Herbs and spices

Photo by Alexander Baxevanis

An herbal mixture used in traditional Chinese medicine can reduce fatigue in cancer patients, results of a phase 1/2 study suggest.

The mixture, Ren Shen Yangrong Tang (RSYRT), is a soup containing 12 herbs.

In the study, cancer patients suffering from moderate to severe fatigue reported significantly less fatigue after taking RSYRT for 2 to 3 weeks.

Researchers reported these results in the Journal of Alternative and Complementary Medicine.

Yichen Xu, MD, of Beijing Cancer Hospital & Institute in China, and colleagues evaluated RSYRT in 33 patients who had completed cancer treatment. The patients had stable disease and no anemia.

Eleven patients had moderate fatigue (a score of 4-6 on a 0-10 scale), and 22 had severe fatigue (a score of 7-10). All patients had experienced fatigue for at least 4 months.

Patients took RSYRT twice a day for 6 weeks and experienced a significant decrease in fatigue severity. The mean fatigue score decreased from 7.06 at baseline to 3.30 at the 6-week mark (P<0.001).

The fatigue category also changed significantly (P=0.024). Among the 22 patients who had severe fatigue before RSYRT, half had mild fatigue after therapy, and half had moderate fatigue.

Among the 11 patients who had moderate fatigue at baseline, only 1 still had moderate fatigue after receiving RSYRT. The rest had mild fatigue.

All of the patients said they felt better after taking RSYRT for 4 weeks.

There were no “uncomfortable events” related to RSYRT, such as gastrointestinal upset, insomnia, headache, or rash. None of the patients required a dose reduction or dose interruption.

None of the patients had blood chemistry abnormalities or abnormal liver/kidney function. Two patients who had a change in ST segment before RSYRT had normal electrocardiogram results after treatment.

Herbs and spices

Photo by Alexander Baxevanis

An herbal mixture used in traditional Chinese medicine can reduce fatigue in cancer patients, results of a phase 1/2 study suggest.

The mixture, Ren Shen Yangrong Tang (RSYRT), is a soup containing 12 herbs.

In the study, cancer patients suffering from moderate to severe fatigue reported significantly less fatigue after taking RSYRT for 2 to 3 weeks.

Researchers reported these results in the Journal of Alternative and Complementary Medicine.

Yichen Xu, MD, of Beijing Cancer Hospital & Institute in China, and colleagues evaluated RSYRT in 33 patients who had completed cancer treatment. The patients had stable disease and no anemia.

Eleven patients had moderate fatigue (a score of 4-6 on a 0-10 scale), and 22 had severe fatigue (a score of 7-10). All patients had experienced fatigue for at least 4 months.

Patients took RSYRT twice a day for 6 weeks and experienced a significant decrease in fatigue severity. The mean fatigue score decreased from 7.06 at baseline to 3.30 at the 6-week mark (P<0.001).

The fatigue category also changed significantly (P=0.024). Among the 22 patients who had severe fatigue before RSYRT, half had mild fatigue after therapy, and half had moderate fatigue.

Among the 11 patients who had moderate fatigue at baseline, only 1 still had moderate fatigue after receiving RSYRT. The rest had mild fatigue.

All of the patients said they felt better after taking RSYRT for 4 weeks.

There were no “uncomfortable events” related to RSYRT, such as gastrointestinal upset, insomnia, headache, or rash. None of the patients required a dose reduction or dose interruption.

None of the patients had blood chemistry abnormalities or abnormal liver/kidney function. Two patients who had a change in ST segment before RSYRT had normal electrocardiogram results after treatment.

Herbs and spices

Photo by Alexander Baxevanis

An herbal mixture used in traditional Chinese medicine can reduce fatigue in cancer patients, results of a phase 1/2 study suggest.

The mixture, Ren Shen Yangrong Tang (RSYRT), is a soup containing 12 herbs.

In the study, cancer patients suffering from moderate to severe fatigue reported significantly less fatigue after taking RSYRT for 2 to 3 weeks.

Researchers reported these results in the Journal of Alternative and Complementary Medicine.

Yichen Xu, MD, of Beijing Cancer Hospital & Institute in China, and colleagues evaluated RSYRT in 33 patients who had completed cancer treatment. The patients had stable disease and no anemia.

Eleven patients had moderate fatigue (a score of 4-6 on a 0-10 scale), and 22 had severe fatigue (a score of 7-10). All patients had experienced fatigue for at least 4 months.

Patients took RSYRT twice a day for 6 weeks and experienced a significant decrease in fatigue severity. The mean fatigue score decreased from 7.06 at baseline to 3.30 at the 6-week mark (P<0.001).

The fatigue category also changed significantly (P=0.024). Among the 22 patients who had severe fatigue before RSYRT, half had mild fatigue after therapy, and half had moderate fatigue.

Among the 11 patients who had moderate fatigue at baseline, only 1 still had moderate fatigue after receiving RSYRT. The rest had mild fatigue.

All of the patients said they felt better after taking RSYRT for 4 weeks.

There were no “uncomfortable events” related to RSYRT, such as gastrointestinal upset, insomnia, headache, or rash. None of the patients required a dose reduction or dose interruption.

None of the patients had blood chemistry abnormalities or abnormal liver/kidney function. Two patients who had a change in ST segment before RSYRT had normal electrocardiogram results after treatment.

CLL cells

PHILADELPHIA—A DNA-dependent protein kinase (DNA-PK) inhibitor can sensitize chronic lymphocytic leukemia (CLL) cells to chemotherapy, according to

preclinical research.

The inhibitor, NDD0004, sensitized CLL cells—even those from patients with high-risk cytogenetics—to treatment with mitoxantrone.

However, not all CLL samples were sensitive to treatment, so researchers are now trying to determine which patients might derive benefit from DNA-PK inhibitors.

Gesa Junge, a PhD student at Newcastle University in the UK, and her colleagues conducted this research and presented the results at the AACR Annual Meeting 2015 (abstract 3624*). The work was supported by AstraZeneca.

The researchers’ goal was to validate that DNA-PK inhibition is a valid approach to chemosensitization in CLL. So the team tested NU7441—a compound that inhibits DNA-PK and PI3 kinase—and NDD0004—a more selective DNA-PK inhibitor.

The team isolated CLL cells from patients’ peripheral blood, cultured the cells, and treated them with mitoxantrone and/or 1μM of NDD0004 or 1μM of NU7441.

Junge and her colleagues found that NDD0004 sensitized cells to mitoxantrone more effectively than NU7441. Sensitization was 202-fold higher with NDD004 plus mitoxantrone than with mitoxantrone alone and 69-fold higher with NU7441 plus mitoxantrone than with mitoxantrone alone (P=0.02).

However, sensitization varied between CLL samples, and the researchers have yet to determine why. Their experiments showed that variability was not a result of DNA-PK levels.

Still, the team found that CLL cells from patients with poor prognostic markers were sensitive to DNA-PK inhibition.

Sensitization with NU7441 plus mitoxantrone was 69-fold higher than mitoxantrone alone in CLL samples with del(13q), 25-fold higher in samples with del(11q), 12-fold higher in samples with TP53 mutation, and 16-fold higher in samples with ATM dysfunction.

Sensitization with NDD0004 plus mitoxantrone was 201-fold higher than mitoxantrone alone in CLL samples with del(13q), 314-fold higher in samples with del(11q), 27-fold higher in samples with TP53 mutation, and 18-fold higher in samples with ATM dysfunction.

To confirm that sensitization was a result of DNA-PK inhibition, Junge and her colleagues tested NDD0004 in an isogenic pair of DNA-PK-deficient and DNA-PK-proficient HCT116 cells. They found that HCT116 cells lacking DNA-PK were not sensitive to NDD0004, but cells with DNA-PK were sensitive.

The researchers also investigated the mechanism of NDD0004. Their results suggest the drug works by inhibiting the repair of DNA double-strand breaks.

“What we think is happening is that we are inducing DNA damage with mitoxantrone, and that gets repaired by 24 hours,” Junge said. “But if the DNA-PK inhibitor is there, the damage persists, and that seems to translate quite nicely into an apoptosis response.”

To further this research, Junge and her colleagues are hoping to identify biomarkers that can help them determine which CLL patients are likely to respond to DNA-PK inhibitors.

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

CLL cells

PHILADELPHIA—A DNA-dependent protein kinase (DNA-PK) inhibitor can sensitize chronic lymphocytic leukemia (CLL) cells to chemotherapy, according to

preclinical research.

The inhibitor, NDD0004, sensitized CLL cells—even those from patients with high-risk cytogenetics—to treatment with mitoxantrone.

However, not all CLL samples were sensitive to treatment, so researchers are now trying to determine which patients might derive benefit from DNA-PK inhibitors.

Gesa Junge, a PhD student at Newcastle University in the UK, and her colleagues conducted this research and presented the results at the AACR Annual Meeting 2015 (abstract 3624*). The work was supported by AstraZeneca.

