LAS VEGAS – Though fertility declines precipitously as menopause nears, women in midlife may still conceive. Clinicians and patients need guidance to develop a rational plan for contraceptive management and a clear path to transition to menopausal symptom management, said Dr. Petra Casey at the NAMS 2015 Annual Meeting.

Dr. Casey, professor of obstetrics and gynecology at the Mayo Clinic, Rochester, Minn., noted that the rate of infertility approaches, but does not reach, 100% by age 50, so women need a game plan to take them through the end of their fertile years. These needs are not always met, she said, noting that 75% of pregnancies in women over the age of 40 are unintended.

The rate of spontaneous abortion may exceed 50% by age 45, and chronic diabetes and hypertension are more likely to result after pregnancies in older women. The substantial increase in risk for undesirable outcomes means that an unexpected pregnancy in midlife may cause considerable distress.

No contraceptive method is contraindicated by a patient’s age alone, said Dr. Casey, though it may be wise to reserve combined hormonal contraception (CHC) for women without cardiovascular disease and thrombotic risk. Reminding the audience that risk stratification for CHC for those over 40 years of age is category 2, meaning that benefits generally outweigh the risks, Dr. Casey said, “ ‘What? So a 55-year-old can use combined hormonal contraception?’ Yes!”

Patients may also wish to consider a progestin-only contraception method, a choice that provides endometrial protection. This option allows the judicious addition of estrogen by the most appropriate method to manage symptoms. Choices include a contraceptive implant, a progestin-only pill, or a levonorgestrel-emitting intrauterine device. Depot medroxyprogesterone acetate (DMPA) may be less desirable because of the theoretical risk of bone loss, said Dr. Casey.

Transdermal estrogen delivery is preferred for menopausal doses of estrogen, according to the North American Menopause Society’s guidance for clinical care for midlife. If perimenopausal women are having cyclic vasomotor symptoms or headaches associated with estrogen nadir, transdermal estrogen therapy can be used during the menstrual week. With this option, a higher-dose patch of 0.1 mg will work better to replace endogenous estrogen.

For women who desire nonhormonal contraceptive and menopausal symptom management, a copper IUD, barrier contraception, or sterilization of the patient or her partner can be used in combination with a nonhormonal medication to manage vasomotor symptoms. Though the only Food and Drug Administration–approved nonhormonal option is paroxetine (Paxil) 7.5 mg/day, a variety of choices have been found effective in clinical trials. These include citalopram (Celexa) and escitalopram (Lexapro), venlafaxine (Effexor), desvenlafaxine (Pristiq), gabapentin (Neurontin), and pregabalin (Lyrica).

Contraception should be continued until the patient has experienced 12 months of continuous amenorrhea if over the age of 50 years, or 2 years of amenorrhea if she is younger than 50 years, said Dr. Casey. A predictive model for onset of menopause has been developed that takes age, smoking, bleeding patterns, and estrogen and follicle-stimulating hormone levels into account, but “further study is needed before applying this model clinically,” said Dr. Casey. The decision about when to discontinue contraception also depends on the impact it will have on the particular couple. “Shared decision making is of the utmost importance,” she said.

Dr. Casey disclosed that she is a certified Nexplanon trainer and has received research grant support from Merck.

[email protected]

On Twitter @karioakes

LAS VEGAS – Though fertility declines precipitously as menopause nears, women in midlife may still conceive. Clinicians and patients need guidance to develop a rational plan for contraceptive management and a clear path to transition to menopausal symptom management, said Dr. Petra Casey at the NAMS 2015 Annual Meeting.

Dr. Casey, professor of obstetrics and gynecology at the Mayo Clinic, Rochester, Minn., noted that the rate of infertility approaches, but does not reach, 100% by age 50, so women need a game plan to take them through the end of their fertile years. These needs are not always met, she said, noting that 75% of pregnancies in women over the age of 40 are unintended.

The rate of spontaneous abortion may exceed 50% by age 45, and chronic diabetes and hypertension are more likely to result after pregnancies in older women. The substantial increase in risk for undesirable outcomes means that an unexpected pregnancy in midlife may cause considerable distress.

No contraceptive method is contraindicated by a patient’s age alone, said Dr. Casey, though it may be wise to reserve combined hormonal contraception (CHC) for women without cardiovascular disease and thrombotic risk. Reminding the audience that risk stratification for CHC for those over 40 years of age is category 2, meaning that benefits generally outweigh the risks, Dr. Casey said, “ ‘What? So a 55-year-old can use combined hormonal contraception?’ Yes!”

Patients may also wish to consider a progestin-only contraception method, a choice that provides endometrial protection. This option allows the judicious addition of estrogen by the most appropriate method to manage symptoms. Choices include a contraceptive implant, a progestin-only pill, or a levonorgestrel-emitting intrauterine device. Depot medroxyprogesterone acetate (DMPA) may be less desirable because of the theoretical risk of bone loss, said Dr. Casey.

Transdermal estrogen delivery is preferred for menopausal doses of estrogen, according to the North American Menopause Society’s guidance for clinical care for midlife. If perimenopausal women are having cyclic vasomotor symptoms or headaches associated with estrogen nadir, transdermal estrogen therapy can be used during the menstrual week. With this option, a higher-dose patch of 0.1 mg will work better to replace endogenous estrogen.

For women who desire nonhormonal contraceptive and menopausal symptom management, a copper IUD, barrier contraception, or sterilization of the patient or her partner can be used in combination with a nonhormonal medication to manage vasomotor symptoms. Though the only Food and Drug Administration–approved nonhormonal option is paroxetine (Paxil) 7.5 mg/day, a variety of choices have been found effective in clinical trials. These include citalopram (Celexa) and escitalopram (Lexapro), venlafaxine (Effexor), desvenlafaxine (Pristiq), gabapentin (Neurontin), and pregabalin (Lyrica).

Contraception should be continued until the patient has experienced 12 months of continuous amenorrhea if over the age of 50 years, or 2 years of amenorrhea if she is younger than 50 years, said Dr. Casey. A predictive model for onset of menopause has been developed that takes age, smoking, bleeding patterns, and estrogen and follicle-stimulating hormone levels into account, but “further study is needed before applying this model clinically,” said Dr. Casey. The decision about when to discontinue contraception also depends on the impact it will have on the particular couple. “Shared decision making is of the utmost importance,” she said.

Dr. Casey disclosed that she is a certified Nexplanon trainer and has received research grant support from Merck.

[email protected]

On Twitter @karioakes

LAS VEGAS – Though fertility declines precipitously as menopause nears, women in midlife may still conceive. Clinicians and patients need guidance to develop a rational plan for contraceptive management and a clear path to transition to menopausal symptom management, said Dr. Petra Casey at the NAMS 2015 Annual Meeting.

Dr. Casey, professor of obstetrics and gynecology at the Mayo Clinic, Rochester, Minn., noted that the rate of infertility approaches, but does not reach, 100% by age 50, so women need a game plan to take them through the end of their fertile years. These needs are not always met, she said, noting that 75% of pregnancies in women over the age of 40 are unintended.

The rate of spontaneous abortion may exceed 50% by age 45, and chronic diabetes and hypertension are more likely to result after pregnancies in older women. The substantial increase in risk for undesirable outcomes means that an unexpected pregnancy in midlife may cause considerable distress.

No contraceptive method is contraindicated by a patient’s age alone, said Dr. Casey, though it may be wise to reserve combined hormonal contraception (CHC) for women without cardiovascular disease and thrombotic risk. Reminding the audience that risk stratification for CHC for those over 40 years of age is category 2, meaning that benefits generally outweigh the risks, Dr. Casey said, “ ‘What? So a 55-year-old can use combined hormonal contraception?’ Yes!”

Patients may also wish to consider a progestin-only contraception method, a choice that provides endometrial protection. This option allows the judicious addition of estrogen by the most appropriate method to manage symptoms. Choices include a contraceptive implant, a progestin-only pill, or a levonorgestrel-emitting intrauterine device. Depot medroxyprogesterone acetate (DMPA) may be less desirable because of the theoretical risk of bone loss, said Dr. Casey.

Transdermal estrogen delivery is preferred for menopausal doses of estrogen, according to the North American Menopause Society’s guidance for clinical care for midlife. If perimenopausal women are having cyclic vasomotor symptoms or headaches associated with estrogen nadir, transdermal estrogen therapy can be used during the menstrual week. With this option, a higher-dose patch of 0.1 mg will work better to replace endogenous estrogen.

