SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

SAN FRANCISCO – An adjuvanted trivalent flu vaccine cuts the risk of hospitalizations in nursing home residents by about 6%, according to a new study presented at an annual scientific meeting on infectious diseases.

“It’s one thing to say you have a more immunogenic vaccine, it’s another thing to be able to say it offers clinical benefit, especially in the oldest old and the frailest frail,” says Stefan Gravenstein, MD, professor of medicine and health services, policy and practice at the Brown University School of Public Health, Providence, R.I. Dr. Gravenstein presented a poster outlying a randomized, clinical trial of the Fluad vaccine in nursing homes.

The study randomized the nursing homes so that some facilities would offer Fluad as part of their standard of care. The design helped address the problem of consent. Any clinical trial that requires individual consent would likely exclude many of the frailest patients, leading to an unrepresentative sample. “So if you want to have a generalizable result, you’d like to have it applied to the population the way you would in the real world, so randomizing the nursing homes rather than the people makes a lot of sense,” said Dr. Gravenstein.

Dr. Gravenstein chose to test the vaccine in nursing home residents, hoping to see a signal in a population in which flu complications are more common. “If you can get a difference in a nursing home population, that’s clinically important, that gives you hope that you can see it in all the other populations, too,” he said.

SOURCE: Gravenstein S et al. IDWeek 2018, Abstract 996.

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

Menopausal women with dyspareunia who received a bioidentical estradiol vaginal insert experienced no cardiovascular or breast effects that would suggest significant systemic absorption.

The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.

These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.

TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.

The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.

Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.

The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.

In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m². African American women made up 12% of the study; the remainder of the women were white.

In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.

Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.

Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.

Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.

Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.

“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.

The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.

[email protected]

SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.

In Episode 26, Lorenzo Norris, MD, welcomes Carl C. Bell, MD, for part 1 of 2 of a conversation about fetal alcohol spectrum disorder at the 2018 annual IPS Mental Health Services Conference. And later, Dr. Renee Kohanski discusses the Frye Test.

In Episode 26, Lorenzo Norris, MD, welcomes Carl C. Bell, MD, for part 1 of 2 of a conversation about fetal alcohol spectrum disorder at the 2018 annual IPS Mental Health Services Conference. And later, Dr. Renee Kohanski discusses the Frye Test.

In Episode 26, Lorenzo Norris, MD, welcomes Carl C. Bell, MD, for part 1 of 2 of a conversation about fetal alcohol spectrum disorder at the 2018 annual IPS Mental Health Services Conference. And later, Dr. Renee Kohanski discusses the Frye Test.

A holiday from bisphosphonates may help reduce atypical femur fracture risk. Also today, most dermatologic drugs are safe for breastfeeding mothers, impressive HbA1c and weight control from a new novel drug, and short-term NSAIDs appear safe for high-risk patients.

A holiday from bisphosphonates may help reduce atypical femur fracture risk. Also today, most dermatologic drugs are safe for breastfeeding mothers, impressive HbA1c and weight control from a new novel drug, and short-term NSAIDs appear safe for high-risk patients.

A holiday from bisphosphonates may help reduce atypical femur fracture risk. Also today, most dermatologic drugs are safe for breastfeeding mothers, impressive HbA1c and weight control from a new novel drug, and short-term NSAIDs appear safe for high-risk patients.

Switching breathing tubes may save more lives. A study funded by the National Heart, Lung, and Blood Institute shows that when a laryngeal tube instead of an endotracheal tube is used to open and access the airway in someone who has suffered cardiac arrest, the patient is more likely to survive.

The Pragmatic Airway Resuscitation Trial, a multicenter study conducted by the Resuscitation Outcomes Consortium, compared survival rates among 3,000 adults treated for cardiac arrest by paramedic crews from 27  emergency medical service (EMS) agencies. In half the cases, the EMS team used the newer laryngeal tube, and the other half used traditional endotracheal intubation.

Outcomes were significantly better in the laryngeal group: 18.3% of patients survived 3 days in the hospital compared with 15.4% of the endotracheal group. Moreover, 10.8% of the laryngeal group survived to discharge compared with 8.1% of the other group. The proportion of patients surviving with good brain function was also higher in the laryngeal group.

Switching breathing tubes may save more lives. A study funded by the National Heart, Lung, and Blood Institute shows that when a laryngeal tube instead of an endotracheal tube is used to open and access the airway in someone who has suffered cardiac arrest, the patient is more likely to survive.

The Pragmatic Airway Resuscitation Trial, a multicenter study conducted by the Resuscitation Outcomes Consortium, compared survival rates among 3,000 adults treated for cardiac arrest by paramedic crews from 27  emergency medical service (EMS) agencies. In half the cases, the EMS team used the newer laryngeal tube, and the other half used traditional endotracheal intubation.

Outcomes were significantly better in the laryngeal group: 18.3% of patients survived 3 days in the hospital compared with 15.4% of the endotracheal group. Moreover, 10.8% of the laryngeal group survived to discharge compared with 8.1% of the other group. The proportion of patients surviving with good brain function was also higher in the laryngeal group.

