Flow cytometry using
laser beam
Photo courtesy of NIH

NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.

The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.

“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”

Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.

In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.

History of MRD analysis

The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10^-4) leukocytes, regardless of the tissue used.

Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.

Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.

“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.

Technologies

Several technologies can be used to assess MRD.

Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.

Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.

“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.

HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.

Flow cytometry and HTS

A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.

According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10^-4).

Assays had to be independent and compatible with older, established therapies as well as newer treatments.

For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).

Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.

And while PCR is more sensitive than flow cytometry (sensitive to 10^-5 to 10^-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.

The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials. 

They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
 
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.

The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10^-4) level.

Peripheral blood or bone marrow?

“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”

Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.

Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the  bone marrow (PB-/BM-) (Rawstron abstract S794).

But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.

And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.

“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.

Prognostic value of MRD assessment

Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.

And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.

Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.

In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).

“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.

Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.

And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.

In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.

For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.

“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.”

Flow cytometry using
laser beam
Photo courtesy of NIH

NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.

The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.

“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”

Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.

In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.

History of MRD analysis

The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10^-4) leukocytes, regardless of the tissue used.

Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.

Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.

“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.

Technologies

Several technologies can be used to assess MRD.

Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.

Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.

“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.

HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.

Flow cytometry and HTS

A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.

According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10^-4).

Assays had to be independent and compatible with older, established therapies as well as newer treatments.

For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).

Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.

And while PCR is more sensitive than flow cytometry (sensitive to 10^-5 to 10^-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.

The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials. 

They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
 
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.

The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10^-4) level.

Peripheral blood or bone marrow?

“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”

Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.

Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the  bone marrow (PB-/BM-) (Rawstron abstract S794).

But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.

And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.

“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.

Prognostic value of MRD assessment

Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.

And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.

Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.

In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).

“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.

Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.

And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.

In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.

For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.

“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.”

Flow cytometry using
laser beam
Photo courtesy of NIH

NEW YORK—Combining 2 technologies—flow cytometry and high-throughput sequencing (HTS)—produces a very sensitive approach to detecting minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL), according to a speaker at Lymphoma & Myeloma 2016.

The approach is both reproducible and widely accessible, added the speaker, Peter Hillmen, MB ChB, PhD, of St James’s University Hospital in Leeds, UK.

“PCR [polymerase chain reaction] is more sensitive than flow cytometry,” he noted, “but it is probably not necessary to assess response by that criteria.”

Features to consider when choosing a technology for detecting MRD include sensitivity, specificity for the patient and/or the disease, applicability to all patients or to an individual, the platform—flow cytometry, conventional molecular PCR, or next-generation sequencing—and which tissue to use, blood or bone marrow.

In the era of immunotherapy, Dr Hillmen said, assessment should be performed at least 2 months after completion of immunotherapy to get a reliable assessment of MRD, particularly after treatment with alemtuzumab, rituximab, and other antibodies targeting CLL.

History of MRD analysis

The definition of MRD hasn’t changed since 2008, when the International Workshop on CLL updated National Cancer Institute guidelines. It is still 1 single cell in 10,000 (10^-4) leukocytes, regardless of the tissue used.

Prior to the mid-1990s, there were limited options for assessing MRD, Dr Hillmen said.

Based on the profound remissions patients experienced with alemtuzumab, investigators began to develop assays to assess MRD.

“[W]e started standardizing these assays around 2007,” Dr Hillmen said, and a standardized assay was used prospectively in clinical trials beginning in 2012.

Technologies

Several technologies can be used to assess MRD.

Flow cytometry using 6 colors or 8 colors—to simplify the assay and to make it more sensitive—is a multiparameter assessment of CLL phenotype that is not clonality-based.

Allele-specific oligonucleotide PCR (ASO-PCR) is laborious to perform, Dr Hillmen said, but it’s very sensitive.

“[I]t probably shouldn’t be considered as an MRD test,” he said, since it uses patient-specific primers, not consensus primers.

HTS provides an increasing amount of information on B-cell sequences and enumeration of the CLL-specific immunoglobulin gene, “and I would move it towards being approved as a regulatory endpoint,” Dr Hillmen asserted.

Flow cytometry and HTS

A consensus document by the European Research Initiative on CLL (ERIC) identified and validated a flow cytometric approach to MRD assessment in parallel with HTS.

According to the ERIC investigators, flow cytometry had to utilize a core panel of 6 antigens used by most labs—CD19, CD20, CD5, CD43, CD79b, and CD81. And the markers used had to quantitate cells to a level of 0.01% (10^-4).

Assays had to be independent and compatible with older, established therapies as well as newer treatments.

For example, 6-color flow had to be effective with fludarabine, cyclophosphamide, and rituximab (FCR) regimens, as well as effective with the novel agents ibrutinib and venetoclax (ABT-199).

Compared to PCR, multiparameter flow cytometry is more convenient, Dr Hillmen noted.

And while PCR is more sensitive than flow cytometry (sensitive to 10^-5 to 10^-6), it is more difficult to apply to large clinical trials because the assay must be validated for each patient.

The investigators validated the flow cytometric approach in 450 patients on FCR-type therapy enrolled in the ADMIRE and ARCTIC trials. 

They assessed MRD in patients’ bone marrow 3 months after the last course of treatment and presented the data at EHA 2015 (Rawstron AC, abstract S794).
 
They found that all patients who were MRD negative, including 9 patients with partial responses, achieved a significantly better progression-free survival (PFS) than patients who had achieved a complete response but were still MRD positive.

The parallel analysis of HTS showed good concordance with flow cytometry at the 0.01% (10^-4) level.

Peripheral blood or bone marrow?

“[T]he blood is a tissue which can be used, but it’s certainly not as sensitive as the bone marrow,” Dr Hillmen said. “And depending upon what we are using MRD for, the marrow is probably a better tissue, with some exceptions.”

Data from the ADMIRE and ARCTIC trials confirmed that 177 patients on FCR-based therapy who were negative in the bone marrow were always negative in the blood. However, a quarter of patients negative in the blood were positive in the bone marrow.

Investigators followed the same patients on FCR-based therapy for 3 years and found no difference in outcome in terms of PFS for patients negative in peripheral blood and positive in the bone marrow (PB-/BM+) and those negative in peripheral blood and negative in the  bone marrow (PB-/BM-) (Rawstron abstract S794).

But for patients on alemtuzumab, with the same analysis, those who were PB-/BM+ did less well and had similar PFS to those who were PB+/BM+.

And at a follow-up of 4 years or longer, patients on FCR-based therapy who were PB-/BM- had superior outcomes than those who were PB-/BM+.

“So as a predictive marker, the bone marrow is a better tissue to look at, but peripheral blood negativity also can predict with FCR but not with agents such as alemtuzumab,” Dr Hillmen summarized.

Prognostic value of MRD assessment

Multivariate analysis of a 10-year follow-up of 133 CLL patients revealed that MRD level and adverse cytogenetics were the only significant parameters in terms of PFS.

And in terms of overall survival (OS), MRD level, prior treatment, Binet stage, and age were significant.

Sixty-seven of these patients had been treated with chemoimmunotherapy, 31 with single-agent chemotherapy, 7 had autologous stem cell transplants, and 28 had prior exposure to alemtuzumab.

In terms of survival beyond 10 or 15 years, previously untreated patients who were MRD negative after their first therapy had significantly better PFS and OS than previously treated patients who were MRD negative and patients with or without prior treatment who were MRD positive (P<0.001).

“Consistently, MRD, regardless of therapy, is the most important prognostic marker,” Dr Hillmen said.