For women who desire nonhormonal contraceptive and menopausal symptom management, a copper IUD, barrier contraception, or sterilization of the patient or her partner can be used in combination with a nonhormonal medication to manage vasomotor symptoms. Though the only Food and Drug Administration–approved nonhormonal option is paroxetine (Paxil) 7.5 mg/day, a variety of choices have been found effective in clinical trials. These include citalopram (Celexa) and escitalopram (Lexapro), venlafaxine (Effexor), desvenlafaxine (Pristiq), gabapentin (Neurontin), and pregabalin (Lyrica).

Contraception should be continued until the patient has experienced 12 months of continuous amenorrhea if over the age of 50 years, or 2 years of amenorrhea if she is younger than 50 years, said Dr. Casey. A predictive model for onset of menopause has been developed that takes age, smoking, bleeding patterns, and estrogen and follicle-stimulating hormone levels into account, but “further study is needed before applying this model clinically,” said Dr. Casey. The decision about when to discontinue contraception also depends on the impact it will have on the particular couple. “Shared decision making is of the utmost importance,” she said.

Dr. Casey disclosed that she is a certified Nexplanon trainer and has received research grant support from Merck.

[email protected]

On Twitter @karioakes

What Matters prides itself on reviewing the literature and presenting thoughtful commentary on articles that are relevant and applicable to the practicing clinician. We separate the wheat from the chaff. We are not, however, above taking on attention-grabbing articles.

Over the years, this column has reported on various methods to facilitate the expulsion of kidney stones, including tamsulosin, phosphodiesterase type 5 (PDE5) inhibitors, and steroids. But this one called out for our assessment: sex to expel kidney stones. Erroneously perceived prurient interests must be forgiven.

Dr. Omer Gokhan Doluoglu of the Clinic of Ankara (Turkey) Training and Research Hospital and colleagues conducted a randomized trial evaluating the effectiveness of sexual intercourse, tamsulosin, or standard medical therapy for kidney stone expulsion (Urology. 2015;86[1]:19-24). Potential subjects were eligible for inclusion if they had radiopaque distal ureteral stones. Subjects were excluded if the stones were larger than 6 mm.

Subjects were randomized to encouragement to have sexual intercourse at least three times per week, tamsulosin 0.4 mg/day, or symptomatic therapy alone. All patients received an antispasmodic and an anti-inflammatory, and were told to drink 2 L of water per day. Sexual intercourse and masturbation were prohibited in groups 2 and 3 during the treatment period, which lasted 4 weeks.

Ninety patients were randomized to the three groups. The mean stone size was 4.7-5.0 mm and not significantly different between the groups.

At 2 weeks, 83.9% (26 of 31) of the patients in the intercourse group, 47.6% (10 of 21) in the tamsulosin group, and 34.8% (8 of 23) passed the stones (P = .001). There was no difference between the groups at 4 weeks. Mean expulsion times were 10 days, 16.6 days, and 18 days, respectively (P = .0001).

The study’s authors propose that nitrous oxide is operant here by causing ureteric relaxation when released to create penile tumescence and during sexual activity. Because masturbation could achieve the same effect, patients in the other groups were told they could not. How effective this instruction was in the current study is unknown, because only “sexual intercourses” were collected on follow-up.

The random-envelope method used is less than ideal, and no data were reported on differences in the number of sexual experiences between groups. If we assume for a moment that a real effect exists, one is left wondering if more would be better. Does the requirement of a partner decrease the likelihood of more frequent stone-expelling sexual experiences? If our patients do not have sexual partners, do we not share these data with them?

And if we use PDE5 inhibitors and encourage sexual activity, do we … kill two birds with one stone?

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter @jonebbert.

What Matters prides itself on reviewing the literature and presenting thoughtful commentary on articles that are relevant and applicable to the practicing clinician. We separate the wheat from the chaff. We are not, however, above taking on attention-grabbing articles.

Over the years, this column has reported on various methods to facilitate the expulsion of kidney stones, including tamsulosin, phosphodiesterase type 5 (PDE5) inhibitors, and steroids. But this one called out for our assessment: sex to expel kidney stones. Erroneously perceived prurient interests must be forgiven.

Dr. Omer Gokhan Doluoglu of the Clinic of Ankara (Turkey) Training and Research Hospital and colleagues conducted a randomized trial evaluating the effectiveness of sexual intercourse, tamsulosin, or standard medical therapy for kidney stone expulsion (Urology. 2015;86[1]:19-24). Potential subjects were eligible for inclusion if they had radiopaque distal ureteral stones. Subjects were excluded if the stones were larger than 6 mm.

Subjects were randomized to encouragement to have sexual intercourse at least three times per week, tamsulosin 0.4 mg/day, or symptomatic therapy alone. All patients received an antispasmodic and an anti-inflammatory, and were told to drink 2 L of water per day. Sexual intercourse and masturbation were prohibited in groups 2 and 3 during the treatment period, which lasted 4 weeks.

Ninety patients were randomized to the three groups. The mean stone size was 4.7-5.0 mm and not significantly different between the groups.

At 2 weeks, 83.9% (26 of 31) of the patients in the intercourse group, 47.6% (10 of 21) in the tamsulosin group, and 34.8% (8 of 23) passed the stones (P = .001). There was no difference between the groups at 4 weeks. Mean expulsion times were 10 days, 16.6 days, and 18 days, respectively (P = .0001).

The study’s authors propose that nitrous oxide is operant here by causing ureteric relaxation when released to create penile tumescence and during sexual activity. Because masturbation could achieve the same effect, patients in the other groups were told they could not. How effective this instruction was in the current study is unknown, because only “sexual intercourses” were collected on follow-up.

The random-envelope method used is less than ideal, and no data were reported on differences in the number of sexual experiences between groups. If we assume for a moment that a real effect exists, one is left wondering if more would be better. Does the requirement of a partner decrease the likelihood of more frequent stone-expelling sexual experiences? If our patients do not have sexual partners, do we not share these data with them?

And if we use PDE5 inhibitors and encourage sexual activity, do we … kill two birds with one stone?

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter @jonebbert.

What Matters prides itself on reviewing the literature and presenting thoughtful commentary on articles that are relevant and applicable to the practicing clinician. We separate the wheat from the chaff. We are not, however, above taking on attention-grabbing articles.

Over the years, this column has reported on various methods to facilitate the expulsion of kidney stones, including tamsulosin, phosphodiesterase type 5 (PDE5) inhibitors, and steroids. But this one called out for our assessment: sex to expel kidney stones. Erroneously perceived prurient interests must be forgiven.

Dr. Omer Gokhan Doluoglu of the Clinic of Ankara (Turkey) Training and Research Hospital and colleagues conducted a randomized trial evaluating the effectiveness of sexual intercourse, tamsulosin, or standard medical therapy for kidney stone expulsion (Urology. 2015;86[1]:19-24). Potential subjects were eligible for inclusion if they had radiopaque distal ureteral stones. Subjects were excluded if the stones were larger than 6 mm.

Subjects were randomized to encouragement to have sexual intercourse at least three times per week, tamsulosin 0.4 mg/day, or symptomatic therapy alone. All patients received an antispasmodic and an anti-inflammatory, and were told to drink 2 L of water per day. Sexual intercourse and masturbation were prohibited in groups 2 and 3 during the treatment period, which lasted 4 weeks.

Ninety patients were randomized to the three groups. The mean stone size was 4.7-5.0 mm and not significantly different between the groups.

At 2 weeks, 83.9% (26 of 31) of the patients in the intercourse group, 47.6% (10 of 21) in the tamsulosin group, and 34.8% (8 of 23) passed the stones (P = .001). There was no difference between the groups at 4 weeks. Mean expulsion times were 10 days, 16.6 days, and 18 days, respectively (P = .0001).

The study’s authors propose that nitrous oxide is operant here by causing ureteric relaxation when released to create penile tumescence and during sexual activity. Because masturbation could achieve the same effect, patients in the other groups were told they could not. How effective this instruction was in the current study is unknown, because only “sexual intercourses” were collected on follow-up.

The random-envelope method used is less than ideal, and no data were reported on differences in the number of sexual experiences between groups. If we assume for a moment that a real effect exists, one is left wondering if more would be better. Does the requirement of a partner decrease the likelihood of more frequent stone-expelling sexual experiences? If our patients do not have sexual partners, do we not share these data with them?

And if we use PDE5 inhibitors and encourage sexual activity, do we … kill two birds with one stone?

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter @jonebbert.

Mads Daugaard, PhD

Photo by Vivian Sum

A protein expressed by the malaria parasite Plasmodium falciparum may prove useful for treating a range of cancers, according to research published in Cancer Cell.

