Research Briefs Novel Screening Test Sparks New Ideas About Old Drugs
Repurposing standard drugs and rethinking drug combinations may lead to more effective ways to combat drug-resistant bacteria, according to findings from a National Institutes of Health study. The researchers developed an assay to screen for effectiveness and used it on 5,170 drugs and other biologically active compounds. They identified 25 that suppress the growth of two strains of Klebsiella pneumoniae that are resistant to most antibiotics: 11 FDA-approved drugs and 14 drugs still under investigation, including antibiotics, antifungals, and antiseptics, and an antiviral, antimalarial, and anticancer drug/compound. They also looked for combinations of drugs and paired newly identified drugs from the repurposing screen with a standard-ofcare antibiotic that did not work by itself. They found four twodrug combinations that work against K. pneumoniae, meaning ineffective antibiotics became active again in the presence of the second drug. For instance, combining colistin with doxycycline, both antibiotics, reversed drug resistance. They also tested three-drug combinations against 10 common strains of multidrug-resistant bacteria and found three different combinations of broad-acting antibiotics that were effective. For example, colistin/auranofin/ceftazidime and colistin/auranofin/ rifabutin suppressed more than 80% of growth for all 10 strains. Rifabutin/colistin/imipenem inhibited more than 75% of growth in all of the strains except two Acinetobacter baumannii isolates. These results demonstrate that this assay has potential as a real-time clinical tool: “The results are very promising,” said Wei Zheng, PhD, one of the study authors. “We think the test can eventually help repurpose approved drugs and other compounds and find clinically relevant drug combinations that can be approved for use in different ways that we have never used before.” Source: National Institutes of Health, November 2016
Assessing Addiction From Multiple Perspectives
It’s time to change addiction assessment and build on advances in neuroscience, say scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA). They’ve proposed an assessment tool to diagnose addictive disorders that takes into account addiction-related behaviors, brain imaging, and genetic data. The Addictions Neuroclinical Assessment could lead to more effective individualized treatments, they say. “We currently approach addiction diagnosis as a ‘yes or no’ proposition,” said Laura Kwako, PhD, lead author of a review article on the subject. Addictive disorders are typically classified by the substance of abuse and the presence or absence of symptoms, such as difficulty controlling consumption. By “leveraging knowledge of the neuroscience” to identify a “package of assessments,” the researchers hope to more precisely identify different subtypes of addictive disorders. They compare the new assessment tool with those used to tailor cancer
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diagnoses, which combine cellular, genetic, molecular, and imaging information with clinical history. The behavioral assessment would include three functional processes most relevant to addiction: altered perception of an object or event or “incentive salience” (where drug-taking makes something seem more attractive or important); negative emotionality (increased negative responses when drugs are no longer available); and executive functioning (e.g., deficits in organizing behavior toward goals). “The assessment framework that we describe recognizes the great advances that continue to be made in our understanding of the neuroscience of addiction,” said NIAAA Director George Koob, PhD, a co-author of the review. “These advances underscore how much we know about the core neurobiological manifestations of addiction in people.” Source: National Institutes of Health, October 2016
Flu Vaccine Offers “Substantial Benefits” to Diabetes Patients
Is it safe to give flu vaccinations to patients with an impaired immune response, such as those with diabetes? The evidence was both sparse and inconclusive, say researchers from Imperial College London. But their seven-year study of 124,503 patients with type-2 diabetes suggests “substantial benefits.” The study covered four periods in each cohort year: preinfluenza, influenza season, postinfluenza, and summer. The outcome measures were hospital admissions for acute myocardial infarction (MI), stroke, pneumonia, influenza, and heart failure, as well as all-cause death. During the study, there were 5,142 admissions for acute MI; 4,515 for stroke; 14,154 for pneumonia or influenza; 12,915 for heart failure; and 21,070 deaths. Vaccine recipients were older and generally more ill; they had more coexisting conditions and were taking more medications than nonrecipients. However, vaccination was associated with significant reductions in all of the outcomes during the flu season. After adjusting for residual confounding, the researchers found 19% lower rates of admissions for acute MI, 30% for stroke, 22% for heart failure, and 15% for pneumonia or influenza. The death rate for vaccinated patients was 24% lower than for nonrecipients. That was during flu season—but vaccination was also associated with significantly fewer events during the pre- and postinfluenza seasons for all outcomes except for acute MI and pneumonia/influenza in the preinfluenza period. Concerns about the benefits of influenza vaccination in older adults and patients with chronic illnesses affect the acceptance and uptake of vaccination, the researchers note. But their findings, they add, “underline the importance of influenza vaccination as part of comprehensive secondary prevention in this high-risk population.” Source: Canadian Medical Association Journal, October 2016
Research Briefs Which Cancer Patients Can Best Survive the ICU?
