Through the Leadership Development and Diversity Committee, the SVS continues its strong commitment to leadership development in women. The Women's Leadership Training Grant seeks to identify female surgeons who want to sharpen their leadership skills. A $5,000 award will defray costs for travel, hotel accommodations and registration expenses to attend relevant courses and/or other leadership training opportunities and activities. Application deadline is March 14.

Through the Leadership Development and Diversity Committee, the SVS continues its strong commitment to leadership development in women. The Women's Leadership Training Grant seeks to identify female surgeons who want to sharpen their leadership skills. A $5,000 award will defray costs for travel, hotel accommodations and registration expenses to attend relevant courses and/or other leadership training opportunities and activities. Application deadline is March 14.

Through the Leadership Development and Diversity Committee, the SVS continues its strong commitment to leadership development in women. The Women's Leadership Training Grant seeks to identify female surgeons who want to sharpen their leadership skills. A $5,000 award will defray costs for travel, hotel accommodations and registration expenses to attend relevant courses and/or other leadership training opportunities and activities. Application deadline is March 14.

The SVS and American Venous Forum seek to update their joint clinical practice guidelines on the care of patients with varicose veins and associated chronic venous diseases (pdf of full text here). This update will address new research and advances in care since the original guidelines were published in 2011.

The SVS Document Oversight Committee seeks current SVS members with significant relevant practice and research experience to participate. All interested members must complete a conflict of interest disclosure for 2018-2019 to be considered. The SVS requires each volunteer to disclose all relevant financial relationships with commercial interests within the past 12 months. Please indicate your interest here by March 1.

The SVS and American Venous Forum seek to update their joint clinical practice guidelines on the care of patients with varicose veins and associated chronic venous diseases (pdf of full text here). This update will address new research and advances in care since the original guidelines were published in 2011.

The SVS Document Oversight Committee seeks current SVS members with significant relevant practice and research experience to participate. All interested members must complete a conflict of interest disclosure for 2018-2019 to be considered. The SVS requires each volunteer to disclose all relevant financial relationships with commercial interests within the past 12 months. Please indicate your interest here by March 1.

The SVS and American Venous Forum seek to update their joint clinical practice guidelines on the care of patients with varicose veins and associated chronic venous diseases (pdf of full text here). This update will address new research and advances in care since the original guidelines were published in 2011.

The SVS Document Oversight Committee seeks current SVS members with significant relevant practice and research experience to participate. All interested members must complete a conflict of interest disclosure for 2018-2019 to be considered. The SVS requires each volunteer to disclose all relevant financial relationships with commercial interests within the past 12 months. Please indicate your interest here by March 1.

California voters passed a law two years ago that allows terminally ill people to take lethal drugs to end their lives, but controversy is growing over a newer rule that effectively bans that option in the state’s eight veterans homes.

Proponents of medical aid-in-dying and residents of the Veterans Home of California-Yountville — the largest in the nation — are protesting a regulation passed last year by the California Department of Veterans Affairs, or CalVet, that requires that anyone living in the facilities must be discharged if they intend to use the law.

That’s a position shared by most — but not all — states where aid-in-dying is allowed. As more U.S. jurisdictions consider whether to legalize the practice, the status of terminally ill veterans living in state-run homes will loom large.

“It would be a terrible hardship, because I have no place to go,” said Bob Sloan, 73, who suffers from congestive heart failure and other serious cardiac problems. He said he intends to seek medical aid-in-dying if doctors certify he has six months or less to live.

“I’m not going to be a vegetable,” said Sloan, a Vietnam War-era veteran who moved into the Yountville center five years ago. “I’m not going to end up living in so much pain it’s unbearable.”

A CalVet official said the agency adopted the rule to avoid violating a federal statute that prohibits using U.S. government resources for physician-assisted death. Otherwise, the agency would jeopardize nearly $68 million in federal funds that helps run the facilities, said June Iljana, CalVet’s deputy secretary of communications.

California is not alone. Three other states where aid-in-dying is legal — Oregon, Colorado and Vermont — all prohibit use of lethal medications in state-run veterans homes.

In Montana, where aid-in-dying is allowed under a state Supreme Court ruling, officials didn’t respond to multiple requests about whether veterans would be able to use the law in the residences. However, Dr. Eric Kress, a Missoula physician who prescribes the lethal medication, says he has transferred patients to hospice, to relatives’ homes, even to extended-stay hotels to avoid conflict.

In Washington, D.C., where an aid-in-dying law took effect last summer, the Armed Forces Retirement Home won’t assist patients in any way. Those who wish to use the law would be referred to an ethics committee for individual consideration, spokesman Christopher Kelly said in an email.

Only Washington state has a policy that allows veterans to remain in government-run residences if they intend to ingest lethal medications.. At least one veteran has died in a state-run home using that law, said Heidi Audette, a spokeswoman for the state’s Department of Veterans Affairs.

Paul Sherbo, a spokesman for the U.S. Department of Veterans Affairs, said the choice is up to the states.

“VA does not mandate how states comply with federal law,” Sherbo said in an email. “There are a number of ways individual states can choose to handle such situations and still be in compliance.”

To date, none of the 2,400 residents of California’s veterans homes has formally requested medical aid-in-dying, said Iljana. That includes the more than 900 residents of the Yountville center, located about 60 miles north of San Francisco.

“We would respectfully and compassionately assist them in transferring to a hospice, family home or other location,” Iljana said in an email. “We will readmit them immediately if they change their minds.”

But Kathryn Tucker, executive director of the End of Life Liberty Project, an advocacy group that supports aid-in-dying, said that CalVet is interpreting the federal regulations too broadly and denying terminally ill veterans the right to choose a “peaceful death” through medical assistance.

“Nothing exists in the federal statute’s language that would prohibit a resident from receiving aid-in-dying services at state homes, so long as they are not provided using federal funds or employees,” she said.

Ed Warren, head of the Allied Council, a group representing veterans at the Yountville site, co-signed a letter to CalVet officials protesting the ruling.

“My point of view is that it is inhumane to expect people in the last stages of dying to go through the hullabaloo of leaving their homes,” he said.

In Washington state, a 60-year-old man diagnosed with terminal chronic obstructive pulmonary disease, or COPD, died in June 2015 after ingesting lethal drugs at the Washington Soldiers Home in Orting, where he lived.

“It was all done very much in the open,” said Chris Fruitrich, a volunteer with the group End of Life Washington, which assisted the man.

There has been no indication that the policy jeopardizes the nearly $47 million the agency receives each year in federal funds, said Audette, the state VA spokeswoman.

In California, additional protests have centered on allegations that CalVet suppressed information about the aid-in-dying law.

Critics at the Yountville home contend that CalVet passed the discharge rule quietly, with little public input. Then the agency refused to broadcast a public meeting about medical aid-in-dying on KVET, the center’s state-run, closed-circuit television station.

Iljana said the Aug. 21 meeting, led by Tucker and Dr. Robert Brody, also a supporter of aid-in-dying, violated state rules that prohibit using public resources to promote political causes.

“Free speech is great and criticizing the government is great, but not using the government’s own resources and paid staff to advocate for a change in the law,” Iljana wrote in an email to prohibit the broadcast.

That decision, however, prompted Jac Warren, 81, who has been KVET’s station manager for eight years, to resign last month in protest, citing censorship.