The researchers’ goal was to validate that DNA-PK inhibition is a valid approach to chemosensitization in CLL. So the team tested NU7441—a compound that inhibits DNA-PK and PI3 kinase—and NDD0004—a more selective DNA-PK inhibitor.

The team isolated CLL cells from patients’ peripheral blood, cultured the cells, and treated them with mitoxantrone and/or 1μM of NDD0004 or 1μM of NU7441.

Junge and her colleagues found that NDD0004 sensitized cells to mitoxantrone more effectively than NU7441. Sensitization was 202-fold higher with NDD004 plus mitoxantrone than with mitoxantrone alone and 69-fold higher with NU7441 plus mitoxantrone than with mitoxantrone alone (P=0.02).

However, sensitization varied between CLL samples, and the researchers have yet to determine why. Their experiments showed that variability was not a result of DNA-PK levels.

Still, the team found that CLL cells from patients with poor prognostic markers were sensitive to DNA-PK inhibition.

Sensitization with NU7441 plus mitoxantrone was 69-fold higher than mitoxantrone alone in CLL samples with del(13q), 25-fold higher in samples with del(11q), 12-fold higher in samples with TP53 mutation, and 16-fold higher in samples with ATM dysfunction.

Sensitization with NDD0004 plus mitoxantrone was 201-fold higher than mitoxantrone alone in CLL samples with del(13q), 314-fold higher in samples with del(11q), 27-fold higher in samples with TP53 mutation, and 18-fold higher in samples with ATM dysfunction.

To confirm that sensitization was a result of DNA-PK inhibition, Junge and her colleagues tested NDD0004 in an isogenic pair of DNA-PK-deficient and DNA-PK-proficient HCT116 cells. They found that HCT116 cells lacking DNA-PK were not sensitive to NDD0004, but cells with DNA-PK were sensitive.

The researchers also investigated the mechanism of NDD0004. Their results suggest the drug works by inhibiting the repair of DNA double-strand breaks.

“What we think is happening is that we are inducing DNA damage with mitoxantrone, and that gets repaired by 24 hours,” Junge said. “But if the DNA-PK inhibitor is there, the damage persists, and that seems to translate quite nicely into an apoptosis response.”

To further this research, Junge and her colleagues are hoping to identify biomarkers that can help them determine which CLL patients are likely to respond to DNA-PK inhibitors.

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

CLL cells

PHILADELPHIA—A DNA-dependent protein kinase (DNA-PK) inhibitor can sensitize chronic lymphocytic leukemia (CLL) cells to chemotherapy, according to

preclinical research.

The inhibitor, NDD0004, sensitized CLL cells—even those from patients with high-risk cytogenetics—to treatment with mitoxantrone.

However, not all CLL samples were sensitive to treatment, so researchers are now trying to determine which patients might derive benefit from DNA-PK inhibitors.

Gesa Junge, a PhD student at Newcastle University in the UK, and her colleagues conducted this research and presented the results at the AACR Annual Meeting 2015 (abstract 3624*). The work was supported by AstraZeneca.

The researchers’ goal was to validate that DNA-PK inhibition is a valid approach to chemosensitization in CLL. So the team tested NU7441—a compound that inhibits DNA-PK and PI3 kinase—and NDD0004—a more selective DNA-PK inhibitor.

The team isolated CLL cells from patients’ peripheral blood, cultured the cells, and treated them with mitoxantrone and/or 1μM of NDD0004 or 1μM of NU7441.

Junge and her colleagues found that NDD0004 sensitized cells to mitoxantrone more effectively than NU7441. Sensitization was 202-fold higher with NDD004 plus mitoxantrone than with mitoxantrone alone and 69-fold higher with NU7441 plus mitoxantrone than with mitoxantrone alone (P=0.02).

However, sensitization varied between CLL samples, and the researchers have yet to determine why. Their experiments showed that variability was not a result of DNA-PK levels.

Still, the team found that CLL cells from patients with poor prognostic markers were sensitive to DNA-PK inhibition.

Sensitization with NU7441 plus mitoxantrone was 69-fold higher than mitoxantrone alone in CLL samples with del(13q), 25-fold higher in samples with del(11q), 12-fold higher in samples with TP53 mutation, and 16-fold higher in samples with ATM dysfunction.

Sensitization with NDD0004 plus mitoxantrone was 201-fold higher than mitoxantrone alone in CLL samples with del(13q), 314-fold higher in samples with del(11q), 27-fold higher in samples with TP53 mutation, and 18-fold higher in samples with ATM dysfunction.

To confirm that sensitization was a result of DNA-PK inhibition, Junge and her colleagues tested NDD0004 in an isogenic pair of DNA-PK-deficient and DNA-PK-proficient HCT116 cells. They found that HCT116 cells lacking DNA-PK were not sensitive to NDD0004, but cells with DNA-PK were sensitive.

The researchers also investigated the mechanism of NDD0004. Their results suggest the drug works by inhibiting the repair of DNA double-strand breaks.

“What we think is happening is that we are inducing DNA damage with mitoxantrone, and that gets repaired by 24 hours,” Junge said. “But if the DNA-PK inhibitor is there, the damage persists, and that seems to translate quite nicely into an apoptosis response.”

To further this research, Junge and her colleagues are hoping to identify biomarkers that can help them determine which CLL patients are likely to respond to DNA-PK inhibitors.

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

Micrograph showing WM

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is  recommending that ibrutinib (Imbruvica) be approved to treat Waldenström’s macroglobulinemia (WM).

The CHMP is recommending the drug for use in WM patients who have received at least 1 prior therapy as well as previously untreated WM patients who are not suitable candidates for chemo-immunotherapy.

The European Commission will review this recommendation and should make a decision later this year.

Ibrutinib is already approved to treat WM in the US. The drug is also approved in the European Union, the US, and other countries to treat chronic lymphocytic leukemia and mantle cell lymphoma.

Janssen-Cilag International NV (Janssen) holds the marketing authorization for ibrutinib in Europe, and its affiliates market the drug in Europe and the rest of the world. In the US, ibrutinib is under joint development by Pharmacyclics and Janssen Biotech, Inc.

Phase 2 study

The CHMP’s recommendation for ibrutinib was based on a multicenter, phase 2 study in which researchers tested the drug in 63 patients with previously treated WM. Initial data showed an overall response rate of 87.3% in patients who received the drug for a median of 11.7 months.

Updated results from the study were published in NEJM in April. After a median treatment duration of 19.1 months, the overall response rate was 91%.

At 24 months, the estimated rate of progression-free survival was 69%, and the estimated rate of overall survival was 95%.

The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.

Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.

Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.

Micrograph showing WM

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is  recommending that ibrutinib (Imbruvica) be approved to treat Waldenström’s macroglobulinemia (WM).

The CHMP is recommending the drug for use in WM patients who have received at least 1 prior therapy as well as previously untreated WM patients who are not suitable candidates for chemo-immunotherapy.

The European Commission will review this recommendation and should make a decision later this year.

Ibrutinib is already approved to treat WM in the US. The drug is also approved in the European Union, the US, and other countries to treat chronic lymphocytic leukemia and mantle cell lymphoma.

Janssen-Cilag International NV (Janssen) holds the marketing authorization for ibrutinib in Europe, and its affiliates market the drug in Europe and the rest of the world. In the US, ibrutinib is under joint development by Pharmacyclics and Janssen Biotech, Inc.

Phase 2 study

The CHMP’s recommendation for ibrutinib was based on a multicenter, phase 2 study in which researchers tested the drug in 63 patients with previously treated WM. Initial data showed an overall response rate of 87.3% in patients who received the drug for a median of 11.7 months.

Updated results from the study were published in NEJM in April. After a median treatment duration of 19.1 months, the overall response rate was 91%.

At 24 months, the estimated rate of progression-free survival was 69%, and the estimated rate of overall survival was 95%.

The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.

Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.

Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.

Micrograph showing WM

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) is  recommending that ibrutinib (Imbruvica) be approved to treat Waldenström’s macroglobulinemia (WM).

The CHMP is recommending the drug for use in WM patients who have received at least 1 prior therapy as well as previously untreated WM patients who are not suitable candidates for chemo-immunotherapy.

The European Commission will review this recommendation and should make a decision later this year.

Ibrutinib is already approved to treat WM in the US. The drug is also approved in the European Union, the US, and other countries to treat chronic lymphocytic leukemia and mantle cell lymphoma.

Janssen-Cilag International NV (Janssen) holds the marketing authorization for ibrutinib in Europe, and its affiliates market the drug in Europe and the rest of the world. In the US, ibrutinib is under joint development by Pharmacyclics and Janssen Biotech, Inc.

Phase 2 study

The CHMP’s recommendation for ibrutinib was based on a multicenter, phase 2 study in which researchers tested the drug in 63 patients with previously treated WM. Initial data showed an overall response rate of 87.3% in patients who received the drug for a median of 11.7 months.

Updated results from the study were published in NEJM in April. After a median treatment duration of 19.1 months, the overall response rate was 91%.

At 24 months, the estimated rate of progression-free survival was 69%, and the estimated rate of overall survival was 95%.

