Micrograph showing CLL

Researchers say they have performed the first large-scale analysis of the chromatin landscape in chronic lymphocytic leukemia (CLL).

And, in doing so, they have identified shared gene regulatory networks as well as heterogeneity between patients and CLL subtypes.

The group says this work should enable deeper investigation into chromatin regulation in CLL and the identification of therapeutically relevant mechanisms of disease.

The work has been published in Nature Communications.

The researchers performed chromatin accessibility mapping—via the assay for transposase-accessible chromatin using sequencing (ATAC-seq)—on 88 CLL samples from 55 patients.

For 10 of the samples, the team also established histone profiles using ChIPmentation for 3 histone marks (H3K4me1, H3K27ac, and H3K27me3) and transcriptome profiles using RNA sequencing.

The researchers then developed a bioinformatic method for linking the chromatin profiles to clinical annotations and molecular diagnostics data, and they analyzed gene regulatory networks that underlie the major disease subtypes of CLL.

The work revealed a “shared core” of regulatory regions in CLL patients as well as variations between the samples.

Furthermore, the chromatin profiles and gene regulatory networks accurately predicted IGHV mutation status and pinpointed differences between IGVH-mutated and IGVH-unmutated CLL.

“Our study has been able to dissect the variability that exists in the epigenome of CLL patients and helped to identify disease-specific changes, which will hopefully be informative for distinguishing disease subtypes or identifying suitable treatments,” said study author Jonathan Strefford, PhD, of the University of Southampton in the UK.

“Epigenetics can offer a useful doorway into ways of improving disease diagnosis and more personalized treatment choices for patients.”

Micrograph showing CLL

Researchers say they have performed the first large-scale analysis of the chromatin landscape in chronic lymphocytic leukemia (CLL).

And, in doing so, they have identified shared gene regulatory networks as well as heterogeneity between patients and CLL subtypes.

The group says this work should enable deeper investigation into chromatin regulation in CLL and the identification of therapeutically relevant mechanisms of disease.

The work has been published in Nature Communications.

The researchers performed chromatin accessibility mapping—via the assay for transposase-accessible chromatin using sequencing (ATAC-seq)—on 88 CLL samples from 55 patients.

For 10 of the samples, the team also established histone profiles using ChIPmentation for 3 histone marks (H3K4me1, H3K27ac, and H3K27me3) and transcriptome profiles using RNA sequencing.

The researchers then developed a bioinformatic method for linking the chromatin profiles to clinical annotations and molecular diagnostics data, and they analyzed gene regulatory networks that underlie the major disease subtypes of CLL.

The work revealed a “shared core” of regulatory regions in CLL patients as well as variations between the samples.

Furthermore, the chromatin profiles and gene regulatory networks accurately predicted IGHV mutation status and pinpointed differences between IGVH-mutated and IGVH-unmutated CLL.

“Our study has been able to dissect the variability that exists in the epigenome of CLL patients and helped to identify disease-specific changes, which will hopefully be informative for distinguishing disease subtypes or identifying suitable treatments,” said study author Jonathan Strefford, PhD, of the University of Southampton in the UK.

“Epigenetics can offer a useful doorway into ways of improving disease diagnosis and more personalized treatment choices for patients.”

Micrograph showing CLL

Researchers say they have performed the first large-scale analysis of the chromatin landscape in chronic lymphocytic leukemia (CLL).

And, in doing so, they have identified shared gene regulatory networks as well as heterogeneity between patients and CLL subtypes.

The group says this work should enable deeper investigation into chromatin regulation in CLL and the identification of therapeutically relevant mechanisms of disease.

The work has been published in Nature Communications.

The researchers performed chromatin accessibility mapping—via the assay for transposase-accessible chromatin using sequencing (ATAC-seq)—on 88 CLL samples from 55 patients.

For 10 of the samples, the team also established histone profiles using ChIPmentation for 3 histone marks (H3K4me1, H3K27ac, and H3K27me3) and transcriptome profiles using RNA sequencing.

The researchers then developed a bioinformatic method for linking the chromatin profiles to clinical annotations and molecular diagnostics data, and they analyzed gene regulatory networks that underlie the major disease subtypes of CLL.

The work revealed a “shared core” of regulatory regions in CLL patients as well as variations between the samples.

Furthermore, the chromatin profiles and gene regulatory networks accurately predicted IGHV mutation status and pinpointed differences between IGVH-mutated and IGVH-unmutated CLL.

“Our study has been able to dissect the variability that exists in the epigenome of CLL patients and helped to identify disease-specific changes, which will hopefully be informative for distinguishing disease subtypes or identifying suitable treatments,” said study author Jonathan Strefford, PhD, of the University of Southampton in the UK.

“Epigenetics can offer a useful doorway into ways of improving disease diagnosis and more personalized treatment choices for patients.”

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

A cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) has been classified as an advanced therapy medicinal product (ATMP) by the European Medicines Agency (EMA).

The EBV-CTLs are being developed by Atara Biotherapeutics, Inc., to treat patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

ATMP classification was established to regulate cell and gene therapy and tissue-engineered medicinal products, support the development of these products, and provide a benchmark for the level of quality compliance for pharmaceutical practices.

ATMP classification can provide developers with scientific regulatory guidance, help clarify the applicable regulatory framework and development path, and provide access to all relevant services and incentives offered by the EMA. It can also be advantageous when submitting clinical trial dossiers to national regulatory authorities within the European Union.

About EBV-CTLs

Atara Bio’s EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens. The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Bio’s EBV-CTL product is currently being studied in phase 2 trials of patients with EBV-associated cancers, including PTLD and nasopharyngeal carcinoma.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and the 2015 ASCO Annual Meeting.

Atara Bio’s EBV-CTL product has orphan designation in the European Union and the US, as well as breakthrough designation in the US.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

A cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) has been classified as an advanced therapy medicinal product (ATMP) by the European Medicines Agency (EMA).

The EBV-CTLs are being developed by Atara Biotherapeutics, Inc., to treat patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

ATMP classification was established to regulate cell and gene therapy and tissue-engineered medicinal products, support the development of these products, and provide a benchmark for the level of quality compliance for pharmaceutical practices.

ATMP classification can provide developers with scientific regulatory guidance, help clarify the applicable regulatory framework and development path, and provide access to all relevant services and incentives offered by the EMA. It can also be advantageous when submitting clinical trial dossiers to national regulatory authorities within the European Union.

About EBV-CTLs

Atara Bio’s EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens. The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Bio’s EBV-CTL product is currently being studied in phase 2 trials of patients with EBV-associated cancers, including PTLD and nasopharyngeal carcinoma.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and the 2015 ASCO Annual Meeting.

Atara Bio’s EBV-CTL product has orphan designation in the European Union and the US, as well as breakthrough designation in the US.

An EBV-infected cell (green/red)

among uninfected cells (blue)

Image courtesy of Benjamin

Chaigne-Delalande

A cytotoxic T-lymphocyte product that targets Epstein-Barr virus (EBV-CTLs) has been classified as an advanced therapy medicinal product (ATMP) by the European Medicines Agency (EMA).

The EBV-CTLs are being developed by Atara Biotherapeutics, Inc., to treat patients with EBV post-transplant lymphoproliferative disorder (EBV-PTLD).

ATMP classification was established to regulate cell and gene therapy and tissue-engineered medicinal products, support the development of these products, and provide a benchmark for the level of quality compliance for pharmaceutical practices.

ATMP classification can provide developers with scientific regulatory guidance, help clarify the applicable regulatory framework and development path, and provide access to all relevant services and incentives offered by the EMA. It can also be advantageous when submitting clinical trial dossiers to national regulatory authorities within the European Union.

About EBV-CTLs

Atara Bio’s EBV-CTL product utilizes a technology in which T cells are collected from the blood of third-party donors and then exposed to EBV antigens. The activated T cells are then expanded, characterized, and stored for future use in a partially HLA-matched patient.

In the context of EBV-PTLD, the EBV-CTLs find the cancer cells expressing EBV and kill them.

Atara Bio’s EBV-CTL product is currently being studied in phase 2 trials of patients with EBV-associated cancers, including PTLD and nasopharyngeal carcinoma.

Results of a phase 1/2 study of EBV-CTLs were presented at the APHON 37th Annual Conference and Exhibit and the 2015 ASCO Annual Meeting.

Atara Bio’s EBV-CTL product has orphan designation in the European Union and the US, as well as breakthrough designation in the US.

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

Genomic research suggests the malaria parasite Plasmodium vivax is evolving rapidly to adapt to conditions in different geographic locations.

Researchers studied more than 200 parasite samples from across the Asia-Pacific region and found that P vivax has evolved differently in different areas.

The team identified substantial differences in the frequency of copy number variations (CNVs) in samples from western Thailand, western Cambodia, and Papua Indonesia.

They believe this is a result of the different antimalarial drugs used in these regions.

The researchers described this work in Nature Genetics.

“For so long, it’s not been possible to study P vivax genomes in detail, on a large-scale, but now we can, and we’re seeing the effect that drug use has on how parasites are evolving,” said study author Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in the UK.

He and his colleagues studied the genomes of 228 parasite samples, identifying the strains carried by each patient and revealing their infection history. Most samples came from Southeast Asia (Thailand, Cambodia, Vietnam, Laos, Myanmar, and Malaysia) and Oceania (Papua Indonesia and Papua New Guinea), but the team also studied samples from China, India, Sri Lanka, Brazil, and Madagascar.

The researchers performed detailed population genetic analyses using 148 samples from western Thailand, western Cambodia, and Papua Indonesia. This revealed CNVs in 9 regions of the core genome, and the frequency of the 4 most common CNVs varied greatly according to geographical location.

The first common CNV was a 9-kb deletion on chromosome 8 that includes the first 3 exons of a gene encoding a cytoadherence-linked asexual protein. The CNV was present in 73% of Papua Indonesia samples, 6% of western Cambodia samples, and 3% of western Thailand samples.

The second common CNV was a 7-kb duplication on chromosome 6 that encompasses pvdbp, the gene that encodes the Duffy-binding protein, which mediates P vivax’s invasion of erythrocytes. It was present in 5% of Papua Indonesia samples, 35% of western Cambodia samples, and 25% of western Thailand samples.

The third common CNV was a 37-kb duplication on chromosome 10 that includes pvmdr1, which has been associated with resistance to mefloquine and is homologous to the pfmdr1 amplification responsible for mefloquine resistance in P falciparum. This CNV was only present in samples from western Thailand.

The fourth common CNV was a 3-kb duplication on chromosome 14 that includes the gene PVX_101445. It was found only in Papua Indonesia samples.