“What is at issue is whether a state may completely suppress the dissemination of concededly truthful information about entirely lawful activity,” Warren wrote in an email to CalVet.

The hour-long meeting, attended by about 50 people, was not propaganda, Tucker said, but “an educational event with information provided by an attorney and a physician who both specialize in their respective fields in end-of-life care.”

Bob Sloan, who works as an engineer at KVET for a $400 monthly stipend, disagreed with the decision not to broadcast the meeting on the system that serves residents of the Yountville home.

Sloan said he knows other residents who would like to be able to use California’s aid-in-dying law if their illnesses progress.

“The only other option that people have in this state is committing suicide,” he said. “If I can’t find some way of doing it legally, I’ll do it illegally.”

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

California voters passed a law two years ago that allows terminally ill people to take lethal drugs to end their lives, but controversy is growing over a newer rule that effectively bans that option in the state’s eight veterans homes.

Proponents of medical aid-in-dying and residents of the Veterans Home of California-Yountville — the largest in the nation — are protesting a regulation passed last year by the California Department of Veterans Affairs, or CalVet, that requires that anyone living in the facilities must be discharged if they intend to use the law.

That’s a position shared by most — but not all — states where aid-in-dying is allowed. As more U.S. jurisdictions consider whether to legalize the practice, the status of terminally ill veterans living in state-run homes will loom large.

“It would be a terrible hardship, because I have no place to go,” said Bob Sloan, 73, who suffers from congestive heart failure and other serious cardiac problems. He said he intends to seek medical aid-in-dying if doctors certify he has six months or less to live.

“I’m not going to be a vegetable,” said Sloan, a Vietnam War-era veteran who moved into the Yountville center five years ago. “I’m not going to end up living in so much pain it’s unbearable.”

A CalVet official said the agency adopted the rule to avoid violating a federal statute that prohibits using U.S. government resources for physician-assisted death. Otherwise, the agency would jeopardize nearly $68 million in federal funds that helps run the facilities, said June Iljana, CalVet’s deputy secretary of communications.

California is not alone. Three other states where aid-in-dying is legal — Oregon, Colorado and Vermont — all prohibit use of lethal medications in state-run veterans homes.

In Montana, where aid-in-dying is allowed under a state Supreme Court ruling, officials didn’t respond to multiple requests about whether veterans would be able to use the law in the residences. However, Dr. Eric Kress, a Missoula physician who prescribes the lethal medication, says he has transferred patients to hospice, to relatives’ homes, even to extended-stay hotels to avoid conflict.

In Washington, D.C., where an aid-in-dying law took effect last summer, the Armed Forces Retirement Home won’t assist patients in any way. Those who wish to use the law would be referred to an ethics committee for individual consideration, spokesman Christopher Kelly said in an email.

Only Washington state has a policy that allows veterans to remain in government-run residences if they intend to ingest lethal medications.. At least one veteran has died in a state-run home using that law, said Heidi Audette, a spokeswoman for the state’s Department of Veterans Affairs.

Paul Sherbo, a spokesman for the U.S. Department of Veterans Affairs, said the choice is up to the states.

“VA does not mandate how states comply with federal law,” Sherbo said in an email. “There are a number of ways individual states can choose to handle such situations and still be in compliance.”

To date, none of the 2,400 residents of California’s veterans homes has formally requested medical aid-in-dying, said Iljana. That includes the more than 900 residents of the Yountville center, located about 60 miles north of San Francisco.

“We would respectfully and compassionately assist them in transferring to a hospice, family home or other location,” Iljana said in an email. “We will readmit them immediately if they change their minds.”

But Kathryn Tucker, executive director of the End of Life Liberty Project, an advocacy group that supports aid-in-dying, said that CalVet is interpreting the federal regulations too broadly and denying terminally ill veterans the right to choose a “peaceful death” through medical assistance.

“Nothing exists in the federal statute’s language that would prohibit a resident from receiving aid-in-dying services at state homes, so long as they are not provided using federal funds or employees,” she said.

Ed Warren, head of the Allied Council, a group representing veterans at the Yountville site, co-signed a letter to CalVet officials protesting the ruling.

“My point of view is that it is inhumane to expect people in the last stages of dying to go through the hullabaloo of leaving their homes,” he said.

In Washington state, a 60-year-old man diagnosed with terminal chronic obstructive pulmonary disease, or COPD, died in June 2015 after ingesting lethal drugs at the Washington Soldiers Home in Orting, where he lived.

“It was all done very much in the open,” said Chris Fruitrich, a volunteer with the group End of Life Washington, which assisted the man.

There has been no indication that the policy jeopardizes the nearly $47 million the agency receives each year in federal funds, said Audette, the state VA spokeswoman.

In California, additional protests have centered on allegations that CalVet suppressed information about the aid-in-dying law.

Critics at the Yountville home contend that CalVet passed the discharge rule quietly, with little public input. Then the agency refused to broadcast a public meeting about medical aid-in-dying on KVET, the center’s state-run, closed-circuit television station.

Iljana said the Aug. 21 meeting, led by Tucker and Dr. Robert Brody, also a supporter of aid-in-dying, violated state rules that prohibit using public resources to promote political causes.

“Free speech is great and criticizing the government is great, but not using the government’s own resources and paid staff to advocate for a change in the law,” Iljana wrote in an email to prohibit the broadcast.

That decision, however, prompted Jac Warren, 81, who has been KVET’s station manager for eight years, to resign last month in protest, citing censorship.

“What is at issue is whether a state may completely suppress the dissemination of concededly truthful information about entirely lawful activity,” Warren wrote in an email to CalVet.

The hour-long meeting, attended by about 50 people, was not propaganda, Tucker said, but “an educational event with information provided by an attorney and a physician who both specialize in their respective fields in end-of-life care.”

Bob Sloan, who works as an engineer at KVET for a $400 monthly stipend, disagreed with the decision not to broadcast the meeting on the system that serves residents of the Yountville home.

Sloan said he knows other residents who would like to be able to use California’s aid-in-dying law if their illnesses progress.

“The only other option that people have in this state is committing suicide,” he said. “If I can’t find some way of doing it legally, I’ll do it illegally.”

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

California voters passed a law two years ago that allows terminally ill people to take lethal drugs to end their lives, but controversy is growing over a newer rule that effectively bans that option in the state’s eight veterans homes.

Proponents of medical aid-in-dying and residents of the Veterans Home of California-Yountville — the largest in the nation — are protesting a regulation passed last year by the California Department of Veterans Affairs, or CalVet, that requires that anyone living in the facilities must be discharged if they intend to use the law.

That’s a position shared by most — but not all — states where aid-in-dying is allowed. As more U.S. jurisdictions consider whether to legalize the practice, the status of terminally ill veterans living in state-run homes will loom large.

“It would be a terrible hardship, because I have no place to go,” said Bob Sloan, 73, who suffers from congestive heart failure and other serious cardiac problems. He said he intends to seek medical aid-in-dying if doctors certify he has six months or less to live.

“I’m not going to be a vegetable,” said Sloan, a Vietnam War-era veteran who moved into the Yountville center five years ago. “I’m not going to end up living in so much pain it’s unbearable.”

A CalVet official said the agency adopted the rule to avoid violating a federal statute that prohibits using U.S. government resources for physician-assisted death. Otherwise, the agency would jeopardize nearly $68 million in federal funds that helps run the facilities, said June Iljana, CalVet’s deputy secretary of communications.

