HT Staff

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

Exome and transcriptome sequencing results can inform the management of young patients with relapsed, refractory, and rare malignancies, a new study suggests.

In a consecutive case series, sequencing data revealed potentially actionable findings for 46% of patients.

As a result, 15% of patients changed treatment, and 10% underwent genetic counseling.

Investigators described this research in JAMA.

“We found that, for some children with rare, difficult-to-treat, and aggressive cancers, this technology can dramatically change the course of their treatment,” said study author Rajen Mody, MBBS, of the University of Michigan in Ann Arbor.

Dr Mody and his colleagues evaluated 102 patients with relapsed, refractory, or rare cancers. Their median age was 11.5 (range, 0-22).

The patients underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing. Ninety-one patients (89%) had adequate tumor tissue to complete sequencing, including 28 patients (31%) with hematologic malignancies and 63 (69%) with solid tumors.

All sequencing results were discussed at a precision medicine tumor board, which included pediatric and adult oncologists, pathologists, genetics specialists, and other professionals. This group discussed the results and assessed the feasibility of pursuing treatment options based on the findings.

Actionable findings

Forty-two patients (46%) had potentially actionable findings, 15 (54%) with hematologic malignancies and 27 (43%) with solid tumors.

Actionable findings included a change in diagnosis (n=2), the presence of a genetic anomaly that could be targeted by an approved or experimental drug (n=31), and the need for genetic counseling for inherited cancer risk that could affect the patient or the whole family (n=9).

“We were excited to see an actionable finding in such a substantial percentage of patients, and we think it could potentially be higher over time,” said study author Arul Chinnaiyan, MD, PhD, also of the University of Michigan.

“These are patients who had exhausted all proven therapeutic options or who had an extremely rare diagnosis. If we can find a clinically actionable event and have a chance to act upon it, we show in this study that it can have a big impact on that patient.”

Actions were taken in 23 of the 42 patients. Fourteen patients (15%) had their treatment changed, and 9 of these patients (10%) had durable partial or complete remissions (CRs) as a result.

Nine patients (10%) underwent genetic counseling because of sequencing results. The researchers noted that 4 of these patients had no notable family history to suggest an inherited risk, and they would not otherwise have been referred for genetic counseling.

Hematologic malignancies

Fifteen patients with hematologic malignancies had potentially actionable findings, and 4 underwent treatment changes as a result. (None of the patients required genetic counseling.)

For a patient with pre-B acute lymphoblastic leukemia (ALL), sequencing revealed a homozygous CDKN2A deletion and an ETV6-ABL1 fusion. So the patient was placed on imatinib and had a sustained CR for 21 months.

A patient with early T-cell precursor ALL had a FLT3-ITD mutation, Chr16p gain, Chr16q loss, and FLT3 overexpression. The patient achieved a CR after transplant, was placed on the FLT3 inhibitor sorafenib, and remained in CR for 15 months.

Another patient with pre-B ALL had a FLT3 nonframeshift deletion and BLK and FLT3 overexpression. The patient was in CR for 9 months after a transplant and received sorafenib for 6 months.

A patient with biphenotypic leukemia had mutations in NRAS and PHF6; SPI1, ASXL1, and CBLC frameshift insertions; a JAK3-activating mutation; and JAK3 overexpression. The patient received the JAK3 inhibitor tofacitinib but could not tolerate the full dose and died of progressive disease.

Cost and turn-around time

The cost for sequencing was approximately $6000 per patient and was covered under the research protocol.

It took the researchers about 7 to 8 weeks to report the sequencing results back to treating physicians and families.

“These are early days, and the full promise of precision medicine is yet to be fully realized,” Dr Mody said. “We need better targeted therapies designed for children, and turnaround time for sequencing needs to be less than 2 weeks for it to be a regular part of a patient’s treatment plan.”

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

Exome and transcriptome sequencing results can inform the management of young patients with relapsed, refractory, and rare malignancies, a new study suggests.

In a consecutive case series, sequencing data revealed potentially actionable findings for 46% of patients.

As a result, 15% of patients changed treatment, and 10% underwent genetic counseling.

Investigators described this research in JAMA.

“We found that, for some children with rare, difficult-to-treat, and aggressive cancers, this technology can dramatically change the course of their treatment,” said study author Rajen Mody, MBBS, of the University of Michigan in Ann Arbor.

Dr Mody and his colleagues evaluated 102 patients with relapsed, refractory, or rare cancers. Their median age was 11.5 (range, 0-22).

The patients underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing. Ninety-one patients (89%) had adequate tumor tissue to complete sequencing, including 28 patients (31%) with hematologic malignancies and 63 (69%) with solid tumors.

All sequencing results were discussed at a precision medicine tumor board, which included pediatric and adult oncologists, pathologists, genetics specialists, and other professionals. This group discussed the results and assessed the feasibility of pursuing treatment options based on the findings.

Actionable findings

Forty-two patients (46%) had potentially actionable findings, 15 (54%) with hematologic malignancies and 27 (43%) with solid tumors.

Actionable findings included a change in diagnosis (n=2), the presence of a genetic anomaly that could be targeted by an approved or experimental drug (n=31), and the need for genetic counseling for inherited cancer risk that could affect the patient or the whole family (n=9).

“We were excited to see an actionable finding in such a substantial percentage of patients, and we think it could potentially be higher over time,” said study author Arul Chinnaiyan, MD, PhD, also of the University of Michigan.

“These are patients who had exhausted all proven therapeutic options or who had an extremely rare diagnosis. If we can find a clinically actionable event and have a chance to act upon it, we show in this study that it can have a big impact on that patient.”

Actions were taken in 23 of the 42 patients. Fourteen patients (15%) had their treatment changed, and 9 of these patients (10%) had durable partial or complete remissions (CRs) as a result.

Nine patients (10%) underwent genetic counseling because of sequencing results. The researchers noted that 4 of these patients had no notable family history to suggest an inherited risk, and they would not otherwise have been referred for genetic counseling.

Hematologic malignancies

Fifteen patients with hematologic malignancies had potentially actionable findings, and 4 underwent treatment changes as a result. (None of the patients required genetic counseling.)

For a patient with pre-B acute lymphoblastic leukemia (ALL), sequencing revealed a homozygous CDKN2A deletion and an ETV6-ABL1 fusion. So the patient was placed on imatinib and had a sustained CR for 21 months.

A patient with early T-cell precursor ALL had a FLT3-ITD mutation, Chr16p gain, Chr16q loss, and FLT3 overexpression. The patient achieved a CR after transplant, was placed on the FLT3 inhibitor sorafenib, and remained in CR for 15 months.

Another patient with pre-B ALL had a FLT3 nonframeshift deletion and BLK and FLT3 overexpression. The patient was in CR for 9 months after a transplant and received sorafenib for 6 months.

A patient with biphenotypic leukemia had mutations in NRAS and PHF6; SPI1, ASXL1, and CBLC frameshift insertions; a JAK3-activating mutation; and JAK3 overexpression. The patient received the JAK3 inhibitor tofacitinib but could not tolerate the full dose and died of progressive disease.

Cost and turn-around time

The cost for sequencing was approximately $6000 per patient and was covered under the research protocol.

It took the researchers about 7 to 8 weeks to report the sequencing results back to treating physicians and families.

“These are early days, and the full promise of precision medicine is yet to be fully realized,” Dr Mody said. “We need better targeted therapies designed for children, and turnaround time for sequencing needs to be less than 2 weeks for it to be a regular part of a patient’s treatment plan.”

Doctor consults with cancer

patient and her father

Photo by Rhoda Baer

Exome and transcriptome sequencing results can inform the management of young patients with relapsed, refractory, and rare malignancies, a new study suggests.

In a consecutive case series, sequencing data revealed potentially actionable findings for 46% of patients.

As a result, 15% of patients changed treatment, and 10% underwent genetic counseling.

Investigators described this research in JAMA.

“We found that, for some children with rare, difficult-to-treat, and aggressive cancers, this technology can dramatically change the course of their treatment,” said study author Rajen Mody, MBBS, of the University of Michigan in Ann Arbor.

Dr Mody and his colleagues evaluated 102 patients with relapsed, refractory, or rare cancers. Their median age was 11.5 (range, 0-22).

The patients underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing. Ninety-one patients (89%) had adequate tumor tissue to complete sequencing, including 28 patients (31%) with hematologic malignancies and 63 (69%) with solid tumors.

All sequencing results were discussed at a precision medicine tumor board, which included pediatric and adult oncologists, pathologists, genetics specialists, and other professionals. This group discussed the results and assessed the feasibility of pursuing treatment options based on the findings.

Actionable findings

Forty-two patients (46%) had potentially actionable findings, 15 (54%) with hematologic malignancies and 27 (43%) with solid tumors.

Actionable findings included a change in diagnosis (n=2), the presence of a genetic anomaly that could be targeted by an approved or experimental drug (n=31), and the need for genetic counseling for inherited cancer risk that could affect the patient or the whole family (n=9).

“We were excited to see an actionable finding in such a substantial percentage of patients, and we think it could potentially be higher over time,” said study author Arul Chinnaiyan, MD, PhD, also of the University of Michigan.

“These are patients who had exhausted all proven therapeutic options or who had an extremely rare diagnosis. If we can find a clinically actionable event and have a chance to act upon it, we show in this study that it can have a big impact on that patient.”

Actions were taken in 23 of the 42 patients. Fourteen patients (15%) had their treatment changed, and 9 of these patients (10%) had durable partial or complete remissions (CRs) as a result.

