The Boswellia serrata exudate or gum (known in India as “guggulu”) that forms an aromatic resin traditionally used as incense – and known as frankincense (especially when retrieved from Boswellia species found in Eritrea and Somalia but also from the Indian variety) – has been considered for thousands of years to possess therapeutic properties. It is used in Ayurvedic medicine, as well as in traditional medicine in China and the Middle East, particularly for its anti-inflammatory effects to treat chronic conditions.^1-8 In fact, such essential oils have been used since 2800 BC to treat various inflammatory conditions, including skin sores and wounds, as well as in perfumes and incense.^2,9 In the West, use of frankincense dates back to thousands of years as well, more often found in the form of incense for religious and cultural ceremonies.⁷ Over the past 2 decades, evidence supporting the use of frankincense for therapeutic medical purposes has increased, particularly because of its purported anti-inflammatory and anticancer properties.³ This column focuses on some of the emerging data on this ancient botanical agent.

Madeleine_Steinbach / iStock / Getty Images Plus

Chemical constituents

Terpenoids and essential oils are the primary components of frankincense and are known to impart anti-inflammatory and anticancer activity. The same is true for myrrh, which has been combined with frankincense in traditional Chinese medicine as a single medication for millennia, with the two acting synergistically and considered still to be a potent combination in conferring various biological benefits.⁷

In 2010, in a systematic review of the anti-inflammatory and anticancer activities of Boswellia species and their chemical ingredients, Efferth and Oesch found that frankincense blocks the production of leukotrienes, cyclooxygenase (COX) 1 and 2, as well as 5-lipoxygenase; and oxidative stress. It also contributes to regulation of immune cells from the innate and acquired immune systems and exerts anticancer activity by influencing signaling transduction responsible for cell cycle arrest, as well as inhibition of proliferation, angiogenesis, invasion, and metastasis. The investigators also reported on clinical trial results that have found efficacy of frankincense and its constituents in ameliorating symptoms of psoriasis and erythematous eczema, among other disorders.³

Anti-inflammatory activity

Li et al. completed a study in 2016 to identify the active ingredients responsible for the anti-inflammatory and analgesic effects of frankincense. They found that alpha-pinene, linalool, and 1-octanol were key contributors. These constituents were noted for suppressing COX-2 overexpression in mice, as well as nociceptive stimulus-induced inflammatory infiltrates.¹⁰

Noting the increasing popularity of frankincense essential oil in skin care, despite a paucity of data, in 2017, Han et al. evaluated the biological activities of the essential oil in pre-inflamed human dermal fibroblasts using 17 key protein biomarkers. Frankincense essential oil displayed significant antiproliferative activity and suppressed collagen III, interferon gamma-induced protein 10, and intracellular adhesion molecule 1. The investigators referred to the overall encouraging potential of frankincense essential oil to exert influence over inflammation and tissue remodeling in human skin and called for additional research into its mechanisms of action and active constituents.¹¹

Anticancer activity

The main active ingredient in frankincense, boswellic acid, has been shown to promote apoptosis, suppress matrix metalloproteinase secretion, and hinder migration in metastatic melanoma cell lines in mice.^6,12

In 2019, Hakkim et al. demonstrated that frankincense essential oil yielded substantial antimelanoma activity in vitro and in vivo and ameliorated hepatotoxicity caused by acetaminophen.¹³

There is one case report in the literature on the use of frankincense as a treatment for skin cancer. A 56-year-old man received frankincense oil multiple times a day for 4 months to treat a nodular basal cell carcinoma on one arm (which resolved) and an infiltrative BCC on the chest (some focal residual tumor remained).^6,14 Topical frankincense or boswellic acid has been given a grade D recommendation for treating skin cancer, however, because of only one level-of-evidence-5 study.⁶

Antimicrobial activity

In 2012, de Rapper et al. collected samples of three essential oils of frankincense (Boswellia rivae, Boswellia neglecta, and Boswellia papyrifera) and two essential oil samples of myrrh and sweet myrrh from different regions of Ethiopia to study their anti-infective properties alone and in combination. The investigators observed synergistic and additive effects, particularly between B. papyrifera and Commiphora myrrha. While noting the long history of the combined use of frankincense and myrrh essential oils since 1500 BC, the investigators highlighted their study as the first antimicrobial work to verify the effectiveness of this combination, validating the use of this combination to thwart particular pathogens.¹⁵

Just 2 years ago, Ljaljević Grbić et al. evaluated the in vitro antimicrobial potential of the liquid and vapor phases of B. carteri and C. myrrha (frankincense and myrrh, respectively) essential oils, finding that frankincense demonstrated marked capacity to act as a natural antimicrobial agent.⁹

Transdermal delivery

In 2017, Zhu et al. showed that frankincense and myrrh essential oils promoted the permeability of the Chinese herb Chuanxiong and may facilitate drug elimination from the epidermis via dermal capillaries by dint of improved cutaneous blood flow, thereby augmenting transdermal drug delivery.¹⁶ The same team also showed that frankincense and myrrh essential oils, by fostering permeation by enhancing drug delivery across the stratum corneum, can also alter the structure of the stratum corneum.¹⁷

Conclusion

The use of frankincense in traditional medicine has a long and impressive track record. Recent research provides reason for optimism, and further investigating the possible incorporation of this botanical agent into modern dermatologic therapies appears warranted. Clearly, however, much more research is needed.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Kimmatkar N et al. Phytomedicine. 2003 Jan;10(1):3-7.

2. Ammon HP. Wien Med Wochenschr. 2002;152(15-16):373-8.

3. Efferth T & Oesch F. Semin Cancer Biol. 2020 Feb 4;S1044-579X(20)30034-1.

4. Banno N et al. J Ethnopharmacol. 2006 Sep 19;107(2):249-53.

5. Poeckel D & Werz O. Curr Med Chem. 2006;13(28):3359-69.

6. Li JY, Kampp JT. Dermatol Surg. 2019 Jan;45(1):58-67.

7. Cao B et al. Molecules. 2019 Aug 24;24(17): 3076.

8. Mertens M et al. Flavour Fragr J. 2009;24:279-300.

9. Ljaljević Grbić M et al. J Ethnopharmacol. 2018 Jun 12;219:1-14.

10. Li XJ et al. J Ethnopharmacol. 2016 Feb 17;179:22-6.

11. Han X et al. Biochim Open. 2017 Feb 3;4:31-5.

12. Zhao W et al. Cancer Detect Prev. 2003;27:67-75.

13. Hakkim FL et al. Oncotarget. 2019 May 28;10(37):3472-90.

14. Fung K et al. OA Altern Med 2013;1:14.

15. de Rapper S et al. Lett Appl Microbiol. 2012 Apr;54(4):352-8.

16. Zhu XF et al. Zhongguo Zhong Yao Za Zhi. 2017 Feb;42(4):680-5.

17. Guan YM et al. Zhongguo Zhong Yao Za Zhi. 2017 Sep;42(17):3350-5.

The Boswellia serrata exudate or gum (known in India as “guggulu”) that forms an aromatic resin traditionally used as incense – and known as frankincense (especially when retrieved from Boswellia species found in Eritrea and Somalia but also from the Indian variety) – has been considered for thousands of years to possess therapeutic properties. It is used in Ayurvedic medicine, as well as in traditional medicine in China and the Middle East, particularly for its anti-inflammatory effects to treat chronic conditions.^1-8 In fact, such essential oils have been used since 2800 BC to treat various inflammatory conditions, including skin sores and wounds, as well as in perfumes and incense.^2,9 In the West, use of frankincense dates back to thousands of years as well, more often found in the form of incense for religious and cultural ceremonies.⁷ Over the past 2 decades, evidence supporting the use of frankincense for therapeutic medical purposes has increased, particularly because of its purported anti-inflammatory and anticancer properties.³ This column focuses on some of the emerging data on this ancient botanical agent.

Madeleine_Steinbach / iStock / Getty Images Plus

Chemical constituents

Terpenoids and essential oils are the primary components of frankincense and are known to impart anti-inflammatory and anticancer activity. The same is true for myrrh, which has been combined with frankincense in traditional Chinese medicine as a single medication for millennia, with the two acting synergistically and considered still to be a potent combination in conferring various biological benefits.⁷

In 2010, in a systematic review of the anti-inflammatory and anticancer activities of Boswellia species and their chemical ingredients, Efferth and Oesch found that frankincense blocks the production of leukotrienes, cyclooxygenase (COX) 1 and 2, as well as 5-lipoxygenase; and oxidative stress. It also contributes to regulation of immune cells from the innate and acquired immune systems and exerts anticancer activity by influencing signaling transduction responsible for cell cycle arrest, as well as inhibition of proliferation, angiogenesis, invasion, and metastasis. The investigators also reported on clinical trial results that have found efficacy of frankincense and its constituents in ameliorating symptoms of psoriasis and erythematous eczema, among other disorders.³

Anti-inflammatory activity

Li et al. completed a study in 2016 to identify the active ingredients responsible for the anti-inflammatory and analgesic effects of frankincense. They found that alpha-pinene, linalool, and 1-octanol were key contributors. These constituents were noted for suppressing COX-2 overexpression in mice, as well as nociceptive stimulus-induced inflammatory infiltrates.¹⁰

Noting the increasing popularity of frankincense essential oil in skin care, despite a paucity of data, in 2017, Han et al. evaluated the biological activities of the essential oil in pre-inflamed human dermal fibroblasts using 17 key protein biomarkers. Frankincense essential oil displayed significant antiproliferative activity and suppressed collagen III, interferon gamma-induced protein 10, and intracellular adhesion molecule 1. The investigators referred to the overall encouraging potential of frankincense essential oil to exert influence over inflammation and tissue remodeling in human skin and called for additional research into its mechanisms of action and active constituents.¹¹

Anticancer activity

The main active ingredient in frankincense, boswellic acid, has been shown to promote apoptosis, suppress matrix metalloproteinase secretion, and hinder migration in metastatic melanoma cell lines in mice.^6,12

In 2019, Hakkim et al. demonstrated that frankincense essential oil yielded substantial antimelanoma activity in vitro and in vivo and ameliorated hepatotoxicity caused by acetaminophen.¹³

There is one case report in the literature on the use of frankincense as a treatment for skin cancer. A 56-year-old man received frankincense oil multiple times a day for 4 months to treat a nodular basal cell carcinoma on one arm (which resolved) and an infiltrative BCC on the chest (some focal residual tumor remained).^6,14 Topical frankincense or boswellic acid has been given a grade D recommendation for treating skin cancer, however, because of only one level-of-evidence-5 study.⁶

Antimicrobial activity

In 2012, de Rapper et al. collected samples of three essential oils of frankincense (Boswellia rivae, Boswellia neglecta, and Boswellia papyrifera) and two essential oil samples of myrrh and sweet myrrh from different regions of Ethiopia to study their anti-infective properties alone and in combination. The investigators observed synergistic and additive effects, particularly between B. papyrifera and Commiphora myrrha. While noting the long history of the combined use of frankincense and myrrh essential oils since 1500 BC, the investigators highlighted their study as the first antimicrobial work to verify the effectiveness of this combination, validating the use of this combination to thwart particular pathogens.¹⁵

Just 2 years ago, Ljaljević Grbić et al. evaluated the in vitro antimicrobial potential of the liquid and vapor phases of B. carteri and C. myrrha (frankincense and myrrh, respectively) essential oils, finding that frankincense demonstrated marked capacity to act as a natural antimicrobial agent.⁹

Transdermal delivery

In 2017, Zhu et al. showed that frankincense and myrrh essential oils promoted the permeability of the Chinese herb Chuanxiong and may facilitate drug elimination from the epidermis via dermal capillaries by dint of improved cutaneous blood flow, thereby augmenting transdermal drug delivery.¹⁶ The same team also showed that frankincense and myrrh essential oils, by fostering permeation by enhancing drug delivery across the stratum corneum, can also alter the structure of the stratum corneum.¹⁷

Conclusion

The use of frankincense in traditional medicine has a long and impressive track record. Recent research provides reason for optimism, and further investigating the possible incorporation of this botanical agent into modern dermatologic therapies appears warranted. Clearly, however, much more research is needed.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Kimmatkar N et al. Phytomedicine. 2003 Jan;10(1):3-7.

2. Ammon HP. Wien Med Wochenschr. 2002;152(15-16):373-8.

3. Efferth T & Oesch F. Semin Cancer Biol. 2020 Feb 4;S1044-579X(20)30034-1.

4. Banno N et al. J Ethnopharmacol. 2006 Sep 19;107(2):249-53.

5. Poeckel D & Werz O. Curr Med Chem. 2006;13(28):3359-69.

6. Li JY, Kampp JT. Dermatol Surg. 2019 Jan;45(1):58-67.

7. Cao B et al. Molecules. 2019 Aug 24;24(17): 3076.

8. Mertens M et al. Flavour Fragr J. 2009;24:279-300.

9. Ljaljević Grbić M et al. J Ethnopharmacol. 2018 Jun 12;219:1-14.

10. Li XJ et al. J Ethnopharmacol. 2016 Feb 17;179:22-6.

11. Han X et al. Biochim Open. 2017 Feb 3;4:31-5.

12. Zhao W et al. Cancer Detect Prev. 2003;27:67-75.

13. Hakkim FL et al. Oncotarget. 2019 May 28;10(37):3472-90.

14. Fung K et al. OA Altern Med 2013;1:14.

15. de Rapper S et al. Lett Appl Microbiol. 2012 Apr;54(4):352-8.