The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.

Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.

Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.

TORONTO – “What if we could detect a mood episode before it happened?” It was with this question that Dr. Andrew A. Nierenberg began his talk on new advances in mood disorders research at the annual meeting of the American Psychiatric Association.

From predictive analytics to big data collaboration to therapeutic apps, Dr. Nierenberg led the audience through a tour of the now and near future.

One company in this space, Ginger.io, uses behavioral analytics to better understand patients’ changing social, mental, and physical health status. The data can then be fed quickly back to clinicians when intervention is warranted. The company’s app collects passive sensor data from patients’ smartphones about their movement, communication, and sleep patterns. Sophisticated analytical methods detect changes in behavior and predict people’s moods and actions.

“It’s a little creepy in some ways, but maybe not,” he said. “If you think about it, when people come to us in distress, it’s not at the very edge or beginning of a mood episode, but they’re deep into it [and that is] when we tend to intervene.”

When a patient is evaluated, he explained, the strength of the evaluation is dependent on accurate self-observation, and accurate storage and recall of the patient’s observations about their emotional states.

“Those are all problems for people with mood disorders,” Dr. Nierenberg said. “So, when we ask someone how they have been in the past week, we’re really getting a window into the past 3-6 hours. What these predictive analytics allow is real time data to look at what is actually happening with people.”

The question really being asked here, said Dr. Nierenberg, is whether it’s possible to see objective changes that are not among the information people are likely to report to their clinicians, that can predict a mood episode.

Harnessing technology

Big data also has come to mood disorders care in a big way. Large registries are being compiled for research purposes, and patient communities are growing that help patients cope with their conditions and help researchers collect huge amounts of data. Based on cognitive-behavioral therapy combined with relaxation and wellness techniques, we believe in holistic daily tools aimed at breaking the anxiety cycle. We’re not about quick fixes or false promises. We are about real progress, a day at a time.

According to its website, Big White Wall is an online community of people “who are anxious, down, or not coping who support and help each other by sharing what’s troubling them, guided by trained professionals.”

Other examples of these tech-based solutions are therapeutic apps and websites. Dr. Nierenberg mentioned just three: MoodGYM, Now Matters Now, and Pacifica, all of which are “cutting edge and evidence-based” and help patients manage their conditions.

• MoodGym is a free, interactive self-help program that provides cognitive-behavior therapy (CBT) training to help users prevent and cope with depression and anxiety.

• Now Matters Now is an online video-based program that uses “real” people, including suicide prevention researchers and clinicians, to teach coping skills such as mindfulness, paced breathing, and opposite action to individuals having suicidal thoughts. The skills taught are part of dialectical behavior therapy, or DBT, proven to be helpful for people considering suicide. Dr. Nierenberg called this community “quite extraordinary” and uniquely valuable, “because the majority of people who are having suicidal thoughts don’t have them when they’re in your office …”

• Pacifica is a self-help app for anxiety that uses CBT combined with relaxation and wellness techniques aimed at “breaking the anxiety cycle,” the company says. 

‘A game changer’

The Patient Centered Outcomes Research Network (PCORnet.org) is “a game changer,” said Dr. Nierenberg. It is part of the Patient-Centered Outcomes Research Institute (PCORI), which is part of the Affordable Care Act, funded at about $500 million a year. One part of PCORnet.org is the Patient-Powered Research Networks, including a mood-focused network, moodnetwork.org.

“It allows the patients to choose how they want to be monitored, through self-report, but also gives them a voice in prioritizing research and research questions.” A goal is to transform research and mood disorder care by creating an infrastructure for both research and clinicians wanting to follow their patients and through prospective comparative effectiveness trials embedded within routine care.

The organizers hope to gather 50,000 patients in the network, a “wild and audacious goal,” admitted Dr. Nierenberg, who is the principal investigator of moodnetwork.org. PCORnet.org ultimately might cover 90 million people and truly be able to answer real-world questions in a way that most research today does not address, he added.

Dr. Nierenberg is a top researcher and educator from Massachusetts General Hospital and Harvard Medical School, Boston. In 2013, he won the prestigious Colvin Prize given by the Brain & Behavior Research Foundation for Outstanding Achievement in Mood Disorders Research.

Dr. Nierenberg reported working with several pharmaceutical companies in drug development.

TORONTO – “What if we could detect a mood episode before it happened?” It was with this question that Dr. Andrew A. Nierenberg began his talk on new advances in mood disorders research at the annual meeting of the American Psychiatric Association.

From predictive analytics to big data collaboration to therapeutic apps, Dr. Nierenberg led the audience through a tour of the now and near future.

One company in this space, Ginger.io, uses behavioral analytics to better understand patients’ changing social, mental, and physical health status. The data can then be fed quickly back to clinicians when intervention is warranted. The company’s app collects passive sensor data from patients’ smartphones about their movement, communication, and sleep patterns. Sophisticated analytical methods detect changes in behavior and predict people’s moods and actions.

“It’s a little creepy in some ways, but maybe not,” he said. “If you think about it, when people come to us in distress, it’s not at the very edge or beginning of a mood episode, but they’re deep into it [and that is] when we tend to intervene.”

When a patient is evaluated, he explained, the strength of the evaluation is dependent on accurate self-observation, and accurate storage and recall of the patient’s observations about their emotional states.

“Those are all problems for people with mood disorders,” Dr. Nierenberg said. “So, when we ask someone how they have been in the past week, we’re really getting a window into the past 3-6 hours. What these predictive analytics allow is real time data to look at what is actually happening with people.”

The question really being asked here, said Dr. Nierenberg, is whether it’s possible to see objective changes that are not among the information people are likely to report to their clinicians, that can predict a mood episode.

Harnessing technology

Big data also has come to mood disorders care in a big way. Large registries are being compiled for research purposes, and patient communities are growing that help patients cope with their conditions and help researchers collect huge amounts of data. Based on cognitive-behavioral therapy combined with relaxation and wellness techniques, we believe in holistic daily tools aimed at breaking the anxiety cycle. We’re not about quick fixes or false promises. We are about real progress, a day at a time.

According to its website, Big White Wall is an online community of people “who are anxious, down, or not coping who support and help each other by sharing what’s troubling them, guided by trained professionals.”

Other examples of these tech-based solutions are therapeutic apps and websites. Dr. Nierenberg mentioned just three: MoodGYM, Now Matters Now, and Pacifica, all of which are “cutting edge and evidence-based” and help patients manage their conditions.

• MoodGym is a free, interactive self-help program that provides cognitive-behavior therapy (CBT) training to help users prevent and cope with depression and anxiety.

• Now Matters Now is an online video-based program that uses “real” people, including suicide prevention researchers and clinicians, to teach coping skills such as mindfulness, paced breathing, and opposite action to individuals having suicidal thoughts. The skills taught are part of dialectical behavior therapy, or DBT, proven to be helpful for people considering suicide. Dr. Nierenberg called this community “quite extraordinary” and uniquely valuable, “because the majority of people who are having suicidal thoughts don’t have them when they’re in your office …”

• Pacifica is a self-help app for anxiety that uses CBT combined with relaxation and wellness techniques aimed at “breaking the anxiety cycle,” the company says. 

‘A game changer’

The Patient Centered Outcomes Research Network (PCORnet.org) is “a game changer,” said Dr. Nierenberg. It is part of the Patient-Centered Outcomes Research Institute (PCORI), which is part of the Affordable Care Act, funded at about $500 million a year. One part of PCORnet.org is the Patient-Powered Research Networks, including a mood-focused network, moodnetwork.org.

“It allows the patients to choose how they want to be monitored, through self-report, but also gives them a voice in prioritizing research and research questions.” A goal is to transform research and mood disorder care by creating an infrastructure for both research and clinicians wanting to follow their patients and through prospective comparative effectiveness trials embedded within routine care.

The organizers hope to gather 50,000 patients in the network, a “wild and audacious goal,” admitted Dr. Nierenberg, who is the principal investigator of moodnetwork.org. PCORnet.org ultimately might cover 90 million people and truly be able to answer real-world questions in a way that most research today does not address, he added.

Dr. Nierenberg is a top researcher and educator from Massachusetts General Hospital and Harvard Medical School, Boston. In 2013, he won the prestigious Colvin Prize given by the Brain & Behavior Research Foundation for Outstanding Achievement in Mood Disorders Research.

Dr. Nierenberg reported working with several pharmaceutical companies in drug development.

TORONTO – “What if we could detect a mood episode before it happened?” It was with this question that Dr. Andrew A. Nierenberg began his talk on new advances in mood disorders research at the annual meeting of the American Psychiatric Association.

From predictive analytics to big data collaboration to therapeutic apps, Dr. Nierenberg led the audience through a tour of the now and near future.

One company in this space, Ginger.io, uses behavioral analytics to better understand patients’ changing social, mental, and physical health status. The data can then be fed quickly back to clinicians when intervention is warranted. The company’s app collects passive sensor data from patients’ smartphones about their movement, communication, and sleep patterns. Sophisticated analytical methods detect changes in behavior and predict people’s moods and actions.

