriers were diagnosed at 58 years old on average, compared with 66 years old for the control group. MSH2-positive men had more clinically significant disease, compared with noncarriers. The incidence of prostate cancer was higher at 4.3% in MSH2 carriers than in controls at 0.5%. In MSH6 carriers, the incidence of prostate cancer was 3.0%, compared with 0% for controls.
Only 4% of men underwent a biopsy and only one cancer was found among the MSH2 noncarriers while no cancers were found in MLH1 carriers, MLH1 noncarriers, or MSH6 noncarriers.
The overall positive predictive value of using a PSA threshold of 3.0 ng/mL was 51.4%; separated by genetic status, the PPV in MSH2 carriers was higher at 72.2% and in MSH6 carriers, the PPV was 80%, the researchers noted.
Limitations of the study include the fact that the number of cancers detected in the study was relatively small, thus requiring further data from subsequent screening rounds.
One study coauthor disclosed a potential conflict of interest by holding a PSA test patent.
FROM LANCET ONCOLOGY
AGA Clinical Practice Update: Managing pain in gut-brain interaction disorders
An American Gastroenterological Association clinical practice update for gastrointestinal pain in disorders of gut-brain interaction (DGBI), published in Clinical Gastroenterology and Hepatology, emphasizes patient-physician collaboration and improvement of patient understanding of the pathways and mechanisms of pain sensations. It is aimed at management of patients in whom pain persists after first-line therapies fail to resolve visceral causes of pain.
DGBIs include irritable bowel syndrome, functional dyspepsia, and centrally mediated abdominal pain syndrome, according to Laurie Keefer, PhD, AGAF, of the division of gastroenterology at Icahn School of Medicine at Mount Sinai, New York, and colleagues. Initial treatment usually focuses on visceral triggers of pain such as food and bowel movements, but this approach is ineffective for many.
Cognitive, affective, and behavioral factors can impact the treatment of these patients, making it a complex clinical problem that calls for a collaborative approach between the patient and clinician. Opioids and other drugs that could be misused should be avoided, according to the authors. Both pharmacologic and nonpharmacologic approaches can be considered, but the update did not address use of marijuana or other complementary or alternative therapies.
Effective management requires empathy and collaboration. The patient has often seen various other clinicians with suboptimal results, which has left them dissatisfied with their care. Cultural sensitivity is crucial because the understanding and interpretation of pain, and preferred management approaches, vary across cultures.
The first step is a nonjudgmental patient history using open-ended questions. Examples include: “How do your symptoms interfere with your ability to do what you want in your daily life?” or “How are these symptoms impacting your life the most?” These types of questions may identify patients who could benefit from behavioral health interventions.
Questions about symptom-related anxiety can improve understanding of patient concerns and offer an opportunity to address fears. Additional understanding of the patient’s perspective can come from questions like: “What do you think is causing your symptoms,” “Why are you coming to see me now?” and “What are you most concerned about with your symptoms?”
The initial assessment should ideally result in shared goals and expectations for pain management.
Providers should educate the patient about the pathogenesis of pain and how it can be modified. Pain signals can result from innocuous signals from the gut that are misinterpreted by the vigilant brain as it scans for injury or illness. That model might explain why some patients with similar diagnoses have widely differing pain experiences, and offers hope that a change in how one approaches pain might lead to improvements. Patients should be encouraged to avoid too much focus on the cause or a solution to pain, because it can interfere with acceptance of pain or, when needed, treatment.
Opioids should not be prescribed for these patients, and if they are already taking them on referral, it’s important to manage them within a multidisciplinary framework until the opioids can be discontinued. Long-term use of opioids can lead to narcotic bowel syndrome, which results in chronic and often heightened abdominal pain even with escalating opioid doses. Opioid stoppage often must be accompanied by behavioral and psychiatric therapies to ensure success.
Nonpharmacological therapies such as brain-gut psychotherapies should be brought up as potential options early in treatment, even though many patients won’t require this type of care. Early mention is likely to keep the patient more open to trying them because they’re less likely to think of it as a sign of failure or a “last-ditch” approach. Cognitive-behavioral therapy works to improve pain management skills and bolster skill deficits, with attention to pain catastrophizing, pain hypervigilance, and visceral anxiety through different techniques.
Gut-directed hypnotherapy deals with somatic awareness and the use of imagery and suggestion to reduce pain sensations. Mindfulness-based stress reduction has been shown to be effective in inflammatory bowel disease and musculoskeletal pain syndromes. The provider should be familiar with these available methods, but should leave choice of interventions to partner mental health providers.
It’s important to distinguish between gastrointestinal pain with visceral causes and centrally mediated pain. Central sensitization can cause intermittent pain to become persistent even in the absence of ongoing peripheral causes of pain.
Peripheral acting agents affect gastrointestinal pain, and a network meta-analysis identified the top three drugs for pain relief in irritable bowel syndrome as tricyclic antidepressants, antispasmodics, and peppermint oil.
Neuromodulator drugs are an option for DGBI pain because the gut nervous system shares embryonic developmental pathways with the brain and spinal cord, which helps explains some of the benefits of low-dose antidepressants, now termed gut-brain neuromodulators. These drugs should be started at a low dose and gradually titrated according to symptom response and tolerability.
The authors have financial relationships with various pharmaceutical companies.
An American Gastroenterological Association clinical practice update for gastrointestinal pain in disorders of gut-brain interaction (DGBI), published in Clinical Gastroenterology and Hepatology, emphasizes patient-physician collaboration and improvement of patient understanding of the pathways and mechanisms of pain sensations. It is aimed at management of patients in whom pain persists after first-line therapies fail to resolve visceral causes of pain.
DGBIs include irritable bowel syndrome, functional dyspepsia, and centrally mediated abdominal pain syndrome, according to Laurie Keefer, PhD, AGAF, of the division of gastroenterology at Icahn School of Medicine at Mount Sinai, New York, and colleagues. Initial treatment usually focuses on visceral triggers of pain such as food and bowel movements, but this approach is ineffective for many.
Cognitive, affective, and behavioral factors can impact the treatment of these patients, making it a complex clinical problem that calls for a collaborative approach between the patient and clinician. Opioids and other drugs that could be misused should be avoided, according to the authors. Both pharmacologic and nonpharmacologic approaches can be considered, but the update did not address use of marijuana or other complementary or alternative therapies.
Effective management requires empathy and collaboration. The patient has often seen various other clinicians with suboptimal results, which has left them dissatisfied with their care. Cultural sensitivity is crucial because the understanding and interpretation of pain, and preferred management approaches, vary across cultures.
The first step is a nonjudgmental patient history using open-ended questions. Examples include: “How do your symptoms interfere with your ability to do what you want in your daily life?” or “How are these symptoms impacting your life the most?” These types of questions may identify patients who could benefit from behavioral health interventions.
Questions about symptom-related anxiety can improve understanding of patient concerns and offer an opportunity to address fears. Additional understanding of the patient’s perspective can come from questions like: “What do you think is causing your symptoms,” “Why are you coming to see me now?” and “What are you most concerned about with your symptoms?”
The initial assessment should ideally result in shared goals and expectations for pain management.
Providers should educate the patient about the pathogenesis of pain and how it can be modified. Pain signals can result from innocuous signals from the gut that are misinterpreted by the vigilant brain as it scans for injury or illness. That model might explain why some patients with similar diagnoses have widely differing pain experiences, and offers hope that a change in how one approaches pain might lead to improvements. Patients should be encouraged to avoid too much focus on the cause or a solution to pain, because it can interfere with acceptance of pain or, when needed, treatment.
Opioids should not be prescribed for these patients, and if they are already taking them on referral, it’s important to manage them within a multidisciplinary framework until the opioids can be discontinued. Long-term use of opioids can lead to narcotic bowel syndrome, which results in chronic and often heightened abdominal pain even with escalating opioid doses. Opioid stoppage often must be accompanied by behavioral and psychiatric therapies to ensure success.
Nonpharmacological therapies such as brain-gut psychotherapies should be brought up as potential options early in treatment, even though many patients won’t require this type of care. Early mention is likely to keep the patient more open to trying them because they’re less likely to think of it as a sign of failure or a “last-ditch” approach. Cognitive-behavioral therapy works to improve pain management skills and bolster skill deficits, with attention to pain catastrophizing, pain hypervigilance, and visceral anxiety through different techniques.
Gut-directed hypnotherapy deals with somatic awareness and the use of imagery and suggestion to reduce pain sensations. Mindfulness-based stress reduction has been shown to be effective in inflammatory bowel disease and musculoskeletal pain syndromes. The provider should be familiar with these available methods, but should leave choice of interventions to partner mental health providers.
It’s important to distinguish between gastrointestinal pain with visceral causes and centrally mediated pain. Central sensitization can cause intermittent pain to become persistent even in the absence of ongoing peripheral causes of pain.
Peripheral acting agents affect gastrointestinal pain, and a network meta-analysis identified the top three drugs for pain relief in irritable bowel syndrome as tricyclic antidepressants, antispasmodics, and peppermint oil.
Neuromodulator drugs are an option for DGBI pain because the gut nervous system shares embryonic developmental pathways with the brain and spinal cord, which helps explains some of the benefits of low-dose antidepressants, now termed gut-brain neuromodulators. These drugs should be started at a low dose and gradually titrated according to symptom response and tolerability.
The authors have financial relationships with various pharmaceutical companies.
An American Gastroenterological Association clinical practice update for gastrointestinal pain in disorders of gut-brain interaction (DGBI), published in Clinical Gastroenterology and Hepatology, emphasizes patient-physician collaboration and improvement of patient understanding of the pathways and mechanisms of pain sensations. It is aimed at management of patients in whom pain persists after first-line therapies fail to resolve visceral causes of pain.
DGBIs include irritable bowel syndrome, functional dyspepsia, and centrally mediated abdominal pain syndrome, according to Laurie Keefer, PhD, AGAF, of the division of gastroenterology at Icahn School of Medicine at Mount Sinai, New York, and colleagues. Initial treatment usually focuses on visceral triggers of pain such as food and bowel movements, but this approach is ineffective for many.
Cognitive, affective, and behavioral factors can impact the treatment of these patients, making it a complex clinical problem that calls for a collaborative approach between the patient and clinician. Opioids and other drugs that could be misused should be avoided, according to the authors. Both pharmacologic and nonpharmacologic approaches can be considered, but the update did not address use of marijuana or other complementary or alternative therapies.
Effective management requires empathy and collaboration. The patient has often seen various other clinicians with suboptimal results, which has left them dissatisfied with their care. Cultural sensitivity is crucial because the understanding and interpretation of pain, and preferred management approaches, vary across cultures.
The first step is a nonjudgmental patient history using open-ended questions. Examples include: “How do your symptoms interfere with your ability to do what you want in your daily life?” or “How are these symptoms impacting your life the most?” These types of questions may identify patients who could benefit from behavioral health interventions.
Questions about symptom-related anxiety can improve understanding of patient concerns and offer an opportunity to address fears. Additional understanding of the patient’s perspective can come from questions like: “What do you think is causing your symptoms,” “Why are you coming to see me now?” and “What are you most concerned about with your symptoms?”
The initial assessment should ideally result in shared goals and expectations for pain management.
Providers should educate the patient about the pathogenesis of pain and how it can be modified. Pain signals can result from innocuous signals from the gut that are misinterpreted by the vigilant brain as it scans for injury or illness. That model might explain why some patients with similar diagnoses have widely differing pain experiences, and offers hope that a change in how one approaches pain might lead to improvements. Patients should be encouraged to avoid too much focus on the cause or a solution to pain, because it can interfere with acceptance of pain or, when needed, treatment.
Opioids should not be prescribed for these patients, and if they are already taking them on referral, it’s important to manage them within a multidisciplinary framework until the opioids can be discontinued. Long-term use of opioids can lead to narcotic bowel syndrome, which results in chronic and often heightened abdominal pain even with escalating opioid doses. Opioid stoppage often must be accompanied by behavioral and psychiatric therapies to ensure success.
Nonpharmacological therapies such as brain-gut psychotherapies should be brought up as potential options early in treatment, even though many patients won’t require this type of care. Early mention is likely to keep the patient more open to trying them because they’re less likely to think of it as a sign of failure or a “last-ditch” approach. Cognitive-behavioral therapy works to improve pain management skills and bolster skill deficits, with attention to pain catastrophizing, pain hypervigilance, and visceral anxiety through different techniques.
Gut-directed hypnotherapy deals with somatic awareness and the use of imagery and suggestion to reduce pain sensations. Mindfulness-based stress reduction has been shown to be effective in inflammatory bowel disease and musculoskeletal pain syndromes. The provider should be familiar with these available methods, but should leave choice of interventions to partner mental health providers.
It’s important to distinguish between gastrointestinal pain with visceral causes and centrally mediated pain. Central sensitization can cause intermittent pain to become persistent even in the absence of ongoing peripheral causes of pain.
Peripheral acting agents affect gastrointestinal pain, and a network meta-analysis identified the top three drugs for pain relief in irritable bowel syndrome as tricyclic antidepressants, antispasmodics, and peppermint oil.
Neuromodulator drugs are an option for DGBI pain because the gut nervous system shares embryonic developmental pathways with the brain and spinal cord, which helps explains some of the benefits of low-dose antidepressants, now termed gut-brain neuromodulators. These drugs should be started at a low dose and gradually titrated according to symptom response and tolerability.
The authors have financial relationships with various pharmaceutical companies.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Expected spike in acute flaccid myelitis did not occur in 2020
suggested researchers at the Centers for Disease Control and Prevention.
Acute flaccid myelitis (AFM) is an uncommon but serious complication of some viral infections, including West Nile virus and nonpolio enteroviruses. It is “characterized by sudden onset of limb weakness and lesions in the gray matter of the spinal cord,” they said, and more than 90% of cases occur in young children.