California is not alone. Three other states where aid-in-dying is legal — Oregon, Colorado and Vermont — all prohibit use of lethal medications in state-run veterans homes.

In Montana, where aid-in-dying is allowed under a state Supreme Court ruling, officials didn’t respond to multiple requests about whether veterans would be able to use the law in the residences. However, Dr. Eric Kress, a Missoula physician who prescribes the lethal medication, says he has transferred patients to hospice, to relatives’ homes, even to extended-stay hotels to avoid conflict.

In Washington, D.C., where an aid-in-dying law took effect last summer, the Armed Forces Retirement Home won’t assist patients in any way. Those who wish to use the law would be referred to an ethics committee for individual consideration, spokesman Christopher Kelly said in an email.

Only Washington state has a policy that allows veterans to remain in government-run residences if they intend to ingest lethal medications.. At least one veteran has died in a state-run home using that law, said Heidi Audette, a spokeswoman for the state’s Department of Veterans Affairs.

Paul Sherbo, a spokesman for the U.S. Department of Veterans Affairs, said the choice is up to the states.

“VA does not mandate how states comply with federal law,” Sherbo said in an email. “There are a number of ways individual states can choose to handle such situations and still be in compliance.”

To date, none of the 2,400 residents of California’s veterans homes has formally requested medical aid-in-dying, said Iljana. That includes the more than 900 residents of the Yountville center, located about 60 miles north of San Francisco.

“We would respectfully and compassionately assist them in transferring to a hospice, family home or other location,” Iljana said in an email. “We will readmit them immediately if they change their minds.”

But Kathryn Tucker, executive director of the End of Life Liberty Project, an advocacy group that supports aid-in-dying, said that CalVet is interpreting the federal regulations too broadly and denying terminally ill veterans the right to choose a “peaceful death” through medical assistance.

“Nothing exists in the federal statute’s language that would prohibit a resident from receiving aid-in-dying services at state homes, so long as they are not provided using federal funds or employees,” she said.

Ed Warren, head of the Allied Council, a group representing veterans at the Yountville site, co-signed a letter to CalVet officials protesting the ruling.

“My point of view is that it is inhumane to expect people in the last stages of dying to go through the hullabaloo of leaving their homes,” he said.

In Washington state, a 60-year-old man diagnosed with terminal chronic obstructive pulmonary disease, or COPD, died in June 2015 after ingesting lethal drugs at the Washington Soldiers Home in Orting, where he lived.

“It was all done very much in the open,” said Chris Fruitrich, a volunteer with the group End of Life Washington, which assisted the man.

There has been no indication that the policy jeopardizes the nearly $47 million the agency receives each year in federal funds, said Audette, the state VA spokeswoman.

In California, additional protests have centered on allegations that CalVet suppressed information about the aid-in-dying law.

Critics at the Yountville home contend that CalVet passed the discharge rule quietly, with little public input. Then the agency refused to broadcast a public meeting about medical aid-in-dying on KVET, the center’s state-run, closed-circuit television station.

Iljana said the Aug. 21 meeting, led by Tucker and Dr. Robert Brody, also a supporter of aid-in-dying, violated state rules that prohibit using public resources to promote political causes.

“Free speech is great and criticizing the government is great, but not using the government’s own resources and paid staff to advocate for a change in the law,” Iljana wrote in an email to prohibit the broadcast.

That decision, however, prompted Jac Warren, 81, who has been KVET’s station manager for eight years, to resign last month in protest, citing censorship.

“What is at issue is whether a state may completely suppress the dissemination of concededly truthful information about entirely lawful activity,” Warren wrote in an email to CalVet.

The hour-long meeting, attended by about 50 people, was not propaganda, Tucker said, but “an educational event with information provided by an attorney and a physician who both specialize in their respective fields in end-of-life care.”

Bob Sloan, who works as an engineer at KVET for a $400 monthly stipend, disagreed with the decision not to broadcast the meeting on the system that serves residents of the Yountville home.

Sloan said he knows other residents who would like to be able to use California’s aid-in-dying law if their illnesses progress.

“The only other option that people have in this state is committing suicide,” he said. “If I can’t find some way of doing it legally, I’ll do it illegally.”

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

The development of new antiepileptic drugs (AEDs) with novel mechanisms of action has not improved overall outcomes for patients with epilepsy, according to an analysis published online ahead of print December 26, 2017, in JAMA Neurology.

“A paradigm shift in treatment and research strategies is needed to improve the long-term outcomes of newly diagnosed epilepsy. Patients with drug-resistant epilepsy should be considered early for nonpharmacologic therapies, such as resective surgery and brain stimulation techniques,” said Patrick Kwan, MD, PhD, Chair of Neurology at the University of Melbourne and Head of Epilepsy at the Royal Melbourne Hospital, and colleagues.

Investigators Examined an Expanded Cohort

In an oft-cited study published in 2000, Dr. Kwan and Martin J. Brodie, MD, followed 470 patients with newly diagnosed epilepsy who presented to the Epilepsy Unit at the Western Infirmary in Glasgow from 1982 to 1998. They observed that seizures persisted despite AED treatment for more than one-third of patients. Participants with an inadequate response to their first or second treatment regimens were likely to develop refractory epilepsy.

To study whether newer AEDs have changed treatment outcomes, Dr. Kwan and colleagues followed 1,795 patients with newly diagnosed epilepsy who presented to the Western Infirmary between July 1, 1982, and October 31, 2012. The investigators followed patients until October 31, 2014, or until their deaths. Patients with poor adherence for reasons unrelated to drug efficacy or tolerability, those whose seizures resulted from drug use, and those with nonepileptic seizures were excluded from the analysis.

Patients visited the clinic every two to six weeks for the first six months after treatment initiation. After month six, participants had follow-up visits at least every four months. Physicians collected data routinely during standard clinical care. Patients recorded seizure descriptions and the number of seizures that occurred between visits.

Nearly Two-Thirds Became Seizure-Free

Of the 1,795 study participants, 969 (53.7%) were male. Patients’ median age at referral was 33. In all, 386 patients (21.5%) had generalized epilepsy, and 1,409 patients (78.5%) had focal epilepsy. Follow-up lasted for a median of 11 years.

As of the final follow-up visit, 1,440 patients (80.2%) were receiving AED monotherapy, and 355 (19.8%) were receiving two or more AEDs. In all, 1,144 participants (63.7%) had been seizure-free for the previous 12 months or longer, of whom 993 (55.3%) had attained this outcome by taking a single AED. The remaining 151 seizure-free patients had achieved this outcome by taking two or more AEDs.

In all, 816 participants (45.4%) achieved at least one year of seizure freedom while taking their first AED, and 212 patients (28.6%) achieved this outcome while taking the second regimen, which was either monotherapy or polytherapy. The first and second regimens together accounted for 1,028 of the 1,144 patients (89.9%) who achieved at least one year of seizure freedom. At the last follow-up, seizure freedom was more common among patients with generalized epilepsy (68.1%) than among those with focal epilepsy (62.5%).

Although the use of newer AEDs increased significantly during the study, the proportion of patients who were seizure-free at the last follow-up was similar in the three time-period subgroups that the investigators examined. The cumulative probability of one year of seizure freedom also was similar in these periods. Adjustment for patient characteristics did not alter these findings.