Switching breathing tubes may save more lives. A study funded by the National Heart, Lung, and Blood Institute shows that when a laryngeal tube instead of an endotracheal tube is used to open and access the airway in someone who has suffered cardiac arrest, the patient is more likely to survive.

The Pragmatic Airway Resuscitation Trial, a multicenter study conducted by the Resuscitation Outcomes Consortium, compared survival rates among 3,000 adults treated for cardiac arrest by paramedic crews from 27  emergency medical service (EMS) agencies. In half the cases, the EMS team used the newer laryngeal tube, and the other half used traditional endotracheal intubation.

Outcomes were significantly better in the laryngeal group: 18.3% of patients survived 3 days in the hospital compared with 15.4% of the endotracheal group. Moreover, 10.8% of the laryngeal group survived to discharge compared with 8.1% of the other group. The proportion of patients surviving with good brain function was also higher in the laryngeal group.

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.

Eliza Majewska, PhD

DUBROVNIK, CROATIA—The CDK8 inhibitor SEL120 has demonstrated preclinical activity against acute myeloid leukemia (AML), but the agent’s mechanism of action is still unclear.

Researchers found that several AML cell lines were “highly sensitive” to SEL120, and the inhibitor was active in primary patient samples.

SEL120 also reduced tumor growth in mouse models of AML and demonstrated synergy with venetoclax.

The researchers believe SEL120 works by affecting the maintenance of AML cells and leukemic stem cells (LSCs), inducing differentiation and, sometimes, apoptosis. However, the mechanism is not well defined.

Eliza Majewska, PhD, of Selvita S.A. in Krakow, Poland, discussed research with SEL120 at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Dr. Majewska explained that CDK8 is a transcriptional kinase working in the context of the Mediator complex, and previous research¹ indicated that CDK8 drives oncogenic transcription in AML.

In a prior study², researchers found that SEL120 inhibits CDK8 activity in AML cells with high levels of STAT phosphorylation.

Dr. Majewska said the MV4-11 cell line responds particularly well to SEL120, and other sensitive cell lines include SKNO-1, Oci-AML5, GDM-1, KG-1, MOLM-16, and Oci-AML3.

“The fact that STAT signaling was upregulated in those cell lines that were very sensitive to SEL120 gave us the hint that perhaps we are looking at a mechanism of action of the compound that has something to do with leukemic stem cells,” Dr. Majewska said.

In fact, she and her colleagues found that cell lines sensitive to SEL120 had upregulation of genes linked to LSCs and high levels of CD34 surface expression.

Experiments in CD34+ TEX cells showed that SEL120 specifically depletes CD34+ cells, leads to downregulation of stemness-related genes, and induces myeloid differentiation.

After 6 days of treatment with SEL120, TEX cells showed decreased expression of the LSC-linked genes MEIS1 and LILRB2, enrichment of gene sets downregulated in LSCs and linked to differentiation, and increased expression of differentiation markers and immune response genes.

SEL120 also demonstrated antileukemic activity in vivo. The researchers tested SEL120 in a CD34+ model of AML (KG-1) and a FLT3-ITD model of AML (MV4-11).

In both models, SEL120 induced “significant tumor regression” of about 80%. In some cases, the researchers observed apoptosis.

Toxicities observed in the mice included weight loss and upregulation of inflammation.

The researchers also found that SEL120 was synergistic with venetoclax. In fact, the combination of these drugs resulted in “almost complete remission cures” in the MV4-11 model, according to Dr. Majewska.

Finally, she and her colleagues discovered that SEL120 was active against primary patient cells. Samples from 3 of 4 AML patients had a significant reduction in cell numbers after 7 days of treatment with SEL120. For one patient, there were no viable cells on day 7.

Dr. Majewska said a phase 1 trial of SEL120 is planned for 2019 or 2020, and SEL120’s mechanism of action is still under investigation.

“The mechanism of action . . . is, in our mind, at least in some cases, linked to the fact that CDK8 functions within the context of the Mediator complex, which contributes to gene expression related to leukemic stem cells,” Dr. Majewska said.

“And when we inhibit this specific transcription, of course, the Mediator complex still works because this is just one of the components of the complex. However, the function that it has is suddenly very different, and it’s actually linked to lack of maintenance of leukemic stem cells, resulting in differentiation [and], in some cases, the induction of apoptosis, but we do not fully understand the mechanism of this induction.”

Dr. Majewska works for Selvita, the company developing SEL120. This research was funded by Selvita, the Leukemia & Lymphoma Society, and the National Centre for Research and Development.

1. Pelish HE et al. Nature. 2015 Oct 8;526(7572):273-276. doi: 10.1038/nature14904

2. Rzymski T et al. Oncotarget. 2017 May 16;8(20):33779-33795. doi: 10.18632/oncotarget.16810.

Photo from Penn Medicine

The anti-IL-6 antibody siltuximab is central to first-line treatment of idiopathic multicentric Castleman disease (iMCD), according to new guidelines on iMCD published in Blood.

The guidelines also say that early intervention with combination chemotherapy may prevent a fatal outcome in patients with severe iMCD.

To create these guidelines, 42 experts from 10 countries reviewed the published literature and a series of 344 clinical cases.