Cases of AFM, which can lead to respiratory insufficiency and permanent paralysis, spiked during the late summer and early fall in 2014, 2016, and 2018 and were expected to do so again in 2020, Sarah Kidd, MD, and associates at the division of viral diseases at the CDC’s National Center for Immunization and Respiratory Diseases, Atlanta, said in the Morbidity and Mortality Weekly Report.
Monthly peaks in those previous years – each occurring in September – reached 51 cases in 2014, 43 cases in 2016, and 88 cases in 2018, but in 2020 there was only 1 case reported in September, with a high of 4 coming in May, CDC data show. The total number of cases for 2020 (32) was, in fact, lower than in 2019, when 47 were reported.
The investigators’ main objective was to see if there were any differences between the 2018 and 2019-2020 cases. Reports from state health departments to the CDC showed that, in 2019-2020, “patients were older; more likely to have lower limb involvement; and less likely to have upper limb involvement, prodromal illness, [cerebrospinal fluid] pleocytosis, or specimens that tested positive for EV [enterovirus]-D68” than patients from 2018, Dr. Kidd and associates said.
Mask wearing and reduced in-school attendance may have decreased circulation of EV-D68 – the enterovirus type most often detected in the stool and respiratory specimens of AFM patients – as was seen with other respiratory viruses, such as influenza and respiratory syncytial virus, in 2020. Previous studies have suggested that EV-D68 drives the increases in cases during peak years, the researchers noted.
The absence of such an increase “in 2020 reflects a deviation from the previously observed biennial pattern, and it is unclear when the next increase in AFM should be expected. Clinicians should continue to maintain vigilance and suspect AFM in any child with acute flaccid limb weakness, particularly in the setting of recent febrile or respiratory illness,” they wrote.
suggested researchers at the Centers for Disease Control and Prevention.
Acute flaccid myelitis (AFM) is an uncommon but serious complication of some viral infections, including West Nile virus and nonpolio enteroviruses. It is “characterized by sudden onset of limb weakness and lesions in the gray matter of the spinal cord,” they said, and more than 90% of cases occur in young children.
Cases of AFM, which can lead to respiratory insufficiency and permanent paralysis, spiked during the late summer and early fall in 2014, 2016, and 2018 and were expected to do so again in 2020, Sarah Kidd, MD, and associates at the division of viral diseases at the CDC’s National Center for Immunization and Respiratory Diseases, Atlanta, said in the Morbidity and Mortality Weekly Report.
Monthly peaks in those previous years – each occurring in September – reached 51 cases in 2014, 43 cases in 2016, and 88 cases in 2018, but in 2020 there was only 1 case reported in September, with a high of 4 coming in May, CDC data show. The total number of cases for 2020 (32) was, in fact, lower than in 2019, when 47 were reported.
The investigators’ main objective was to see if there were any differences between the 2018 and 2019-2020 cases. Reports from state health departments to the CDC showed that, in 2019-2020, “patients were older; more likely to have lower limb involvement; and less likely to have upper limb involvement, prodromal illness, [cerebrospinal fluid] pleocytosis, or specimens that tested positive for EV [enterovirus]-D68” than patients from 2018, Dr. Kidd and associates said.
Mask wearing and reduced in-school attendance may have decreased circulation of EV-D68 – the enterovirus type most often detected in the stool and respiratory specimens of AFM patients – as was seen with other respiratory viruses, such as influenza and respiratory syncytial virus, in 2020. Previous studies have suggested that EV-D68 drives the increases in cases during peak years, the researchers noted.
The absence of such an increase “in 2020 reflects a deviation from the previously observed biennial pattern, and it is unclear when the next increase in AFM should be expected. Clinicians should continue to maintain vigilance and suspect AFM in any child with acute flaccid limb weakness, particularly in the setting of recent febrile or respiratory illness,” they wrote.
suggested researchers at the Centers for Disease Control and Prevention.
Acute flaccid myelitis (AFM) is an uncommon but serious complication of some viral infections, including West Nile virus and nonpolio enteroviruses. It is “characterized by sudden onset of limb weakness and lesions in the gray matter of the spinal cord,” they said, and more than 90% of cases occur in young children.
Cases of AFM, which can lead to respiratory insufficiency and permanent paralysis, spiked during the late summer and early fall in 2014, 2016, and 2018 and were expected to do so again in 2020, Sarah Kidd, MD, and associates at the division of viral diseases at the CDC’s National Center for Immunization and Respiratory Diseases, Atlanta, said in the Morbidity and Mortality Weekly Report.
Monthly peaks in those previous years – each occurring in September – reached 51 cases in 2014, 43 cases in 2016, and 88 cases in 2018, but in 2020 there was only 1 case reported in September, with a high of 4 coming in May, CDC data show. The total number of cases for 2020 (32) was, in fact, lower than in 2019, when 47 were reported.
The investigators’ main objective was to see if there were any differences between the 2018 and 2019-2020 cases. Reports from state health departments to the CDC showed that, in 2019-2020, “patients were older; more likely to have lower limb involvement; and less likely to have upper limb involvement, prodromal illness, [cerebrospinal fluid] pleocytosis, or specimens that tested positive for EV [enterovirus]-D68” than patients from 2018, Dr. Kidd and associates said.
Mask wearing and reduced in-school attendance may have decreased circulation of EV-D68 – the enterovirus type most often detected in the stool and respiratory specimens of AFM patients – as was seen with other respiratory viruses, such as influenza and respiratory syncytial virus, in 2020. Previous studies have suggested that EV-D68 drives the increases in cases during peak years, the researchers noted.
The absence of such an increase “in 2020 reflects a deviation from the previously observed biennial pattern, and it is unclear when the next increase in AFM should be expected. Clinicians should continue to maintain vigilance and suspect AFM in any child with acute flaccid limb weakness, particularly in the setting of recent febrile or respiratory illness,” they wrote.
FROM MMWR
Does zinc really help treat colds?
A new study published in BMJ Open adds to the evidence that zinc is effective against viral respiratory infections, such as colds.
Jennifer Hunter, PhD, BMed, of Western Sydney University’s NICM Health Research Institute, New South Wales, Australia, and colleagues conducted a meta-analysis of 28 randomized controlled trials (RCTs). They searched 17 English and Chinese databases to identify the trials and then used the Cochrane rapid review technique for the analysis.
The trials included 5,446 adults who had received zinc in a variety of formulations and routes — oral, sublingual, and nasal spray. The researchers separately analyzed whether zinc prevented or treated respiratory tract infections (RTIs)
Oral or intranasal zinc prevented five RTIs per 100 person-months (95% CI, 1 – 8; numbers needed to treat, 20). There was a 32% lower relative risk (RR) of developing mild to moderate symptoms consistent with a viral RTI.
Use of zinc was also associated with an 87% lower risk of developing moderately severe symptoms (incidence rate ratio, 0.13; 95% CI, 0.04 – 0.38) and a 28% lower risk of developing milder symptoms. The largest reductions in RR were for moderately severe symptoms consistent with an influenza-like illness.
Symptoms resolved 2 days earlier with sublingual or intranasal zinc compared with placebo (95% CI, 0.61 – 3.50; very low-certainty quality of evidence). There were clinically significant reductions in day 3 symptom severity scores (mean difference, -1.20 points; 95% CI, -0.66 to -1.74; low-certainty quality of evidence) but not in overall symptom severity. Participants who used sublingual or topical nasal zinc early in the course of illness were 1.8 times more likely to recover before those who used a placebo.
However, the investigators found no benefit of zinc when patients were inoculated with rhinovirus; there was no reduction in the risk of developing a cold. Asked about this disparity, Dr. Hunter said, “It might well be that when inoculating people to make sure they get infected, you give them a really high dose of the virus. [This] doesn’t really mimic what happens in the real world.”
On the downside of supplemental zinc, there were more side effects among those who used zinc, including nausea or gastrointestinal discomfort, mouth irritation, or soreness from sublingual lozenges (RR, 1.41; 95% CI, 1.17 – 1.69; number needed to harm, 7; moderate-certainty quality of evidence). The risk for a serious adverse event, such as loss of smell or copper deficiency, was low. Although not found in these studies, postmarketing studies have found that there is a risk for severe and in some cases permanent loss of smell associated with the use of nasal gels or sprays containing zinc. Three such products were recalled from the market.
The trial could not provide answers about the comparative efficacy of different types of zinc formulations, nor could the investigators recommend specific doses. The trial was not designed to assess zinc for the prevention or treatment of COVID-19.
Asked for independent comment, pediatrician Aamer Imdad, MBBS, assistant professor at the State University of New York Upstate Medical University, Syracuse, told this news organization, “It’s a very comprehensive review for zinc-related studies in adults” but was challenging because of the “significant clinical heterogeneity in the population.”
Dr. Imdad explained that zinc has “absolutely” been shown to be effective for children with diarrhea. The World Health Organization has recommended it since 2004. “The way it works in diarrhea is that it helps with the regeneration of the epithelium.... It also improves the immunity itself, especially the cell-mediated immunity.” He raised the question of whether it might work similarly in the respiratory tract. Dr. Imdad has a long-standing interest in the use of zinc for pediatric infections. Regarding this study, he concluded, “I think we still need to know the nuts and bolts of this intervention before we can recommend it more specifically.”
Dr. Hunter said, “We don’t have any high-quality studies that have evaluated zinc orally as treatment once you’re actually infected and have symptoms of the cold or influenza, or COVID.”
Asked about zinc’s possible role, Dr. Hunter said, “So I do think it gives us a viable alternative. More people are going, ‘What can I do?’ And you know as well as I do people come to you, and [they say], ‘Well, just give me something. Even if it’s a day or a little bit of symptom relief, anything to make me feel better that isn’t going to hurt me and doesn’t have any major risks.’ So I think in the short term, clinicians and consumers can consider trying it.”
Dr. Hunter was not keen on giving zinc to family members after they develop an RTI: “Consider it. But I don’t think we have enough evidence to say definitely yes.” But she does see a potential role for “people who are at risk of suboptimal zinc absorption, like people who are taking a variety of pharmaceuticals [notably proton pump inhibitors] that block or reduce the absorption of zinc, people with a whole lot of the chronic diseases that we know are associated with an increased risk of worse outcomes from respiratory viral infections, and older adults. Yes, I think [for] those high-risk groups, you could consider using zinc, either in a moderate dose longer term or in a higher dose for very short bursts of, like, 1 to 2 weeks.”
Dr. Hunter concluded, “Up until now, we all commonly thought that zinc’s role was only for people who were zinc deficient, and now we’ve got some signals pointing towards its potential role as an anti-infective and anti-inflammatory agent in people who don’t have zinc deficiency.”
But both Dr. Hunter and Dr. Imdad emphasized that zinc is not a game changer. There is a hint that it produces a small benefit in prevention and may slightly shorten the duration of RTIs. More research is needed.
Dr. Hunter has received payment for providing expert advice about traditional, complementary, and integrative medicine, including nutraceuticals, to industry, government bodies, and nongovernmental organizations and has spoken at workshops, seminars, and conferences for which registration, travel, and/or accommodation has been paid for by the organizers. Dr. Imdad has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new study published in BMJ Open adds to the evidence that zinc is effective against viral respiratory infections, such as colds.
Jennifer Hunter, PhD, BMed, of Western Sydney University’s NICM Health Research Institute, New South Wales, Australia, and colleagues conducted a meta-analysis of 28 randomized controlled trials (RCTs). They searched 17 English and Chinese databases to identify the trials and then used the Cochrane rapid review technique for the analysis.
The trials included 5,446 adults who had received zinc in a variety of formulations and routes — oral, sublingual, and nasal spray. The researchers separately analyzed whether zinc prevented or treated respiratory tract infections (RTIs)
Oral or intranasal zinc prevented five RTIs per 100 person-months (95% CI, 1 – 8; numbers needed to treat, 20). There was a 32% lower relative risk (RR) of developing mild to moderate symptoms consistent with a viral RTI.
Use of zinc was also associated with an 87% lower risk of developing moderately severe symptoms (incidence rate ratio, 0.13; 95% CI, 0.04 – 0.38) and a 28% lower risk of developing milder symptoms. The largest reductions in RR were for moderately severe symptoms consistent with an influenza-like illness.
Symptoms resolved 2 days earlier with sublingual or intranasal zinc compared with placebo (95% CI, 0.61 – 3.50; very low-certainty quality of evidence). There were clinically significant reductions in day 3 symptom severity scores (mean difference, -1.20 points; 95% CI, -0.66 to -1.74; low-certainty quality of evidence) but not in overall symptom severity. Participants who used sublingual or topical nasal zinc early in the course of illness were 1.8 times more likely to recover before those who used a placebo.
However, the investigators found no benefit of zinc when patients were inoculated with rhinovirus; there was no reduction in the risk of developing a cold. Asked about this disparity, Dr. Hunter said, “It might well be that when inoculating people to make sure they get infected, you give them a really high dose of the virus. [This] doesn’t really mimic what happens in the real world.”
On the downside of supplemental zinc, there were more side effects among those who used zinc, including nausea or gastrointestinal discomfort, mouth irritation, or soreness from sublingual lozenges (RR, 1.41; 95% CI, 1.17 – 1.69; number needed to harm, 7; moderate-certainty quality of evidence). The risk for a serious adverse event, such as loss of smell or copper deficiency, was low. Although not found in these studies, postmarketing studies have found that there is a risk for severe and in some cases permanent loss of smell associated with the use of nasal gels or sprays containing zinc. Three such products were recalled from the market.
The trial could not provide answers about the comparative efficacy of different types of zinc formulations, nor could the investigators recommend specific doses. The trial was not designed to assess zinc for the prevention or treatment of COVID-19.
Asked for independent comment, pediatrician Aamer Imdad, MBBS, assistant professor at the State University of New York Upstate Medical University, Syracuse, told this news organization, “It’s a very comprehensive review for zinc-related studies in adults” but was challenging because of the “significant clinical heterogeneity in the population.”
