Routine finger-stick testing for hepatitis C virus infection is the best screening strategy for 15- to 30-year-olds, provided that at least 6 in every 1,000 have injected drugs, according to the results of a modeling study.

“Currently, nearly all hepatitis C virus (HCV) transmission in the United States occurs among young persons who inject drugs,” wrote Sabrina A. Assoumou, MD, of Boston Medical Center and Boston University and her associates. “We show that routine testing provides the most clinical benefit and best value for money in an urban community health setting where HCV prevalence is high.”

Rapid routine testing consistently yielded more quality-adjusted life years (QALYs) at a lower cost than did the current practice of reflexive, risk-based venipuncture testing, the researchers said. They recommended that urban health centers either replace venipuncture diagnostics with routine finger-stick testing or that they ensure follow-up RNA testing when needed so they can link HCV-positive patients to treatment (Clin Infect Dis. 2017 Sep 9. doi: 10.1093/cid/cix798).

The Centers for Disease Control and Prevention has recommended risk-based HCV testing, but studies indicate that primary care providers often miss the chance to test and have trouble identifying high-risk patients, Dr. Assoumou and her associates said. The standard HCV test is a blood draw for antibody testing followed by confirmatory RNA testing, but a two-step process complicates follow-up.

To compare one-time HCV screening strategies in high-risk settings, the researchers created a decision analytic model using TreeAge Pro 2014 software and input data on prevalence, mortality, treatment costs, and efficacy from an extensive literature review.

Compared with targeted risk-based HCV testing, routine rapid testing performed by dedicated counselors yielded an incremental cost-effectiveness ratio of less than $100,000 per quality-adjusted life year unless the prevalence of injection drug use was less than 0.59%, the prevalence of HCV infection among injection drug users was less than 16%, the reinfection rate exceeded 26 cases per 100 person-years, or all venipuncture antibody tests were followed by confirmatory testing. Routine rapid testing identified 20% of HCV infections in the model, which is four times the rate under current practice. Rates of sustained virologic response were 18% with routine rapid testing and 2% with standard practice.

Routine rapid testing did not dramatically boost QALYs at a population level, the researchers acknowledged, but diagnosing and treating an injection drug user increased life span by an average of 2 years and saved $214,000 per patient in additional costs.

“Rapid testing always provided greater life expectancy than venipuncture testing at either a lower lifetime medical cost or a lower cost/QALY gained,” the investigators concluded. “Future studies are needed to define the programmatic effectiveness of HCV treatment among youth, and testing and treatment acceptability in this population.”

The National Institute on Drug Abuse and the National Institute of Allergy and Infectious Diseases provided funding. The researchers reported having no conflicts of interest.

Routine finger-stick testing for hepatitis C virus infection is the best screening strategy for 15- to 30-year-olds, provided that at least 6 in every 1,000 have injected drugs, according to the results of a modeling study.

“Currently, nearly all hepatitis C virus (HCV) transmission in the United States occurs among young persons who inject drugs,” wrote Sabrina A. Assoumou, MD, of Boston Medical Center and Boston University and her associates. “We show that routine testing provides the most clinical benefit and best value for money in an urban community health setting where HCV prevalence is high.”

Rapid routine testing consistently yielded more quality-adjusted life years (QALYs) at a lower cost than did the current practice of reflexive, risk-based venipuncture testing, the researchers said. They recommended that urban health centers either replace venipuncture diagnostics with routine finger-stick testing or that they ensure follow-up RNA testing when needed so they can link HCV-positive patients to treatment (Clin Infect Dis. 2017 Sep 9. doi: 10.1093/cid/cix798).

The Centers for Disease Control and Prevention has recommended risk-based HCV testing, but studies indicate that primary care providers often miss the chance to test and have trouble identifying high-risk patients, Dr. Assoumou and her associates said. The standard HCV test is a blood draw for antibody testing followed by confirmatory RNA testing, but a two-step process complicates follow-up.

To compare one-time HCV screening strategies in high-risk settings, the researchers created a decision analytic model using TreeAge Pro 2014 software and input data on prevalence, mortality, treatment costs, and efficacy from an extensive literature review.

Compared with targeted risk-based HCV testing, routine rapid testing performed by dedicated counselors yielded an incremental cost-effectiveness ratio of less than $100,000 per quality-adjusted life year unless the prevalence of injection drug use was less than 0.59%, the prevalence of HCV infection among injection drug users was less than 16%, the reinfection rate exceeded 26 cases per 100 person-years, or all venipuncture antibody tests were followed by confirmatory testing. Routine rapid testing identified 20% of HCV infections in the model, which is four times the rate under current practice. Rates of sustained virologic response were 18% with routine rapid testing and 2% with standard practice.

Routine rapid testing did not dramatically boost QALYs at a population level, the researchers acknowledged, but diagnosing and treating an injection drug user increased life span by an average of 2 years and saved $214,000 per patient in additional costs.

“Rapid testing always provided greater life expectancy than venipuncture testing at either a lower lifetime medical cost or a lower cost/QALY gained,” the investigators concluded. “Future studies are needed to define the programmatic effectiveness of HCV treatment among youth, and testing and treatment acceptability in this population.”

The National Institute on Drug Abuse and the National Institute of Allergy and Infectious Diseases provided funding. The researchers reported having no conflicts of interest.

Routine finger-stick testing for hepatitis C virus infection is the best screening strategy for 15- to 30-year-olds, provided that at least 6 in every 1,000 have injected drugs, according to the results of a modeling study.

“Currently, nearly all hepatitis C virus (HCV) transmission in the United States occurs among young persons who inject drugs,” wrote Sabrina A. Assoumou, MD, of Boston Medical Center and Boston University and her associates. “We show that routine testing provides the most clinical benefit and best value for money in an urban community health setting where HCV prevalence is high.”