The guidelines should help clinicians select therapy, evaluate response, and thereby improve outcomes for this difficult-to-treat disease, according to author David C. Fajgenbaum, MD, an assistant professor at the University of Pennsylvania in Philadelphia and an iMCD patient himself.

“Right now, we recommend siltuximab first-line for everyone,” Dr. Fajgenbaum said, “but if we continue to dig deeper, it may be that there are clinical cases within idiopathic MCD that we think are even better candidates than others, and there may be alternative therapies for other patients.”

Treating iMCD is challenging because of the rarity and heterogeneity of the disease, among other factors, Dr. Fajgenbaum noted.

Some 6,000 to 7,000 cases of Castleman disease are diagnosed yearly, and of those, only about 1,000 cases are iMCD, according to Dr. Fajgenbaum.

“Even within idiopathic MCD, there is some heterogeneity,” he said. “Some patients present in the intensive care unit with life-threatening multiple organ failure and will die within weeks of presentation, whereas others will have a slower presentation and certainly not nearly as aggressive presentation.”

Although the exact etiology of iMCD is unknown, human IL-6 is the most common pathological driver, the experts said in the guidelines.

Siltuximab and tocilizumab are two IL-6–directed therapies used to treat MCD, with siltuximab targeting IL-6 itself and tocilizumab targeting the IL-6 receptor. Siltuximab is recommended as the first choice because of rigorous data supporting its use, including randomized clinical trial data, while tocilizumab is recommended if siltuximab is not available.

However, clinicians need to carefully monitor laboratory results and clinical features for patients on these drugs because about 50% of iMCD patients don’t have a satisfactory response to first-line anti–IL-6 treatments, Dr. Fajgenbaum said.

“Once you get to second-line therapies, that’s really where the level of evidence is lower,” he said.

Second-line therapy should include rituximab, and immunomodulatory/immunosuppressive agents or steroids may be added, according to the guidelines.

Third-line therapy is “less well defined,” according to the guidelines, and experts generally recommended immunomodulatory/immunosuppressive agents such as cyclosporine A, sirolimus, thalidomide, and lenalidomide.

Cytotoxic chemotherapy has a high response rate but also a high rate of relapse and significant toxicities, according to the data analysis conducted as part of the guideline development process. Based on that, the experts said to avoid it unless the patient progresses to severe iMCD.

“Patients who are literally dying in the intensive care unit, given the right combination chemotherapy, can improve within days to weeks and can even leave the hospital,” Dr. Fajgenbaum said. “It’s not necessarily going to be the answer long-term, but it can be life-saving in the short term. So we recommended a really quite aggressive approach for these patients.”

To bolster the evidence base, investigators in the Castleman Disease Collaborative Network (CDCN) set up an international registry to collect treatment and outcome data for 500 patients. After the first year and a half, 150 patients were enrolled, and the investigators have identified more than 30 drugs that have been used off-label to treat iMCD, according to Dr. Fajgenbaum.

“Some of the drugs are demonstrating efficacy in small numbers,” he said. “With the goal of 500 patients total, we can certainly hope to see some trends.”

Dr. Fajgenbaum was diagnosed with iMCD as a medical student.

“That certainly served as a very strong personal motivator for me to get involved in the disease,” he said. “But as I’ve gotten more and more involved, I’ve obviously met a lot of other patients, and that really is a huge motivator for all members of the CDCN. We want more options for more patients more quickly so we can help as many people as possible.”

Dr. Fajgenbaum reported research funding from Janssen. Coauthors reported disclosures related to Janssen, Bristol-Myers Squibb, Genentech, Merck, Celgene, Incyte, Pfizer, Sequenom, and Foundation Medicine, among others.

Photo from Penn Medicine

The anti-IL-6 antibody siltuximab is central to first-line treatment of idiopathic multicentric Castleman disease (iMCD), according to new guidelines on iMCD published in Blood.

The guidelines also say that early intervention with combination chemotherapy may prevent a fatal outcome in patients with severe iMCD.

To create these guidelines, 42 experts from 10 countries reviewed the published literature and a series of 344 clinical cases.

The guidelines should help clinicians select therapy, evaluate response, and thereby improve outcomes for this difficult-to-treat disease, according to author David C. Fajgenbaum, MD, an assistant professor at the University of Pennsylvania in Philadelphia and an iMCD patient himself.

“Right now, we recommend siltuximab first-line for everyone,” Dr. Fajgenbaum said, “but if we continue to dig deeper, it may be that there are clinical cases within idiopathic MCD that we think are even better candidates than others, and there may be alternative therapies for other patients.”

Treating iMCD is challenging because of the rarity and heterogeneity of the disease, among other factors, Dr. Fajgenbaum noted.

Some 6,000 to 7,000 cases of Castleman disease are diagnosed yearly, and of those, only about 1,000 cases are iMCD, according to Dr. Fajgenbaum.

“Even within idiopathic MCD, there is some heterogeneity,” he said. “Some patients present in the intensive care unit with life-threatening multiple organ failure and will die within weeks of presentation, whereas others will have a slower presentation and certainly not nearly as aggressive presentation.”

Although the exact etiology of iMCD is unknown, human IL-6 is the most common pathological driver, the experts said in the guidelines.