Dr. Imdad explained that zinc has “absolutely” been shown to be effective for children with diarrhea. The World Health Organization has recommended it since 2004. “The way it works in diarrhea is that it helps with the regeneration of the epithelium.... It also improves the immunity itself, especially the cell-mediated immunity.” He raised the question of whether it might work similarly in the respiratory tract. Dr. Imdad has a long-standing interest in the use of zinc for pediatric infections. Regarding this study, he concluded, “I think we still need to know the nuts and bolts of this intervention before we can recommend it more specifically.”
Dr. Hunter said, “We don’t have any high-quality studies that have evaluated zinc orally as treatment once you’re actually infected and have symptoms of the cold or influenza, or COVID.”
Asked about zinc’s possible role, Dr. Hunter said, “So I do think it gives us a viable alternative. More people are going, ‘What can I do?’ And you know as well as I do people come to you, and [they say], ‘Well, just give me something. Even if it’s a day or a little bit of symptom relief, anything to make me feel better that isn’t going to hurt me and doesn’t have any major risks.’ So I think in the short term, clinicians and consumers can consider trying it.”
Dr. Hunter was not keen on giving zinc to family members after they develop an RTI: “Consider it. But I don’t think we have enough evidence to say definitely yes.” But she does see a potential role for “people who are at risk of suboptimal zinc absorption, like people who are taking a variety of pharmaceuticals [notably proton pump inhibitors] that block or reduce the absorption of zinc, people with a whole lot of the chronic diseases that we know are associated with an increased risk of worse outcomes from respiratory viral infections, and older adults. Yes, I think [for] those high-risk groups, you could consider using zinc, either in a moderate dose longer term or in a higher dose for very short bursts of, like, 1 to 2 weeks.”
Dr. Hunter concluded, “Up until now, we all commonly thought that zinc’s role was only for people who were zinc deficient, and now we’ve got some signals pointing towards its potential role as an anti-infective and anti-inflammatory agent in people who don’t have zinc deficiency.”
But both Dr. Hunter and Dr. Imdad emphasized that zinc is not a game changer. There is a hint that it produces a small benefit in prevention and may slightly shorten the duration of RTIs. More research is needed.
Dr. Hunter has received payment for providing expert advice about traditional, complementary, and integrative medicine, including nutraceuticals, to industry, government bodies, and nongovernmental organizations and has spoken at workshops, seminars, and conferences for which registration, travel, and/or accommodation has been paid for by the organizers. Dr. Imdad has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new study published in BMJ Open adds to the evidence that zinc is effective against viral respiratory infections, such as colds.
Jennifer Hunter, PhD, BMed, of Western Sydney University’s NICM Health Research Institute, New South Wales, Australia, and colleagues conducted a meta-analysis of 28 randomized controlled trials (RCTs). They searched 17 English and Chinese databases to identify the trials and then used the Cochrane rapid review technique for the analysis.
The trials included 5,446 adults who had received zinc in a variety of formulations and routes — oral, sublingual, and nasal spray. The researchers separately analyzed whether zinc prevented or treated respiratory tract infections (RTIs)
Oral or intranasal zinc prevented five RTIs per 100 person-months (95% CI, 1 – 8; numbers needed to treat, 20). There was a 32% lower relative risk (RR) of developing mild to moderate symptoms consistent with a viral RTI.
Use of zinc was also associated with an 87% lower risk of developing moderately severe symptoms (incidence rate ratio, 0.13; 95% CI, 0.04 – 0.38) and a 28% lower risk of developing milder symptoms. The largest reductions in RR were for moderately severe symptoms consistent with an influenza-like illness.
Symptoms resolved 2 days earlier with sublingual or intranasal zinc compared with placebo (95% CI, 0.61 – 3.50; very low-certainty quality of evidence). There were clinically significant reductions in day 3 symptom severity scores (mean difference, -1.20 points; 95% CI, -0.66 to -1.74; low-certainty quality of evidence) but not in overall symptom severity. Participants who used sublingual or topical nasal zinc early in the course of illness were 1.8 times more likely to recover before those who used a placebo.
However, the investigators found no benefit of zinc when patients were inoculated with rhinovirus; there was no reduction in the risk of developing a cold. Asked about this disparity, Dr. Hunter said, “It might well be that when inoculating people to make sure they get infected, you give them a really high dose of the virus. [This] doesn’t really mimic what happens in the real world.”
On the downside of supplemental zinc, there were more side effects among those who used zinc, including nausea or gastrointestinal discomfort, mouth irritation, or soreness from sublingual lozenges (RR, 1.41; 95% CI, 1.17 – 1.69; number needed to harm, 7; moderate-certainty quality of evidence). The risk for a serious adverse event, such as loss of smell or copper deficiency, was low. Although not found in these studies, postmarketing studies have found that there is a risk for severe and in some cases permanent loss of smell associated with the use of nasal gels or sprays containing zinc. Three such products were recalled from the market.
The trial could not provide answers about the comparative efficacy of different types of zinc formulations, nor could the investigators recommend specific doses. The trial was not designed to assess zinc for the prevention or treatment of COVID-19.
Asked for independent comment, pediatrician Aamer Imdad, MBBS, assistant professor at the State University of New York Upstate Medical University, Syracuse, told this news organization, “It’s a very comprehensive review for zinc-related studies in adults” but was challenging because of the “significant clinical heterogeneity in the population.”
Dr. Imdad explained that zinc has “absolutely” been shown to be effective for children with diarrhea. The World Health Organization has recommended it since 2004. “The way it works in diarrhea is that it helps with the regeneration of the epithelium.... It also improves the immunity itself, especially the cell-mediated immunity.” He raised the question of whether it might work similarly in the respiratory tract. Dr. Imdad has a long-standing interest in the use of zinc for pediatric infections. Regarding this study, he concluded, “I think we still need to know the nuts and bolts of this intervention before we can recommend it more specifically.”
Dr. Hunter said, “We don’t have any high-quality studies that have evaluated zinc orally as treatment once you’re actually infected and have symptoms of the cold or influenza, or COVID.”
Asked about zinc’s possible role, Dr. Hunter said, “So I do think it gives us a viable alternative. More people are going, ‘What can I do?’ And you know as well as I do people come to you, and [they say], ‘Well, just give me something. Even if it’s a day or a little bit of symptom relief, anything to make me feel better that isn’t going to hurt me and doesn’t have any major risks.’ So I think in the short term, clinicians and consumers can consider trying it.”
Dr. Hunter was not keen on giving zinc to family members after they develop an RTI: “Consider it. But I don’t think we have enough evidence to say definitely yes.” But she does see a potential role for “people who are at risk of suboptimal zinc absorption, like people who are taking a variety of pharmaceuticals [notably proton pump inhibitors] that block or reduce the absorption of zinc, people with a whole lot of the chronic diseases that we know are associated with an increased risk of worse outcomes from respiratory viral infections, and older adults. Yes, I think [for] those high-risk groups, you could consider using zinc, either in a moderate dose longer term or in a higher dose for very short bursts of, like, 1 to 2 weeks.”
Dr. Hunter concluded, “Up until now, we all commonly thought that zinc’s role was only for people who were zinc deficient, and now we’ve got some signals pointing towards its potential role as an anti-infective and anti-inflammatory agent in people who don’t have zinc deficiency.”
But both Dr. Hunter and Dr. Imdad emphasized that zinc is not a game changer. There is a hint that it produces a small benefit in prevention and may slightly shorten the duration of RTIs. More research is needed.
Dr. Hunter has received payment for providing expert advice about traditional, complementary, and integrative medicine, including nutraceuticals, to industry, government bodies, and nongovernmental organizations and has spoken at workshops, seminars, and conferences for which registration, travel, and/or accommodation has been paid for by the organizers. Dr. Imdad has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM BMJ OPEN
‘First reliable estimate’ of breast cancer metastasis
The data come from a massive meta-analysis of more than 400 studies conducted around the world, involving tens of thousands of women.
It found that the overall risk of metastasis is between 6% and 22%, with younger women having a higher risk.
While women aged 50 years or older when they were diagnosed with breast cancer have a risk of developing metastasis that ranged from 3.7% to 28.6%, women diagnosed with breast cancer before age 35 had a higher risk – 12.7% to 38%. The investigators speculate that this may be because younger women have a more aggressive form of breast cancer or because they are diagnosed at a later stage.
The risk of metastasis also varies by tumor type, with luminal B cancers having a 4.2% to 35.5% risk of metastasis versus a 2.3% to 11.8% risk with luminal A tumors.
“The quantification of recurrence and disease progression is important to assess the effectiveness of treatment, evaluate prognosis, and allocate resources,” commented lead investigator Eileen Morgan, PhD, of the International Agency for Research on Cancer.
Dr. Morgan and colleagues presented the new meta-analysis at the virtual Advanced Breast Cancer Sixth International Consensus Conference.
She added that this information has not been available until now “because cancer registries have not been routinely collecting this data.”
In fact, the U.S. National Cancer Institute began a project earlier this year to track this information, after 48 years of not doing so.
Reacting to the findings, Shani Paluch-Shimon, MBBS, director of the Breast Unit at Hadassah University Hospital, Jerusalem, commented that this work “provides the first reliable estimate of how many breast cancer patients go on to develop advanced disease in contemporary cohorts.”
“This information is, of course, important for patients who want to understand their prognosis,” she continued.
“But it’s also vital at a public health level for those of us working to treat and prevent advanced breast cancer, to help us understand the scale of the disease around the world,” she said. “It will help us identify at-risk groups across different populations and demonstrate how disease course is changing with contemporary treatments.”
“It will also help us understand what resources are needed and where, to ensure we can collect and analyze quality data in real-time as this is key for resource allocation and planning future studies.”
The work was funded by a grant from the Susan G. Komen Foundation.
A version of this article first appeared on Medscape.com.
The data come from a massive meta-analysis of more than 400 studies conducted around the world, involving tens of thousands of women.
It found that the overall risk of metastasis is between 6% and 22%, with younger women having a higher risk.
While women aged 50 years or older when they were diagnosed with breast cancer have a risk of developing metastasis that ranged from 3.7% to 28.6%, women diagnosed with breast cancer before age 35 had a higher risk – 12.7% to 38%. The investigators speculate that this may be because younger women have a more aggressive form of breast cancer or because they are diagnosed at a later stage.
The risk of metastasis also varies by tumor type, with luminal B cancers having a 4.2% to 35.5% risk of metastasis versus a 2.3% to 11.8% risk with luminal A tumors.
“The quantification of recurrence and disease progression is important to assess the effectiveness of treatment, evaluate prognosis, and allocate resources,” commented lead investigator Eileen Morgan, PhD, of the International Agency for Research on Cancer.
Dr. Morgan and colleagues presented the new meta-analysis at the virtual Advanced Breast Cancer Sixth International Consensus Conference.
She added that this information has not been available until now “because cancer registries have not been routinely collecting this data.”
In fact, the U.S. National Cancer Institute began a project earlier this year to track this information, after 48 years of not doing so.
Reacting to the findings, Shani Paluch-Shimon, MBBS, director of the Breast Unit at Hadassah University Hospital, Jerusalem, commented that this work “provides the first reliable estimate of how many breast cancer patients go on to develop advanced disease in contemporary cohorts.”
“This information is, of course, important for patients who want to understand their prognosis,” she continued.
“But it’s also vital at a public health level for those of us working to treat and prevent advanced breast cancer, to help us understand the scale of the disease around the world,” she said. “It will help us identify at-risk groups across different populations and demonstrate how disease course is changing with contemporary treatments.”
“It will also help us understand what resources are needed and where, to ensure we can collect and analyze quality data in real-time as this is key for resource allocation and planning future studies.”
The work was funded by a grant from the Susan G. Komen Foundation.
A version of this article first appeared on Medscape.com.
The data come from a massive meta-analysis of more than 400 studies conducted around the world, involving tens of thousands of women.
It found that the overall risk of metastasis is between 6% and 22%, with younger women having a higher risk.
While women aged 50 years or older when they were diagnosed with breast cancer have a risk of developing metastasis that ranged from 3.7% to 28.6%, women diagnosed with breast cancer before age 35 had a higher risk – 12.7% to 38%. The investigators speculate that this may be because younger women have a more aggressive form of breast cancer or because they are diagnosed at a later stage.
The risk of metastasis also varies by tumor type, with luminal B cancers having a 4.2% to 35.5% risk of metastasis versus a 2.3% to 11.8% risk with luminal A tumors.
“The quantification of recurrence and disease progression is important to assess the effectiveness of treatment, evaluate prognosis, and allocate resources,” commented lead investigator Eileen Morgan, PhD, of the International Agency for Research on Cancer.
Dr. Morgan and colleagues presented the new meta-analysis at the virtual Advanced Breast Cancer Sixth International Consensus Conference.
She added that this information has not been available until now “because cancer registries have not been routinely collecting this data.”
In fact, the U.S. National Cancer Institute began a project earlier this year to track this information, after 48 years of not doing so.
Reacting to the findings, Shani Paluch-Shimon, MBBS, director of the Breast Unit at Hadassah University Hospital, Jerusalem, commented that this work “provides the first reliable estimate of how many breast cancer patients go on to develop advanced disease in contemporary cohorts.”
“This information is, of course, important for patients who want to understand their prognosis,” she continued.
“But it’s also vital at a public health level for those of us working to treat and prevent advanced breast cancer, to help us understand the scale of the disease around the world,” she said. “It will help us identify at-risk groups across different populations and demonstrate how disease course is changing with contemporary treatments.”
“It will also help us understand what resources are needed and where, to ensure we can collect and analyze quality data in real-time as this is key for resource allocation and planning future studies.”
The work was funded by a grant from the Susan G. Komen Foundation.
A version of this article first appeared on Medscape.com.
Improving Unadjusted and Adjusted Mortality With an Early Warning Sepsis System in the Emergency Department and Inpatient Wards
In 1997, Elizabeth McGlynn wrote, “Measuring quality is no simple task.”1 We are reminded of this seminal Health Affairs article at a very pertinent point—as health care practice progresses, measuring the impact of performance improvement initiatives on clinical care delivery remains integral to monitoring overall effectiveness of quality. Mortality outcomes are a major focus of quality.