“Our study shows that the strongest evidence of evolution is in Papua, Indonesia, where resistance of P vivax to chloroquine is now rampant,” said Ric Price, MD, of the University of Oxford in the UK.

“These data provide crucial information from which we can start to identify the mechanisms of drug resistance in P vivax.”

“We can see in the genome that drug resistance is a huge driver for evolution,” added Richard Pearson, PhD, of the Wellcome Trust Sanger Institute.

“Intriguingly, in some places, this process appears to be happening in response to drugs used primarily to treat a different malaria parasite, P falciparum. Although the exact cause isn’t known, this is a worrying sign that drug resistance is becoming deeply entrenched in the parasite population.”

The researchers said there are a few possible reasons why P vivax may be evolving to evade drugs used against P falciparum.

Many people carry mixed infections of both species of parasite, so, in treating one species, the other automatically gets exposed to the drug. Another culprit may be unsupervised drug use—where many people take the most readily available, rather than the most suitable, antimalarial drug.

Another finding from this study was that, when the researchers identified patients who were carrying multiple strains of parasite, the genomic data made it possible to determine how closely the different strains were related to one another.

“This means that we can now start to pull apart the genetic complexity of individual Plasmodium vivax infections and work out whether the parasites came from one or more mosquito bites,” Kwiatkowski said. “It provides a way of addressing fundamental questions about how P vivax is transmitted and how it persists within a community and, in particular, about the biology of relapsing infections.”

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

Genomic research suggests the malaria parasite Plasmodium vivax is evolving rapidly to adapt to conditions in different geographic locations.

Researchers studied more than 200 parasite samples from across the Asia-Pacific region and found that P vivax has evolved differently in different areas.

The team identified substantial differences in the frequency of copy number variations (CNVs) in samples from western Thailand, western Cambodia, and Papua Indonesia.

They believe this is a result of the different antimalarial drugs used in these regions.

The researchers described this work in Nature Genetics.

“For so long, it’s not been possible to study P vivax genomes in detail, on a large-scale, but now we can, and we’re seeing the effect that drug use has on how parasites are evolving,” said study author Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in the UK.

He and his colleagues studied the genomes of 228 parasite samples, identifying the strains carried by each patient and revealing their infection history. Most samples came from Southeast Asia (Thailand, Cambodia, Vietnam, Laos, Myanmar, and Malaysia) and Oceania (Papua Indonesia and Papua New Guinea), but the team also studied samples from China, India, Sri Lanka, Brazil, and Madagascar.

The researchers performed detailed population genetic analyses using 148 samples from western Thailand, western Cambodia, and Papua Indonesia. This revealed CNVs in 9 regions of the core genome, and the frequency of the 4 most common CNVs varied greatly according to geographical location.

The first common CNV was a 9-kb deletion on chromosome 8 that includes the first 3 exons of a gene encoding a cytoadherence-linked asexual protein. The CNV was present in 73% of Papua Indonesia samples, 6% of western Cambodia samples, and 3% of western Thailand samples.

The second common CNV was a 7-kb duplication on chromosome 6 that encompasses pvdbp, the gene that encodes the Duffy-binding protein, which mediates P vivax’s invasion of erythrocytes. It was present in 5% of Papua Indonesia samples, 35% of western Cambodia samples, and 25% of western Thailand samples.

The third common CNV was a 37-kb duplication on chromosome 10 that includes pvmdr1, which has been associated with resistance to mefloquine and is homologous to the pfmdr1 amplification responsible for mefloquine resistance in P falciparum. This CNV was only present in samples from western Thailand.

The fourth common CNV was a 3-kb duplication on chromosome 14 that includes the gene PVX_101445. It was found only in Papua Indonesia samples.

“Our study shows that the strongest evidence of evolution is in Papua, Indonesia, where resistance of P vivax to chloroquine is now rampant,” said Ric Price, MD, of the University of Oxford in the UK.

“These data provide crucial information from which we can start to identify the mechanisms of drug resistance in P vivax.”

“We can see in the genome that drug resistance is a huge driver for evolution,” added Richard Pearson, PhD, of the Wellcome Trust Sanger Institute.

“Intriguingly, in some places, this process appears to be happening in response to drugs used primarily to treat a different malaria parasite, P falciparum. Although the exact cause isn’t known, this is a worrying sign that drug resistance is becoming deeply entrenched in the parasite population.”

The researchers said there are a few possible reasons why P vivax may be evolving to evade drugs used against P falciparum.

Many people carry mixed infections of both species of parasite, so, in treating one species, the other automatically gets exposed to the drug. Another culprit may be unsupervised drug use—where many people take the most readily available, rather than the most suitable, antimalarial drug.

Another finding from this study was that, when the researchers identified patients who were carrying multiple strains of parasite, the genomic data made it possible to determine how closely the different strains were related to one another.

“This means that we can now start to pull apart the genetic complexity of individual Plasmodium vivax infections and work out whether the parasites came from one or more mosquito bites,” Kwiatkowski said. “It provides a way of addressing fundamental questions about how P vivax is transmitted and how it persists within a community and, in particular, about the biology of relapsing infections.”

Blood smear showing

Plasmodium vivax

Image by Mae Melvin

Genomic research suggests the malaria parasite Plasmodium vivax is evolving rapidly to adapt to conditions in different geographic locations.

Researchers studied more than 200 parasite samples from across the Asia-Pacific region and found that P vivax has evolved differently in different areas.

The team identified substantial differences in the frequency of copy number variations (CNVs) in samples from western Thailand, western Cambodia, and Papua Indonesia.

They believe this is a result of the different antimalarial drugs used in these regions.

The researchers described this work in Nature Genetics.

“For so long, it’s not been possible to study P vivax genomes in detail, on a large-scale, but now we can, and we’re seeing the effect that drug use has on how parasites are evolving,” said study author Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in the UK.

He and his colleagues studied the genomes of 228 parasite samples, identifying the strains carried by each patient and revealing their infection history. Most samples came from Southeast Asia (Thailand, Cambodia, Vietnam, Laos, Myanmar, and Malaysia) and Oceania (Papua Indonesia and Papua New Guinea), but the team also studied samples from China, India, Sri Lanka, Brazil, and Madagascar.

The researchers performed detailed population genetic analyses using 148 samples from western Thailand, western Cambodia, and Papua Indonesia. This revealed CNVs in 9 regions of the core genome, and the frequency of the 4 most common CNVs varied greatly according to geographical location.

The first common CNV was a 9-kb deletion on chromosome 8 that includes the first 3 exons of a gene encoding a cytoadherence-linked asexual protein. The CNV was present in 73% of Papua Indonesia samples, 6% of western Cambodia samples, and 3% of western Thailand samples.

The second common CNV was a 7-kb duplication on chromosome 6 that encompasses pvdbp, the gene that encodes the Duffy-binding protein, which mediates P vivax’s invasion of erythrocytes. It was present in 5% of Papua Indonesia samples, 35% of western Cambodia samples, and 25% of western Thailand samples.

The third common CNV was a 37-kb duplication on chromosome 10 that includes pvmdr1, which has been associated with resistance to mefloquine and is homologous to the pfmdr1 amplification responsible for mefloquine resistance in P falciparum. This CNV was only present in samples from western Thailand.

The fourth common CNV was a 3-kb duplication on chromosome 14 that includes the gene PVX_101445. It was found only in Papua Indonesia samples.

“Our study shows that the strongest evidence of evolution is in Papua, Indonesia, where resistance of P vivax to chloroquine is now rampant,” said Ric Price, MD, of the University of Oxford in the UK.

“These data provide crucial information from which we can start to identify the mechanisms of drug resistance in P vivax.”

“We can see in the genome that drug resistance is a huge driver for evolution,” added Richard Pearson, PhD, of the Wellcome Trust Sanger Institute.

“Intriguingly, in some places, this process appears to be happening in response to drugs used primarily to treat a different malaria parasite, P falciparum. Although the exact cause isn’t known, this is a worrying sign that drug resistance is becoming deeply entrenched in the parasite population.”

The researchers said there are a few possible reasons why P vivax may be evolving to evade drugs used against P falciparum.

Many people carry mixed infections of both species of parasite, so, in treating one species, the other automatically gets exposed to the drug. Another culprit may be unsupervised drug use—where many people take the most readily available, rather than the most suitable, antimalarial drug.

Another finding from this study was that, when the researchers identified patients who were carrying multiple strains of parasite, the genomic data made it possible to determine how closely the different strains were related to one another.

“This means that we can now start to pull apart the genetic complexity of individual Plasmodium vivax infections and work out whether the parasites came from one or more mosquito bites,” Kwiatkowski said. “It provides a way of addressing fundamental questions about how P vivax is transmitted and how it persists within a community and, in particular, about the biology of relapsing infections.”

Vials of drug

Photo by Bill Branson

Several case reports have suggested that cancer patients taking the immunotherapy drugs nivolumab and ipilimumab may have a higher-than-normal risk of developing rheumatic diseases.

Between 2012 and 2016, 13 patients at the Johns Hopkins Kimmel Cancer Center who were taking one or both drugs developed inflammatory arthritis or sicca syndrome, a set of autoimmune conditions causing dry eyes and mouth.

The cases were described in Annals of Rheumatic Diseases.

Nivolumab and ipilimumab are both designed to turn off the molecular “checkpoints” some cancers—including lymphoma—use to evade the immune system. When the drugs work, they allow the immune system to detect and attack tumor cells. However, they also turn up the activity of the immune system as a whole and can therefore trigger immune-related side effects.

Clinical trials of ipilimumab and nivolumab have indicated that the drugs confer an increased risk of inflammatory bowel diseases, lung inflammation, autoimmune thyroid disease, and pituitary gland inflammation.

However, those trials were designed primarily to determine efficacy against cancer and not to fully examine all features of rheumatologic side effects, said Laura C. Cappelli, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

With this in mind, she and her colleagues decided to take a closer look at 13 adults (older than 18) who were treated at the Johns Hopkins Kimmel Cancer Center and reported rheumatologic symptoms after their treatment with nivolumab and/or ipilimumab.

Eight patients were taking both ipilimumab and nivolumab, and 5 were taking 1 of the 2 drugs. They were receiving the drugs to treat melanoma (n=6), non-small-cell lung cancer (n=5), small-cell lung cancer (n=1), and renal cell carcinoma (n=1).

Nine of the patients developed inflammatory arthritis—4 with synovitis confirmed via imaging and 4 with inflammatory synovial fluid—and the remaining 4 patients were diagnosed with sicca syndrome. Other immune-related adverse events included pneumonitis, colitis, interstitial nephritis, and thyroiditis.