Siltuximab and tocilizumab are two IL-6–directed therapies used to treat MCD, with siltuximab targeting IL-6 itself and tocilizumab targeting the IL-6 receptor. Siltuximab is recommended as the first choice because of rigorous data supporting its use, including randomized clinical trial data, while tocilizumab is recommended if siltuximab is not available.

However, clinicians need to carefully monitor laboratory results and clinical features for patients on these drugs because about 50% of iMCD patients don’t have a satisfactory response to first-line anti–IL-6 treatments, Dr. Fajgenbaum said.

“Once you get to second-line therapies, that’s really where the level of evidence is lower,” he said.

Second-line therapy should include rituximab, and immunomodulatory/immunosuppressive agents or steroids may be added, according to the guidelines.

Third-line therapy is “less well defined,” according to the guidelines, and experts generally recommended immunomodulatory/immunosuppressive agents such as cyclosporine A, sirolimus, thalidomide, and lenalidomide.

Cytotoxic chemotherapy has a high response rate but also a high rate of relapse and significant toxicities, according to the data analysis conducted as part of the guideline development process. Based on that, the experts said to avoid it unless the patient progresses to severe iMCD.

“Patients who are literally dying in the intensive care unit, given the right combination chemotherapy, can improve within days to weeks and can even leave the hospital,” Dr. Fajgenbaum said. “It’s not necessarily going to be the answer long-term, but it can be life-saving in the short term. So we recommended a really quite aggressive approach for these patients.”

To bolster the evidence base, investigators in the Castleman Disease Collaborative Network (CDCN) set up an international registry to collect treatment and outcome data for 500 patients. After the first year and a half, 150 patients were enrolled, and the investigators have identified more than 30 drugs that have been used off-label to treat iMCD, according to Dr. Fajgenbaum.

“Some of the drugs are demonstrating efficacy in small numbers,” he said. “With the goal of 500 patients total, we can certainly hope to see some trends.”

Dr. Fajgenbaum was diagnosed with iMCD as a medical student.

“That certainly served as a very strong personal motivator for me to get involved in the disease,” he said. “But as I’ve gotten more and more involved, I’ve obviously met a lot of other patients, and that really is a huge motivator for all members of the CDCN. We want more options for more patients more quickly so we can help as many people as possible.”

Dr. Fajgenbaum reported research funding from Janssen. Coauthors reported disclosures related to Janssen, Bristol-Myers Squibb, Genentech, Merck, Celgene, Incyte, Pfizer, Sequenom, and Foundation Medicine, among others.

Photo from Penn Medicine

The anti-IL-6 antibody siltuximab is central to first-line treatment of idiopathic multicentric Castleman disease (iMCD), according to new guidelines on iMCD published in Blood.

The guidelines also say that early intervention with combination chemotherapy may prevent a fatal outcome in patients with severe iMCD.

To create these guidelines, 42 experts from 10 countries reviewed the published literature and a series of 344 clinical cases.

The guidelines should help clinicians select therapy, evaluate response, and thereby improve outcomes for this difficult-to-treat disease, according to author David C. Fajgenbaum, MD, an assistant professor at the University of Pennsylvania in Philadelphia and an iMCD patient himself.

“Right now, we recommend siltuximab first-line for everyone,” Dr. Fajgenbaum said, “but if we continue to dig deeper, it may be that there are clinical cases within idiopathic MCD that we think are even better candidates than others, and there may be alternative therapies for other patients.”

Treating iMCD is challenging because of the rarity and heterogeneity of the disease, among other factors, Dr. Fajgenbaum noted.

Some 6,000 to 7,000 cases of Castleman disease are diagnosed yearly, and of those, only about 1,000 cases are iMCD, according to Dr. Fajgenbaum.

“Even within idiopathic MCD, there is some heterogeneity,” he said. “Some patients present in the intensive care unit with life-threatening multiple organ failure and will die within weeks of presentation, whereas others will have a slower presentation and certainly not nearly as aggressive presentation.”

Although the exact etiology of iMCD is unknown, human IL-6 is the most common pathological driver, the experts said in the guidelines.

Siltuximab and tocilizumab are two IL-6–directed therapies used to treat MCD, with siltuximab targeting IL-6 itself and tocilizumab targeting the IL-6 receptor. Siltuximab is recommended as the first choice because of rigorous data supporting its use, including randomized clinical trial data, while tocilizumab is recommended if siltuximab is not available.

However, clinicians need to carefully monitor laboratory results and clinical features for patients on these drugs because about 50% of iMCD patients don’t have a satisfactory response to first-line anti–IL-6 treatments, Dr. Fajgenbaum said.

“Once you get to second-line therapies, that’s really where the level of evidence is lower,” he said.

Second-line therapy should include rituximab, and immunomodulatory/immunosuppressive agents or steroids may be added, according to the guidelines.

Third-line therapy is “less well defined,” according to the guidelines, and experts generally recommended immunomodulatory/immunosuppressive agents such as cyclosporine A, sirolimus, thalidomide, and lenalidomide.