Inpatient mortality within the Veterans Health Administration (VHA) was measured as actual number of deaths (unadjusted mortality), and adjusted mortality was calculated using the standardized mortality ratio (SMR). SMR included actual number of deaths during hospitalization or within 1 day of hospital discharge divided by predicted number of deaths using a risk-adjusted formula and was calculated separately for acute level of care (LOC) and the intensive care unit (ICU). Using risk-adjusted SMR, if an observed/expected ratio was > 1.0, there were more inpatient deaths than expected; if < 1.0, fewer inpatient deaths occurred than predicted; and if 1.0, observed number of inpatient deaths was equivalent to expected number of deaths.2
Mortality reduction is a complex area of performance improvement. Health care facilities often focus their efforts on the biggest mortality contributors. According to Dantes and Epstein, sepsis results in about 265,000 deaths annually in the United States.3 Reinhart and colleagues demonstrated that sepsis is a worldwide issue resulting in approximately 30 million cases and 6 million deaths annually.4 Furthermore, Kumar and colleagues have noted that when sepsis progresses to septic shock, survival decreases by almost 8% for each hour delay in sepsis identification and treatment.5
Improvements in sepsis management have been multifaceted. The Surviving Sepsis Campaign guidelines created sepsis treatment bundles to guide early diagnosis/treatment of sepsis.6 In addition to awareness and sepsis care bundles, a plethora of informatics solutions within electronic health record (EHR) systems have demonstrated improved sepsis care.7-16 Various approaches to early diagnosis and management of sepsis have been collectively referred to as an early warning sepsis system (EWSS).
An EWSS typically contains automated decision support tools that are integrated in the EHR and meant to assist health care professionals with clinical workflow decision-making. Automated decision support tools within the EHR have a variety of functions, such as clinical care reminders and alerts.17
Sepsis screening tools function as a form of automated decision support and may be incorporated into the EHR to support the EWSS. Although sepsis screening tools vary, they frequently include a combination of data involving vital signs, laboratory values and/or physical examination findings, such as mental status evaluation.The Modified Early Warning Signs (MEWS) + Sepsis Recognition Score (SRS) is one example of a sepsis screening tool.7,16
At Malcom Randall Veterans Affairs Medical Center (MRVAMC) in Gainesville, Florida, we identified a quality improvement project opportunity to improve sepsis care in the emergency department (ED) and inpatient wards using the VHA EHR system, the Computerized Patient Record System (CPRS), which is supported by the Veterans Information Systems and Technology Architecture (VistA).18 A VistA/CPRS EWSS was developed using Lean Six Sigma DMAIC (define, measure, analyze, improve, and control) methodology.19 During the improve stage, informatics solutions were applied and included a combination of EHR interventions, such as template design, an order set, and clinical reminders. Clinical reminders have a wide variety of use, such as reminders for clinical tasks and as automated decision support within clinical workflows using Boolean logic.
To the best of our knowledge, there has been no published application of an EWSS within VistA/CPRS. In this study, we outline the strategic development of an EWSS in VistA/CPRS that assisted clinical staff with identification and treatment of sepsis; improved documentation of sepsis when present; and associated with improvement in unadjusted and adjusted inpatient mortality.
Methods
According to policy activities that constitute research at MRVAMC, no institutional review board approval was required as this work met criteria for operational improvement activities exempt from ethics review.
The North Florida/South Georgia Veterans Health System (NF/SGVHS) includes MRVAMC, a large academic hospital with rotating residents/fellows and multiple specialty care services. MRVAMC comprised 144 beds on the medicine/surgery wards; 48 beds in the psychiatry unit; 18 intermediate LOC beds; and 27 ICU beds. The MRVAMC SMR was identified as an improvement opportunity during fiscal year (FY) 2017 (Table 1). Its adjusted mortality for acute LOC demonstrated an observed/expected ratio of > 1.0 suggesting more inpatient deaths were observed than expected. The number of deaths (unadjusted mortality) on acute LOC at MRVAMC was noted to be rising during the first 3 quarters of FY 2017. A deeper examination of data by Pyramid Analytics (www.pyramidanalytics.com) discovered that sepsis was the primary driver for inpatient mortality on acute LOC at MRVAMC. Our goal was to reduce inpatient sepsis-related mortality via development of an EWSS that leveraged VistA/CPRS to improve early identification and treatment of sepsis in the ED and inpatient wards.
Emergency Department
Given the importance of recognizing sepsis early, the sepsis team focused on improvement opportunities at the initial point of patient contact: ED triage. The goal was to incorporate automated VistA/CPRS decision support to assist clinicians with identifying sepsis in triage using MEWS, which was chosen to optimize immediate hospital-wide buy-in. Clinical staff were already familiar with MEWS, which was in use on the inpatient wards.
Flow through the ED and availability of resources differed from the wards. Hence, modification to MEWS on the wards was necessary to fit clinical workflow in the ED. Temperature, heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), mental status, and white blood cell count (WBC) factored into a MEWS + SRS score on the wards (Table 2). For the ED, MEWS included temperature, HR, RR and SBP, but excluded mental status and WBC. Mental status assessment was excluded due to technical infeasibility (while vital signs could be automatically calculated in real time for a MEWS score, that was not possible for mental status changes). WBC was excluded from the ED as laboratory test results would not be available in triage.
MEWS + SRS scores were calculated in VistA by using clinical reminders. Clinical reminder logic included a series of conditional statements based on various combinations of MEWS + SRS clinical data entered in the EHR. When ED triage vital signs data were entered in CPRS, clinical data were stored and processed according to clinical reminder logic in VistA and displayed to the user in CPRS. While MEWS of ≥ 5 triggered a sepsis alert on the wards, the ≥ 4 threshold was used in the ED given mental status and WBC were excluded from calculations in triage (eAppendix 1 available at doi:10.12788/fp.0194).
Once a sepsis alert was triggered in triage for MEWS ≥ 4, ED nursing staff prioritized bed location and expedited staffing with an ED attending physician for early assessment. The ED attending then performed an assessment to confirm whether sepsis was present and direct early treatment. Although every patient who triggered a sepsis alert in triage did not meet clinical findings of sepsis, patients with MEWS ≥ 4 were frequently ill and required timely intervention.
If an ED attending physician agreed with a sepsis diagnosis, the physician had access to a sepsis workup and treatment order set in CPRS (eAppendix 2 available at doi:10.12788/fp.0194). The sepsis order set incorporated recommendations from the Surviving Sepsis Campaign guidelines and included orders for 2 large-bore peripheral IV lines; aggressive fluid resuscitation (30 mL/kg) for patients with clinical findings of hypoperfusion; broad-spectrum antibiotics; and frequent ordering of laboratory tests and imaging during initial sepsis workup.6 Vancomycin and cefepime were selected as routine broad-spectrum antibiotics in the order set when sepsis was suspected based on local antimicrobial stewardship and safety-efficacy profiles. For example, Luther and colleagues demonstrated that cefepime has lower rates of acute kidney injury when combined with vancomycin vs vancomycin + piperacillin-tazobactam.20 If a β-lactam antibiotic could not be used due to a patient’s drug allergy history, aztreonam was available as an alternative option.
The design of the order set also functioned as a communication interface with clinical pharmacists. Given the large volume of antibiotics ordered in the ED, it was difficult for pharmacists to prioritize antibiotic order verification. While stat orders convey high priority, they often lack specificity. When antibiotic orders were selected from the sepsis order set, comments were already included that stated: “STAT. First dose for sepsis protocol” (eAppendix 3 available at doi:10.12788/fp.0194). This standardized communication conveyed a sense of urgency and a collective understanding that patients with suspected sepsis required timely order verification and administration of antibiotics.
Hospital Ward
Mental status and WBC were included on the wards to monitor for possible signs of sepsis, using MEWS + SRS, which was routinely monitored by nursing every 4 to 8 hours. When MEWS + SRS was ≥ 5 points, ward nursing staff called a sepsis alert.7,16 Early response team (ERT) members received telephone notifications of the alert. ERT staff proceeded with immediate evaluation and treatment at the bedside along with determination for most appropriate LOC. The ERT members included an ICU physician and nurse; respiratory therapist; and nursing supervisor/bed flow coordinator. During bedside evaluation, if the ERT or primary team agreed with a sepsis diagnosis, the ERT or primary team used the sepsis order set to ensure standardized procedures. Stat orders generated through the sepsis order set pathway conveyed a sense of urgency and need for immediate order verification and administration of antibiotics.
In addition to clinical care process improvement, accurate documentation also was emphasized in the EWSS. When a sepsis alert was called, a clinician from the primary team was expected to complete a standardized progress note, which communicated clinical findings, a treatment plan, and captured severity of illness (eAppendix 4 available at doi:10.12788/fp.0194). It included sections for subjective, objective, assessment, and plan. In addition, data objects were created for vital signs and common laboratory findings that retrieved important clinical data from VistA and inserted it into the CPRS note.21
Nursing staff on the wards were expected to communicate results with the primary team for clinical decision making when a patient had a MEWS + SRS of 3 to 4. A sepsis alert may have been called at the discretion of clinical team members but was not required if the score was < 5. Additionally, vital signs were expected to be checked by the nursing staff on the wards at least every 4 hours for closer monitoring.
Sepsis Review Meetings
Weekly meetings were scheduled to review sepsis cases to assess diagnosis, treatment, and documentation entered in the patient record. The team conducting sepsis reviews comprised the chief of staff, chief of quality management, director of patient safety, physician utilization management advisor, chief resident in quality and patient safety (CRQS), and inpatient pharmacy supervisor. In addition, ad hoc physicians and nurses from different specialty areas, such as infectious diseases, hospitalist section, ICU, and the ED participated on request for subject matter expertise when needed. At the conclusion of weekly sepsis meetings, sepsis team members provided feedback to the clinical staff for continuous improvement purposes.
Results
Before implementation of an EWSS at NF/SGVHS, a plan was devised to increase awareness and educate staff on sepsis-related mortality in late FY 2017. Awareness and education about sepsis-related mortality was organized at physician, nursing, and pharmacy leadership clinical staff meetings. Posters about early warning signs of sepsis also were displayed on the nursing units for educational purposes and to convey the importance of early recognition/treatment of sepsis. In addition, the CRQS was the quality leader for house staff and led sepsis campaign change efforts for residents/fellows. An immediate improvement in unadjusted mortality at MRVAMC was noted with initial sepsis awareness and education. From FY 2017, quarter 3 to FY 2018, quarter 1, the number of acute LOC inpatient deaths decreased from 48 to 28, a 42% reduction in unadjusted mortality at MRVAMC (Figure 1). Additionally, the acute LOC SMR improved from 1.20 during FY 2017, quarter 3 down to as low as 0.71 during FY 2018, quarter 1 (Figure 2).
The number of MRVAMC inpatient deaths increased from 28 in FY 2018, quarter 1 to 45 in FY 2018, quarter 3. While acute LOC showed improvement in unadjusted mortality after sepsis education/awareness, it was felt continuous improvement could not be sustained with education alone. An EWSS was designed and implemented within the EHR system in FY 2018. Following implementation of EWSS and reeducating staff on early recognition and treatment of sepsis, acute LOC inpatient deaths decreased from 45 in FY 2018, quarter 3 through FY 2019 where unadjusted mortality was as low as 27 during FY 2019, quarter 4. The MRVAMC acute LOC SMR was consistently < 1.0 from FY 2018, quarter 4 through FY 2019, quarter 4.
In addition to the observed decrease in acute LOC inpatient deaths and improved SMR, the number of ERT alerts and sepsis alerts on the inpatient wards were monitored from FY 2017 through FY 2019. ERT alerts listed in Table 3 were nonspecific and initiated by nursing staff on the wards where a patient’s clinical status was identified as worsening while sepsis alerts were specific ERT alerts called by the ward nursing staff due to concerns for sepsis. The inpatient wards included inpatient medicine, surgery, and psychiatry acute care and the intermediate level of care unit while outpatient clinical areas of treatment, intensive care units, stroke alerts, and STEMI alerts were excluded.
From FY 2017 to FY 2018, quarter 1, the number of nonspecific ERT alerts varied between 75 to 100. Sepsis alerts were not available until December 2017 while the EWSS was in development. Afterward, nonspecific ERT alerts and sepsis alerts were monitored each quarter. Sepsis alerts ranged from 4 to 18. Nonspecific ERT alerts + sepsis alerts continued to increase from FY 2018, quarter 3 through FY 2019, quarter 4.
Discussion
Implementation of the EWSS was associated with improved unadjusted mortality and adjusted mortality for acute LOC at MRVAMC. Although variation exists with application of EWSS at other medical centers, there was similarity with improved sepsis outcomes reported at other health care systems after EWSS implementation.7-16
Improved unadjusted mortality and adjusted mortality for acute LOC at MRVAMC was likely due to multiple contributing factors. First, during design and implementation of the EWSS, project work was interdisciplinary with input from physicians, nurses, and pharmacists from multiple specialties (ie, ED, ICU, and the medicine service); quality management and data analysis specialists; and clinical informatics. Second, facility commitment to improving early recognition and treatment of sepsis from leadership level down to front-line staff was evident. Weekly sepsis meetings with the NF/SGVHS chief of staff helped to sustain EWSS efforts and to identify additional improvement opportunities. Third, integrated informatics solutions within the EHR helped identify early sepsis and minimized human error as well as assisted with coordination of sepsis care across services. Fourth, the focus was on both early identification and treatment of sepsis in the ED and hospital wards. Although it cannot be deduced whether there was causation between reduced inpatient mortality and an increased number of nonspecific ERT alerts+ sepsis alerts on the inpatient wards after EWSS implementation, inpatient deaths decreased and SMR improved. Finally, the EWSS emphasized both the importance of evidence-based clinical care of sepsis and standardized documentation to appropriately capture clinical severity of illness.
Limitations
This program has limitations. The EWSS was studied at a single VHA facility. Veteran demographics and local epidemiology may limit conclusion of outcomes to an individual VHA facility located in a specific geographical region. Additional research is necessary to demonstrate reproducibility and determine whether applicable to other VHA facilities and community care settings.