Number of AEDs Affected Likelihood of Seizure Freedom

For patients who did not achieve one year of seizure freedom with their first AED, the likelihood of uncontrolled epilepsy increased with each subsequent AED tried (odds ratio [OR], 1.73). Dr. Kwan and colleagues found a significant difference in the probability of seizure freedom between patients treated with the first and second AED regimens (hazard ratio [HR], 0.52). The difference in this outcome between participants treated with their second and third AED regimen was also significant (HR, 0.71). Whether epilepsy was focal or generalized did not affect these findings.

When the investigators adjusted their data for sex and epilepsy classification, they found that a high number of seizures in the year before treatment initiation, a history of smoking, a history of recreational drug use, a family history of epilepsy in first-degree relatives, previous brain injury, and psychiatric comorbidity were significantly associated with an adverse prognosis. Each increase in the number of seizures in the year before treatment was associated with a 6% decrease in the chance of seizure freedom at the last follow-up.

Is Better Seizure Control Possible?

“The observation that newer drugs have not increased the percentage of people who are rendered seizure-free is not new and should not be surprising,” said W. Allen Hauser, MD, Special Lecturer in the Gertrude H. Sergievsky Center at Columbia University in New York, in an accompanying editorial. “Even though mechanisms of action of specific drugs may differ, the same animal models have been used to predict successful suppression of seizures in preclinical studies for the last 80 years, and successful response has been the basis for clinical drug development for both old and new therapeutic agents.”

Nevertheless, the data “are sobering and somewhat disconcerting,” Dr. Hauser added. “In 1881, pioneering neurologist Sir William Gowers reported that he could not control seizures in 36% of the patients to whom he prescribed bromide compounds. It seems that we might not have improved our initial management results for a much longer period than the 30 years covered in the current study. While biologically unlikely, it is possible that a two-thirds proportion represents a ceiling for the initial control of epilepsy.”

—Erik Greb

Suggested Reading

Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].

Hauser WA. Questioning the effectiveness of newer antiseizure medications. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].

The development of new antiepileptic drugs (AEDs) with novel mechanisms of action has not improved overall outcomes for patients with epilepsy, according to an analysis published online ahead of print December 26, 2017, in JAMA Neurology.

“A paradigm shift in treatment and research strategies is needed to improve the long-term outcomes of newly diagnosed epilepsy. Patients with drug-resistant epilepsy should be considered early for nonpharmacologic therapies, such as resective surgery and brain stimulation techniques,” said Patrick Kwan, MD, PhD, Chair of Neurology at the University of Melbourne and Head of Epilepsy at the Royal Melbourne Hospital, and colleagues.

Investigators Examined an Expanded Cohort

In an oft-cited study published in 2000, Dr. Kwan and Martin J. Brodie, MD, followed 470 patients with newly diagnosed epilepsy who presented to the Epilepsy Unit at the Western Infirmary in Glasgow from 1982 to 1998. They observed that seizures persisted despite AED treatment for more than one-third of patients. Participants with an inadequate response to their first or second treatment regimens were likely to develop refractory epilepsy.

To study whether newer AEDs have changed treatment outcomes, Dr. Kwan and colleagues followed 1,795 patients with newly diagnosed epilepsy who presented to the Western Infirmary between July 1, 1982, and October 31, 2012. The investigators followed patients until October 31, 2014, or until their deaths. Patients with poor adherence for reasons unrelated to drug efficacy or tolerability, those whose seizures resulted from drug use, and those with nonepileptic seizures were excluded from the analysis.

Patients visited the clinic every two to six weeks for the first six months after treatment initiation. After month six, participants had follow-up visits at least every four months. Physicians collected data routinely during standard clinical care. Patients recorded seizure descriptions and the number of seizures that occurred between visits.

Nearly Two-Thirds Became Seizure-Free

Of the 1,795 study participants, 969 (53.7%) were male. Patients’ median age at referral was 33. In all, 386 patients (21.5%) had generalized epilepsy, and 1,409 patients (78.5%) had focal epilepsy. Follow-up lasted for a median of 11 years.

As of the final follow-up visit, 1,440 patients (80.2%) were receiving AED monotherapy, and 355 (19.8%) were receiving two or more AEDs. In all, 1,144 participants (63.7%) had been seizure-free for the previous 12 months or longer, of whom 993 (55.3%) had attained this outcome by taking a single AED. The remaining 151 seizure-free patients had achieved this outcome by taking two or more AEDs.

In all, 816 participants (45.4%) achieved at least one year of seizure freedom while taking their first AED, and 212 patients (28.6%) achieved this outcome while taking the second regimen, which was either monotherapy or polytherapy. The first and second regimens together accounted for 1,028 of the 1,144 patients (89.9%) who achieved at least one year of seizure freedom. At the last follow-up, seizure freedom was more common among patients with generalized epilepsy (68.1%) than among those with focal epilepsy (62.5%).

Although the use of newer AEDs increased significantly during the study, the proportion of patients who were seizure-free at the last follow-up was similar in the three time-period subgroups that the investigators examined. The cumulative probability of one year of seizure freedom also was similar in these periods. Adjustment for patient characteristics did not alter these findings.

Number of AEDs Affected Likelihood of Seizure Freedom

For patients who did not achieve one year of seizure freedom with their first AED, the likelihood of uncontrolled epilepsy increased with each subsequent AED tried (odds ratio [OR], 1.73). Dr. Kwan and colleagues found a significant difference in the probability of seizure freedom between patients treated with the first and second AED regimens (hazard ratio [HR], 0.52). The difference in this outcome between participants treated with their second and third AED regimen was also significant (HR, 0.71). Whether epilepsy was focal or generalized did not affect these findings.

When the investigators adjusted their data for sex and epilepsy classification, they found that a high number of seizures in the year before treatment initiation, a history of smoking, a history of recreational drug use, a family history of epilepsy in first-degree relatives, previous brain injury, and psychiatric comorbidity were significantly associated with an adverse prognosis. Each increase in the number of seizures in the year before treatment was associated with a 6% decrease in the chance of seizure freedom at the last follow-up.

Is Better Seizure Control Possible?

“The observation that newer drugs have not increased the percentage of people who are rendered seizure-free is not new and should not be surprising,” said W. Allen Hauser, MD, Special Lecturer in the Gertrude H. Sergievsky Center at Columbia University in New York, in an accompanying editorial. “Even though mechanisms of action of specific drugs may differ, the same animal models have been used to predict successful suppression of seizures in preclinical studies for the last 80 years, and successful response has been the basis for clinical drug development for both old and new therapeutic agents.”

Nevertheless, the data “are sobering and somewhat disconcerting,” Dr. Hauser added. “In 1881, pioneering neurologist Sir William Gowers reported that he could not control seizures in 36% of the patients to whom he prescribed bromide compounds. It seems that we might not have improved our initial management results for a much longer period than the 30 years covered in the current study. While biologically unlikely, it is possible that a two-thirds proportion represents a ceiling for the initial control of epilepsy.”

—Erik Greb

Suggested Reading

Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].

Hauser WA. Questioning the effectiveness of newer antiseizure medications. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].

The development of new antiepileptic drugs (AEDs) with novel mechanisms of action has not improved overall outcomes for patients with epilepsy, according to an analysis published online ahead of print December 26, 2017, in JAMA Neurology.