Cytotoxic chemotherapy has a high response rate but also a high rate of relapse and significant toxicities, according to the data analysis conducted as part of the guideline development process. Based on that, the experts said to avoid it unless the patient progresses to severe iMCD.

“Patients who are literally dying in the intensive care unit, given the right combination chemotherapy, can improve within days to weeks and can even leave the hospital,” Dr. Fajgenbaum said. “It’s not necessarily going to be the answer long-term, but it can be life-saving in the short term. So we recommended a really quite aggressive approach for these patients.”

To bolster the evidence base, investigators in the Castleman Disease Collaborative Network (CDCN) set up an international registry to collect treatment and outcome data for 500 patients. After the first year and a half, 150 patients were enrolled, and the investigators have identified more than 30 drugs that have been used off-label to treat iMCD, according to Dr. Fajgenbaum.

“Some of the drugs are demonstrating efficacy in small numbers,” he said. “With the goal of 500 patients total, we can certainly hope to see some trends.”

Dr. Fajgenbaum was diagnosed with iMCD as a medical student.

“That certainly served as a very strong personal motivator for me to get involved in the disease,” he said. “But as I’ve gotten more and more involved, I’ve obviously met a lot of other patients, and that really is a huge motivator for all members of the CDCN. We want more options for more patients more quickly so we can help as many people as possible.”

Dr. Fajgenbaum reported research funding from Janssen. Coauthors reported disclosures related to Janssen, Bristol-Myers Squibb, Genentech, Merck, Celgene, Incyte, Pfizer, Sequenom, and Foundation Medicine, among others.

Image from NIAID

Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.

Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.

AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.

This included a death in the ALL study and two life-threatening events in the NHL study.

The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.

A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.

Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.

Affimed intends to provide an update on AFM11 upon completing the evaluation.

Image from NIAID

Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.

Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.

AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.

This included a death in the ALL study and two life-threatening events in the NHL study.

The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.

A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.

Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.

Affimed intends to provide an update on AFM11 upon completing the evaluation.

Image from NIAID

Update: On October 12, 2018, Affimed N.V. received a notification from the U.S. Food and Drug Administration (FDA) saying the agency concurred with Affimed’s decision and formally placed the investigational new drug application for AFM11 on full clinical hold. Affimed said it will comply with the FDA and other global health authorities’ requests for information to resolve the clinical hold.

Affimed N.V. has placed trials of AFM11 on clinical hold and notified the global health authorities of its decision.

AFM11 is a CD19/CD3-targeting T-cell engager being evaluated in two phase 1 trials—one in patients with relapsed or refractory, CD19-positive B-cell non-Hodgkin lymphoma (NHL) and one in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

Affimed initiated the clinical hold on these trials after serious adverse events occurred in three patients treated with AFM11.

This included a death in the ALL study and two life-threatening events in the NHL study.

The serious adverse events occurred in patients enrolled in the highest dose cohorts of each study.

A total of 33 patients have been treated in the two studies (NCT02848911 and NCT02106091), and preliminary signs of clinical activity have been observed in several patients.

Affimed said it will be working closely with the global health authorities, safety monitoring committees, and the studies’ clinical investigators to review the adverse events, assess all the data, and determine next steps for the AFM11 program.

Affimed intends to provide an update on AFM11 upon completing the evaluation.

One of the primary goals of the American College of Surgeons (ACS) is to provide surgeons with knowledge and skills to deliver the highest quality of patient care. The guidelines and statements developed by the ACS are intended to inform and guide Fellows in the care of their patients and to educate their patients and their institutions on best practices in those situations that may warrant specific guidance and direction.

Guidelines

Over the last decade, the College has participated in the development of guidelines and “point of care” modules that address those diagnoses most relevant to general surgeons. The Evidence-Based Decisions in Surgery (EBDS) are clinical guideline summaries that provide recommendations based on the latest practice guidelines in an easy-to-use, widely accessible format, including mobile devices and tablets. Module development involves a rigorous multi-step process, including contributions from experts on the ACS Board of Governors and the ACS Advisory Council for General Surgery. It is important to note that EBDS is not intended to reflect standards of care as defined by the ACS, but rather to serve as educational resources that practicing surgeons can use within the context of their respective practices. These guidelines should be used when appropriate based on the surgical condition and the surgeon’s experience, as well as the patient’s needs and preferences.

EBDS now comprises more than 70 point of care modules covering the following categories—bariatric surgery, biliary tract and pancreas, breast disease, colon, rectum and anus, critical care, endocrine, gastrointestinal surgery, geriatrics and palliative care, miscellaneous surgical conditions, perioperative care, surgical oncology, and vascular.

The complete list of guidelines is available at ebds.facs.org/topics, and new modules are released regularly. To access individual guidelines, members are required to log in. Contact [email protected] for member log-in information, and go to facs.org/ebds for more information about the program.