The researchers said this is the largest published case series showing a link between checkpoint inhibitors and rheumatic diseases.

The patients described in this case report make up about 1.3% of all patients treated with the drugs—singly or in combination—at The Johns Hopkins Hospital from 2012 to 2016. However, the researchers believe that rate is likely an underestimation of how common rheumatic diseases are in patients taking immune checkpoint inhibitors.

“We keep having referrals coming in from our oncologists as more patients are treated with these drugs,” said Clifton Bingham, MD, of the Johns Hopkins University School of Medicine.

“In particular, as more patients are treated with combinations of multiple immunotherapies, we expect the rate to go up.”

Dr Cappelli said she wants the case report to raise awareness among patients and clinicians that rheumatologic side effects may occur with checkpoint inhibitors.

“It is important when weighing the risk-benefit ratio of prescribing these drugs,” she said. “And it’s important for people to be on the lookout for symptoms so they can see a rheumatologist early in an effort to prevent or limit joint damage.”

Drs Cappelli and Bingham and their colleagues are planning further collaboration with Johns Hopkins oncologists to better track the incidence of rheumatic disease in patients taking immunotherapy drugs and determine whether any particular characteristics put cancer patients at higher risk of such complications.

Vials of drug

Photo by Bill Branson

Several case reports have suggested that cancer patients taking the immunotherapy drugs nivolumab and ipilimumab may have a higher-than-normal risk of developing rheumatic diseases.

Between 2012 and 2016, 13 patients at the Johns Hopkins Kimmel Cancer Center who were taking one or both drugs developed inflammatory arthritis or sicca syndrome, a set of autoimmune conditions causing dry eyes and mouth.

The cases were described in Annals of Rheumatic Diseases.

Nivolumab and ipilimumab are both designed to turn off the molecular “checkpoints” some cancers—including lymphoma—use to evade the immune system. When the drugs work, they allow the immune system to detect and attack tumor cells. However, they also turn up the activity of the immune system as a whole and can therefore trigger immune-related side effects.

Clinical trials of ipilimumab and nivolumab have indicated that the drugs confer an increased risk of inflammatory bowel diseases, lung inflammation, autoimmune thyroid disease, and pituitary gland inflammation.

However, those trials were designed primarily to determine efficacy against cancer and not to fully examine all features of rheumatologic side effects, said Laura C. Cappelli, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

With this in mind, she and her colleagues decided to take a closer look at 13 adults (older than 18) who were treated at the Johns Hopkins Kimmel Cancer Center and reported rheumatologic symptoms after their treatment with nivolumab and/or ipilimumab.

Eight patients were taking both ipilimumab and nivolumab, and 5 were taking 1 of the 2 drugs. They were receiving the drugs to treat melanoma (n=6), non-small-cell lung cancer (n=5), small-cell lung cancer (n=1), and renal cell carcinoma (n=1).

Nine of the patients developed inflammatory arthritis—4 with synovitis confirmed via imaging and 4 with inflammatory synovial fluid—and the remaining 4 patients were diagnosed with sicca syndrome. Other immune-related adverse events included pneumonitis, colitis, interstitial nephritis, and thyroiditis.

The researchers said this is the largest published case series showing a link between checkpoint inhibitors and rheumatic diseases.

The patients described in this case report make up about 1.3% of all patients treated with the drugs—singly or in combination—at The Johns Hopkins Hospital from 2012 to 2016. However, the researchers believe that rate is likely an underestimation of how common rheumatic diseases are in patients taking immune checkpoint inhibitors.

“We keep having referrals coming in from our oncologists as more patients are treated with these drugs,” said Clifton Bingham, MD, of the Johns Hopkins University School of Medicine.

“In particular, as more patients are treated with combinations of multiple immunotherapies, we expect the rate to go up.”

Dr Cappelli said she wants the case report to raise awareness among patients and clinicians that rheumatologic side effects may occur with checkpoint inhibitors.

“It is important when weighing the risk-benefit ratio of prescribing these drugs,” she said. “And it’s important for people to be on the lookout for symptoms so they can see a rheumatologist early in an effort to prevent or limit joint damage.”

Drs Cappelli and Bingham and their colleagues are planning further collaboration with Johns Hopkins oncologists to better track the incidence of rheumatic disease in patients taking immunotherapy drugs and determine whether any particular characteristics put cancer patients at higher risk of such complications.

Vials of drug

Photo by Bill Branson

Several case reports have suggested that cancer patients taking the immunotherapy drugs nivolumab and ipilimumab may have a higher-than-normal risk of developing rheumatic diseases.

Between 2012 and 2016, 13 patients at the Johns Hopkins Kimmel Cancer Center who were taking one or both drugs developed inflammatory arthritis or sicca syndrome, a set of autoimmune conditions causing dry eyes and mouth.

The cases were described in Annals of Rheumatic Diseases.

Nivolumab and ipilimumab are both designed to turn off the molecular “checkpoints” some cancers—including lymphoma—use to evade the immune system. When the drugs work, they allow the immune system to detect and attack tumor cells. However, they also turn up the activity of the immune system as a whole and can therefore trigger immune-related side effects.

Clinical trials of ipilimumab and nivolumab have indicated that the drugs confer an increased risk of inflammatory bowel diseases, lung inflammation, autoimmune thyroid disease, and pituitary gland inflammation.

However, those trials were designed primarily to determine efficacy against cancer and not to fully examine all features of rheumatologic side effects, said Laura C. Cappelli, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

With this in mind, she and her colleagues decided to take a closer look at 13 adults (older than 18) who were treated at the Johns Hopkins Kimmel Cancer Center and reported rheumatologic symptoms after their treatment with nivolumab and/or ipilimumab.

Eight patients were taking both ipilimumab and nivolumab, and 5 were taking 1 of the 2 drugs. They were receiving the drugs to treat melanoma (n=6), non-small-cell lung cancer (n=5), small-cell lung cancer (n=1), and renal cell carcinoma (n=1).

Nine of the patients developed inflammatory arthritis—4 with synovitis confirmed via imaging and 4 with inflammatory synovial fluid—and the remaining 4 patients were diagnosed with sicca syndrome. Other immune-related adverse events included pneumonitis, colitis, interstitial nephritis, and thyroiditis.

The researchers said this is the largest published case series showing a link between checkpoint inhibitors and rheumatic diseases.

The patients described in this case report make up about 1.3% of all patients treated with the drugs—singly or in combination—at The Johns Hopkins Hospital from 2012 to 2016. However, the researchers believe that rate is likely an underestimation of how common rheumatic diseases are in patients taking immune checkpoint inhibitors.

“We keep having referrals coming in from our oncologists as more patients are treated with these drugs,” said Clifton Bingham, MD, of the Johns Hopkins University School of Medicine.

“In particular, as more patients are treated with combinations of multiple immunotherapies, we expect the rate to go up.”

Dr Cappelli said she wants the case report to raise awareness among patients and clinicians that rheumatologic side effects may occur with checkpoint inhibitors.

“It is important when weighing the risk-benefit ratio of prescribing these drugs,” she said. “And it’s important for people to be on the lookout for symptoms so they can see a rheumatologist early in an effort to prevent or limit joint damage.”

Drs Cappelli and Bingham and their colleagues are planning further collaboration with Johns Hopkins oncologists to better track the incidence of rheumatic disease in patients taking immunotherapy drugs and determine whether any particular characteristics put cancer patients at higher risk of such complications.

Premenopausal risk-reducing salpingo-oophorectomy becomes cost-effective in women who have a 4% or greater lifetime risk of ovarian cancer, according to a modeling study published online in the Journal of Medical Genetics.

The procedure, which is usually undertaken in women aged over 35 years who have completed their families, is available in the United Kingdom to women with a greater than 10% lifetime risk of ovarian cancer. However, the researchers, led by Dr. Ranjit Manchanda of Barts Cancer Institute at Queen Mary University of London, suggested that this threshold has not been tested for cost-effectiveness.

The decision analysis model evaluated lifetime costs as well as the effects of risk-reducing salpingo-oophorectomy in 40-year-old premenopausal women by comparing it with no procedure in women whose lifetime ovarian cancer risk ranged from 2%-10%. The final outcomes were development of breast cancer, ovarian cancer, and excess deaths from coronary heart disease, while cost-effectiveness was judged against the National Institute for Health and Care Excellence threshold of £20,000-£30,000 per quality-adjusted life-years (QALY).

Researchers found that premenopausal risk-reducing salpingo-oophorectomy was cost-effective in women with a 4% or greater lifetime risk of ovarian cancer, largely because of the reduction in their risk of breast cancer. At this level of risk, surgery gained 42.7 days of life-expectancy, with an incremental cost-effectiveness ratio of £19,536($26,186)/QALY.

Premenopausal risk-reducing salpingo-oophorectomy was not cost-effective at the baseline risk rate of 2%, with an incremental cost-effectiveness ratio of £46,480($62,267)/QALY and 19.9 days gain in life expectancy (J Med Genetics 2016 June 27. doi: 10.1136/jmedgenet-2016-103800).

The cost-effectiveness was predicated on the assumption of at least an 80% compliance rate with hormone therapy (HT) in women who underwent the procedure; without HT, the cost-effectiveness threshold increased to a lifetime risk of over 8.2%.

“Our results are of major significance for clinical practice and risk management in view of declining genetic testing costs and the improvements in estimating an individual’s OC risk,” the authors wrote.

“With routine clinical testing for certain moderate penetrance genes around the corner and lack of an effective OC screening programme, these findings are timely as it provides evidence supporting a surgical prevention strategy for ‘lower-risk’ (lifetime risk less than 10%) individuals,” noted Dr. Manchanda and colleagues.

They stressed that symptom levels after salpingo-oophorectomy, particularly for sexual function, were still higher even in women taking HT compared to those who hadn’t undergone salpingo-oophorectomy.

“This limitation needs to be discussed as part of informed consent for the surgical procedure and incorporated into [the risk-reducing salpingo-oophorectomy] decision-making process,” they wrote.

One author declared a financial interest in Abcodia, which has an interest in ovarian cancer screening and biomarkers for screening and risk prediction. No other conflicts of interest were declared.

Premenopausal risk-reducing salpingo-oophorectomy becomes cost-effective in women who have a 4% or greater lifetime risk of ovarian cancer, according to a modeling study published online in the Journal of Medical Genetics.

The procedure, which is usually undertaken in women aged over 35 years who have completed their families, is available in the United Kingdom to women with a greater than 10% lifetime risk of ovarian cancer. However, the researchers, led by Dr. Ranjit Manchanda of Barts Cancer Institute at Queen Mary University of London, suggested that this threshold has not been tested for cost-effectiveness.