Nine patients (10%) underwent genetic counseling because of sequencing results. The researchers noted that 4 of these patients had no notable family history to suggest an inherited risk, and they would not otherwise have been referred for genetic counseling.

Hematologic malignancies

Fifteen patients with hematologic malignancies had potentially actionable findings, and 4 underwent treatment changes as a result. (None of the patients required genetic counseling.)

For a patient with pre-B acute lymphoblastic leukemia (ALL), sequencing revealed a homozygous CDKN2A deletion and an ETV6-ABL1 fusion. So the patient was placed on imatinib and had a sustained CR for 21 months.

A patient with early T-cell precursor ALL had a FLT3-ITD mutation, Chr16p gain, Chr16q loss, and FLT3 overexpression. The patient achieved a CR after transplant, was placed on the FLT3 inhibitor sorafenib, and remained in CR for 15 months.

Another patient with pre-B ALL had a FLT3 nonframeshift deletion and BLK and FLT3 overexpression. The patient was in CR for 9 months after a transplant and received sorafenib for 6 months.

A patient with biphenotypic leukemia had mutations in NRAS and PHF6; SPI1, ASXL1, and CBLC frameshift insertions; a JAK3-activating mutation; and JAK3 overexpression. The patient received the JAK3 inhibitor tofacitinib but could not tolerate the full dose and died of progressive disease.

Cost and turn-around time

The cost for sequencing was approximately $6000 per patient and was covered under the research protocol.

It took the researchers about 7 to 8 weeks to report the sequencing results back to treating physicians and families.

“These are early days, and the full promise of precision medicine is yet to be fully realized,” Dr Mody said. “We need better targeted therapies designed for children, and turnaround time for sequencing needs to be less than 2 weeks for it to be a regular part of a patient’s treatment plan.”

The Brazilain wasp

Polybia paulista

Photo by Mario Palma/

São Paulo State University

The wasp Polybia paulista protects itself from predators by producing venom known to contain a cancer-fighting toxin.

A study published in Biophysical Journal helps explain how the venom’s toxin, MP1 (Polybia-MP1), selectively kills cancer cells without harming normal cells.

MP1 interacts with lipids that are abnormally distributed on the surface of cancer cells, creating holes that facilitate the escape of molecules crucial for cell function.

“Cancer therapies that attack the lipid composition of the cell membrane would be an entirely new class of anticancer drugs,” said study author Paul Beales, PhD, of the University of Leeds in the UK.

MP1 is known to act against microbial pathogens by disrupting the bacterial cell membrane. The peptide has shown promise for treating cancers, as it can inhibit the growth of prostate and bladder cancer cells, as well as multi-drug resistant leukemic cells.

However, it has not been clear how MP1 selectively destroys cancer cells without harming normal cells. Dr Beales and his colleagues thought an explanation might lie in the unique properties of cancer cell membranes.

In healthy cell membranes, the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) are located in the inner membrane leaflet facing the inside of the cell. But in cancer cells, PS and PE are embedded in the outer membrane leaflet facing the cell surroundings.

The researchers tested their theory by creating model membranes, some of which contained PE and/or PS, and exposing them to MP1. They used a wide range of imaging and biophysical techniques to characterize MP1’s destructive effects on the membranes.

The team found that PS increased the binding of MP1 to the membrane by a factor of 7 to 8. On the other hand, PE enhanced MP1’s ability to quickly disrupt the membrane, increasing the size of holes by a factor of 20 to 30.

“Formed in only seconds, these large pores are big enough to allow critical molecules such as RNA and proteins to easily escape cells,” said study author João Ruggiero Neto, of São Paulo State University in Brazil.

“The dramatic enhancement of the permeabilization induced by the peptide in the presence of PE and the dimensions of the pores in these membranes was surprising.”

In future studies, the researchers plan to alter MP1’s amino acid sequence to examine how the peptide’s structure relates to its function and further improve the peptide’s selectivity and potency for clinical purposes.

“Understanding the mechanism of action of this peptide will help in translational studies to further assess the potential for this peptide to be used in medicine,” Dr Beales said.

“As it has been shown to be selective to cancer cells and non-toxic to normal cells in the lab, this peptide has the potential to be safe, but further work would be required to prove that.”

The Brazilain wasp

Polybia paulista

Photo by Mario Palma/

São Paulo State University

The wasp Polybia paulista protects itself from predators by producing venom known to contain a cancer-fighting toxin.

A study published in Biophysical Journal helps explain how the venom’s toxin, MP1 (Polybia-MP1), selectively kills cancer cells without harming normal cells.

MP1 interacts with lipids that are abnormally distributed on the surface of cancer cells, creating holes that facilitate the escape of molecules crucial for cell function.

“Cancer therapies that attack the lipid composition of the cell membrane would be an entirely new class of anticancer drugs,” said study author Paul Beales, PhD, of the University of Leeds in the UK.

MP1 is known to act against microbial pathogens by disrupting the bacterial cell membrane. The peptide has shown promise for treating cancers, as it can inhibit the growth of prostate and bladder cancer cells, as well as multi-drug resistant leukemic cells.

However, it has not been clear how MP1 selectively destroys cancer cells without harming normal cells. Dr Beales and his colleagues thought an explanation might lie in the unique properties of cancer cell membranes.

In healthy cell membranes, the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) are located in the inner membrane leaflet facing the inside of the cell. But in cancer cells, PS and PE are embedded in the outer membrane leaflet facing the cell surroundings.

The researchers tested their theory by creating model membranes, some of which contained PE and/or PS, and exposing them to MP1. They used a wide range of imaging and biophysical techniques to characterize MP1’s destructive effects on the membranes.

The team found that PS increased the binding of MP1 to the membrane by a factor of 7 to 8. On the other hand, PE enhanced MP1’s ability to quickly disrupt the membrane, increasing the size of holes by a factor of 20 to 30.

“Formed in only seconds, these large pores are big enough to allow critical molecules such as RNA and proteins to easily escape cells,” said study author João Ruggiero Neto, of São Paulo State University in Brazil.

“The dramatic enhancement of the permeabilization induced by the peptide in the presence of PE and the dimensions of the pores in these membranes was surprising.”

In future studies, the researchers plan to alter MP1’s amino acid sequence to examine how the peptide’s structure relates to its function and further improve the peptide’s selectivity and potency for clinical purposes.

“Understanding the mechanism of action of this peptide will help in translational studies to further assess the potential for this peptide to be used in medicine,” Dr Beales said.

“As it has been shown to be selective to cancer cells and non-toxic to normal cells in the lab, this peptide has the potential to be safe, but further work would be required to prove that.”

The Brazilain wasp

Polybia paulista

Photo by Mario Palma/

São Paulo State University

The wasp Polybia paulista protects itself from predators by producing venom known to contain a cancer-fighting toxin.

A study published in Biophysical Journal helps explain how the venom’s toxin, MP1 (Polybia-MP1), selectively kills cancer cells without harming normal cells.

MP1 interacts with lipids that are abnormally distributed on the surface of cancer cells, creating holes that facilitate the escape of molecules crucial for cell function.

“Cancer therapies that attack the lipid composition of the cell membrane would be an entirely new class of anticancer drugs,” said study author Paul Beales, PhD, of the University of Leeds in the UK.

MP1 is known to act against microbial pathogens by disrupting the bacterial cell membrane. The peptide has shown promise for treating cancers, as it can inhibit the growth of prostate and bladder cancer cells, as well as multi-drug resistant leukemic cells.

However, it has not been clear how MP1 selectively destroys cancer cells without harming normal cells. Dr Beales and his colleagues thought an explanation might lie in the unique properties of cancer cell membranes.

In healthy cell membranes, the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) are located in the inner membrane leaflet facing the inside of the cell. But in cancer cells, PS and PE are embedded in the outer membrane leaflet facing the cell surroundings.

The researchers tested their theory by creating model membranes, some of which contained PE and/or PS, and exposing them to MP1. They used a wide range of imaging and biophysical techniques to characterize MP1’s destructive effects on the membranes.

The team found that PS increased the binding of MP1 to the membrane by a factor of 7 to 8. On the other hand, PE enhanced MP1’s ability to quickly disrupt the membrane, increasing the size of holes by a factor of 20 to 30.

“Formed in only seconds, these large pores are big enough to allow critical molecules such as RNA and proteins to easily escape cells,” said study author João Ruggiero Neto, of São Paulo State University in Brazil.

“The dramatic enhancement of the permeabilization induced by the peptide in the presence of PE and the dimensions of the pores in these membranes was surprising.”

In future studies, the researchers plan to alter MP1’s amino acid sequence to examine how the peptide’s structure relates to its function and further improve the peptide’s selectivity and potency for clinical purposes.

“Understanding the mechanism of action of this peptide will help in translational studies to further assess the potential for this peptide to be used in medicine,” Dr Beales said.

“As it has been shown to be selective to cancer cells and non-toxic to normal cells in the lab, this peptide has the potential to be safe, but further work would be required to prove that.”

Dendritic cells

Researchers believe they have discovered how therapy targeting CD47 harnesses the immune system to fight lymphoma and other cancers.

Conducting experiments in immune-competent mice, the team found that anti-CD47 therapy drives T-cell mediated elimination of lymphoma, colon cancer, and breast cancer.

The group’s research also revealed how the timing of chemotherapy administration affects anti-CD47 therapy.

Yang-Xin Fu, MD, PhD, of the University of Chicago in Illinois, and his colleagues described this research in Nature Medicine.