Data from MD Anderson Cancer Center showed that 75% of patients treated first-line with FCR who achieved a complete response were MRD negative.

And patients who achieved MRD negativity had significantly better PFS (P<0.001) and OS (P=0.006) than patients who remained MRD positive.

In the ADMIRE and ARCTIC trials mentioned earlier, patients who achieved MRD negativity in the marrow at 3 months post-therapy also had significantly better PFS (P<0.0001) and OS (P=0.0002) than those who were MRD positive.

For every log of positivity, Dr Hillmen said, patients have a worse survival. Conversely, for every log reduction in MRD level, there is a 33% reduction in risk for disease progression.

“MRD is probably the most important prognostic marker we have,” he said. “We need to look at MRD levels with novel agents and use it to define duration of therapy, maybe use it to define additional therapy if patients are stalled in their response.”

Micrograph showing

Plasmodium falciparum

Image from CDC/Mae Melvin

Two studies have revealed genetic markers associated with resistance to piperaquine, one of the most commonly used malaria drugs in Southeast Asia.

Investigators found that Plasmodium falciparum parasites were less sensitive to piperaquine if they had the exo-E415G variant or multiple copies of the plasmepsin 2 and plasmepsin 3 genes.

Furthermore, the presence of these markers could identify which malaria patients would fail piperaquine treatment.

However, investigators said more research is needed to establish whether plasmepsin gene amplification and the exo-E415G variant actually cause piperaquine resistance and to explore whether this association extends to other parts of the world.

The 2 groups of investigators reported the findings of their studies in The Lancet Infectious Diseases.

About resistance

The combination of artemisinin and piperaquine (dihydroartemisinin-piperaquine) is a frontline treatment for malaria in Southeast Asia.

However, in recent years, the emergence of resistance to these drugs in Cambodia means that up to 60% of patients fail treatment in several provinces. There are fears that resistance could spread to other regions where malaria is endemic.

Genome-wide association studies have been conducted to identify genetic variations among P falciparum parasites that can be linked to variations in drug resistance.

Recent studies have revealed genetic markers linked to resistance to artemisinin (K13) and mefloquine (Pfmdr1), but, until now, markers for resistance to other combination drugs had not been identified.

Plasmepsin genes

In the first study, Didier Ménard, PhD, of the Institut Pasteur in Phnom Penh, Cambodia, and his colleagues found that amplification of plasmepsin genes in the P falciparum genome was linked to piperaquine resistance.

The investigators first analyzed artemisinin-resistant, Cambodian P falciparum parasite lines, comparing the exomes of lines that were piperaquine-susceptible and those that were piperaquine-resistant.

The team said this revealed an increased copy number of the plasmepsin 2-plasmepsin 3 gene cluster as a putative genetic signature associated with piperaquine resistance.

The investigators then confirmed their findings in a set of 725 P falciparum parasites collected from patients across Cambodia since 2009.

Individuals infected with parasites with multiple copies of the plasmepsin 2 gene were, on average, 20.4 times more likely to experience dihydroartemisinin-piperaquine treatment failure.

Furthermore, the geographical distribution and rise in the proportion of parasites with multiple copies of the plasmepsin 2 and 3 genes in Cambodia corresponded with areas that had reported increases in dihydroartemisinin-piperaquine treatment failures in recent years.

“We now know that amplification of the plasmepsin 2 and plasmepsin 3 genes is an important factor in determining how well piperaquine kills malaria parasites,” Dr Ménard said. “A genetic toolkit combining this new marker with markers of artemisinin and mefloquine resistance could be used to track the spread of resistance and provide timely information for containment policies.”

“Piperaquine resistance, although currently confined to Cambodia, is a major concern, because patients suffering malaria are almost untreatable. At present, alternative treatments are scarce, and the reduced cure rates lead to prolonged parasite carriage, increasing the potential of transmitting the resistant parasites and endangering efforts to control and eliminate malaria.”

Exo-E415G variant

The second study was conducted by Rick Fairhurst, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues.

The investigators analyzed 486 P falciparum parasites collected between July 9, 2010, and December 31, 2013, from 3 different provinces in Cambodia where artemisinin resistance and dihydroartemisinin-piperaquine treatment failure are common (Pursat), emerging (Preah Vihear), or uncommon (Ratanakiri).

The investigators exposed the parasites to therapeutic levels of piperaquine and measured how well each strain grew. At the same time, they sequenced the entire genome of each parasite.

Parasites were more likely to survive exposure to piperaquine if they had 2 or more copies of the plasmepsin 2 and plasmepsin 3 genes, as well as the exo-E415G variant on chromosome 13.

Similarly, in a further analysis of 133 patient samples, the investigators found that individuals infected with parasites carrying multiple copies of the plasmepsin genes were much more likely to fail treatment with dihydroartemisinin-piperaquine, as were individuals who had parasites with the exo-E415G variant.

The team also noted that the prevalence of exo-E415G and plasmepsin 2-3 markers has risen substantially in recent years in Pursat and Preah Vihear, where artemisinin resistance is common and dihydroartemisinin-piperaquine has been the frontline treatment for at least 6 years.

“By surveying the piperaquine resistance marker across Southeast Asia in real-time, we can identify those areas where dihydroartemisinin-piperaquine will not be effective, and this could enable national malaria control programs to immediately recommend alternative therapies, such as artesunate-mefloquine,” Dr Fairhurst said.

“This approach will be crucial to eliminating multidrug-resistant parasites in Southeast Asia before they spread to sub-Saharan Africa, where most of the world’s malaria transmission, illness, and death occur.”

Micrograph showing

Plasmodium falciparum

Image from CDC/Mae Melvin

Two studies have revealed genetic markers associated with resistance to piperaquine, one of the most commonly used malaria drugs in Southeast Asia.

Investigators found that Plasmodium falciparum parasites were less sensitive to piperaquine if they had the exo-E415G variant or multiple copies of the plasmepsin 2 and plasmepsin 3 genes.

Furthermore, the presence of these markers could identify which malaria patients would fail piperaquine treatment.

However, investigators said more research is needed to establish whether plasmepsin gene amplification and the exo-E415G variant actually cause piperaquine resistance and to explore whether this association extends to other parts of the world.

The 2 groups of investigators reported the findings of their studies in The Lancet Infectious Diseases.

About resistance

The combination of artemisinin and piperaquine (dihydroartemisinin-piperaquine) is a frontline treatment for malaria in Southeast Asia.

However, in recent years, the emergence of resistance to these drugs in Cambodia means that up to 60% of patients fail treatment in several provinces. There are fears that resistance could spread to other regions where malaria is endemic.

Genome-wide association studies have been conducted to identify genetic variations among P falciparum parasites that can be linked to variations in drug resistance.

Recent studies have revealed genetic markers linked to resistance to artemisinin (K13) and mefloquine (Pfmdr1), but, until now, markers for resistance to other combination drugs had not been identified.

Plasmepsin genes

In the first study, Didier Ménard, PhD, of the Institut Pasteur in Phnom Penh, Cambodia, and his colleagues found that amplification of plasmepsin genes in the P falciparum genome was linked to piperaquine resistance.

The investigators first analyzed artemisinin-resistant, Cambodian P falciparum parasite lines, comparing the exomes of lines that were piperaquine-susceptible and those that were piperaquine-resistant.

The team said this revealed an increased copy number of the plasmepsin 2-plasmepsin 3 gene cluster as a putative genetic signature associated with piperaquine resistance.

The investigators then confirmed their findings in a set of 725 P falciparum parasites collected from patients across Cambodia since 2009.