This protein, VAR2CSA, binds a chondroitin sulfate (CS) that is found in placenta but is also present in many different cancer cells.

So investigators combined recombinant VAR2CSA (rVAR2) with 2 different toxins to create cancer-targeting treatments.

The treatments effectively targeted cancers in vitro and in vivo, impeding tumor growth and even eradicating cancer in some mice.

An idea is born

This research was born while the investigators were exploring why pregnant women are particularly susceptible to malaria. The team found that P falciparum produces VAR2CSA, which binds to a particular CS in the placenta, and that placenta-like CS (pl-CS) is found in most cancers.

This suggested the pl-CS could be a target for anticancer drugs, and VAR2CSA could provide the tool for carrying such drugs to tumors.

“Scientists have spent decades trying to find biochemical similarities between placenta tissue and cancer, but we just didn’t have the technology to find it,” said project leader Mads Daugaard, PhD, of the University of British Columbia in Vancouver, Canada.

“When my colleagues discovered how malaria uses VAR2CSA to embed itself in the placenta, we immediately saw its potential to deliver cancer drugs in a precise, controlled way to tumors.”

Testing rVAR2

After demonstrating that rVAR2 binds only to pl-CS, the investigators tested rVAR2 in patient-derived cancer cell lines of hematopoietic, epithelial, and mesenchymal origin. rVAR2 reacted with 95% (106/111) of these cell lines.

To determine whether rVAR2 could be used as a pl-CS-specific tumor-targeting system, the investigators fused the cytotoxic domain of diphtheria toxin (DT388) to rVAR2, creating a recombinant rDT388-VAR2 (rVAR2-DT) fusion protein.

The rVAR2-DT protein killed tumor cell lines of epithelial and mesenchymal origin, but it had no effect on normal primary human endothelial cells.

The investigators also tested rVAR2-DT in mouse models of prostate cancer and found that as few as 3 doses were enough to significantly inhibit tumor growth.

However, the team noted that clinical trials with DT fusions have shown that high drug concentrations are not well-tolerated.

So they chemically conjugated a hemiasterlin analog (KT886) to rVAR2 via a protease cleavable linker. The rVAR2-KT886 drug conjugate (VDC886) carried an average of 3 toxins per rVAR2 molecule.

The investigators tested VDC886 in 33 cancer cell lines and observed cytotoxicity in all cell lines.

So the team went on to test VDC886 in mouse models of non-Hodgkin lymphoma, prostate cancer, and metastatic breast cancer. VDC886 significantly inhibited tumor growth in all 3 models.

In mice with non-Hodgkin lymphoma, treated tumors were about a quarter the size of tumors in control mice. For the mice with prostate cancer, tumors completely disappeared in 2 of the 6 treated mice a month after they received the first dose of VDC886.

In mice with metastatic breast cancer, 5 of the 6 treated mice were cured and alive after almost 8 weeks. None of the control mice with metastatic breast cancer survived that long.

The investigators said they did not observe any adverse effects in the mice, and their organs were unharmed by the therapy.

“It appears that the malaria protein attaches itself to the tumor without any significant attachment to other tissue,” said Thomas Mandel Clausen, a PhD student at the University of Copenhagen in Denmark.

“And the mice that were given doses of protein and toxin showed far higher survival rates than the untreated mice. We have seen that 3 doses can arrest growth in a tumor and even make it shrink.”

Based on these results, 2 companies—Vancouver-based Kairos Therapeutics and Copenhagen-based VAR2 Pharmaceuticals—are developing the compound for clinical trials. The investigators believe this will take a few years.

Mads Daugaard, PhD

Photo by Vivian Sum

A protein expressed by the malaria parasite Plasmodium falciparum may prove useful for treating a range of cancers, according to research published in Cancer Cell.

This protein, VAR2CSA, binds a chondroitin sulfate (CS) that is found in placenta but is also present in many different cancer cells.

So investigators combined recombinant VAR2CSA (rVAR2) with 2 different toxins to create cancer-targeting treatments.

The treatments effectively targeted cancers in vitro and in vivo, impeding tumor growth and even eradicating cancer in some mice.

An idea is born

This research was born while the investigators were exploring why pregnant women are particularly susceptible to malaria. The team found that P falciparum produces VAR2CSA, which binds to a particular CS in the placenta, and that placenta-like CS (pl-CS) is found in most cancers.

This suggested the pl-CS could be a target for anticancer drugs, and VAR2CSA could provide the tool for carrying such drugs to tumors.

“Scientists have spent decades trying to find biochemical similarities between placenta tissue and cancer, but we just didn’t have the technology to find it,” said project leader Mads Daugaard, PhD, of the University of British Columbia in Vancouver, Canada.

“When my colleagues discovered how malaria uses VAR2CSA to embed itself in the placenta, we immediately saw its potential to deliver cancer drugs in a precise, controlled way to tumors.”

Testing rVAR2

After demonstrating that rVAR2 binds only to pl-CS, the investigators tested rVAR2 in patient-derived cancer cell lines of hematopoietic, epithelial, and mesenchymal origin. rVAR2 reacted with 95% (106/111) of these cell lines.

To determine whether rVAR2 could be used as a pl-CS-specific tumor-targeting system, the investigators fused the cytotoxic domain of diphtheria toxin (DT388) to rVAR2, creating a recombinant rDT388-VAR2 (rVAR2-DT) fusion protein.

The rVAR2-DT protein killed tumor cell lines of epithelial and mesenchymal origin, but it had no effect on normal primary human endothelial cells.

The investigators also tested rVAR2-DT in mouse models of prostate cancer and found that as few as 3 doses were enough to significantly inhibit tumor growth.

However, the team noted that clinical trials with DT fusions have shown that high drug concentrations are not well-tolerated.

So they chemically conjugated a hemiasterlin analog (KT886) to rVAR2 via a protease cleavable linker. The rVAR2-KT886 drug conjugate (VDC886) carried an average of 3 toxins per rVAR2 molecule.

The investigators tested VDC886 in 33 cancer cell lines and observed cytotoxicity in all cell lines.

So the team went on to test VDC886 in mouse models of non-Hodgkin lymphoma, prostate cancer, and metastatic breast cancer. VDC886 significantly inhibited tumor growth in all 3 models.

In mice with non-Hodgkin lymphoma, treated tumors were about a quarter the size of tumors in control mice. For the mice with prostate cancer, tumors completely disappeared in 2 of the 6 treated mice a month after they received the first dose of VDC886.

In mice with metastatic breast cancer, 5 of the 6 treated mice were cured and alive after almost 8 weeks. None of the control mice with metastatic breast cancer survived that long.

The investigators said they did not observe any adverse effects in the mice, and their organs were unharmed by the therapy.

“It appears that the malaria protein attaches itself to the tumor without any significant attachment to other tissue,” said Thomas Mandel Clausen, a PhD student at the University of Copenhagen in Denmark.

“And the mice that were given doses of protein and toxin showed far higher survival rates than the untreated mice. We have seen that 3 doses can arrest growth in a tumor and even make it shrink.”

Based on these results, 2 companies—Vancouver-based Kairos Therapeutics and Copenhagen-based VAR2 Pharmaceuticals—are developing the compound for clinical trials. The investigators believe this will take a few years.

Mads Daugaard, PhD

Photo by Vivian Sum

A protein expressed by the malaria parasite Plasmodium falciparum may prove useful for treating a range of cancers, according to research published in Cancer Cell.

This protein, VAR2CSA, binds a chondroitin sulfate (CS) that is found in placenta but is also present in many different cancer cells.

So investigators combined recombinant VAR2CSA (rVAR2) with 2 different toxins to create cancer-targeting treatments.

The treatments effectively targeted cancers in vitro and in vivo, impeding tumor growth and even eradicating cancer in some mice.

An idea is born

This research was born while the investigators were exploring why pregnant women are particularly susceptible to malaria. The team found that P falciparum produces VAR2CSA, which binds to a particular CS in the placenta, and that placenta-like CS (pl-CS) is found in most cancers.

This suggested the pl-CS could be a target for anticancer drugs, and VAR2CSA could provide the tool for carrying such drugs to tumors.

“Scientists have spent decades trying to find biochemical similarities between placenta tissue and cancer, but we just didn’t have the technology to find it,” said project leader Mads Daugaard, PhD, of the University of British Columbia in Vancouver, Canada.

“When my colleagues discovered how malaria uses VAR2CSA to embed itself in the placenta, we immediately saw its potential to deliver cancer drugs in a precise, controlled way to tumors.”

Testing rVAR2

After demonstrating that rVAR2 binds only to pl-CS, the investigators tested rVAR2 in patient-derived cancer cell lines of hematopoietic, epithelial, and mesenchymal origin. rVAR2 reacted with 95% (106/111) of these cell lines.