SMR is a risk-adjusted formula developed by the VHA Inpatient Evaluation Center, which included numerous factors such as diagnosis, comorbid conditions, age, marital status, procedures, source of admission, specific laboratory values, medical or surgical diagnosis-related group, ICU stays, immunosuppressive status, and a COVID-19 positive indicator (added after this study). Further research is needed to evaluate sepsis-related outcomes using the EWSS during the COVID-19 pandemic.
EWSS in the literature have demonstrated various approaches to early identification and treatment of sepsis and have used different sepsis screening tools.22 Evidence suggests that the MEWS + SRS sepsis screening tool may result in false-positive screenings.23-27 Additional research into the specificity of this sepsis screening tool is needed. Ward nursing staff were encouraged to initiate automatic sepsis alerts when MEWS + SRS was ≥ 5; however, this still depended on human factors. Because sepsis alerts are software-specific and others were incompatible with the VHA EHR, it was necessary to design our own EWSS.
Despite improvement with MRVAMC acute LOC unadjusted and adjusted mortality with our EWSS, we did not identify any actual improvement in earlier antibiotic administration times once sepsis was recognized. While accurate documentation regarding degree of sepsis improved, a MRVAMC clinical documentation improvement program was expanded in FY 2018. Therefore, it is difficult to demonstrate causation related to improved sepsis documentation with template changes alone. While sepsis alerts on the inpatient wards were variable since EWSS implementation, nonspecific ERT alerts increased. It is unclear whether some sepsis alerts were called as nonspecific ERT alerts, making it impossible to know the true number of sepsis alerts.
MRVAMC experienced an increase in nurse turnover during FY 2018 and as a teaching hospital had frequent rotating residents and fellows new to processes/protocols. These factors may have contributed to variations in unadjusted mortality. Also the decrease in inpatient mortality and improvement in SMR on acute LOC could have been the result of factors other than the EWSS and the effect of education alone may have been at least as good as that of the EWSS intervention.
Conclusions
Education along with the possible implementation of an EWSS at NF/SGVHS was associated with a decrease in the number of inpatient deaths on MRVAMC’s acute LOC wards from as high as 48 in FY 2017, quarter 3 to as low as 27 in FY 2019, quarter 4 resulting in as large of an improvement as a 44% reduction in unadjusted mortality from FY 2017 to FY 2019. In addition, MRVAMC’s acute LOC SMR improved from > 1.0 to < 1.0, demonstrating fewer inpatient mortalities than predicted from FY 2017 to FY 2019.
This multifaceted interventional strategy may be effectively applied at other VHA health care facilities that use the same EHR system. Next steps may include determining the specificity of MEWS + SRS as a sepsis screening tool; studying outcomes of MRVAMC’s EWSS during the COVID-19 era; and conducting a multicentered study on this EWSS across multiple VHA facilities.
1. McGlynn EA. Six challenges in measuring the quality of health care. Health Aff (Millwood). 1997;16(3):7-21. doi:10.1377/hlthaff.16.3.7
2. US Department of Veterans Affairs, Veterans Health Administration. Strategic Analytics for Improvement and Learning (SAIL) value model measure definitions. Updated May 15, 2019. Accessed October 11, 2021. https://www.va.gov/QUALITYOFCARE/measure-up/SAIL_definitions.asp
3. Dantes RB, Epstein L. Combatting sepsis: a public health perspective. Clin Infect Dis. 2018;67(8):1300-1302. doi:10.1093/cid/ciy342
4. Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing sepsis as a global health priority - a WHO resolution. N Engl J Med. 2017;377(5):414-417. doi:10.1056/NEJMp1707170
5. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596. doi:10.1097/01.CCM.0000217961.75225.E9
6. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552. doi:10.1097/CCM.0000000000002255
7. Guirgis FW, Jones L, Esma R, et al. Managing sepsis: electronic recognition, rapid response teams, and standardized care save lives. J Crit Care. 2017;40:296-302. doi:10.1016/j.jcrc.2017.04.005
8. Whippy A, Skeath M, Crawford B, et al. Kaiser Permanente’s performance improvement system, part 3: multisite improvements in care for patients with sepsis. Jt Comm J Qual Patient Saf. 2011;37(11):483-493. doi:10.1016/s1553-7250(11)37061-4
9. Harrison AM, Thongprayoon C, Kashyap R, et al. Developing the surveillance algorithm for detection of failure to recognize and treat severe sepsis. Mayo Clin Proc. 2015;90(2):166-175. doi:10.1016/j.mayocp.2014.11.014
10. Rothman M, Levy M, Dellinger RP, et al. Sepsis as 2 problems: identifying sepsis at admission and predicting onset in the hospital using an electronic medical record-based acuity score. J Crit Care. 2017;38:237-244. doi:10.1016/j.jcrc.2016.11.037
11. Back JS, Jin Y, Jin T, Lee SM. Development and validation of an automated sepsis risk assessment system. Res Nurs Health. 2016;39(5):317-327. doi:10.1002/nur.21734
12. Khurana HS, Groves RH Jr, Simons MP, et al. Real-time automated sampling of electronic medical records predicts hospital mortality. Am J Med. 2016;129(7):688-698.e2. doi:10.1016/j.amjmed.2016.02.037
13. Umscheid CA, Betesh J, VanZandbergen C, et al. Development, implementation, and impact of an automated early warning and response system for sepsis. J Hosp Med. 2015;10(1):26-31. doi:10.1002/jhm.2259
14. Vogel L. EMR alert cuts sepsis deaths. CMAJ. 2014;186(2):E80. doi:10.1503/cmaj.109-4686
15. Jones SL, Ashton CM, Kiehne L, et al. Reductions in sepsis mortality and costs after design and implementation of a nurse-based early recognition and response program. Jt Comm J Qual Patient Saf. 2015;41(11):483-491. doi:10.1016/s1553-7250(15)41063-3
16. Croft CA, Moore FA, Efron PA, et al. Computer versus paper system for recognition and management of sepsis in surgical intensive care. J Trauma Acute Care Surg. 2014;76(2):311-319. doi:10.1097/TA.0000000000000121
17. Tcheng JE, Bakken S, Bates DW, et al, eds. Optimizing Strategies for Clinical Decision Support: Summary of a Meeting Series. National Academy of Medicine; 2017. Accessed October 11, 2021. https://nam.edu/wp-content/uploads/2017/11/Optimizing-Strategies-for-Clinical-Decision-Support.pdf
18. US Department of Veterans Affairs. History of IT at VA. Updated January 1, 2020. Accessed October 11, 2021. https://www.oit.va.gov/about/history.cfm
19. GoLeanSixSigma. DMAIC: The 5 Phases of Lean Six Sigma. Published 2012. Accessed October 11, 2021. https://goleansixsigma.com/wp-content/uploads/2012/02/DMAIC-The-5-Phases-of-Lean-Six-Sigma-www.GoLeanSixSigma.com_.pdf
20. Luther MK, Timbrook TT, Caffrey AR, Dosa D, Lodise TP, LaPlante KL. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: a systematic review and meta-analysis. Crit Care Med. 2018;46(1):12-20. doi:10.1097/CCM.0000000000002769
21. International Business Machines Corp. Overview of data objects. Accessed October 11, 2021. https://www.ibm.com/support/knowledgecenter/en/SSLTBW_2.3.0/com.ibm.zos.v2r3.cbclx01/data_objects.htm
22. Churpek MM, Snyder A, Han X, et al. Quick sepsis-related organ failure assessment, systemic inflammatory response syndrome, and early warning scores for detecting clinical deterioration in infected patients outside the intensive care unit. Am J Respir Crit Care Med. 2017;195(7):906-911. doi:10.1164/rccm.201604-0854OC
23. Ghanem-Zoubi NO, Vardi M, Laor A, Weber G, Bitterman H. Assessment of disease-severity scoring systems for patients with sepsis in general internal medicine departments. Crit Care. 2011;15(2):R95. doi:10.1186/cc10102
24. Hamilton F, Arnold D, Baird A, Albur M, Whiting P. Early Warning scores do not accurately predict mortality in sepsis: a meta-analysis and systematic review of the literature. J Infect. 2018;76(3):241-248. doi:10.1016/j.jinf.2018.01.002
25. Martino IF, Figgiaconi V, Seminari E, Muzzi A, Corbella M, Perlini S. The role of qSOFA compared to other prognostic scores in septic patients upon admission to the emergency department. Eur J Intern Med. 2018;53:e11-e13. doi:10.1016/j.ejim.2018.05.022
26. Nannan Panday RS, Minderhoud TC, Alam N, Nanayakkara PWB. Prognostic value of early warning scores in the emergency department (ED) and acute medical unit (AMU): A narrative review. Eur J Intern Med. 2017;45:20-31. doi:10.1016/j.ejim.2017.09.027
27. Jayasundera R, Neilly M, Smith TO, Myint PK. Are early warning scores useful predictors for mortality and morbidity in hospitalised acutely unwell older patients? A systematic review. J Clin Med. 2018;7(10):309. Published 2018 Sep 28. doi:10.3390/jcm7100309
In 1997, Elizabeth McGlynn wrote, “Measuring quality is no simple task.”1 We are reminded of this seminal Health Affairs article at a very pertinent point—as health care practice progresses, measuring the impact of performance improvement initiatives on clinical care delivery remains integral to monitoring overall effectiveness of quality. Mortality outcomes are a major focus of quality.
Inpatient mortality within the Veterans Health Administration (VHA) was measured as actual number of deaths (unadjusted mortality), and adjusted mortality was calculated using the standardized mortality ratio (SMR). SMR included actual number of deaths during hospitalization or within 1 day of hospital discharge divided by predicted number of deaths using a risk-adjusted formula and was calculated separately for acute level of care (LOC) and the intensive care unit (ICU). Using risk-adjusted SMR, if an observed/expected ratio was > 1.0, there were more inpatient deaths than expected; if < 1.0, fewer inpatient deaths occurred than predicted; and if 1.0, observed number of inpatient deaths was equivalent to expected number of deaths.2
Mortality reduction is a complex area of performance improvement. Health care facilities often focus their efforts on the biggest mortality contributors. According to Dantes and Epstein, sepsis results in about 265,000 deaths annually in the United States.3 Reinhart and colleagues demonstrated that sepsis is a worldwide issue resulting in approximately 30 million cases and 6 million deaths annually.4 Furthermore, Kumar and colleagues have noted that when sepsis progresses to septic shock, survival decreases by almost 8% for each hour delay in sepsis identification and treatment.5
Improvements in sepsis management have been multifaceted. The Surviving Sepsis Campaign guidelines created sepsis treatment bundles to guide early diagnosis/treatment of sepsis.6 In addition to awareness and sepsis care bundles, a plethora of informatics solutions within electronic health record (EHR) systems have demonstrated improved sepsis care.7-16 Various approaches to early diagnosis and management of sepsis have been collectively referred to as an early warning sepsis system (EWSS).
An EWSS typically contains automated decision support tools that are integrated in the EHR and meant to assist health care professionals with clinical workflow decision-making. Automated decision support tools within the EHR have a variety of functions, such as clinical care reminders and alerts.17
Sepsis screening tools function as a form of automated decision support and may be incorporated into the EHR to support the EWSS. Although sepsis screening tools vary, they frequently include a combination of data involving vital signs, laboratory values and/or physical examination findings, such as mental status evaluation.The Modified Early Warning Signs (MEWS) + Sepsis Recognition Score (SRS) is one example of a sepsis screening tool.7,16
At Malcom Randall Veterans Affairs Medical Center (MRVAMC) in Gainesville, Florida, we identified a quality improvement project opportunity to improve sepsis care in the emergency department (ED) and inpatient wards using the VHA EHR system, the Computerized Patient Record System (CPRS), which is supported by the Veterans Information Systems and Technology Architecture (VistA).18 A VistA/CPRS EWSS was developed using Lean Six Sigma DMAIC (define, measure, analyze, improve, and control) methodology.19 During the improve stage, informatics solutions were applied and included a combination of EHR interventions, such as template design, an order set, and clinical reminders. Clinical reminders have a wide variety of use, such as reminders for clinical tasks and as automated decision support within clinical workflows using Boolean logic.
To the best of our knowledge, there has been no published application of an EWSS within VistA/CPRS. In this study, we outline the strategic development of an EWSS in VistA/CPRS that assisted clinical staff with identification and treatment of sepsis; improved documentation of sepsis when present; and associated with improvement in unadjusted and adjusted inpatient mortality.
Methods
According to policy activities that constitute research at MRVAMC, no institutional review board approval was required as this work met criteria for operational improvement activities exempt from ethics review.
The North Florida/South Georgia Veterans Health System (NF/SGVHS) includes MRVAMC, a large academic hospital with rotating residents/fellows and multiple specialty care services. MRVAMC comprised 144 beds on the medicine/surgery wards; 48 beds in the psychiatry unit; 18 intermediate LOC beds; and 27 ICU beds. The MRVAMC SMR was identified as an improvement opportunity during fiscal year (FY) 2017 (Table 1). Its adjusted mortality for acute LOC demonstrated an observed/expected ratio of > 1.0 suggesting more inpatient deaths were observed than expected. The number of deaths (unadjusted mortality) on acute LOC at MRVAMC was noted to be rising during the first 3 quarters of FY 2017. A deeper examination of data by Pyramid Analytics (www.pyramidanalytics.com) discovered that sepsis was the primary driver for inpatient mortality on acute LOC at MRVAMC. Our goal was to reduce inpatient sepsis-related mortality via development of an EWSS that leveraged VistA/CPRS to improve early identification and treatment of sepsis in the ED and inpatient wards.
Emergency Department
Given the importance of recognizing sepsis early, the sepsis team focused on improvement opportunities at the initial point of patient contact: ED triage. The goal was to incorporate automated VistA/CPRS decision support to assist clinicians with identifying sepsis in triage using MEWS, which was chosen to optimize immediate hospital-wide buy-in. Clinical staff were already familiar with MEWS, which was in use on the inpatient wards.