Individuals infected with parasites with multiple copies of the plasmepsin 2 gene were, on average, 20.4 times more likely to experience dihydroartemisinin-piperaquine treatment failure.

Furthermore, the geographical distribution and rise in the proportion of parasites with multiple copies of the plasmepsin 2 and 3 genes in Cambodia corresponded with areas that had reported increases in dihydroartemisinin-piperaquine treatment failures in recent years.

“We now know that amplification of the plasmepsin 2 and plasmepsin 3 genes is an important factor in determining how well piperaquine kills malaria parasites,” Dr Ménard said. “A genetic toolkit combining this new marker with markers of artemisinin and mefloquine resistance could be used to track the spread of resistance and provide timely information for containment policies.”

“Piperaquine resistance, although currently confined to Cambodia, is a major concern, because patients suffering malaria are almost untreatable. At present, alternative treatments are scarce, and the reduced cure rates lead to prolonged parasite carriage, increasing the potential of transmitting the resistant parasites and endangering efforts to control and eliminate malaria.”

Exo-E415G variant

The second study was conducted by Rick Fairhurst, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues.

The investigators analyzed 486 P falciparum parasites collected between July 9, 2010, and December 31, 2013, from 3 different provinces in Cambodia where artemisinin resistance and dihydroartemisinin-piperaquine treatment failure are common (Pursat), emerging (Preah Vihear), or uncommon (Ratanakiri).

The investigators exposed the parasites to therapeutic levels of piperaquine and measured how well each strain grew. At the same time, they sequenced the entire genome of each parasite.

Parasites were more likely to survive exposure to piperaquine if they had 2 or more copies of the plasmepsin 2 and plasmepsin 3 genes, as well as the exo-E415G variant on chromosome 13.

Similarly, in a further analysis of 133 patient samples, the investigators found that individuals infected with parasites carrying multiple copies of the plasmepsin genes were much more likely to fail treatment with dihydroartemisinin-piperaquine, as were individuals who had parasites with the exo-E415G variant.

The team also noted that the prevalence of exo-E415G and plasmepsin 2-3 markers has risen substantially in recent years in Pursat and Preah Vihear, where artemisinin resistance is common and dihydroartemisinin-piperaquine has been the frontline treatment for at least 6 years.

“By surveying the piperaquine resistance marker across Southeast Asia in real-time, we can identify those areas where dihydroartemisinin-piperaquine will not be effective, and this could enable national malaria control programs to immediately recommend alternative therapies, such as artesunate-mefloquine,” Dr Fairhurst said.

“This approach will be crucial to eliminating multidrug-resistant parasites in Southeast Asia before they spread to sub-Saharan Africa, where most of the world’s malaria transmission, illness, and death occur.”

Micrograph showing

Plasmodium falciparum

Image from CDC/Mae Melvin

Two studies have revealed genetic markers associated with resistance to piperaquine, one of the most commonly used malaria drugs in Southeast Asia.

Investigators found that Plasmodium falciparum parasites were less sensitive to piperaquine if they had the exo-E415G variant or multiple copies of the plasmepsin 2 and plasmepsin 3 genes.

Furthermore, the presence of these markers could identify which malaria patients would fail piperaquine treatment.

However, investigators said more research is needed to establish whether plasmepsin gene amplification and the exo-E415G variant actually cause piperaquine resistance and to explore whether this association extends to other parts of the world.

The 2 groups of investigators reported the findings of their studies in The Lancet Infectious Diseases.

About resistance

The combination of artemisinin and piperaquine (dihydroartemisinin-piperaquine) is a frontline treatment for malaria in Southeast Asia.

However, in recent years, the emergence of resistance to these drugs in Cambodia means that up to 60% of patients fail treatment in several provinces. There are fears that resistance could spread to other regions where malaria is endemic.

Genome-wide association studies have been conducted to identify genetic variations among P falciparum parasites that can be linked to variations in drug resistance.

Recent studies have revealed genetic markers linked to resistance to artemisinin (K13) and mefloquine (Pfmdr1), but, until now, markers for resistance to other combination drugs had not been identified.

Plasmepsin genes

In the first study, Didier Ménard, PhD, of the Institut Pasteur in Phnom Penh, Cambodia, and his colleagues found that amplification of plasmepsin genes in the P falciparum genome was linked to piperaquine resistance.

The investigators first analyzed artemisinin-resistant, Cambodian P falciparum parasite lines, comparing the exomes of lines that were piperaquine-susceptible and those that were piperaquine-resistant.

The team said this revealed an increased copy number of the plasmepsin 2-plasmepsin 3 gene cluster as a putative genetic signature associated with piperaquine resistance.

The investigators then confirmed their findings in a set of 725 P falciparum parasites collected from patients across Cambodia since 2009.

Individuals infected with parasites with multiple copies of the plasmepsin 2 gene were, on average, 20.4 times more likely to experience dihydroartemisinin-piperaquine treatment failure.

Furthermore, the geographical distribution and rise in the proportion of parasites with multiple copies of the plasmepsin 2 and 3 genes in Cambodia corresponded with areas that had reported increases in dihydroartemisinin-piperaquine treatment failures in recent years.

“We now know that amplification of the plasmepsin 2 and plasmepsin 3 genes is an important factor in determining how well piperaquine kills malaria parasites,” Dr Ménard said. “A genetic toolkit combining this new marker with markers of artemisinin and mefloquine resistance could be used to track the spread of resistance and provide timely information for containment policies.”

“Piperaquine resistance, although currently confined to Cambodia, is a major concern, because patients suffering malaria are almost untreatable. At present, alternative treatments are scarce, and the reduced cure rates lead to prolonged parasite carriage, increasing the potential of transmitting the resistant parasites and endangering efforts to control and eliminate malaria.”

Exo-E415G variant

The second study was conducted by Rick Fairhurst, MD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues.

The investigators analyzed 486 P falciparum parasites collected between July 9, 2010, and December 31, 2013, from 3 different provinces in Cambodia where artemisinin resistance and dihydroartemisinin-piperaquine treatment failure are common (Pursat), emerging (Preah Vihear), or uncommon (Ratanakiri).

The investigators exposed the parasites to therapeutic levels of piperaquine and measured how well each strain grew. At the same time, they sequenced the entire genome of each parasite.

Parasites were more likely to survive exposure to piperaquine if they had 2 or more copies of the plasmepsin 2 and plasmepsin 3 genes, as well as the exo-E415G variant on chromosome 13.

Similarly, in a further analysis of 133 patient samples, the investigators found that individuals infected with parasites carrying multiple copies of the plasmepsin genes were much more likely to fail treatment with dihydroartemisinin-piperaquine, as were individuals who had parasites with the exo-E415G variant.

The team also noted that the prevalence of exo-E415G and plasmepsin 2-3 markers has risen substantially in recent years in Pursat and Preah Vihear, where artemisinin resistance is common and dihydroartemisinin-piperaquine has been the frontline treatment for at least 6 years.

“By surveying the piperaquine resistance marker across Southeast Asia in real-time, we can identify those areas where dihydroartemisinin-piperaquine will not be effective, and this could enable national malaria control programs to immediately recommend alternative therapies, such as artesunate-mefloquine,” Dr Fairhurst said.

“This approach will be crucial to eliminating multidrug-resistant parasites in Southeast Asia before they spread to sub-Saharan Africa, where most of the world’s malaria transmission, illness, and death occur.”

Wei Jia, PhD

Photo from the University

of Hawaii Cancer Center

Researchers say they have discovered a novel treatment strategy for acute myeloid leukemia (AML)—inhibiting fructose utilization.