The decision analysis model evaluated lifetime costs as well as the effects of risk-reducing salpingo-oophorectomy in 40-year-old premenopausal women by comparing it with no procedure in women whose lifetime ovarian cancer risk ranged from 2%-10%. The final outcomes were development of breast cancer, ovarian cancer, and excess deaths from coronary heart disease, while cost-effectiveness was judged against the National Institute for Health and Care Excellence threshold of £20,000-£30,000 per quality-adjusted life-years (QALY).

Researchers found that premenopausal risk-reducing salpingo-oophorectomy was cost-effective in women with a 4% or greater lifetime risk of ovarian cancer, largely because of the reduction in their risk of breast cancer. At this level of risk, surgery gained 42.7 days of life-expectancy, with an incremental cost-effectiveness ratio of £19,536($26,186)/QALY.

Premenopausal risk-reducing salpingo-oophorectomy was not cost-effective at the baseline risk rate of 2%, with an incremental cost-effectiveness ratio of £46,480($62,267)/QALY and 19.9 days gain in life expectancy (J Med Genetics 2016 June 27. doi: 10.1136/jmedgenet-2016-103800).

The cost-effectiveness was predicated on the assumption of at least an 80% compliance rate with hormone therapy (HT) in women who underwent the procedure; without HT, the cost-effectiveness threshold increased to a lifetime risk of over 8.2%.

“Our results are of major significance for clinical practice and risk management in view of declining genetic testing costs and the improvements in estimating an individual’s OC risk,” the authors wrote.

“With routine clinical testing for certain moderate penetrance genes around the corner and lack of an effective OC screening programme, these findings are timely as it provides evidence supporting a surgical prevention strategy for ‘lower-risk’ (lifetime risk less than 10%) individuals,” noted Dr. Manchanda and colleagues.

They stressed that symptom levels after salpingo-oophorectomy, particularly for sexual function, were still higher even in women taking HT compared to those who hadn’t undergone salpingo-oophorectomy.

“This limitation needs to be discussed as part of informed consent for the surgical procedure and incorporated into [the risk-reducing salpingo-oophorectomy] decision-making process,” they wrote.

One author declared a financial interest in Abcodia, which has an interest in ovarian cancer screening and biomarkers for screening and risk prediction. No other conflicts of interest were declared.

Premenopausal risk-reducing salpingo-oophorectomy becomes cost-effective in women who have a 4% or greater lifetime risk of ovarian cancer, according to a modeling study published online in the Journal of Medical Genetics.

The procedure, which is usually undertaken in women aged over 35 years who have completed their families, is available in the United Kingdom to women with a greater than 10% lifetime risk of ovarian cancer. However, the researchers, led by Dr. Ranjit Manchanda of Barts Cancer Institute at Queen Mary University of London, suggested that this threshold has not been tested for cost-effectiveness.

The decision analysis model evaluated lifetime costs as well as the effects of risk-reducing salpingo-oophorectomy in 40-year-old premenopausal women by comparing it with no procedure in women whose lifetime ovarian cancer risk ranged from 2%-10%. The final outcomes were development of breast cancer, ovarian cancer, and excess deaths from coronary heart disease, while cost-effectiveness was judged against the National Institute for Health and Care Excellence threshold of £20,000-£30,000 per quality-adjusted life-years (QALY).

Researchers found that premenopausal risk-reducing salpingo-oophorectomy was cost-effective in women with a 4% or greater lifetime risk of ovarian cancer, largely because of the reduction in their risk of breast cancer. At this level of risk, surgery gained 42.7 days of life-expectancy, with an incremental cost-effectiveness ratio of £19,536($26,186)/QALY.

Premenopausal risk-reducing salpingo-oophorectomy was not cost-effective at the baseline risk rate of 2%, with an incremental cost-effectiveness ratio of £46,480($62,267)/QALY and 19.9 days gain in life expectancy (J Med Genetics 2016 June 27. doi: 10.1136/jmedgenet-2016-103800).

The cost-effectiveness was predicated on the assumption of at least an 80% compliance rate with hormone therapy (HT) in women who underwent the procedure; without HT, the cost-effectiveness threshold increased to a lifetime risk of over 8.2%.

“Our results are of major significance for clinical practice and risk management in view of declining genetic testing costs and the improvements in estimating an individual’s OC risk,” the authors wrote.

“With routine clinical testing for certain moderate penetrance genes around the corner and lack of an effective OC screening programme, these findings are timely as it provides evidence supporting a surgical prevention strategy for ‘lower-risk’ (lifetime risk less than 10%) individuals,” noted Dr. Manchanda and colleagues.

They stressed that symptom levels after salpingo-oophorectomy, particularly for sexual function, were still higher even in women taking HT compared to those who hadn’t undergone salpingo-oophorectomy.

“This limitation needs to be discussed as part of informed consent for the surgical procedure and incorporated into [the risk-reducing salpingo-oophorectomy] decision-making process,” they wrote.

One author declared a financial interest in Abcodia, which has an interest in ovarian cancer screening and biomarkers for screening and risk prediction. No other conflicts of interest were declared.

LONDON – Tumor necrosis factor–inhibitor treatment improved refractory skin disease in juvenile dermatomyositis patients in the largest observational study of its kind from the United Kingdom and Ireland Juvenile Dermatomyositis Research Group.

Muscle disease in the juvenile dermatomyositis (JDM) patients largely had already improved with conventional therapies prior to treatment with anti–tumor necrosis factor (TNF)-alpha agents, but it did improve further with anti-TNFs.

The effect of TNF inhibitors was most notable for those with skin calcinosis, lead author Dr. Raquel Campanilho-Marques reported at the European Congress of Rheumatology on behalf of her colleagues in the Juvenile Dermatomyositis Research Group.

Some evidence suggests that TNF-alpha might be involved in the pathogenesis of idiopathic inflammatory myopathies, particularly in more prolonged courses of JDM.

But there is limited prior evidence for the efficacy of TNF inhibitors in JDM patients, where small observational studies and case series have shown improved core-set measures of disease activity in patients treated with anti-TNF agents, noted Dr. Campanilho-Marques, a pediatric rheumatologist in the infection, inflammation and rheumatology section at the University College London Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust in London.

The 67 patients in the study involved those who were enrolled in the JDM Cohort and Biomarker Study, met Bohan and Peter criteria for JDM, and were on anti-TNF therapy at the time of analysis because of nonresponse to conventional therapy, active skin disease, calcinosis, or muscle weakness. They had at least 3 months of anti-TNF therapy and received either infliximab 6 mg/kg every 4 weeks (after a standard initial induction regimen) or adalimumab (Humira) 24 mg/m² every other week.

A majority of the patients in the study were female (n = 41) and white (n = 54), with a mean age at disease onset of about 5 years. At the time of first use of anti-TNF agents, the patients had a mean age of about 10 years and a mean disease duration of 3.2 years. Treatment with TNF inhibitors lasted for a mean of about 2.5 years.

Of the 67 patients, data were not analyzed for 4 patients; there was insufficient information for 1 patient, while 3 patients had allergic reactions to their anti-TNF therapy on the first or second infusion. The remaining 63 patients included 43 who received infliximab, 4 on adalimumab, and 16 who used both.

Prior to anti-TNF treatment, 52 of 53 patients (98%) were taking methotrexate, azathioprine, hydroxychloroquine, or a combination of those. That declined to 45 of 56 (80%) at the start of anti-TNF therapy and then increased to 44 of 49 (89%) after 12 months of using an anti-TNF agent.

The use of cyclophosphamide declined markedly, from 26 of 65 patients (40%) to 3 of 65 (5%) at the start of TNF inhibition, and then to none after 12 months of anti-TNF therapy. Immunoglobulin therapy also declined, from use in 10%-12% of patients before and at the start of anti-TNF treatment to just 1 of 41 patients (2%) after 12 months of TNF inhibitor therapy.

The median modified Disease Activity Score for skin involvement significantly improved over the course of 12 months of treatment with infliximab, decreasing from 4 to 1. That was also the case for Physician Global Assessment score, as well as muscle outcome measurements on the Childhood Myositis Assessment Scale (CMAS) and the 8-item Manual Muscle Testing (MMT8).

For the 31 patients in the study who had calcinosis, lesions improved (reduced in number and/or size) in 17 patients, including 8 with complete resolution of their lesions. In the other 14 patients, lesions remained stable in 3 (fewer than three lesions) and were widespread or did not improve in 4; the other 7 patients had insufficient data to determine outcomes.

Most patients with muscle involvement already had improved with steroids prior to using anti-TNF drugs. Thus, the improvement in CMAS and MMT8 scores on anti-TNF treatment was not very large, going from about 45 to 53 and from about 74 to 79, respectively.

The investigators did not examine treatment response in relation to muscle-specific antibodies, but Dr. Campanilho-Marques said that it is something they would like to do in the future.

The main indication for anti-TNF agents was active skin disease that had not responded to conventional treatment, noted Dr. Campanilho-Marques, who is also with the departments of rheumatology at the Santa Maria Hospital and the Instituto Português de Reumatologia, both in Lisbon.

For 16 patients who switched from infliximab to adalimumab, the changes in outcome measures were not statistically significant. The switches occurred at a median of 2.35 months after starting infliximab; 10 patients switched because of inefficacy, 4 because of adverse events, and 2 because of patient preference.

After 12 months of anti-TNF therapy, the median prednisolone dose declined from 6 mg to 2.5 mg, but the decline appeared to be driven by five patients who sharply decreased their dose. Seven patients successfully stopped anti-TNF therapy after improvement occurred, Dr. Campanilho-Marques said.

Serious adverse events occurred 12 times during the year-long study period, including nine allergic reactions and three hospitalizations because of infection. Another 19 mild-to-moderate adverse events took place, which involved 15 infections and three local site reactions and skin rash, which led five patients to discontinue the biologic.

Overall, adverse events occurred at a rate of 13.3/100 patient-years, including 5.2 serious events/100 patient-years. One patient died because of a small bowel perforation that was probably secondary to disease-related damage. There were no malignancies or tuberculosis cases.

In a video interview at the meeting, Dr. Campanilho-Marques discussed the study findings and their implications.

The researchers had no relevant disclosures.

[email protected]

LONDON – Tumor necrosis factor–inhibitor treatment improved refractory skin disease in juvenile dermatomyositis patients in the largest observational study of its kind from the United Kingdom and Ireland Juvenile Dermatomyositis Research Group.