Flow through the ED and availability of resources differed from the wards. Hence, modification to MEWS on the wards was necessary to fit clinical workflow in the ED. Temperature, heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), mental status, and white blood cell count (WBC) factored into a MEWS + SRS score on the wards (Table 2). For the ED, MEWS included temperature, HR, RR and SBP, but excluded mental status and WBC. Mental status assessment was excluded due to technical infeasibility (while vital signs could be automatically calculated in real time for a MEWS score, that was not possible for mental status changes). WBC was excluded from the ED as laboratory test results would not be available in triage.
MEWS + SRS scores were calculated in VistA by using clinical reminders. Clinical reminder logic included a series of conditional statements based on various combinations of MEWS + SRS clinical data entered in the EHR. When ED triage vital signs data were entered in CPRS, clinical data were stored and processed according to clinical reminder logic in VistA and displayed to the user in CPRS. While MEWS of ≥ 5 triggered a sepsis alert on the wards, the ≥ 4 threshold was used in the ED given mental status and WBC were excluded from calculations in triage (eAppendix 1 available at doi:10.12788/fp.0194).
Once a sepsis alert was triggered in triage for MEWS ≥ 4, ED nursing staff prioritized bed location and expedited staffing with an ED attending physician for early assessment. The ED attending then performed an assessment to confirm whether sepsis was present and direct early treatment. Although every patient who triggered a sepsis alert in triage did not meet clinical findings of sepsis, patients with MEWS ≥ 4 were frequently ill and required timely intervention.
If an ED attending physician agreed with a sepsis diagnosis, the physician had access to a sepsis workup and treatment order set in CPRS (eAppendix 2 available at doi:10.12788/fp.0194). The sepsis order set incorporated recommendations from the Surviving Sepsis Campaign guidelines and included orders for 2 large-bore peripheral IV lines; aggressive fluid resuscitation (30 mL/kg) for patients with clinical findings of hypoperfusion; broad-spectrum antibiotics; and frequent ordering of laboratory tests and imaging during initial sepsis workup.6 Vancomycin and cefepime were selected as routine broad-spectrum antibiotics in the order set when sepsis was suspected based on local antimicrobial stewardship and safety-efficacy profiles. For example, Luther and colleagues demonstrated that cefepime has lower rates of acute kidney injury when combined with vancomycin vs vancomycin + piperacillin-tazobactam.20 If a β-lactam antibiotic could not be used due to a patient’s drug allergy history, aztreonam was available as an alternative option.
The design of the order set also functioned as a communication interface with clinical pharmacists. Given the large volume of antibiotics ordered in the ED, it was difficult for pharmacists to prioritize antibiotic order verification. While stat orders convey high priority, they often lack specificity. When antibiotic orders were selected from the sepsis order set, comments were already included that stated: “STAT. First dose for sepsis protocol” (eAppendix 3 available at doi:10.12788/fp.0194). This standardized communication conveyed a sense of urgency and a collective understanding that patients with suspected sepsis required timely order verification and administration of antibiotics.
Hospital Ward
Mental status and WBC were included on the wards to monitor for possible signs of sepsis, using MEWS + SRS, which was routinely monitored by nursing every 4 to 8 hours. When MEWS + SRS was ≥ 5 points, ward nursing staff called a sepsis alert.7,16 Early response team (ERT) members received telephone notifications of the alert. ERT staff proceeded with immediate evaluation and treatment at the bedside along with determination for most appropriate LOC. The ERT members included an ICU physician and nurse; respiratory therapist; and nursing supervisor/bed flow coordinator. During bedside evaluation, if the ERT or primary team agreed with a sepsis diagnosis, the ERT or primary team used the sepsis order set to ensure standardized procedures. Stat orders generated through the sepsis order set pathway conveyed a sense of urgency and need for immediate order verification and administration of antibiotics.
In addition to clinical care process improvement, accurate documentation also was emphasized in the EWSS. When a sepsis alert was called, a clinician from the primary team was expected to complete a standardized progress note, which communicated clinical findings, a treatment plan, and captured severity of illness (eAppendix 4 available at doi:10.12788/fp.0194). It included sections for subjective, objective, assessment, and plan. In addition, data objects were created for vital signs and common laboratory findings that retrieved important clinical data from VistA and inserted it into the CPRS note.21
Nursing staff on the wards were expected to communicate results with the primary team for clinical decision making when a patient had a MEWS + SRS of 3 to 4. A sepsis alert may have been called at the discretion of clinical team members but was not required if the score was < 5. Additionally, vital signs were expected to be checked by the nursing staff on the wards at least every 4 hours for closer monitoring.
Sepsis Review Meetings
Weekly meetings were scheduled to review sepsis cases to assess diagnosis, treatment, and documentation entered in the patient record. The team conducting sepsis reviews comprised the chief of staff, chief of quality management, director of patient safety, physician utilization management advisor, chief resident in quality and patient safety (CRQS), and inpatient pharmacy supervisor. In addition, ad hoc physicians and nurses from different specialty areas, such as infectious diseases, hospitalist section, ICU, and the ED participated on request for subject matter expertise when needed. At the conclusion of weekly sepsis meetings, sepsis team members provided feedback to the clinical staff for continuous improvement purposes.
Results
Before implementation of an EWSS at NF/SGVHS, a plan was devised to increase awareness and educate staff on sepsis-related mortality in late FY 2017. Awareness and education about sepsis-related mortality was organized at physician, nursing, and pharmacy leadership clinical staff meetings. Posters about early warning signs of sepsis also were displayed on the nursing units for educational purposes and to convey the importance of early recognition/treatment of sepsis. In addition, the CRQS was the quality leader for house staff and led sepsis campaign change efforts for residents/fellows. An immediate improvement in unadjusted mortality at MRVAMC was noted with initial sepsis awareness and education. From FY 2017, quarter 3 to FY 2018, quarter 1, the number of acute LOC inpatient deaths decreased from 48 to 28, a 42% reduction in unadjusted mortality at MRVAMC (Figure 1). Additionally, the acute LOC SMR improved from 1.20 during FY 2017, quarter 3 down to as low as 0.71 during FY 2018, quarter 1 (Figure 2).
The number of MRVAMC inpatient deaths increased from 28 in FY 2018, quarter 1 to 45 in FY 2018, quarter 3. While acute LOC showed improvement in unadjusted mortality after sepsis education/awareness, it was felt continuous improvement could not be sustained with education alone. An EWSS was designed and implemented within the EHR system in FY 2018. Following implementation of EWSS and reeducating staff on early recognition and treatment of sepsis, acute LOC inpatient deaths decreased from 45 in FY 2018, quarter 3 through FY 2019 where unadjusted mortality was as low as 27 during FY 2019, quarter 4. The MRVAMC acute LOC SMR was consistently < 1.0 from FY 2018, quarter 4 through FY 2019, quarter 4.
In addition to the observed decrease in acute LOC inpatient deaths and improved SMR, the number of ERT alerts and sepsis alerts on the inpatient wards were monitored from FY 2017 through FY 2019. ERT alerts listed in Table 3 were nonspecific and initiated by nursing staff on the wards where a patient’s clinical status was identified as worsening while sepsis alerts were specific ERT alerts called by the ward nursing staff due to concerns for sepsis. The inpatient wards included inpatient medicine, surgery, and psychiatry acute care and the intermediate level of care unit while outpatient clinical areas of treatment, intensive care units, stroke alerts, and STEMI alerts were excluded.
From FY 2017 to FY 2018, quarter 1, the number of nonspecific ERT alerts varied between 75 to 100. Sepsis alerts were not available until December 2017 while the EWSS was in development. Afterward, nonspecific ERT alerts and sepsis alerts were monitored each quarter. Sepsis alerts ranged from 4 to 18. Nonspecific ERT alerts + sepsis alerts continued to increase from FY 2018, quarter 3 through FY 2019, quarter 4.
Discussion
Implementation of the EWSS was associated with improved unadjusted mortality and adjusted mortality for acute LOC at MRVAMC. Although variation exists with application of EWSS at other medical centers, there was similarity with improved sepsis outcomes reported at other health care systems after EWSS implementation.7-16
Improved unadjusted mortality and adjusted mortality for acute LOC at MRVAMC was likely due to multiple contributing factors. First, during design and implementation of the EWSS, project work was interdisciplinary with input from physicians, nurses, and pharmacists from multiple specialties (ie, ED, ICU, and the medicine service); quality management and data analysis specialists; and clinical informatics. Second, facility commitment to improving early recognition and treatment of sepsis from leadership level down to front-line staff was evident. Weekly sepsis meetings with the NF/SGVHS chief of staff helped to sustain EWSS efforts and to identify additional improvement opportunities. Third, integrated informatics solutions within the EHR helped identify early sepsis and minimized human error as well as assisted with coordination of sepsis care across services. Fourth, the focus was on both early identification and treatment of sepsis in the ED and hospital wards. Although it cannot be deduced whether there was causation between reduced inpatient mortality and an increased number of nonspecific ERT alerts+ sepsis alerts on the inpatient wards after EWSS implementation, inpatient deaths decreased and SMR improved. Finally, the EWSS emphasized both the importance of evidence-based clinical care of sepsis and standardized documentation to appropriately capture clinical severity of illness.
Limitations
This program has limitations. The EWSS was studied at a single VHA facility. Veteran demographics and local epidemiology may limit conclusion of outcomes to an individual VHA facility located in a specific geographical region. Additional research is necessary to demonstrate reproducibility and determine whether applicable to other VHA facilities and community care settings.
SMR is a risk-adjusted formula developed by the VHA Inpatient Evaluation Center, which included numerous factors such as diagnosis, comorbid conditions, age, marital status, procedures, source of admission, specific laboratory values, medical or surgical diagnosis-related group, ICU stays, immunosuppressive status, and a COVID-19 positive indicator (added after this study). Further research is needed to evaluate sepsis-related outcomes using the EWSS during the COVID-19 pandemic.
EWSS in the literature have demonstrated various approaches to early identification and treatment of sepsis and have used different sepsis screening tools.22 Evidence suggests that the MEWS + SRS sepsis screening tool may result in false-positive screenings.23-27 Additional research into the specificity of this sepsis screening tool is needed. Ward nursing staff were encouraged to initiate automatic sepsis alerts when MEWS + SRS was ≥ 5; however, this still depended on human factors. Because sepsis alerts are software-specific and others were incompatible with the VHA EHR, it was necessary to design our own EWSS.
Despite improvement with MRVAMC acute LOC unadjusted and adjusted mortality with our EWSS, we did not identify any actual improvement in earlier antibiotic administration times once sepsis was recognized. While accurate documentation regarding degree of sepsis improved, a MRVAMC clinical documentation improvement program was expanded in FY 2018. Therefore, it is difficult to demonstrate causation related to improved sepsis documentation with template changes alone. While sepsis alerts on the inpatient wards were variable since EWSS implementation, nonspecific ERT alerts increased. It is unclear whether some sepsis alerts were called as nonspecific ERT alerts, making it impossible to know the true number of sepsis alerts.
MRVAMC experienced an increase in nurse turnover during FY 2018 and as a teaching hospital had frequent rotating residents and fellows new to processes/protocols. These factors may have contributed to variations in unadjusted mortality. Also the decrease in inpatient mortality and improvement in SMR on acute LOC could have been the result of factors other than the EWSS and the effect of education alone may have been at least as good as that of the EWSS intervention.
Conclusions
Education along with the possible implementation of an EWSS at NF/SGVHS was associated with a decrease in the number of inpatient deaths on MRVAMC’s acute LOC wards from as high as 48 in FY 2017, quarter 3 to as low as 27 in FY 2019, quarter 4 resulting in as large of an improvement as a 44% reduction in unadjusted mortality from FY 2017 to FY 2019. In addition, MRVAMC’s acute LOC SMR improved from > 1.0 to < 1.0, demonstrating fewer inpatient mortalities than predicted from FY 2017 to FY 2019.
This multifaceted interventional strategy may be effectively applied at other VHA health care facilities that use the same EHR system. Next steps may include determining the specificity of MEWS + SRS as a sepsis screening tool; studying outcomes of MRVAMC’s EWSS during the COVID-19 era; and conducting a multicentered study on this EWSS across multiple VHA facilities.
In 1997, Elizabeth McGlynn wrote, “Measuring quality is no simple task.”1 We are reminded of this seminal Health Affairs article at a very pertinent point—as health care practice progresses, measuring the impact of performance improvement initiatives on clinical care delivery remains integral to monitoring overall effectiveness of quality. Mortality outcomes are a major focus of quality.
Inpatient mortality within the Veterans Health Administration (VHA) was measured as actual number of deaths (unadjusted mortality), and adjusted mortality was calculated using the standardized mortality ratio (SMR). SMR included actual number of deaths during hospitalization or within 1 day of hospital discharge divided by predicted number of deaths using a risk-adjusted formula and was calculated separately for acute level of care (LOC) and the intensive care unit (ICU). Using risk-adjusted SMR, if an observed/expected ratio was > 1.0, there were more inpatient deaths than expected; if < 1.0, fewer inpatient deaths occurred than predicted; and if 1.0, observed number of inpatient deaths was equivalent to expected number of deaths.2
Mortality reduction is a complex area of performance improvement. Health care facilities often focus their efforts on the biggest mortality contributors. According to Dantes and Epstein, sepsis results in about 265,000 deaths annually in the United States.3 Reinhart and colleagues demonstrated that sepsis is a worldwide issue resulting in approximately 30 million cases and 6 million deaths annually.4 Furthermore, Kumar and colleagues have noted that when sepsis progresses to septic shock, survival decreases by almost 8% for each hour delay in sepsis identification and treatment.5
Improvements in sepsis management have been multifaceted. The Surviving Sepsis Campaign guidelines created sepsis treatment bundles to guide early diagnosis/treatment of sepsis.6 In addition to awareness and sepsis care bundles, a plethora of informatics solutions within electronic health record (EHR) systems have demonstrated improved sepsis care.7-16 Various approaches to early diagnosis and management of sepsis have been collectively referred to as an early warning sepsis system (EWSS).