“It’s a little creepy in some ways, but maybe not,” he said. “If you think about it, when people come to us in distress, it’s not at the very edge or beginning of a mood episode, but they’re deep into it [and that is] when we tend to intervene.”

When a patient is evaluated, he explained, the strength of the evaluation is dependent on accurate self-observation, and accurate storage and recall of the patient’s observations about their emotional states.

“Those are all problems for people with mood disorders,” Dr. Nierenberg said. “So, when we ask someone how they have been in the past week, we’re really getting a window into the past 3-6 hours. What these predictive analytics allow is real time data to look at what is actually happening with people.”

The question really being asked here, said Dr. Nierenberg, is whether it’s possible to see objective changes that are not among the information people are likely to report to their clinicians, that can predict a mood episode.

Harnessing technology

Big data also has come to mood disorders care in a big way. Large registries are being compiled for research purposes, and patient communities are growing that help patients cope with their conditions and help researchers collect huge amounts of data. Based on cognitive-behavioral therapy combined with relaxation and wellness techniques, we believe in holistic daily tools aimed at breaking the anxiety cycle. We’re not about quick fixes or false promises. We are about real progress, a day at a time.

According to its website, Big White Wall is an online community of people “who are anxious, down, or not coping who support and help each other by sharing what’s troubling them, guided by trained professionals.”

Other examples of these tech-based solutions are therapeutic apps and websites. Dr. Nierenberg mentioned just three: MoodGYM, Now Matters Now, and Pacifica, all of which are “cutting edge and evidence-based” and help patients manage their conditions.

• MoodGym is a free, interactive self-help program that provides cognitive-behavior therapy (CBT) training to help users prevent and cope with depression and anxiety.

• Now Matters Now is an online video-based program that uses “real” people, including suicide prevention researchers and clinicians, to teach coping skills such as mindfulness, paced breathing, and opposite action to individuals having suicidal thoughts. The skills taught are part of dialectical behavior therapy, or DBT, proven to be helpful for people considering suicide. Dr. Nierenberg called this community “quite extraordinary” and uniquely valuable, “because the majority of people who are having suicidal thoughts don’t have them when they’re in your office …”

• Pacifica is a self-help app for anxiety that uses CBT combined with relaxation and wellness techniques aimed at “breaking the anxiety cycle,” the company says. 

‘A game changer’

The Patient Centered Outcomes Research Network (PCORnet.org) is “a game changer,” said Dr. Nierenberg. It is part of the Patient-Centered Outcomes Research Institute (PCORI), which is part of the Affordable Care Act, funded at about $500 million a year. One part of PCORnet.org is the Patient-Powered Research Networks, including a mood-focused network, moodnetwork.org.

“It allows the patients to choose how they want to be monitored, through self-report, but also gives them a voice in prioritizing research and research questions.” A goal is to transform research and mood disorder care by creating an infrastructure for both research and clinicians wanting to follow their patients and through prospective comparative effectiveness trials embedded within routine care.

The organizers hope to gather 50,000 patients in the network, a “wild and audacious goal,” admitted Dr. Nierenberg, who is the principal investigator of moodnetwork.org. PCORnet.org ultimately might cover 90 million people and truly be able to answer real-world questions in a way that most research today does not address, he added.

Dr. Nierenberg is a top researcher and educator from Massachusetts General Hospital and Harvard Medical School, Boston. In 2013, he won the prestigious Colvin Prize given by the Brain & Behavior Research Foundation for Outstanding Achievement in Mood Disorders Research.

Dr. Nierenberg reported working with several pharmaceutical companies in drug development.

What happens when you give children everything they ask for? They get spoiled, of course. Any parent can tell you that.

The problem is that you’re trying to raise children to (eventually) be responsible adults. Part of this is teaching them that you can’t always win, you should always share, and you can’t always get what you want.

Most kids don’t like it. (I know I didn’t.) They only see that the candy or toy they want is being refused and don’t grasp the long-term plan of growing up to be a decent person. Across a thousand human cultures, any parent would agree.

But the same principle doesn’t seem to apply in modern health care. What would you think is more important in a hospital: competent staff or having a beverage offered to you after being checked into the emergency department?

Sadly, things like the latter seem to be winning because of the recent emphasis on patient satisfaction scores. In today’s world, 30% of a hospital’s Medicare reimbursement is based on these scores. That’s a lot of money.

Unfortunately, quality of care doesn’t necessarily have the same meaning between doctors and patients. The former will say it means you left the hospital with a good outcome. The latter will agree but also will throw in things like whether they got enough pain meds or their call light answered fast enough. If you’re having chest pain or severe dyspnea, getting that call light answered quickly is pretty important. But if all you want is a soda or for someone to hand you the TV remote … not so much.

The problem is that the patient satisfaction surveys (and yes, speed of call-light response is on there) don’t take that key point into account. What might make some patients happy isn’t necessarily in their best interest. The post-CABG patient who wants a double cheeseburger won’t be thrilled if he gets a salad instead. Another patient in for detox won’t be pleased if she doesn’t get Dilaudid on demand. A third will be angry that he’s not allowed to smoke. Those refusals are an integral part of their successful treatment and recovery plan, but they may not see it that way. And they’ll be sure to mark it on the survey.

As a result, the hospital gets penalized in spite of the fact that they’re doing their best to provide quality care. And the business-minded CEOs, who generally have no medical background, only care about this part of it.

Measuring what counts is important. But the idea that hospital care should be held to the same standards as Burger King and Walmart is fundamentally flawed. The things that are done in hospitals – cut people open, draw blood, biopsy bone marrow, put in endotracheal and feeding tubes – aren’t intended as recreational experiences. We try to make them as painless as possible, but in health care “do no harm” often means doing some harm in order to prevent a catastrophe.

The side effects of chemotherapy are (hopefully) offset by the successful treatment of cancer. But that doesn’t mean hair loss, nausea, vomiting, diarrhea, and other toxic symptoms are part of “customer satisfaction.” One study even found that the most satisfied patients had the highest mortality.

We owe patients the very best care we can give them, but they also need to understand that “best care” doesn’t always mean what they want in the short term. We’re focused on a goal that’s beyond the immediate horizon.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

What happens when you give children everything they ask for? They get spoiled, of course. Any parent can tell you that.

The problem is that you’re trying to raise children to (eventually) be responsible adults. Part of this is teaching them that you can’t always win, you should always share, and you can’t always get what you want.

Most kids don’t like it. (I know I didn’t.) They only see that the candy or toy they want is being refused and don’t grasp the long-term plan of growing up to be a decent person. Across a thousand human cultures, any parent would agree.

But the same principle doesn’t seem to apply in modern health care. What would you think is more important in a hospital: competent staff or having a beverage offered to you after being checked into the emergency department?

Sadly, things like the latter seem to be winning because of the recent emphasis on patient satisfaction scores. In today’s world, 30% of a hospital’s Medicare reimbursement is based on these scores. That’s a lot of money.

Unfortunately, quality of care doesn’t necessarily have the same meaning between doctors and patients. The former will say it means you left the hospital with a good outcome. The latter will agree but also will throw in things like whether they got enough pain meds or their call light answered fast enough. If you’re having chest pain or severe dyspnea, getting that call light answered quickly is pretty important. But if all you want is a soda or for someone to hand you the TV remote … not so much.

The problem is that the patient satisfaction surveys (and yes, speed of call-light response is on there) don’t take that key point into account. What might make some patients happy isn’t necessarily in their best interest. The post-CABG patient who wants a double cheeseburger won’t be thrilled if he gets a salad instead. Another patient in for detox won’t be pleased if she doesn’t get Dilaudid on demand. A third will be angry that he’s not allowed to smoke. Those refusals are an integral part of their successful treatment and recovery plan, but they may not see it that way. And they’ll be sure to mark it on the survey.

As a result, the hospital gets penalized in spite of the fact that they’re doing their best to provide quality care. And the business-minded CEOs, who generally have no medical background, only care about this part of it.

Measuring what counts is important. But the idea that hospital care should be held to the same standards as Burger King and Walmart is fundamentally flawed. The things that are done in hospitals – cut people open, draw blood, biopsy bone marrow, put in endotracheal and feeding tubes – aren’t intended as recreational experiences. We try to make them as painless as possible, but in health care “do no harm” often means doing some harm in order to prevent a catastrophe.

The side effects of chemotherapy are (hopefully) offset by the successful treatment of cancer. But that doesn’t mean hair loss, nausea, vomiting, diarrhea, and other toxic symptoms are part of “customer satisfaction.” One study even found that the most satisfied patients had the highest mortality.

We owe patients the very best care we can give them, but they also need to understand that “best care” doesn’t always mean what they want in the short term. We’re focused on a goal that’s beyond the immediate horizon.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

What happens when you give children everything they ask for? They get spoiled, of course. Any parent can tell you that.

The problem is that you’re trying to raise children to (eventually) be responsible adults. Part of this is teaching them that you can’t always win, you should always share, and you can’t always get what you want.