Rapid routine testing consistently yielded more quality-adjusted life years (QALYs) at a lower cost than did the current practice of reflexive, risk-based venipuncture testing, the researchers said. They recommended that urban health centers either replace venipuncture diagnostics with routine finger-stick testing or that they ensure follow-up RNA testing when needed so they can link HCV-positive patients to treatment (Clin Infect Dis. 2017 Sep 9. doi: 10.1093/cid/cix798).

The Centers for Disease Control and Prevention has recommended risk-based HCV testing, but studies indicate that primary care providers often miss the chance to test and have trouble identifying high-risk patients, Dr. Assoumou and her associates said. The standard HCV test is a blood draw for antibody testing followed by confirmatory RNA testing, but a two-step process complicates follow-up.

To compare one-time HCV screening strategies in high-risk settings, the researchers created a decision analytic model using TreeAge Pro 2014 software and input data on prevalence, mortality, treatment costs, and efficacy from an extensive literature review.

Compared with targeted risk-based HCV testing, routine rapid testing performed by dedicated counselors yielded an incremental cost-effectiveness ratio of less than $100,000 per quality-adjusted life year unless the prevalence of injection drug use was less than 0.59%, the prevalence of HCV infection among injection drug users was less than 16%, the reinfection rate exceeded 26 cases per 100 person-years, or all venipuncture antibody tests were followed by confirmatory testing. Routine rapid testing identified 20% of HCV infections in the model, which is four times the rate under current practice. Rates of sustained virologic response were 18% with routine rapid testing and 2% with standard practice.

Routine rapid testing did not dramatically boost QALYs at a population level, the researchers acknowledged, but diagnosing and treating an injection drug user increased life span by an average of 2 years and saved $214,000 per patient in additional costs.

“Rapid testing always provided greater life expectancy than venipuncture testing at either a lower lifetime medical cost or a lower cost/QALY gained,” the investigators concluded. “Future studies are needed to define the programmatic effectiveness of HCV treatment among youth, and testing and treatment acceptability in this population.”

The National Institute on Drug Abuse and the National Institute of Allergy and Infectious Diseases provided funding. The researchers reported having no conflicts of interest.

The U.S. Food and Drug Administration on Oct. 6 approved an implantable device for the treatment of moderate to severe central sleep apnea.

The remedē System consists of a battery pack and small, thin wires placed under the skin in the upper chest area. The wires are inserted into the blood vessels in the chest to stimulate the phrenic nerve. The system monitors respiratory signals and, when it stimulates the nerve, the diaphragm moves to restore normal breathing.

[email protected]

The U.S. Food and Drug Administration on Oct. 6 approved an implantable device for the treatment of moderate to severe central sleep apnea.

The remedē System consists of a battery pack and small, thin wires placed under the skin in the upper chest area. The wires are inserted into the blood vessels in the chest to stimulate the phrenic nerve. The system monitors respiratory signals and, when it stimulates the nerve, the diaphragm moves to restore normal breathing.

[email protected]

The U.S. Food and Drug Administration on Oct. 6 approved an implantable device for the treatment of moderate to severe central sleep apnea.

The remedē System consists of a battery pack and small, thin wires placed under the skin in the upper chest area. The wires are inserted into the blood vessels in the chest to stimulate the phrenic nerve. The system monitors respiratory signals and, when it stimulates the nerve, the diaphragm moves to restore normal breathing.

[email protected]

More than 1.5 million Americans develop sepsis each year, and at least 250,000 die of it. “Detecting sepsis early and starting immediate treatment is often the difference between life and death. It starts with preventing the infections that lead to sepsis,” said CDC Director Brenda Fitzgerald, MD, introducing the CDC’s Get Ahead of Sepsis campaign, which launched in August. “We created Get Ahead of Sepsis to give people the resources they need to help stop this medical emergency in its tracks.”  

The campaign is an educational initiative for both the public and health care professionals in hospitals, home care, long-term care, and urgent care. For many patients, the CDC says, sepsis develops from an infection that begins outside the hospital. Health care professionals are not only in prime positions to monitor for signs and symptoms of sepsis in the health care setting—they can also help educate patients about things they can do to prevent sepsis. For instance, people with chronic conditions can take good care to avoid infections that could lead to sepsis.  

The campaign website, www.cdc.gov/sepsis, provides fact sheets, infographics, brochures, and other materials to help spread the word.

More than 1.5 million Americans develop sepsis each year, and at least 250,000 die of it. “Detecting sepsis early and starting immediate treatment is often the difference between life and death. It starts with preventing the infections that lead to sepsis,” said CDC Director Brenda Fitzgerald, MD, introducing the CDC’s Get Ahead of Sepsis campaign, which launched in August. “We created Get Ahead of Sepsis to give people the resources they need to help stop this medical emergency in its tracks.”  

The campaign is an educational initiative for both the public and health care professionals in hospitals, home care, long-term care, and urgent care. For many patients, the CDC says, sepsis develops from an infection that begins outside the hospital. Health care professionals are not only in prime positions to monitor for signs and symptoms of sepsis in the health care setting—they can also help educate patients about things they can do to prevent sepsis. For instance, people with chronic conditions can take good care to avoid infections that could lead to sepsis.  

The campaign website, www.cdc.gov/sepsis, provides fact sheets, infographics, brochures, and other materials to help spread the word.

More than 1.5 million Americans develop sepsis each year, and at least 250,000 die of it. “Detecting sepsis early and starting immediate treatment is often the difference between life and death. It starts with preventing the infections that lead to sepsis,” said CDC Director Brenda Fitzgerald, MD, introducing the CDC’s Get Ahead of Sepsis campaign, which launched in August. “We created Get Ahead of Sepsis to give people the resources they need to help stop this medical emergency in its tracks.”  