An EWSS typically contains automated decision support tools that are integrated in the EHR and meant to assist health care professionals with clinical workflow decision-making. Automated decision support tools within the EHR have a variety of functions, such as clinical care reminders and alerts.17
Sepsis screening tools function as a form of automated decision support and may be incorporated into the EHR to support the EWSS. Although sepsis screening tools vary, they frequently include a combination of data involving vital signs, laboratory values and/or physical examination findings, such as mental status evaluation.The Modified Early Warning Signs (MEWS) + Sepsis Recognition Score (SRS) is one example of a sepsis screening tool.7,16
At Malcom Randall Veterans Affairs Medical Center (MRVAMC) in Gainesville, Florida, we identified a quality improvement project opportunity to improve sepsis care in the emergency department (ED) and inpatient wards using the VHA EHR system, the Computerized Patient Record System (CPRS), which is supported by the Veterans Information Systems and Technology Architecture (VistA).18 A VistA/CPRS EWSS was developed using Lean Six Sigma DMAIC (define, measure, analyze, improve, and control) methodology.19 During the improve stage, informatics solutions were applied and included a combination of EHR interventions, such as template design, an order set, and clinical reminders. Clinical reminders have a wide variety of use, such as reminders for clinical tasks and as automated decision support within clinical workflows using Boolean logic.
To the best of our knowledge, there has been no published application of an EWSS within VistA/CPRS. In this study, we outline the strategic development of an EWSS in VistA/CPRS that assisted clinical staff with identification and treatment of sepsis; improved documentation of sepsis when present; and associated with improvement in unadjusted and adjusted inpatient mortality.
Methods
According to policy activities that constitute research at MRVAMC, no institutional review board approval was required as this work met criteria for operational improvement activities exempt from ethics review.
The North Florida/South Georgia Veterans Health System (NF/SGVHS) includes MRVAMC, a large academic hospital with rotating residents/fellows and multiple specialty care services. MRVAMC comprised 144 beds on the medicine/surgery wards; 48 beds in the psychiatry unit; 18 intermediate LOC beds; and 27 ICU beds. The MRVAMC SMR was identified as an improvement opportunity during fiscal year (FY) 2017 (Table 1). Its adjusted mortality for acute LOC demonstrated an observed/expected ratio of > 1.0 suggesting more inpatient deaths were observed than expected. The number of deaths (unadjusted mortality) on acute LOC at MRVAMC was noted to be rising during the first 3 quarters of FY 2017. A deeper examination of data by Pyramid Analytics (www.pyramidanalytics.com) discovered that sepsis was the primary driver for inpatient mortality on acute LOC at MRVAMC. Our goal was to reduce inpatient sepsis-related mortality via development of an EWSS that leveraged VistA/CPRS to improve early identification and treatment of sepsis in the ED and inpatient wards.
Emergency Department
Given the importance of recognizing sepsis early, the sepsis team focused on improvement opportunities at the initial point of patient contact: ED triage. The goal was to incorporate automated VistA/CPRS decision support to assist clinicians with identifying sepsis in triage using MEWS, which was chosen to optimize immediate hospital-wide buy-in. Clinical staff were already familiar with MEWS, which was in use on the inpatient wards.
Flow through the ED and availability of resources differed from the wards. Hence, modification to MEWS on the wards was necessary to fit clinical workflow in the ED. Temperature, heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), mental status, and white blood cell count (WBC) factored into a MEWS + SRS score on the wards (Table 2). For the ED, MEWS included temperature, HR, RR and SBP, but excluded mental status and WBC. Mental status assessment was excluded due to technical infeasibility (while vital signs could be automatically calculated in real time for a MEWS score, that was not possible for mental status changes). WBC was excluded from the ED as laboratory test results would not be available in triage.
MEWS + SRS scores were calculated in VistA by using clinical reminders. Clinical reminder logic included a series of conditional statements based on various combinations of MEWS + SRS clinical data entered in the EHR. When ED triage vital signs data were entered in CPRS, clinical data were stored and processed according to clinical reminder logic in VistA and displayed to the user in CPRS. While MEWS of ≥ 5 triggered a sepsis alert on the wards, the ≥ 4 threshold was used in the ED given mental status and WBC were excluded from calculations in triage (eAppendix 1 available at doi:10.12788/fp.0194).
Once a sepsis alert was triggered in triage for MEWS ≥ 4, ED nursing staff prioritized bed location and expedited staffing with an ED attending physician for early assessment. The ED attending then performed an assessment to confirm whether sepsis was present and direct early treatment. Although every patient who triggered a sepsis alert in triage did not meet clinical findings of sepsis, patients with MEWS ≥ 4 were frequently ill and required timely intervention.
If an ED attending physician agreed with a sepsis diagnosis, the physician had access to a sepsis workup and treatment order set in CPRS (eAppendix 2 available at doi:10.12788/fp.0194). The sepsis order set incorporated recommendations from the Surviving Sepsis Campaign guidelines and included orders for 2 large-bore peripheral IV lines; aggressive fluid resuscitation (30 mL/kg) for patients with clinical findings of hypoperfusion; broad-spectrum antibiotics; and frequent ordering of laboratory tests and imaging during initial sepsis workup.6 Vancomycin and cefepime were selected as routine broad-spectrum antibiotics in the order set when sepsis was suspected based on local antimicrobial stewardship and safety-efficacy profiles. For example, Luther and colleagues demonstrated that cefepime has lower rates of acute kidney injury when combined with vancomycin vs vancomycin + piperacillin-tazobactam.20 If a β-lactam antibiotic could not be used due to a patient’s drug allergy history, aztreonam was available as an alternative option.
The design of the order set also functioned as a communication interface with clinical pharmacists. Given the large volume of antibiotics ordered in the ED, it was difficult for pharmacists to prioritize antibiotic order verification. While stat orders convey high priority, they often lack specificity. When antibiotic orders were selected from the sepsis order set, comments were already included that stated: “STAT. First dose for sepsis protocol” (eAppendix 3 available at doi:10.12788/fp.0194). This standardized communication conveyed a sense of urgency and a collective understanding that patients with suspected sepsis required timely order verification and administration of antibiotics.
Hospital Ward
Mental status and WBC were included on the wards to monitor for possible signs of sepsis, using MEWS + SRS, which was routinely monitored by nursing every 4 to 8 hours. When MEWS + SRS was ≥ 5 points, ward nursing staff called a sepsis alert.7,16 Early response team (ERT) members received telephone notifications of the alert. ERT staff proceeded with immediate evaluation and treatment at the bedside along with determination for most appropriate LOC. The ERT members included an ICU physician and nurse; respiratory therapist; and nursing supervisor/bed flow coordinator. During bedside evaluation, if the ERT or primary team agreed with a sepsis diagnosis, the ERT or primary team used the sepsis order set to ensure standardized procedures. Stat orders generated through the sepsis order set pathway conveyed a sense of urgency and need for immediate order verification and administration of antibiotics.
In addition to clinical care process improvement, accurate documentation also was emphasized in the EWSS. When a sepsis alert was called, a clinician from the primary team was expected to complete a standardized progress note, which communicated clinical findings, a treatment plan, and captured severity of illness (eAppendix 4 available at doi:10.12788/fp.0194). It included sections for subjective, objective, assessment, and plan. In addition, data objects were created for vital signs and common laboratory findings that retrieved important clinical data from VistA and inserted it into the CPRS note.21
Nursing staff on the wards were expected to communicate results with the primary team for clinical decision making when a patient had a MEWS + SRS of 3 to 4. A sepsis alert may have been called at the discretion of clinical team members but was not required if the score was < 5. Additionally, vital signs were expected to be checked by the nursing staff on the wards at least every 4 hours for closer monitoring.
Sepsis Review Meetings
Weekly meetings were scheduled to review sepsis cases to assess diagnosis, treatment, and documentation entered in the patient record. The team conducting sepsis reviews comprised the chief of staff, chief of quality management, director of patient safety, physician utilization management advisor, chief resident in quality and patient safety (CRQS), and inpatient pharmacy supervisor. In addition, ad hoc physicians and nurses from different specialty areas, such as infectious diseases, hospitalist section, ICU, and the ED participated on request for subject matter expertise when needed. At the conclusion of weekly sepsis meetings, sepsis team members provided feedback to the clinical staff for continuous improvement purposes.
Results
Before implementation of an EWSS at NF/SGVHS, a plan was devised to increase awareness and educate staff on sepsis-related mortality in late FY 2017. Awareness and education about sepsis-related mortality was organized at physician, nursing, and pharmacy leadership clinical staff meetings. Posters about early warning signs of sepsis also were displayed on the nursing units for educational purposes and to convey the importance of early recognition/treatment of sepsis. In addition, the CRQS was the quality leader for house staff and led sepsis campaign change efforts for residents/fellows. An immediate improvement in unadjusted mortality at MRVAMC was noted with initial sepsis awareness and education. From FY 2017, quarter 3 to FY 2018, quarter 1, the number of acute LOC inpatient deaths decreased from 48 to 28, a 42% reduction in unadjusted mortality at MRVAMC (Figure 1). Additionally, the acute LOC SMR improved from 1.20 during FY 2017, quarter 3 down to as low as 0.71 during FY 2018, quarter 1 (Figure 2).
The number of MRVAMC inpatient deaths increased from 28 in FY 2018, quarter 1 to 45 in FY 2018, quarter 3. While acute LOC showed improvement in unadjusted mortality after sepsis education/awareness, it was felt continuous improvement could not be sustained with education alone. An EWSS was designed and implemented within the EHR system in FY 2018. Following implementation of EWSS and reeducating staff on early recognition and treatment of sepsis, acute LOC inpatient deaths decreased from 45 in FY 2018, quarter 3 through FY 2019 where unadjusted mortality was as low as 27 during FY 2019, quarter 4. The MRVAMC acute LOC SMR was consistently < 1.0 from FY 2018, quarter 4 through FY 2019, quarter 4.
In addition to the observed decrease in acute LOC inpatient deaths and improved SMR, the number of ERT alerts and sepsis alerts on the inpatient wards were monitored from FY 2017 through FY 2019. ERT alerts listed in Table 3 were nonspecific and initiated by nursing staff on the wards where a patient’s clinical status was identified as worsening while sepsis alerts were specific ERT alerts called by the ward nursing staff due to concerns for sepsis. The inpatient wards included inpatient medicine, surgery, and psychiatry acute care and the intermediate level of care unit while outpatient clinical areas of treatment, intensive care units, stroke alerts, and STEMI alerts were excluded.
From FY 2017 to FY 2018, quarter 1, the number of nonspecific ERT alerts varied between 75 to 100. Sepsis alerts were not available until December 2017 while the EWSS was in development. Afterward, nonspecific ERT alerts and sepsis alerts were monitored each quarter. Sepsis alerts ranged from 4 to 18. Nonspecific ERT alerts + sepsis alerts continued to increase from FY 2018, quarter 3 through FY 2019, quarter 4.
Discussion
Implementation of the EWSS was associated with improved unadjusted mortality and adjusted mortality for acute LOC at MRVAMC. Although variation exists with application of EWSS at other medical centers, there was similarity with improved sepsis outcomes reported at other health care systems after EWSS implementation.7-16
Improved unadjusted mortality and adjusted mortality for acute LOC at MRVAMC was likely due to multiple contributing factors. First, during design and implementation of the EWSS, project work was interdisciplinary with input from physicians, nurses, and pharmacists from multiple specialties (ie, ED, ICU, and the medicine service); quality management and data analysis specialists; and clinical informatics. Second, facility commitment to improving early recognition and treatment of sepsis from leadership level down to front-line staff was evident. Weekly sepsis meetings with the NF/SGVHS chief of staff helped to sustain EWSS efforts and to identify additional improvement opportunities. Third, integrated informatics solutions within the EHR helped identify early sepsis and minimized human error as well as assisted with coordination of sepsis care across services. Fourth, the focus was on both early identification and treatment of sepsis in the ED and hospital wards. Although it cannot be deduced whether there was causation between reduced inpatient mortality and an increased number of nonspecific ERT alerts+ sepsis alerts on the inpatient wards after EWSS implementation, inpatient deaths decreased and SMR improved. Finally, the EWSS emphasized both the importance of evidence-based clinical care of sepsis and standardized documentation to appropriately capture clinical severity of illness.
Limitations
This program has limitations. The EWSS was studied at a single VHA facility. Veteran demographics and local epidemiology may limit conclusion of outcomes to an individual VHA facility located in a specific geographical region. Additional research is necessary to demonstrate reproducibility and determine whether applicable to other VHA facilities and community care settings.
SMR is a risk-adjusted formula developed by the VHA Inpatient Evaluation Center, which included numerous factors such as diagnosis, comorbid conditions, age, marital status, procedures, source of admission, specific laboratory values, medical or surgical diagnosis-related group, ICU stays, immunosuppressive status, and a COVID-19 positive indicator (added after this study). Further research is needed to evaluate sepsis-related outcomes using the EWSS during the COVID-19 pandemic.
EWSS in the literature have demonstrated various approaches to early identification and treatment of sepsis and have used different sepsis screening tools.22 Evidence suggests that the MEWS + SRS sepsis screening tool may result in false-positive screenings.23-27 Additional research into the specificity of this sepsis screening tool is needed. Ward nursing staff were encouraged to initiate automatic sepsis alerts when MEWS + SRS was ≥ 5; however, this still depended on human factors. Because sepsis alerts are software-specific and others were incompatible with the VHA EHR, it was necessary to design our own EWSS.
Despite improvement with MRVAMC acute LOC unadjusted and adjusted mortality with our EWSS, we did not identify any actual improvement in earlier antibiotic administration times once sepsis was recognized. While accurate documentation regarding degree of sepsis improved, a MRVAMC clinical documentation improvement program was expanded in FY 2018. Therefore, it is difficult to demonstrate causation related to improved sepsis documentation with template changes alone. While sepsis alerts on the inpatient wards were variable since EWSS implementation, nonspecific ERT alerts increased. It is unclear whether some sepsis alerts were called as nonspecific ERT alerts, making it impossible to know the true number of sepsis alerts.