The team discovered that AML cells are prone to using fructose for energy, and increased fructose utilization predicts poor treatment outcomes in AML patients.

The researchers also found that 2,5-anhydro-D-mannitol (2,5-AM) could inhibit fructose use in AML cells and therefore hinder their growth.

Wei Jia, PhD, of the University of Hawaii Cancer Center in Honolulu, and his colleagues reported these findings in Cancer Cell.

The researchers said their findings highlight the unique ability of AML cells to switch their energy supply from glucose to fructose, when glucose is in short supply.

Fructose is the second most abundant blood sugar in the body and is used as a glucose alternative by AML cells to retain energy. After the switch, AML cells begin to multiply faster.

The study revealed a potential treatment by stopping the glucose transporter GLUT5. This restricts the AML energy supply and effectively slows AML growth.

To target GLUT5, the researchers used 2,5-AM, a fructose analog with high affinity for GLUT5.

The team tested 2,5-AM in AML cells with enhanced fructose utilization and found the drug significantly suppressed fructose-induced proliferation, colony growth, and migration in the absence of glucose or when glucose levels were low.

The researchers tested 2,5-AM in 4 different AML cell lines and found the drug suppressed fructose-induced cell proliferation in a dose-dependent manner in all of the cell lines under glucose-limiting conditions. However, 2,5-AM had little effect on glucose-induced cell proliferation.

The team tested 2,5-AM in normal monocytes as well. They said the drug had a negligible effect on glucose-induced cell growth.

“Our normal cells hardly rely on fructose for growth,” Dr Jia noted. “This makes the fructose transport in cancer cells an attractive drug target.”

Finally, the researchers tested 2,5-AM in combination with ara-C in the 4 AML cell lines. They observed a synergistic effect between the drugs in all cell lines in the absence of glucose or when glucose levels were low.

“We are in the process of developing a GLUT5 inhibitor, thus cutting the cancer cells’ energy source and eventually killing them,” Dr Jia said. “The new GLUT5 inhibitor can potentially be used alone or in addition to the current chemotherapy drugs to enhance anticancer effects.”

Wei Jia, PhD

Photo from the University

of Hawaii Cancer Center

Researchers say they have discovered a novel treatment strategy for acute myeloid leukemia (AML)—inhibiting fructose utilization.

The team discovered that AML cells are prone to using fructose for energy, and increased fructose utilization predicts poor treatment outcomes in AML patients.

The researchers also found that 2,5-anhydro-D-mannitol (2,5-AM) could inhibit fructose use in AML cells and therefore hinder their growth.

Wei Jia, PhD, of the University of Hawaii Cancer Center in Honolulu, and his colleagues reported these findings in Cancer Cell.

The researchers said their findings highlight the unique ability of AML cells to switch their energy supply from glucose to fructose, when glucose is in short supply.

Fructose is the second most abundant blood sugar in the body and is used as a glucose alternative by AML cells to retain energy. After the switch, AML cells begin to multiply faster.

The study revealed a potential treatment by stopping the glucose transporter GLUT5. This restricts the AML energy supply and effectively slows AML growth.

To target GLUT5, the researchers used 2,5-AM, a fructose analog with high affinity for GLUT5.

The team tested 2,5-AM in AML cells with enhanced fructose utilization and found the drug significantly suppressed fructose-induced proliferation, colony growth, and migration in the absence of glucose or when glucose levels were low.

The researchers tested 2,5-AM in 4 different AML cell lines and found the drug suppressed fructose-induced cell proliferation in a dose-dependent manner in all of the cell lines under glucose-limiting conditions. However, 2,5-AM had little effect on glucose-induced cell proliferation.

The team tested 2,5-AM in normal monocytes as well. They said the drug had a negligible effect on glucose-induced cell growth.

“Our normal cells hardly rely on fructose for growth,” Dr Jia noted. “This makes the fructose transport in cancer cells an attractive drug target.”

Finally, the researchers tested 2,5-AM in combination with ara-C in the 4 AML cell lines. They observed a synergistic effect between the drugs in all cell lines in the absence of glucose or when glucose levels were low.

“We are in the process of developing a GLUT5 inhibitor, thus cutting the cancer cells’ energy source and eventually killing them,” Dr Jia said. “The new GLUT5 inhibitor can potentially be used alone or in addition to the current chemotherapy drugs to enhance anticancer effects.”

Wei Jia, PhD

Photo from the University

of Hawaii Cancer Center

Researchers say they have discovered a novel treatment strategy for acute myeloid leukemia (AML)—inhibiting fructose utilization.

The team discovered that AML cells are prone to using fructose for energy, and increased fructose utilization predicts poor treatment outcomes in AML patients.

The researchers also found that 2,5-anhydro-D-mannitol (2,5-AM) could inhibit fructose use in AML cells and therefore hinder their growth.

Wei Jia, PhD, of the University of Hawaii Cancer Center in Honolulu, and his colleagues reported these findings in Cancer Cell.

The researchers said their findings highlight the unique ability of AML cells to switch their energy supply from glucose to fructose, when glucose is in short supply.

Fructose is the second most abundant blood sugar in the body and is used as a glucose alternative by AML cells to retain energy. After the switch, AML cells begin to multiply faster.

The study revealed a potential treatment by stopping the glucose transporter GLUT5. This restricts the AML energy supply and effectively slows AML growth.

To target GLUT5, the researchers used 2,5-AM, a fructose analog with high affinity for GLUT5.

The team tested 2,5-AM in AML cells with enhanced fructose utilization and found the drug significantly suppressed fructose-induced proliferation, colony growth, and migration in the absence of glucose or when glucose levels were low.

The researchers tested 2,5-AM in 4 different AML cell lines and found the drug suppressed fructose-induced cell proliferation in a dose-dependent manner in all of the cell lines under glucose-limiting conditions. However, 2,5-AM had little effect on glucose-induced cell proliferation.

The team tested 2,5-AM in normal monocytes as well. They said the drug had a negligible effect on glucose-induced cell growth.

“Our normal cells hardly rely on fructose for growth,” Dr Jia noted. “This makes the fructose transport in cancer cells an attractive drug target.”

Finally, the researchers tested 2,5-AM in combination with ara-C in the 4 AML cell lines. They observed a synergistic effect between the drugs in all cell lines in the absence of glucose or when glucose levels were low.

“We are in the process of developing a GLUT5 inhibitor, thus cutting the cancer cells’ energy source and eventually killing them,” Dr Jia said. “The new GLUT5 inhibitor can potentially be used alone or in addition to the current chemotherapy drugs to enhance anticancer effects.”

Many of my patients ask, “Why do you have fortune cookies on your desk?” Then, I offer them one. I considered having other treats, but decided on fortune cookies because of

Comfort. The cookie is a small treat for those who want one.

Diet. You don’t have to eat the cookie to enjoy it; you can still read the fortune. For patients who have an eating disorder, the cookie allows us to naturally transition the conversation to issues they are experiencing.

Cultural competency. I treat patients of many backgrounds. Some have never seen a fortune cookie (remember to warn them there is a fortune inside!). Others know the fortune cookie is not a Chinese invention, as it is popu­larly thought to be.¹

Impulsivity. Do patients grab a cookie immediately, wait for one to be offered, or ask for one?

At this point, I ask patients to tell me their fortune. This allows me to assess:

Fine motor skills. Do they have a hand tremor or weakness, or a problem with involuntary movement? How well do they open the individually wrapped cookie?