The campaign is an educational initiative for both the public and health care professionals in hospitals, home care, long-term care, and urgent care. For many patients, the CDC says, sepsis develops from an infection that begins outside the hospital. Health care professionals are not only in prime positions to monitor for signs and symptoms of sepsis in the health care setting—they can also help educate patients about things they can do to prevent sepsis. For instance, people with chronic conditions can take good care to avoid infections that could lead to sepsis.  

The campaign website, www.cdc.gov/sepsis, provides fact sheets, infographics, brochures, and other materials to help spread the word.

A “wealth of evidence” suggests that nutrition and immunologic status on admission is closely associated with the outcome of patients with cardiovascular disease—especially high-risk elderly patients, say researchers from Chinese People’s Liberation Army General Hospital, Beijing. The researchers note that malnutrition is an independent factor influencing post myocardial infarction complications and mortality in geriatric patients with coronary artery disease (CAD). According to their study of 336 hospitalized patients with hypertension, the Controlling Nutritional Status (CONUT) score can help predict who is at highest risk.

Nutrition indexes are widely used. CONUT scores, which are calculated based on serum albumin concentration, total peripheral lymphocyte count, and total cholesterol concentration, have been found useful in a variety of areas, including cancer. The Geriatric Nutritional Risk Index (GNRI), although a relatively new index for nutrition assessment in the elderly, is the most-used tool to evaluate patients with chronic kidney disease, the researchers say. Both indexes are “widely applied” in evaluation of patients with tumors who are also undergoing dialysis. Some studies also have reported on GNRI as a prognostic factor in cardiovascular diseases.

The researchers conducted their study to assess the effect of nutrition status on survival in patients aged ≥ 80 years, with hypertension, measuring outcomes at 90 days postadmission. All patients had a history of CAD, 167 had type 2 diabetes, and 124 had anemia. Of the enrolled patients, 192 were admitted for respiratory tract infection, with a significantly high proportion of poor nutrition status. Five patients scored > 9 on the CONUT scale. A score of ≥ 5 indicated moderate to severe malnutrition.

During the 90-day follow-up, 27 patients died. No differences in systolic blood pressure were found. The surviving patients, however, showed increased body mass index, hemoglobin, and albumin levels, as well as lower diastolic blood pressure and fasting blood glucose. Surviving patients had improved GRNI scores and reduced CONUT scores, both of which indicated improved nutrition status. Respiratory tract infection, CONUT, and albumin were independent predictors of all-cause mortality.

However, only CONUT accurately predicted all-cause mortality among patients with hypertension during the 90-day follow-up. A CONUT score above 3.0 at admission predicted all-cause mortality with a sensitivity of 77.8% and specificity of 64.7%.

Source:

Sun X, Luo L, Zhao X, Ye P. BMJ Open. 2017;7(9):e015649.

doi: 10.1136/bmjopen-2016-015649.

A “wealth of evidence” suggests that nutrition and immunologic status on admission is closely associated with the outcome of patients with cardiovascular disease—especially high-risk elderly patients, say researchers from Chinese People’s Liberation Army General Hospital, Beijing. The researchers note that malnutrition is an independent factor influencing post myocardial infarction complications and mortality in geriatric patients with coronary artery disease (CAD). According to their study of 336 hospitalized patients with hypertension, the Controlling Nutritional Status (CONUT) score can help predict who is at highest risk.

Nutrition indexes are widely used. CONUT scores, which are calculated based on serum albumin concentration, total peripheral lymphocyte count, and total cholesterol concentration, have been found useful in a variety of areas, including cancer. The Geriatric Nutritional Risk Index (GNRI), although a relatively new index for nutrition assessment in the elderly, is the most-used tool to evaluate patients with chronic kidney disease, the researchers say. Both indexes are “widely applied” in evaluation of patients with tumors who are also undergoing dialysis. Some studies also have reported on GNRI as a prognostic factor in cardiovascular diseases.

The researchers conducted their study to assess the effect of nutrition status on survival in patients aged ≥ 80 years, with hypertension, measuring outcomes at 90 days postadmission. All patients had a history of CAD, 167 had type 2 diabetes, and 124 had anemia. Of the enrolled patients, 192 were admitted for respiratory tract infection, with a significantly high proportion of poor nutrition status. Five patients scored > 9 on the CONUT scale. A score of ≥ 5 indicated moderate to severe malnutrition.

During the 90-day follow-up, 27 patients died. No differences in systolic blood pressure were found. The surviving patients, however, showed increased body mass index, hemoglobin, and albumin levels, as well as lower diastolic blood pressure and fasting blood glucose. Surviving patients had improved GRNI scores and reduced CONUT scores, both of which indicated improved nutrition status. Respiratory tract infection, CONUT, and albumin were independent predictors of all-cause mortality.

However, only CONUT accurately predicted all-cause mortality among patients with hypertension during the 90-day follow-up. A CONUT score above 3.0 at admission predicted all-cause mortality with a sensitivity of 77.8% and specificity of 64.7%.

Source:

Sun X, Luo L, Zhao X, Ye P. BMJ Open. 2017;7(9):e015649.

doi: 10.1136/bmjopen-2016-015649.

A “wealth of evidence” suggests that nutrition and immunologic status on admission is closely associated with the outcome of patients with cardiovascular disease—especially high-risk elderly patients, say researchers from Chinese People’s Liberation Army General Hospital, Beijing. The researchers note that malnutrition is an independent factor influencing post myocardial infarction complications and mortality in geriatric patients with coronary artery disease (CAD). According to their study of 336 hospitalized patients with hypertension, the Controlling Nutritional Status (CONUT) score can help predict who is at highest risk.

Nutrition indexes are widely used. CONUT scores, which are calculated based on serum albumin concentration, total peripheral lymphocyte count, and total cholesterol concentration, have been found useful in a variety of areas, including cancer. The Geriatric Nutritional Risk Index (GNRI), although a relatively new index for nutrition assessment in the elderly, is the most-used tool to evaluate patients with chronic kidney disease, the researchers say. Both indexes are “widely applied” in evaluation of patients with tumors who are also undergoing dialysis. Some studies also have reported on GNRI as a prognostic factor in cardiovascular diseases.