Muscle disease in the juvenile dermatomyositis (JDM) patients largely had already improved with conventional therapies prior to treatment with anti–tumor necrosis factor (TNF)-alpha agents, but it did improve further with anti-TNFs.

The effect of TNF inhibitors was most notable for those with skin calcinosis, lead author Dr. Raquel Campanilho-Marques reported at the European Congress of Rheumatology on behalf of her colleagues in the Juvenile Dermatomyositis Research Group.

Some evidence suggests that TNF-alpha might be involved in the pathogenesis of idiopathic inflammatory myopathies, particularly in more prolonged courses of JDM.

But there is limited prior evidence for the efficacy of TNF inhibitors in JDM patients, where small observational studies and case series have shown improved core-set measures of disease activity in patients treated with anti-TNF agents, noted Dr. Campanilho-Marques, a pediatric rheumatologist in the infection, inflammation and rheumatology section at the University College London Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust in London.

The 67 patients in the study involved those who were enrolled in the JDM Cohort and Biomarker Study, met Bohan and Peter criteria for JDM, and were on anti-TNF therapy at the time of analysis because of nonresponse to conventional therapy, active skin disease, calcinosis, or muscle weakness. They had at least 3 months of anti-TNF therapy and received either infliximab 6 mg/kg every 4 weeks (after a standard initial induction regimen) or adalimumab (Humira) 24 mg/m² every other week.

A majority of the patients in the study were female (n = 41) and white (n = 54), with a mean age at disease onset of about 5 years. At the time of first use of anti-TNF agents, the patients had a mean age of about 10 years and a mean disease duration of 3.2 years. Treatment with TNF inhibitors lasted for a mean of about 2.5 years.

Of the 67 patients, data were not analyzed for 4 patients; there was insufficient information for 1 patient, while 3 patients had allergic reactions to their anti-TNF therapy on the first or second infusion. The remaining 63 patients included 43 who received infliximab, 4 on adalimumab, and 16 who used both.

Prior to anti-TNF treatment, 52 of 53 patients (98%) were taking methotrexate, azathioprine, hydroxychloroquine, or a combination of those. That declined to 45 of 56 (80%) at the start of anti-TNF therapy and then increased to 44 of 49 (89%) after 12 months of using an anti-TNF agent.

The use of cyclophosphamide declined markedly, from 26 of 65 patients (40%) to 3 of 65 (5%) at the start of TNF inhibition, and then to none after 12 months of anti-TNF therapy. Immunoglobulin therapy also declined, from use in 10%-12% of patients before and at the start of anti-TNF treatment to just 1 of 41 patients (2%) after 12 months of TNF inhibitor therapy.

The median modified Disease Activity Score for skin involvement significantly improved over the course of 12 months of treatment with infliximab, decreasing from 4 to 1. That was also the case for Physician Global Assessment score, as well as muscle outcome measurements on the Childhood Myositis Assessment Scale (CMAS) and the 8-item Manual Muscle Testing (MMT8).

For the 31 patients in the study who had calcinosis, lesions improved (reduced in number and/or size) in 17 patients, including 8 with complete resolution of their lesions. In the other 14 patients, lesions remained stable in 3 (fewer than three lesions) and were widespread or did not improve in 4; the other 7 patients had insufficient data to determine outcomes.

Most patients with muscle involvement already had improved with steroids prior to using anti-TNF drugs. Thus, the improvement in CMAS and MMT8 scores on anti-TNF treatment was not very large, going from about 45 to 53 and from about 74 to 79, respectively.

The investigators did not examine treatment response in relation to muscle-specific antibodies, but Dr. Campanilho-Marques said that it is something they would like to do in the future.

The main indication for anti-TNF agents was active skin disease that had not responded to conventional treatment, noted Dr. Campanilho-Marques, who is also with the departments of rheumatology at the Santa Maria Hospital and the Instituto Português de Reumatologia, both in Lisbon.

For 16 patients who switched from infliximab to adalimumab, the changes in outcome measures were not statistically significant. The switches occurred at a median of 2.35 months after starting infliximab; 10 patients switched because of inefficacy, 4 because of adverse events, and 2 because of patient preference.

After 12 months of anti-TNF therapy, the median prednisolone dose declined from 6 mg to 2.5 mg, but the decline appeared to be driven by five patients who sharply decreased their dose. Seven patients successfully stopped anti-TNF therapy after improvement occurred, Dr. Campanilho-Marques said.

Serious adverse events occurred 12 times during the year-long study period, including nine allergic reactions and three hospitalizations because of infection. Another 19 mild-to-moderate adverse events took place, which involved 15 infections and three local site reactions and skin rash, which led five patients to discontinue the biologic.

Overall, adverse events occurred at a rate of 13.3/100 patient-years, including 5.2 serious events/100 patient-years. One patient died because of a small bowel perforation that was probably secondary to disease-related damage. There were no malignancies or tuberculosis cases.

In a video interview at the meeting, Dr. Campanilho-Marques discussed the study findings and their implications.

The researchers had no relevant disclosures.

[email protected]

LONDON – Tumor necrosis factor–inhibitor treatment improved refractory skin disease in juvenile dermatomyositis patients in the largest observational study of its kind from the United Kingdom and Ireland Juvenile Dermatomyositis Research Group.

Muscle disease in the juvenile dermatomyositis (JDM) patients largely had already improved with conventional therapies prior to treatment with anti–tumor necrosis factor (TNF)-alpha agents, but it did improve further with anti-TNFs.

The effect of TNF inhibitors was most notable for those with skin calcinosis, lead author Dr. Raquel Campanilho-Marques reported at the European Congress of Rheumatology on behalf of her colleagues in the Juvenile Dermatomyositis Research Group.

Some evidence suggests that TNF-alpha might be involved in the pathogenesis of idiopathic inflammatory myopathies, particularly in more prolonged courses of JDM.

But there is limited prior evidence for the efficacy of TNF inhibitors in JDM patients, where small observational studies and case series have shown improved core-set measures of disease activity in patients treated with anti-TNF agents, noted Dr. Campanilho-Marques, a pediatric rheumatologist in the infection, inflammation and rheumatology section at the University College London Institute of Child Health and the Great Ormond Street Hospital for Children NHS Trust in London.

The 67 patients in the study involved those who were enrolled in the JDM Cohort and Biomarker Study, met Bohan and Peter criteria for JDM, and were on anti-TNF therapy at the time of analysis because of nonresponse to conventional therapy, active skin disease, calcinosis, or muscle weakness. They had at least 3 months of anti-TNF therapy and received either infliximab 6 mg/kg every 4 weeks (after a standard initial induction regimen) or adalimumab (Humira) 24 mg/m² every other week.

A majority of the patients in the study were female (n = 41) and white (n = 54), with a mean age at disease onset of about 5 years. At the time of first use of anti-TNF agents, the patients had a mean age of about 10 years and a mean disease duration of 3.2 years. Treatment with TNF inhibitors lasted for a mean of about 2.5 years.

Of the 67 patients, data were not analyzed for 4 patients; there was insufficient information for 1 patient, while 3 patients had allergic reactions to their anti-TNF therapy on the first or second infusion. The remaining 63 patients included 43 who received infliximab, 4 on adalimumab, and 16 who used both.

Prior to anti-TNF treatment, 52 of 53 patients (98%) were taking methotrexate, azathioprine, hydroxychloroquine, or a combination of those. That declined to 45 of 56 (80%) at the start of anti-TNF therapy and then increased to 44 of 49 (89%) after 12 months of using an anti-TNF agent.

The use of cyclophosphamide declined markedly, from 26 of 65 patients (40%) to 3 of 65 (5%) at the start of TNF inhibition, and then to none after 12 months of anti-TNF therapy. Immunoglobulin therapy also declined, from use in 10%-12% of patients before and at the start of anti-TNF treatment to just 1 of 41 patients (2%) after 12 months of TNF inhibitor therapy.

The median modified Disease Activity Score for skin involvement significantly improved over the course of 12 months of treatment with infliximab, decreasing from 4 to 1. That was also the case for Physician Global Assessment score, as well as muscle outcome measurements on the Childhood Myositis Assessment Scale (CMAS) and the 8-item Manual Muscle Testing (MMT8).

For the 31 patients in the study who had calcinosis, lesions improved (reduced in number and/or size) in 17 patients, including 8 with complete resolution of their lesions. In the other 14 patients, lesions remained stable in 3 (fewer than three lesions) and were widespread or did not improve in 4; the other 7 patients had insufficient data to determine outcomes.

Most patients with muscle involvement already had improved with steroids prior to using anti-TNF drugs. Thus, the improvement in CMAS and MMT8 scores on anti-TNF treatment was not very large, going from about 45 to 53 and from about 74 to 79, respectively.

The investigators did not examine treatment response in relation to muscle-specific antibodies, but Dr. Campanilho-Marques said that it is something they would like to do in the future.

The main indication for anti-TNF agents was active skin disease that had not responded to conventional treatment, noted Dr. Campanilho-Marques, who is also with the departments of rheumatology at the Santa Maria Hospital and the Instituto Português de Reumatologia, both in Lisbon.

For 16 patients who switched from infliximab to adalimumab, the changes in outcome measures were not statistically significant. The switches occurred at a median of 2.35 months after starting infliximab; 10 patients switched because of inefficacy, 4 because of adverse events, and 2 because of patient preference.

After 12 months of anti-TNF therapy, the median prednisolone dose declined from 6 mg to 2.5 mg, but the decline appeared to be driven by five patients who sharply decreased their dose. Seven patients successfully stopped anti-TNF therapy after improvement occurred, Dr. Campanilho-Marques said.

Serious adverse events occurred 12 times during the year-long study period, including nine allergic reactions and three hospitalizations because of infection. Another 19 mild-to-moderate adverse events took place, which involved 15 infections and three local site reactions and skin rash, which led five patients to discontinue the biologic.

Overall, adverse events occurred at a rate of 13.3/100 patient-years, including 5.2 serious events/100 patient-years. One patient died because of a small bowel perforation that was probably secondary to disease-related damage. There were no malignancies or tuberculosis cases.

In a video interview at the meeting, Dr. Campanilho-Marques discussed the study findings and their implications.

The researchers had no relevant disclosures.

[email protected]

DENVER – The surgically implanted Inspire system for controlled upper airway stimulation as therapy for moderate to severe obstructive sleep apnea demonstrated sustained benefit at 42 months of prospective follow-up in the STAR trial, Dr. Patrick J. Strollo Jr. reported at the annual meeting of the Associated Professional Sleep Societies.