The Trauma Quality Improvement Program (TQIP^®) generates the ACS TQIP Best Practice Guidelines to provide recommendations for managing patient populations or injury types. The TQIP Best Practices Project Team and a panel of guest experts from appropriate specialties work together over the course of the year to create each guideline. The guidelines are created from evidence-based literature when available and the consensus of the group when evidence is lacking. To date, the following guidelines have been created for use by trauma centers and are available for download at facs.org/quality-programs/trauma/tqip/best-practice:

• Geriatric Trauma Management

• Massive Transfusion in Trauma

• Management of Traumatic Brain Injury

• Management of Orthopaedic Trauma

• Palliative Care

The College’s National Surgical Quality Improvement Program (ACS NSQIP®) and the American Geriatrics Society’s Geriatrics for Specialists Initiative have developed two best practice guidelines that address management of older patients: Optimal Preoperative Assessment of the Geriatric Surgical Patient and Optimal Perioperative Management of the Geriatric Patient. These consensus-based recommendations were developed with support from the John A. Hartford Foundation and are available for download at facs.org/quality-programs/acs-nsqip/geriatric-periop-guideline.



Statements

Founded to provide opportunities for the continuing education of surgeons, the ACS has had a deep concern for the improvement of patient care and for the ethical practice of medicine. These values are reflected in the ACS Statements on Principles, which serve as the guidepost resource for all ACS Fellows. In addition to the Fellowship Pledge and Code of Professional Conduct, the Statements on Principles address the qualifications of the responsible surgeon, the surgeon-patient relationship, interprofessional relations, medical education, and surgeons and society. Fellows are encouraged to familiarize themselves with the contents of the Statements on Principles, which can be accessed at facs.org/about-acs/statements/stonprin.

In addition to the Statements on Principles, the ACS has issued more than 90 statements that have been adopted by the Board of Regents and address topics of importance to surgeons and the surgical profession. These statements have been developed by a range of volunteer committees and workgroups within the College, including the ACS Board of Governors, the ACS Advisory Councils, and various ACS standing committees. Statements are reviewed and updated annually, and new statements are created as appropriate. Statements are generally communicated to the membership via the Bulletin and are posted to the ACS website. Thus far in 2018, the Board of Regents has approved seven new statements and two revised statements. To review the complete list of ACS statements, go to facs.org/about-acs/statements and share those of interest with your colleagues and your institution.



Ms. Bura is Associate Director, ACS Division of Member Services, Chicago, IL.

One of the primary goals of the American College of Surgeons (ACS) is to provide surgeons with knowledge and skills to deliver the highest quality of patient care. The guidelines and statements developed by the ACS are intended to inform and guide Fellows in the care of their patients and to educate their patients and their institutions on best practices in those situations that may warrant specific guidance and direction.

Guidelines

Over the last decade, the College has participated in the development of guidelines and “point of care” modules that address those diagnoses most relevant to general surgeons. The Evidence-Based Decisions in Surgery (EBDS) are clinical guideline summaries that provide recommendations based on the latest practice guidelines in an easy-to-use, widely accessible format, including mobile devices and tablets. Module development involves a rigorous multi-step process, including contributions from experts on the ACS Board of Governors and the ACS Advisory Council for General Surgery. It is important to note that EBDS is not intended to reflect standards of care as defined by the ACS, but rather to serve as educational resources that practicing surgeons can use within the context of their respective practices. These guidelines should be used when appropriate based on the surgical condition and the surgeon’s experience, as well as the patient’s needs and preferences.

EBDS now comprises more than 70 point of care modules covering the following categories—bariatric surgery, biliary tract and pancreas, breast disease, colon, rectum and anus, critical care, endocrine, gastrointestinal surgery, geriatrics and palliative care, miscellaneous surgical conditions, perioperative care, surgical oncology, and vascular.

The complete list of guidelines is available at ebds.facs.org/topics, and new modules are released regularly. To access individual guidelines, members are required to log in. Contact [email protected] for member log-in information, and go to facs.org/ebds for more information about the program.

The Trauma Quality Improvement Program (TQIP^®) generates the ACS TQIP Best Practice Guidelines to provide recommendations for managing patient populations or injury types. The TQIP Best Practices Project Team and a panel of guest experts from appropriate specialties work together over the course of the year to create each guideline. The guidelines are created from evidence-based literature when available and the consensus of the group when evidence is lacking. To date, the following guidelines have been created for use by trauma centers and are available for download at facs.org/quality-programs/trauma/tqip/best-practice:

• Geriatric Trauma Management

• Massive Transfusion in Trauma

• Management of Traumatic Brain Injury

• Management of Orthopaedic Trauma

• Palliative Care

The College’s National Surgical Quality Improvement Program (ACS NSQIP®) and the American Geriatrics Society’s Geriatrics for Specialists Initiative have developed two best practice guidelines that address management of older patients: Optimal Preoperative Assessment of the Geriatric Surgical Patient and Optimal Perioperative Management of the Geriatric Patient. These consensus-based recommendations were developed with support from the John A. Hartford Foundation and are available for download at facs.org/quality-programs/acs-nsqip/geriatric-periop-guideline.



Statements

Founded to provide opportunities for the continuing education of surgeons, the ACS has had a deep concern for the improvement of patient care and for the ethical practice of medicine. These values are reflected in the ACS Statements on Principles, which serve as the guidepost resource for all ACS Fellows. In addition to the Fellowship Pledge and Code of Professional Conduct, the Statements on Principles address the qualifications of the responsible surgeon, the surgeon-patient relationship, interprofessional relations, medical education, and surgeons and society. Fellows are encouraged to familiarize themselves with the contents of the Statements on Principles, which can be accessed at facs.org/about-acs/statements/stonprin.