The researchers conducted their study to assess the effect of nutrition status on survival in patients aged ≥ 80 years, with hypertension, measuring outcomes at 90 days postadmission. All patients had a history of CAD, 167 had type 2 diabetes, and 124 had anemia. Of the enrolled patients, 192 were admitted for respiratory tract infection, with a significantly high proportion of poor nutrition status. Five patients scored > 9 on the CONUT scale. A score of ≥ 5 indicated moderate to severe malnutrition.

During the 90-day follow-up, 27 patients died. No differences in systolic blood pressure were found. The surviving patients, however, showed increased body mass index, hemoglobin, and albumin levels, as well as lower diastolic blood pressure and fasting blood glucose. Surviving patients had improved GRNI scores and reduced CONUT scores, both of which indicated improved nutrition status. Respiratory tract infection, CONUT, and albumin were independent predictors of all-cause mortality.

However, only CONUT accurately predicted all-cause mortality among patients with hypertension during the 90-day follow-up. A CONUT score above 3.0 at admission predicted all-cause mortality with a sensitivity of 77.8% and specificity of 64.7%.

Source:

Sun X, Luo L, Zhao X, Ye P. BMJ Open. 2017;7(9):e015649.

doi: 10.1136/bmjopen-2016-015649.

Photo by Larry Young

Research published in Cell has revealed 150 genetic drivers of diffuse large B-cell lymphoma (DLBCL).

Among these drivers are 27 genes newly implicated in DLBCL, 35 functional oncogenes, and 9 genes that can be targeted with existing drugs.

Researchers used these findings to create a prognostic model that, they say, outperformed existing risk predictors in DLBCL.

“This work provides a comprehensive road map in terms of research and clinical priorities,” said study author Sandeep Dave, MD, of Duke University in Durham, North Carolina.

“We have very good data now to pursue new and existing therapies that might target the genetic mutations we identified. Additionally, this data could also be used to develop genetic markers that steer patients to therapies that would be most effective.”

Dr Dave and his colleagues began this research by analyzing tumor samples from 1001 patients who had been diagnosed with DLBCL over the past decade and were treated at 12 institutions around the world. There were 313 patients with ABC DLBCL, 331 with GCB DLBCL, and the rest were unclassified DLBCLs.

Using whole-exome sequencing, the researchers pinpointed 150 driver genes that were recurrently mutated in the DLBCL patients. This included 27 genes that, the researchers believe, had never before been implicated in DLBCL.

The team also found that ABC and GCB DLBCLs “shared the vast majority of driver genes at statistically indistinguishable frequencies.”

However, there were 20 genes that were differentially mutated between the 2 groups. For instance, EZH2, SGK1, GNA13, SOCS1, STAT6, and TNFRSF14 were more frequently mutated in GCB DLBCLs. And ETV6, MYD88, PIM1, and TBL1XR1 were more frequently mutated in ABC DLBCLs.

Essential genes

To identify genes essential to the development and maintenance of DLBCL, the researchers used CRISPR. The team knocked out genes in 6 cell lines—3 ABC DLBCLs (LY3, TMD8, and HBL1), 2 GCB DLBCLs (SUDHL4 and Pfeiffer), and 1 Burkitt lymphoma (BJAB) that phenotypically resembles GCB DLBCL.

This revealed 1956 essential genes. Knocking out these genes resulted in a significant decrease in cell fitness in at least 1 cell line.

The work also revealed 35 driver genes that, when knocked out, resulted in decreased viability of DLBCL cells, which classified them as functional oncogenes.

The researchers found that knockout of EBF1, IRF4, CARD11, MYD88, and IKBKB was selectively lethal in ABC DLBCL. And knockout of ZBTB7A, XPO1, TGFBR2, and PTPN6 was selectively lethal in GCB DLBCL.

In addition, the team noted that 9 of the driver genes are direct targets of drugs that are already approved or under investigation in clinical trials—MTOR, BCL2, SF3B1, SYK, PIM2, PIK3R1, XPO1, MCL1, and BTK.

Patient outcomes

The researchers also looked at the driver genes in the context of patient outcomes. The team found that mutations in MYC, CD79B, and ZFAT were strongly associated with poorer survival, while mutations in NF1 and SGK1 were associated with more favorable survival.

Mutations in KLHL14, BTG1, PAX5, and CDKN2A were associated with significantly poorer survival in ABC DLBCL, while mutations in CREBBP were associated with favorable survival in ABC DLBCL.

In GCB DLBCL, mutations in NFKBIA and NCOR1 were associated with poorer prognosis, while mutations in EZH2, MYD88, and ARID5B were associated with better prognosis.

Finally, the researchers developed a prognostic model based on combinations of genetic markers (the 150 driver genes) and gene expression markers (cell of origin, MYC, and BCL2).

The team found their prognostic model could predict survival more effectively than the International Prognostic Index, cell of origin alone, and MYC and BCL2 expression alone or together.

Photo by Larry Young

Research published in Cell has revealed 150 genetic drivers of diffuse large B-cell lymphoma (DLBCL).

Among these drivers are 27 genes newly implicated in DLBCL, 35 functional oncogenes, and 9 genes that can be targeted with existing drugs.

Researchers used these findings to create a prognostic model that, they say, outperformed existing risk predictors in DLBCL.

“This work provides a comprehensive road map in terms of research and clinical priorities,” said study author Sandeep Dave, MD, of Duke University in Durham, North Carolina.

“We have very good data now to pursue new and existing therapies that might target the genetic mutations we identified. Additionally, this data could also be used to develop genetic markers that steer patients to therapies that would be most effective.”