“A paradigm shift in treatment and research strategies is needed to improve the long-term outcomes of newly diagnosed epilepsy. Patients with drug-resistant epilepsy should be considered early for nonpharmacologic therapies, such as resective surgery and brain stimulation techniques,” said Patrick Kwan, MD, PhD, Chair of Neurology at the University of Melbourne and Head of Epilepsy at the Royal Melbourne Hospital, and colleagues.

Investigators Examined an Expanded Cohort

In an oft-cited study published in 2000, Dr. Kwan and Martin J. Brodie, MD, followed 470 patients with newly diagnosed epilepsy who presented to the Epilepsy Unit at the Western Infirmary in Glasgow from 1982 to 1998. They observed that seizures persisted despite AED treatment for more than one-third of patients. Participants with an inadequate response to their first or second treatment regimens were likely to develop refractory epilepsy.

To study whether newer AEDs have changed treatment outcomes, Dr. Kwan and colleagues followed 1,795 patients with newly diagnosed epilepsy who presented to the Western Infirmary between July 1, 1982, and October 31, 2012. The investigators followed patients until October 31, 2014, or until their deaths. Patients with poor adherence for reasons unrelated to drug efficacy or tolerability, those whose seizures resulted from drug use, and those with nonepileptic seizures were excluded from the analysis.

Patients visited the clinic every two to six weeks for the first six months after treatment initiation. After month six, participants had follow-up visits at least every four months. Physicians collected data routinely during standard clinical care. Patients recorded seizure descriptions and the number of seizures that occurred between visits.

Nearly Two-Thirds Became Seizure-Free

Of the 1,795 study participants, 969 (53.7%) were male. Patients’ median age at referral was 33. In all, 386 patients (21.5%) had generalized epilepsy, and 1,409 patients (78.5%) had focal epilepsy. Follow-up lasted for a median of 11 years.

As of the final follow-up visit, 1,440 patients (80.2%) were receiving AED monotherapy, and 355 (19.8%) were receiving two or more AEDs. In all, 1,144 participants (63.7%) had been seizure-free for the previous 12 months or longer, of whom 993 (55.3%) had attained this outcome by taking a single AED. The remaining 151 seizure-free patients had achieved this outcome by taking two or more AEDs.

In all, 816 participants (45.4%) achieved at least one year of seizure freedom while taking their first AED, and 212 patients (28.6%) achieved this outcome while taking the second regimen, which was either monotherapy or polytherapy. The first and second regimens together accounted for 1,028 of the 1,144 patients (89.9%) who achieved at least one year of seizure freedom. At the last follow-up, seizure freedom was more common among patients with generalized epilepsy (68.1%) than among those with focal epilepsy (62.5%).

Although the use of newer AEDs increased significantly during the study, the proportion of patients who were seizure-free at the last follow-up was similar in the three time-period subgroups that the investigators examined. The cumulative probability of one year of seizure freedom also was similar in these periods. Adjustment for patient characteristics did not alter these findings.

Number of AEDs Affected Likelihood of Seizure Freedom

For patients who did not achieve one year of seizure freedom with their first AED, the likelihood of uncontrolled epilepsy increased with each subsequent AED tried (odds ratio [OR], 1.73). Dr. Kwan and colleagues found a significant difference in the probability of seizure freedom between patients treated with the first and second AED regimens (hazard ratio [HR], 0.52). The difference in this outcome between participants treated with their second and third AED regimen was also significant (HR, 0.71). Whether epilepsy was focal or generalized did not affect these findings.

When the investigators adjusted their data for sex and epilepsy classification, they found that a high number of seizures in the year before treatment initiation, a history of smoking, a history of recreational drug use, a family history of epilepsy in first-degree relatives, previous brain injury, and psychiatric comorbidity were significantly associated with an adverse prognosis. Each increase in the number of seizures in the year before treatment was associated with a 6% decrease in the chance of seizure freedom at the last follow-up.

Is Better Seizure Control Possible?

“The observation that newer drugs have not increased the percentage of people who are rendered seizure-free is not new and should not be surprising,” said W. Allen Hauser, MD, Special Lecturer in the Gertrude H. Sergievsky Center at Columbia University in New York, in an accompanying editorial. “Even though mechanisms of action of specific drugs may differ, the same animal models have been used to predict successful suppression of seizures in preclinical studies for the last 80 years, and successful response has been the basis for clinical drug development for both old and new therapeutic agents.”

Nevertheless, the data “are sobering and somewhat disconcerting,” Dr. Hauser added. “In 1881, pioneering neurologist Sir William Gowers reported that he could not control seizures in 36% of the patients to whom he prescribed bromide compounds. It seems that we might not have improved our initial management results for a much longer period than the 30 years covered in the current study. While biologically unlikely, it is possible that a two-thirds proportion represents a ceiling for the initial control of epilepsy.”

—Erik Greb

Suggested Reading

Chen Z, Brodie MJ, Liew D, Kwan P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].

Hauser WA. Questioning the effectiveness of newer antiseizure medications. JAMA Neurol. 2017 Dec 26 [Epub ahead of print].

SAN DIEGO—Current practice related to screening patients with multiple sclerosis (MS) for cognitive impairment and depression may need improvement, according to a study presented at the ACTRIMS 2018 Forum. Not all patients undergo screening for these comorbidities, and patients who undergo screening are not necessarily those most likely to have cognitive impairment or depression, said the researchers. In addition, the vast majority of clinicians who perform this screening do not use validated tools.

“Education on validated screening tools, development of more accessible tools, and the sharing of best practices by MS experts may all help address these barriers,” said Guy J. Buckle, MD, MPH, Director of Neuroimaging Research at Shepherd Center in Atlanta, and colleagues. “Assisting MS clinicians in cognitive and depression screening and early referral and treatment may all positively impact outcomes for patients with MS.”

Study Included Chart Review and Survey

The National MS Society reported that as much as half of patients with MS may have cognitive impairment. A meta-analysis by Foley et al suggested that 35% of patients with MS met the criteria for clinically significant depression. Yet not all patients with MS undergo screening for these comorbidities.

Dr. Buckle and colleagues examined neurologists’ current screening practices, perceptions about screening, and barriers to screening. The investigators reviewed charts for 300 patients with MS who were seen at two large specialty clinics (150 charts per clinic). Eligible patients were 18 or older and had two or more visits during the study period. The investigators also conducted informal email interviews with 13 MS specialists recognized as leaders in research and treatment.

Dr. Buckle’s group sought to determine the extent to which screening for cognitive impairment and depression are documented in practice, as well as the extent to which clinicians use validated tools for this screening. In addition, the researchers solicited neurologists’ perceptions of the clinical value of formal screening, along with barriers to using screening tools.

Rate of Screening May Have Been Suboptimal

Participants’ median age was 52, and 76% of participants were female. Average time since diagnosis was 13 years. Fifteen patients had had one or more relapse in the previous 24 months.

Screening for cognitive impairment was documented for 52% of patients in the previous 12 months, and cognitive impairment was documented in 37% of those screened. About 2% of clinicians used a validated tool for screening, and 28% of patients were referred for more specialized care.

Screening for depression was documented for 63% of patients in the previous 12 months, and depression was documented in 42% of those screened. About 4% of clinicians used a validated tool for screening, and 25% of patients were referred for specialized care.