Problem solving. On the slip of paper in the cookie, fortunes are printed on one side; on the other side are lucky numbers and a Chinese phrase. Some patients fail to turn the slip of paper over; they look it and say, “There are only numbers on this piece of paper.”

Eyesight. Can they see without glasses? Did they bring their glasses? (By extension, I can gauge whether they need, and use, glasses when reaching for a pill bottle in the medicine cabinet.)

Literacy. Can they read their fortune aloud?

Last, I ask what the fortune means and how it might apply to them. This helps me understand their:

Mindset. Having them explain how the fortune applies to them can be helpful to understanding their thinking.

Thought process. I am looking for how they think: Abstractly? Concretely? How well do they ar­ticulate and explain the meaning of the fortune?

Many of my patients ask, “Why do you have fortune cookies on your desk?” Then, I offer them one. I considered having other treats, but decided on fortune cookies because of

Comfort. The cookie is a small treat for those who want one.

Diet. You don’t have to eat the cookie to enjoy it; you can still read the fortune. For patients who have an eating disorder, the cookie allows us to naturally transition the conversation to issues they are experiencing.

Cultural competency. I treat patients of many backgrounds. Some have never seen a fortune cookie (remember to warn them there is a fortune inside!). Others know the fortune cookie is not a Chinese invention, as it is popu­larly thought to be.¹

Impulsivity. Do patients grab a cookie immediately, wait for one to be offered, or ask for one?

At this point, I ask patients to tell me their fortune. This allows me to assess:

Fine motor skills. Do they have a hand tremor or weakness, or a problem with involuntary movement? How well do they open the individually wrapped cookie?

Problem solving. On the slip of paper in the cookie, fortunes are printed on one side; on the other side are lucky numbers and a Chinese phrase. Some patients fail to turn the slip of paper over; they look it and say, “There are only numbers on this piece of paper.”

Eyesight. Can they see without glasses? Did they bring their glasses? (By extension, I can gauge whether they need, and use, glasses when reaching for a pill bottle in the medicine cabinet.)

Literacy. Can they read their fortune aloud?

Last, I ask what the fortune means and how it might apply to them. This helps me understand their:

Mindset. Having them explain how the fortune applies to them can be helpful to understanding their thinking.

Thought process. I am looking for how they think: Abstractly? Concretely? How well do they ar­ticulate and explain the meaning of the fortune?

Many of my patients ask, “Why do you have fortune cookies on your desk?” Then, I offer them one. I considered having other treats, but decided on fortune cookies because of

Comfort. The cookie is a small treat for those who want one.

Diet. You don’t have to eat the cookie to enjoy it; you can still read the fortune. For patients who have an eating disorder, the cookie allows us to naturally transition the conversation to issues they are experiencing.

Cultural competency. I treat patients of many backgrounds. Some have never seen a fortune cookie (remember to warn them there is a fortune inside!). Others know the fortune cookie is not a Chinese invention, as it is popu­larly thought to be.¹

Impulsivity. Do patients grab a cookie immediately, wait for one to be offered, or ask for one?

At this point, I ask patients to tell me their fortune. This allows me to assess:

Fine motor skills. Do they have a hand tremor or weakness, or a problem with involuntary movement? How well do they open the individually wrapped cookie?

Problem solving. On the slip of paper in the cookie, fortunes are printed on one side; on the other side are lucky numbers and a Chinese phrase. Some patients fail to turn the slip of paper over; they look it and say, “There are only numbers on this piece of paper.”

Eyesight. Can they see without glasses? Did they bring their glasses? (By extension, I can gauge whether they need, and use, glasses when reaching for a pill bottle in the medicine cabinet.)

Literacy. Can they read their fortune aloud?

Last, I ask what the fortune means and how it might apply to them. This helps me understand their:

Mindset. Having them explain how the fortune applies to them can be helpful to understanding their thinking.

Thought process. I am looking for how they think: Abstractly? Concretely? How well do they ar­ticulate and explain the meaning of the fortune?

The CHEST Foundation has announced Michael E. Nelson, MD, FCCP, as its new President, effective November 1. At CHEST 2016, the annual meeting of the American College of Chest Physicians (CHEST), the CHEST board also confirmed the appointments of Lisa K. Moores, MD, FCCP, as President-Elect of the CHEST Foundation; Doreen J. Addrizzo-Harris, MD, FCCP, as CHEST Foundation President-Designate; and John A. Howington, MD, FCCP, as CHEST Foundation Immediate Past President.

Michael E. Nelson, MD, FCCP, is a private practice pulmonologist at Shawnee Mission Pulmonary Consultants, Kan., specializing in pulmonary diseases, critical care, and sleep medicine. A CHEST Foundation Trustee since 2012, Dr. Nelson has served the last 2 years as Foundation President-Elect, and has been affiliated with the American College of Chest Physicians for almost 22 years, holding a variety of roles. Dr. Nelson is board-certified in internal medicine, pulmonary disease, critical care medicine, and sleep medicine.

Lisa K. Moores, MD, FCCP, is the Associate Dean of Students and Professor of Medicine at F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md. Currently, Dr. Moores is on active duty with the U.S. Army Medical Corps. She has been a member of the American College of Chest Physicians since 1994, and she has played a very active role in her time with the College, including serving as a CHEST Foundation Trustee-at-Large since 2011. Dr. Moores was awarded the Edward C. Rosenow III, Master FCCP/Master Teacher Honor Lecture Award at CHEST 2013. She is board-certified in critical care medicine, pulmonary disease, and internal medicine.

Doreen J. Addrizzo-Harris, MD, FCCP, is a graduate in medicine from New York University Medical Center, where she currently serves as a Professor of Medicine in the Division of Pulmonary and Critical Care. A CHEST Foundation Trustee-at-Large since 2013, she has been a Fellow of the American College of Chest Physicians for more than 20 years. Dr. Addrizzo-Harris was awarded Teacher of the Year in Pulmonary and Critical Care at NYU in 2000 and then again in 2013, showcasing her outstanding commitment and dedication to teaching.

John A. Howington, MD, FCCP, is a thoracic surgeon oncologist at St. Thomas Health, Nashville, Tenn., specializing in minimally invasive treatment options for thoracic cancer. He serves as the Chairman of Thoracic Surgery and is also the Co-Director of the Thoracic Oncology Program. A CHEST Foundation Trustee since 2012 and CHEST Foundation President for the last 2 years, he has been involved with the American College of Chest Physicians for nearly 20 years. In that time, he has held a variety of roles.
 

The CHEST Foundation has announced Michael E. Nelson, MD, FCCP, as its new President, effective November 1. At CHEST 2016, the annual meeting of the American College of Chest Physicians (CHEST), the CHEST board also confirmed the appointments of Lisa K. Moores, MD, FCCP, as President-Elect of the CHEST Foundation; Doreen J. Addrizzo-Harris, MD, FCCP, as CHEST Foundation President-Designate; and John A. Howington, MD, FCCP, as CHEST Foundation Immediate Past President.

Michael E. Nelson, MD, FCCP, is a private practice pulmonologist at Shawnee Mission Pulmonary Consultants, Kan., specializing in pulmonary diseases, critical care, and sleep medicine. A CHEST Foundation Trustee since 2012, Dr. Nelson has served the last 2 years as Foundation President-Elect, and has been affiliated with the American College of Chest Physicians for almost 22 years, holding a variety of roles. Dr. Nelson is board-certified in internal medicine, pulmonary disease, critical care medicine, and sleep medicine.