16. Zhu XF et al. Zhongguo Zhong Yao Za Zhi. 2017 Feb;42(4):680-5.

17. Guan YM et al. Zhongguo Zhong Yao Za Zhi. 2017 Sep;42(17):3350-5.

The Boswellia serrata exudate or gum (known in India as “guggulu”) that forms an aromatic resin traditionally used as incense – and known as frankincense (especially when retrieved from Boswellia species found in Eritrea and Somalia but also from the Indian variety) – has been considered for thousands of years to possess therapeutic properties. It is used in Ayurvedic medicine, as well as in traditional medicine in China and the Middle East, particularly for its anti-inflammatory effects to treat chronic conditions.^1-8 In fact, such essential oils have been used since 2800 BC to treat various inflammatory conditions, including skin sores and wounds, as well as in perfumes and incense.^2,9 In the West, use of frankincense dates back to thousands of years as well, more often found in the form of incense for religious and cultural ceremonies.⁷ Over the past 2 decades, evidence supporting the use of frankincense for therapeutic medical purposes has increased, particularly because of its purported anti-inflammatory and anticancer properties.³ This column focuses on some of the emerging data on this ancient botanical agent.

Madeleine_Steinbach / iStock / Getty Images Plus

Chemical constituents

Terpenoids and essential oils are the primary components of frankincense and are known to impart anti-inflammatory and anticancer activity. The same is true for myrrh, which has been combined with frankincense in traditional Chinese medicine as a single medication for millennia, with the two acting synergistically and considered still to be a potent combination in conferring various biological benefits.⁷

In 2010, in a systematic review of the anti-inflammatory and anticancer activities of Boswellia species and their chemical ingredients, Efferth and Oesch found that frankincense blocks the production of leukotrienes, cyclooxygenase (COX) 1 and 2, as well as 5-lipoxygenase; and oxidative stress. It also contributes to regulation of immune cells from the innate and acquired immune systems and exerts anticancer activity by influencing signaling transduction responsible for cell cycle arrest, as well as inhibition of proliferation, angiogenesis, invasion, and metastasis. The investigators also reported on clinical trial results that have found efficacy of frankincense and its constituents in ameliorating symptoms of psoriasis and erythematous eczema, among other disorders.³

Anti-inflammatory activity

Li et al. completed a study in 2016 to identify the active ingredients responsible for the anti-inflammatory and analgesic effects of frankincense. They found that alpha-pinene, linalool, and 1-octanol were key contributors. These constituents were noted for suppressing COX-2 overexpression in mice, as well as nociceptive stimulus-induced inflammatory infiltrates.¹⁰

Noting the increasing popularity of frankincense essential oil in skin care, despite a paucity of data, in 2017, Han et al. evaluated the biological activities of the essential oil in pre-inflamed human dermal fibroblasts using 17 key protein biomarkers. Frankincense essential oil displayed significant antiproliferative activity and suppressed collagen III, interferon gamma-induced protein 10, and intracellular adhesion molecule 1. The investigators referred to the overall encouraging potential of frankincense essential oil to exert influence over inflammation and tissue remodeling in human skin and called for additional research into its mechanisms of action and active constituents.¹¹

Anticancer activity

The main active ingredient in frankincense, boswellic acid, has been shown to promote apoptosis, suppress matrix metalloproteinase secretion, and hinder migration in metastatic melanoma cell lines in mice.^6,12

In 2019, Hakkim et al. demonstrated that frankincense essential oil yielded substantial antimelanoma activity in vitro and in vivo and ameliorated hepatotoxicity caused by acetaminophen.¹³

There is one case report in the literature on the use of frankincense as a treatment for skin cancer. A 56-year-old man received frankincense oil multiple times a day for 4 months to treat a nodular basal cell carcinoma on one arm (which resolved) and an infiltrative BCC on the chest (some focal residual tumor remained).^6,14 Topical frankincense or boswellic acid has been given a grade D recommendation for treating skin cancer, however, because of only one level-of-evidence-5 study.⁶

Antimicrobial activity

In 2012, de Rapper et al. collected samples of three essential oils of frankincense (Boswellia rivae, Boswellia neglecta, and Boswellia papyrifera) and two essential oil samples of myrrh and sweet myrrh from different regions of Ethiopia to study their anti-infective properties alone and in combination. The investigators observed synergistic and additive effects, particularly between B. papyrifera and Commiphora myrrha. While noting the long history of the combined use of frankincense and myrrh essential oils since 1500 BC, the investigators highlighted their study as the first antimicrobial work to verify the effectiveness of this combination, validating the use of this combination to thwart particular pathogens.¹⁵

Just 2 years ago, Ljaljević Grbić et al. evaluated the in vitro antimicrobial potential of the liquid and vapor phases of B. carteri and C. myrrha (frankincense and myrrh, respectively) essential oils, finding that frankincense demonstrated marked capacity to act as a natural antimicrobial agent.⁹

Transdermal delivery

In 2017, Zhu et al. showed that frankincense and myrrh essential oils promoted the permeability of the Chinese herb Chuanxiong and may facilitate drug elimination from the epidermis via dermal capillaries by dint of improved cutaneous blood flow, thereby augmenting transdermal drug delivery.¹⁶ The same team also showed that frankincense and myrrh essential oils, by fostering permeation by enhancing drug delivery across the stratum corneum, can also alter the structure of the stratum corneum.¹⁷

Conclusion

The use of frankincense in traditional medicine has a long and impressive track record. Recent research provides reason for optimism, and further investigating the possible incorporation of this botanical agent into modern dermatologic therapies appears warranted. Clearly, however, much more research is needed.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at [email protected].

References

1. Kimmatkar N et al. Phytomedicine. 2003 Jan;10(1):3-7.

2. Ammon HP. Wien Med Wochenschr. 2002;152(15-16):373-8.

3. Efferth T & Oesch F. Semin Cancer Biol. 2020 Feb 4;S1044-579X(20)30034-1.

4. Banno N et al. J Ethnopharmacol. 2006 Sep 19;107(2):249-53.

5. Poeckel D & Werz O. Curr Med Chem. 2006;13(28):3359-69.

6. Li JY, Kampp JT. Dermatol Surg. 2019 Jan;45(1):58-67.

7. Cao B et al. Molecules. 2019 Aug 24;24(17): 3076.

8. Mertens M et al. Flavour Fragr J. 2009;24:279-300.

9. Ljaljević Grbić M et al. J Ethnopharmacol. 2018 Jun 12;219:1-14.

10. Li XJ et al. J Ethnopharmacol. 2016 Feb 17;179:22-6.

11. Han X et al. Biochim Open. 2017 Feb 3;4:31-5.

12. Zhao W et al. Cancer Detect Prev. 2003;27:67-75.

13. Hakkim FL et al. Oncotarget. 2019 May 28;10(37):3472-90.

14. Fung K et al. OA Altern Med 2013;1:14.

15. de Rapper S et al. Lett Appl Microbiol. 2012 Apr;54(4):352-8.

16. Zhu XF et al. Zhongguo Zhong Yao Za Zhi. 2017 Feb;42(4):680-5.

17. Guan YM et al. Zhongguo Zhong Yao Za Zhi. 2017 Sep;42(17):3350-5.

The Supreme Court’s usual processes were disrupted this term. The COVID-19 pandemic required audio hearings rather than in-person, and it resulted in a number of emergency legal appeals. As the Court began its regular sessions on October 5, 2020, there were only 8 justices—Justice Ruth Bader Ginsburg had passed away and Amy Coney Barrett had not yet been confirmed by the Senate. The Court decided many important cases this term, including dealing with the delivery of drugs to induce abortions, a Centers for Disease Control and Prevention (CDC) moratorium on housing evictions, yet another case on the Affordable Care Act, state laws concerning pharmacy benefit managers, and the Hologic and Minerva endometrial ablation systems patents. After considering these cases, we also will briefly look at other cases of general interest.

Abortion

Patient access to mifepristone

In May 2020, the American College of Obstetricians and Gynecologists (ACOG) was the named plaintiff in a lawsuit against the US Food and Drug Administration (FDA) regarding the drugs mifepristone and misoprostol that are used to induce medical abortions.¹ The case was filed by the American Civil Liberties Union on behalf of ACOG and others^2,3 and raised the issue of patients’ access to these medications. The basic claim of the case was that during the pandemic, the FDA’s regulation of mifepristone was unconstitutional in that they imposed an undue burden on the decision of women to have an abortion.⁴ (Although misoprostol is a part of the medical abortion regimen, it is not subject to special regulation and was not part of the litigation.)

The FDA regulation of mifepristone, begun in 2000 but modified since then, includes 3 elements to assure safe use:

• prescribers must have special training or certification
• the drug can be dispensed to patients only in a hospital, clinic, or medical office under the supervision of a certified health care provider (known as the “in-person dispensing requirement” because retail pharmacy or mail distribution are prohibited)
• the health care provider must review a “patient agreement form” with the patient and have the patient sign the consent form in the provider’s presence.⁵

The pandemic made fulfilling these requirements substantially more burdensome and difficult. The question was whether the FDA was constitutionally required to modify its regulations during a pandemic to take account of the undue burden of the regulation created by the pandemic. That is, the question was not whether the FDA could have or should have chosen to make the modification, but whether it was required to do so.

In July 2020, a federal district court in Maryland held that the FDA regulation was an unconstitutional burden on the abortion rights of women during the pandemic and issued a preliminary injunction to stop the FDA from enforcing the in-person dispensing and signature rules. The district judge applied the injunction to Maryland, but also made it a nationwide injunction. (The issue of district court nationwide injunctions is considered in, “District court ‘nationwide injunctions’”). 

The FDA asked the Fourth Circuit Court of Appeals to stay the enforcement of the injunction, which the appeals court denied. The FDA then appealed to the Supreme Court, asking it to stay the injunction. In October 2020, the Court announced that it was holding the FDA’s request “in abeyance” to allow the district court to consider a motion by the FDA to dissolve or change the injunction. It gave the district court 40 days in which to act. That decision by the Court was in the “Shadow Docket” (see sidebar on page XX), so the exact vote of the Court in October is not clear, but 2 Justices (Alito and Thomas) dissented and would have stayed the injunction.⁶ Over the next 40 days, the district court did not withdraw its nationwide injunction.

Thus, on January 12, 2021, the case was again before the Supreme Court, which let the FDA’s regulations regarding mifepristone remain in place by lifting the district court’s injunction. Most of the justices supporting the stay did not write to explain their decision, although their dissent in the earlier cases may have served that purpose. (Maryland was permitting many kinds of activity that were more risky than visiting a clinic—indoor dining, with open hair salons, gyms, and casinos.)⁷ Chief Justice Roberts wrote a concurrence to indicate that, in his view, the issue was not whether the FDA’s regulations placed an undue burden on a right to an abortion generally, but that “My view is that courts owe significant deference” to the public health authorities (here meaning the FDA). Justices Sotomayor and Kagan dissented, saying that the issue was the undue burden on women, given the difficulties of the pandemic, particularly going to medical facilities during the COVID-19 pandemic.⁸

The injunction, sought by ACOG and others, was issued by the district court and was in effect for several months before it was dissolved by the Supreme Court. Following the change in presidential administrations, in April 2021 the FDA announced that it was going to “exercise enforcement discretion with respect to the in-person dispensing requirement…during the COVID-19 public health emergency.”⁹

Continue to: The Texas abortion case...

The Texas abortion case

The Court, on September 1, 2021, declined to block a Texas abortion statute from taking effect.¹⁰ This law precludes abortions after a fetal heartbeat is present at about 6 weeks of gestation. The Fifth Circuit declined to grant an injunction delaying implementation of the Texas law, and the Court did not reverse that decision.

Over the years, a variety of states have placed limitations on abortion, and those almost always have been enjoined by federal courts before they went into effect. However, the Texas statute, which undoubtedly is unconstitutional, was creatively constructed to avoid an early injunction.¹¹ The statute does not allow state officials to enforce the new law, but rather it allows almost any private citizen to seek monetary damages from anyone performing an abortion or who “aids and abets” an abortion. Thus, it is difficult to tailor a lawsuit before this law is enforced. First, courts do not enjoin laws; they usually enjoin individuals from enforcing the law, and in this case it is difficult to know which individuals will be enforcing the laws and what their decisions might be. There also are some questions about the degree to which federal courts can enjoin state courts from deciding lawsuits under state law. For these procedural reasons, the majority of the Court found that those attacking the Texas law had not met their burden of showing that that they would win their case.