About 48% of patients younger than 65 were screened for cognitive impairment, compared with 73% of patients age 65 or older. Cognitive impairment was diagnosed in 69% of patients younger than 65 and in 78% of patients 65 or older. Patients younger than 65 were less likely to be screened for depression than those 65 or older (60% vs 73%), but more likely to be diagnosed with depression (71% vs 54%).

White patients were more likely to be screened for cognitive impairment than black patients (57% vs 52%), but less likely to be diagnosed with cognitive impairment (68% vs 82%). Similarly, white patients were more likely to be screened for depression (71% vs 53%), but less likely to be diagnosed with depression (65% vs 75%).

Patients who were employed were more likely to undergo cognitive screening than unemployed, retired, or disabled patients, but the latter were more likely to be diagnosed with cognitive impairment. “The analyses support previous findings suggesting links between cognitive dysfunction, patient age, and physical disability,” said Dr. Buckle and colleagues.

Specialists Cited Time as a Barrier

About 54% of the MS specialists surveyed reported that they used validated tools to assess cognitive impairment. Among the tools they named were the Symbol Digit Modalities Test, the Mini-Mental State Examination, the California Verbal Learning Test II, and the Brief International Cognitive Assessment for MS. Among the reasons the specialists gave for not using validated tools were time constraints, lack of qualified staff for administration, lack of integration of the tests into electronic medical records, and lack of reimbursement.

Approximately 46% of the MS specialists reported that they used validated tools to assess depression. The tools that they reported using included the Patient Health Questionnaire-9, the Beck Depression Inventory-II, CNS Vital Signs, and routine questions about appetite, weight loss, sleep, sexual activity, and suicidal ideation. The specialists cited time constraints, lack of compensation, cost, and inability to document results in the electronic medical record as reasons for not using validated tools.

“Integration of formal tools in clinical practice may support clinicians in appropriate and consistent identification of patient populations with these conditions,” said the investigators.

Study May Have Limited Generalizability

The study results may not accurately reflect current practice throughout the country. “The small sample size and relatively low proportions of racial minorities may limit the ability to generalize these results and necessitate large-scale studies,” said Dr. Buckle and colleagues. “Future research should examine healthcare disparities in MS and underlying contributors (eg, bias and perceptions) that hinder the use of formal screening tools in MS patients.”

—Erik Greb

Suggested Reading

Benedict RH, Cox D, Thompson LL, et al. Reliable screening for neuropsychological impairment in multiple sclerosis. Mult Scler. 2004;10(6):675-658.

Parmenter BA, Weinstock-Guttman B, Garg N, et al. Screening for cognitive impairment in multiple sclerosis using the Symbol digit Modalities Test. Mult Scler. 2007;13(1):52-57.

SAN DIEGO—Current practice related to screening patients with multiple sclerosis (MS) for cognitive impairment and depression may need improvement, according to a study presented at the ACTRIMS 2018 Forum. Not all patients undergo screening for these comorbidities, and patients who undergo screening are not necessarily those most likely to have cognitive impairment or depression, said the researchers. In addition, the vast majority of clinicians who perform this screening do not use validated tools.

“Education on validated screening tools, development of more accessible tools, and the sharing of best practices by MS experts may all help address these barriers,” said Guy J. Buckle, MD, MPH, Director of Neuroimaging Research at Shepherd Center in Atlanta, and colleagues. “Assisting MS clinicians in cognitive and depression screening and early referral and treatment may all positively impact outcomes for patients with MS.”

Study Included Chart Review and Survey

The National MS Society reported that as much as half of patients with MS may have cognitive impairment. A meta-analysis by Foley et al suggested that 35% of patients with MS met the criteria for clinically significant depression. Yet not all patients with MS undergo screening for these comorbidities.

Dr. Buckle and colleagues examined neurologists’ current screening practices, perceptions about screening, and barriers to screening. The investigators reviewed charts for 300 patients with MS who were seen at two large specialty clinics (150 charts per clinic). Eligible patients were 18 or older and had two or more visits during the study period. The investigators also conducted informal email interviews with 13 MS specialists recognized as leaders in research and treatment.

Dr. Buckle’s group sought to determine the extent to which screening for cognitive impairment and depression are documented in practice, as well as the extent to which clinicians use validated tools for this screening. In addition, the researchers solicited neurologists’ perceptions of the clinical value of formal screening, along with barriers to using screening tools.

Rate of Screening May Have Been Suboptimal

Participants’ median age was 52, and 76% of participants were female. Average time since diagnosis was 13 years. Fifteen patients had had one or more relapse in the previous 24 months.

Screening for cognitive impairment was documented for 52% of patients in the previous 12 months, and cognitive impairment was documented in 37% of those screened. About 2% of clinicians used a validated tool for screening, and 28% of patients were referred for more specialized care.

Screening for depression was documented for 63% of patients in the previous 12 months, and depression was documented in 42% of those screened. About 4% of clinicians used a validated tool for screening, and 25% of patients were referred for specialized care.

About 48% of patients younger than 65 were screened for cognitive impairment, compared with 73% of patients age 65 or older. Cognitive impairment was diagnosed in 69% of patients younger than 65 and in 78% of patients 65 or older. Patients younger than 65 were less likely to be screened for depression than those 65 or older (60% vs 73%), but more likely to be diagnosed with depression (71% vs 54%).

White patients were more likely to be screened for cognitive impairment than black patients (57% vs 52%), but less likely to be diagnosed with cognitive impairment (68% vs 82%). Similarly, white patients were more likely to be screened for depression (71% vs 53%), but less likely to be diagnosed with depression (65% vs 75%).

Patients who were employed were more likely to undergo cognitive screening than unemployed, retired, or disabled patients, but the latter were more likely to be diagnosed with cognitive impairment. “The analyses support previous findings suggesting links between cognitive dysfunction, patient age, and physical disability,” said Dr. Buckle and colleagues.

Specialists Cited Time as a Barrier

About 54% of the MS specialists surveyed reported that they used validated tools to assess cognitive impairment. Among the tools they named were the Symbol Digit Modalities Test, the Mini-Mental State Examination, the California Verbal Learning Test II, and the Brief International Cognitive Assessment for MS. Among the reasons the specialists gave for not using validated tools were time constraints, lack of qualified staff for administration, lack of integration of the tests into electronic medical records, and lack of reimbursement.

Approximately 46% of the MS specialists reported that they used validated tools to assess depression. The tools that they reported using included the Patient Health Questionnaire-9, the Beck Depression Inventory-II, CNS Vital Signs, and routine questions about appetite, weight loss, sleep, sexual activity, and suicidal ideation. The specialists cited time constraints, lack of compensation, cost, and inability to document results in the electronic medical record as reasons for not using validated tools.

“Integration of formal tools in clinical practice may support clinicians in appropriate and consistent identification of patient populations with these conditions,” said the investigators.

Study May Have Limited Generalizability

The study results may not accurately reflect current practice throughout the country. “The small sample size and relatively low proportions of racial minorities may limit the ability to generalize these results and necessitate large-scale studies,” said Dr. Buckle and colleagues. “Future research should examine healthcare disparities in MS and underlying contributors (eg, bias and perceptions) that hinder the use of formal screening tools in MS patients.”

—Erik Greb

Suggested Reading

Benedict RH, Cox D, Thompson LL, et al. Reliable screening for neuropsychological impairment in multiple sclerosis. Mult Scler. 2004;10(6):675-658.