Dr Dave and his colleagues began this research by analyzing tumor samples from 1001 patients who had been diagnosed with DLBCL over the past decade and were treated at 12 institutions around the world. There were 313 patients with ABC DLBCL, 331 with GCB DLBCL, and the rest were unclassified DLBCLs.

Using whole-exome sequencing, the researchers pinpointed 150 driver genes that were recurrently mutated in the DLBCL patients. This included 27 genes that, the researchers believe, had never before been implicated in DLBCL.

The team also found that ABC and GCB DLBCLs “shared the vast majority of driver genes at statistically indistinguishable frequencies.”

However, there were 20 genes that were differentially mutated between the 2 groups. For instance, EZH2, SGK1, GNA13, SOCS1, STAT6, and TNFRSF14 were more frequently mutated in GCB DLBCLs. And ETV6, MYD88, PIM1, and TBL1XR1 were more frequently mutated in ABC DLBCLs.

Essential genes

To identify genes essential to the development and maintenance of DLBCL, the researchers used CRISPR. The team knocked out genes in 6 cell lines—3 ABC DLBCLs (LY3, TMD8, and HBL1), 2 GCB DLBCLs (SUDHL4 and Pfeiffer), and 1 Burkitt lymphoma (BJAB) that phenotypically resembles GCB DLBCL.

This revealed 1956 essential genes. Knocking out these genes resulted in a significant decrease in cell fitness in at least 1 cell line.

The work also revealed 35 driver genes that, when knocked out, resulted in decreased viability of DLBCL cells, which classified them as functional oncogenes.

The researchers found that knockout of EBF1, IRF4, CARD11, MYD88, and IKBKB was selectively lethal in ABC DLBCL. And knockout of ZBTB7A, XPO1, TGFBR2, and PTPN6 was selectively lethal in GCB DLBCL.

In addition, the team noted that 9 of the driver genes are direct targets of drugs that are already approved or under investigation in clinical trials—MTOR, BCL2, SF3B1, SYK, PIM2, PIK3R1, XPO1, MCL1, and BTK.

Patient outcomes

The researchers also looked at the driver genes in the context of patient outcomes. The team found that mutations in MYC, CD79B, and ZFAT were strongly associated with poorer survival, while mutations in NF1 and SGK1 were associated with more favorable survival.

Mutations in KLHL14, BTG1, PAX5, and CDKN2A were associated with significantly poorer survival in ABC DLBCL, while mutations in CREBBP were associated with favorable survival in ABC DLBCL.

In GCB DLBCL, mutations in NFKBIA and NCOR1 were associated with poorer prognosis, while mutations in EZH2, MYD88, and ARID5B were associated with better prognosis.

Finally, the researchers developed a prognostic model based on combinations of genetic markers (the 150 driver genes) and gene expression markers (cell of origin, MYC, and BCL2).

The team found their prognostic model could predict survival more effectively than the International Prognostic Index, cell of origin alone, and MYC and BCL2 expression alone or together.

Photo by Larry Young

Research published in Cell has revealed 150 genetic drivers of diffuse large B-cell lymphoma (DLBCL).

Among these drivers are 27 genes newly implicated in DLBCL, 35 functional oncogenes, and 9 genes that can be targeted with existing drugs.

Researchers used these findings to create a prognostic model that, they say, outperformed existing risk predictors in DLBCL.

“This work provides a comprehensive road map in terms of research and clinical priorities,” said study author Sandeep Dave, MD, of Duke University in Durham, North Carolina.

“We have very good data now to pursue new and existing therapies that might target the genetic mutations we identified. Additionally, this data could also be used to develop genetic markers that steer patients to therapies that would be most effective.”

Dr Dave and his colleagues began this research by analyzing tumor samples from 1001 patients who had been diagnosed with DLBCL over the past decade and were treated at 12 institutions around the world. There were 313 patients with ABC DLBCL, 331 with GCB DLBCL, and the rest were unclassified DLBCLs.

Using whole-exome sequencing, the researchers pinpointed 150 driver genes that were recurrently mutated in the DLBCL patients. This included 27 genes that, the researchers believe, had never before been implicated in DLBCL.

The team also found that ABC and GCB DLBCLs “shared the vast majority of driver genes at statistically indistinguishable frequencies.”

However, there were 20 genes that were differentially mutated between the 2 groups. For instance, EZH2, SGK1, GNA13, SOCS1, STAT6, and TNFRSF14 were more frequently mutated in GCB DLBCLs. And ETV6, MYD88, PIM1, and TBL1XR1 were more frequently mutated in ABC DLBCLs.

Essential genes

To identify genes essential to the development and maintenance of DLBCL, the researchers used CRISPR. The team knocked out genes in 6 cell lines—3 ABC DLBCLs (LY3, TMD8, and HBL1), 2 GCB DLBCLs (SUDHL4 and Pfeiffer), and 1 Burkitt lymphoma (BJAB) that phenotypically resembles GCB DLBCL.

This revealed 1956 essential genes. Knocking out these genes resulted in a significant decrease in cell fitness in at least 1 cell line.

The work also revealed 35 driver genes that, when knocked out, resulted in decreased viability of DLBCL cells, which classified them as functional oncogenes.

The researchers found that knockout of EBF1, IRF4, CARD11, MYD88, and IKBKB was selectively lethal in ABC DLBCL. And knockout of ZBTB7A, XPO1, TGFBR2, and PTPN6 was selectively lethal in GCB DLBCL.

In addition, the team noted that 9 of the driver genes are direct targets of drugs that are already approved or under investigation in clinical trials—MTOR, BCL2, SF3B1, SYK, PIM2, PIK3R1, XPO1, MCL1, and BTK.

Patient outcomes

The researchers also looked at the driver genes in the context of patient outcomes. The team found that mutations in MYC, CD79B, and ZFAT were strongly associated with poorer survival, while mutations in NF1 and SGK1 were associated with more favorable survival.