Most kids don’t like it. (I know I didn’t.) They only see that the candy or toy they want is being refused and don’t grasp the long-term plan of growing up to be a decent person. Across a thousand human cultures, any parent would agree.

But the same principle doesn’t seem to apply in modern health care. What would you think is more important in a hospital: competent staff or having a beverage offered to you after being checked into the emergency department?

Sadly, things like the latter seem to be winning because of the recent emphasis on patient satisfaction scores. In today’s world, 30% of a hospital’s Medicare reimbursement is based on these scores. That’s a lot of money.

Unfortunately, quality of care doesn’t necessarily have the same meaning between doctors and patients. The former will say it means you left the hospital with a good outcome. The latter will agree but also will throw in things like whether they got enough pain meds or their call light answered fast enough. If you’re having chest pain or severe dyspnea, getting that call light answered quickly is pretty important. But if all you want is a soda or for someone to hand you the TV remote … not so much.

The problem is that the patient satisfaction surveys (and yes, speed of call-light response is on there) don’t take that key point into account. What might make some patients happy isn’t necessarily in their best interest. The post-CABG patient who wants a double cheeseburger won’t be thrilled if he gets a salad instead. Another patient in for detox won’t be pleased if she doesn’t get Dilaudid on demand. A third will be angry that he’s not allowed to smoke. Those refusals are an integral part of their successful treatment and recovery plan, but they may not see it that way. And they’ll be sure to mark it on the survey.

As a result, the hospital gets penalized in spite of the fact that they’re doing their best to provide quality care. And the business-minded CEOs, who generally have no medical background, only care about this part of it.

Measuring what counts is important. But the idea that hospital care should be held to the same standards as Burger King and Walmart is fundamentally flawed. The things that are done in hospitals – cut people open, draw blood, biopsy bone marrow, put in endotracheal and feeding tubes – aren’t intended as recreational experiences. We try to make them as painless as possible, but in health care “do no harm” often means doing some harm in order to prevent a catastrophe.

The side effects of chemotherapy are (hopefully) offset by the successful treatment of cancer. But that doesn’t mean hair loss, nausea, vomiting, diarrhea, and other toxic symptoms are part of “customer satisfaction.” One study even found that the most satisfied patients had the highest mortality.

We owe patients the very best care we can give them, but they also need to understand that “best care” doesn’t always mean what they want in the short term. We’re focused on a goal that’s beyond the immediate horizon.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

James Bradner, MD

Photo by Sam Ogden

A chemical strategy may allow researchers to target “undruggable” proteins and overcome resistance to current targeted therapies, according to a report published in Science.

The strategy uses tumor cells’ own protein-elimination system to break down and dispose of the proteins that drive cancer growth.

When tested in vitro and in vivo, the approach caused leukemia cells to die more quickly than they do with conventional targeted

therapies.

“One of the reasons [treatment] resistance occurs is that cancer-related proteins often have multiple functions within the cell, and conventional targeted therapies inhibit just one or a few of those functions,” said study author James Bradner, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“Conventional drugs allow the targeted protein to adapt to the drug, and the cell finds alternate routes for its growth signals. We began designing approaches that cause the target protein to disintegrate, rather than merely be inhibited. It would be very powerful if we could chemically convert an inhibitor drug into a degrader drug.”

With this in mind, Dr Bradner’s team designed a chemical adapter that attaches to a targeted drug molecule. The adapter enables the drug to tow the cell’s protein-degradation machinery directly to the protein of interest. Once bound to the protein, the combination drug-and-protein-degrader essentially demolishes it.

The investigators tested the technology in leukemia cells. They built an adapter out of phthalimide, a chemical derivative of the drug thalidomide, and attached it to the BRD4 inhibitor JQ1. The phthalimide was designed to “hijack” the cereblon E3 ubiquitin ligase complex.

When the researchers treated the leukemia cells with a JQ1-phthalimide conjugate called dBET1, the BRD4 protein within the cells was degraded in less than an hour. The team said such rapid and extensive degradation suggests conjugates may be able to prevent or hinder cancer cells from developing resistance to targeted therapies.

“The potency, selectivity, and rapidity of this approach—namely, the ability to home in specifically on BRD4—are unprecedented in clinical approaches to protein degradation,” Dr Bradner said.

To determine how selective dBET1 actually is, the investigators measured the levels of all proteins in leukemia cells at 1 hour and 2 hours after treatment.

“We were stunned to find that only 3 proteins of more than 7000 in the entire cell were degraded: BRD2, 3, and 4, an exceptional degree of selectivity guided by the intended targets of JQ1,” Dr Bradner said. “It’s as though dBET1 is laser-guided to deliver protein-degrading machinery to targeted proteins.”

The researchers then tested dBET1 in mice bearing leukemia. As in the cell samples, there was a rapid degradation of BRD4 in the tumor cells and a potent anti-leukemic effect, with few noticeable side effects.

To see if compounds other than JQ1 can be used as a guidance system for a conjugate, the investigators created a set of molecules that lock the protein-degradation machinery onto a compound called SLF, which targets the protein FKBP12.

When they treated cancer cells with SLF, the team found it degraded the vast majority of FKBP12 in the cells within a few hours.

Buoyed by these results, the researchers are working to create a derivative of dBET1 that can be used as a drug in humans and to extend the conjugate strategy for the treatment of other diseases.

“The dBET1 and the dFKBP12 compounds are presently in a late stage of lead optimization for therapeutic development in both cancer and non-malignant diseases,” said Prem Das, PhD, chief research business development officer at Dana-Farber.

“Composition-of-matter and method-of-use patent applications have been filed on these and other additional targeted agents, as well as on the chemistry platform. They will be licensed for commercialization to an appropriate company according to standard Dana-Farber practice.”

James Bradner, MD

Photo by Sam Ogden

A chemical strategy may allow researchers to target “undruggable” proteins and overcome resistance to current targeted therapies, according to a report published in Science.

The strategy uses tumor cells’ own protein-elimination system to break down and dispose of the proteins that drive cancer growth.

When tested in vitro and in vivo, the approach caused leukemia cells to die more quickly than they do with conventional targeted

therapies.

“One of the reasons [treatment] resistance occurs is that cancer-related proteins often have multiple functions within the cell, and conventional targeted therapies inhibit just one or a few of those functions,” said study author James Bradner, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“Conventional drugs allow the targeted protein to adapt to the drug, and the cell finds alternate routes for its growth signals. We began designing approaches that cause the target protein to disintegrate, rather than merely be inhibited. It would be very powerful if we could chemically convert an inhibitor drug into a degrader drug.”

With this in mind, Dr Bradner’s team designed a chemical adapter that attaches to a targeted drug molecule. The adapter enables the drug to tow the cell’s protein-degradation machinery directly to the protein of interest. Once bound to the protein, the combination drug-and-protein-degrader essentially demolishes it.

The investigators tested the technology in leukemia cells. They built an adapter out of phthalimide, a chemical derivative of the drug thalidomide, and attached it to the BRD4 inhibitor JQ1. The phthalimide was designed to “hijack” the cereblon E3 ubiquitin ligase complex.

When the researchers treated the leukemia cells with a JQ1-phthalimide conjugate called dBET1, the BRD4 protein within the cells was degraded in less than an hour. The team said such rapid and extensive degradation suggests conjugates may be able to prevent or hinder cancer cells from developing resistance to targeted therapies.

“The potency, selectivity, and rapidity of this approach—namely, the ability to home in specifically on BRD4—are unprecedented in clinical approaches to protein degradation,” Dr Bradner said.

To determine how selective dBET1 actually is, the investigators measured the levels of all proteins in leukemia cells at 1 hour and 2 hours after treatment.

“We were stunned to find that only 3 proteins of more than 7000 in the entire cell were degraded: BRD2, 3, and 4, an exceptional degree of selectivity guided by the intended targets of JQ1,” Dr Bradner said. “It’s as though dBET1 is laser-guided to deliver protein-degrading machinery to targeted proteins.”

The researchers then tested dBET1 in mice bearing leukemia. As in the cell samples, there was a rapid degradation of BRD4 in the tumor cells and a potent anti-leukemic effect, with few noticeable side effects.

To see if compounds other than JQ1 can be used as a guidance system for a conjugate, the investigators created a set of molecules that lock the protein-degradation machinery onto a compound called SLF, which targets the protein FKBP12.

When they treated cancer cells with SLF, the team found it degraded the vast majority of FKBP12 in the cells within a few hours.

Buoyed by these results, the researchers are working to create a derivative of dBET1 that can be used as a drug in humans and to extend the conjugate strategy for the treatment of other diseases.

“The dBET1 and the dFKBP12 compounds are presently in a late stage of lead optimization for therapeutic development in both cancer and non-malignant diseases,” said Prem Das, PhD, chief research business development officer at Dana-Farber.

“Composition-of-matter and method-of-use patent applications have been filed on these and other additional targeted agents, as well as on the chemistry platform. They will be licensed for commercialization to an appropriate company according to standard Dana-Farber practice.”