Lisa K. Moores, MD, FCCP, is the Associate Dean of Students and Professor of Medicine at F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md. Currently, Dr. Moores is on active duty with the U.S. Army Medical Corps. She has been a member of the American College of Chest Physicians since 1994, and she has played a very active role in her time with the College, including serving as a CHEST Foundation Trustee-at-Large since 2011. Dr. Moores was awarded the Edward C. Rosenow III, Master FCCP/Master Teacher Honor Lecture Award at CHEST 2013. She is board-certified in critical care medicine, pulmonary disease, and internal medicine.

Doreen J. Addrizzo-Harris, MD, FCCP, is a graduate in medicine from New York University Medical Center, where she currently serves as a Professor of Medicine in the Division of Pulmonary and Critical Care. A CHEST Foundation Trustee-at-Large since 2013, she has been a Fellow of the American College of Chest Physicians for more than 20 years. Dr. Addrizzo-Harris was awarded Teacher of the Year in Pulmonary and Critical Care at NYU in 2000 and then again in 2013, showcasing her outstanding commitment and dedication to teaching.

John A. Howington, MD, FCCP, is a thoracic surgeon oncologist at St. Thomas Health, Nashville, Tenn., specializing in minimally invasive treatment options for thoracic cancer. He serves as the Chairman of Thoracic Surgery and is also the Co-Director of the Thoracic Oncology Program. A CHEST Foundation Trustee since 2012 and CHEST Foundation President for the last 2 years, he has been involved with the American College of Chest Physicians for nearly 20 years. In that time, he has held a variety of roles.
 

The CHEST Foundation has announced Michael E. Nelson, MD, FCCP, as its new President, effective November 1. At CHEST 2016, the annual meeting of the American College of Chest Physicians (CHEST), the CHEST board also confirmed the appointments of Lisa K. Moores, MD, FCCP, as President-Elect of the CHEST Foundation; Doreen J. Addrizzo-Harris, MD, FCCP, as CHEST Foundation President-Designate; and John A. Howington, MD, FCCP, as CHEST Foundation Immediate Past President.

Michael E. Nelson, MD, FCCP, is a private practice pulmonologist at Shawnee Mission Pulmonary Consultants, Kan., specializing in pulmonary diseases, critical care, and sleep medicine. A CHEST Foundation Trustee since 2012, Dr. Nelson has served the last 2 years as Foundation President-Elect, and has been affiliated with the American College of Chest Physicians for almost 22 years, holding a variety of roles. Dr. Nelson is board-certified in internal medicine, pulmonary disease, critical care medicine, and sleep medicine.

Lisa K. Moores, MD, FCCP, is the Associate Dean of Students and Professor of Medicine at F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md. Currently, Dr. Moores is on active duty with the U.S. Army Medical Corps. She has been a member of the American College of Chest Physicians since 1994, and she has played a very active role in her time with the College, including serving as a CHEST Foundation Trustee-at-Large since 2011. Dr. Moores was awarded the Edward C. Rosenow III, Master FCCP/Master Teacher Honor Lecture Award at CHEST 2013. She is board-certified in critical care medicine, pulmonary disease, and internal medicine.

Doreen J. Addrizzo-Harris, MD, FCCP, is a graduate in medicine from New York University Medical Center, where she currently serves as a Professor of Medicine in the Division of Pulmonary and Critical Care. A CHEST Foundation Trustee-at-Large since 2013, she has been a Fellow of the American College of Chest Physicians for more than 20 years. Dr. Addrizzo-Harris was awarded Teacher of the Year in Pulmonary and Critical Care at NYU in 2000 and then again in 2013, showcasing her outstanding commitment and dedication to teaching.

John A. Howington, MD, FCCP, is a thoracic surgeon oncologist at St. Thomas Health, Nashville, Tenn., specializing in minimally invasive treatment options for thoracic cancer. He serves as the Chairman of Thoracic Surgery and is also the Co-Director of the Thoracic Oncology Program. A CHEST Foundation Trustee since 2012 and CHEST Foundation President for the last 2 years, he has been involved with the American College of Chest Physicians for nearly 20 years. In that time, he has held a variety of roles.
 

CHEST Physician Editorial Board Member

Confusion in EBUS Coding

There has been some confusion about appropriate coding using the new endobronchial ultrasound codes with some of the other bronchoscopy codes. Notably, when CPT code 31629 bronchoscopy with transbronchial needle aspiration biopsy(s), trachea, main stem and/or lobar bronchus(i) is appropriate to use with code 31652 with endobronchial ultrasound (EBUS) guided transtracheal and/or transbronchial sampling (e.g., aspiration[s]/biopsy[ies]), one or two mediastinal and/or hilar lymph node stations or structures and code 31653 with endobronchial ultrasound (EBUS) guided transtracheal and/or transbronchial sampling (e.g., aspiration[s]/biopsy[ies]), 3 or more mediastinal and/or hilar lymph node stations or structures. Both 31652 and 31653 include needle sampling as a part of the work and therefore, if the bronchoscopy involves only one these procedures, it would be inappropriate to include 31629.

However, mediastinal sampling is often done in conjunction with evaluation of a more peripheral lesion. If a bronchoscopy is performed with needle biopsy(ies) of a peripheral lesion and subsequently an EBUS scope is used to sample mediastinal or hilar lymph node stations, one could utilize 31629 and either 31652 or 31653. As an illustrative example, a 75-year-old man is found to have a 2-cm peripheral nodule in the anterior segment of the right-upper lobe with enlarged right hilar and subcarinal lymph nodes on CT scan. Bronchoscopy is performed, and, initially, the patient has a survey bronchoscopy using a non-EBUS scope, and no lesion is visible. A radial ultrasound probe is used to help identify the peripheral lesion, and multiple needle biopsies are performed as are brushings and washings. Subsequently, an EBUS scope is introduced, and right hilar, right paratracheal, and subcarinal needle biopsies were performed. The appropriate codes to utilize to describe the work done in this procedure include 31623, 31629, 31653, and 31654. Had no peripheral needle biopsies been performed, then code 31629 would NOT be used. Hopefully, this clarifies the issue further.

CMS Ceases Use of HCPCS G Codes for Smoking Cessation

Effective on or after October 1, the Centers for Medicare & Medicaid Services (CMS) will no longer allow use of Healthcare Common Procedural Coding System (HCPCS) codes G0436 (Smoking and tobacco cessation counseling visit for the asymptomatic patient; intermediate, greater than 3 minutes, up to 10 minutes) and G0437 (Smoking and tobacco cessation counseling visit for the asymptomatic patient; intensive, greater than 10 minutes). Instead, CMS will utilize the new codes developed for the Current Procedural Terminology (CPT) code set.

CMS has advised its Medicare contractors to replace code G0436 with CPT code 99406 (Smoking and tobacco use cessation counseling visit; intermediate, greater than 3 minutes up to 10 minutes) and code G0437 with CPT code 99407 (Smoking and tobacco use cessation counseling visit; intensive, greater than 10 minutes). According to the Medicare National Coverage Determination Manual, tobacco cessation counseling is covered both for symptomatic and asymptomatic smokers. CMS will allow health-care providers two attempts per 12 months to encourage Medicare patients to cease tobacco use but does not define an attempt. Rather, either of the codes may be used up to four times per attempt; so 99406 and 99407 or a combination of these codes may be used up to 8 times in a 12-month period. These codes may be used either as a stand-alone or with an evaluation and management (E&M) service with appropriate documentation. Remember, however, if one uses these codes during an E&M visit, a 25 modifier will need to be appended to the E&M code.
 