STAR was the pivotal trial whose previously reported 12-month outcomes led to Food and Drug Administration clearance of the device. Dr. Strollo was first author of that paper (N Engl J Med. 2014 Jan 9;370:139-49). At SLEEP 2016, he presented patient- and partner-reported outcomes at 42 months. Bottom line: The device had continued safety and no loss in efficacy.

“So far it seems to be a useful option for people who frequently didn’t have an option. And the technology is improving and will only get better,” said Dr. Strollo, professor of medicine and clinical and translational science, director of the Sleep Medicine Center, and codirector of the Sleep Medicine Institute at the University of Pittsburgh.

The Inspire system consists of three parts implanted by an otolaryngologist in an outpatient procedure: a small impulse generator, a breathing sensor lead inserted in the intercostal muscle, and a stimulator lead attached to the distal branch of the 10th cranial nerve, the hypoglossal nerve controlling the tongue muscles.

The device is programmed to discharge at the end of expiration and continue through the inspiratory phase, causing the tongue to move forward and the retrolingual and retropalatal airways to open, he explained in an interview.

Upper airway stimulation is approved for commercial use in patients such as those enrolled in the STAR trial on the basis of pilot studies that identified most likely responders. The key selection criteria include moderate to severe obstructive sleep apnea as defined by an apnea-hypopnea index of 20-50, nonadherence to continuous positive airway pressure (CPAP), a body mass index of 32 kg/m² or less, and absence of concentric collapse of the airway at the level of the palate during sedated endoscopy.

STAR included 126 participants who received the upper airway stimulation device. There have been two explants: one from septic arthritis, the other elective.

A total of 97 STAR participants had 42-month follow-up data available. Among the key findings were that:

• Mean scores on the Epworth Sleepiness Scale decreased from 11.6 at baseline to 7 at 12 months and 7.1 at 42 months.

• Scores on the Functional Outcomes of Sleep Questionnaire improved from 14.3 at baseline to 17.3 at 12 months and 17.5 at 42 months.

• The scores on both the Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire were abnormal at baseline and converted to normal range at both 12 and 42 months of follow-up.

• At baseline, 29% of the patients’ sleeping partners characterized the snoring as loud, 24% rated it ‘very intense,’ and 30% left the bedroom. At 32 months, 11% of partners called the snoring loud, 3% deemed it very intense, and only 4% left the room.

• At 42 months, 81% of patients reported using the device nightly. That’s consistent with the objective evidence of adherence Dr. Strollo and his coinvestigators obtained in a study of postmarketing device implants in which they found device usage averaged about 7 hours per night.

“That’s much better than we see with CPAP in patients who can tolerate that therapy,” Dr. Strollo observed.

The planned 5-year follow-up of STAR participants includes a full laboratory polysomnography study to obtain objective apnea-hypopnea index figures.

The other major development is the launch of a comprehensive registry of patients who receive a post-marketing commercial implant. Roughly 1,000 implants have been done worldwide to date, but now that the device is approved, that number will quickly grow. The registry should prove a rich source for research.

“The goal is to try to refine the selection criteria,” according to Dr. Strollo.

Given that only about 50% of patients with moderate to severe sleep apnea are able to tolerate CPAP long term, where does the Inspire system fit into today’s practice of sleep medicine?

“Upper airway stimulation is another tool, another option for patients,” he said. “In my practice, normally I’d let patients try positive pressure first. I want to make sure they’ve tried CPAP, and they’ve tried more advanced therapy like autotitrating bilevel positive airway pressure, which is more comfortable than CPAP. Bilevel positive airway pressure allows you to salvage a fair number of patients who can’t tolerate CPAP. And I also offer an oral appliance, although the robustness of an oral appliance is not great as apnea becomes more severe.”

The STAR trial is supported by Inspire Medical Systems. Dr. Strollo reported receiving a research grant from the company.

[email protected]

DENVER – The surgically implanted Inspire system for controlled upper airway stimulation as therapy for moderate to severe obstructive sleep apnea demonstrated sustained benefit at 42 months of prospective follow-up in the STAR trial, Dr. Patrick J. Strollo Jr. reported at the annual meeting of the Associated Professional Sleep Societies.

STAR was the pivotal trial whose previously reported 12-month outcomes led to Food and Drug Administration clearance of the device. Dr. Strollo was first author of that paper (N Engl J Med. 2014 Jan 9;370:139-49). At SLEEP 2016, he presented patient- and partner-reported outcomes at 42 months. Bottom line: The device had continued safety and no loss in efficacy.

“So far it seems to be a useful option for people who frequently didn’t have an option. And the technology is improving and will only get better,” said Dr. Strollo, professor of medicine and clinical and translational science, director of the Sleep Medicine Center, and codirector of the Sleep Medicine Institute at the University of Pittsburgh.

The Inspire system consists of three parts implanted by an otolaryngologist in an outpatient procedure: a small impulse generator, a breathing sensor lead inserted in the intercostal muscle, and a stimulator lead attached to the distal branch of the 10th cranial nerve, the hypoglossal nerve controlling the tongue muscles.

The device is programmed to discharge at the end of expiration and continue through the inspiratory phase, causing the tongue to move forward and the retrolingual and retropalatal airways to open, he explained in an interview.

Upper airway stimulation is approved for commercial use in patients such as those enrolled in the STAR trial on the basis of pilot studies that identified most likely responders. The key selection criteria include moderate to severe obstructive sleep apnea as defined by an apnea-hypopnea index of 20-50, nonadherence to continuous positive airway pressure (CPAP), a body mass index of 32 kg/m² or less, and absence of concentric collapse of the airway at the level of the palate during sedated endoscopy.

STAR included 126 participants who received the upper airway stimulation device. There have been two explants: one from septic arthritis, the other elective.

A total of 97 STAR participants had 42-month follow-up data available. Among the key findings were that:

• Mean scores on the Epworth Sleepiness Scale decreased from 11.6 at baseline to 7 at 12 months and 7.1 at 42 months.

• Scores on the Functional Outcomes of Sleep Questionnaire improved from 14.3 at baseline to 17.3 at 12 months and 17.5 at 42 months.

• The scores on both the Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire were abnormal at baseline and converted to normal range at both 12 and 42 months of follow-up.

• At baseline, 29% of the patients’ sleeping partners characterized the snoring as loud, 24% rated it ‘very intense,’ and 30% left the bedroom. At 32 months, 11% of partners called the snoring loud, 3% deemed it very intense, and only 4% left the room.

• At 42 months, 81% of patients reported using the device nightly. That’s consistent with the objective evidence of adherence Dr. Strollo and his coinvestigators obtained in a study of postmarketing device implants in which they found device usage averaged about 7 hours per night.

“That’s much better than we see with CPAP in patients who can tolerate that therapy,” Dr. Strollo observed.

The planned 5-year follow-up of STAR participants includes a full laboratory polysomnography study to obtain objective apnea-hypopnea index figures.

The other major development is the launch of a comprehensive registry of patients who receive a post-marketing commercial implant. Roughly 1,000 implants have been done worldwide to date, but now that the device is approved, that number will quickly grow. The registry should prove a rich source for research.

“The goal is to try to refine the selection criteria,” according to Dr. Strollo.

Given that only about 50% of patients with moderate to severe sleep apnea are able to tolerate CPAP long term, where does the Inspire system fit into today’s practice of sleep medicine?

“Upper airway stimulation is another tool, another option for patients,” he said. “In my practice, normally I’d let patients try positive pressure first. I want to make sure they’ve tried CPAP, and they’ve tried more advanced therapy like autotitrating bilevel positive airway pressure, which is more comfortable than CPAP. Bilevel positive airway pressure allows you to salvage a fair number of patients who can’t tolerate CPAP. And I also offer an oral appliance, although the robustness of an oral appliance is not great as apnea becomes more severe.”

The STAR trial is supported by Inspire Medical Systems. Dr. Strollo reported receiving a research grant from the company.

[email protected]

DENVER – The surgically implanted Inspire system for controlled upper airway stimulation as therapy for moderate to severe obstructive sleep apnea demonstrated sustained benefit at 42 months of prospective follow-up in the STAR trial, Dr. Patrick J. Strollo Jr. reported at the annual meeting of the Associated Professional Sleep Societies.

STAR was the pivotal trial whose previously reported 12-month outcomes led to Food and Drug Administration clearance of the device. Dr. Strollo was first author of that paper (N Engl J Med. 2014 Jan 9;370:139-49). At SLEEP 2016, he presented patient- and partner-reported outcomes at 42 months. Bottom line: The device had continued safety and no loss in efficacy.

“So far it seems to be a useful option for people who frequently didn’t have an option. And the technology is improving and will only get better,” said Dr. Strollo, professor of medicine and clinical and translational science, director of the Sleep Medicine Center, and codirector of the Sleep Medicine Institute at the University of Pittsburgh.

The Inspire system consists of three parts implanted by an otolaryngologist in an outpatient procedure: a small impulse generator, a breathing sensor lead inserted in the intercostal muscle, and a stimulator lead attached to the distal branch of the 10th cranial nerve, the hypoglossal nerve controlling the tongue muscles.

The device is programmed to discharge at the end of expiration and continue through the inspiratory phase, causing the tongue to move forward and the retrolingual and retropalatal airways to open, he explained in an interview.

Upper airway stimulation is approved for commercial use in patients such as those enrolled in the STAR trial on the basis of pilot studies that identified most likely responders. The key selection criteria include moderate to severe obstructive sleep apnea as defined by an apnea-hypopnea index of 20-50, nonadherence to continuous positive airway pressure (CPAP), a body mass index of 32 kg/m² or less, and absence of concentric collapse of the airway at the level of the palate during sedated endoscopy.

STAR included 126 participants who received the upper airway stimulation device. There have been two explants: one from septic arthritis, the other elective.

A total of 97 STAR participants had 42-month follow-up data available. Among the key findings were that:

• Mean scores on the Epworth Sleepiness Scale decreased from 11.6 at baseline to 7 at 12 months and 7.1 at 42 months.

• Scores on the Functional Outcomes of Sleep Questionnaire improved from 14.3 at baseline to 17.3 at 12 months and 17.5 at 42 months.

• The scores on both the Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire were abnormal at baseline and converted to normal range at both 12 and 42 months of follow-up.

• At baseline, 29% of the patients’ sleeping partners characterized the snoring as loud, 24% rated it ‘very intense,’ and 30% left the bedroom. At 32 months, 11% of partners called the snoring loud, 3% deemed it very intense, and only 4% left the room.

• At 42 months, 81% of patients reported using the device nightly. That’s consistent with the objective evidence of adherence Dr. Strollo and his coinvestigators obtained in a study of postmarketing device implants in which they found device usage averaged about 7 hours per night.