Even 3 of the dissenting justices said the defendants may be right that “existing doctrines preclude judicial intervention,” but that the consequences are such that the Court should delay the law until there is time for briefing and argument. The other 3 dissenting justices thought there would be ways of getting around the clever roadblock Texas had erected for the federal courts.

There has been some commentary that this case portends the abandonment of Roe v Wade and Casey,¹² but that conclusion does not seem warranted by this case. The Court has accepted a Mississippi abortion law to be heard next term.¹³ In addition, the Texas statute is likely to be back in federal court once a private individual has filed a claim for money from an abortion provider (and likely even before that).

COVID-19 cases

The Supreme Court decided several cases related to COVID-19, including adjustments to election procedures, church services, and CDC eviction moratoria. As a general matter early in the pandemic, the Court deferred to government authorities, generally upholding government actions. Chief Justice Roberts emphasized the importance of the Court deferring to government officials in emergencies. As the pandemic progressed into 2021, however, the Court became less and less sympathetic to government actions that were not consistent, permitted by existing law, or reasonably necessary. For example, regulations of churches that were inconsistent with the regulation of similar organizations were struck down.¹⁴

Among the most interesting of the summer 2021 cases was the CDC eviction moratorium that essentially prohibited landlords nationwide from evicting tenants for nonpayment of rent. When the challenges to these CDC regulations first reached the Court, the moratorium was about to expire; in a 5-4 decision, the Court did not enjoin the CDC from continuing that policy. Justice Kavanaugh (the fifth vote) warned that “clear and specific congressional authorization…would be necessary to extend the moratorium past July 31.”¹⁵ Despite telling the Court that the moratorium would expire on July 31, just 3 days after the expiration and without any congressional authorization, the CDC reinstated what was practically the same moratorium.¹⁶ On August 26, the Court struck down the reinstated regulation, probably by a 6-3 margin. (Because this case arose in the “Shadow Docket,” the vote of some justices is not certain).¹⁷

Continue to: The Affordable Care Act...

The Affordable Care Act

The Affordable Care Act was challenged in the Court for the third time.¹⁸ In this term’s case, several states argued that when Congress essentially eliminated the penalty/tax for not purchasing insurance coverage, there was no longer a constitutional basis for the individual mandate. With that centerpiece gone, they claimed, the whole statute should be declared unconstitutional.

Along with many other specialty groups, ACOG joined an amicus curiae brief sponsored by the American Medical Association (AMA).¹⁹ An amicus brief is one not filed by the parties to the case, but by organizations or individuals who have information that may be of use to the Court in considering the case. Among other things, the filing of an amicus brief indicates the interest of the organization in the outcome of the case. In this case, the crux of the amicus was that even if the individual mandate currently is not constitutional, the Court should sever that provision and retain the rest of the ACA.

Despite some wild predictions about what the Court might do, it did not decide any substantive issue. Rather, it found that none of the parties to the case had “standing” to challenge the constitutionality of the ACA. Therefore, in effect, the Court dismissed the case without deciding the substantive legal issues.
 

Pharmacy Benefit Managers

The powerful Pharmacy Benefit Managers (PBMs) are a hidden part of the health care system; however, in recent years there has been increasing regulatory attention paid to them. Some states have begun regulating aspects of PBMs. In this term, the Court considered an Arkansas law that sought to protect local pharmacies from PBM pricing practices.²⁰ The AMA filed an amicus brief in the case which made legal arguments, most of which had been made by the parties to the litigation.²¹

PBMs generally tell pharmacies how much they will reimburse the pharmacy for filling a prescription for a particular drug. In some instances, PBMs will set a reimbursement price that is lower than the wholesale price at which local pharmacies can purchase the drug. The Arkansas law prohibited PBMs in the state from reimbursing pharmacies for less than the wholesale cost the pharmacy paid for the drug.

The claim of the PBMs was that the Arkansas law violated the Employee Retirement Income Security Act (ERISA). In part, this act preempts state law that relates to fringe benefit plans. States have the authority to regulate insurance, but ERISA limits what they can do when the insurance relates to fringe benefits. The Court held that ERISA does not preempt the Arkansas law or similar state laws in other states. Because the state law was not preempted by the state law, the Arkansas regulation was upheld. The fact that this was a unanimous decision (8-0, because Justice Barrett was not on the Court when the case was heard) suggests that states may have leeway in additional regulations of PBMs, and it would not be surprising to see more of that state regulation in the future.

Continue to: Patent uncertainty...

Patent uncertainty

Csaba Truckai invented and patented the NovaSure System ablation device with a “moisture permeable” head. He sold his company and the related patents, which eventually were purchased by Hologic. Over time, Hologic added claims to the original patent. In the meantime, Truckai went on to invent another device, the Minerva Endometrial Ablation System (MEAS), which had a “moisture impermeable” head. (Note that the “Minerva Surgical, Inc.” involved in this case is not related to the company “Minerva Industries,” which some identified as a “patent troll.”)²²

Hologic sued Minerva, claiming that Truckai’s second device (MEAS) infringed on its patent for the first device (NovaSure). Truckai’s defense was that the patent on NovaSure was invalid. Hologic felt that since Truckai had obtained that patent and then sold it, it was improper for him now to claim it was invalid. There is a doctrine for that: assignor estoppel—the person who sold (assigned) the patent is prevented from later claiming it was invalid. The question in this case was whether assignor estoppel is part of the patent law of the United States. It is not in the patent statutes, so it is a court-determined part of the law.

In a 5-4 decision this Term, the Court held that assignor estoppel is recognized, but that it is narrow.²³ The Court identified several exceptions to assignor estoppel, notably for this case, including the situation in which the purchaser of the patent, after the purchase, returns to the Patent and Trademark Office to expand (amend) the patent’s claims. In that case, the seller could not be estopped by the amended terms of the patent. Minerva claimed that it was attacking the expanded patent that included changes made after it sold the patent. The Court, therefore, returned the case to the Federal Circuit to apply the principles it laid out about assignor estoppel.

Biotech and other fast-moving fields frequently have new technology building on slightly earlier technology. The current patent system often leaves uncertainty about who owns which part of a valid patent. This uncertainty is a drag on innovation, and the patent system is supposed to spur innovation. Assignor estoppel is likely to create additional complexity and uncertainty in some patents, which is regrettable.
 

Review of the Term

In addition to the other disruptions of the Term, during the first part of the Term, Amy Coney Barrett was not yet confirmed by the Senate, so there were only 8 justices until October 27. She did not participate in those cases that were heard before she joined the Court. The consensus is that the Court heard 67 cases: 57 were formally briefed and argued along with 8 summary reversals and 2 religious cases in the Shadow Docket. In my opinion, this undercounts both the number and the importance of the Shadow Docket cases, but the following data use the 67 case convention.²⁴

The Court was unanimous in 43% of the cases, including some of the most divisive issues. That unanimity reflects very narrow decisions. There were (by conventional count) only eight 5-4 opinions (12%), an unusually low number. Justice Kavanaugh is viewed as the “median” justice. He was in the majority in 97% of all cases. Chief Justice Roberts and Justice Barrett were in the majority 91%, and Justice Gorsuch 90%. As for the other justices, they were in the majority (all cases) most of the time: Justice Alito, 83%; Justice Thomas, 81%; Justice Breyer, 76%; Justice Kagan, 75%; and Justice Sotomayor, 69%. In “divided cases” (when unanimous cases are removed), the percentages are: Justice Kavanaugh, 95%; Chief Justice Roberts and Justice Barrett, 84%; Justice Gorsuch, 82%; Justice Alito, 70%; Justice Thomas, 66%; Justice Breyer, 58%; Justice Kagan, 55%; and Justice Sotomayor, 45%.

When the term began, many Court watchers expected a relatively uninteresting term, dealing with many technical legal details. In fact, it turned out to be more interesting and important than expected, even with narrow holdings in important cases. Part of the secret of the term was that a lot of the real action was in the Shadow Docket. The end of the term is sometimes the moment when a justice announces a plan to retire. Many commentators expected Justice Breyer might announce—he has been under pressure to do so, to allow President Biden to nominate and a Democratic Senate to confirm a progressive justice. However, he did not do so. It is possible that he will announce his retirement to be effective when his successor is confirmed, but that is pure speculation.
 

Continue to: Next Term...

Next Term

The next term began on Monday, October 4, 2021. With the considerable current activity in the Shadow Docket, there was not much of a summer break. The coming term looks extraordinary. The headline case is an abortion case from Mississippi, Dobbs v Jackson Women’s Health Organization.²⁵ The legal question is the constitutionality of Mississippi law that prohibits most abortions after 15 weeks of gestation. The Texas abortion law will also be back before the Court. As we saw this term, big cases may produce very narrow results, but this case has the potential for being a notable abortion decision.

In a different case the Court will decide whether a state attorney general can step in to defend an abortion law when the state health secretary does not do so.²⁶

The Court also has accepted 3 cases dealing with reimbursement for health services. One deals with whether or not the Department of Health and Human Services can set reimbursement rates without good survey data regarding costs,²⁷ another involves the calculation of additional payments for hospitals that serve a “disproportionate number of low-income patients,”²⁸ and the third whether state Medicaid programs can take funds from an injured beneficiary’s tort recovery to cover future Medicaid costs.²⁹

In other cases, the Court will review a gun control law from New York. The Court’s earlier Second Amendment cases involved guns in the home used for self-defense, but this case raises the question of whether a state can practically preclude “concealed-carry licenses.”³⁰ Many experts believe the Court will accept a case dealing with racial preferences in college admissions, perhaps the Harvard case in which the claim is discrimination against Asian Americans.³¹

The ACOG mifepristone case was interesting, in part because the federal district court issued a nationwide injunction against the Americans with Disabilities Act, enforcing its rules anywhere in the country. The effect of these orders is for a single district judge to create the “law of the land,” at least until that is reviewed—which can take months. The advantage of the nationwide injunction is that it avoids having to repeatedly litigate the same issues in multiple courts around the country. The downside is that plaintiffs can seek out a nonrepresentative judge or circuit and receive an injunction that would be granted by few other circuits. In addition, a nationwide injunction can apply to specific circumstances that are not before the court issuing the injunction. In the mifepristone case, for example, 10 states requested to intervene in the ACOG case. The court rejected the request, but the nationwide injunction applied to those states.¹

Although federal judges have had the authority to issue nationwide injunctions for years, they are becoming much more common. One reason is the ease of forum shopping noted earlier—organizations can cherry-pick district courts and circuits sympathetic to their views. Both left- and right-leaning organizations have learned this lesson, so left-leaning groups are likely to file in specific districts in the Ninth Circuit, and right-leaning groups to districts in the Fifth Circuit.

If the current trend of increasing nationwide injunctions continues, either the rules for the federal courts or congressional action may be required to reduce some of the abuses by both sides of the political spectrum.

The Supreme Court’s usual processes were disrupted this term. The COVID-19 pandemic required audio hearings rather than in-person, and it resulted in a number of emergency legal appeals. As the Court began its regular sessions on October 5, 2020, there were only 8 justices—Justice Ruth Bader Ginsburg had passed away and Amy Coney Barrett had not yet been confirmed by the Senate. The Court decided many important cases this term, including dealing with the delivery of drugs to induce abortions, a Centers for Disease Control and Prevention (CDC) moratorium on housing evictions, yet another case on the Affordable Care Act, state laws concerning pharmacy benefit managers, and the Hologic and Minerva endometrial ablation systems patents. After considering these cases, we also will briefly look at other cases of general interest.

Abortion

Patient access to mifepristone

In May 2020, the American College of Obstetricians and Gynecologists (ACOG) was the named plaintiff in a lawsuit against the US Food and Drug Administration (FDA) regarding the drugs mifepristone and misoprostol that are used to induce medical abortions.¹ The case was filed by the American Civil Liberties Union on behalf of ACOG and others^2,3 and raised the issue of patients’ access to these medications. The basic claim of the case was that during the pandemic, the FDA’s regulation of mifepristone was unconstitutional in that they imposed an undue burden on the decision of women to have an abortion.⁴ (Although misoprostol is a part of the medical abortion regimen, it is not subject to special regulation and was not part of the litigation.)

The FDA regulation of mifepristone, begun in 2000 but modified since then, includes 3 elements to assure safe use:

• prescribers must have special training or certification
• the drug can be dispensed to patients only in a hospital, clinic, or medical office under the supervision of a certified health care provider (known as the “in-person dispensing requirement” because retail pharmacy or mail distribution are prohibited)
• the health care provider must review a “patient agreement form” with the patient and have the patient sign the consent form in the provider’s presence.⁵

The pandemic made fulfilling these requirements substantially more burdensome and difficult. The question was whether the FDA was constitutionally required to modify its regulations during a pandemic to take account of the undue burden of the regulation created by the pandemic. That is, the question was not whether the FDA could have or should have chosen to make the modification, but whether it was required to do so.