Previous research had shown that many cancer cells have CD47 on their surface. The protein instructs circulating macrophages not to devour the cells, but anti-CD47 therapy can negate this effect. This research relied on human tumors transplanted in immunocompromised mice.

With the current study, Dr Fu and his colleagues transplanted tumors from mice into genetically identical hosts with intact immune systems.

The team’s experiments revealed that anti-CD47-mediated tumor rejection requires both innate and adaptive immune responses. And the bulk of the therapeutic effect from CD47 blockade relies not on macrophages but on dendritic cells.

Dendritic cells proved more potent than macrophages at priming CD8⁺ T cells. Dendritic cells also caused type-1 interferon to boost adaptive immunity and activated the STING pathway, which was “absolutely essential for the antitumor effect of anti-CD47 therapy.”

The researchers also found evidence to suggest that chemotherapy should be administered before, rather than after, anti-CD47 therapy.

The team tested the anti-CD47 monoclonal antibody (mAb) MIAP301 in combination with clinically equivalent doses of cyclophosphamide or paclitaxel in mouse models of lymphoma (established A20 tumors).

When the chemotherapy was administered after the mAb, tumor regression was no faster than when the mAb was given alone.

In fact, the chemotherapy appeared to hinder antitumor memory responses generated by the mAb. When the researchers removed all tumors and rechallenged the mice with A20 cells, all of the mice that had received the mAb alone rejected the tumor rechallenge.

But mice that had received the mAb followed by chemotherapy were susceptible to tumor outgrowth—50% of cyclophosphamide-treated mice and 80% of paclitaxel-treated mice.

When chemotherapy was given before the mAb, however, it conferred benefits. A single dose of either chemotherapy drug synergized with the mAb to fight lymphoma.

And the treatment preserved the host memory response against relapsing tumors. All of the cyclophosphamide-treated mice and 80% of the paclitaxel-treated mice were resistant to tumor rechallenge.

The researchers said this suggests the order of treatment administration could have a major impact on primary and memory immune responses to tumors and alter outcomes of anti-CD47 therapy.

“Our results point to a new and more personalized strategy to modulate the tumor microenvironment,” Dr Fu said. “We think our approach, along with further investigation of scheduling and dosing, could improve survival and quality of life for patients battling advanced cancer.”

Dendritic cells

Researchers believe they have discovered how therapy targeting CD47 harnesses the immune system to fight lymphoma and other cancers.

Conducting experiments in immune-competent mice, the team found that anti-CD47 therapy drives T-cell mediated elimination of lymphoma, colon cancer, and breast cancer.

The group’s research also revealed how the timing of chemotherapy administration affects anti-CD47 therapy.

Yang-Xin Fu, MD, PhD, of the University of Chicago in Illinois, and his colleagues described this research in Nature Medicine.

Previous research had shown that many cancer cells have CD47 on their surface. The protein instructs circulating macrophages not to devour the cells, but anti-CD47 therapy can negate this effect. This research relied on human tumors transplanted in immunocompromised mice.

With the current study, Dr Fu and his colleagues transplanted tumors from mice into genetically identical hosts with intact immune systems.

The team’s experiments revealed that anti-CD47-mediated tumor rejection requires both innate and adaptive immune responses. And the bulk of the therapeutic effect from CD47 blockade relies not on macrophages but on dendritic cells.

Dendritic cells proved more potent than macrophages at priming CD8⁺ T cells. Dendritic cells also caused type-1 interferon to boost adaptive immunity and activated the STING pathway, which was “absolutely essential for the antitumor effect of anti-CD47 therapy.”

The researchers also found evidence to suggest that chemotherapy should be administered before, rather than after, anti-CD47 therapy.

The team tested the anti-CD47 monoclonal antibody (mAb) MIAP301 in combination with clinically equivalent doses of cyclophosphamide or paclitaxel in mouse models of lymphoma (established A20 tumors).

When the chemotherapy was administered after the mAb, tumor regression was no faster than when the mAb was given alone.

In fact, the chemotherapy appeared to hinder antitumor memory responses generated by the mAb. When the researchers removed all tumors and rechallenged the mice with A20 cells, all of the mice that had received the mAb alone rejected the tumor rechallenge.

But mice that had received the mAb followed by chemotherapy were susceptible to tumor outgrowth—50% of cyclophosphamide-treated mice and 80% of paclitaxel-treated mice.

When chemotherapy was given before the mAb, however, it conferred benefits. A single dose of either chemotherapy drug synergized with the mAb to fight lymphoma.

And the treatment preserved the host memory response against relapsing tumors. All of the cyclophosphamide-treated mice and 80% of the paclitaxel-treated mice were resistant to tumor rechallenge.

The researchers said this suggests the order of treatment administration could have a major impact on primary and memory immune responses to tumors and alter outcomes of anti-CD47 therapy.

“Our results point to a new and more personalized strategy to modulate the tumor microenvironment,” Dr Fu said. “We think our approach, along with further investigation of scheduling and dosing, could improve survival and quality of life for patients battling advanced cancer.”

Dendritic cells

Researchers believe they have discovered how therapy targeting CD47 harnesses the immune system to fight lymphoma and other cancers.

Conducting experiments in immune-competent mice, the team found that anti-CD47 therapy drives T-cell mediated elimination of lymphoma, colon cancer, and breast cancer.

The group’s research also revealed how the timing of chemotherapy administration affects anti-CD47 therapy.

Yang-Xin Fu, MD, PhD, of the University of Chicago in Illinois, and his colleagues described this research in Nature Medicine.

Previous research had shown that many cancer cells have CD47 on their surface. The protein instructs circulating macrophages not to devour the cells, but anti-CD47 therapy can negate this effect. This research relied on human tumors transplanted in immunocompromised mice.

With the current study, Dr Fu and his colleagues transplanted tumors from mice into genetically identical hosts with intact immune systems.

The team’s experiments revealed that anti-CD47-mediated tumor rejection requires both innate and adaptive immune responses. And the bulk of the therapeutic effect from CD47 blockade relies not on macrophages but on dendritic cells.

Dendritic cells proved more potent than macrophages at priming CD8⁺ T cells. Dendritic cells also caused type-1 interferon to boost adaptive immunity and activated the STING pathway, which was “absolutely essential for the antitumor effect of anti-CD47 therapy.”

The researchers also found evidence to suggest that chemotherapy should be administered before, rather than after, anti-CD47 therapy.

The team tested the anti-CD47 monoclonal antibody (mAb) MIAP301 in combination with clinically equivalent doses of cyclophosphamide or paclitaxel in mouse models of lymphoma (established A20 tumors).

When the chemotherapy was administered after the mAb, tumor regression was no faster than when the mAb was given alone.

In fact, the chemotherapy appeared to hinder antitumor memory responses generated by the mAb. When the researchers removed all tumors and rechallenged the mice with A20 cells, all of the mice that had received the mAb alone rejected the tumor rechallenge.

But mice that had received the mAb followed by chemotherapy were susceptible to tumor outgrowth—50% of cyclophosphamide-treated mice and 80% of paclitaxel-treated mice.

When chemotherapy was given before the mAb, however, it conferred benefits. A single dose of either chemotherapy drug synergized with the mAb to fight lymphoma.

And the treatment preserved the host memory response against relapsing tumors. All of the cyclophosphamide-treated mice and 80% of the paclitaxel-treated mice were resistant to tumor rechallenge.

The researchers said this suggests the order of treatment administration could have a major impact on primary and memory immune responses to tumors and alter outcomes of anti-CD47 therapy.

“Our results point to a new and more personalized strategy to modulate the tumor microenvironment,” Dr Fu said. “We think our approach, along with further investigation of scheduling and dosing, could improve survival and quality of life for patients battling advanced cancer.”

Aspirin tablets

Photo by Sage Ross

LONDON—Fatal bleeding is rare with extended dual antiplatelet therapy (DAPT), according to research presented at the ESC Congress 2015.

The study included patients with a coronary stent who were receiving 30 months or 12 months of DAPT to prevent stent thrombosis and major cardiovascular and cerebrovascular events.

The results showed that bleeding-related mortality accounted for a minority of deaths in both patient groups.

Laura Mauri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results as abstract 3916. The study, known as the DAPT trial, was funded by a consortium of 8 device and drug manufacturers and other entities.

The trial enrolled patients who were set to receive a drug-eluting or bare-metal stent. After stent placement, they received DAPT—aspirin plus thienopyridine (clopidogrel or prasugrel)—for at least 12 months.

After 12 months of therapy, patients who were treatment-compliant and event-free (no myocardial infarction, stroke, or moderate or severe bleeding) were randomized to continued thienopyridine or placebo, each in addition to aspirin, for an additional 18 months. At month 30, patients discontinued randomized treatment but remained on aspirin for 3 months.

Results from patients with drug-eluting stents were published in NEJM in 2014.

But Dr Mauri reported on causes of death in all 11,648 randomized patients. All deaths were reviewed and adjudicated by an independent committee of cardiologists and oncologists who were blinded to the randomized treatment groups.

Any death that was possibly, probably, or definitely related to any prior clinically evident bleeding event was adjudicated as “bleeding-related,” and any death that was possibly, probably, or definitely related to a malignancy or to complications from treatments specifically administered for the malignancy was adjudicated as “cancer-related.” Fatal bleeding was defined using the Bleeding Academic Research Consortium (BARC) definition.

All-cause mortality

At 30 months (end of the randomization period), the mortality rate was 1.9% in the 30-month treatment group and 1.5% in 12-month group (P=0.07).

There was no significant difference between the groups for cardiovascular mortality—both about 1% (P=0.97)—but there was a significant difference for non-cardiovascular mortality—0.9% and 0.5%, respectively (P=0.01).