James Bradner, MD

Photo by Sam Ogden

A chemical strategy may allow researchers to target “undruggable” proteins and overcome resistance to current targeted therapies, according to a report published in Science.

The strategy uses tumor cells’ own protein-elimination system to break down and dispose of the proteins that drive cancer growth.

When tested in vitro and in vivo, the approach caused leukemia cells to die more quickly than they do with conventional targeted

therapies.

“One of the reasons [treatment] resistance occurs is that cancer-related proteins often have multiple functions within the cell, and conventional targeted therapies inhibit just one or a few of those functions,” said study author James Bradner, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“Conventional drugs allow the targeted protein to adapt to the drug, and the cell finds alternate routes for its growth signals. We began designing approaches that cause the target protein to disintegrate, rather than merely be inhibited. It would be very powerful if we could chemically convert an inhibitor drug into a degrader drug.”

With this in mind, Dr Bradner’s team designed a chemical adapter that attaches to a targeted drug molecule. The adapter enables the drug to tow the cell’s protein-degradation machinery directly to the protein of interest. Once bound to the protein, the combination drug-and-protein-degrader essentially demolishes it.

The investigators tested the technology in leukemia cells. They built an adapter out of phthalimide, a chemical derivative of the drug thalidomide, and attached it to the BRD4 inhibitor JQ1. The phthalimide was designed to “hijack” the cereblon E3 ubiquitin ligase complex.

When the researchers treated the leukemia cells with a JQ1-phthalimide conjugate called dBET1, the BRD4 protein within the cells was degraded in less than an hour. The team said such rapid and extensive degradation suggests conjugates may be able to prevent or hinder cancer cells from developing resistance to targeted therapies.

“The potency, selectivity, and rapidity of this approach—namely, the ability to home in specifically on BRD4—are unprecedented in clinical approaches to protein degradation,” Dr Bradner said.

To determine how selective dBET1 actually is, the investigators measured the levels of all proteins in leukemia cells at 1 hour and 2 hours after treatment.

“We were stunned to find that only 3 proteins of more than 7000 in the entire cell were degraded: BRD2, 3, and 4, an exceptional degree of selectivity guided by the intended targets of JQ1,” Dr Bradner said. “It’s as though dBET1 is laser-guided to deliver protein-degrading machinery to targeted proteins.”

The researchers then tested dBET1 in mice bearing leukemia. As in the cell samples, there was a rapid degradation of BRD4 in the tumor cells and a potent anti-leukemic effect, with few noticeable side effects.

To see if compounds other than JQ1 can be used as a guidance system for a conjugate, the investigators created a set of molecules that lock the protein-degradation machinery onto a compound called SLF, which targets the protein FKBP12.

When they treated cancer cells with SLF, the team found it degraded the vast majority of FKBP12 in the cells within a few hours.

Buoyed by these results, the researchers are working to create a derivative of dBET1 that can be used as a drug in humans and to extend the conjugate strategy for the treatment of other diseases.

“The dBET1 and the dFKBP12 compounds are presently in a late stage of lead optimization for therapeutic development in both cancer and non-malignant diseases,” said Prem Das, PhD, chief research business development officer at Dana-Farber.

“Composition-of-matter and method-of-use patent applications have been filed on these and other additional targeted agents, as well as on the chemistry platform. They will be licensed for commercialization to an appropriate company according to standard Dana-Farber practice.”

Vial of heparin

PARIS—New research suggests that patients who have undergone primary percutaneous coronary intervention (PCI) have a low risk of stent thrombosis, regardless of the anticoagulant therapy they receive.

In a large, registry-based study, stent thrombosis occurred in less than 1% of patients, regardless of whether they received bivalirudin with or without heparin, heparin alone, or a GP IIb/IIIa inhibitor (GPI) with or without heparin.

The study also showed that patients who experienced stent thrombosis between days 2 and 30, regardless of drug regimen, were more likely to die within a year than patients who developed stent thrombosis within the first 24 hours of their procedure.

Per Grimfjard, of Vasteras Hospital/Uppsala University in Sweden, presented these findings at EuroPCR 2015.

A number of recent studies have raised concerns that bivalirudin may increase the risk of stent thrombosis compared with heparin. But rates of stent thrombosis have differed substantially between studies.

So Dr Grimfjard and his colleagues decided to review stent thrombosis rates by drug choice among more than 30,000 patients who were treated with primary PCI for ST-elevation myocardial infarction (STEMI) between January 2007 and July 2014 in the Swedish Coronary Angiography and Angioplasty Register (SCAAR).

The researchers divided patients into 3 treatment groups: bivalirudin, heparin, and GPI. However, 77% of patients in the bivalirudin group also received heparin, and 3.6% received a GPI prior to or during the PCI procedure. In the GPI group, 77% of patients also received heparin.

The rates of stent thrombosis were low in all 3 groups—0.84% in the bivalirudin group, 0.94% in the heparin group, and 0.83% in the GPI group.

For all 3 drugs, mortality at 1 year was numerically higher if the stent thrombosis occurred between 2 and 30 days, as compared with day 0 to 1 post-PCI.

“[A] possible explanation is that a stent thrombosis that happens once the patient has left the hospital is likely to cause a more substantial infarction, the reason being longer delay from symptoms to revascularization,” Dr Grimfjard said.

He added that a more substantial myocardial infarction typically leads to more heart failure and arrhythmia long-term. Unfortunately, the findings regarding the timing of stent thrombosis do not offer any guidance for choosing optimal antithrombotic treatment.

He and his colleagues are currently enrolling patients in a 6000-patient, registry-based, randomized clinical trial called SWEDEHART-Validate. The team will compare heparin alone to bivalirudin and optional low-dose heparin in STEMI and non-STEMI patients undergoing PCI.

“Hopefully, this large, randomized trial will bring clarity to the choice of antithrombotic treatment strategy in these patients,” Dr Grimfjard said.

Vial of heparin

PARIS—New research suggests that patients who have undergone primary percutaneous coronary intervention (PCI) have a low risk of stent thrombosis, regardless of the anticoagulant therapy they receive.

In a large, registry-based study, stent thrombosis occurred in less than 1% of patients, regardless of whether they received bivalirudin with or without heparin, heparin alone, or a GP IIb/IIIa inhibitor (GPI) with or without heparin.

The study also showed that patients who experienced stent thrombosis between days 2 and 30, regardless of drug regimen, were more likely to die within a year than patients who developed stent thrombosis within the first 24 hours of their procedure.

Per Grimfjard, of Vasteras Hospital/Uppsala University in Sweden, presented these findings at EuroPCR 2015.

A number of recent studies have raised concerns that bivalirudin may increase the risk of stent thrombosis compared with heparin. But rates of stent thrombosis have differed substantially between studies.

So Dr Grimfjard and his colleagues decided to review stent thrombosis rates by drug choice among more than 30,000 patients who were treated with primary PCI for ST-elevation myocardial infarction (STEMI) between January 2007 and July 2014 in the Swedish Coronary Angiography and Angioplasty Register (SCAAR).

The researchers divided patients into 3 treatment groups: bivalirudin, heparin, and GPI. However, 77% of patients in the bivalirudin group also received heparin, and 3.6% received a GPI prior to or during the PCI procedure. In the GPI group, 77% of patients also received heparin.

The rates of stent thrombosis were low in all 3 groups—0.84% in the bivalirudin group, 0.94% in the heparin group, and 0.83% in the GPI group.

For all 3 drugs, mortality at 1 year was numerically higher if the stent thrombosis occurred between 2 and 30 days, as compared with day 0 to 1 post-PCI.

“[A] possible explanation is that a stent thrombosis that happens once the patient has left the hospital is likely to cause a more substantial infarction, the reason being longer delay from symptoms to revascularization,” Dr Grimfjard said.

He added that a more substantial myocardial infarction typically leads to more heart failure and arrhythmia long-term. Unfortunately, the findings regarding the timing of stent thrombosis do not offer any guidance for choosing optimal antithrombotic treatment.

He and his colleagues are currently enrolling patients in a 6000-patient, registry-based, randomized clinical trial called SWEDEHART-Validate. The team will compare heparin alone to bivalirudin and optional low-dose heparin in STEMI and non-STEMI patients undergoing PCI.

“Hopefully, this large, randomized trial will bring clarity to the choice of antithrombotic treatment strategy in these patients,” Dr Grimfjard said.

Vial of heparin

PARIS—New research suggests that patients who have undergone primary percutaneous coronary intervention (PCI) have a low risk of stent thrombosis, regardless of the anticoagulant therapy they receive.

In a large, registry-based study, stent thrombosis occurred in less than 1% of patients, regardless of whether they received bivalirudin with or without heparin, heparin alone, or a GP IIb/IIIa inhibitor (GPI) with or without heparin.

The study also showed that patients who experienced stent thrombosis between days 2 and 30, regardless of drug regimen, were more likely to die within a year than patients who developed stent thrombosis within the first 24 hours of their procedure.