In July 2020, a federal district court in Maryland held that the FDA regulation was an unconstitutional burden on the abortion rights of women during the pandemic and issued a preliminary injunction to stop the FDA from enforcing the in-person dispensing and signature rules. The district judge applied the injunction to Maryland, but also made it a nationwide injunction. (The issue of district court nationwide injunctions is considered in, “District court ‘nationwide injunctions’”). 

The FDA asked the Fourth Circuit Court of Appeals to stay the enforcement of the injunction, which the appeals court denied. The FDA then appealed to the Supreme Court, asking it to stay the injunction. In October 2020, the Court announced that it was holding the FDA’s request “in abeyance” to allow the district court to consider a motion by the FDA to dissolve or change the injunction. It gave the district court 40 days in which to act. That decision by the Court was in the “Shadow Docket” (see sidebar on page XX), so the exact vote of the Court in October is not clear, but 2 Justices (Alito and Thomas) dissented and would have stayed the injunction.⁶ Over the next 40 days, the district court did not withdraw its nationwide injunction.

Thus, on January 12, 2021, the case was again before the Supreme Court, which let the FDA’s regulations regarding mifepristone remain in place by lifting the district court’s injunction. Most of the justices supporting the stay did not write to explain their decision, although their dissent in the earlier cases may have served that purpose. (Maryland was permitting many kinds of activity that were more risky than visiting a clinic—indoor dining, with open hair salons, gyms, and casinos.)⁷ Chief Justice Roberts wrote a concurrence to indicate that, in his view, the issue was not whether the FDA’s regulations placed an undue burden on a right to an abortion generally, but that “My view is that courts owe significant deference” to the public health authorities (here meaning the FDA). Justices Sotomayor and Kagan dissented, saying that the issue was the undue burden on women, given the difficulties of the pandemic, particularly going to medical facilities during the COVID-19 pandemic.⁸

The injunction, sought by ACOG and others, was issued by the district court and was in effect for several months before it was dissolved by the Supreme Court. Following the change in presidential administrations, in April 2021 the FDA announced that it was going to “exercise enforcement discretion with respect to the in-person dispensing requirement…during the COVID-19 public health emergency.”⁹

Continue to: The Texas abortion case...

The Texas abortion case

The Court, on September 1, 2021, declined to block a Texas abortion statute from taking effect.¹⁰ This law precludes abortions after a fetal heartbeat is present at about 6 weeks of gestation. The Fifth Circuit declined to grant an injunction delaying implementation of the Texas law, and the Court did not reverse that decision.

Over the years, a variety of states have placed limitations on abortion, and those almost always have been enjoined by federal courts before they went into effect. However, the Texas statute, which undoubtedly is unconstitutional, was creatively constructed to avoid an early injunction.¹¹ The statute does not allow state officials to enforce the new law, but rather it allows almost any private citizen to seek monetary damages from anyone performing an abortion or who “aids and abets” an abortion. Thus, it is difficult to tailor a lawsuit before this law is enforced. First, courts do not enjoin laws; they usually enjoin individuals from enforcing the law, and in this case it is difficult to know which individuals will be enforcing the laws and what their decisions might be. There also are some questions about the degree to which federal courts can enjoin state courts from deciding lawsuits under state law. For these procedural reasons, the majority of the Court found that those attacking the Texas law had not met their burden of showing that that they would win their case.

Even 3 of the dissenting justices said the defendants may be right that “existing doctrines preclude judicial intervention,” but that the consequences are such that the Court should delay the law until there is time for briefing and argument. The other 3 dissenting justices thought there would be ways of getting around the clever roadblock Texas had erected for the federal courts.

There has been some commentary that this case portends the abandonment of Roe v Wade and Casey,¹² but that conclusion does not seem warranted by this case. The Court has accepted a Mississippi abortion law to be heard next term.¹³ In addition, the Texas statute is likely to be back in federal court once a private individual has filed a claim for money from an abortion provider (and likely even before that).

COVID-19 cases

The Supreme Court decided several cases related to COVID-19, including adjustments to election procedures, church services, and CDC eviction moratoria. As a general matter early in the pandemic, the Court deferred to government authorities, generally upholding government actions. Chief Justice Roberts emphasized the importance of the Court deferring to government officials in emergencies. As the pandemic progressed into 2021, however, the Court became less and less sympathetic to government actions that were not consistent, permitted by existing law, or reasonably necessary. For example, regulations of churches that were inconsistent with the regulation of similar organizations were struck down.¹⁴

Among the most interesting of the summer 2021 cases was the CDC eviction moratorium that essentially prohibited landlords nationwide from evicting tenants for nonpayment of rent. When the challenges to these CDC regulations first reached the Court, the moratorium was about to expire; in a 5-4 decision, the Court did not enjoin the CDC from continuing that policy. Justice Kavanaugh (the fifth vote) warned that “clear and specific congressional authorization…would be necessary to extend the moratorium past July 31.”¹⁵ Despite telling the Court that the moratorium would expire on July 31, just 3 days after the expiration and without any congressional authorization, the CDC reinstated what was practically the same moratorium.¹⁶ On August 26, the Court struck down the reinstated regulation, probably by a 6-3 margin. (Because this case arose in the “Shadow Docket,” the vote of some justices is not certain).¹⁷

Continue to: The Affordable Care Act...

The Affordable Care Act

The Affordable Care Act was challenged in the Court for the third time.¹⁸ In this term’s case, several states argued that when Congress essentially eliminated the penalty/tax for not purchasing insurance coverage, there was no longer a constitutional basis for the individual mandate. With that centerpiece gone, they claimed, the whole statute should be declared unconstitutional.

Along with many other specialty groups, ACOG joined an amicus curiae brief sponsored by the American Medical Association (AMA).¹⁹ An amicus brief is one not filed by the parties to the case, but by organizations or individuals who have information that may be of use to the Court in considering the case. Among other things, the filing of an amicus brief indicates the interest of the organization in the outcome of the case. In this case, the crux of the amicus was that even if the individual mandate currently is not constitutional, the Court should sever that provision and retain the rest of the ACA.

Despite some wild predictions about what the Court might do, it did not decide any substantive issue. Rather, it found that none of the parties to the case had “standing” to challenge the constitutionality of the ACA. Therefore, in effect, the Court dismissed the case without deciding the substantive legal issues.
 

Pharmacy Benefit Managers

The powerful Pharmacy Benefit Managers (PBMs) are a hidden part of the health care system; however, in recent years there has been increasing regulatory attention paid to them. Some states have begun regulating aspects of PBMs. In this term, the Court considered an Arkansas law that sought to protect local pharmacies from PBM pricing practices.²⁰ The AMA filed an amicus brief in the case which made legal arguments, most of which had been made by the parties to the litigation.²¹

PBMs generally tell pharmacies how much they will reimburse the pharmacy for filling a prescription for a particular drug. In some instances, PBMs will set a reimbursement price that is lower than the wholesale price at which local pharmacies can purchase the drug. The Arkansas law prohibited PBMs in the state from reimbursing pharmacies for less than the wholesale cost the pharmacy paid for the drug.

The claim of the PBMs was that the Arkansas law violated the Employee Retirement Income Security Act (ERISA). In part, this act preempts state law that relates to fringe benefit plans. States have the authority to regulate insurance, but ERISA limits what they can do when the insurance relates to fringe benefits. The Court held that ERISA does not preempt the Arkansas law or similar state laws in other states. Because the state law was not preempted by the state law, the Arkansas regulation was upheld. The fact that this was a unanimous decision (8-0, because Justice Barrett was not on the Court when the case was heard) suggests that states may have leeway in additional regulations of PBMs, and it would not be surprising to see more of that state regulation in the future.

Continue to: Patent uncertainty...

Patent uncertainty

Csaba Truckai invented and patented the NovaSure System ablation device with a “moisture permeable” head. He sold his company and the related patents, which eventually were purchased by Hologic. Over time, Hologic added claims to the original patent. In the meantime, Truckai went on to invent another device, the Minerva Endometrial Ablation System (MEAS), which had a “moisture impermeable” head. (Note that the “Minerva Surgical, Inc.” involved in this case is not related to the company “Minerva Industries,” which some identified as a “patent troll.”)²²

Hologic sued Minerva, claiming that Truckai’s second device (MEAS) infringed on its patent for the first device (NovaSure). Truckai’s defense was that the patent on NovaSure was invalid. Hologic felt that since Truckai had obtained that patent and then sold it, it was improper for him now to claim it was invalid. There is a doctrine for that: assignor estoppel—the person who sold (assigned) the patent is prevented from later claiming it was invalid. The question in this case was whether assignor estoppel is part of the patent law of the United States. It is not in the patent statutes, so it is a court-determined part of the law.

In a 5-4 decision this Term, the Court held that assignor estoppel is recognized, but that it is narrow.²³ The Court identified several exceptions to assignor estoppel, notably for this case, including the situation in which the purchaser of the patent, after the purchase, returns to the Patent and Trademark Office to expand (amend) the patent’s claims. In that case, the seller could not be estopped by the amended terms of the patent. Minerva claimed that it was attacking the expanded patent that included changes made after it sold the patent. The Court, therefore, returned the case to the Federal Circuit to apply the principles it laid out about assignor estoppel.

Biotech and other fast-moving fields frequently have new technology building on slightly earlier technology. The current patent system often leaves uncertainty about who owns which part of a valid patent. This uncertainty is a drag on innovation, and the patent system is supposed to spur innovation. Assignor estoppel is likely to create additional complexity and uncertainty in some patents, which is regrettable.
 

Review of the Term

In addition to the other disruptions of the Term, during the first part of the Term, Amy Coney Barrett was not yet confirmed by the Senate, so there were only 8 justices until October 27. She did not participate in those cases that were heard before she joined the Court. The consensus is that the Court heard 67 cases: 57 were formally briefed and argued along with 8 summary reversals and 2 religious cases in the Shadow Docket. In my opinion, this undercounts both the number and the importance of the Shadow Docket cases, but the following data use the 67 case convention.²⁴

The Court was unanimous in 43% of the cases, including some of the most divisive issues. That unanimity reflects very narrow decisions. There were (by conventional count) only eight 5-4 opinions (12%), an unusually low number. Justice Kavanaugh is viewed as the “median” justice. He was in the majority in 97% of all cases. Chief Justice Roberts and Justice Barrett were in the majority 91%, and Justice Gorsuch 90%. As for the other justices, they were in the majority (all cases) most of the time: Justice Alito, 83%; Justice Thomas, 81%; Justice Breyer, 76%; Justice Kagan, 75%; and Justice Sotomayor, 69%. In “divided cases” (when unanimous cases are removed), the percentages are: Justice Kavanaugh, 95%; Chief Justice Roberts and Justice Barrett, 84%; Justice Gorsuch, 82%; Justice Alito, 70%; Justice Thomas, 66%; Justice Breyer, 58%; Justice Kagan, 55%; and Justice Sotomayor, 45%.

When the term began, many Court watchers expected a relatively uninteresting term, dealing with many technical legal details. In fact, it turned out to be more interesting and important than expected, even with narrow holdings in important cases. Part of the secret of the term was that a lot of the real action was in the Shadow Docket. The end of the term is sometimes the moment when a justice announces a plan to retire. Many commentators expected Justice Breyer might announce—he has been under pressure to do so, to allow President Biden to nominate and a Democratic Senate to confirm a progressive justice. However, he did not do so. It is possible that he will announce his retirement to be effective when his successor is confirmed, but that is pure speculation.
 

Continue to: Next Term...

Next Term

The next term began on Monday, October 4, 2021. With the considerable current activity in the Shadow Docket, there was not much of a summer break. The coming term looks extraordinary. The headline case is an abortion case from Mississippi, Dobbs v Jackson Women’s Health Organization.²⁵ The legal question is the constitutionality of Mississippi law that prohibits most abortions after 15 weeks of gestation. The Texas abortion law will also be back before the Court. As we saw this term, big cases may produce very narrow results, but this case has the potential for being a notable abortion decision.