Parmenter BA, Weinstock-Guttman B, Garg N, et al. Screening for cognitive impairment in multiple sclerosis using the Symbol digit Modalities Test. Mult Scler. 2007;13(1):52-57.

SAN DIEGO—Current practice related to screening patients with multiple sclerosis (MS) for cognitive impairment and depression may need improvement, according to a study presented at the ACTRIMS 2018 Forum. Not all patients undergo screening for these comorbidities, and patients who undergo screening are not necessarily those most likely to have cognitive impairment or depression, said the researchers. In addition, the vast majority of clinicians who perform this screening do not use validated tools.

“Education on validated screening tools, development of more accessible tools, and the sharing of best practices by MS experts may all help address these barriers,” said Guy J. Buckle, MD, MPH, Director of Neuroimaging Research at Shepherd Center in Atlanta, and colleagues. “Assisting MS clinicians in cognitive and depression screening and early referral and treatment may all positively impact outcomes for patients with MS.”

Study Included Chart Review and Survey

The National MS Society reported that as much as half of patients with MS may have cognitive impairment. A meta-analysis by Foley et al suggested that 35% of patients with MS met the criteria for clinically significant depression. Yet not all patients with MS undergo screening for these comorbidities.

Dr. Buckle and colleagues examined neurologists’ current screening practices, perceptions about screening, and barriers to screening. The investigators reviewed charts for 300 patients with MS who were seen at two large specialty clinics (150 charts per clinic). Eligible patients were 18 or older and had two or more visits during the study period. The investigators also conducted informal email interviews with 13 MS specialists recognized as leaders in research and treatment.

Dr. Buckle’s group sought to determine the extent to which screening for cognitive impairment and depression are documented in practice, as well as the extent to which clinicians use validated tools for this screening. In addition, the researchers solicited neurologists’ perceptions of the clinical value of formal screening, along with barriers to using screening tools.

Rate of Screening May Have Been Suboptimal

Participants’ median age was 52, and 76% of participants were female. Average time since diagnosis was 13 years. Fifteen patients had had one or more relapse in the previous 24 months.

Screening for cognitive impairment was documented for 52% of patients in the previous 12 months, and cognitive impairment was documented in 37% of those screened. About 2% of clinicians used a validated tool for screening, and 28% of patients were referred for more specialized care.

Screening for depression was documented for 63% of patients in the previous 12 months, and depression was documented in 42% of those screened. About 4% of clinicians used a validated tool for screening, and 25% of patients were referred for specialized care.

About 48% of patients younger than 65 were screened for cognitive impairment, compared with 73% of patients age 65 or older. Cognitive impairment was diagnosed in 69% of patients younger than 65 and in 78% of patients 65 or older. Patients younger than 65 were less likely to be screened for depression than those 65 or older (60% vs 73%), but more likely to be diagnosed with depression (71% vs 54%).

White patients were more likely to be screened for cognitive impairment than black patients (57% vs 52%), but less likely to be diagnosed with cognitive impairment (68% vs 82%). Similarly, white patients were more likely to be screened for depression (71% vs 53%), but less likely to be diagnosed with depression (65% vs 75%).

Patients who were employed were more likely to undergo cognitive screening than unemployed, retired, or disabled patients, but the latter were more likely to be diagnosed with cognitive impairment. “The analyses support previous findings suggesting links between cognitive dysfunction, patient age, and physical disability,” said Dr. Buckle and colleagues.

Specialists Cited Time as a Barrier

About 54% of the MS specialists surveyed reported that they used validated tools to assess cognitive impairment. Among the tools they named were the Symbol Digit Modalities Test, the Mini-Mental State Examination, the California Verbal Learning Test II, and the Brief International Cognitive Assessment for MS. Among the reasons the specialists gave for not using validated tools were time constraints, lack of qualified staff for administration, lack of integration of the tests into electronic medical records, and lack of reimbursement.

Approximately 46% of the MS specialists reported that they used validated tools to assess depression. The tools that they reported using included the Patient Health Questionnaire-9, the Beck Depression Inventory-II, CNS Vital Signs, and routine questions about appetite, weight loss, sleep, sexual activity, and suicidal ideation. The specialists cited time constraints, lack of compensation, cost, and inability to document results in the electronic medical record as reasons for not using validated tools.

“Integration of formal tools in clinical practice may support clinicians in appropriate and consistent identification of patient populations with these conditions,” said the investigators.

Study May Have Limited Generalizability

The study results may not accurately reflect current practice throughout the country. “The small sample size and relatively low proportions of racial minorities may limit the ability to generalize these results and necessitate large-scale studies,” said Dr. Buckle and colleagues. “Future research should examine healthcare disparities in MS and underlying contributors (eg, bias and perceptions) that hinder the use of formal screening tools in MS patients.”

—Erik Greb

Suggested Reading

Benedict RH, Cox D, Thompson LL, et al. Reliable screening for neuropsychological impairment in multiple sclerosis. Mult Scler. 2004;10(6):675-658.

Parmenter BA, Weinstock-Guttman B, Garg N, et al. Screening for cognitive impairment in multiple sclerosis using the Symbol digit Modalities Test. Mult Scler. 2007;13(1):52-57.

LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.

“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”

Courtesy Larry Young

Better approaches by subtype?

The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.

In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).

A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.

For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
 

Timing may also matter

Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.

The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.

Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.

Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.

“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”

Courtesy Larry Young

Better approaches by subtype?

The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.

In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).

A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.

For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
 

Timing may also matter

Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.

The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.

Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.

Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.

“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”

Courtesy Larry Young

Better approaches by subtype?

The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.

In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).

A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.

For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
 

Timing may also matter

Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.

The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.

Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.

Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.

[email protected]

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

[email protected]

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

[email protected]

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

[email protected]

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.

Question: Paramedics brought an unconscious 70-year-old man to a Florida hospital emergency department. The patient had the words “Do Not Resuscitate” tattooed onto his chest. No one accompanied him, and he had no identifications on his person. His blood alcohol level was elevated, and a few hours after his arrival, he lapsed into severe metabolic acidosis and hypotensive shock. The treating team decided to enter a DNR order, and the patient died shortly thereafter without benefit of cardiopulmonary resuscitation.

Which of the following is best?

A. An ethics consult may suggest honoring the patient’s DNR wishes, as it is reasonable to infer that the tattoo expressed an authentic preference.

B. It has been said, but remains debatable, that tattoos might represent “permanent reminders of regretted decisions made while the person was intoxicated.”

C. An earlier case report in the literature cautioned that the tattooed expression of a DNR request did not reflect that particular patient’s current wishes.

D. If this patient’s Florida Department of Health out-of-hospital DNR order confirms his DNR preference, then it is appropriate to withhold resuscitation.

E. All are correct.


ANSWER: E. The above hypothetical situation is modified from a recent case report in the correspondence section of the New England Journal of Medicine.¹ It can be read as offering a sharp and dramatic focus on the issue of consent surrounding decisions to withhold CPR.

In 1983, the President’s Commission for the Study of Ethical Problems in Medicine supported DNR protocols (“no code”) based on three value considerations: self-determination, well-being, and equity.²

Daisy-Daisy/Thinkstock

Dr. Tan is emeritus professor of medicine and a former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].