At 33 months (combined randomization and aspirin monotherapy periods), the mortality rate was 2.2% in the 30-month treatment group and 1.8% in the 12-month treatment group (P=0.05).

The rates of cardiovascular mortality were 1.2% and 1.1%, respectively (P=0.51). And the rates of non-cardiovascular mortality were 1.0% and 0.7%, respectively (P=0.02).

Bleeding-related deaths

At 33 months, there was no significant difference in bleeding-related mortality. Fatal bleeding occurred in 0.3% of patients in the 30-month group and 0.2% of those in the 12-month group (P=0.36).

There was no significant difference between the groups for bleeding-related death without cancer or trauma (P>0.99), bleeding-related death with cancer (P=0.25), bleeding-related death with trauma (P=0.58), trauma-related death (P=0.30), or trauma-related death without bleeding (P=0.50).

“This analysis of the DAPT study provides valuable insight to suggest that fatal bleeding is rare with extended dual antiplatelet therapy and may be avoided with careful patient selection,” Dr Mauri said.

Cancer-related deaths

Dr Mauri noted that there was no significant difference in the incidence of cancer between the randomized groups (P=0.12). But there was a significant difference in the incidence of cancer-related mortality at 33 months. It was 0.6% in the 30-month group and 0.3% in the 12-month group (P=0.02).

However, when the investigators excluded the cancer-related deaths that occurred in patients whose cancer was diagnosed before they enrolled in the DAPT study, the difference in cancer-related death became non-significant (0.4% and 0.3%, respectively, P=0.16).

“Given the clear benefits of dual antiplatelet therapy in reducing myocardial infarction, these medications remain essential for patients with acute coronary syndromes or coronary stents,” Dr Mauri said. “The relationship with cancer requires further investigation.”

Aspirin tablets

Photo by Sage Ross

LONDON—Fatal bleeding is rare with extended dual antiplatelet therapy (DAPT), according to research presented at the ESC Congress 2015.

The study included patients with a coronary stent who were receiving 30 months or 12 months of DAPT to prevent stent thrombosis and major cardiovascular and cerebrovascular events.

The results showed that bleeding-related mortality accounted for a minority of deaths in both patient groups.

Laura Mauri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results as abstract 3916. The study, known as the DAPT trial, was funded by a consortium of 8 device and drug manufacturers and other entities.

The trial enrolled patients who were set to receive a drug-eluting or bare-metal stent. After stent placement, they received DAPT—aspirin plus thienopyridine (clopidogrel or prasugrel)—for at least 12 months.

After 12 months of therapy, patients who were treatment-compliant and event-free (no myocardial infarction, stroke, or moderate or severe bleeding) were randomized to continued thienopyridine or placebo, each in addition to aspirin, for an additional 18 months. At month 30, patients discontinued randomized treatment but remained on aspirin for 3 months.

Results from patients with drug-eluting stents were published in NEJM in 2014.

But Dr Mauri reported on causes of death in all 11,648 randomized patients. All deaths were reviewed and adjudicated by an independent committee of cardiologists and oncologists who were blinded to the randomized treatment groups.

Any death that was possibly, probably, or definitely related to any prior clinically evident bleeding event was adjudicated as “bleeding-related,” and any death that was possibly, probably, or definitely related to a malignancy or to complications from treatments specifically administered for the malignancy was adjudicated as “cancer-related.” Fatal bleeding was defined using the Bleeding Academic Research Consortium (BARC) definition.

All-cause mortality

At 30 months (end of the randomization period), the mortality rate was 1.9% in the 30-month treatment group and 1.5% in 12-month group (P=0.07).

There was no significant difference between the groups for cardiovascular mortality—both about 1% (P=0.97)—but there was a significant difference for non-cardiovascular mortality—0.9% and 0.5%, respectively (P=0.01).

At 33 months (combined randomization and aspirin monotherapy periods), the mortality rate was 2.2% in the 30-month treatment group and 1.8% in the 12-month treatment group (P=0.05).

The rates of cardiovascular mortality were 1.2% and 1.1%, respectively (P=0.51). And the rates of non-cardiovascular mortality were 1.0% and 0.7%, respectively (P=0.02).

Bleeding-related deaths

At 33 months, there was no significant difference in bleeding-related mortality. Fatal bleeding occurred in 0.3% of patients in the 30-month group and 0.2% of those in the 12-month group (P=0.36).

There was no significant difference between the groups for bleeding-related death without cancer or trauma (P>0.99), bleeding-related death with cancer (P=0.25), bleeding-related death with trauma (P=0.58), trauma-related death (P=0.30), or trauma-related death without bleeding (P=0.50).

“This analysis of the DAPT study provides valuable insight to suggest that fatal bleeding is rare with extended dual antiplatelet therapy and may be avoided with careful patient selection,” Dr Mauri said.

Cancer-related deaths

Dr Mauri noted that there was no significant difference in the incidence of cancer between the randomized groups (P=0.12). But there was a significant difference in the incidence of cancer-related mortality at 33 months. It was 0.6% in the 30-month group and 0.3% in the 12-month group (P=0.02).

However, when the investigators excluded the cancer-related deaths that occurred in patients whose cancer was diagnosed before they enrolled in the DAPT study, the difference in cancer-related death became non-significant (0.4% and 0.3%, respectively, P=0.16).

“Given the clear benefits of dual antiplatelet therapy in reducing myocardial infarction, these medications remain essential for patients with acute coronary syndromes or coronary stents,” Dr Mauri said. “The relationship with cancer requires further investigation.”

Aspirin tablets

Photo by Sage Ross

LONDON—Fatal bleeding is rare with extended dual antiplatelet therapy (DAPT), according to research presented at the ESC Congress 2015.

The study included patients with a coronary stent who were receiving 30 months or 12 months of DAPT to prevent stent thrombosis and major cardiovascular and cerebrovascular events.

The results showed that bleeding-related mortality accounted for a minority of deaths in both patient groups.

Laura Mauri, MD, of Harvard Medical School in Boston, Massachusetts, presented these results as abstract 3916. The study, known as the DAPT trial, was funded by a consortium of 8 device and drug manufacturers and other entities.

The trial enrolled patients who were set to receive a drug-eluting or bare-metal stent. After stent placement, they received DAPT—aspirin plus thienopyridine (clopidogrel or prasugrel)—for at least 12 months.

After 12 months of therapy, patients who were treatment-compliant and event-free (no myocardial infarction, stroke, or moderate or severe bleeding) were randomized to continued thienopyridine or placebo, each in addition to aspirin, for an additional 18 months. At month 30, patients discontinued randomized treatment but remained on aspirin for 3 months.

Results from patients with drug-eluting stents were published in NEJM in 2014.

But Dr Mauri reported on causes of death in all 11,648 randomized patients. All deaths were reviewed and adjudicated by an independent committee of cardiologists and oncologists who were blinded to the randomized treatment groups.

Any death that was possibly, probably, or definitely related to any prior clinically evident bleeding event was adjudicated as “bleeding-related,” and any death that was possibly, probably, or definitely related to a malignancy or to complications from treatments specifically administered for the malignancy was adjudicated as “cancer-related.” Fatal bleeding was defined using the Bleeding Academic Research Consortium (BARC) definition.

All-cause mortality

At 30 months (end of the randomization period), the mortality rate was 1.9% in the 30-month treatment group and 1.5% in 12-month group (P=0.07).

There was no significant difference between the groups for cardiovascular mortality—both about 1% (P=0.97)—but there was a significant difference for non-cardiovascular mortality—0.9% and 0.5%, respectively (P=0.01).

At 33 months (combined randomization and aspirin monotherapy periods), the mortality rate was 2.2% in the 30-month treatment group and 1.8% in the 12-month treatment group (P=0.05).

The rates of cardiovascular mortality were 1.2% and 1.1%, respectively (P=0.51). And the rates of non-cardiovascular mortality were 1.0% and 0.7%, respectively (P=0.02).

Bleeding-related deaths

At 33 months, there was no significant difference in bleeding-related mortality. Fatal bleeding occurred in 0.3% of patients in the 30-month group and 0.2% of those in the 12-month group (P=0.36).

There was no significant difference between the groups for bleeding-related death without cancer or trauma (P>0.99), bleeding-related death with cancer (P=0.25), bleeding-related death with trauma (P=0.58), trauma-related death (P=0.30), or trauma-related death without bleeding (P=0.50).

“This analysis of the DAPT study provides valuable insight to suggest that fatal bleeding is rare with extended dual antiplatelet therapy and may be avoided with careful patient selection,” Dr Mauri said.

Cancer-related deaths

Dr Mauri noted that there was no significant difference in the incidence of cancer between the randomized groups (P=0.12). But there was a significant difference in the incidence of cancer-related mortality at 33 months. It was 0.6% in the 30-month group and 0.3% in the 12-month group (P=0.02).

However, when the investigators excluded the cancer-related deaths that occurred in patients whose cancer was diagnosed before they enrolled in the DAPT study, the difference in cancer-related death became non-significant (0.4% and 0.3%, respectively, P=0.16).

“Given the clear benefits of dual antiplatelet therapy in reducing myocardial infarction, these medications remain essential for patients with acute coronary syndromes or coronary stents,” Dr Mauri said. “The relationship with cancer requires further investigation.”

Thrombus

Image by Kevin MacKEnzie

LONDON—A score used to predict the risk of thromboembolic events, ischemic stroke, and death is only modestly accurate in patients with heart failure (HF), according to researchers.