In a different case the Court will decide whether a state attorney general can step in to defend an abortion law when the state health secretary does not do so.²⁶

The Court also has accepted 3 cases dealing with reimbursement for health services. One deals with whether or not the Department of Health and Human Services can set reimbursement rates without good survey data regarding costs,²⁷ another involves the calculation of additional payments for hospitals that serve a “disproportionate number of low-income patients,”²⁸ and the third whether state Medicaid programs can take funds from an injured beneficiary’s tort recovery to cover future Medicaid costs.²⁹

In other cases, the Court will review a gun control law from New York. The Court’s earlier Second Amendment cases involved guns in the home used for self-defense, but this case raises the question of whether a state can practically preclude “concealed-carry licenses.”³⁰ Many experts believe the Court will accept a case dealing with racial preferences in college admissions, perhaps the Harvard case in which the claim is discrimination against Asian Americans.³¹

The ACOG mifepristone case was interesting, in part because the federal district court issued a nationwide injunction against the Americans with Disabilities Act, enforcing its rules anywhere in the country. The effect of these orders is for a single district judge to create the “law of the land,” at least until that is reviewed—which can take months. The advantage of the nationwide injunction is that it avoids having to repeatedly litigate the same issues in multiple courts around the country. The downside is that plaintiffs can seek out a nonrepresentative judge or circuit and receive an injunction that would be granted by few other circuits. In addition, a nationwide injunction can apply to specific circumstances that are not before the court issuing the injunction. In the mifepristone case, for example, 10 states requested to intervene in the ACOG case. The court rejected the request, but the nationwide injunction applied to those states.¹

Although federal judges have had the authority to issue nationwide injunctions for years, they are becoming much more common. One reason is the ease of forum shopping noted earlier—organizations can cherry-pick district courts and circuits sympathetic to their views. Both left- and right-leaning organizations have learned this lesson, so left-leaning groups are likely to file in specific districts in the Ninth Circuit, and right-leaning groups to districts in the Fifth Circuit.

If the current trend of increasing nationwide injunctions continues, either the rules for the federal courts or congressional action may be required to reduce some of the abuses by both sides of the political spectrum.

The Supreme Court’s usual processes were disrupted this term. The COVID-19 pandemic required audio hearings rather than in-person, and it resulted in a number of emergency legal appeals. As the Court began its regular sessions on October 5, 2020, there were only 8 justices—Justice Ruth Bader Ginsburg had passed away and Amy Coney Barrett had not yet been confirmed by the Senate. The Court decided many important cases this term, including dealing with the delivery of drugs to induce abortions, a Centers for Disease Control and Prevention (CDC) moratorium on housing evictions, yet another case on the Affordable Care Act, state laws concerning pharmacy benefit managers, and the Hologic and Minerva endometrial ablation systems patents. After considering these cases, we also will briefly look at other cases of general interest.

Abortion

Patient access to mifepristone

In May 2020, the American College of Obstetricians and Gynecologists (ACOG) was the named plaintiff in a lawsuit against the US Food and Drug Administration (FDA) regarding the drugs mifepristone and misoprostol that are used to induce medical abortions.¹ The case was filed by the American Civil Liberties Union on behalf of ACOG and others^2,3 and raised the issue of patients’ access to these medications. The basic claim of the case was that during the pandemic, the FDA’s regulation of mifepristone was unconstitutional in that they imposed an undue burden on the decision of women to have an abortion.⁴ (Although misoprostol is a part of the medical abortion regimen, it is not subject to special regulation and was not part of the litigation.)

The FDA regulation of mifepristone, begun in 2000 but modified since then, includes 3 elements to assure safe use:

• prescribers must have special training or certification
• the drug can be dispensed to patients only in a hospital, clinic, or medical office under the supervision of a certified health care provider (known as the “in-person dispensing requirement” because retail pharmacy or mail distribution are prohibited)
• the health care provider must review a “patient agreement form” with the patient and have the patient sign the consent form in the provider’s presence.⁵

The pandemic made fulfilling these requirements substantially more burdensome and difficult. The question was whether the FDA was constitutionally required to modify its regulations during a pandemic to take account of the undue burden of the regulation created by the pandemic. That is, the question was not whether the FDA could have or should have chosen to make the modification, but whether it was required to do so.

In July 2020, a federal district court in Maryland held that the FDA regulation was an unconstitutional burden on the abortion rights of women during the pandemic and issued a preliminary injunction to stop the FDA from enforcing the in-person dispensing and signature rules. The district judge applied the injunction to Maryland, but also made it a nationwide injunction. (The issue of district court nationwide injunctions is considered in, “District court ‘nationwide injunctions’”). 

The FDA asked the Fourth Circuit Court of Appeals to stay the enforcement of the injunction, which the appeals court denied. The FDA then appealed to the Supreme Court, asking it to stay the injunction. In October 2020, the Court announced that it was holding the FDA’s request “in abeyance” to allow the district court to consider a motion by the FDA to dissolve or change the injunction. It gave the district court 40 days in which to act. That decision by the Court was in the “Shadow Docket” (see sidebar on page XX), so the exact vote of the Court in October is not clear, but 2 Justices (Alito and Thomas) dissented and would have stayed the injunction.⁶ Over the next 40 days, the district court did not withdraw its nationwide injunction.

Thus, on January 12, 2021, the case was again before the Supreme Court, which let the FDA’s regulations regarding mifepristone remain in place by lifting the district court’s injunction. Most of the justices supporting the stay did not write to explain their decision, although their dissent in the earlier cases may have served that purpose. (Maryland was permitting many kinds of activity that were more risky than visiting a clinic—indoor dining, with open hair salons, gyms, and casinos.)⁷ Chief Justice Roberts wrote a concurrence to indicate that, in his view, the issue was not whether the FDA’s regulations placed an undue burden on a right to an abortion generally, but that “My view is that courts owe significant deference” to the public health authorities (here meaning the FDA). Justices Sotomayor and Kagan dissented, saying that the issue was the undue burden on women, given the difficulties of the pandemic, particularly going to medical facilities during the COVID-19 pandemic.⁸

The injunction, sought by ACOG and others, was issued by the district court and was in effect for several months before it was dissolved by the Supreme Court. Following the change in presidential administrations, in April 2021 the FDA announced that it was going to “exercise enforcement discretion with respect to the in-person dispensing requirement…during the COVID-19 public health emergency.”⁹

Continue to: The Texas abortion case...

The Texas abortion case

The Court, on September 1, 2021, declined to block a Texas abortion statute from taking effect.¹⁰ This law precludes abortions after a fetal heartbeat is present at about 6 weeks of gestation. The Fifth Circuit declined to grant an injunction delaying implementation of the Texas law, and the Court did not reverse that decision.

Over the years, a variety of states have placed limitations on abortion, and those almost always have been enjoined by federal courts before they went into effect. However, the Texas statute, which undoubtedly is unconstitutional, was creatively constructed to avoid an early injunction.¹¹ The statute does not allow state officials to enforce the new law, but rather it allows almost any private citizen to seek monetary damages from anyone performing an abortion or who “aids and abets” an abortion. Thus, it is difficult to tailor a lawsuit before this law is enforced. First, courts do not enjoin laws; they usually enjoin individuals from enforcing the law, and in this case it is difficult to know which individuals will be enforcing the laws and what their decisions might be. There also are some questions about the degree to which federal courts can enjoin state courts from deciding lawsuits under state law. For these procedural reasons, the majority of the Court found that those attacking the Texas law had not met their burden of showing that that they would win their case.

Even 3 of the dissenting justices said the defendants may be right that “existing doctrines preclude judicial intervention,” but that the consequences are such that the Court should delay the law until there is time for briefing and argument. The other 3 dissenting justices thought there would be ways of getting around the clever roadblock Texas had erected for the federal courts.

There has been some commentary that this case portends the abandonment of Roe v Wade and Casey,¹² but that conclusion does not seem warranted by this case. The Court has accepted a Mississippi abortion law to be heard next term.¹³ In addition, the Texas statute is likely to be back in federal court once a private individual has filed a claim for money from an abortion provider (and likely even before that).

COVID-19 cases

The Supreme Court decided several cases related to COVID-19, including adjustments to election procedures, church services, and CDC eviction moratoria. As a general matter early in the pandemic, the Court deferred to government authorities, generally upholding government actions. Chief Justice Roberts emphasized the importance of the Court deferring to government officials in emergencies. As the pandemic progressed into 2021, however, the Court became less and less sympathetic to government actions that were not consistent, permitted by existing law, or reasonably necessary. For example, regulations of churches that were inconsistent with the regulation of similar organizations were struck down.¹⁴

Among the most interesting of the summer 2021 cases was the CDC eviction moratorium that essentially prohibited landlords nationwide from evicting tenants for nonpayment of rent. When the challenges to these CDC regulations first reached the Court, the moratorium was about to expire; in a 5-4 decision, the Court did not enjoin the CDC from continuing that policy. Justice Kavanaugh (the fifth vote) warned that “clear and specific congressional authorization…would be necessary to extend the moratorium past July 31.”¹⁵ Despite telling the Court that the moratorium would expire on July 31, just 3 days after the expiration and without any congressional authorization, the CDC reinstated what was practically the same moratorium.¹⁶ On August 26, the Court struck down the reinstated regulation, probably by a 6-3 margin. (Because this case arose in the “Shadow Docket,” the vote of some justices is not certain).¹⁷

Continue to: The Affordable Care Act...

The Affordable Care Act

The Affordable Care Act was challenged in the Court for the third time.¹⁸ In this term’s case, several states argued that when Congress essentially eliminated the penalty/tax for not purchasing insurance coverage, there was no longer a constitutional basis for the individual mandate. With that centerpiece gone, they claimed, the whole statute should be declared unconstitutional.

Along with many other specialty groups, ACOG joined an amicus curiae brief sponsored by the American Medical Association (AMA).¹⁹ An amicus brief is one not filed by the parties to the case, but by organizations or individuals who have information that may be of use to the Court in considering the case. Among other things, the filing of an amicus brief indicates the interest of the organization in the outcome of the case. In this case, the crux of the amicus was that even if the individual mandate currently is not constitutional, the Court should sever that provision and retain the rest of the ACA.

Despite some wild predictions about what the Court might do, it did not decide any substantive issue. Rather, it found that none of the parties to the case had “standing” to challenge the constitutionality of the ACA. Therefore, in effect, the Court dismissed the case without deciding the substantive legal issues.
 

Pharmacy Benefit Managers

The powerful Pharmacy Benefit Managers (PBMs) are a hidden part of the health care system; however, in recent years there has been increasing regulatory attention paid to them. Some states have begun regulating aspects of PBMs. In this term, the Court considered an Arkansas law that sought to protect local pharmacies from PBM pricing practices.²⁰ The AMA filed an amicus brief in the case which made legal arguments, most of which had been made by the parties to the litigation.²¹

PBMs generally tell pharmacies how much they will reimburse the pharmacy for filling a prescription for a particular drug. In some instances, PBMs will set a reimbursement price that is lower than the wholesale price at which local pharmacies can purchase the drug. The Arkansas law prohibited PBMs in the state from reimbursing pharmacies for less than the wholesale cost the pharmacy paid for the drug.

The claim of the PBMs was that the Arkansas law violated the Employee Retirement Income Security Act (ERISA). In part, this act preempts state law that relates to fringe benefit plans. States have the authority to regulate insurance, but ERISA limits what they can do when the insurance relates to fringe benefits. The Court held that ERISA does not preempt the Arkansas law or similar state laws in other states. Because the state law was not preempted by the state law, the Arkansas regulation was upheld. The fact that this was a unanimous decision (8-0, because Justice Barrett was not on the Court when the case was heard) suggests that states may have leeway in additional regulations of PBMs, and it would not be surprising to see more of that state regulation in the future.

Continue to: Patent uncertainty...

Patent uncertainty

Csaba Truckai invented and patented the NovaSure System ablation device with a “moisture permeable” head. He sold his company and the related patents, which eventually were purchased by Hologic. Over time, Hologic added claims to the original patent. In the meantime, Truckai went on to invent another device, the Minerva Endometrial Ablation System (MEAS), which had a “moisture impermeable” head. (Note that the “Minerva Surgical, Inc.” involved in this case is not related to the company “Minerva Industries,” which some identified as a “patent troll.”)²²

Hologic sued Minerva, claiming that Truckai’s second device (MEAS) infringed on its patent for the first device (NovaSure). Truckai’s defense was that the patent on NovaSure was invalid. Hologic felt that since Truckai had obtained that patent and then sold it, it was improper for him now to claim it was invalid. There is a doctrine for that: assignor estoppel—the person who sold (assigned) the patent is prevented from later claiming it was invalid. The question in this case was whether assignor estoppel is part of the patent law of the United States. It is not in the patent statutes, so it is a court-determined part of the law.

In a 5-4 decision this Term, the Court held that assignor estoppel is recognized, but that it is narrow.²³ The Court identified several exceptions to assignor estoppel, notably for this case, including the situation in which the purchaser of the patent, after the purchase, returns to the Patent and Trademark Office to expand (amend) the patent’s claims. In that case, the seller could not be estopped by the amended terms of the patent. Minerva claimed that it was attacking the expanded patent that included changes made after it sold the patent. The Court, therefore, returned the case to the Federal Circuit to apply the principles it laid out about assignor estoppel.

Biotech and other fast-moving fields frequently have new technology building on slightly earlier technology. The current patent system often leaves uncertainty about who owns which part of a valid patent. This uncertainty is a drag on innovation, and the patent system is supposed to spur innovation. Assignor estoppel is likely to create additional complexity and uncertainty in some patents, which is regrettable.
 