MRVAMC experienced an increase in nurse turnover during FY 2018 and as a teaching hospital had frequent rotating residents and fellows new to processes/protocols. These factors may have contributed to variations in unadjusted mortality. Also the decrease in inpatient mortality and improvement in SMR on acute LOC could have been the result of factors other than the EWSS and the effect of education alone may have been at least as good as that of the EWSS intervention.
Conclusions
Education along with the possible implementation of an EWSS at NF/SGVHS was associated with a decrease in the number of inpatient deaths on MRVAMC’s acute LOC wards from as high as 48 in FY 2017, quarter 3 to as low as 27 in FY 2019, quarter 4 resulting in as large of an improvement as a 44% reduction in unadjusted mortality from FY 2017 to FY 2019. In addition, MRVAMC’s acute LOC SMR improved from > 1.0 to < 1.0, demonstrating fewer inpatient mortalities than predicted from FY 2017 to FY 2019.
This multifaceted interventional strategy may be effectively applied at other VHA health care facilities that use the same EHR system. Next steps may include determining the specificity of MEWS + SRS as a sepsis screening tool; studying outcomes of MRVAMC’s EWSS during the COVID-19 era; and conducting a multicentered study on this EWSS across multiple VHA facilities.
1. McGlynn EA. Six challenges in measuring the quality of health care. Health Aff (Millwood). 1997;16(3):7-21. doi:10.1377/hlthaff.16.3.7
2. US Department of Veterans Affairs, Veterans Health Administration. Strategic Analytics for Improvement and Learning (SAIL) value model measure definitions. Updated May 15, 2019. Accessed October 11, 2021. https://www.va.gov/QUALITYOFCARE/measure-up/SAIL_definitions.asp
3. Dantes RB, Epstein L. Combatting sepsis: a public health perspective. Clin Infect Dis. 2018;67(8):1300-1302. doi:10.1093/cid/ciy342
4. Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing sepsis as a global health priority - a WHO resolution. N Engl J Med. 2017;377(5):414-417. doi:10.1056/NEJMp1707170
5. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596. doi:10.1097/01.CCM.0000217961.75225.E9
6. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552. doi:10.1097/CCM.0000000000002255
7. Guirgis FW, Jones L, Esma R, et al. Managing sepsis: electronic recognition, rapid response teams, and standardized care save lives. J Crit Care. 2017;40:296-302. doi:10.1016/j.jcrc.2017.04.005
8. Whippy A, Skeath M, Crawford B, et al. Kaiser Permanente’s performance improvement system, part 3: multisite improvements in care for patients with sepsis. Jt Comm J Qual Patient Saf. 2011;37(11):483-493. doi:10.1016/s1553-7250(11)37061-4
9. Harrison AM, Thongprayoon C, Kashyap R, et al. Developing the surveillance algorithm for detection of failure to recognize and treat severe sepsis. Mayo Clin Proc. 2015;90(2):166-175. doi:10.1016/j.mayocp.2014.11.014
10. Rothman M, Levy M, Dellinger RP, et al. Sepsis as 2 problems: identifying sepsis at admission and predicting onset in the hospital using an electronic medical record-based acuity score. J Crit Care. 2017;38:237-244. doi:10.1016/j.jcrc.2016.11.037
11. Back JS, Jin Y, Jin T, Lee SM. Development and validation of an automated sepsis risk assessment system. Res Nurs Health. 2016;39(5):317-327. doi:10.1002/nur.21734
12. Khurana HS, Groves RH Jr, Simons MP, et al. Real-time automated sampling of electronic medical records predicts hospital mortality. Am J Med. 2016;129(7):688-698.e2. doi:10.1016/j.amjmed.2016.02.037
13. Umscheid CA, Betesh J, VanZandbergen C, et al. Development, implementation, and impact of an automated early warning and response system for sepsis. J Hosp Med. 2015;10(1):26-31. doi:10.1002/jhm.2259
14. Vogel L. EMR alert cuts sepsis deaths. CMAJ. 2014;186(2):E80. doi:10.1503/cmaj.109-4686
15. Jones SL, Ashton CM, Kiehne L, et al. Reductions in sepsis mortality and costs after design and implementation of a nurse-based early recognition and response program. Jt Comm J Qual Patient Saf. 2015;41(11):483-491. doi:10.1016/s1553-7250(15)41063-3
16. Croft CA, Moore FA, Efron PA, et al. Computer versus paper system for recognition and management of sepsis in surgical intensive care. J Trauma Acute Care Surg. 2014;76(2):311-319. doi:10.1097/TA.0000000000000121
17. Tcheng JE, Bakken S, Bates DW, et al, eds. Optimizing Strategies for Clinical Decision Support: Summary of a Meeting Series. National Academy of Medicine; 2017. Accessed October 11, 2021. https://nam.edu/wp-content/uploads/2017/11/Optimizing-Strategies-for-Clinical-Decision-Support.pdf
18. US Department of Veterans Affairs. History of IT at VA. Updated January 1, 2020. Accessed October 11, 2021. https://www.oit.va.gov/about/history.cfm
19. GoLeanSixSigma. DMAIC: The 5 Phases of Lean Six Sigma. Published 2012. Accessed October 11, 2021. https://goleansixsigma.com/wp-content/uploads/2012/02/DMAIC-The-5-Phases-of-Lean-Six-Sigma-www.GoLeanSixSigma.com_.pdf
20. Luther MK, Timbrook TT, Caffrey AR, Dosa D, Lodise TP, LaPlante KL. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: a systematic review and meta-analysis. Crit Care Med. 2018;46(1):12-20. doi:10.1097/CCM.0000000000002769
21. International Business Machines Corp. Overview of data objects. Accessed October 11, 2021. https://www.ibm.com/support/knowledgecenter/en/SSLTBW_2.3.0/com.ibm.zos.v2r3.cbclx01/data_objects.htm
22. Churpek MM, Snyder A, Han X, et al. Quick sepsis-related organ failure assessment, systemic inflammatory response syndrome, and early warning scores for detecting clinical deterioration in infected patients outside the intensive care unit. Am J Respir Crit Care Med. 2017;195(7):906-911. doi:10.1164/rccm.201604-0854OC
23. Ghanem-Zoubi NO, Vardi M, Laor A, Weber G, Bitterman H. Assessment of disease-severity scoring systems for patients with sepsis in general internal medicine departments. Crit Care. 2011;15(2):R95. doi:10.1186/cc10102
24. Hamilton F, Arnold D, Baird A, Albur M, Whiting P. Early Warning scores do not accurately predict mortality in sepsis: a meta-analysis and systematic review of the literature. J Infect. 2018;76(3):241-248. doi:10.1016/j.jinf.2018.01.002
25. Martino IF, Figgiaconi V, Seminari E, Muzzi A, Corbella M, Perlini S. The role of qSOFA compared to other prognostic scores in septic patients upon admission to the emergency department. Eur J Intern Med. 2018;53:e11-e13. doi:10.1016/j.ejim.2018.05.022
26. Nannan Panday RS, Minderhoud TC, Alam N, Nanayakkara PWB. Prognostic value of early warning scores in the emergency department (ED) and acute medical unit (AMU): A narrative review. Eur J Intern Med. 2017;45:20-31. doi:10.1016/j.ejim.2017.09.027
27. Jayasundera R, Neilly M, Smith TO, Myint PK. Are early warning scores useful predictors for mortality and morbidity in hospitalised acutely unwell older patients? A systematic review. J Clin Med. 2018;7(10):309. Published 2018 Sep 28. doi:10.3390/jcm7100309
1. McGlynn EA. Six challenges in measuring the quality of health care. Health Aff (Millwood). 1997;16(3):7-21. doi:10.1377/hlthaff.16.3.7
2. US Department of Veterans Affairs, Veterans Health Administration. Strategic Analytics for Improvement and Learning (SAIL) value model measure definitions. Updated May 15, 2019. Accessed October 11, 2021. https://www.va.gov/QUALITYOFCARE/measure-up/SAIL_definitions.asp
3. Dantes RB, Epstein L. Combatting sepsis: a public health perspective. Clin Infect Dis. 2018;67(8):1300-1302. doi:10.1093/cid/ciy342
4. Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing sepsis as a global health priority - a WHO resolution. N Engl J Med. 2017;377(5):414-417. doi:10.1056/NEJMp1707170
5. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596. doi:10.1097/01.CCM.0000217961.75225.E9
6. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552. doi:10.1097/CCM.0000000000002255
7. Guirgis FW, Jones L, Esma R, et al. Managing sepsis: electronic recognition, rapid response teams, and standardized care save lives. J Crit Care. 2017;40:296-302. doi:10.1016/j.jcrc.2017.04.005
8. Whippy A, Skeath M, Crawford B, et al. Kaiser Permanente’s performance improvement system, part 3: multisite improvements in care for patients with sepsis. Jt Comm J Qual Patient Saf. 2011;37(11):483-493. doi:10.1016/s1553-7250(11)37061-4
9. Harrison AM, Thongprayoon C, Kashyap R, et al. Developing the surveillance algorithm for detection of failure to recognize and treat severe sepsis. Mayo Clin Proc. 2015;90(2):166-175. doi:10.1016/j.mayocp.2014.11.014
10. Rothman M, Levy M, Dellinger RP, et al. Sepsis as 2 problems: identifying sepsis at admission and predicting onset in the hospital using an electronic medical record-based acuity score. J Crit Care. 2017;38:237-244. doi:10.1016/j.jcrc.2016.11.037
11. Back JS, Jin Y, Jin T, Lee SM. Development and validation of an automated sepsis risk assessment system. Res Nurs Health. 2016;39(5):317-327. doi:10.1002/nur.21734
12. Khurana HS, Groves RH Jr, Simons MP, et al. Real-time automated sampling of electronic medical records predicts hospital mortality. Am J Med. 2016;129(7):688-698.e2. doi:10.1016/j.amjmed.2016.02.037
13. Umscheid CA, Betesh J, VanZandbergen C, et al. Development, implementation, and impact of an automated early warning and response system for sepsis. J Hosp Med. 2015;10(1):26-31. doi:10.1002/jhm.2259
14. Vogel L. EMR alert cuts sepsis deaths. CMAJ. 2014;186(2):E80. doi:10.1503/cmaj.109-4686
15. Jones SL, Ashton CM, Kiehne L, et al. Reductions in sepsis mortality and costs after design and implementation of a nurse-based early recognition and response program. Jt Comm J Qual Patient Saf. 2015;41(11):483-491. doi:10.1016/s1553-7250(15)41063-3
16. Croft CA, Moore FA, Efron PA, et al. Computer versus paper system for recognition and management of sepsis in surgical intensive care. J Trauma Acute Care Surg. 2014;76(2):311-319. doi:10.1097/TA.0000000000000121
17. Tcheng JE, Bakken S, Bates DW, et al, eds. Optimizing Strategies for Clinical Decision Support: Summary of a Meeting Series. National Academy of Medicine; 2017. Accessed October 11, 2021. https://nam.edu/wp-content/uploads/2017/11/Optimizing-Strategies-for-Clinical-Decision-Support.pdf
18. US Department of Veterans Affairs. History of IT at VA. Updated January 1, 2020. Accessed October 11, 2021. https://www.oit.va.gov/about/history.cfm
19. GoLeanSixSigma. DMAIC: The 5 Phases of Lean Six Sigma. Published 2012. Accessed October 11, 2021. https://goleansixsigma.com/wp-content/uploads/2012/02/DMAIC-The-5-Phases-of-Lean-Six-Sigma-www.GoLeanSixSigma.com_.pdf
20. Luther MK, Timbrook TT, Caffrey AR, Dosa D, Lodise TP, LaPlante KL. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: a systematic review and meta-analysis. Crit Care Med. 2018;46(1):12-20. doi:10.1097/CCM.0000000000002769
21. International Business Machines Corp. Overview of data objects. Accessed October 11, 2021. https://www.ibm.com/support/knowledgecenter/en/SSLTBW_2.3.0/com.ibm.zos.v2r3.cbclx01/data_objects.htm
22. Churpek MM, Snyder A, Han X, et al. Quick sepsis-related organ failure assessment, systemic inflammatory response syndrome, and early warning scores for detecting clinical deterioration in infected patients outside the intensive care unit. Am J Respir Crit Care Med. 2017;195(7):906-911. doi:10.1164/rccm.201604-0854OC
23. Ghanem-Zoubi NO, Vardi M, Laor A, Weber G, Bitterman H. Assessment of disease-severity scoring systems for patients with sepsis in general internal medicine departments. Crit Care. 2011;15(2):R95. doi:10.1186/cc10102
24. Hamilton F, Arnold D, Baird A, Albur M, Whiting P. Early Warning scores do not accurately predict mortality in sepsis: a meta-analysis and systematic review of the literature. J Infect. 2018;76(3):241-248. doi:10.1016/j.jinf.2018.01.002
25. Martino IF, Figgiaconi V, Seminari E, Muzzi A, Corbella M, Perlini S. The role of qSOFA compared to other prognostic scores in septic patients upon admission to the emergency department. Eur J Intern Med. 2018;53:e11-e13. doi:10.1016/j.ejim.2018.05.022
26. Nannan Panday RS, Minderhoud TC, Alam N, Nanayakkara PWB. Prognostic value of early warning scores in the emergency department (ED) and acute medical unit (AMU): A narrative review. Eur J Intern Med. 2017;45:20-31. doi:10.1016/j.ejim.2017.09.027
27. Jayasundera R, Neilly M, Smith TO, Myint PK. Are early warning scores useful predictors for mortality and morbidity in hospitalised acutely unwell older patients? A systematic review. J Clin Med. 2018;7(10):309. Published 2018 Sep 28. doi:10.3390/jcm7100309