To determine whether rVAR2 could be used as a pl-CS-specific tumor-targeting system, the investigators fused the cytotoxic domain of diphtheria toxin (DT388) to rVAR2, creating a recombinant rDT388-VAR2 (rVAR2-DT) fusion protein.

The rVAR2-DT protein killed tumor cell lines of epithelial and mesenchymal origin, but it had no effect on normal primary human endothelial cells.

The investigators also tested rVAR2-DT in mouse models of prostate cancer and found that as few as 3 doses were enough to significantly inhibit tumor growth.

However, the team noted that clinical trials with DT fusions have shown that high drug concentrations are not well-tolerated.

So they chemically conjugated a hemiasterlin analog (KT886) to rVAR2 via a protease cleavable linker. The rVAR2-KT886 drug conjugate (VDC886) carried an average of 3 toxins per rVAR2 molecule.

The investigators tested VDC886 in 33 cancer cell lines and observed cytotoxicity in all cell lines.

So the team went on to test VDC886 in mouse models of non-Hodgkin lymphoma, prostate cancer, and metastatic breast cancer. VDC886 significantly inhibited tumor growth in all 3 models.

In mice with non-Hodgkin lymphoma, treated tumors were about a quarter the size of tumors in control mice. For the mice with prostate cancer, tumors completely disappeared in 2 of the 6 treated mice a month after they received the first dose of VDC886.

In mice with metastatic breast cancer, 5 of the 6 treated mice were cured and alive after almost 8 weeks. None of the control mice with metastatic breast cancer survived that long.

The investigators said they did not observe any adverse effects in the mice, and their organs were unharmed by the therapy.

“It appears that the malaria protein attaches itself to the tumor without any significant attachment to other tissue,” said Thomas Mandel Clausen, a PhD student at the University of Copenhagen in Denmark.

“And the mice that were given doses of protein and toxin showed far higher survival rates than the untreated mice. We have seen that 3 doses can arrest growth in a tumor and even make it shrink.”

Based on these results, 2 companies—Vancouver-based Kairos Therapeutics and Copenhagen-based VAR2 Pharmaceuticals—are developing the compound for clinical trials. The investigators believe this will take a few years.

Study authors Heather

Conklin and Jason Ashford

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Cognitive training presented as a video game can help improve cognitive skills in childhood cancer survivors (CCSs), new research suggests.

CCSs who completed 20 to 30 training sessions with this game experienced significant improvements in working memory, attention, and the speed at which their brains process information.

However, these improvements did not translate to improved math or reading performance.

Heather Conklin, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues conducted this research and described the results in the Journal of Clinical Oncology.

Study design

This study included 68 CCSs who had received cranial irradiation, intrathecal chemotherapy, or both for the treatment of acute lymphoblastic leukemia or brain tumors.

Participants were 8 to 16 years old, had completed treatment, and had been disease-free for at least a year. Prior to joining the study, all scored below expectations on measures of working memory.

The computerized intervention the CCSs used is called Cogmed (http://www.cogmed.com). It’s a working memory intervention that has previously demonstrated efficacy for individuals with developmental and acquired attention disorders as well as for healthy adults.

For this study, half the CCSs were randomized to begin using Cogmed immediately. The remaining survivors, who served as the control group, were given the opportunity to use Cogmed about 6 months later.

The CCSs assigned to Cogmed first were asked to complete 25 training sessions at home, along with weekly, telephone-based coaching. The training sessions lasted 30 to 45 minutes and included verbal and visual-spatial exercises that were presented as games and are designed to improve working memory.

CCSs who began training immediately underwent functional brain MRI before and soon after completing the intervention. The imaging tracked brain activity as the survivors completed a working memory exercise.

Results

CCSs who completed the intervention (n=30) showed greater improvements than controls on measures of working memory (P=0.002), attention (P=0.01), and processing speed (P=0.02).

The researchers said the benefits to working memory and attention were comparable to gains reported in previous studies of stimulant medications. And the gains from cognitive training moved the CCSs’ performance into the normal range.

Caregivers also reported significant improvement in the attention and executive functioning of CCSs who completed the training. (Executive functioning includes skills like planning and focus needed to juggle multiple tasks and get things done.)

“These results suggest that computerized cognitive training may help fill a void in management of cognitive late effects that impact quality of life for childhood cancer survivors, such as the likelihood they will complete school and live independently,” Dr Conklin said.

In addition, post-intervention brain imaging showed decreased activation of left lateral prefrontal and bilateral medial frontal areas.

“That suggests the intervention exercised and strengthened the well-established working memory network,” Dr Conklin said. “The implication is that the brain may operate more efficiently and have less need for compensatory strategies. Such training-induced neuroplasticity suggests the benefits might be sustained going forward.”

The researchers are now studying the possible benefits of starting brain training during treatment or combining it with other interventions. The team is also tracking whether the cognitive benefits are sustained and might eventually translate to the improved academic performance reported for other populations.

Study authors Heather

Conklin and Jason Ashford

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Cognitive training presented as a video game can help improve cognitive skills in childhood cancer survivors (CCSs), new research suggests.

CCSs who completed 20 to 30 training sessions with this game experienced significant improvements in working memory, attention, and the speed at which their brains process information.

However, these improvements did not translate to improved math or reading performance.

Heather Conklin, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues conducted this research and described the results in the Journal of Clinical Oncology.

Study design

This study included 68 CCSs who had received cranial irradiation, intrathecal chemotherapy, or both for the treatment of acute lymphoblastic leukemia or brain tumors.

Participants were 8 to 16 years old, had completed treatment, and had been disease-free for at least a year. Prior to joining the study, all scored below expectations on measures of working memory.

The computerized intervention the CCSs used is called Cogmed (http://www.cogmed.com). It’s a working memory intervention that has previously demonstrated efficacy for individuals with developmental and acquired attention disorders as well as for healthy adults.

For this study, half the CCSs were randomized to begin using Cogmed immediately. The remaining survivors, who served as the control group, were given the opportunity to use Cogmed about 6 months later.

The CCSs assigned to Cogmed first were asked to complete 25 training sessions at home, along with weekly, telephone-based coaching. The training sessions lasted 30 to 45 minutes and included verbal and visual-spatial exercises that were presented as games and are designed to improve working memory.

CCSs who began training immediately underwent functional brain MRI before and soon after completing the intervention. The imaging tracked brain activity as the survivors completed a working memory exercise.

Results

CCSs who completed the intervention (n=30) showed greater improvements than controls on measures of working memory (P=0.002), attention (P=0.01), and processing speed (P=0.02).

The researchers said the benefits to working memory and attention were comparable to gains reported in previous studies of stimulant medications. And the gains from cognitive training moved the CCSs’ performance into the normal range.

Caregivers also reported significant improvement in the attention and executive functioning of CCSs who completed the training. (Executive functioning includes skills like planning and focus needed to juggle multiple tasks and get things done.)

“These results suggest that computerized cognitive training may help fill a void in management of cognitive late effects that impact quality of life for childhood cancer survivors, such as the likelihood they will complete school and live independently,” Dr Conklin said.

In addition, post-intervention brain imaging showed decreased activation of left lateral prefrontal and bilateral medial frontal areas.

“That suggests the intervention exercised and strengthened the well-established working memory network,” Dr Conklin said. “The implication is that the brain may operate more efficiently and have less need for compensatory strategies. Such training-induced neuroplasticity suggests the benefits might be sustained going forward.”

The researchers are now studying the possible benefits of starting brain training during treatment or combining it with other interventions. The team is also tracking whether the cognitive benefits are sustained and might eventually translate to the improved academic performance reported for other populations.

Study authors Heather

Conklin and Jason Ashford

Photo courtesy of St. Jude

Children’s Research Hospital

and Peter Barta

Cognitive training presented as a video game can help improve cognitive skills in childhood cancer survivors (CCSs), new research suggests.

CCSs who completed 20 to 30 training sessions with this game experienced significant improvements in working memory, attention, and the speed at which their brains process information.

However, these improvements did not translate to improved math or reading performance.

Heather Conklin, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues conducted this research and described the results in the Journal of Clinical Oncology.

Study design

This study included 68 CCSs who had received cranial irradiation, intrathecal chemotherapy, or both for the treatment of acute lymphoblastic leukemia or brain tumors.

Participants were 8 to 16 years old, had completed treatment, and had been disease-free for at least a year. Prior to joining the study, all scored below expectations on measures of working memory.