Review of the Term

In addition to the other disruptions of the Term, during the first part of the Term, Amy Coney Barrett was not yet confirmed by the Senate, so there were only 8 justices until October 27. She did not participate in those cases that were heard before she joined the Court. The consensus is that the Court heard 67 cases: 57 were formally briefed and argued along with 8 summary reversals and 2 religious cases in the Shadow Docket. In my opinion, this undercounts both the number and the importance of the Shadow Docket cases, but the following data use the 67 case convention.²⁴

The Court was unanimous in 43% of the cases, including some of the most divisive issues. That unanimity reflects very narrow decisions. There were (by conventional count) only eight 5-4 opinions (12%), an unusually low number. Justice Kavanaugh is viewed as the “median” justice. He was in the majority in 97% of all cases. Chief Justice Roberts and Justice Barrett were in the majority 91%, and Justice Gorsuch 90%. As for the other justices, they were in the majority (all cases) most of the time: Justice Alito, 83%; Justice Thomas, 81%; Justice Breyer, 76%; Justice Kagan, 75%; and Justice Sotomayor, 69%. In “divided cases” (when unanimous cases are removed), the percentages are: Justice Kavanaugh, 95%; Chief Justice Roberts and Justice Barrett, 84%; Justice Gorsuch, 82%; Justice Alito, 70%; Justice Thomas, 66%; Justice Breyer, 58%; Justice Kagan, 55%; and Justice Sotomayor, 45%.

When the term began, many Court watchers expected a relatively uninteresting term, dealing with many technical legal details. In fact, it turned out to be more interesting and important than expected, even with narrow holdings in important cases. Part of the secret of the term was that a lot of the real action was in the Shadow Docket. The end of the term is sometimes the moment when a justice announces a plan to retire. Many commentators expected Justice Breyer might announce—he has been under pressure to do so, to allow President Biden to nominate and a Democratic Senate to confirm a progressive justice. However, he did not do so. It is possible that he will announce his retirement to be effective when his successor is confirmed, but that is pure speculation.
 

Continue to: Next Term...

Next Term

The next term began on Monday, October 4, 2021. With the considerable current activity in the Shadow Docket, there was not much of a summer break. The coming term looks extraordinary. The headline case is an abortion case from Mississippi, Dobbs v Jackson Women’s Health Organization.²⁵ The legal question is the constitutionality of Mississippi law that prohibits most abortions after 15 weeks of gestation. The Texas abortion law will also be back before the Court. As we saw this term, big cases may produce very narrow results, but this case has the potential for being a notable abortion decision.

In a different case the Court will decide whether a state attorney general can step in to defend an abortion law when the state health secretary does not do so.²⁶

The Court also has accepted 3 cases dealing with reimbursement for health services. One deals with whether or not the Department of Health and Human Services can set reimbursement rates without good survey data regarding costs,²⁷ another involves the calculation of additional payments for hospitals that serve a “disproportionate number of low-income patients,”²⁸ and the third whether state Medicaid programs can take funds from an injured beneficiary’s tort recovery to cover future Medicaid costs.²⁹

In other cases, the Court will review a gun control law from New York. The Court’s earlier Second Amendment cases involved guns in the home used for self-defense, but this case raises the question of whether a state can practically preclude “concealed-carry licenses.”³⁰ Many experts believe the Court will accept a case dealing with racial preferences in college admissions, perhaps the Harvard case in which the claim is discrimination against Asian Americans.³¹

The ACOG mifepristone case was interesting, in part because the federal district court issued a nationwide injunction against the Americans with Disabilities Act, enforcing its rules anywhere in the country. The effect of these orders is for a single district judge to create the “law of the land,” at least until that is reviewed—which can take months. The advantage of the nationwide injunction is that it avoids having to repeatedly litigate the same issues in multiple courts around the country. The downside is that plaintiffs can seek out a nonrepresentative judge or circuit and receive an injunction that would be granted by few other circuits. In addition, a nationwide injunction can apply to specific circumstances that are not before the court issuing the injunction. In the mifepristone case, for example, 10 states requested to intervene in the ACOG case. The court rejected the request, but the nationwide injunction applied to those states.¹

Although federal judges have had the authority to issue nationwide injunctions for years, they are becoming much more common. One reason is the ease of forum shopping noted earlier—organizations can cherry-pick district courts and circuits sympathetic to their views. Both left- and right-leaning organizations have learned this lesson, so left-leaning groups are likely to file in specific districts in the Ninth Circuit, and right-leaning groups to districts in the Fifth Circuit.

If the current trend of increasing nationwide injunctions continues, either the rules for the federal courts or congressional action may be required to reduce some of the abuses by both sides of the political spectrum.

A newly discovered vascular brain barrier that blocks the passage of inflammatory molecules triggered by gut bacteria may be why patients with inflammatory bowel disease (IBD) are at increased risk for certain mental health disorders, including anxiety and depression, early research suggests.

The discovery, which was based on a preclinical model, could lead to new therapeutic targets that could have applications for both gastrointestinal and psychiatric conditions, investigators note.

The research team, which was led by immunologist Maria Rescigno, PhD, and neuroscientist Simona Lodato, PhD, both from Humanitas University, Milan, notes that the barrier resides in the choroid plexus, a region of the brain that is involved in filtering cerebrospinal fluid. The researchers found that the region closes in response to inflammatory molecules produced in reaction to the presence of intestinal bacteria in patients with gut disorders.

Dr. Lodato said in an interview that the brain’s choroid plexus vascular barrier, along with another barrier between the gut and liver, known as the gut vascular barrier, appear to control the movement of molecules along the gut-brain axis.

“We show that in addition to the epithelial barrier in the choroid plexus, there is a functional vascular barrier that only becomes evident in blocking entry of various inflammatory molecules under conditions of systemic inflammation,” Dr. Lodato said.

“This interruption of the gut-brain interaction has developed to protect the brain from inflammation. Why this happens is not yet known, but it is likely to prevent epileptic seizures and imbalanced neuronal activity,” added Dr. Rescigno.

The study was published online October 22 in Science.
 

The gut a root cause of mental illness?

Nearly 40% of patients with IBD also experience depression and anxiety. It was once thought that these conditions arose because of patients’ difficulties in coping with their disease, said Dr. Rescigno.

“People with these disorders conventionally thought to be caused by an imbalance in the brain may actually find the root cause is located in the intestine. This is the first time these symptoms have been associated with the choroid plexus vascular brain barrier and its closure,” she noted.

Dr. Rescigno added that subtle, rather than overt, inflammation may be all that’s required for closure of the choroid plexus and the subsequent effects on mental health.

In 2015, Dr. Rescigno’s group first described the gut vascular barrier that protects the systemic circulation from gut bacteria or associated bacteria-derived molecules. During intestinal inflammation, such as occurs in IBD, this barrier is compromised and becomes more permeable. This allows microbes to pass across the epithelium of the gut barrier and enter the systemic circulation, including the liver and spleen, explained Dr. Rescigno.

Dr. Rescigno and Dr. Lodato then explored whether this systemic inflammatory condition was connected to the brain along a gut-brain axis and found that it was.

The researchers tested the hypothesis that central nervous system symptoms may be due to vascular changes at the interface between the gut or the brain and elsewhere in the body.

“We set out to test whether opening of the gut vascular barrier would allow gut bacteria to trigger the release of inflammatory molecules that spread to more distant areas, possibly leading to a deficiency of certain nutrients and precipitating mental disorders,” they said.

An experimental preclinical model of the choroid plexus vascular barrier closure led to anxiety-like behavior, as well as short-term memory loss. That this behavior occurred independently of inflammation suggested that it was likely a response to closure itself, they note.

In the noninflammatory state, the epithelium of the choroid plexus filters molecules. Those that are ≤70 kDa are allowed to pass through to the brain. However, the investigators found that during systemic inflammation, this filtration stops, and the blood capillaries of the choroid plexus prevent entry of inflammatory molecules such as cytokines.

Dr. Lodato speculated that when the vascular barrier of the choroid plexus shuts off during the systemic inflammatory state, it responds by bathing the brain in cerebrospinal fluid.

“When the choroid plexus closes, like a door slamming shut, then communication between the brain and the rest of the body is halted. This means that the brain is deprived of certain nutrients and other beneficial molecules that usually enter via the cerebrospinal fluid or enriched of potentially dangerous ones, as drainage could also be affected,” she said.

If confirmed in further studies, these results may open the way to new interventions.
 

‘A significant leap forward’

Commenting on the findings, David T. Rubin, MD, professor of medicine at the University of Chicago, noted that the study’s results represent “a significant leap forward” and that it highlights “another important cost to uncontrolled gut inflammation that is the potential for worsened mental health disorders.”

Dr. Rubin, whose research involves measuring metabolites of the dietary amino acid tryptophan, including melatonin and serotonin, in patients with IBD, added that the findings offer a possible explanation for the association of both Crohn’s disease and ulcerative colitis with anxiety and depressive disorders.

“There was a belief that the association was in the opposite direction, that the mental health disorder was causing or worsening the gut inflammation, but this has been disavowed,” Dr. Rubin said.

“Most recently, the recognition that the major sources of serotonin and other metabolites of tryptophan that come from the gut microbiome has led to the hypothesis that the inflamed bowel and dysbiotic gut biome may in fact be driving the mental health disorders due to the effect of neurotransmitter imbalance,” he added. Dr. Rubin also suggested that the shutdown of the choroid plexus vascular barrier may contribute to this imbalance but that this needs additional study.

“This further supports my ongoing contention that the gut really is the center of the universe,” said Dr. Rubin.

Also commenting on the findings, Miguel Rigueiro, MD, professor in the department of medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, said, “There’s an implication that anxiety and depression and other behavioral health disorders may be explained by this mechanism. If that is the case, there may be a way to target medications against the choroid plexus and potentially treat depression or anxiety.”

This prospect was echoed by Dr. Rubin, who said, “The clinical implication is that treatment of gut inflammation may restore a balance to the neurotransmitters and resolve anxiety or depressive disorders.”

To identify new therapeutic targets, investigators will study the regions and circuits of the brain that are more susceptible to this closure of the choroid plexus, said Dr. Lodato.

“If these regions are associated with depression or other psychosocial disorders, then this new understanding around the choroid plexus vascular barrier might eventually have implications for helping treat such disorders,” she noted.

Reflecting a general shift from a brain-centric view of some psychosocial disorders to an intestinal-centric one, Dr. Lodato added, “The brain cannot be considered in isolation. It is part of a much larger body, and we need to think this way.”

Dr. Rescigno, Dr. Lodato, and Dr. Rubin report no relevant financial relationships. Dr. Rigueiro has served on advisory boards and as consultant for AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, SpA, and Bristol-Meyer Squibb.

A version of this article first appeared on Medscape.com.

A newly discovered vascular brain barrier that blocks the passage of inflammatory molecules triggered by gut bacteria may be why patients with inflammatory bowel disease (IBD) are at increased risk for certain mental health disorders, including anxiety and depression, early research suggests.

The discovery, which was based on a preclinical model, could lead to new therapeutic targets that could have applications for both gastrointestinal and psychiatric conditions, investigators note.

The research team, which was led by immunologist Maria Rescigno, PhD, and neuroscientist Simona Lodato, PhD, both from Humanitas University, Milan, notes that the barrier resides in the choroid plexus, a region of the brain that is involved in filtering cerebrospinal fluid. The researchers found that the region closes in response to inflammatory molecules produced in reaction to the presence of intestinal bacteria in patients with gut disorders.

Dr. Lodato said in an interview that the brain’s choroid plexus vascular barrier, along with another barrier between the gut and liver, known as the gut vascular barrier, appear to control the movement of molecules along the gut-brain axis.

“We show that in addition to the epithelial barrier in the choroid plexus, there is a functional vascular barrier that only becomes evident in blocking entry of various inflammatory molecules under conditions of systemic inflammation,” Dr. Lodato said.

“This interruption of the gut-brain interaction has developed to protect the brain from inflammation. Why this happens is not yet known, but it is likely to prevent epileptic seizures and imbalanced neuronal activity,” added Dr. Rescigno.

The study was published online October 22 in Science.
 

The gut a root cause of mental illness?

Nearly 40% of patients with IBD also experience depression and anxiety. It was once thought that these conditions arose because of patients’ difficulties in coping with their disease, said Dr. Rescigno.

“People with these disorders conventionally thought to be caused by an imbalance in the brain may actually find the root cause is located in the intestine. This is the first time these symptoms have been associated with the choroid plexus vascular brain barrier and its closure,” she noted.

Dr. Rescigno added that subtle, rather than overt, inflammation may be all that’s required for closure of the choroid plexus and the subsequent effects on mental health.