Because cancer is so complex, admitting a patient with cancer to the intensive care unti (ICU) can be challenging triage. Often the reason for the admission is acute complications related to the cancer or its treatment. Understanding how those complications might affect the patient’s outcome is critical to planning care, gauging use of ICU resources, and counseling patients and their families. Some studies have identified important determinants of mortality, but the existing literature is “scarce,” say researchers who studied outcomes in ICU patients with cancer. The researchers analyzed data from two cohort studies of 1,737 patients with solid tumors and 291 with hematological malignancies. Of those, 456 (23%) had cancer-related complications at ICU admission, most frequently chemotherapy and radiation therapy toxicity, venous thromboembolism (VTE), and respiratory failure by tumor. Patients with complications tended to have worse performance status scores and active disease. They also were more likely to have more severe organ dysfunction, greater need for invasive support, and infection at ICU admission. Complications were more frequent in patients with metastatic solid tumors, particularly lung and breast cancer (although less common in patients with gastrointestinal [GI] tumors), and in patients with more aggressive hematological malignancies, especially acute leukemia and aggressive non-Hodgkin’s lymphoma. The study had several major findings, the researchers say. First, one in four patients with cancer admitted to the ICU has acute complications related to the underlying cancer or treatment side effects. However, while there were many cancer-related complications and their prognostic impact was quite variable, and despite high mortality rates, outcome in these patients was “better than perceived a priori,” the researchers say. High sequential organ failure assessment score on the first day of ICU stay, worse performance status, and need for mechanical ventilation were all independent predictors of mortality, which is in accord with current literature. However, among the individual cancer-related complications studied, only vena cava syndrome, GI involvement, and respiratory failure were independently associated with in-hospital mortality. A “substantial” mortality rate (73%) among patients with GI involvement emphasizes the importance of discussing the appropriateness of ICU admission in these patients, the researchers caution. Although VTE was one of the most common complications, it was not a major determinant of outcome. Another important point, the researchers note, was the high frequency of chemotherapy- and radiation therapy-induced toxicity. Treatment-related neutropenia is not a good predictor of outcome, they say, because research has found it is not a relevant predictor of mortality. Source: PLOS One, October 2016
A Better Way to Predict Colorectal Cancer Relapse?
Carcinoembryonic antigen (CEA) is often used as a marker for relapse in colorectal cancer (CRC). But in as many as 40% of recurrences, the serum CEA shows unmeasurable elevations. And some patients with resected CRC have transient elevations of CEA levels; the false-positive rate during followup has been as high as 16%, say researchers from Kaohsiung Medical University in Taiwan. They propose “a more powerful tool”: a membrane array-based multigene biomarker assay, or biomarker chip, that detects circulating tumor cells in the peripheral blood. The researchers conducted a study in 298 patients with CRC to test that alternative. The patients were enrolled after radical curative resection for primary CRC tumor: 82 were stage I, 102 were stage II, and 114 were stage III. Patients were followed for a median of 28.4 months, every three months for three years, then every six months. At each follow-up visit, laboratory studies included serum CEA levels. Elevated CEA levels were defined as two consecutive measurements greater than 5 ng/mL at a three-month interval. During the study period, 48 patients (16.1%) had postoperative relapse, and 26 (8.7%) died. Of all 298 patients, 62 (20.8%) had a total biomarker chip score higher than the cutoff value. Of the 48 who relapsed, 42 (87.5%) showed positive biochip results prior to relapse. The positive biochip results were significantly associated with postoperative relapse. In fact, the biomarker chip was better all around than postoperative serum CEA levels for predicting relapse: with higher sensitivity (87.5% versus 60.4%), specificity (92.0% versus 83.2%), positive predictive value (67.7% versus 40.8%), negative predictive value (97.5% versus 91.6%), and accuracy (91.3% versus 79.5%). Moreover, the biochip predicted relapse “considerably earlier” than did CEA levels (10.7 versus 2.8 months). The researchers note that CRC-related deaths are largely attributable to clinical relapse. The sooner a relapse is diagnosed, the more amenable the tumor may be to resection, increasing the likelihood of long-term survival. In sum, the biomarker chip would be a more accurate tool for predicting relapse, the researchers say. They also suggest that, in clinical practice, combining the two tests could enhance confidence in the diagnosis. Source: PLOS One, October 2016
Vol. 42 No. 1 • January 2017 • P&T 55 ®