The computerized intervention the CCSs used is called Cogmed (http://www.cogmed.com). It’s a working memory intervention that has previously demonstrated efficacy for individuals with developmental and acquired attention disorders as well as for healthy adults.

For this study, half the CCSs were randomized to begin using Cogmed immediately. The remaining survivors, who served as the control group, were given the opportunity to use Cogmed about 6 months later.

The CCSs assigned to Cogmed first were asked to complete 25 training sessions at home, along with weekly, telephone-based coaching. The training sessions lasted 30 to 45 minutes and included verbal and visual-spatial exercises that were presented as games and are designed to improve working memory.

CCSs who began training immediately underwent functional brain MRI before and soon after completing the intervention. The imaging tracked brain activity as the survivors completed a working memory exercise.

Results

CCSs who completed the intervention (n=30) showed greater improvements than controls on measures of working memory (P=0.002), attention (P=0.01), and processing speed (P=0.02).

The researchers said the benefits to working memory and attention were comparable to gains reported in previous studies of stimulant medications. And the gains from cognitive training moved the CCSs’ performance into the normal range.

Caregivers also reported significant improvement in the attention and executive functioning of CCSs who completed the training. (Executive functioning includes skills like planning and focus needed to juggle multiple tasks and get things done.)

“These results suggest that computerized cognitive training may help fill a void in management of cognitive late effects that impact quality of life for childhood cancer survivors, such as the likelihood they will complete school and live independently,” Dr Conklin said.

In addition, post-intervention brain imaging showed decreased activation of left lateral prefrontal and bilateral medial frontal areas.

“That suggests the intervention exercised and strengthened the well-established working memory network,” Dr Conklin said. “The implication is that the brain may operate more efficiently and have less need for compensatory strategies. Such training-induced neuroplasticity suggests the benefits might be sustained going forward.”

The researchers are now studying the possible benefits of starting brain training during treatment or combining it with other interventions. The team is also tracking whether the cognitive benefits are sustained and might eventually translate to the improved academic performance reported for other populations.

Gordon Ginder, MD

Photo courtesy of VCU

Massey Cancer Center

Preclinical experiments have shown that blocking production of the protein CHD4 may help increase the effectiveness of first-line treatments for acute myeloid leukemia (AML).

Researchers found that depleting AML cells of CHD4 makes them more susceptible to standard chemotherapeutic agents by reducing the cells’ ability to repair DNA damage.

Depleting CHD4 also decreased AML cells’ ability to form colonies in vitro and tumors in vivo.

On the other hand, CHD4 depletion did not have detrimental effects on healthy bone marrow cells. The cells were no more sensitive to chemotherapy, and their growth was not affected.

Researchers reported these results in Blood.

“We are very encouraged by these findings,” said study author Gordon Ginder, MD, of Virginia Commonwealth University in Richmond.

“Targeting the CHD4 protein could allow us to reduce chemotherapy doses, which could potentially mean more effective first- and second-line treatments with fewer serious side effects.”

CHD4 is involved in silencing tumor suppressor genes in cancer cells. Recently, it has been shown to play a role in repairing DNA damage.

With their experiments, Dr Ginder and his colleagues found that CHD4 depletion severely restricted the ability of AML cells to develop colonies in soft agar models and establish tumors in mouse models.

In addition, blocking the production of CHD4 rendered AML cells more sensitive to daunorubicin and cytarabine, both in vitro and in vivo.

“This study builds on our team’s efforts to understand the molecular processes through which epigenetic regulators impact gene expression,” Dr Ginder said.

“Future studies will attempt to uncover the detailed mechanism through which CHD4 decreases the ability of AML cells to initiate leukemia and will look for potential ways to target this important protein. The fact that it functions as an enzyme suggests it may be druggable.”

Gordon Ginder, MD

Photo courtesy of VCU

Massey Cancer Center

Preclinical experiments have shown that blocking production of the protein CHD4 may help increase the effectiveness of first-line treatments for acute myeloid leukemia (AML).

Researchers found that depleting AML cells of CHD4 makes them more susceptible to standard chemotherapeutic agents by reducing the cells’ ability to repair DNA damage.

Depleting CHD4 also decreased AML cells’ ability to form colonies in vitro and tumors in vivo.

On the other hand, CHD4 depletion did not have detrimental effects on healthy bone marrow cells. The cells were no more sensitive to chemotherapy, and their growth was not affected.

Researchers reported these results in Blood.

“We are very encouraged by these findings,” said study author Gordon Ginder, MD, of Virginia Commonwealth University in Richmond.

“Targeting the CHD4 protein could allow us to reduce chemotherapy doses, which could potentially mean more effective first- and second-line treatments with fewer serious side effects.”

CHD4 is involved in silencing tumor suppressor genes in cancer cells. Recently, it has been shown to play a role in repairing DNA damage.

With their experiments, Dr Ginder and his colleagues found that CHD4 depletion severely restricted the ability of AML cells to develop colonies in soft agar models and establish tumors in mouse models.

In addition, blocking the production of CHD4 rendered AML cells more sensitive to daunorubicin and cytarabine, both in vitro and in vivo.

“This study builds on our team’s efforts to understand the molecular processes through which epigenetic regulators impact gene expression,” Dr Ginder said.

“Future studies will attempt to uncover the detailed mechanism through which CHD4 decreases the ability of AML cells to initiate leukemia and will look for potential ways to target this important protein. The fact that it functions as an enzyme suggests it may be druggable.”

Gordon Ginder, MD

Photo courtesy of VCU

Massey Cancer Center

Preclinical experiments have shown that blocking production of the protein CHD4 may help increase the effectiveness of first-line treatments for acute myeloid leukemia (AML).

Researchers found that depleting AML cells of CHD4 makes them more susceptible to standard chemotherapeutic agents by reducing the cells’ ability to repair DNA damage.

Depleting CHD4 also decreased AML cells’ ability to form colonies in vitro and tumors in vivo.

On the other hand, CHD4 depletion did not have detrimental effects on healthy bone marrow cells. The cells were no more sensitive to chemotherapy, and their growth was not affected.

Researchers reported these results in Blood.

“We are very encouraged by these findings,” said study author Gordon Ginder, MD, of Virginia Commonwealth University in Richmond.

“Targeting the CHD4 protein could allow us to reduce chemotherapy doses, which could potentially mean more effective first- and second-line treatments with fewer serious side effects.”

CHD4 is involved in silencing tumor suppressor genes in cancer cells. Recently, it has been shown to play a role in repairing DNA damage.

With their experiments, Dr Ginder and his colleagues found that CHD4 depletion severely restricted the ability of AML cells to develop colonies in soft agar models and establish tumors in mouse models.

In addition, blocking the production of CHD4 rendered AML cells more sensitive to daunorubicin and cytarabine, both in vitro and in vivo.

“This study builds on our team’s efforts to understand the molecular processes through which epigenetic regulators impact gene expression,” Dr Ginder said.

“Future studies will attempt to uncover the detailed mechanism through which CHD4 decreases the ability of AML cells to initiate leukemia and will look for potential ways to target this important protein. The fact that it functions as an enzyme suggests it may be druggable.”

Lab mouse

Sleep-deprived mice make poor donors for hematopoietic stem cell transplants (HSCTs), according to a study published in Nature Communications.

The research showed that a sleep deficit of just 4 hours can reduce—by more than 50%—the ability of HSCs to engraft and reconstitute the blood and bone marrow of an irradiated recipient mouse.

Researchers believe these findings may also apply to humans.

“Considering how little attention we typically pay to sleep in the hospital setting, this finding is troubling,” said study author Asya Rolls, PhD, of Technion–Israel Institute of Technology in Haifa.

“We go to all this trouble to find a matching donor, but this research suggests that, if the donor is not well-rested, it can impact the outcome of the transplantation. However, it’s heartening to think that this is not an insurmountable obstacle. A short period of recovery sleep before transplant can restore the donor’s cells’ ability to function normally.”

Dr Rolls and her colleagues studied mice that had been gently handled for 4 hours to prevent them from sleeping while control mice dozed. The team then collected HSCs from the sleep-deprived and well-rested mice and injected the cells into 12 irradiated mice.

The recipient mice also received an injection of their own HSCs collected prior to radiation so the researchers could quantify the relative abilities of the donated HSCs to engraft successfully.

The team then assessed the prevalence of myeloid cells derived from donated HSCs at 8 weeks and 16 weeks after transplant. At 16 weeks, donor myeloid chimerism was about 26% in HSCT recipients with well-rested donors and about 12% in recipients with sleep-deprived donors (P<0.0001).