“That’s much better than we see with CPAP in patients who can tolerate that therapy,” Dr. Strollo observed.

The planned 5-year follow-up of STAR participants includes a full laboratory polysomnography study to obtain objective apnea-hypopnea index figures.

The other major development is the launch of a comprehensive registry of patients who receive a post-marketing commercial implant. Roughly 1,000 implants have been done worldwide to date, but now that the device is approved, that number will quickly grow. The registry should prove a rich source for research.

“The goal is to try to refine the selection criteria,” according to Dr. Strollo.

Given that only about 50% of patients with moderate to severe sleep apnea are able to tolerate CPAP long term, where does the Inspire system fit into today’s practice of sleep medicine?

“Upper airway stimulation is another tool, another option for patients,” he said. “In my practice, normally I’d let patients try positive pressure first. I want to make sure they’ve tried CPAP, and they’ve tried more advanced therapy like autotitrating bilevel positive airway pressure, which is more comfortable than CPAP. Bilevel positive airway pressure allows you to salvage a fair number of patients who can’t tolerate CPAP. And I also offer an oral appliance, although the robustness of an oral appliance is not great as apnea becomes more severe.”

The STAR trial is supported by Inspire Medical Systems. Dr. Strollo reported receiving a research grant from the company.

[email protected]

CHICAGO – Physical function, role function, global health status and abdominal/gastrointestinal symptoms (AGIS) each predicted overall survival and were significantly associated with the early cessation of chemotherapy among women with platinum-resistant/refractory recurrent ovarian cancer in the Gynecologic Cancer InterGroup (GCIG) Symptom Benefit Study.

The findings from the international prospective cohort study suggest that baseline assessment of quality of life could help identify patients with platinum-resistant/refractory recurrent ovarian cancer (PRR-ROC) who are unlikely to benefit from palliative chemotherapy, Dr. Felicia Roncolato reported at the annual meeting of the American Society of Clinical Oncology.

In 570 women with PRR-ROC enrolled in the Symptom Benefit Study, median overall survival was 11.1 months and median progression-free survival was 3.6 months.

Factors shown on multivariable analysis to predict overall survival included hemoglobin (hazard ratio, 0.94 per 10 g/L increase), ascites (HR, 1.60), AGIS (HR, 1.24), platelets (HR, 1.10 per 100 x 10⁹ unit increase), Log CA125 (HR, 1.18 per unit increase), and neutrophil:lymphocyte ratio (HR, 1.79 for 5 or more). These were all statistically significant predictors of overall survival, said Dr. Roncolato of St. George Hospital, Sydney.

As for baseline quality of life data as a predictor of overall survival, the hazard ratios were 1.60 for low physical function, 1.54 for low role function, 1.55 for global health status, 2.37 for worst vs. least AGIS, and 1.75 for intermediate vs. least AGIS. After adjusting for all of these clinical factors, the multivariable analysis showed that low physical function, role function, and global health status, and worst AGIS remained statistically significant predictors of overall survival (HR, 1,45, 1.37, 1.34, 1.49, and 1.49, respectively). Median overall survival was 7 vs. 12 months in those with lower vs. higher physical function, role function, and global health status, 9 months vs. 14 months for those with lower vs. higher role function scores, and 8, 11, and 18 months in those with worst, intermediate, and least AGIS.

A sensitivity analysis supported the validity of the cut-points used for each of these scores, Dr. Roncolato noted.

As for early cessation of chemotherapy, 110 of the 570 women (19%) stopped chemotherapy within 8 weeks. Most (46%) stopped due to disease progression; other reasons for early cessation included death (18%), patient preference (12%), “other” (12%), adverse event (7%), and clinician preference (6%).

In these women, median progression-free survival and median overall survival were 1.3 months and 2.9 months, respectively, Dr. Roncolato said.

On univariable analysis, the same four quality of life domains (physical function, role function, global health status, and AGIS) each were significantly associated with overall survival (odds ratios were 2.45 for low physical function, 2.71 for low role function, 2.38 for global health status, 2.31 for worst vs. least AGIS, and 1.17 for intermediate vs. least AGIS).

Most patients with ovarian cancer have advanced stage disease at diagnosis and develop recurrent disease despite initial response, and most ultimately develop platinum resistant/refractory disease, Dr. Roncolato said.

The goals of treatment are to improve length and quality of life, but response rates are low; median progression-free survival is 3 months, and median overall survival is less than 12 months, she noted.

“To date there is no evidence that chemotherapy actually increases overall survival in the resistant/refractory setting, and one of our biggest challenges is identifying the patients who are most and least likely to benefit,” she said, adding that over the last decade, little has changed in terms of chemotherapy outcomes remaining poor in patients with PRR-ROC (median overall survival of about 45% at 12 months).

A substantial number of patients stop treatment early.

The Symptom Benefit Study was designed based on a recommendation of the 3rd GCIG Ovarian Cancer Consensus meeting, which called for more robust and reliable methods to quantify symptom improvement in patients with platinum-resistant/refractory ovarian cancer. The primary aim of the study was to develop criteria for quantifying symptom benefit for clinical trials in such patients. The initial portion of the study was known as MOST (Measure of Ovarian Cancer Symptoms and Treatment Concerns). The aim of the current portion of the study was to identify baseline characteristics associated with early cessation of chemotherapy and with poor overall survival.

Patients included in the study were women with PRR-ROC and patients receiving a third or subsequent line of treatment. All had a life expectancy of more than 3 months, and had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3.

Quality of life measures, including EORTC QLQ-C30, QLQ-OV28, and others were performed at baseline and before each cycle of chemotherapy.

“The health-related quality of life scores identified a subset of women with resistant/refractory disease who have a very poor prognosis. It’s more informative than a clinician-assigned ECOG performance status, and including baseline health-related quality of life together with clinical prognostic factors improved the prediction of survival in women with PRR-ROC,” Dr. Roncolato said, adding that having this additional prognostic information could improve stratification in clinical trials, patient-doctor communication about prognosis, and clinical decision-making.

This study was funded by the Australian National Health and Medical Research Council. Dr. Roncolato reported having no disclosures.

[email protected]

CHICAGO – Physical function, role function, global health status and abdominal/gastrointestinal symptoms (AGIS) each predicted overall survival and were significantly associated with the early cessation of chemotherapy among women with platinum-resistant/refractory recurrent ovarian cancer in the Gynecologic Cancer InterGroup (GCIG) Symptom Benefit Study.

The findings from the international prospective cohort study suggest that baseline assessment of quality of life could help identify patients with platinum-resistant/refractory recurrent ovarian cancer (PRR-ROC) who are unlikely to benefit from palliative chemotherapy, Dr. Felicia Roncolato reported at the annual meeting of the American Society of Clinical Oncology.

In 570 women with PRR-ROC enrolled in the Symptom Benefit Study, median overall survival was 11.1 months and median progression-free survival was 3.6 months.

Factors shown on multivariable analysis to predict overall survival included hemoglobin (hazard ratio, 0.94 per 10 g/L increase), ascites (HR, 1.60), AGIS (HR, 1.24), platelets (HR, 1.10 per 100 x 10⁹ unit increase), Log CA125 (HR, 1.18 per unit increase), and neutrophil:lymphocyte ratio (HR, 1.79 for 5 or more). These were all statistically significant predictors of overall survival, said Dr. Roncolato of St. George Hospital, Sydney.

As for baseline quality of life data as a predictor of overall survival, the hazard ratios were 1.60 for low physical function, 1.54 for low role function, 1.55 for global health status, 2.37 for worst vs. least AGIS, and 1.75 for intermediate vs. least AGIS. After adjusting for all of these clinical factors, the multivariable analysis showed that low physical function, role function, and global health status, and worst AGIS remained statistically significant predictors of overall survival (HR, 1,45, 1.37, 1.34, 1.49, and 1.49, respectively). Median overall survival was 7 vs. 12 months in those with lower vs. higher physical function, role function, and global health status, 9 months vs. 14 months for those with lower vs. higher role function scores, and 8, 11, and 18 months in those with worst, intermediate, and least AGIS.

A sensitivity analysis supported the validity of the cut-points used for each of these scores, Dr. Roncolato noted.

As for early cessation of chemotherapy, 110 of the 570 women (19%) stopped chemotherapy within 8 weeks. Most (46%) stopped due to disease progression; other reasons for early cessation included death (18%), patient preference (12%), “other” (12%), adverse event (7%), and clinician preference (6%).

In these women, median progression-free survival and median overall survival were 1.3 months and 2.9 months, respectively, Dr. Roncolato said.

On univariable analysis, the same four quality of life domains (physical function, role function, global health status, and AGIS) each were significantly associated with overall survival (odds ratios were 2.45 for low physical function, 2.71 for low role function, 2.38 for global health status, 2.31 for worst vs. least AGIS, and 1.17 for intermediate vs. least AGIS).

Most patients with ovarian cancer have advanced stage disease at diagnosis and develop recurrent disease despite initial response, and most ultimately develop platinum resistant/refractory disease, Dr. Roncolato said.

The goals of treatment are to improve length and quality of life, but response rates are low; median progression-free survival is 3 months, and median overall survival is less than 12 months, she noted.

“To date there is no evidence that chemotherapy actually increases overall survival in the resistant/refractory setting, and one of our biggest challenges is identifying the patients who are most and least likely to benefit,” she said, adding that over the last decade, little has changed in terms of chemotherapy outcomes remaining poor in patients with PRR-ROC (median overall survival of about 45% at 12 months).

A substantial number of patients stop treatment early.

The Symptom Benefit Study was designed based on a recommendation of the 3rd GCIG Ovarian Cancer Consensus meeting, which called for more robust and reliable methods to quantify symptom improvement in patients with platinum-resistant/refractory ovarian cancer. The primary aim of the study was to develop criteria for quantifying symptom benefit for clinical trials in such patients. The initial portion of the study was known as MOST (Measure of Ovarian Cancer Symptoms and Treatment Concerns). The aim of the current portion of the study was to identify baseline characteristics associated with early cessation of chemotherapy and with poor overall survival.

Patients included in the study were women with PRR-ROC and patients receiving a third or subsequent line of treatment. All had a life expectancy of more than 3 months, and had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3.

Quality of life measures, including EORTC QLQ-C30, QLQ-OV28, and others were performed at baseline and before each cycle of chemotherapy.

“The health-related quality of life scores identified a subset of women with resistant/refractory disease who have a very poor prognosis. It’s more informative than a clinician-assigned ECOG performance status, and including baseline health-related quality of life together with clinical prognostic factors improved the prediction of survival in women with PRR-ROC,” Dr. Roncolato said, adding that having this additional prognostic information could improve stratification in clinical trials, patient-doctor communication about prognosis, and clinical decision-making.