Per Grimfjard, of Vasteras Hospital/Uppsala University in Sweden, presented these findings at EuroPCR 2015.

A number of recent studies have raised concerns that bivalirudin may increase the risk of stent thrombosis compared with heparin. But rates of stent thrombosis have differed substantially between studies.

So Dr Grimfjard and his colleagues decided to review stent thrombosis rates by drug choice among more than 30,000 patients who were treated with primary PCI for ST-elevation myocardial infarction (STEMI) between January 2007 and July 2014 in the Swedish Coronary Angiography and Angioplasty Register (SCAAR).

The researchers divided patients into 3 treatment groups: bivalirudin, heparin, and GPI. However, 77% of patients in the bivalirudin group also received heparin, and 3.6% received a GPI prior to or during the PCI procedure. In the GPI group, 77% of patients also received heparin.

The rates of stent thrombosis were low in all 3 groups—0.84% in the bivalirudin group, 0.94% in the heparin group, and 0.83% in the GPI group.

For all 3 drugs, mortality at 1 year was numerically higher if the stent thrombosis occurred between 2 and 30 days, as compared with day 0 to 1 post-PCI.

“[A] possible explanation is that a stent thrombosis that happens once the patient has left the hospital is likely to cause a more substantial infarction, the reason being longer delay from symptoms to revascularization,” Dr Grimfjard said.

He added that a more substantial myocardial infarction typically leads to more heart failure and arrhythmia long-term. Unfortunately, the findings regarding the timing of stent thrombosis do not offer any guidance for choosing optimal antithrombotic treatment.

He and his colleagues are currently enrolling patients in a 6000-patient, registry-based, randomized clinical trial called SWEDEHART-Validate. The team will compare heparin alone to bivalirudin and optional low-dose heparin in STEMI and non-STEMI patients undergoing PCI.

“Hopefully, this large, randomized trial will bring clarity to the choice of antithrombotic treatment strategy in these patients,” Dr Grimfjard said.

Blood samples

Photo by Graham Colm

A new method for identifying immune cells could pave the way for rapid detection of hematologic malignancies from a small blood sample, according to researchers.

The team found they could use wavelength modulated Raman spectroscopy (WMRS) to identify subsets of T cells, natural killer cells, and dendritic cells.

Traditional methods of identifying these cells usually involve labeling them with fluorescent or magnetically labeled antibodies.

Using WMRS, the researchers were able to identify immune cells with no labeling at all, thus permitting rapid identification and further analysis to take place with no potential alteration to the cells.

Simon Powis, PhD, of the University of St Andrews in Fife, Scotland, and his colleagues described this work in PLOS ONE.

Raman scattering refers to light scattering from molecules in a sample where the light energy can be shifted up or down and recorded as a “molecular fingerprint” that can be used for identification. Normally, this process is very weak and further hampered by other background light (eg, fluorescence).

WMRS subtly changes the incident laser light that, in turn, results in a modulation of the Raman signal, allowing it to be extracted from any (stationary) interfering signal.

Using WMRS, Dr Powis and his colleagues found they could identify CD4⁺ T cells, CD8⁺ T cells, CD56⁺ natural killer cells, CD303⁺ lymphoid/plasmacytoid dendritic cells, and CD1c⁺ myeloid dendritic cells.

“Under a normal light microscope, these immune cells essentially all look identical,” Dr Powis said. “With this new method, we can identify key cell types without any labeling.”

“Our next goal is to make a full catalogue of all the normal cell types of the immune system that can be detected in the bloodstream. Once we have this completed, we can then collaborate with our clinical colleagues to start identifying when these immune cells are altered, in conditions such as leukemia and lymphoma, potentially providing a rapid detection system from just a small blood sample.”

Blood samples

Photo by Graham Colm

A new method for identifying immune cells could pave the way for rapid detection of hematologic malignancies from a small blood sample, according to researchers.

The team found they could use wavelength modulated Raman spectroscopy (WMRS) to identify subsets of T cells, natural killer cells, and dendritic cells.

Traditional methods of identifying these cells usually involve labeling them with fluorescent or magnetically labeled antibodies.

Using WMRS, the researchers were able to identify immune cells with no labeling at all, thus permitting rapid identification and further analysis to take place with no potential alteration to the cells.

Simon Powis, PhD, of the University of St Andrews in Fife, Scotland, and his colleagues described this work in PLOS ONE.

Raman scattering refers to light scattering from molecules in a sample where the light energy can be shifted up or down and recorded as a “molecular fingerprint” that can be used for identification. Normally, this process is very weak and further hampered by other background light (eg, fluorescence).

WMRS subtly changes the incident laser light that, in turn, results in a modulation of the Raman signal, allowing it to be extracted from any (stationary) interfering signal.

Using WMRS, Dr Powis and his colleagues found they could identify CD4⁺ T cells, CD8⁺ T cells, CD56⁺ natural killer cells, CD303⁺ lymphoid/plasmacytoid dendritic cells, and CD1c⁺ myeloid dendritic cells.

“Under a normal light microscope, these immune cells essentially all look identical,” Dr Powis said. “With this new method, we can identify key cell types without any labeling.”

“Our next goal is to make a full catalogue of all the normal cell types of the immune system that can be detected in the bloodstream. Once we have this completed, we can then collaborate with our clinical colleagues to start identifying when these immune cells are altered, in conditions such as leukemia and lymphoma, potentially providing a rapid detection system from just a small blood sample.”

Blood samples

Photo by Graham Colm

A new method for identifying immune cells could pave the way for rapid detection of hematologic malignancies from a small blood sample, according to researchers.

The team found they could use wavelength modulated Raman spectroscopy (WMRS) to identify subsets of T cells, natural killer cells, and dendritic cells.

Traditional methods of identifying these cells usually involve labeling them with fluorescent or magnetically labeled antibodies.

Using WMRS, the researchers were able to identify immune cells with no labeling at all, thus permitting rapid identification and further analysis to take place with no potential alteration to the cells.

Simon Powis, PhD, of the University of St Andrews in Fife, Scotland, and his colleagues described this work in PLOS ONE.

Raman scattering refers to light scattering from molecules in a sample where the light energy can be shifted up or down and recorded as a “molecular fingerprint” that can be used for identification. Normally, this process is very weak and further hampered by other background light (eg, fluorescence).

WMRS subtly changes the incident laser light that, in turn, results in a modulation of the Raman signal, allowing it to be extracted from any (stationary) interfering signal.

Using WMRS, Dr Powis and his colleagues found they could identify CD4⁺ T cells, CD8⁺ T cells, CD56⁺ natural killer cells, CD303⁺ lymphoid/plasmacytoid dendritic cells, and CD1c⁺ myeloid dendritic cells.

“Under a normal light microscope, these immune cells essentially all look identical,” Dr Powis said. “With this new method, we can identify key cell types without any labeling.”

“Our next goal is to make a full catalogue of all the normal cell types of the immune system that can be detected in the bloodstream. Once we have this completed, we can then collaborate with our clinical colleagues to start identifying when these immune cells are altered, in conditions such as leukemia and lymphoma, potentially providing a rapid detection system from just a small blood sample.”

Lab mouse

Co-infection with malaria and a virus closely related to the Epstein-Barr virus (EBV) may make the malaria lethal, according to preclinical research published in PLOS Pathogens.

Children in sub-Saharan Africa become infected with EBV in infancy.

Within the same time period, they become susceptible to malaria parasite infection because protective antibodies from their mothers fade away.

“Where we think kids get into trouble is when both infections are happening at the same time, because case reports show EBV can produce a weeks-long suppression of the immune system,” said Tracey Lamb, PhD, of Emory University School of Medicine in Atlanta, Georgia.

Dr Lamb and her colleagues studied mice infected by the malaria parasite Plasmodium yoelii, which is usually non-lethal because the mice develop antibodies that control the parasites.

The researchers found that co-infection with murine gammaherpesvirus 68 (MHV68), a close relative of EBV that infects mice, made P yoelii lethal.

However, mice that had entered the chronic phase of MHV68 infection (several weeks to months after primary infection) were not affected.

The experiments indicated that MHV68 infection hinders the immune system in developing antibodies against P yoelii.

“These results are part of a pattern of evidence suggesting that clinicians treating severe malaria should check for acute EBV co-infection, and that ongoing malaria studies should include EBV as a potential risk factor for more severe forms of the disease,” said Caline Matar, a graduate student at Emory University School of Medicine.

“This phenomenon may not be unique to EBV,” added Sam Speck, PhD, also of Emory University School of Medicine.

“[I]nfections with other pathogens may also exacerbate malarial disease, since many pathogens have the capacity to suppress various components of the host immune response.”

Lab mouse

Co-infection with malaria and a virus closely related to the Epstein-Barr virus (EBV) may make the malaria lethal, according to preclinical research published in PLOS Pathogens.

Children in sub-Saharan Africa become infected with EBV in infancy.

Within the same time period, they become susceptible to malaria parasite infection because protective antibodies from their mothers fade away.