In 2015, Dr. Rescigno’s group first described the gut vascular barrier that protects the systemic circulation from gut bacteria or associated bacteria-derived molecules. During intestinal inflammation, such as occurs in IBD, this barrier is compromised and becomes more permeable. This allows microbes to pass across the epithelium of the gut barrier and enter the systemic circulation, including the liver and spleen, explained Dr. Rescigno.

Dr. Rescigno and Dr. Lodato then explored whether this systemic inflammatory condition was connected to the brain along a gut-brain axis and found that it was.

The researchers tested the hypothesis that central nervous system symptoms may be due to vascular changes at the interface between the gut or the brain and elsewhere in the body.

“We set out to test whether opening of the gut vascular barrier would allow gut bacteria to trigger the release of inflammatory molecules that spread to more distant areas, possibly leading to a deficiency of certain nutrients and precipitating mental disorders,” they said.

An experimental preclinical model of the choroid plexus vascular barrier closure led to anxiety-like behavior, as well as short-term memory loss. That this behavior occurred independently of inflammation suggested that it was likely a response to closure itself, they note.

In the noninflammatory state, the epithelium of the choroid plexus filters molecules. Those that are ≤70 kDa are allowed to pass through to the brain. However, the investigators found that during systemic inflammation, this filtration stops, and the blood capillaries of the choroid plexus prevent entry of inflammatory molecules such as cytokines.

Dr. Lodato speculated that when the vascular barrier of the choroid plexus shuts off during the systemic inflammatory state, it responds by bathing the brain in cerebrospinal fluid.

“When the choroid plexus closes, like a door slamming shut, then communication between the brain and the rest of the body is halted. This means that the brain is deprived of certain nutrients and other beneficial molecules that usually enter via the cerebrospinal fluid or enriched of potentially dangerous ones, as drainage could also be affected,” she said.

If confirmed in further studies, these results may open the way to new interventions.
 

‘A significant leap forward’

Commenting on the findings, David T. Rubin, MD, professor of medicine at the University of Chicago, noted that the study’s results represent “a significant leap forward” and that it highlights “another important cost to uncontrolled gut inflammation that is the potential for worsened mental health disorders.”

Dr. Rubin, whose research involves measuring metabolites of the dietary amino acid tryptophan, including melatonin and serotonin, in patients with IBD, added that the findings offer a possible explanation for the association of both Crohn’s disease and ulcerative colitis with anxiety and depressive disorders.

“There was a belief that the association was in the opposite direction, that the mental health disorder was causing or worsening the gut inflammation, but this has been disavowed,” Dr. Rubin said.

“Most recently, the recognition that the major sources of serotonin and other metabolites of tryptophan that come from the gut microbiome has led to the hypothesis that the inflamed bowel and dysbiotic gut biome may in fact be driving the mental health disorders due to the effect of neurotransmitter imbalance,” he added. Dr. Rubin also suggested that the shutdown of the choroid plexus vascular barrier may contribute to this imbalance but that this needs additional study.

“This further supports my ongoing contention that the gut really is the center of the universe,” said Dr. Rubin.

Also commenting on the findings, Miguel Rigueiro, MD, professor in the department of medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, said, “There’s an implication that anxiety and depression and other behavioral health disorders may be explained by this mechanism. If that is the case, there may be a way to target medications against the choroid plexus and potentially treat depression or anxiety.”

This prospect was echoed by Dr. Rubin, who said, “The clinical implication is that treatment of gut inflammation may restore a balance to the neurotransmitters and resolve anxiety or depressive disorders.”

To identify new therapeutic targets, investigators will study the regions and circuits of the brain that are more susceptible to this closure of the choroid plexus, said Dr. Lodato.

“If these regions are associated with depression or other psychosocial disorders, then this new understanding around the choroid plexus vascular barrier might eventually have implications for helping treat such disorders,” she noted.

Reflecting a general shift from a brain-centric view of some psychosocial disorders to an intestinal-centric one, Dr. Lodato added, “The brain cannot be considered in isolation. It is part of a much larger body, and we need to think this way.”

Dr. Rescigno, Dr. Lodato, and Dr. Rubin report no relevant financial relationships. Dr. Rigueiro has served on advisory boards and as consultant for AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, SpA, and Bristol-Meyer Squibb.

A version of this article first appeared on Medscape.com.

A newly discovered vascular brain barrier that blocks the passage of inflammatory molecules triggered by gut bacteria may be why patients with inflammatory bowel disease (IBD) are at increased risk for certain mental health disorders, including anxiety and depression, early research suggests.

The discovery, which was based on a preclinical model, could lead to new therapeutic targets that could have applications for both gastrointestinal and psychiatric conditions, investigators note.

The research team, which was led by immunologist Maria Rescigno, PhD, and neuroscientist Simona Lodato, PhD, both from Humanitas University, Milan, notes that the barrier resides in the choroid plexus, a region of the brain that is involved in filtering cerebrospinal fluid. The researchers found that the region closes in response to inflammatory molecules produced in reaction to the presence of intestinal bacteria in patients with gut disorders.

Dr. Lodato said in an interview that the brain’s choroid plexus vascular barrier, along with another barrier between the gut and liver, known as the gut vascular barrier, appear to control the movement of molecules along the gut-brain axis.

“We show that in addition to the epithelial barrier in the choroid plexus, there is a functional vascular barrier that only becomes evident in blocking entry of various inflammatory molecules under conditions of systemic inflammation,” Dr. Lodato said.

“This interruption of the gut-brain interaction has developed to protect the brain from inflammation. Why this happens is not yet known, but it is likely to prevent epileptic seizures and imbalanced neuronal activity,” added Dr. Rescigno.

The study was published online October 22 in Science.
 

The gut a root cause of mental illness?

Nearly 40% of patients with IBD also experience depression and anxiety. It was once thought that these conditions arose because of patients’ difficulties in coping with their disease, said Dr. Rescigno.

“People with these disorders conventionally thought to be caused by an imbalance in the brain may actually find the root cause is located in the intestine. This is the first time these symptoms have been associated with the choroid plexus vascular brain barrier and its closure,” she noted.

Dr. Rescigno added that subtle, rather than overt, inflammation may be all that’s required for closure of the choroid plexus and the subsequent effects on mental health.

In 2015, Dr. Rescigno’s group first described the gut vascular barrier that protects the systemic circulation from gut bacteria or associated bacteria-derived molecules. During intestinal inflammation, such as occurs in IBD, this barrier is compromised and becomes more permeable. This allows microbes to pass across the epithelium of the gut barrier and enter the systemic circulation, including the liver and spleen, explained Dr. Rescigno.

Dr. Rescigno and Dr. Lodato then explored whether this systemic inflammatory condition was connected to the brain along a gut-brain axis and found that it was.

The researchers tested the hypothesis that central nervous system symptoms may be due to vascular changes at the interface between the gut or the brain and elsewhere in the body.

“We set out to test whether opening of the gut vascular barrier would allow gut bacteria to trigger the release of inflammatory molecules that spread to more distant areas, possibly leading to a deficiency of certain nutrients and precipitating mental disorders,” they said.

An experimental preclinical model of the choroid plexus vascular barrier closure led to anxiety-like behavior, as well as short-term memory loss. That this behavior occurred independently of inflammation suggested that it was likely a response to closure itself, they note.

In the noninflammatory state, the epithelium of the choroid plexus filters molecules. Those that are ≤70 kDa are allowed to pass through to the brain. However, the investigators found that during systemic inflammation, this filtration stops, and the blood capillaries of the choroid plexus prevent entry of inflammatory molecules such as cytokines.

Dr. Lodato speculated that when the vascular barrier of the choroid plexus shuts off during the systemic inflammatory state, it responds by bathing the brain in cerebrospinal fluid.

“When the choroid plexus closes, like a door slamming shut, then communication between the brain and the rest of the body is halted. This means that the brain is deprived of certain nutrients and other beneficial molecules that usually enter via the cerebrospinal fluid or enriched of potentially dangerous ones, as drainage could also be affected,” she said.

If confirmed in further studies, these results may open the way to new interventions.
 

‘A significant leap forward’

Commenting on the findings, David T. Rubin, MD, professor of medicine at the University of Chicago, noted that the study’s results represent “a significant leap forward” and that it highlights “another important cost to uncontrolled gut inflammation that is the potential for worsened mental health disorders.”

Dr. Rubin, whose research involves measuring metabolites of the dietary amino acid tryptophan, including melatonin and serotonin, in patients with IBD, added that the findings offer a possible explanation for the association of both Crohn’s disease and ulcerative colitis with anxiety and depressive disorders.

“There was a belief that the association was in the opposite direction, that the mental health disorder was causing or worsening the gut inflammation, but this has been disavowed,” Dr. Rubin said.

“Most recently, the recognition that the major sources of serotonin and other metabolites of tryptophan that come from the gut microbiome has led to the hypothesis that the inflamed bowel and dysbiotic gut biome may in fact be driving the mental health disorders due to the effect of neurotransmitter imbalance,” he added. Dr. Rubin also suggested that the shutdown of the choroid plexus vascular barrier may contribute to this imbalance but that this needs additional study.

“This further supports my ongoing contention that the gut really is the center of the universe,” said Dr. Rubin.

Also commenting on the findings, Miguel Rigueiro, MD, professor in the department of medicine in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, said, “There’s an implication that anxiety and depression and other behavioral health disorders may be explained by this mechanism. If that is the case, there may be a way to target medications against the choroid plexus and potentially treat depression or anxiety.”

This prospect was echoed by Dr. Rubin, who said, “The clinical implication is that treatment of gut inflammation may restore a balance to the neurotransmitters and resolve anxiety or depressive disorders.”

To identify new therapeutic targets, investigators will study the regions and circuits of the brain that are more susceptible to this closure of the choroid plexus, said Dr. Lodato.

“If these regions are associated with depression or other psychosocial disorders, then this new understanding around the choroid plexus vascular barrier might eventually have implications for helping treat such disorders,” she noted.

Reflecting a general shift from a brain-centric view of some psychosocial disorders to an intestinal-centric one, Dr. Lodato added, “The brain cannot be considered in isolation. It is part of a much larger body, and we need to think this way.”

Dr. Rescigno, Dr. Lodato, and Dr. Rubin report no relevant financial relationships. Dr. Rigueiro has served on advisory boards and as consultant for AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, SpA, and Bristol-Meyer Squibb.

A version of this article first appeared on Medscape.com.

LAS VEGAS – People with obesity may be able to reduce their risk of colorectal cancer with weight loss surgery or medication, researchers say.

“We need to have conversations with our patients in the clinic and educate them that they have these resources available,” said Aakash Desai, MD, a hospitalist at MetroHealth Medical Center, Cleveland, in an interview with this news organization.

Dr. Desai and colleagues found that sleeve gastrectomy and four medications were associated with a reduced risk of colorectal cancer but Roux-en-Y gastrojejunostomy and orlistat were not.

Coauthor Zryan Shwani, MD, a gastroenterology fellow at Sibley Memorial Hospital, Washington, D.C., presented the findings here at the American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting.

Working with an underserved population with high rates of obesity in northeastern Ohio, the researchers wondered how surgery and medication could affect these patients.

They analyzed data from the IBM Explorys clinical database, which compiles and standardizes data from electronic medical records on about 74 million patients from more than 300 U.S. hospitals. Consistent with previous studies, they determined that patients with obesity in the database were 2.5 times more likely than people with a healthy weight to be diagnosed with colorectal cancer (odds ratio, 2.48; 95% CI, 2.45-2.51).

Zeroing in on people who had weight loss interventions, they included adults aged 18-75 years who had undergone either Roux-en-Y gastrojejunostomy or sleeve gastrectomy, or had taken the medications liraglutide, orlistat, phentermine/topiramate, bupropion/naltrexone, or lorcaserin.

They excluded patients with Lynch syndrome, intestinal polyposis syndrome, a family history of gastrointestinal malignancy, inflammatory bowel disease, or tobacco or alcohol abuse. Patients who had taken one of the weight loss medications and also had type 2 diabetes were excluded. They did not include patients who had undergone gastric banding because it has become less popular.

For the weight loss medication group, they found 117,730 patients who met their criteria. For the surgery group, 43,050 patients met the criteria.

In analyzing the colorectal cancer rates, they included only diagnoses of malignant neoplasms made 2 years after the interventions.

They compared these patients to a control group of 52,540 people matched in age, with a body mass index (BMI) greater than 30 kg/m² who did not undergo weight loss surgery or take weight loss medication.

Among the 9,370 patients who underwent Roux-en-Y gastrojejunostomy, 50 were diagnosed with colorectal cancer and 400 had benign polyps. Their rate of colorectal cancer was not statistically different from people who didn’t have surgery (OR, 1.09; 95% CI, 0.82-1.43). The rate of benign polyps after Roux-en-Y gastrojejunostomy was greater (OR, 1.72; 95% CI, 1.55-1.90).