This study was funded by the Australian National Health and Medical Research Council. Dr. Roncolato reported having no disclosures.

[email protected]

CHICAGO – Physical function, role function, global health status and abdominal/gastrointestinal symptoms (AGIS) each predicted overall survival and were significantly associated with the early cessation of chemotherapy among women with platinum-resistant/refractory recurrent ovarian cancer in the Gynecologic Cancer InterGroup (GCIG) Symptom Benefit Study.

The findings from the international prospective cohort study suggest that baseline assessment of quality of life could help identify patients with platinum-resistant/refractory recurrent ovarian cancer (PRR-ROC) who are unlikely to benefit from palliative chemotherapy, Dr. Felicia Roncolato reported at the annual meeting of the American Society of Clinical Oncology.

In 570 women with PRR-ROC enrolled in the Symptom Benefit Study, median overall survival was 11.1 months and median progression-free survival was 3.6 months.

Factors shown on multivariable analysis to predict overall survival included hemoglobin (hazard ratio, 0.94 per 10 g/L increase), ascites (HR, 1.60), AGIS (HR, 1.24), platelets (HR, 1.10 per 100 x 10⁹ unit increase), Log CA125 (HR, 1.18 per unit increase), and neutrophil:lymphocyte ratio (HR, 1.79 for 5 or more). These were all statistically significant predictors of overall survival, said Dr. Roncolato of St. George Hospital, Sydney.

As for baseline quality of life data as a predictor of overall survival, the hazard ratios were 1.60 for low physical function, 1.54 for low role function, 1.55 for global health status, 2.37 for worst vs. least AGIS, and 1.75 for intermediate vs. least AGIS. After adjusting for all of these clinical factors, the multivariable analysis showed that low physical function, role function, and global health status, and worst AGIS remained statistically significant predictors of overall survival (HR, 1,45, 1.37, 1.34, 1.49, and 1.49, respectively). Median overall survival was 7 vs. 12 months in those with lower vs. higher physical function, role function, and global health status, 9 months vs. 14 months for those with lower vs. higher role function scores, and 8, 11, and 18 months in those with worst, intermediate, and least AGIS.

A sensitivity analysis supported the validity of the cut-points used for each of these scores, Dr. Roncolato noted.

As for early cessation of chemotherapy, 110 of the 570 women (19%) stopped chemotherapy within 8 weeks. Most (46%) stopped due to disease progression; other reasons for early cessation included death (18%), patient preference (12%), “other” (12%), adverse event (7%), and clinician preference (6%).

In these women, median progression-free survival and median overall survival were 1.3 months and 2.9 months, respectively, Dr. Roncolato said.

On univariable analysis, the same four quality of life domains (physical function, role function, global health status, and AGIS) each were significantly associated with overall survival (odds ratios were 2.45 for low physical function, 2.71 for low role function, 2.38 for global health status, 2.31 for worst vs. least AGIS, and 1.17 for intermediate vs. least AGIS).

Most patients with ovarian cancer have advanced stage disease at diagnosis and develop recurrent disease despite initial response, and most ultimately develop platinum resistant/refractory disease, Dr. Roncolato said.

The goals of treatment are to improve length and quality of life, but response rates are low; median progression-free survival is 3 months, and median overall survival is less than 12 months, she noted.

“To date there is no evidence that chemotherapy actually increases overall survival in the resistant/refractory setting, and one of our biggest challenges is identifying the patients who are most and least likely to benefit,” she said, adding that over the last decade, little has changed in terms of chemotherapy outcomes remaining poor in patients with PRR-ROC (median overall survival of about 45% at 12 months).

A substantial number of patients stop treatment early.

The Symptom Benefit Study was designed based on a recommendation of the 3rd GCIG Ovarian Cancer Consensus meeting, which called for more robust and reliable methods to quantify symptom improvement in patients with platinum-resistant/refractory ovarian cancer. The primary aim of the study was to develop criteria for quantifying symptom benefit for clinical trials in such patients. The initial portion of the study was known as MOST (Measure of Ovarian Cancer Symptoms and Treatment Concerns). The aim of the current portion of the study was to identify baseline characteristics associated with early cessation of chemotherapy and with poor overall survival.

Patients included in the study were women with PRR-ROC and patients receiving a third or subsequent line of treatment. All had a life expectancy of more than 3 months, and had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3.

Quality of life measures, including EORTC QLQ-C30, QLQ-OV28, and others were performed at baseline and before each cycle of chemotherapy.

“The health-related quality of life scores identified a subset of women with resistant/refractory disease who have a very poor prognosis. It’s more informative than a clinician-assigned ECOG performance status, and including baseline health-related quality of life together with clinical prognostic factors improved the prediction of survival in women with PRR-ROC,” Dr. Roncolato said, adding that having this additional prognostic information could improve stratification in clinical trials, patient-doctor communication about prognosis, and clinical decision-making.

This study was funded by the Australian National Health and Medical Research Council. Dr. Roncolato reported having no disclosures.

[email protected]

Cognitive-behavioral therapy, lisdexamfetamine, and second-generation antidepressants are the most effective treatments for adult binge-eating disorder, a systematic review by Kimberly A. Brownley, PhD, and her associates found.

A total of 34 trials were included in the review. Patients who received therapist-led cognitive-behavioral therapy (CBT) achieved binge eating abstinence at a rate of 58.8%, compared with 11.2% of those on a wait list. Just over 40% of patients achieved abstinence on lisdexamfetamine, compared with 14.9% on a placebo, and 39.9% of patients achieved abstinence on second-generation antipsychotics (SGAs), compared with 23.6% on a placebo.

BananaStock/thinkstockphotos.com

Total eating-related obsessions and compulsions were significantly reduced in patients receiving lisdexamfetamine and SGAs, and CBT significantly improved eating-related psychopathology. Body mass index was not reduced in patients receiving SGAs or CBT, but was reduced in those receiving lisdexamfetamine and topiramate, compared with placebo. Symptoms of depression were reduced by SGAs, but not by CBT.

In a related editorial, Dr. Michael J. Devlin of the New York State Psychiatric Institute and Columbia University, New York, praised the review by Dr. Brownley and her associates as an expert summary of the “current evidence on binge-eating disorder.” He went on to make the connection between eating disorders and obesity, and discuss the prospects for interventions.

“The seeds of unhealthy eating that eventually lead to obesity, disordered eating, or both often are sown during childhood or adolescence, and interventions at the community and family levels in the context of enlightened public policy likely would yield significant benefit,” Dr. Devlin wrote. “Only by understanding binge-eating disorder at various levels of analysis and through different professional lenses will we ensure that its life span is shortened, to the benefit of our own.”

Find the full study (doi: 10.7326/M15-2455) and editorial (doi: 10.7326/M16-1398) in the Annals of Internal Medicine.

[email protected]

Cognitive-behavioral therapy, lisdexamfetamine, and second-generation antidepressants are the most effective treatments for adult binge-eating disorder, a systematic review by Kimberly A. Brownley, PhD, and her associates found.

A total of 34 trials were included in the review. Patients who received therapist-led cognitive-behavioral therapy (CBT) achieved binge eating abstinence at a rate of 58.8%, compared with 11.2% of those on a wait list. Just over 40% of patients achieved abstinence on lisdexamfetamine, compared with 14.9% on a placebo, and 39.9% of patients achieved abstinence on second-generation antipsychotics (SGAs), compared with 23.6% on a placebo.

BananaStock/thinkstockphotos.com

Total eating-related obsessions and compulsions were significantly reduced in patients receiving lisdexamfetamine and SGAs, and CBT significantly improved eating-related psychopathology. Body mass index was not reduced in patients receiving SGAs or CBT, but was reduced in those receiving lisdexamfetamine and topiramate, compared with placebo. Symptoms of depression were reduced by SGAs, but not by CBT.

In a related editorial, Dr. Michael J. Devlin of the New York State Psychiatric Institute and Columbia University, New York, praised the review by Dr. Brownley and her associates as an expert summary of the “current evidence on binge-eating disorder.” He went on to make the connection between eating disorders and obesity, and discuss the prospects for interventions.

“The seeds of unhealthy eating that eventually lead to obesity, disordered eating, or both often are sown during childhood or adolescence, and interventions at the community and family levels in the context of enlightened public policy likely would yield significant benefit,” Dr. Devlin wrote. “Only by understanding binge-eating disorder at various levels of analysis and through different professional lenses will we ensure that its life span is shortened, to the benefit of our own.”

Find the full study (doi: 10.7326/M15-2455) and editorial (doi: 10.7326/M16-1398) in the Annals of Internal Medicine.

[email protected]

Cognitive-behavioral therapy, lisdexamfetamine, and second-generation antidepressants are the most effective treatments for adult binge-eating disorder, a systematic review by Kimberly A. Brownley, PhD, and her associates found.

A total of 34 trials were included in the review. Patients who received therapist-led cognitive-behavioral therapy (CBT) achieved binge eating abstinence at a rate of 58.8%, compared with 11.2% of those on a wait list. Just over 40% of patients achieved abstinence on lisdexamfetamine, compared with 14.9% on a placebo, and 39.9% of patients achieved abstinence on second-generation antipsychotics (SGAs), compared with 23.6% on a placebo.

BananaStock/thinkstockphotos.com

Total eating-related obsessions and compulsions were significantly reduced in patients receiving lisdexamfetamine and SGAs, and CBT significantly improved eating-related psychopathology. Body mass index was not reduced in patients receiving SGAs or CBT, but was reduced in those receiving lisdexamfetamine and topiramate, compared with placebo. Symptoms of depression were reduced by SGAs, but not by CBT.

In a related editorial, Dr. Michael J. Devlin of the New York State Psychiatric Institute and Columbia University, New York, praised the review by Dr. Brownley and her associates as an expert summary of the “current evidence on binge-eating disorder.” He went on to make the connection between eating disorders and obesity, and discuss the prospects for interventions.

“The seeds of unhealthy eating that eventually lead to obesity, disordered eating, or both often are sown during childhood or adolescence, and interventions at the community and family levels in the context of enlightened public policy likely would yield significant benefit,” Dr. Devlin wrote. “Only by understanding binge-eating disorder at various levels of analysis and through different professional lenses will we ensure that its life span is shortened, to the benefit of our own.”

Find the full study (doi: 10.7326/M15-2455) and editorial (doi: 10.7326/M16-1398) in the Annals of Internal Medicine.

[email protected]