They found the accuracy of the CHA2DS2-VASc score was dependent upon the endpoint being assessed and the duration of follow-up.

The score proved least effective for predicting thromboembolism, and its negative predictive values (NPVs) were inferior at 5 years of follow-up compared to 1 year.

Gregory Y. H Lip, MD, of Aalborg University in Denmark, and his colleagues reported these findings in JAMA and at the ESC Congress 2015 (abstract 1830*).

The team noted that the CHA2DS2-VASc score (congestive heart failure, hypertension, age 75 years or older [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior heart attack, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) is already used clinically for stroke risk stratification in patients with atrial fibrillation (AF).

But its usefulness in a population of patients with HF has been unclear. So the researchers investigated whether CHA2DS2-VASc predicts ischemic stroke, thromboembolism, and death in patients with a new diagnosis of HF, with or without AF.

Using Danish registries, the researchers compiled data from 42,987 patients (22% with concomitant AF). The patients were not receiving anticoagulation and had been diagnosed with new-onset HF from 2000 to 2012.

The end of follow-up was December 31, 2012. Levels of the CHA2DS2-VASc score (based on 10 possible points, with higher scores indicating higher risk) were stratified by the presence of AF at study entry.

Among patients without AF, the incidence of thromboembolism was 3.5%, the rate of ischemic stroke was 1%, and the death rate was 7.2%. Among patients with AF, the rates were 4.2%, 2%, and 13.2%, respectively.

Predictive accuracy

For predicting thromboembolism in patients without AF, the C statistics were 0.63 at 1 year and 0.67 at 5 years. The NPVs were 88% and 73%, respectively.

For predicting thromboembolism in patients with AF, the C statistics were 0.62 at 1 year and 0.69 at 5 years. The NPVs were 88% and 61%, respectively.

For predicting ischemic stroke in patients without AF, the C statistics were 0.67 at 1 year and 0.69 at 5 years. The NPVs were 92% and 78%, respectively.

For predicting ischemic stroke in patients with AF, the C statistics were 0.64 at 1 year and 0.71 at 5 years. The NPVs were 91% and 69%, respectively.

For predicting death in patients without AF, the C statistics were 0.64 at 1 year and 0.68 at 5 years. The NPVs were 93% and 81%, respectively.

For predicting death in patients with AF, the C statistics were 0.63 at 1 year and 0.70 at 5 years. The NPVs were 94% and 76%, respectively.

Based on these results, the researchers said the clinical usefulness of the CHA2DS2-VASc score for patients with HF remains to be determined. And preventative strategies to reduce thromboembolism and ischemic stroke among these patients require further investigation.

*Information in the abstract differs from that presented.

Thrombus

Image by Kevin MacKEnzie

LONDON—A score used to predict the risk of thromboembolic events, ischemic stroke, and death is only modestly accurate in patients with heart failure (HF), according to researchers.

They found the accuracy of the CHA2DS2-VASc score was dependent upon the endpoint being assessed and the duration of follow-up.

The score proved least effective for predicting thromboembolism, and its negative predictive values (NPVs) were inferior at 5 years of follow-up compared to 1 year.

Gregory Y. H Lip, MD, of Aalborg University in Denmark, and his colleagues reported these findings in JAMA and at the ESC Congress 2015 (abstract 1830*).

The team noted that the CHA2DS2-VASc score (congestive heart failure, hypertension, age 75 years or older [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior heart attack, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) is already used clinically for stroke risk stratification in patients with atrial fibrillation (AF).

But its usefulness in a population of patients with HF has been unclear. So the researchers investigated whether CHA2DS2-VASc predicts ischemic stroke, thromboembolism, and death in patients with a new diagnosis of HF, with or without AF.

Using Danish registries, the researchers compiled data from 42,987 patients (22% with concomitant AF). The patients were not receiving anticoagulation and had been diagnosed with new-onset HF from 2000 to 2012.

The end of follow-up was December 31, 2012. Levels of the CHA2DS2-VASc score (based on 10 possible points, with higher scores indicating higher risk) were stratified by the presence of AF at study entry.

Among patients without AF, the incidence of thromboembolism was 3.5%, the rate of ischemic stroke was 1%, and the death rate was 7.2%. Among patients with AF, the rates were 4.2%, 2%, and 13.2%, respectively.

Predictive accuracy

For predicting thromboembolism in patients without AF, the C statistics were 0.63 at 1 year and 0.67 at 5 years. The NPVs were 88% and 73%, respectively.

For predicting thromboembolism in patients with AF, the C statistics were 0.62 at 1 year and 0.69 at 5 years. The NPVs were 88% and 61%, respectively.

For predicting ischemic stroke in patients without AF, the C statistics were 0.67 at 1 year and 0.69 at 5 years. The NPVs were 92% and 78%, respectively.

For predicting ischemic stroke in patients with AF, the C statistics were 0.64 at 1 year and 0.71 at 5 years. The NPVs were 91% and 69%, respectively.

For predicting death in patients without AF, the C statistics were 0.64 at 1 year and 0.68 at 5 years. The NPVs were 93% and 81%, respectively.

For predicting death in patients with AF, the C statistics were 0.63 at 1 year and 0.70 at 5 years. The NPVs were 94% and 76%, respectively.

Based on these results, the researchers said the clinical usefulness of the CHA2DS2-VASc score for patients with HF remains to be determined. And preventative strategies to reduce thromboembolism and ischemic stroke among these patients require further investigation.

*Information in the abstract differs from that presented.

Thrombus

Image by Kevin MacKEnzie

LONDON—A score used to predict the risk of thromboembolic events, ischemic stroke, and death is only modestly accurate in patients with heart failure (HF), according to researchers.

They found the accuracy of the CHA2DS2-VASc score was dependent upon the endpoint being assessed and the duration of follow-up.

The score proved least effective for predicting thromboembolism, and its negative predictive values (NPVs) were inferior at 5 years of follow-up compared to 1 year.

Gregory Y. H Lip, MD, of Aalborg University in Denmark, and his colleagues reported these findings in JAMA and at the ESC Congress 2015 (abstract 1830*).

The team noted that the CHA2DS2-VASc score (congestive heart failure, hypertension, age 75 years or older [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior heart attack, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) is already used clinically for stroke risk stratification in patients with atrial fibrillation (AF).

But its usefulness in a population of patients with HF has been unclear. So the researchers investigated whether CHA2DS2-VASc predicts ischemic stroke, thromboembolism, and death in patients with a new diagnosis of HF, with or without AF.

Using Danish registries, the researchers compiled data from 42,987 patients (22% with concomitant AF). The patients were not receiving anticoagulation and had been diagnosed with new-onset HF from 2000 to 2012.

The end of follow-up was December 31, 2012. Levels of the CHA2DS2-VASc score (based on 10 possible points, with higher scores indicating higher risk) were stratified by the presence of AF at study entry.

Among patients without AF, the incidence of thromboembolism was 3.5%, the rate of ischemic stroke was 1%, and the death rate was 7.2%. Among patients with AF, the rates were 4.2%, 2%, and 13.2%, respectively.

Predictive accuracy

For predicting thromboembolism in patients without AF, the C statistics were 0.63 at 1 year and 0.67 at 5 years. The NPVs were 88% and 73%, respectively.

For predicting thromboembolism in patients with AF, the C statistics were 0.62 at 1 year and 0.69 at 5 years. The NPVs were 88% and 61%, respectively.

For predicting ischemic stroke in patients without AF, the C statistics were 0.67 at 1 year and 0.69 at 5 years. The NPVs were 92% and 78%, respectively.

For predicting ischemic stroke in patients with AF, the C statistics were 0.64 at 1 year and 0.71 at 5 years. The NPVs were 91% and 69%, respectively.

For predicting death in patients without AF, the C statistics were 0.64 at 1 year and 0.68 at 5 years. The NPVs were 93% and 81%, respectively.

For predicting death in patients with AF, the C statistics were 0.63 at 1 year and 0.70 at 5 years. The NPVs were 94% and 76%, respectively.

Based on these results, the researchers said the clinical usefulness of the CHA2DS2-VASc score for patients with HF remains to be determined. And preventative strategies to reduce thromboembolism and ischemic stroke among these patients require further investigation.

*Information in the abstract differs from that presented.

Neutrophil engulfing bacteria

Image by Volker Brinkmann

LONDON—Immune cells may represent an important therapeutic target for preventing stent thrombosis, according to investigators from the PRESTIGE study.

The team analyzed more than 250 thrombus specimens and observed leukocyte infiltration in the context of early and late stent thrombosis.

Neutrophils were the most common leukocyte detected, and eosinophils were present in thrombi from all stent types.

The investigators reported these findings in the European Heart Journal and at the ESC Congress 2015 (abstract 1996*).

“Our results suggest that immune-cell-mediated thrombotic processes may be a realistic target for novel therapies to prevent [stent thrombosis],” said study investigator Steffen Massberg, PhD, of Ludwig-Maximilians University in Munich, Germany.

“Inhibition of triggers, such as extracellular nucleic acids activating the contact phase, may not only result in efficient anticoagulation in the setting of [stent thrombosis] but might also yield less therapy-associated bleeding. Future studies should evaluate whether inhibition of immune-cell-driven thrombotic pathways are effective and safe in clinical practice.”

The PRESTIGE study included patients with stent thrombosis who underwent thrombus aspiration at 9 centers in Europe between 2010 and 2014. In all, the investigators analyzed 253 thrombus specimens from these patients.