Repurposing standard drugs and rethinking drug combinations may lead to more effective ways to combat drug-resistant bacteria, according to findings from a National Institutes of Health study. The researchers developed an assay to screen for effectiveness and used it on 5,170 drugs and other biologically active compounds. They identified 25 that suppress the growth of two strains of Klebsiella pneumoniae that are resistant to most antibiotics: 11 FDA-approved drugs and 14 drugs still under investigation, including antibiotics, antifungals, and antiseptics, and an antiviral, antimalarial, and anticancer drug/compound. They also looked for combinations of drugs and paired newly identified drugs from the repurposing screen with a standard-ofcare antibiotic that did not work by itself. They found four twodrug combinations that work against K. pneumoniae, meaning ineffective antibiotics became active again in the presence of the second drug. For instance, combining colistin with doxycycline, both antibiotics, reversed drug resistance. They also tested three-drug combinations against 10 common strains of multidrug-resistant bacteria and found three different combinations of broad-acting antibiotics that were effective. For example, colistin/auranofin/ceftazidime and colistin/auranofin/ rifabutin suppressed more than 80% of growth for all 10 strains. Rifabutin/colistin/imipenem inhibited more than 75% of growth in all of the strains except two Acinetobacter baumannii isolates. These results demonstrate that this assay has potential as a real-time clinical tool: “The results are very promising,” said Wei Zheng, PhD, one of the study authors. “We think the test can eventually help repurpose approved drugs and other compounds and find clinically relevant drug combinations that can be approved for use in different ways that we have never used before.” Source: National Institutes of Health, November 2016
Assessing Addiction From Multiple Perspectives
It’s time to change addiction assessment and build on advances in neuroscience, say scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA). They’ve proposed an assessment tool to diagnose addictive disorders that takes into account addiction-related behaviors, brain imaging, and genetic data. The Addictions Neuroclinical Assessment could lead to more effective individualized treatments, they say. “We currently approach addiction diagnosis as a ‘yes or no’ proposition,” said Laura Kwako, PhD, lead author of a review article on the subject. Addictive disorders are typically classified by the substance of abuse and the presence or absence of symptoms, such as difficulty controlling consumption. By “leveraging knowledge of the neuroscience” to identify a “package of assessments,” the researchers hope to more precisely identify different subtypes of addictive disorders. They compare the new assessment tool with those used to tailor cancer
54
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January 2017 • Vol. 42 No. 1
diagnoses, which combine cellular, genetic, molecular, and imaging information with clinical history. The behavioral assessment would include three functional processes most relevant to addiction: altered perception of an object or event or “incentive salience” (where drug-taking makes something seem more attractive or important); negative emotionality (increased negative responses when drugs are no longer available); and executive functioning (e.g., deficits in organizing behavior toward goals). “The assessment framework that we describe recognizes the great advances that continue to be made in our understanding of the neuroscience of addiction,” said NIAAA Director George Koob, PhD, a co-author of the review. “These advances underscore how much we know about the core neurobiological manifestations of addiction in people.” Source: National Institutes of Health, October 2016
Flu Vaccine Offers “Substantial Benefits” to Diabetes Patients
Is it safe to give flu vaccinations to patients with an impaired immune response, such as those with diabetes? The evidence was both sparse and inconclusive, say researchers from Imperial College London. But their seven-year study of 124,503 patients with type-2 diabetes suggests “substantial benefits.” The study covered four periods in each cohort year: preinfluenza, influenza season, postinfluenza, and summer. The outcome measures were hospital admissions for acute myocardial infarction (MI), stroke, pneumonia, influenza, and heart failure, as well as all-cause death. During the study, there were 5,142 admissions for acute MI; 4,515 for stroke; 14,154 for pneumonia or influenza; 12,915 for heart failure; and 21,070 deaths. Vaccine recipients were older and generally more ill; they had more coexisting conditions and were taking more medications than nonrecipients. However, vaccination was associated with significant reductions in all of the outcomes during the flu season. After adjusting for residual confounding, the researchers found 19% lower rates of admissions for acute MI, 30% for stroke, 22% for heart failure, and 15% for pneumonia or influenza. The death rate for vaccinated patients was 24% lower than for nonrecipients. That was during flu season—but vaccination was also associated with significantly fewer events during the pre- and postinfluenza seasons for all outcomes except for acute MI and pneumonia/influenza in the preinfluenza period. Concerns about the benefits of influenza vaccination in older adults and patients with chronic illnesses affect the acceptance and uptake of vaccination, the researchers note. But their findings, they add, “underline the importance of influenza vaccination as part of comprehensive secondary prevention in this high-risk population.” Source: Canadian Medical Association Journal, October 2016
Research Briefs Which Cancer Patients Can Best Survive the ICU?