Dr Rolls and her colleagues also compared the ability of fluorescently labeled HSCs from sleep-deprived mice and rested mice to home to the bone marrow. After 12 hours, 3.3% percent of HSCs from rested mice were found in the bone marrow, compared to 1.7% of HSCs from sleep-deprived mice (P<0.05).

Further investigation revealed that sleep deprivation downregulates the expression of miR-19b, a negative regulator of the suppressor of cytokine signaling (SOCS) genes, which inhibit HSC migration and homing.

Finally, Dr Rolls and her colleagues found the effects of sleep deprivation on HSCs could be reversed by letting mice catch up on sleep. Even 2 hours of recovery sleep restored the HSCs’ ability to function normally in transplantation tests.

“We still don’t know how sleep deprivation affects us all, not just bone marrow donors,” Dr Rolls said. “The fact that recovery sleep is so helpful only emphasizes how important it is to pay attention to sleep.”

Lab mouse

Sleep-deprived mice make poor donors for hematopoietic stem cell transplants (HSCTs), according to a study published in Nature Communications.

The research showed that a sleep deficit of just 4 hours can reduce—by more than 50%—the ability of HSCs to engraft and reconstitute the blood and bone marrow of an irradiated recipient mouse.

Researchers believe these findings may also apply to humans.

“Considering how little attention we typically pay to sleep in the hospital setting, this finding is troubling,” said study author Asya Rolls, PhD, of Technion–Israel Institute of Technology in Haifa.

“We go to all this trouble to find a matching donor, but this research suggests that, if the donor is not well-rested, it can impact the outcome of the transplantation. However, it’s heartening to think that this is not an insurmountable obstacle. A short period of recovery sleep before transplant can restore the donor’s cells’ ability to function normally.”

Dr Rolls and her colleagues studied mice that had been gently handled for 4 hours to prevent them from sleeping while control mice dozed. The team then collected HSCs from the sleep-deprived and well-rested mice and injected the cells into 12 irradiated mice.

The recipient mice also received an injection of their own HSCs collected prior to radiation so the researchers could quantify the relative abilities of the donated HSCs to engraft successfully.

The team then assessed the prevalence of myeloid cells derived from donated HSCs at 8 weeks and 16 weeks after transplant. At 16 weeks, donor myeloid chimerism was about 26% in HSCT recipients with well-rested donors and about 12% in recipients with sleep-deprived donors (P<0.0001).

Dr Rolls and her colleagues also compared the ability of fluorescently labeled HSCs from sleep-deprived mice and rested mice to home to the bone marrow. After 12 hours, 3.3% percent of HSCs from rested mice were found in the bone marrow, compared to 1.7% of HSCs from sleep-deprived mice (P<0.05).

Further investigation revealed that sleep deprivation downregulates the expression of miR-19b, a negative regulator of the suppressor of cytokine signaling (SOCS) genes, which inhibit HSC migration and homing.

Finally, Dr Rolls and her colleagues found the effects of sleep deprivation on HSCs could be reversed by letting mice catch up on sleep. Even 2 hours of recovery sleep restored the HSCs’ ability to function normally in transplantation tests.

“We still don’t know how sleep deprivation affects us all, not just bone marrow donors,” Dr Rolls said. “The fact that recovery sleep is so helpful only emphasizes how important it is to pay attention to sleep.”

Lab mouse

Sleep-deprived mice make poor donors for hematopoietic stem cell transplants (HSCTs), according to a study published in Nature Communications.

The research showed that a sleep deficit of just 4 hours can reduce—by more than 50%—the ability of HSCs to engraft and reconstitute the blood and bone marrow of an irradiated recipient mouse.

Researchers believe these findings may also apply to humans.

“Considering how little attention we typically pay to sleep in the hospital setting, this finding is troubling,” said study author Asya Rolls, PhD, of Technion–Israel Institute of Technology in Haifa.

“We go to all this trouble to find a matching donor, but this research suggests that, if the donor is not well-rested, it can impact the outcome of the transplantation. However, it’s heartening to think that this is not an insurmountable obstacle. A short period of recovery sleep before transplant can restore the donor’s cells’ ability to function normally.”

Dr Rolls and her colleagues studied mice that had been gently handled for 4 hours to prevent them from sleeping while control mice dozed. The team then collected HSCs from the sleep-deprived and well-rested mice and injected the cells into 12 irradiated mice.

The recipient mice also received an injection of their own HSCs collected prior to radiation so the researchers could quantify the relative abilities of the donated HSCs to engraft successfully.

The team then assessed the prevalence of myeloid cells derived from donated HSCs at 8 weeks and 16 weeks after transplant. At 16 weeks, donor myeloid chimerism was about 26% in HSCT recipients with well-rested donors and about 12% in recipients with sleep-deprived donors (P<0.0001).

Dr Rolls and her colleagues also compared the ability of fluorescently labeled HSCs from sleep-deprived mice and rested mice to home to the bone marrow. After 12 hours, 3.3% percent of HSCs from rested mice were found in the bone marrow, compared to 1.7% of HSCs from sleep-deprived mice (P<0.05).

Further investigation revealed that sleep deprivation downregulates the expression of miR-19b, a negative regulator of the suppressor of cytokine signaling (SOCS) genes, which inhibit HSC migration and homing.

Finally, Dr Rolls and her colleagues found the effects of sleep deprivation on HSCs could be reversed by letting mice catch up on sleep. Even 2 hours of recovery sleep restored the HSCs’ ability to function normally in transplantation tests.

“We still don’t know how sleep deprivation affects us all, not just bone marrow donors,” Dr Rolls said. “The fact that recovery sleep is so helpful only emphasizes how important it is to pay attention to sleep.”

A novel drug-coated stent halved the need for repeat revascularization and had a superior safety profile, compared with a bare-metal stent, in patients with a high risk of bleeding in the LEADERS FREE trial.

The results could mean that these typically older, sicker patients in whom dual antiplatelet therapy is contraindicated because of hemorrhage risk now have a wider range of revascularization options, said lead investigator Dr. Philip Urban.

“Patients who have a high risk of bleeding during percutaneous coronary intervention (PCI) are often excluded from stent and drug trials but constitute a rapidly growing proportion of PCI candidates, and they suffer high event rates,” said Dr. Urban, director of interventional cardiology at La Tour Hospital in Geneva. As the life expectancy increases, the implications are profound because roughly one-fifth of all PCI patients globally could be candidates for this type of treatment.

The data were presented at the Transcatheter Cardiovascular Therapeutics annual meeting, which was sponsored by the Cardiovascular Research Foundation. The results also were published online (N Engl J Med. 2015 Oct 14. doi: 10.1056/NEJMoa1503943).

“I hope these results will change practice as early as next week in Europe and elsewhere,” he said. The device is currently CE marked in Europe and is available in some parts of Asia. A clinical trial for the device is currently in the preliminary stages in the United States.

The current standard for PCI in patients at high risk for hemorrhage is to use bare-metal, instead of drug-eluting, stents. Although this protocol lowers the potential risk for bleeding and other complications often caused by extended dual antiplatelet therapy (DAPT), it exposes these patients to a higher risk of restenosis.

Rather than use a drug delivery polymer, the Biolimus A9-coated BioFreedom (Biosensors International) is polymer free and uses a stainless steel stent microstructured to hold a proprietary lipophilic drug on its outer surface. The drug is absorbed by the body within a month of placement.

The first of its kind, the double-blinded LEADERS FREE trial randomly assigned 2,466 PCI patients at high risk for bleeding to receive either the test stent or the standard platform Gazelle bare-metal stent. The procedures were performed at nearly 70 participating sites around the world, excluding the United States. More than half of all patients were accessed transradially, which was preferable to transfemoral access, according to Dr. Urban, because of the lower associated bleeding rates.

All patients were given 1 month of antiplatelet therapy after their intervention: about two-thirds of each group received DAPT and one-third received triple antiplatelet therapy. All were then switched to aspirin alone for 1 year.

At 390 days, there was nearly a 50% reduction in the need for repeat revascularization in the 1,221 patients receiving the drug-coated stent (5.1%), compared with 1,221 receiving the bare-metal stent (9.8%), with the difference reaching statistical significance for superiority for this primary efficacy endpoint (P < .001 for superiority).

Patients in the study arm also had a 29% reduction in risk of cardiac death, myocardial infarction, or stent thrombosis, the primary safety endpoint. At 390 days, these events occurred in 9.4% of the drug coated–stent patients, compared with 12.9% of the controls, a statistically significant difference for both noninferiority (P < .0001) and superiority (P = .005).