Seventy-nine specimens (31.2%) were from patients presenting with early stent thrombosis, and 174 (68.8%) were from patients with late stent thrombosis. Seventy-nine (31.2%) were from bare metal stents, 166 (65.6%) were from drug-eluting stents, and 8 (3.2%) were from stents of unknown type.

The thrombus specimens had heterogeneous morphology, with platelet-rich thrombus and fibrin/fibrinogen fragments being most abundant.

The investigators said leukocyte infiltrations were hallmarks of both early and late stent thrombosis, with neutrophils representing the most prominent subset. Neutrophils were found in similar amounts in early and late stent thrombosis.

“It is important to note that leukocyte counts were significantly higher compared with a control group of patients with thrombus aspiration in spontaneous myocardial infarction,” Dr Massberg said.

He and his colleagues also observed neutrophil extracellular traps (NETs) in 23% of samples.

And they found that eosinophils were present in all stent types, but there were higher numbers in patients with late stent thrombosis in sirolimus-eluting and everolimus-eluting stents.

“The presence of NETs supports their pathophysiological relevance in [stent thrombosis], while eosinophil recruitment suggests an allergic component to the process of [stent thrombosis],” Dr Massberg said.

*Information in the abstract differs from that presented.

Neutrophil engulfing bacteria

Image by Volker Brinkmann

LONDON—Immune cells may represent an important therapeutic target for preventing stent thrombosis, according to investigators from the PRESTIGE study.

The team analyzed more than 250 thrombus specimens and observed leukocyte infiltration in the context of early and late stent thrombosis.

Neutrophils were the most common leukocyte detected, and eosinophils were present in thrombi from all stent types.

The investigators reported these findings in the European Heart Journal and at the ESC Congress 2015 (abstract 1996*).

“Our results suggest that immune-cell-mediated thrombotic processes may be a realistic target for novel therapies to prevent [stent thrombosis],” said study investigator Steffen Massberg, PhD, of Ludwig-Maximilians University in Munich, Germany.

“Inhibition of triggers, such as extracellular nucleic acids activating the contact phase, may not only result in efficient anticoagulation in the setting of [stent thrombosis] but might also yield less therapy-associated bleeding. Future studies should evaluate whether inhibition of immune-cell-driven thrombotic pathways are effective and safe in clinical practice.”

The PRESTIGE study included patients with stent thrombosis who underwent thrombus aspiration at 9 centers in Europe between 2010 and 2014. In all, the investigators analyzed 253 thrombus specimens from these patients.

Seventy-nine specimens (31.2%) were from patients presenting with early stent thrombosis, and 174 (68.8%) were from patients with late stent thrombosis. Seventy-nine (31.2%) were from bare metal stents, 166 (65.6%) were from drug-eluting stents, and 8 (3.2%) were from stents of unknown type.

The thrombus specimens had heterogeneous morphology, with platelet-rich thrombus and fibrin/fibrinogen fragments being most abundant.

The investigators said leukocyte infiltrations were hallmarks of both early and late stent thrombosis, with neutrophils representing the most prominent subset. Neutrophils were found in similar amounts in early and late stent thrombosis.

“It is important to note that leukocyte counts were significantly higher compared with a control group of patients with thrombus aspiration in spontaneous myocardial infarction,” Dr Massberg said.

He and his colleagues also observed neutrophil extracellular traps (NETs) in 23% of samples.

And they found that eosinophils were present in all stent types, but there were higher numbers in patients with late stent thrombosis in sirolimus-eluting and everolimus-eluting stents.

“The presence of NETs supports their pathophysiological relevance in [stent thrombosis], while eosinophil recruitment suggests an allergic component to the process of [stent thrombosis],” Dr Massberg said.

*Information in the abstract differs from that presented.

Neutrophil engulfing bacteria

Image by Volker Brinkmann

LONDON—Immune cells may represent an important therapeutic target for preventing stent thrombosis, according to investigators from the PRESTIGE study.

The team analyzed more than 250 thrombus specimens and observed leukocyte infiltration in the context of early and late stent thrombosis.

Neutrophils were the most common leukocyte detected, and eosinophils were present in thrombi from all stent types.

The investigators reported these findings in the European Heart Journal and at the ESC Congress 2015 (abstract 1996*).

“Our results suggest that immune-cell-mediated thrombotic processes may be a realistic target for novel therapies to prevent [stent thrombosis],” said study investigator Steffen Massberg, PhD, of Ludwig-Maximilians University in Munich, Germany.

“Inhibition of triggers, such as extracellular nucleic acids activating the contact phase, may not only result in efficient anticoagulation in the setting of [stent thrombosis] but might also yield less therapy-associated bleeding. Future studies should evaluate whether inhibition of immune-cell-driven thrombotic pathways are effective and safe in clinical practice.”

The PRESTIGE study included patients with stent thrombosis who underwent thrombus aspiration at 9 centers in Europe between 2010 and 2014. In all, the investigators analyzed 253 thrombus specimens from these patients.

Seventy-nine specimens (31.2%) were from patients presenting with early stent thrombosis, and 174 (68.8%) were from patients with late stent thrombosis. Seventy-nine (31.2%) were from bare metal stents, 166 (65.6%) were from drug-eluting stents, and 8 (3.2%) were from stents of unknown type.

The thrombus specimens had heterogeneous morphology, with platelet-rich thrombus and fibrin/fibrinogen fragments being most abundant.

The investigators said leukocyte infiltrations were hallmarks of both early and late stent thrombosis, with neutrophils representing the most prominent subset. Neutrophils were found in similar amounts in early and late stent thrombosis.

“It is important to note that leukocyte counts were significantly higher compared with a control group of patients with thrombus aspiration in spontaneous myocardial infarction,” Dr Massberg said.

He and his colleagues also observed neutrophil extracellular traps (NETs) in 23% of samples.

And they found that eosinophils were present in all stent types, but there were higher numbers in patients with late stent thrombosis in sirolimus-eluting and everolimus-eluting stents.

“The presence of NETs supports their pathophysiological relevance in [stent thrombosis], while eosinophil recruitment suggests an allergic component to the process of [stent thrombosis],” Dr Massberg said.

*Information in the abstract differs from that presented.

LONDON—Results of a large study suggest that watching television for prolonged periods may increase a person’s risk of fatal pulmonary embolism (PE).

The study, which included more than 86,000 subjects, showed that watching an average of 5 or more hours of TV per day was associated with more than twice the risk of fatal PE as watching less than 2.5 hours daily.

And the risk was higher among younger subjects than older ones.

Toru Shirakawa, of Osaka University in Japan, presented this research at the ESC Congress 2015 (abstract P2686*).

“We showed that prolonged television viewing may be a risky behavior for death from pulmonary embolism,” Shirakawa said. “Leg immobility during television viewing may, in part, explain the finding. Public awareness of the risk of pulmonary embolism from lengthy leg immobility is essential.”

For this research, Shirakawa and his colleagues evaluated 86,024 individuals—36,007 men and 50,017 women ages 40 to 79—who were participating in the Japanese Collaborative Cohort Study.

The subjects completed a self-administered questionnaire that included information about average time spent watching TV each day. They were followed for a median of 18.4 years until 2009. Mortality from PE was determined from death certificates.

Subjects were divided into 3 groups according to the amount of TV they watched per day: less than 2.5 hours, 2.5 to 4.9 hours, and 5 or more hours.

The researchers calculated the risk of death from PE according to the amount of TV watched after adjusting for subjects’ age at baseline, gender, history of hypertension, history of diabetes, smoking status, drinking status, body mass index, walking and sports habits, and menopausal status.

During the follow-up period, there were 59 deaths from PE. And the multiavariate analysis revealed a link between extended TV viewing and fatal PE.

Compared to subjects who tended to watch less than 2.5 hours of TV per day, those who watched an average of 2.5 to 4.9 hours had an increased risk of fatal PE (hazard ratio [HR]=1.59). And the risk was greater among subjects whose average TV viewing time was more than 5 hours per day (HR=2.36).

Among subjects ages 40 to 59, the association between prolonged TV watching and fatal PE was more prominent.

Watching 2.5 to 4.9 hours of TV a day more than tripled the risk of fatal PE when compared to watching less than 2.5 hours (HR=3.24). And watching TV for more than 5 hours a day was associated with a more than 6-fold greater risk of fatal PE than watching less than 2.5 hours (HR=6.49).

Because prolonged leg immobility may explain these findings, Shirakawa and his colleagues recommend taking simple steps to prevent PE while watching TV for extended periods.

“[T]ake a break, stand up, and walk around during the television viewing,” he said. “Drinking water for preventing dehydration is also important.”

Shirakawa also noted that other media-based activities involving prolonged sitting may pose a risk of fatal PE.

“In this era of information technology, use of other visual-based media devices, such as personal computers or smartphones, is popular,” he said.

“Prolonged computer gaming has been associated with death from pulmonary embolism, but, to our knowledge, a relationship with prolonged smartphone use has not yet been reported. More research is needed to assess the risks of prolonged use of new technologies on pulmonary embolism morbidity and mortality.”

*Information in the abstract differs from that presented at the meeting.

LONDON—Results of a large study suggest that watching television for prolonged periods may increase a person’s risk of fatal pulmonary embolism (PE).

The study, which included more than 86,000 subjects, showed that watching an average of 5 or more hours of TV per day was associated with more than twice the risk of fatal PE as watching less than 2.5 hours daily.

And the risk was higher among younger subjects than older ones.

Toru Shirakawa, of Osaka University in Japan, presented this research at the ESC Congress 2015 (abstract P2686*).