Mutations in KLHL14, BTG1, PAX5, and CDKN2A were associated with significantly poorer survival in ABC DLBCL, while mutations in CREBBP were associated with favorable survival in ABC DLBCL.

In GCB DLBCL, mutations in NFKBIA and NCOR1 were associated with poorer prognosis, while mutations in EZH2, MYD88, and ARID5B were associated with better prognosis.

Finally, the researchers developed a prognostic model based on combinations of genetic markers (the 150 driver genes) and gene expression markers (cell of origin, MYC, and BCL2).

The team found their prognostic model could predict survival more effectively than the International Prognostic Index, cell of origin alone, and MYC and BCL2 expression alone or together.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to PCM-075 for the treatment of patients with acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which appears to be overexpressed in several hematologic and solid tumor malignancies.

PCM-075 is being developed by Trovagene, Inc.

The company is initiating a phase 1b/2 trial of PCM-075 in combination with standard care (low-dose cytarabine or decitabine) in patients with AML (NCT03303339).

Trovagene has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. This study was recently published in Investigational New Drugs.

According to Trovagene, preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene believes the combination of PCM-075 with other compounds has the potential for improved clinical efficacy in AML, non-Hodgkin lymphoma, castration-resistant prostate cancer, triple-negative breast cancer, and adrenocortical carcinoma.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to PCM-075 for the treatment of patients with acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which appears to be overexpressed in several hematologic and solid tumor malignancies.

PCM-075 is being developed by Trovagene, Inc.

The company is initiating a phase 1b/2 trial of PCM-075 in combination with standard care (low-dose cytarabine or decitabine) in patients with AML (NCT03303339).

Trovagene has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. This study was recently published in Investigational New Drugs.

According to Trovagene, preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene believes the combination of PCM-075 with other compounds has the potential for improved clinical efficacy in AML, non-Hodgkin lymphoma, castration-resistant prostate cancer, triple-negative breast cancer, and adrenocortical carcinoma.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to PCM-075 for the treatment of patients with acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which appears to be overexpressed in several hematologic and solid tumor malignancies.

PCM-075 is being developed by Trovagene, Inc.

The company is initiating a phase 1b/2 trial of PCM-075 in combination with standard care (low-dose cytarabine or decitabine) in patients with AML (NCT03303339).

Trovagene has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. This study was recently published in Investigational New Drugs.

According to Trovagene, preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene believes the combination of PCM-075 with other compounds has the potential for improved clinical efficacy in AML, non-Hodgkin lymphoma, castration-resistant prostate cancer, triple-negative breast cancer, and adrenocortical carcinoma.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Rivaroxaban

The companies developing rivaroxaban have announced an early end to the phase 3 NAVIGATE ESUS study.

In this trial, researchers were evaluating the efficacy and safety of rivaroxaban for the secondary prevention of stroke and systemic embolism in patients with a recent embolic stroke of undetermined source (ESUS).

The study was stopped early after it became evident that rivaroxaban was unlikely to provide a benefit over aspirin.

Results showed comparable efficacy between rivaroxaban and aspirin and an increase in bleeding in the rivaroxaban arm, although bleeding rates were considered low overall.

The NAVIGATE ESUS trial enrolled 7214 patients from 459 sites across 31 countries. Patients were randomized to receive either rivaroxaban at 15 mg once daily or aspirin at 100 mg once daily.

The primary efficacy endpoint was a composite of stroke and systemic embolism. The primary safety endpoint was major bleeding according to the criteria of the International Society on Thrombosis and Haemostasis.

A complete analysis of NAVIGATE ESUS data is expected to be presented in 2018.

About rivaroxaban

Rivaroxaban was discovered by Bayer, which is developing the drug with Janssen Research & Development, LLC.

Rivaroxaban is approved for use in more than 130 countries for a total of 7 indications:

• The prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation and 1 or more risk factors
• The treatment of pulmonary embolism (PE) in adults
• The treatment of deep vein thrombosis (DVT) in adults
• The prevention of recurrent PE and DVT in adults
• The prevention of venous thromboembolism (VTE) in adults undergoing elective hip replacement surgery
• The prevention of VTE in adults undergoing elective knee replacement surgery
• The prevention of atherothrombotic events (cardiovascular death, myocardial infarction, or stroke) after an acute coronary syndrome in adults with elevated cardiac biomarkers and no prior stroke or transient ischemic attack when co-administered with acetylsalicylic acid alone or with acetylsalicylic acid plus clopidogrel or ticlopidine.
  

Rivaroxaban

The companies developing rivaroxaban have announced an early end to the phase 3 NAVIGATE ESUS study.

In this trial, researchers were evaluating the efficacy and safety of rivaroxaban for the secondary prevention of stroke and systemic embolism in patients with a recent embolic stroke of undetermined source (ESUS).

The study was stopped early after it became evident that rivaroxaban was unlikely to provide a benefit over aspirin.

Results showed comparable efficacy between rivaroxaban and aspirin and an increase in bleeding in the rivaroxaban arm, although bleeding rates were considered low overall.

The NAVIGATE ESUS trial enrolled 7214 patients from 459 sites across 31 countries. Patients were randomized to receive either rivaroxaban at 15 mg once daily or aspirin at 100 mg once daily.

The primary efficacy endpoint was a composite of stroke and systemic embolism. The primary safety endpoint was major bleeding according to the criteria of the International Society on Thrombosis and Haemostasis.

A complete analysis of NAVIGATE ESUS data is expected to be presented in 2018.

About rivaroxaban

Rivaroxaban was discovered by Bayer, which is developing the drug with Janssen Research & Development, LLC.