In addition to the Statements on Principles, the ACS has issued more than 90 statements that have been adopted by the Board of Regents and address topics of importance to surgeons and the surgical profession. These statements have been developed by a range of volunteer committees and workgroups within the College, including the ACS Board of Governors, the ACS Advisory Councils, and various ACS standing committees. Statements are reviewed and updated annually, and new statements are created as appropriate. Statements are generally communicated to the membership via the Bulletin and are posted to the ACS website. Thus far in 2018, the Board of Regents has approved seven new statements and two revised statements. To review the complete list of ACS statements, go to facs.org/about-acs/statements and share those of interest with your colleagues and your institution.



Ms. Bura is Associate Director, ACS Division of Member Services, Chicago, IL.

One of the primary goals of the American College of Surgeons (ACS) is to provide surgeons with knowledge and skills to deliver the highest quality of patient care. The guidelines and statements developed by the ACS are intended to inform and guide Fellows in the care of their patients and to educate their patients and their institutions on best practices in those situations that may warrant specific guidance and direction.

Guidelines

Over the last decade, the College has participated in the development of guidelines and “point of care” modules that address those diagnoses most relevant to general surgeons. The Evidence-Based Decisions in Surgery (EBDS) are clinical guideline summaries that provide recommendations based on the latest practice guidelines in an easy-to-use, widely accessible format, including mobile devices and tablets. Module development involves a rigorous multi-step process, including contributions from experts on the ACS Board of Governors and the ACS Advisory Council for General Surgery. It is important to note that EBDS is not intended to reflect standards of care as defined by the ACS, but rather to serve as educational resources that practicing surgeons can use within the context of their respective practices. These guidelines should be used when appropriate based on the surgical condition and the surgeon’s experience, as well as the patient’s needs and preferences.

EBDS now comprises more than 70 point of care modules covering the following categories—bariatric surgery, biliary tract and pancreas, breast disease, colon, rectum and anus, critical care, endocrine, gastrointestinal surgery, geriatrics and palliative care, miscellaneous surgical conditions, perioperative care, surgical oncology, and vascular.

The complete list of guidelines is available at ebds.facs.org/topics, and new modules are released regularly. To access individual guidelines, members are required to log in. Contact [email protected] for member log-in information, and go to facs.org/ebds for more information about the program.

The Trauma Quality Improvement Program (TQIP^®) generates the ACS TQIP Best Practice Guidelines to provide recommendations for managing patient populations or injury types. The TQIP Best Practices Project Team and a panel of guest experts from appropriate specialties work together over the course of the year to create each guideline. The guidelines are created from evidence-based literature when available and the consensus of the group when evidence is lacking. To date, the following guidelines have been created for use by trauma centers and are available for download at facs.org/quality-programs/trauma/tqip/best-practice:

• Geriatric Trauma Management

• Massive Transfusion in Trauma

• Management of Traumatic Brain Injury

• Management of Orthopaedic Trauma

• Palliative Care

The College’s National Surgical Quality Improvement Program (ACS NSQIP®) and the American Geriatrics Society’s Geriatrics for Specialists Initiative have developed two best practice guidelines that address management of older patients: Optimal Preoperative Assessment of the Geriatric Surgical Patient and Optimal Perioperative Management of the Geriatric Patient. These consensus-based recommendations were developed with support from the John A. Hartford Foundation and are available for download at facs.org/quality-programs/acs-nsqip/geriatric-periop-guideline.



Statements

Founded to provide opportunities for the continuing education of surgeons, the ACS has had a deep concern for the improvement of patient care and for the ethical practice of medicine. These values are reflected in the ACS Statements on Principles, which serve as the guidepost resource for all ACS Fellows. In addition to the Fellowship Pledge and Code of Professional Conduct, the Statements on Principles address the qualifications of the responsible surgeon, the surgeon-patient relationship, interprofessional relations, medical education, and surgeons and society. Fellows are encouraged to familiarize themselves with the contents of the Statements on Principles, which can be accessed at facs.org/about-acs/statements/stonprin.

In addition to the Statements on Principles, the ACS has issued more than 90 statements that have been adopted by the Board of Regents and address topics of importance to surgeons and the surgical profession. These statements have been developed by a range of volunteer committees and workgroups within the College, including the ACS Board of Governors, the ACS Advisory Councils, and various ACS standing committees. Statements are reviewed and updated annually, and new statements are created as appropriate. Statements are generally communicated to the membership via the Bulletin and are posted to the ACS website. Thus far in 2018, the Board of Regents has approved seven new statements and two revised statements. To review the complete list of ACS statements, go to facs.org/about-acs/statements and share those of interest with your colleagues and your institution.



Ms. Bura is Associate Director, ACS Division of Member Services, Chicago, IL.

Clinical question: Do pharmacotherapies used in tobacco cessation treatment significantly increase the risk of cardiovascular events?