CHEST Physician Editorial Board Member

Confusion in EBUS Coding

There has been some confusion about appropriate coding using the new endobronchial ultrasound codes with some of the other bronchoscopy codes. Notably, when CPT code 31629 bronchoscopy with transbronchial needle aspiration biopsy(s), trachea, main stem and/or lobar bronchus(i) is appropriate to use with code 31652 with endobronchial ultrasound (EBUS) guided transtracheal and/or transbronchial sampling (e.g., aspiration[s]/biopsy[ies]), one or two mediastinal and/or hilar lymph node stations or structures and code 31653 with endobronchial ultrasound (EBUS) guided transtracheal and/or transbronchial sampling (e.g., aspiration[s]/biopsy[ies]), 3 or more mediastinal and/or hilar lymph node stations or structures. Both 31652 and 31653 include needle sampling as a part of the work and therefore, if the bronchoscopy involves only one these procedures, it would be inappropriate to include 31629.

However, mediastinal sampling is often done in conjunction with evaluation of a more peripheral lesion. If a bronchoscopy is performed with needle biopsy(ies) of a peripheral lesion and subsequently an EBUS scope is used to sample mediastinal or hilar lymph node stations, one could utilize 31629 and either 31652 or 31653. As an illustrative example, a 75-year-old man is found to have a 2-cm peripheral nodule in the anterior segment of the right-upper lobe with enlarged right hilar and subcarinal lymph nodes on CT scan. Bronchoscopy is performed, and, initially, the patient has a survey bronchoscopy using a non-EBUS scope, and no lesion is visible. A radial ultrasound probe is used to help identify the peripheral lesion, and multiple needle biopsies are performed as are brushings and washings. Subsequently, an EBUS scope is introduced, and right hilar, right paratracheal, and subcarinal needle biopsies were performed. The appropriate codes to utilize to describe the work done in this procedure include 31623, 31629, 31653, and 31654. Had no peripheral needle biopsies been performed, then code 31629 would NOT be used. Hopefully, this clarifies the issue further.

CMS Ceases Use of HCPCS G Codes for Smoking Cessation

Effective on or after October 1, the Centers for Medicare & Medicaid Services (CMS) will no longer allow use of Healthcare Common Procedural Coding System (HCPCS) codes G0436 (Smoking and tobacco cessation counseling visit for the asymptomatic patient; intermediate, greater than 3 minutes, up to 10 minutes) and G0437 (Smoking and tobacco cessation counseling visit for the asymptomatic patient; intensive, greater than 10 minutes). Instead, CMS will utilize the new codes developed for the Current Procedural Terminology (CPT) code set.

CMS has advised its Medicare contractors to replace code G0436 with CPT code 99406 (Smoking and tobacco use cessation counseling visit; intermediate, greater than 3 minutes up to 10 minutes) and code G0437 with CPT code 99407 (Smoking and tobacco use cessation counseling visit; intensive, greater than 10 minutes). According to the Medicare National Coverage Determination Manual, tobacco cessation counseling is covered both for symptomatic and asymptomatic smokers. CMS will allow health-care providers two attempts per 12 months to encourage Medicare patients to cease tobacco use but does not define an attempt. Rather, either of the codes may be used up to four times per attempt; so 99406 and 99407 or a combination of these codes may be used up to 8 times in a 12-month period. These codes may be used either as a stand-alone or with an evaluation and management (E&M) service with appropriate documentation. Remember, however, if one uses these codes during an E&M visit, a 25 modifier will need to be appended to the E&M code.
 

CHEST Physician Editorial Board Member

Confusion in EBUS Coding

There has been some confusion about appropriate coding using the new endobronchial ultrasound codes with some of the other bronchoscopy codes. Notably, when CPT code 31629 bronchoscopy with transbronchial needle aspiration biopsy(s), trachea, main stem and/or lobar bronchus(i) is appropriate to use with code 31652 with endobronchial ultrasound (EBUS) guided transtracheal and/or transbronchial sampling (e.g., aspiration[s]/biopsy[ies]), one or two mediastinal and/or hilar lymph node stations or structures and code 31653 with endobronchial ultrasound (EBUS) guided transtracheal and/or transbronchial sampling (e.g., aspiration[s]/biopsy[ies]), 3 or more mediastinal and/or hilar lymph node stations or structures. Both 31652 and 31653 include needle sampling as a part of the work and therefore, if the bronchoscopy involves only one these procedures, it would be inappropriate to include 31629.

However, mediastinal sampling is often done in conjunction with evaluation of a more peripheral lesion. If a bronchoscopy is performed with needle biopsy(ies) of a peripheral lesion and subsequently an EBUS scope is used to sample mediastinal or hilar lymph node stations, one could utilize 31629 and either 31652 or 31653. As an illustrative example, a 75-year-old man is found to have a 2-cm peripheral nodule in the anterior segment of the right-upper lobe with enlarged right hilar and subcarinal lymph nodes on CT scan. Bronchoscopy is performed, and, initially, the patient has a survey bronchoscopy using a non-EBUS scope, and no lesion is visible. A radial ultrasound probe is used to help identify the peripheral lesion, and multiple needle biopsies are performed as are brushings and washings. Subsequently, an EBUS scope is introduced, and right hilar, right paratracheal, and subcarinal needle biopsies were performed. The appropriate codes to utilize to describe the work done in this procedure include 31623, 31629, 31653, and 31654. Had no peripheral needle biopsies been performed, then code 31629 would NOT be used. Hopefully, this clarifies the issue further.

CMS Ceases Use of HCPCS G Codes for Smoking Cessation

Effective on or after October 1, the Centers for Medicare & Medicaid Services (CMS) will no longer allow use of Healthcare Common Procedural Coding System (HCPCS) codes G0436 (Smoking and tobacco cessation counseling visit for the asymptomatic patient; intermediate, greater than 3 minutes, up to 10 minutes) and G0437 (Smoking and tobacco cessation counseling visit for the asymptomatic patient; intensive, greater than 10 minutes). Instead, CMS will utilize the new codes developed for the Current Procedural Terminology (CPT) code set.

CMS has advised its Medicare contractors to replace code G0436 with CPT code 99406 (Smoking and tobacco use cessation counseling visit; intermediate, greater than 3 minutes up to 10 minutes) and code G0437 with CPT code 99407 (Smoking and tobacco use cessation counseling visit; intensive, greater than 10 minutes). According to the Medicare National Coverage Determination Manual, tobacco cessation counseling is covered both for symptomatic and asymptomatic smokers. CMS will allow health-care providers two attempts per 12 months to encourage Medicare patients to cease tobacco use but does not define an attempt. Rather, either of the codes may be used up to four times per attempt; so 99406 and 99407 or a combination of these codes may be used up to 8 times in a 12-month period. These codes may be used either as a stand-alone or with an evaluation and management (E&M) service with appropriate documentation. Remember, however, if one uses these codes during an E&M visit, a 25 modifier will need to be appended to the E&M code.
 

Where are they now? What have they been up to? CHEST’s Past Presidents each forged the way for the many successes of the American College of Chest Physicians (CHEST), leading to enhanced patient care around the globe. Their outstanding leadership and vision are evidenced today in many of CHEST’s current initiatives, and now it is time to check in with these past leaders to give us a look at what’s new.

Paul Stein, MD, FCCP

President 1992-1993

It is now 24 years since I was president of the American College of Chest Physicians (CHEST). Dr. Al Soffer had just retired, and it was Al Lever’s first year. Dr. Roger Bone preceded me as President and Dr. Ron George followed me.