The study was done in patients typically excluded from such a trial, although, according to Dr. Urban, the PCI procedures performed were no more complex than usual. More than half the patients, three-quarters of whom were men in their mid- to late-70s, also had a range of comorbidities such as diabetes, kidney disease, and atrial fibrillation. Patients taking anticoagulants, those who had experienced a stroke within the past year, those expected to have major surgery within the year, and those who had undergone cancer treatment within the past 3 years also were included.

Bleeding events in the year following did not differ significantly between groups: 18.1% in the study group and 19.1% of controls had BARC 1-5 bleeding; 13.9% in the test arm and 14.7% of controls had BARC 2-5 events; and 7.2% in the study group and 7.3% of controls experienced BARC 3-5 events.

In the past, Dr. Urban had theorized that the trial would help to quantify not only risk for hemorrhage, but also the thrombotic risk in this patient population. In an interview, Dr. Urban said that, while the stent thrombosis rate was nearly identical in both groups in the trial, “the safety advantage of the drug-coated stent was especially apparent in the more thrombotic milieu.”

LEADERS FREE was underwritten by Biosensors International, maker of the BioFreedom stent. Dr. Urban and several of his coinvestigators disclosed relationships with device makers, including Edward Lifesciences, Terumo, Abbott Vascular, and Quest Medical.

[email protected]

On Twitter @whitneymcknight

A novel drug-coated stent halved the need for repeat revascularization and had a superior safety profile, compared with a bare-metal stent, in patients with a high risk of bleeding in the LEADERS FREE trial.

The results could mean that these typically older, sicker patients in whom dual antiplatelet therapy is contraindicated because of hemorrhage risk now have a wider range of revascularization options, said lead investigator Dr. Philip Urban.

“Patients who have a high risk of bleeding during percutaneous coronary intervention (PCI) are often excluded from stent and drug trials but constitute a rapidly growing proportion of PCI candidates, and they suffer high event rates,” said Dr. Urban, director of interventional cardiology at La Tour Hospital in Geneva. As the life expectancy increases, the implications are profound because roughly one-fifth of all PCI patients globally could be candidates for this type of treatment.

The data were presented at the Transcatheter Cardiovascular Therapeutics annual meeting, which was sponsored by the Cardiovascular Research Foundation. The results also were published online (N Engl J Med. 2015 Oct 14. doi: 10.1056/NEJMoa1503943).

“I hope these results will change practice as early as next week in Europe and elsewhere,” he said. The device is currently CE marked in Europe and is available in some parts of Asia. A clinical trial for the device is currently in the preliminary stages in the United States.

The current standard for PCI in patients at high risk for hemorrhage is to use bare-metal, instead of drug-eluting, stents. Although this protocol lowers the potential risk for bleeding and other complications often caused by extended dual antiplatelet therapy (DAPT), it exposes these patients to a higher risk of restenosis.

Rather than use a drug delivery polymer, the Biolimus A9-coated BioFreedom (Biosensors International) is polymer free and uses a stainless steel stent microstructured to hold a proprietary lipophilic drug on its outer surface. The drug is absorbed by the body within a month of placement.

The first of its kind, the double-blinded LEADERS FREE trial randomly assigned 2,466 PCI patients at high risk for bleeding to receive either the test stent or the standard platform Gazelle bare-metal stent. The procedures were performed at nearly 70 participating sites around the world, excluding the United States. More than half of all patients were accessed transradially, which was preferable to transfemoral access, according to Dr. Urban, because of the lower associated bleeding rates.

All patients were given 1 month of antiplatelet therapy after their intervention: about two-thirds of each group received DAPT and one-third received triple antiplatelet therapy. All were then switched to aspirin alone for 1 year.

At 390 days, there was nearly a 50% reduction in the need for repeat revascularization in the 1,221 patients receiving the drug-coated stent (5.1%), compared with 1,221 receiving the bare-metal stent (9.8%), with the difference reaching statistical significance for superiority for this primary efficacy endpoint (P < .001 for superiority).

Patients in the study arm also had a 29% reduction in risk of cardiac death, myocardial infarction, or stent thrombosis, the primary safety endpoint. At 390 days, these events occurred in 9.4% of the drug coated–stent patients, compared with 12.9% of the controls, a statistically significant difference for both noninferiority (P < .0001) and superiority (P = .005).

The study was done in patients typically excluded from such a trial, although, according to Dr. Urban, the PCI procedures performed were no more complex than usual. More than half the patients, three-quarters of whom were men in their mid- to late-70s, also had a range of comorbidities such as diabetes, kidney disease, and atrial fibrillation. Patients taking anticoagulants, those who had experienced a stroke within the past year, those expected to have major surgery within the year, and those who had undergone cancer treatment within the past 3 years also were included.

Bleeding events in the year following did not differ significantly between groups: 18.1% in the study group and 19.1% of controls had BARC 1-5 bleeding; 13.9% in the test arm and 14.7% of controls had BARC 2-5 events; and 7.2% in the study group and 7.3% of controls experienced BARC 3-5 events.

In the past, Dr. Urban had theorized that the trial would help to quantify not only risk for hemorrhage, but also the thrombotic risk in this patient population. In an interview, Dr. Urban said that, while the stent thrombosis rate was nearly identical in both groups in the trial, “the safety advantage of the drug-coated stent was especially apparent in the more thrombotic milieu.”

LEADERS FREE was underwritten by Biosensors International, maker of the BioFreedom stent. Dr. Urban and several of his coinvestigators disclosed relationships with device makers, including Edward Lifesciences, Terumo, Abbott Vascular, and Quest Medical.

[email protected]

On Twitter @whitneymcknight

A novel drug-coated stent halved the need for repeat revascularization and had a superior safety profile, compared with a bare-metal stent, in patients with a high risk of bleeding in the LEADERS FREE trial.

The results could mean that these typically older, sicker patients in whom dual antiplatelet therapy is contraindicated because of hemorrhage risk now have a wider range of revascularization options, said lead investigator Dr. Philip Urban.

“Patients who have a high risk of bleeding during percutaneous coronary intervention (PCI) are often excluded from stent and drug trials but constitute a rapidly growing proportion of PCI candidates, and they suffer high event rates,” said Dr. Urban, director of interventional cardiology at La Tour Hospital in Geneva. As the life expectancy increases, the implications are profound because roughly one-fifth of all PCI patients globally could be candidates for this type of treatment.

The data were presented at the Transcatheter Cardiovascular Therapeutics annual meeting, which was sponsored by the Cardiovascular Research Foundation. The results also were published online (N Engl J Med. 2015 Oct 14. doi: 10.1056/NEJMoa1503943).

“I hope these results will change practice as early as next week in Europe and elsewhere,” he said. The device is currently CE marked in Europe and is available in some parts of Asia. A clinical trial for the device is currently in the preliminary stages in the United States.

The current standard for PCI in patients at high risk for hemorrhage is to use bare-metal, instead of drug-eluting, stents. Although this protocol lowers the potential risk for bleeding and other complications often caused by extended dual antiplatelet therapy (DAPT), it exposes these patients to a higher risk of restenosis.

Rather than use a drug delivery polymer, the Biolimus A9-coated BioFreedom (Biosensors International) is polymer free and uses a stainless steel stent microstructured to hold a proprietary lipophilic drug on its outer surface. The drug is absorbed by the body within a month of placement.

The first of its kind, the double-blinded LEADERS FREE trial randomly assigned 2,466 PCI patients at high risk for bleeding to receive either the test stent or the standard platform Gazelle bare-metal stent. The procedures were performed at nearly 70 participating sites around the world, excluding the United States. More than half of all patients were accessed transradially, which was preferable to transfemoral access, according to Dr. Urban, because of the lower associated bleeding rates.

All patients were given 1 month of antiplatelet therapy after their intervention: about two-thirds of each group received DAPT and one-third received triple antiplatelet therapy. All were then switched to aspirin alone for 1 year.

At 390 days, there was nearly a 50% reduction in the need for repeat revascularization in the 1,221 patients receiving the drug-coated stent (5.1%), compared with 1,221 receiving the bare-metal stent (9.8%), with the difference reaching statistical significance for superiority for this primary efficacy endpoint (P < .001 for superiority).

Patients in the study arm also had a 29% reduction in risk of cardiac death, myocardial infarction, or stent thrombosis, the primary safety endpoint. At 390 days, these events occurred in 9.4% of the drug coated–stent patients, compared with 12.9% of the controls, a statistically significant difference for both noninferiority (P < .0001) and superiority (P = .005).