Background: Although it is known that smoking cessation is the most beneficial enhancement of cardiovascular health, many clinicians may be hesitant to prescribe pharmacotherapies because of concerns regarding adverse events. This study reports the cardiovascular safety findings from EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study) and its nontreatment extension trial.

Study design: Double-blind, randomized, triple-dummy, placebo- and active-controlled trial and its nontreatment extension trial.

Setting: Conducted by 140 multinational centers, EAGLES was a trial in cohorts of smokers with and without psychiatric disease that assessed the safety and efficacy of pharmacotherapies used for smoking cessation.

The EAGLES extension trial is a nontreatment extension of EAGLES. It began with the first dose of medication and included those who completed an additional 28 weeks of observation.

Synopsis: The study included approximately 8,000 participants aged 18-75 years who smoked 10 or more cigarettes per day and were interested in quitting. The study monitored the development of a major adverse cardiovascular event (MACE), such as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, during treatment with varenicline, bupropion hydrochloride, nicotine replacement therapy, and placebo therapy. Other end points included determining the occurrence of MACE along with other peripheral vascular disease that required either intervention, coronary revascularization, or hospitalization for unstable angina (MACE+).

There were no significant differences in time to MACE or MACE+ overall across all observation periods.

Bottom line: The findings provide evidence that, in a general population of smokers, smoking cessation medications do not increase the risk of serious cardiovascular events.

Citation: Benowitz N et al. Cardiovascular safety of varenicline, bupropion, and nicotine patch in smoker. JAMA Intern Med. 2018 May;178(5):622-31.

Dr. White is a hospitalist in the division of hospital medicine in the department of medicine at Loyola University Chicago, Maywood, Ill.

Clinical question: Do pharmacotherapies used in tobacco cessation treatment significantly increase the risk of cardiovascular events?

Background: Although it is known that smoking cessation is the most beneficial enhancement of cardiovascular health, many clinicians may be hesitant to prescribe pharmacotherapies because of concerns regarding adverse events. This study reports the cardiovascular safety findings from EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study) and its nontreatment extension trial.

Study design: Double-blind, randomized, triple-dummy, placebo- and active-controlled trial and its nontreatment extension trial.

Setting: Conducted by 140 multinational centers, EAGLES was a trial in cohorts of smokers with and without psychiatric disease that assessed the safety and efficacy of pharmacotherapies used for smoking cessation.

The EAGLES extension trial is a nontreatment extension of EAGLES. It began with the first dose of medication and included those who completed an additional 28 weeks of observation.

Synopsis: The study included approximately 8,000 participants aged 18-75 years who smoked 10 or more cigarettes per day and were interested in quitting. The study monitored the development of a major adverse cardiovascular event (MACE), such as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, during treatment with varenicline, bupropion hydrochloride, nicotine replacement therapy, and placebo therapy. Other end points included determining the occurrence of MACE along with other peripheral vascular disease that required either intervention, coronary revascularization, or hospitalization for unstable angina (MACE+).

There were no significant differences in time to MACE or MACE+ overall across all observation periods.

Bottom line: The findings provide evidence that, in a general population of smokers, smoking cessation medications do not increase the risk of serious cardiovascular events.

Citation: Benowitz N et al. Cardiovascular safety of varenicline, bupropion, and nicotine patch in smoker. JAMA Intern Med. 2018 May;178(5):622-31.

Dr. White is a hospitalist in the division of hospital medicine in the department of medicine at Loyola University Chicago, Maywood, Ill.

Clinical question: Do pharmacotherapies used in tobacco cessation treatment significantly increase the risk of cardiovascular events?

Background: Although it is known that smoking cessation is the most beneficial enhancement of cardiovascular health, many clinicians may be hesitant to prescribe pharmacotherapies because of concerns regarding adverse events. This study reports the cardiovascular safety findings from EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study) and its nontreatment extension trial.

Study design: Double-blind, randomized, triple-dummy, placebo- and active-controlled trial and its nontreatment extension trial.

Setting: Conducted by 140 multinational centers, EAGLES was a trial in cohorts of smokers with and without psychiatric disease that assessed the safety and efficacy of pharmacotherapies used for smoking cessation.

The EAGLES extension trial is a nontreatment extension of EAGLES. It began with the first dose of medication and included those who completed an additional 28 weeks of observation.

Synopsis: The study included approximately 8,000 participants aged 18-75 years who smoked 10 or more cigarettes per day and were interested in quitting. The study monitored the development of a major adverse cardiovascular event (MACE), such as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, during treatment with varenicline, bupropion hydrochloride, nicotine replacement therapy, and placebo therapy. Other end points included determining the occurrence of MACE along with other peripheral vascular disease that required either intervention, coronary revascularization, or hospitalization for unstable angina (MACE+).

There were no significant differences in time to MACE or MACE+ overall across all observation periods.

Bottom line: The findings provide evidence that, in a general population of smokers, smoking cessation medications do not increase the risk of serious cardiovascular events.

Citation: Benowitz N et al. Cardiovascular safety of varenicline, bupropion, and nicotine patch in smoker. JAMA Intern Med. 2018 May;178(5):622-31.

Dr. White is a hospitalist in the division of hospital medicine in the department of medicine at Loyola University Chicago, Maywood, Ill.