Where are they now? What have they been up to? CHEST’s Past Presidents each forged the way for the many successes of the American College of Chest Physicians (CHEST), leading to enhanced patient care around the globe. Their outstanding leadership and vision are evidenced today in many of CHEST’s current initiatives, and now it is time to check in with these past leaders to give us a look at what’s new.

Paul Stein, MD, FCCP

President 1992-1993

It is now 24 years since I was president of the American College of Chest Physicians (CHEST). Dr. Al Soffer had just retired, and it was Al Lever’s first year. Dr. Roger Bone preceded me as President and Dr. Ron George followed me.

Where are they now? What have they been up to? CHEST’s Past Presidents each forged the way for the many successes of the American College of Chest Physicians (CHEST), leading to enhanced patient care around the globe. Their outstanding leadership and vision are evidenced today in many of CHEST’s current initiatives, and now it is time to check in with these past leaders to give us a look at what’s new.

Paul Stein, MD, FCCP

President 1992-1993

It is now 24 years since I was president of the American College of Chest Physicians (CHEST). Dr. Al Soffer had just retired, and it was Al Lever’s first year. Dr. Roger Bone preceded me as President and Dr. Ron George followed me.

The American College of Chest Physicians (CHEST) was awarded The Power of a Summit Award from the American Society of Association Executives (ASAE) in October for the China-CHEST Pulmonary and Critical Care Medicine (PCCM) Fellowship Program (Fig 1). CHEST is one of only six associations chosen for this honor.

The American College of Chest Physicians (CHEST) was awarded The Power of a Summit Award from the American Society of Association Executives (ASAE) in October for the China-CHEST Pulmonary and Critical Care Medicine (PCCM) Fellowship Program (Fig 1). CHEST is one of only six associations chosen for this honor.

The American College of Chest Physicians (CHEST) was awarded The Power of a Summit Award from the American Society of Association Executives (ASAE) in October for the China-CHEST Pulmonary and Critical Care Medicine (PCCM) Fellowship Program (Fig 1). CHEST is one of only six associations chosen for this honor.

The American Board of Internal Medicine (ABIM) announced in May 2016 it would be offering an alternate option to the 10-year MOC exam, beginning in January 2018. This announcement came in response to ongoing feedback from physicians and other stakeholders regarding the high-stakes recertification exam every 10 years.

The new option will include shorter, more-frequent assessments that can be completed from a physician’s office or home. These shorter assessments will identify knowledge gaps, so physicians can tailor their continuing education in order to stay current in knowledge and practice. Successful performance on the shorter assessments will allow physicians to opt out of the longer 10-year exam.

Prior to the launch of an alternative assessment model, ABIM has been soliciting input from diplomates through surveys and live conversations at society meetings.

The program will be piloted for internal medicine and select subspecialties, and based on feedback, will be extended to additional subspecialties at a later date. Physicians whose certifications expire prior to the new assessment option becoming available will need to pass the current exam in order to maintain certification, but then will not need to take another assessment for 10 years. Additional details regarding these alternative assessment options will be announced by the end of 2016 and can be tracked via ABIM’s blog. They also have an FAQ document online to address common questions regarding the alternative assessment pathway, as well as other topics related to MOC.
 

The American Board of Internal Medicine (ABIM) announced in May 2016 it would be offering an alternate option to the 10-year MOC exam, beginning in January 2018. This announcement came in response to ongoing feedback from physicians and other stakeholders regarding the high-stakes recertification exam every 10 years.

The new option will include shorter, more-frequent assessments that can be completed from a physician’s office or home. These shorter assessments will identify knowledge gaps, so physicians can tailor their continuing education in order to stay current in knowledge and practice. Successful performance on the shorter assessments will allow physicians to opt out of the longer 10-year exam.

Prior to the launch of an alternative assessment model, ABIM has been soliciting input from diplomates through surveys and live conversations at society meetings.

The program will be piloted for internal medicine and select subspecialties, and based on feedback, will be extended to additional subspecialties at a later date. Physicians whose certifications expire prior to the new assessment option becoming available will need to pass the current exam in order to maintain certification, but then will not need to take another assessment for 10 years. Additional details regarding these alternative assessment options will be announced by the end of 2016 and can be tracked via ABIM’s blog. They also have an FAQ document online to address common questions regarding the alternative assessment pathway, as well as other topics related to MOC.
 

The American Board of Internal Medicine (ABIM) announced in May 2016 it would be offering an alternate option to the 10-year MOC exam, beginning in January 2018. This announcement came in response to ongoing feedback from physicians and other stakeholders regarding the high-stakes recertification exam every 10 years.

The new option will include shorter, more-frequent assessments that can be completed from a physician’s office or home. These shorter assessments will identify knowledge gaps, so physicians can tailor their continuing education in order to stay current in knowledge and practice. Successful performance on the shorter assessments will allow physicians to opt out of the longer 10-year exam.

Prior to the launch of an alternative assessment model, ABIM has been soliciting input from diplomates through surveys and live conversations at society meetings.

The program will be piloted for internal medicine and select subspecialties, and based on feedback, will be extended to additional subspecialties at a later date. Physicians whose certifications expire prior to the new assessment option becoming available will need to pass the current exam in order to maintain certification, but then will not need to take another assessment for 10 years. Additional details regarding these alternative assessment options will be announced by the end of 2016 and can be tracked via ABIM’s blog. They also have an FAQ document online to address common questions regarding the alternative assessment pathway, as well as other topics related to MOC.
 

Editor’s Picks

Giants in Chest Medicine: Bartolome Celli, MD, FCCP. By Dr. G. J. Criner

Elevated Plasma Levels of sRAGE Are Associated With Nonfocal CT-Based Lung Imaging in Patients With ARDS: A Prospective Multicenter Study. By Dr. S. Mrozek, et al.

A Case-Control Study Assessing the Impact of Nonventilated Hospital-Acquired Pneumonia on Patient Outcomes. By Dr. S. T. Micek, et al.

Low Prevalence of High-Grade Lesions Detected With Autofluorescence Bronchoscopy in the Setting of Lung Cancer Screening in the Pan-Canadian Lung Cancer Screening Study. By Dr. A. Tremblay, et al.
 

Editor’s Picks

Giants in Chest Medicine: Bartolome Celli, MD, FCCP. By Dr. G. J. Criner

Elevated Plasma Levels of sRAGE Are Associated With Nonfocal CT-Based Lung Imaging in Patients With ARDS: A Prospective Multicenter Study. By Dr. S. Mrozek, et al.

A Case-Control Study Assessing the Impact of Nonventilated Hospital-Acquired Pneumonia on Patient Outcomes. By Dr. S. T. Micek, et al.

Low Prevalence of High-Grade Lesions Detected With Autofluorescence Bronchoscopy in the Setting of Lung Cancer Screening in the Pan-Canadian Lung Cancer Screening Study. By Dr. A. Tremblay, et al.
 

Editor’s Picks

Giants in Chest Medicine: Bartolome Celli, MD, FCCP. By Dr. G. J. Criner

Elevated Plasma Levels of sRAGE Are Associated With Nonfocal CT-Based Lung Imaging in Patients With ARDS: A Prospective Multicenter Study. By Dr. S. Mrozek, et al.

A Case-Control Study Assessing the Impact of Nonventilated Hospital-Acquired Pneumonia on Patient Outcomes. By Dr. S. T. Micek, et al.

Low Prevalence of High-Grade Lesions Detected With Autofluorescence Bronchoscopy in the Setting of Lung Cancer Screening in the Pan-Canadian Lung Cancer Screening Study. By Dr. A. Tremblay, et al.