“Where we think kids get into trouble is when both infections are happening at the same time, because case reports show EBV can produce a weeks-long suppression of the immune system,” said Tracey Lamb, PhD, of Emory University School of Medicine in Atlanta, Georgia.

Dr Lamb and her colleagues studied mice infected by the malaria parasite Plasmodium yoelii, which is usually non-lethal because the mice develop antibodies that control the parasites.

The researchers found that co-infection with murine gammaherpesvirus 68 (MHV68), a close relative of EBV that infects mice, made P yoelii lethal.

However, mice that had entered the chronic phase of MHV68 infection (several weeks to months after primary infection) were not affected.

The experiments indicated that MHV68 infection hinders the immune system in developing antibodies against P yoelii.

“These results are part of a pattern of evidence suggesting that clinicians treating severe malaria should check for acute EBV co-infection, and that ongoing malaria studies should include EBV as a potential risk factor for more severe forms of the disease,” said Caline Matar, a graduate student at Emory University School of Medicine.

“This phenomenon may not be unique to EBV,” added Sam Speck, PhD, also of Emory University School of Medicine.

“[I]nfections with other pathogens may also exacerbate malarial disease, since many pathogens have the capacity to suppress various components of the host immune response.”

Lab mouse

Co-infection with malaria and a virus closely related to the Epstein-Barr virus (EBV) may make the malaria lethal, according to preclinical research published in PLOS Pathogens.

Children in sub-Saharan Africa become infected with EBV in infancy.

Within the same time period, they become susceptible to malaria parasite infection because protective antibodies from their mothers fade away.

“Where we think kids get into trouble is when both infections are happening at the same time, because case reports show EBV can produce a weeks-long suppression of the immune system,” said Tracey Lamb, PhD, of Emory University School of Medicine in Atlanta, Georgia.

Dr Lamb and her colleagues studied mice infected by the malaria parasite Plasmodium yoelii, which is usually non-lethal because the mice develop antibodies that control the parasites.

The researchers found that co-infection with murine gammaherpesvirus 68 (MHV68), a close relative of EBV that infects mice, made P yoelii lethal.

However, mice that had entered the chronic phase of MHV68 infection (several weeks to months after primary infection) were not affected.

The experiments indicated that MHV68 infection hinders the immune system in developing antibodies against P yoelii.

“These results are part of a pattern of evidence suggesting that clinicians treating severe malaria should check for acute EBV co-infection, and that ongoing malaria studies should include EBV as a potential risk factor for more severe forms of the disease,” said Caline Matar, a graduate student at Emory University School of Medicine.

“This phenomenon may not be unique to EBV,” added Sam Speck, PhD, also of Emory University School of Medicine.

“[I]nfections with other pathogens may also exacerbate malarial disease, since many pathogens have the capacity to suppress various components of the host immune response.”

With the increase in cesarean sections worldwide, it is imperative that physicians properly inform their patients as to potential procedure risks. One potential postcesarean section problem that is receiving increasing attention is the isthmocele or niche.

Defined as an anechoic area in the cesarean section scar, it has been noted to occur in 24%-69% of women undergoing transvaginal sonography, and 56%-78% of women evaluated with transvaginal saline infused sonogram. While most cesarean section defects are asymptomatic, the isthmocele has been noted to be associated with abnormal uterine bleeding, including prolonged menstruation or postmenopausal spotting, and fertility concerns (BJOG. 2014;121:145-56).

Interestingly, it has been 40 years since Stewart, et al. first reported the relationship of abnormal uterine bleeding and cesarean section (Br. J. Gynaecol. 1975;82:682-6). Bloody fluid can be generated at the isthmocele site, which travels up the endometrial canal, thus impacting implantation. The niche can also be the site of ectopic pregnancy implantation.

In this edition of Master Class in gynecologic surgery, I have asked my newest partner, Dr. Kirsten Sasaki, to share our views on this increasingly important subject. Dr. Sasaki completed her internship and residency at Tufts Medical Center, Boston, where she was awarded the Outstanding Chief Resident Clinician Award. Dr. Sasaki then went on to become our second fellow in the Fellowship in Minimally Invasive Gynecologic Surgery in affiliation with AAGL and SRS at Advocate Lutheran General Hospital, Park Ridge, Ill. Once again, Dr. Sasaki was singled out for her excellent teaching and research capabilities. Ultimately however, it was her tremendous surgical skills and surgical sense that led Dr. Aarathi Cholkeri-Singh and I to invite her into our practice.

Dr. Miller is clinical associate professor at the University of Illinois at Chicago, immediate past president of the International Society for Gynecologic Endoscopy (ISGE), and a past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville, Ill., and Schaumburg, Ill.; the director of minimally invasive gynecologic surgery and the director of the AAGL/SRS fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column, Master Class. Dr. Miller is a consultant and on the speakers bureau for Ethicon. He is also a consultant, on the speakers bureau, and has received grant and research support from Intuitive Surgical.

With the increase in cesarean sections worldwide, it is imperative that physicians properly inform their patients as to potential procedure risks. One potential postcesarean section problem that is receiving increasing attention is the isthmocele or niche.

Defined as an anechoic area in the cesarean section scar, it has been noted to occur in 24%-69% of women undergoing transvaginal sonography, and 56%-78% of women evaluated with transvaginal saline infused sonogram. While most cesarean section defects are asymptomatic, the isthmocele has been noted to be associated with abnormal uterine bleeding, including prolonged menstruation or postmenopausal spotting, and fertility concerns (BJOG. 2014;121:145-56).

Interestingly, it has been 40 years since Stewart, et al. first reported the relationship of abnormal uterine bleeding and cesarean section (Br. J. Gynaecol. 1975;82:682-6). Bloody fluid can be generated at the isthmocele site, which travels up the endometrial canal, thus impacting implantation. The niche can also be the site of ectopic pregnancy implantation.

In this edition of Master Class in gynecologic surgery, I have asked my newest partner, Dr. Kirsten Sasaki, to share our views on this increasingly important subject. Dr. Sasaki completed her internship and residency at Tufts Medical Center, Boston, where she was awarded the Outstanding Chief Resident Clinician Award. Dr. Sasaki then went on to become our second fellow in the Fellowship in Minimally Invasive Gynecologic Surgery in affiliation with AAGL and SRS at Advocate Lutheran General Hospital, Park Ridge, Ill. Once again, Dr. Sasaki was singled out for her excellent teaching and research capabilities. Ultimately however, it was her tremendous surgical skills and surgical sense that led Dr. Aarathi Cholkeri-Singh and I to invite her into our practice.

Dr. Miller is clinical associate professor at the University of Illinois at Chicago, immediate past president of the International Society for Gynecologic Endoscopy (ISGE), and a past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville, Ill., and Schaumburg, Ill.; the director of minimally invasive gynecologic surgery and the director of the AAGL/SRS fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column, Master Class. Dr. Miller is a consultant and on the speakers bureau for Ethicon. He is also a consultant, on the speakers bureau, and has received grant and research support from Intuitive Surgical.

With the increase in cesarean sections worldwide, it is imperative that physicians properly inform their patients as to potential procedure risks. One potential postcesarean section problem that is receiving increasing attention is the isthmocele or niche.

Defined as an anechoic area in the cesarean section scar, it has been noted to occur in 24%-69% of women undergoing transvaginal sonography, and 56%-78% of women evaluated with transvaginal saline infused sonogram. While most cesarean section defects are asymptomatic, the isthmocele has been noted to be associated with abnormal uterine bleeding, including prolonged menstruation or postmenopausal spotting, and fertility concerns (BJOG. 2014;121:145-56).

Interestingly, it has been 40 years since Stewart, et al. first reported the relationship of abnormal uterine bleeding and cesarean section (Br. J. Gynaecol. 1975;82:682-6). Bloody fluid can be generated at the isthmocele site, which travels up the endometrial canal, thus impacting implantation. The niche can also be the site of ectopic pregnancy implantation.

In this edition of Master Class in gynecologic surgery, I have asked my newest partner, Dr. Kirsten Sasaki, to share our views on this increasingly important subject. Dr. Sasaki completed her internship and residency at Tufts Medical Center, Boston, where she was awarded the Outstanding Chief Resident Clinician Award. Dr. Sasaki then went on to become our second fellow in the Fellowship in Minimally Invasive Gynecologic Surgery in affiliation with AAGL and SRS at Advocate Lutheran General Hospital, Park Ridge, Ill. Once again, Dr. Sasaki was singled out for her excellent teaching and research capabilities. Ultimately however, it was her tremendous surgical skills and surgical sense that led Dr. Aarathi Cholkeri-Singh and I to invite her into our practice.

Dr. Miller is clinical associate professor at the University of Illinois at Chicago, immediate past president of the International Society for Gynecologic Endoscopy (ISGE), and a past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville, Ill., and Schaumburg, Ill.; the director of minimally invasive gynecologic surgery and the director of the AAGL/SRS fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column, Master Class. Dr. Miller is a consultant and on the speakers bureau for Ethicon. He is also a consultant, on the speakers bureau, and has received grant and research support from Intuitive Surgical.