Rivaroxaban is approved for use in more than 130 countries for a total of 7 indications:

• The prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation and 1 or more risk factors
• The treatment of pulmonary embolism (PE) in adults
• The treatment of deep vein thrombosis (DVT) in adults
• The prevention of recurrent PE and DVT in adults
• The prevention of venous thromboembolism (VTE) in adults undergoing elective hip replacement surgery
• The prevention of VTE in adults undergoing elective knee replacement surgery
• The prevention of atherothrombotic events (cardiovascular death, myocardial infarction, or stroke) after an acute coronary syndrome in adults with elevated cardiac biomarkers and no prior stroke or transient ischemic attack when co-administered with acetylsalicylic acid alone or with acetylsalicylic acid plus clopidogrel or ticlopidine.
  

Rivaroxaban

The companies developing rivaroxaban have announced an early end to the phase 3 NAVIGATE ESUS study.

In this trial, researchers were evaluating the efficacy and safety of rivaroxaban for the secondary prevention of stroke and systemic embolism in patients with a recent embolic stroke of undetermined source (ESUS).

The study was stopped early after it became evident that rivaroxaban was unlikely to provide a benefit over aspirin.

Results showed comparable efficacy between rivaroxaban and aspirin and an increase in bleeding in the rivaroxaban arm, although bleeding rates were considered low overall.

The NAVIGATE ESUS trial enrolled 7214 patients from 459 sites across 31 countries. Patients were randomized to receive either rivaroxaban at 15 mg once daily or aspirin at 100 mg once daily.

The primary efficacy endpoint was a composite of stroke and systemic embolism. The primary safety endpoint was major bleeding according to the criteria of the International Society on Thrombosis and Haemostasis.

A complete analysis of NAVIGATE ESUS data is expected to be presented in 2018.

About rivaroxaban

Rivaroxaban was discovered by Bayer, which is developing the drug with Janssen Research & Development, LLC.

Rivaroxaban is approved for use in more than 130 countries for a total of 7 indications:

• The prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation and 1 or more risk factors
• The treatment of pulmonary embolism (PE) in adults
• The treatment of deep vein thrombosis (DVT) in adults
• The prevention of recurrent PE and DVT in adults
• The prevention of venous thromboembolism (VTE) in adults undergoing elective hip replacement surgery
• The prevention of VTE in adults undergoing elective knee replacement surgery
• The prevention of atherothrombotic events (cardiovascular death, myocardial infarction, or stroke) after an acute coronary syndrome in adults with elevated cardiac biomarkers and no prior stroke or transient ischemic attack when co-administered with acetylsalicylic acid alone or with acetylsalicylic acid plus clopidogrel or ticlopidine.
  

Q) Recently, when I have sent my patients with chronic kidney disease (CKD) to the emergency department (ED) for complaints of chest pain or shortness of breath, their troponin levels are high. I know CKD increases risk for cardiovascular disease, but I find it hard to believe that every CKD patient is having an MI. What gives?

Cardiovascular disease remains the most common cause of death in patients with CKD, accounting for 45% to 50% of all deaths. Therefore, accurate diagnosis of acute myocardial infarction (AMI) in this patient population is vital to assure prompt identification and treatment.^1,2

Cardiac troponins are the gold standard for detecting myocardial injury in patients presenting to the ED with suggestive symptoms.¹ But the chronic baseline elevation in serum troponin levels among patients with CKD often results in a false-positive reading, making the detection of AMI difficult.¹

With the recent introduction of high-sensitivity troponin assays, as many as 97% of patients on hemodialysis exhibit elevated troponin levels; this is also true for patients with CKD, on a sliding scale (lower kidney function = higher baseline troponins).² The use of high-sensitivity testing has increased substantially in the past 15 years, and it is expected to become the benchmark for troponin evaluation. While older troponin tests had a false-positive rate of 30% to 85% in patients with stage 5 CKD, the newer troponin tests display elevated troponins in almost 100% of these patients.^1,2

Numerous studies have been conducted to determine the best way to interpret positive troponin tests in patients with CKD to ensure an accurate diagnosis of AMI.² One study determined that a 20% increase in troponin levels was a more accurate determinant of AMI in patients with CKD than one isolated positive level.³ Another study demonstrated that serial troponin measurements conducted over time yielded higher diagnostic accuracy than one measurement above the 99th percentile.⁴

The American College of Cardiology Foundation task force found that monitoring changes in troponin concentration over time (3-6 h) is more accurate than a single elevated troponin when diagnosing AMI in symptomatic patients.³ Correlation between elevated troponin levels and clinical suspicion proved helpful in determining the significance of troponin results and the probability of AMI in patients with CKD.²

The significance and interpretation of elevated troponin levels in patients with CKD remains an important topic for further study, as cardiovascular disease continues to be the leading cause of mortality in patients with kidney dysfunction.^1,2 More definitive studies need to be conducted on patients with CKD as high-sensitivity troponin assay testing becomes standard for diagnosing AMI.

So, the reason you see more positive troponin results in your CKD population is due to both the increased accuracy of the newer tests and the fact that CKD often causes a false-positive result. Monitoring your patients with serial troponins for at least three hours is essential to confirm or rule out an AMI. —MS-G

Marlene Shaw-Gallagher, MS, PA-C
University of Detroit Mercy, Michigan
Division of Nephrology, University of Michigan, Ann Arbor

Q) Recently, when I have sent my patients with chronic kidney disease (CKD) to the emergency department (ED) for complaints of chest pain or shortness of breath, their troponin levels are high. I know CKD increases risk for cardiovascular disease, but I find it hard to believe that every CKD patient is having an MI. What gives?