“We showed that prolonged television viewing may be a risky behavior for death from pulmonary embolism,” Shirakawa said. “Leg immobility during television viewing may, in part, explain the finding. Public awareness of the risk of pulmonary embolism from lengthy leg immobility is essential.”

For this research, Shirakawa and his colleagues evaluated 86,024 individuals—36,007 men and 50,017 women ages 40 to 79—who were participating in the Japanese Collaborative Cohort Study.

The subjects completed a self-administered questionnaire that included information about average time spent watching TV each day. They were followed for a median of 18.4 years until 2009. Mortality from PE was determined from death certificates.

Subjects were divided into 3 groups according to the amount of TV they watched per day: less than 2.5 hours, 2.5 to 4.9 hours, and 5 or more hours.

The researchers calculated the risk of death from PE according to the amount of TV watched after adjusting for subjects’ age at baseline, gender, history of hypertension, history of diabetes, smoking status, drinking status, body mass index, walking and sports habits, and menopausal status.

During the follow-up period, there were 59 deaths from PE. And the multiavariate analysis revealed a link between extended TV viewing and fatal PE.

Compared to subjects who tended to watch less than 2.5 hours of TV per day, those who watched an average of 2.5 to 4.9 hours had an increased risk of fatal PE (hazard ratio [HR]=1.59). And the risk was greater among subjects whose average TV viewing time was more than 5 hours per day (HR=2.36).

Among subjects ages 40 to 59, the association between prolonged TV watching and fatal PE was more prominent.

Watching 2.5 to 4.9 hours of TV a day more than tripled the risk of fatal PE when compared to watching less than 2.5 hours (HR=3.24). And watching TV for more than 5 hours a day was associated with a more than 6-fold greater risk of fatal PE than watching less than 2.5 hours (HR=6.49).

Because prolonged leg immobility may explain these findings, Shirakawa and his colleagues recommend taking simple steps to prevent PE while watching TV for extended periods.

“[T]ake a break, stand up, and walk around during the television viewing,” he said. “Drinking water for preventing dehydration is also important.”

Shirakawa also noted that other media-based activities involving prolonged sitting may pose a risk of fatal PE.

“In this era of information technology, use of other visual-based media devices, such as personal computers or smartphones, is popular,” he said.

“Prolonged computer gaming has been associated with death from pulmonary embolism, but, to our knowledge, a relationship with prolonged smartphone use has not yet been reported. More research is needed to assess the risks of prolonged use of new technologies on pulmonary embolism morbidity and mortality.”

*Information in the abstract differs from that presented at the meeting.

LONDON—Results of a large study suggest that watching television for prolonged periods may increase a person’s risk of fatal pulmonary embolism (PE).

The study, which included more than 86,000 subjects, showed that watching an average of 5 or more hours of TV per day was associated with more than twice the risk of fatal PE as watching less than 2.5 hours daily.

And the risk was higher among younger subjects than older ones.

Toru Shirakawa, of Osaka University in Japan, presented this research at the ESC Congress 2015 (abstract P2686*).

“We showed that prolonged television viewing may be a risky behavior for death from pulmonary embolism,” Shirakawa said. “Leg immobility during television viewing may, in part, explain the finding. Public awareness of the risk of pulmonary embolism from lengthy leg immobility is essential.”

For this research, Shirakawa and his colleagues evaluated 86,024 individuals—36,007 men and 50,017 women ages 40 to 79—who were participating in the Japanese Collaborative Cohort Study.

The subjects completed a self-administered questionnaire that included information about average time spent watching TV each day. They were followed for a median of 18.4 years until 2009. Mortality from PE was determined from death certificates.

Subjects were divided into 3 groups according to the amount of TV they watched per day: less than 2.5 hours, 2.5 to 4.9 hours, and 5 or more hours.

The researchers calculated the risk of death from PE according to the amount of TV watched after adjusting for subjects’ age at baseline, gender, history of hypertension, history of diabetes, smoking status, drinking status, body mass index, walking and sports habits, and menopausal status.

During the follow-up period, there were 59 deaths from PE. And the multiavariate analysis revealed a link between extended TV viewing and fatal PE.

Compared to subjects who tended to watch less than 2.5 hours of TV per day, those who watched an average of 2.5 to 4.9 hours had an increased risk of fatal PE (hazard ratio [HR]=1.59). And the risk was greater among subjects whose average TV viewing time was more than 5 hours per day (HR=2.36).

Among subjects ages 40 to 59, the association between prolonged TV watching and fatal PE was more prominent.

Watching 2.5 to 4.9 hours of TV a day more than tripled the risk of fatal PE when compared to watching less than 2.5 hours (HR=3.24). And watching TV for more than 5 hours a day was associated with a more than 6-fold greater risk of fatal PE than watching less than 2.5 hours (HR=6.49).

Because prolonged leg immobility may explain these findings, Shirakawa and his colleagues recommend taking simple steps to prevent PE while watching TV for extended periods.

“[T]ake a break, stand up, and walk around during the television viewing,” he said. “Drinking water for preventing dehydration is also important.”

Shirakawa also noted that other media-based activities involving prolonged sitting may pose a risk of fatal PE.

“In this era of information technology, use of other visual-based media devices, such as personal computers or smartphones, is popular,” he said.

“Prolonged computer gaming has been associated with death from pulmonary embolism, but, to our knowledge, a relationship with prolonged smartphone use has not yet been reported. More research is needed to assess the risks of prolonged use of new technologies on pulmonary embolism morbidity and mortality.”

*Information in the abstract differs from that presented at the meeting.

Apixaban (Eliquis)

Photo courtesy of Pfizer

and Bristol-Myers Squibb

LONDON—An educational program designed to improve adherence to the anticoagulant apixaban proved ineffective in a phase 4 trial of patients with atrial fibrillation (AF).

But that’s because adherence was high whether patients completed the program or not.

This suggests current measures used to inform patients about apixaban may be sufficient to ensure treatment adherence, researchers said.

They presented these findings at the ESC Congress 2015 (abstract 2191).

The research, known as the AEGEAN trial, was sponsored by Bristol-Myers Squibb, the company co-developing apixaban (Eliquis) with Pfizer.

“We used the best possible tools for the educational program, including the usual staff and procedures of the anticoagulation clinics, and all of this was useless,” said study investigator Gilles Montalescot, MD, PhD, of Hospitalier Universitaire Pitié-Salpêtrière in Paris, France.

“However, the trial showed very good adherence to apixaban, leaving little room for improvement with an educational program, suggesting one more advantage of prescribing non-vitamin K antagonists (VKAs) over VKAs in that there is apparently no need for additional education and information.”

Dr Montalescot and his colleagues conducted this study in 1162 AF patients receiving apixaban as stroke prophylaxis.

Roughly half of the patients (n=579) completed an educational program promoting treatment adherence, and the other half (n=583) received the usual information about their disease and the treatment.

The educational program included a patient information booklet explaining AF and anticoagulant treatment for stroke prevention, reminder tools (eg, a key ring and mobile phone alerts), and access to a virtual clinic utilizing staff from existing VKA monitoring clinics.

The researchers assessed differences between the 2 patient groups with regard to treatment adherence (defined as continuous, twice-daily dosing, with an occasional missed dose allowed) and treatment persistence (defined as absence of discontinuation for 30 consecutive days) over a 6-month observational period.

Adherence/persistence was measured using an electronic device that holds a blister pack of medication and records each time the pack is removed.

The researchers found no additional value of the educational program for either outcome.

At 24 weeks, the adherence rate was 88.5% in the control group and 88.3% in the education group (P=0.89). Treatment persistence rates were 90.5% and 91.1%, respectively (P=0.76).

For the second part of this study, the researchers are investigating long-term treatment adherence and the value of an educational program beyond 6 months.

“Future studies may want to test more aggressive and more costly educational programs,” Dr Montalescot noted. “But, in the meantime, the adherence and persistence rates we measured are quite reassuring with the common practice and usual mode of prescription of this medication.”

Apixaban (Eliquis)

Photo courtesy of Pfizer

and Bristol-Myers Squibb

LONDON—An educational program designed to improve adherence to the anticoagulant apixaban proved ineffective in a phase 4 trial of patients with atrial fibrillation (AF).

But that’s because adherence was high whether patients completed the program or not.

This suggests current measures used to inform patients about apixaban may be sufficient to ensure treatment adherence, researchers said.

They presented these findings at the ESC Congress 2015 (abstract 2191).

The research, known as the AEGEAN trial, was sponsored by Bristol-Myers Squibb, the company co-developing apixaban (Eliquis) with Pfizer.

“We used the best possible tools for the educational program, including the usual staff and procedures of the anticoagulation clinics, and all of this was useless,” said study investigator Gilles Montalescot, MD, PhD, of Hospitalier Universitaire Pitié-Salpêtrière in Paris, France.

“However, the trial showed very good adherence to apixaban, leaving little room for improvement with an educational program, suggesting one more advantage of prescribing non-vitamin K antagonists (VKAs) over VKAs in that there is apparently no need for additional education and information.”

Dr Montalescot and his colleagues conducted this study in 1162 AF patients receiving apixaban as stroke prophylaxis.

Roughly half of the patients (n=579) completed an educational program promoting treatment adherence, and the other half (n=583) received the usual information about their disease and the treatment.

The educational program included a patient information booklet explaining AF and anticoagulant treatment for stroke prevention, reminder tools (eg, a key ring and mobile phone alerts), and access to a virtual clinic utilizing staff from existing VKA monitoring clinics.