The study was done in patients typically excluded from such a trial, although, according to Dr. Urban, the PCI procedures performed were no more complex than usual. More than half the patients, three-quarters of whom were men in their mid- to late-70s, also had a range of comorbidities such as diabetes, kidney disease, and atrial fibrillation. Patients taking anticoagulants, those who had experienced a stroke within the past year, those expected to have major surgery within the year, and those who had undergone cancer treatment within the past 3 years also were included.

Bleeding events in the year following did not differ significantly between groups: 18.1% in the study group and 19.1% of controls had BARC 1-5 bleeding; 13.9% in the test arm and 14.7% of controls had BARC 2-5 events; and 7.2% in the study group and 7.3% of controls experienced BARC 3-5 events.

In the past, Dr. Urban had theorized that the trial would help to quantify not only risk for hemorrhage, but also the thrombotic risk in this patient population. In an interview, Dr. Urban said that, while the stent thrombosis rate was nearly identical in both groups in the trial, “the safety advantage of the drug-coated stent was especially apparent in the more thrombotic milieu.”

LEADERS FREE was underwritten by Biosensors International, maker of the BioFreedom stent. Dr. Urban and several of his coinvestigators disclosed relationships with device makers, including Edward Lifesciences, Terumo, Abbott Vascular, and Quest Medical.

[email protected]

On Twitter @whitneymcknight

CHICAGO – Tranexamic acid was not independently associated with any infection within 30 days of injury in U.S. soldiers undergoing trauma surgery, a case-control study showed.

The antifibrinolytic has been used for years to reduce morbidity and the risk of death associated with hemorrhage in the military setting. Tranexamic acid (TXA) made its way into the civilian setting after the 2010 provocative CRASH-2 trial in adult trauma patients.

Because TXA (Cyklokapron, Lysteda) also has anti-inflammatory properties, Dr. Clayton Lewis of Brooke Army Medical Center in San Antonio and his colleagues decided to evaluate the effect of TXA on the development of posttraumatic infections, including time to first infection, in combat casualties.

The findings were presented at the annual clinical congress of the American College of Surgeons, where we caught up with Dr. Lewis for an interview.

Dr. Lewis reported having no relevant financial disclosures.

[email protected]

CHICAGO – Tranexamic acid was not independently associated with any infection within 30 days of injury in U.S. soldiers undergoing trauma surgery, a case-control study showed.

The antifibrinolytic has been used for years to reduce morbidity and the risk of death associated with hemorrhage in the military setting. Tranexamic acid (TXA) made its way into the civilian setting after the 2010 provocative CRASH-2 trial in adult trauma patients.

Because TXA (Cyklokapron, Lysteda) also has anti-inflammatory properties, Dr. Clayton Lewis of Brooke Army Medical Center in San Antonio and his colleagues decided to evaluate the effect of TXA on the development of posttraumatic infections, including time to first infection, in combat casualties.

The findings were presented at the annual clinical congress of the American College of Surgeons, where we caught up with Dr. Lewis for an interview.

Dr. Lewis reported having no relevant financial disclosures.

[email protected]

CHICAGO – Tranexamic acid was not independently associated with any infection within 30 days of injury in U.S. soldiers undergoing trauma surgery, a case-control study showed.

The antifibrinolytic has been used for years to reduce morbidity and the risk of death associated with hemorrhage in the military setting. Tranexamic acid (TXA) made its way into the civilian setting after the 2010 provocative CRASH-2 trial in adult trauma patients.

Because TXA (Cyklokapron, Lysteda) also has anti-inflammatory properties, Dr. Clayton Lewis of Brooke Army Medical Center in San Antonio and his colleagues decided to evaluate the effect of TXA on the development of posttraumatic infections, including time to first infection, in combat casualties.

The findings were presented at the annual clinical congress of the American College of Surgeons, where we caught up with Dr. Lewis for an interview.

Dr. Lewis reported having no relevant financial disclosures.

[email protected]

The social determinants of health are a root cause of readmissions in the most heavily readmitted patients, according to data analyzed in a recent study published in the Journal of Hospital Medicine. The study's lead author, Marilyn Szekendi, PhD, discusses the research, and Dr. Bradley Flansbaum weighs in on the difficulty of effecting a policy solution for a population without much political voice.

The social determinants of health are a root cause of readmissions in the most heavily readmitted patients, according to data analyzed in a recent study published in the Journal of Hospital Medicine. The study's lead author, Marilyn Szekendi, PhD, discusses the research, and Dr. Bradley Flansbaum weighs in on the difficulty of effecting a policy solution for a population without much political voice.

The social determinants of health are a root cause of readmissions in the most heavily readmitted patients, according to data analyzed in a recent study published in the Journal of Hospital Medicine. The study's lead author, Marilyn Szekendi, PhD, discusses the research, and Dr. Bradley Flansbaum weighs in on the difficulty of effecting a policy solution for a population without much political voice.

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]

CHICAGO – Chronic myeloid leukemia is highly treatable, and a “functional cure” appears to be within reach, according to Dr. Michael J. Mauro.

In fact, an “embarrassment of riches” exists when it comes to initial therapy for CML: In the United States there are five approved tyrosine kinase inhibitors (TKIs), and three are approved for front-line therapy, Dr. Mauro of Memorial Sloan Kettering Cancer Center, New York, said at the American Society of Hematology Meeting on Hematologic Malignancies.

Success, however, is contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and remaining vigilant for late effects of therapy, he said.

Given the multitude of treatment options and the breadth of available data, Dr. Mauro said he counsels newly diagnosed patients that various treatment options are valid, and that “there may not be a right or wrong answer” for initial therapy. He also counsels patients that tolerability is manageable – and finding the right fit is an important process, and that response milestones are crucial and should be optimized.

It is important, he said, to discuss late toxicity concerns, to review comorbid conditions to help predict potential problems and identify risk, to consider the ramifications of potential toxicity, and to consider adherence.

“We need to portray therapy as really being medium- to long-term,” he said, noting that the urgency to think about treatment-free remission should be tempered by the reality that years of treatment are required first.

Risks and benefits of treatment should be discussed, and the acceptable balance determined in conjunction with the patient, he said, explaining that toxicities vary for the different TKIs.

Imatinib, for example, can be associated with edema/fluid retention, myalgias, hypophosphatemia, and gastrointestinal effects. Dasatinib can be associated with pleural/pericardial effusion, pulmonary arterial hypertension, and bleeding risk. Other toxicities associated with certain TKIs include pancreatic enzyme elevation, rash, and vascular adverse events.

Whether newly diagnosed patients should be directed away from certain agents remains unclear, as available data are open to interpretation, and the mechanism of action for some crucial late effects is unknown. Vascular disease should, however, be considered when making the decision, he said.

Given the available data on late toxicity with various therapies, a cardiovascular evaluation is advisable when initiating TKI therapy, he added.

Consider partnering with primary care, cardiology, or cardio-oncology specialists, and manage risk factors and findings of the evaluation as appropriate, irrespective of the CML, he said. Monitor for progression of cardiovascular risks or adverse events carefully, he added.

His approach for following recently diagnosed CML patients involves:

• A cardiovascular evaluation, at least including age- and comorbidity-appropriate studies, and an up-to-date cardiovascular risk profile. If nilotinib is used, he screens for peripheral, cerebral, and cardiovascular disease – an approach increasingly supported by data. If dasatinib is used, echocardiography is warranted to look for changes that suggest pulmonary hypertension. “And of course we should monitor blood pressure, lipid, and glycemic control,” he added.

• Initial studies, including bone marrow and quantitative polymerase chain reaction – international scale (qPCR IS).

• Lab studies every 1-2 weeks for at least 6 weeks, with titration thereafter as indicated, including for change in therapy.

• A 3-month assessment using qPCR IS. This is very important for following patient response, he said, noting that if the response surpasses compete cytogenetic remission and blood count is acceptable and stable, a repeat bone marrow study may be unnecessary.

• Sequential molecular analyses at least every 3 months.

• Repeat cardiovascular evaluation if/when indicated.

The 3-month response is an opportunity to critically appraise therapy choice and response trajectory; a therapy change is possible based on this assessment, he said. Responses at 6 and 12 months are also important, and changes in therapy for missed milestones at these time points are warranted as deeper remissions are sought.

At 18 months, the focus is on major molecular response, he added, noting that as patients get into deeper molecular remissions, plateaus and fluctuations are common; the nuances of determining who is well enough to consider for treatment-free remission remain to be sorted out in clinical trials.

In general, it appears that 3 years of therapy with about 2 years of optimal minimal residual disease is required prior to consideration for treatment-free remission, he said.

Dr. Mauro has consulted for and/or received research funding from Ariad, Bristol-Myers Squibb, Novartis, and Oregon Health & Science University.

[email protected]