Cardiovascular disease remains the most common cause of death in patients with CKD, accounting for 45% to 50% of all deaths. Therefore, accurate diagnosis of acute myocardial infarction (AMI) in this patient population is vital to assure prompt identification and treatment.^1,2

Cardiac troponins are the gold standard for detecting myocardial injury in patients presenting to the ED with suggestive symptoms.¹ But the chronic baseline elevation in serum troponin levels among patients with CKD often results in a false-positive reading, making the detection of AMI difficult.¹

With the recent introduction of high-sensitivity troponin assays, as many as 97% of patients on hemodialysis exhibit elevated troponin levels; this is also true for patients with CKD, on a sliding scale (lower kidney function = higher baseline troponins).² The use of high-sensitivity testing has increased substantially in the past 15 years, and it is expected to become the benchmark for troponin evaluation. While older troponin tests had a false-positive rate of 30% to 85% in patients with stage 5 CKD, the newer troponin tests display elevated troponins in almost 100% of these patients.^1,2

Numerous studies have been conducted to determine the best way to interpret positive troponin tests in patients with CKD to ensure an accurate diagnosis of AMI.² One study determined that a 20% increase in troponin levels was a more accurate determinant of AMI in patients with CKD than one isolated positive level.³ Another study demonstrated that serial troponin measurements conducted over time yielded higher diagnostic accuracy than one measurement above the 99th percentile.⁴

The American College of Cardiology Foundation task force found that monitoring changes in troponin concentration over time (3-6 h) is more accurate than a single elevated troponin when diagnosing AMI in symptomatic patients.³ Correlation between elevated troponin levels and clinical suspicion proved helpful in determining the significance of troponin results and the probability of AMI in patients with CKD.²

The significance and interpretation of elevated troponin levels in patients with CKD remains an important topic for further study, as cardiovascular disease continues to be the leading cause of mortality in patients with kidney dysfunction.^1,2 More definitive studies need to be conducted on patients with CKD as high-sensitivity troponin assay testing becomes standard for diagnosing AMI.

So, the reason you see more positive troponin results in your CKD population is due to both the increased accuracy of the newer tests and the fact that CKD often causes a false-positive result. Monitoring your patients with serial troponins for at least three hours is essential to confirm or rule out an AMI. —MS-G

Marlene Shaw-Gallagher, MS, PA-C
University of Detroit Mercy, Michigan
Division of Nephrology, University of Michigan, Ann Arbor

Q) Recently, when I have sent my patients with chronic kidney disease (CKD) to the emergency department (ED) for complaints of chest pain or shortness of breath, their troponin levels are high. I know CKD increases risk for cardiovascular disease, but I find it hard to believe that every CKD patient is having an MI. What gives?

Cardiovascular disease remains the most common cause of death in patients with CKD, accounting for 45% to 50% of all deaths. Therefore, accurate diagnosis of acute myocardial infarction (AMI) in this patient population is vital to assure prompt identification and treatment.^1,2

Cardiac troponins are the gold standard for detecting myocardial injury in patients presenting to the ED with suggestive symptoms.¹ But the chronic baseline elevation in serum troponin levels among patients with CKD often results in a false-positive reading, making the detection of AMI difficult.¹

With the recent introduction of high-sensitivity troponin assays, as many as 97% of patients on hemodialysis exhibit elevated troponin levels; this is also true for patients with CKD, on a sliding scale (lower kidney function = higher baseline troponins).² The use of high-sensitivity testing has increased substantially in the past 15 years, and it is expected to become the benchmark for troponin evaluation. While older troponin tests had a false-positive rate of 30% to 85% in patients with stage 5 CKD, the newer troponin tests display elevated troponins in almost 100% of these patients.^1,2

Numerous studies have been conducted to determine the best way to interpret positive troponin tests in patients with CKD to ensure an accurate diagnosis of AMI.² One study determined that a 20% increase in troponin levels was a more accurate determinant of AMI in patients with CKD than one isolated positive level.³ Another study demonstrated that serial troponin measurements conducted over time yielded higher diagnostic accuracy than one measurement above the 99th percentile.⁴

The American College of Cardiology Foundation task force found that monitoring changes in troponin concentration over time (3-6 h) is more accurate than a single elevated troponin when diagnosing AMI in symptomatic patients.³ Correlation between elevated troponin levels and clinical suspicion proved helpful in determining the significance of troponin results and the probability of AMI in patients with CKD.²

The significance and interpretation of elevated troponin levels in patients with CKD remains an important topic for further study, as cardiovascular disease continues to be the leading cause of mortality in patients with kidney dysfunction.^1,2 More definitive studies need to be conducted on patients with CKD as high-sensitivity troponin assay testing becomes standard for diagnosing AMI.

So, the reason you see more positive troponin results in your CKD population is due to both the increased accuracy of the newer tests and the fact that CKD often causes a false-positive result. Monitoring your patients with serial troponins for at least three hours is essential to confirm or rule out an AMI. —MS-G

Marlene Shaw-Gallagher, MS, PA-C
University of Detroit Mercy, Michigan
Division of Nephrology, University of Michigan, Ann Arbor

Although the incidence of measles cases in the United States is low, it is increasing – and it appears the majority of cases occur in unvaccinated people, especially in the very young.

So, the importance of maintaining high vaccine coverage remains essential, concluded the authors of an analysis of confirmed U.S. measles cases, because endemic measles was eliminated nationwide in 2000.

CDC/Molly Kurnit, M.P.H.

Although the incidence of measles cases in the United States is low, it is increasing – and it appears the majority of cases occur in unvaccinated people, especially in the very young.

So, the importance of maintaining high vaccine coverage remains essential, concluded the authors of an analysis of confirmed U.S. measles cases, because endemic measles was eliminated nationwide in 2000.

CDC/Molly Kurnit, M.P.H.

Although the incidence of measles cases in the United States is low, it is increasing – and it appears the majority of cases occur in unvaccinated people, especially in the very young.

So, the importance of maintaining high vaccine coverage remains essential, concluded the authors of an analysis of confirmed U.S. measles cases, because endemic measles was eliminated nationwide in 2000.

CDC/Molly Kurnit, M.P.H.