The researchers assessed differences between the 2 patient groups with regard to treatment adherence (defined as continuous, twice-daily dosing, with an occasional missed dose allowed) and treatment persistence (defined as absence of discontinuation for 30 consecutive days) over a 6-month observational period.

Adherence/persistence was measured using an electronic device that holds a blister pack of medication and records each time the pack is removed.

The researchers found no additional value of the educational program for either outcome.

At 24 weeks, the adherence rate was 88.5% in the control group and 88.3% in the education group (P=0.89). Treatment persistence rates were 90.5% and 91.1%, respectively (P=0.76).

For the second part of this study, the researchers are investigating long-term treatment adherence and the value of an educational program beyond 6 months.

“Future studies may want to test more aggressive and more costly educational programs,” Dr Montalescot noted. “But, in the meantime, the adherence and persistence rates we measured are quite reassuring with the common practice and usual mode of prescription of this medication.”

Apixaban (Eliquis)

Photo courtesy of Pfizer

and Bristol-Myers Squibb

LONDON—An educational program designed to improve adherence to the anticoagulant apixaban proved ineffective in a phase 4 trial of patients with atrial fibrillation (AF).

But that’s because adherence was high whether patients completed the program or not.

This suggests current measures used to inform patients about apixaban may be sufficient to ensure treatment adherence, researchers said.

They presented these findings at the ESC Congress 2015 (abstract 2191).

The research, known as the AEGEAN trial, was sponsored by Bristol-Myers Squibb, the company co-developing apixaban (Eliquis) with Pfizer.

“We used the best possible tools for the educational program, including the usual staff and procedures of the anticoagulation clinics, and all of this was useless,” said study investigator Gilles Montalescot, MD, PhD, of Hospitalier Universitaire Pitié-Salpêtrière in Paris, France.

“However, the trial showed very good adherence to apixaban, leaving little room for improvement with an educational program, suggesting one more advantage of prescribing non-vitamin K antagonists (VKAs) over VKAs in that there is apparently no need for additional education and information.”

Dr Montalescot and his colleagues conducted this study in 1162 AF patients receiving apixaban as stroke prophylaxis.

Roughly half of the patients (n=579) completed an educational program promoting treatment adherence, and the other half (n=583) received the usual information about their disease and the treatment.

The educational program included a patient information booklet explaining AF and anticoagulant treatment for stroke prevention, reminder tools (eg, a key ring and mobile phone alerts), and access to a virtual clinic utilizing staff from existing VKA monitoring clinics.

The researchers assessed differences between the 2 patient groups with regard to treatment adherence (defined as continuous, twice-daily dosing, with an occasional missed dose allowed) and treatment persistence (defined as absence of discontinuation for 30 consecutive days) over a 6-month observational period.

Adherence/persistence was measured using an electronic device that holds a blister pack of medication and records each time the pack is removed.

The researchers found no additional value of the educational program for either outcome.

At 24 weeks, the adherence rate was 88.5% in the control group and 88.3% in the education group (P=0.89). Treatment persistence rates were 90.5% and 91.1%, respectively (P=0.76).

For the second part of this study, the researchers are investigating long-term treatment adherence and the value of an educational program beyond 6 months.

“Future studies may want to test more aggressive and more costly educational programs,” Dr Montalescot noted. “But, in the meantime, the adherence and persistence rates we measured are quite reassuring with the common practice and usual mode of prescription of this medication.”

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.

Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.

But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.

Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.

The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.

The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.

Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.

Survey questions and responses were as follows.

Radiotherapy

Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?

Other cancer treatments

Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?

NHS funding

What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.

Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.

But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.

Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.

The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.

The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.

Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.

Survey questions and responses were as follows.

Radiotherapy

Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?

Other cancer treatments

Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?

NHS funding

What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?

Cancer patient

receiving chemotherapy

Photo by Rhoda Baer

Results of a new survey suggest many adults in the UK may be uninformed about cancer treatment options, despite broad media coverage of these therapies.

Personalized drug treatment, immunotherapy, and proton beam therapy have all been covered by the lay media and featured in news stories across the globe.

But a survey of more than 2000 UK adults showed that most respondents were not aware of these treatment types.

Only 19% of respondents said they had heard about immunotherapy, 29% had heard of personalized drug treatment, and 30% had heard of proton beam therapy.

The survey, which included 2081 adults, was conducted online by YouGov in June. It was commissioned by Cancer Research UK and other members of the Radiotherapy Awareness Programme.

The primary goal of the survey was to examine public awareness of radiotherapy. And the results showed that many respondents were unaware of newer, more targeted radiotherapy options.

Respondents were largely uninformed about other types of cancer treatment as well. However, of the respondents who elected to give their opinion (n=1877), most said the National Health Service (NHS) should fund chemotherapy and other drug treatments over radiotherapy.

Survey questions and responses were as follows.

Radiotherapy

Before taking this survey, which, if any, of the following types of radiotherapy had you heard of?

Other cancer treatments

Which, if any, of the following specific types of cancer treatments/tests had you heard of before taking this survey?

NHS funding

What level of priority do you think the NHS should give to funding each of the following 4 types of cancer treatments?

KHSV-infected cells (yellow)

Image courtesy of the

University of North Carolina

Researchers say they have uncovered a viral protein that inhibits cGAS, the principal cytosolic DNA sensor that detects invading viral DNA and triggers antiviral responses.

The protein, Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF52, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity.

The team believes this finding could have a range of therapeutic implications.

“We can manipulate the protein and/or the sensor to boost or tune down the immune response in order to fight infectious and autoimmune diseases, as well as cancers,” said Fanxiu Zhu, PhD, of Florida State University in Tallahassee.

Dr Zhu and his colleagues described this research in Cell Host and Microbe.

The authors noted that, although cGAS senses several DNA viruses, viral strategies targeting cGAS are “virtually unknown.”

To uncover a cGAS inhibitor, the researchers screened every protein in a KSHV cell—90 in total. This revealed KSHV ORF52, which the team renamed “KicGas,” an abbreviation for “KSHV inhibitor of cGAS.”

Further investigation revealed how KicGas inhibits cGAS activity: it must bind to both DNA and cGAS.

The researchers then found that ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA.

Finally, the team infected human cell lines with KSHV to mimic natural infection. They found that KSHV triggers a cGAS-dependent immune response that can be partially mitigated by KicGas.

When the researchers eliminated KicGas from infected cells, the cells produced a much stronger immune response.

For the next phase of research, the team is building a 3-dimensional model to help them better understand how KicGas functions. They hope this will help them utilize KicGas to fight disease.

KHSV-infected cells (yellow)

Image courtesy of the

University of North Carolina

Researchers say they have uncovered a viral protein that inhibits cGAS, the principal cytosolic DNA sensor that detects invading viral DNA and triggers antiviral responses.

The protein, Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF52, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity.

The team believes this finding could have a range of therapeutic implications.

“We can manipulate the protein and/or the sensor to boost or tune down the immune response in order to fight infectious and autoimmune diseases, as well as cancers,” said Fanxiu Zhu, PhD, of Florida State University in Tallahassee.

Dr Zhu and his colleagues described this research in Cell Host and Microbe.

The authors noted that, although cGAS senses several DNA viruses, viral strategies targeting cGAS are “virtually unknown.”

To uncover a cGAS inhibitor, the researchers screened every protein in a KSHV cell—90 in total. This revealed KSHV ORF52, which the team renamed “KicGas,” an abbreviation for “KSHV inhibitor of cGAS.”

Further investigation revealed how KicGas inhibits cGAS activity: it must bind to both DNA and cGAS.

The researchers then found that ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA.

Finally, the team infected human cell lines with KSHV to mimic natural infection. They found that KSHV triggers a cGAS-dependent immune response that can be partially mitigated by KicGas.

When the researchers eliminated KicGas from infected cells, the cells produced a much stronger immune response.

For the next phase of research, the team is building a 3-dimensional model to help them better understand how KicGas functions. They hope this will help them utilize KicGas to fight disease.

KHSV-infected cells (yellow)

Image courtesy of the

University of North Carolina

Researchers say they have uncovered a viral protein that inhibits cGAS, the principal cytosolic DNA sensor that detects invading viral DNA and triggers antiviral responses.

The protein, Kaposi’s sarcoma-associated herpesvirus (KSHV) ORF52, subverts cytosolic DNA sensing by directly inhibiting cGAS enzymatic activity.

The team believes this finding could have a range of therapeutic implications.

“We can manipulate the protein and/or the sensor to boost or tune down the immune response in order to fight infectious and autoimmune diseases, as well as cancers,” said Fanxiu Zhu, PhD, of Florida State University in Tallahassee.

Dr Zhu and his colleagues described this research in Cell Host and Microbe.

The authors noted that, although cGAS senses several DNA viruses, viral strategies targeting cGAS are “virtually unknown.”

To uncover a cGAS inhibitor, the researchers screened every protein in a KSHV cell—90 in total. This revealed KSHV ORF52, which the team renamed “KicGas,” an abbreviation for “KSHV inhibitor of cGAS.”

Further investigation revealed how KicGas inhibits cGAS activity: it must bind to both DNA and cGAS.

The researchers then found that ORF52 homologs in other gammaherpesviruses also inhibit cGAS activity and similarly bind cGAS and DNA.

Finally, the team infected human cell lines with KSHV to mimic natural infection. They found that KSHV triggers a cGAS-dependent immune response that can be partially mitigated by KicGas.

When the researchers eliminated KicGas from infected cells, the cells produced a much stronger immune response.

For the next phase of research, the team is building a 3-dimensional model to help them better understand how KicGas functions. They hope this will help them utilize KicGas to fight disease.