References

1. N Engl J Med. 2017 Nov 30;377(22):2192-3.

2. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Deciding to Forego Life-Sustaining Treatment. Washington, DC: Government Printing Office, 1983.

3. J Gen Intern Med. 2011 Jul;26(7):791-7.

4. JAMA. 1995 Nov 22-29;274(20):1591-8.

5. Hawaii Med J. 2001 Mar;60(3):64-7.

6. N Engl J Med. 1997 Jun 26;336(26):1908-10.

7. Tan SY. Futility and DNR Orders. Internal Medicine News, March 21, 2014.

8. Gilgunn v. Mass. General Hosp. No. 92-4820 (Mass. Super Ct. Apr. 21, 1995).

9. In re Baby K, 16 F.3d 590 (4th Cir. 1994).

Question: Paramedics brought an unconscious 70-year-old man to a Florida hospital emergency department. The patient had the words “Do Not Resuscitate” tattooed onto his chest. No one accompanied him, and he had no identifications on his person. His blood alcohol level was elevated, and a few hours after his arrival, he lapsed into severe metabolic acidosis and hypotensive shock. The treating team decided to enter a DNR order, and the patient died shortly thereafter without benefit of cardiopulmonary resuscitation.

Which of the following is best?

A. An ethics consult may suggest honoring the patient’s DNR wishes, as it is reasonable to infer that the tattoo expressed an authentic preference.

B. It has been said, but remains debatable, that tattoos might represent “permanent reminders of regretted decisions made while the person was intoxicated.”

C. An earlier case report in the literature cautioned that the tattooed expression of a DNR request did not reflect that particular patient’s current wishes.

D. If this patient’s Florida Department of Health out-of-hospital DNR order confirms his DNR preference, then it is appropriate to withhold resuscitation.

E. All are correct.


ANSWER: E. The above hypothetical situation is modified from a recent case report in the correspondence section of the New England Journal of Medicine.¹ It can be read as offering a sharp and dramatic focus on the issue of consent surrounding decisions to withhold CPR.

In 1983, the President’s Commission for the Study of Ethical Problems in Medicine supported DNR protocols (“no code”) based on three value considerations: self-determination, well-being, and equity.²

Daisy-Daisy/Thinkstock

Dr. Tan is emeritus professor of medicine and a former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].

References

1. N Engl J Med. 2017 Nov 30;377(22):2192-3.

2. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Deciding to Forego Life-Sustaining Treatment. Washington, DC: Government Printing Office, 1983.

3. J Gen Intern Med. 2011 Jul;26(7):791-7.

4. JAMA. 1995 Nov 22-29;274(20):1591-8.

5. Hawaii Med J. 2001 Mar;60(3):64-7.

6. N Engl J Med. 1997 Jun 26;336(26):1908-10.

7. Tan SY. Futility and DNR Orders. Internal Medicine News, March 21, 2014.

8. Gilgunn v. Mass. General Hosp. No. 92-4820 (Mass. Super Ct. Apr. 21, 1995).

9. In re Baby K, 16 F.3d 590 (4th Cir. 1994).

Question: Paramedics brought an unconscious 70-year-old man to a Florida hospital emergency department. The patient had the words “Do Not Resuscitate” tattooed onto his chest. No one accompanied him, and he had no identifications on his person. His blood alcohol level was elevated, and a few hours after his arrival, he lapsed into severe metabolic acidosis and hypotensive shock. The treating team decided to enter a DNR order, and the patient died shortly thereafter without benefit of cardiopulmonary resuscitation.

Which of the following is best?

A. An ethics consult may suggest honoring the patient’s DNR wishes, as it is reasonable to infer that the tattoo expressed an authentic preference.

B. It has been said, but remains debatable, that tattoos might represent “permanent reminders of regretted decisions made while the person was intoxicated.”

C. An earlier case report in the literature cautioned that the tattooed expression of a DNR request did not reflect that particular patient’s current wishes.

D. If this patient’s Florida Department of Health out-of-hospital DNR order confirms his DNR preference, then it is appropriate to withhold resuscitation.

E. All are correct.


ANSWER: E. The above hypothetical situation is modified from a recent case report in the correspondence section of the New England Journal of Medicine.¹ It can be read as offering a sharp and dramatic focus on the issue of consent surrounding decisions to withhold CPR.

In 1983, the President’s Commission for the Study of Ethical Problems in Medicine supported DNR protocols (“no code”) based on three value considerations: self-determination, well-being, and equity.²

Daisy-Daisy/Thinkstock

Dr. Tan is emeritus professor of medicine and a former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected].

References

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MONTREAL – A 4% drop in all-cause mortality occurred in case-managed patients with hypertension who received phone calls, care coordination, and coaching from a nurse case manager, according to a retrospective population-based cohort study of almost 85,000 patients with hypertension.

The reduction yielded a hazard ratio for all-cause mortality of 0.504, with a number needed to treat (NNT) of 25 (P less than .05).

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Yu, Esther et al. NAPCRG 2017, Abstract HY33.

MONTREAL – A 4% drop in all-cause mortality occurred in case-managed patients with hypertension who received phone calls, care coordination, and coaching from a nurse case manager, according to a retrospective population-based cohort study of almost 85,000 patients with hypertension.

The reduction yielded a hazard ratio for all-cause mortality of 0.504, with a number needed to treat (NNT) of 25 (P less than .05).

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Yu, Esther et al. NAPCRG 2017, Abstract HY33.

MONTREAL – A 4% drop in all-cause mortality occurred in case-managed patients with hypertension who received phone calls, care coordination, and coaching from a nurse case manager, according to a retrospective population-based cohort study of almost 85,000 patients with hypertension.

The reduction yielded a hazard ratio for all-cause mortality of 0.504, with a number needed to treat (NNT) of 25 (P less than .05).

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Yu, Esther et al. NAPCRG 2017, Abstract HY33.

Patients admitted to medical intensive care units may be exposed to doses of radiation that are substantial and exceed federal annual occupational limits, according to results of a recent observational study.

These “substantial” radiation doses in some patients suggest that efforts are warranted to “justify, restrict and optimize” the use of radiological resources when possible, said Sudhir Krishnan, MD, of the Cleveland Clinic, and his coauthors.

Blend Images/Fotolia

SOURCE: Krishnan S et al. Chest. 2018 Feb 4. doi: 10.1016/j.chest.2018.01.019.

Patients admitted to medical intensive care units may be exposed to doses of radiation that are substantial and exceed federal annual occupational limits, according to results of a recent observational study.

These “substantial” radiation doses in some patients suggest that efforts are warranted to “justify, restrict and optimize” the use of radiological resources when possible, said Sudhir Krishnan, MD, of the Cleveland Clinic, and his coauthors.

Blend Images/Fotolia

SOURCE: Krishnan S et al. Chest. 2018 Feb 4. doi: 10.1016/j.chest.2018.01.019.

Patients admitted to medical intensive care units may be exposed to doses of radiation that are substantial and exceed federal annual occupational limits, according to results of a recent observational study.

These “substantial” radiation doses in some patients suggest that efforts are warranted to “justify, restrict and optimize” the use of radiological resources when possible, said Sudhir Krishnan, MD, of the Cleveland Clinic, and his coauthors.

Blend Images/Fotolia

SOURCE: Krishnan S et al. Chest. 2018 Feb 4. doi: 10.1016/j.chest.2018.01.019.