Because cancer is so complex, admitting a patient with cancer to the intensive care unti (ICU) can be challenging triage. Often the reason for the admission is acute complications related to the cancer or its treatment. Understanding how those complications might affect the patient’s outcome is critical to planning care, gauging use of ICU resources, and counseling patients and their families. Some studies have identified important determinants of mortality, but the existing literature is “scarce,” say researchers who studied outcomes in ICU patients with cancer. The researchers analyzed data from two cohort studies of 1,737 patients with solid tumors and 291 with hematological malignancies. Of those, 456 (23%) had cancer-related complications at ICU admission, most frequently chemotherapy and radiation therapy toxicity, venous thromboembolism (VTE), and respiratory failure by tumor. Patients with complications tended to have worse performance status scores and active disease. They also were more likely to have more severe organ dysfunction, greater need for invasive support, and infection at ICU admission. Complications were more frequent in patients with metastatic solid tumors, particularly lung and breast cancer (although less common in patients with gastrointestinal [GI] tumors), and in patients with more aggressive hematological malignancies, especially acute leukemia and aggressive non-Hodgkin’s lymphoma. The study had several major findings, the researchers say. First, one in four patients with cancer admitted to the ICU has acute complications related to the underlying cancer or treatment side effects. However, while there were many cancer-related complications and their prognostic impact was quite variable, and despite high mortality rates, outcome in these patients was “better than perceived a priori,” the researchers say. High sequential organ failure assessment score on the first day of ICU stay, worse performance status, and need for mechanical ventilation were all independent predictors of mortality, which is in accord with current literature. However, among the individual cancer-related complications studied, only vena cava syndrome, GI involvement, and respiratory failure were independently associated with in-hospital mortality. A “substantial” mortality rate (73%) among patients with GI involvement emphasizes the importance of discussing the appropriateness of ICU admission in these patients, the researchers caution. Although VTE was one of the most common complications, it was not a major determinant of outcome. Another important point, the researchers note, was the high frequency of chemotherapy- and radiation therapy-induced toxicity. Treatment-related neutropenia is not a good predictor of outcome, they say, because research has found it is not a relevant predictor of mortality. Source: PLOS One, October 2016
A Better Way to Predict Colorectal Cancer Relapse?
Carcinoembryonic antigen (CEA) is often used as a marker for relapse in colorectal cancer (CRC). But in as many as 40% of recurrences, the serum CEA shows unmeasurable elevations. And some patients with resected CRC have transient elevations of CEA levels; the false-positive rate during followup has been as high as 16%, say researchers from Kaohsiung Medical University in Taiwan. They propose “a more powerful tool”: a membrane array-based multigene biomarker assay, or biomarker chip, that detects circulating tumor cells in the peripheral blood. The researchers conducted a study in 298 patients with CRC to test that alternative. The patients were enrolled after radical curative resection for primary CRC tumor: 82 were stage I, 102 were stage II, and 114 were stage III. Patients were followed for a median of 28.4 months, every three months for three years, then every six months. At each follow-up visit, laboratory studies included serum CEA levels. Elevated CEA levels were defined as two consecutive measurements greater than 5 ng/mL at a three-month interval. During the study period, 48 patients (16.1%) had postoperative relapse, and 26 (8.7%) died. Of all 298 patients, 62 (20.8%) had a total biomarker chip score higher than the cutoff value. Of the 48 who relapsed, 42 (87.5%) showed positive biochip results prior to relapse. The positive biochip results were significantly associated with postoperative relapse. In fact, the biomarker chip was better all around than postoperative serum CEA levels for predicting relapse: with higher sensitivity (87.5% versus 60.4%), specificity (92.0% versus 83.2%), positive predictive value (67.7% versus 40.8%), negative predictive value (97.5% versus 91.6%), and accuracy (91.3% versus 79.5%). Moreover, the biochip predicted relapse “considerably earlier” than did CEA levels (10.7 versus 2.8 months). The researchers note that CRC-related deaths are largely attributable to clinical relapse. The sooner a relapse is diagnosed, the more amenable the tumor may be to resection, increasing the likelihood of long-term survival. In sum, the biomarker chip would be a more accurate tool for predicting relapse, the researchers say. They also suggest that, in clinical practice, combining the two tests could enhance confidence in the diagnosis. Source: PLOS One, October 2016
Vol. 42 No. 1 • January 2017 • P&T 55 ®