On the other hand, among the 33,680 patients who underwent sleeve gastrectomy, 50 were diagnosed with colorectal cancer, a lower rate than in the population who didn’t have surgery (OR, 0.30; 95% CI, 0.22-0.39). Their risk of benign polyps was also reduced (OR, 0.45; 95% CI, 0.40-0.50).

All of the medications were significantly associated with a lower risk of colorectal cancer, except orlistat (OR, 0.94; 95% CI, 0.72-1.25).

The finding on Roux-en-Y gastrojejunostomy agreed with studies from England and Nordic countries showing double the risk of colorectal cancer in those patients but conflicted with a French study showing decreased risk, Dr. Shwani said.

While the study doesn’t establish a reason why Roux-en-Y gastrojejunostomy was less beneficial, other researchers have associated the procedure with biomarkers of inflammation, Dr. Shwani said. “It’s inconsistent, and I don’t think we have a clear answer why.”

As a retrospective analysis, the study could not establish a cause-and-effect relationship between surgery or medication and cancer, or adjust for such factors as diet, exercise, or genes, he acknowledged.

Colorectal cancer is just one outcome to consider when deciding whether to undergo weight loss surgery or take weight loss drugs, said session moderator Mohammad Yaghoobi, MD, an associate professor of medicine at McMaster University, Hamilton, Ont.

“The most important outcome that should be investigated is the survival of the patients after obesity surgery,” he told this news organization. “The second would be the quality of life of those patients. Colon cancer is preventable if you are having regular colonoscopies.”

Other studies have not shown much difference between patients who have weight loss surgery and those who don’t, he added.

The study was funded by Merck. Dr. Desai and Dr. Shwani have reported receiving grant funding from Merck. Dr. Yaghoobi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LAS VEGAS – People with obesity may be able to reduce their risk of colorectal cancer with weight loss surgery or medication, researchers say.

“We need to have conversations with our patients in the clinic and educate them that they have these resources available,” said Aakash Desai, MD, a hospitalist at MetroHealth Medical Center, Cleveland, in an interview with this news organization.

Dr. Desai and colleagues found that sleeve gastrectomy and four medications were associated with a reduced risk of colorectal cancer but Roux-en-Y gastrojejunostomy and orlistat were not.

Coauthor Zryan Shwani, MD, a gastroenterology fellow at Sibley Memorial Hospital, Washington, D.C., presented the findings here at the American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting.

Working with an underserved population with high rates of obesity in northeastern Ohio, the researchers wondered how surgery and medication could affect these patients.

They analyzed data from the IBM Explorys clinical database, which compiles and standardizes data from electronic medical records on about 74 million patients from more than 300 U.S. hospitals. Consistent with previous studies, they determined that patients with obesity in the database were 2.5 times more likely than people with a healthy weight to be diagnosed with colorectal cancer (odds ratio, 2.48; 95% CI, 2.45-2.51).

Zeroing in on people who had weight loss interventions, they included adults aged 18-75 years who had undergone either Roux-en-Y gastrojejunostomy or sleeve gastrectomy, or had taken the medications liraglutide, orlistat, phentermine/topiramate, bupropion/naltrexone, or lorcaserin.

They excluded patients with Lynch syndrome, intestinal polyposis syndrome, a family history of gastrointestinal malignancy, inflammatory bowel disease, or tobacco or alcohol abuse. Patients who had taken one of the weight loss medications and also had type 2 diabetes were excluded. They did not include patients who had undergone gastric banding because it has become less popular.

For the weight loss medication group, they found 117,730 patients who met their criteria. For the surgery group, 43,050 patients met the criteria.

In analyzing the colorectal cancer rates, they included only diagnoses of malignant neoplasms made 2 years after the interventions.

They compared these patients to a control group of 52,540 people matched in age, with a body mass index (BMI) greater than 30 kg/m² who did not undergo weight loss surgery or take weight loss medication.

Among the 9,370 patients who underwent Roux-en-Y gastrojejunostomy, 50 were diagnosed with colorectal cancer and 400 had benign polyps. Their rate of colorectal cancer was not statistically different from people who didn’t have surgery (OR, 1.09; 95% CI, 0.82-1.43). The rate of benign polyps after Roux-en-Y gastrojejunostomy was greater (OR, 1.72; 95% CI, 1.55-1.90).

On the other hand, among the 33,680 patients who underwent sleeve gastrectomy, 50 were diagnosed with colorectal cancer, a lower rate than in the population who didn’t have surgery (OR, 0.30; 95% CI, 0.22-0.39). Their risk of benign polyps was also reduced (OR, 0.45; 95% CI, 0.40-0.50).

All of the medications were significantly associated with a lower risk of colorectal cancer, except orlistat (OR, 0.94; 95% CI, 0.72-1.25).

The finding on Roux-en-Y gastrojejunostomy agreed with studies from England and Nordic countries showing double the risk of colorectal cancer in those patients but conflicted with a French study showing decreased risk, Dr. Shwani said.

While the study doesn’t establish a reason why Roux-en-Y gastrojejunostomy was less beneficial, other researchers have associated the procedure with biomarkers of inflammation, Dr. Shwani said. “It’s inconsistent, and I don’t think we have a clear answer why.”

As a retrospective analysis, the study could not establish a cause-and-effect relationship between surgery or medication and cancer, or adjust for such factors as diet, exercise, or genes, he acknowledged.

Colorectal cancer is just one outcome to consider when deciding whether to undergo weight loss surgery or take weight loss drugs, said session moderator Mohammad Yaghoobi, MD, an associate professor of medicine at McMaster University, Hamilton, Ont.

“The most important outcome that should be investigated is the survival of the patients after obesity surgery,” he told this news organization. “The second would be the quality of life of those patients. Colon cancer is preventable if you are having regular colonoscopies.”

Other studies have not shown much difference between patients who have weight loss surgery and those who don’t, he added.

The study was funded by Merck. Dr. Desai and Dr. Shwani have reported receiving grant funding from Merck. Dr. Yaghoobi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

LAS VEGAS – People with obesity may be able to reduce their risk of colorectal cancer with weight loss surgery or medication, researchers say.

“We need to have conversations with our patients in the clinic and educate them that they have these resources available,” said Aakash Desai, MD, a hospitalist at MetroHealth Medical Center, Cleveland, in an interview with this news organization.

Dr. Desai and colleagues found that sleeve gastrectomy and four medications were associated with a reduced risk of colorectal cancer but Roux-en-Y gastrojejunostomy and orlistat were not.

Coauthor Zryan Shwani, MD, a gastroenterology fellow at Sibley Memorial Hospital, Washington, D.C., presented the findings here at the American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting.

Working with an underserved population with high rates of obesity in northeastern Ohio, the researchers wondered how surgery and medication could affect these patients.

They analyzed data from the IBM Explorys clinical database, which compiles and standardizes data from electronic medical records on about 74 million patients from more than 300 U.S. hospitals. Consistent with previous studies, they determined that patients with obesity in the database were 2.5 times more likely than people with a healthy weight to be diagnosed with colorectal cancer (odds ratio, 2.48; 95% CI, 2.45-2.51).

Zeroing in on people who had weight loss interventions, they included adults aged 18-75 years who had undergone either Roux-en-Y gastrojejunostomy or sleeve gastrectomy, or had taken the medications liraglutide, orlistat, phentermine/topiramate, bupropion/naltrexone, or lorcaserin.

They excluded patients with Lynch syndrome, intestinal polyposis syndrome, a family history of gastrointestinal malignancy, inflammatory bowel disease, or tobacco or alcohol abuse. Patients who had taken one of the weight loss medications and also had type 2 diabetes were excluded. They did not include patients who had undergone gastric banding because it has become less popular.

For the weight loss medication group, they found 117,730 patients who met their criteria. For the surgery group, 43,050 patients met the criteria.

In analyzing the colorectal cancer rates, they included only diagnoses of malignant neoplasms made 2 years after the interventions.

They compared these patients to a control group of 52,540 people matched in age, with a body mass index (BMI) greater than 30 kg/m² who did not undergo weight loss surgery or take weight loss medication.

Among the 9,370 patients who underwent Roux-en-Y gastrojejunostomy, 50 were diagnosed with colorectal cancer and 400 had benign polyps. Their rate of colorectal cancer was not statistically different from people who didn’t have surgery (OR, 1.09; 95% CI, 0.82-1.43). The rate of benign polyps after Roux-en-Y gastrojejunostomy was greater (OR, 1.72; 95% CI, 1.55-1.90).

On the other hand, among the 33,680 patients who underwent sleeve gastrectomy, 50 were diagnosed with colorectal cancer, a lower rate than in the population who didn’t have surgery (OR, 0.30; 95% CI, 0.22-0.39). Their risk of benign polyps was also reduced (OR, 0.45; 95% CI, 0.40-0.50).

All of the medications were significantly associated with a lower risk of colorectal cancer, except orlistat (OR, 0.94; 95% CI, 0.72-1.25).

The finding on Roux-en-Y gastrojejunostomy agreed with studies from England and Nordic countries showing double the risk of colorectal cancer in those patients but conflicted with a French study showing decreased risk, Dr. Shwani said.

While the study doesn’t establish a reason why Roux-en-Y gastrojejunostomy was less beneficial, other researchers have associated the procedure with biomarkers of inflammation, Dr. Shwani said. “It’s inconsistent, and I don’t think we have a clear answer why.”

As a retrospective analysis, the study could not establish a cause-and-effect relationship between surgery or medication and cancer, or adjust for such factors as diet, exercise, or genes, he acknowledged.

Colorectal cancer is just one outcome to consider when deciding whether to undergo weight loss surgery or take weight loss drugs, said session moderator Mohammad Yaghoobi, MD, an associate professor of medicine at McMaster University, Hamilton, Ont.

“The most important outcome that should be investigated is the survival of the patients after obesity surgery,” he told this news organization. “The second would be the quality of life of those patients. Colon cancer is preventable if you are having regular colonoscopies.”

Other studies have not shown much difference between patients who have weight loss surgery and those who don’t, he added.

The study was funded by Merck. Dr. Desai and Dr. Shwani have reported receiving grant funding from Merck. Dr. Yaghoobi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Four years after new infant feeding guidelines were issued to prevent allergies to peanut and other foods, 70% of surveyed parents and caregivers in the United States said they had never heard about the new recommendation.

Food allergies in developed countries have doubled in each of the last decades and now affect 7.6% of U.S. children. About 1 in 50 are allergic to peanut. Data from the 2015 LEAP study and other research has convincingly shown that early, sustained feeding of peanuts, eggs, and other allergens can prevent babies from developing allergies to these foods.

Based on those findings, the National Institute of Allergy and Infectious Diseases (NIAID) updated its feeding guidelines in 2017, urging parents to introduce these foods to babies around 4-6 months of age rather than wait until 1-3 years of age, as previously recommended. The American Academy of Pediatrics approved those guidelines too, and in 2019 changed its own feeding recommendations.

To assess awareness of this new guidance and to what extent these recommendations are being translated into clinical practice, researchers surveyed a demographically representative U.S. sample of 3,062 parents and caregivers with children between 7 months and 3½ years old. The survey was conducted in English and Spanish over the web or by phone.

More than one-third reported that their child’s primary care physician never discussed when to start feeding peanut-containing foods. And among those whose doctors did offer guidance, fewer than 1 in 4 specifically recommended introducing peanut by 6 months of age.

These data show that “despite strong evidence that early introduction of peanut within the first year of life can prevent the development of peanut allergy, this evidence is simply not making its way to parents of infants,” said Christopher Warren, PhD, assistant professor of preventive medicine at the Northwestern University Feinberg School of Medicine, Chicago. Dr. Warren led the study and presented the findings on a poster at this year’s American College of Allergy, Asthma & Immunology annual meeting in New Orleans.

In addition to caregivers, the Northwestern team surveyed U.S. allergists and pediatricians about the new feeding guidelines. Uptake was fairly good among allergists, with 65% reporting full implementation. On the other hand, while most pediatricians seemed familiar with the 2017 recommendations, fewer than one-third said they were following them.

“What’s unique about this challenge is that it’s not just a guideline change – it’s a guideline reversal,” said Wendy Sue Swanson, MD, chief medical officer for SpoonfulONE, a company that makes mix-ins and other products for multi-allergen feeding. After telling families for years to avoid these allergens in early life because food allergies were rising, “it’s harder advice to say, actually, we were wrong. Not only should you not wait, you should get peanut in while your baby’s immune system has this critical moment to learn and develop, and you should keep getting it in,” Dr. Swanson said in an interview.

Making matters worse, pediatricians are time pressed. Typically, at 4- to 6-month-old well-check visits, “they’re talking about sleep and development and feeding and milestones,” said Ruchi Gupta, MD, MPH, professor of pediatrics and medicine at Northwestern Feinberg, who led the allergist and pediatrician analyses.

Another challenge: Guidelines differ depending on the child’s level of food allergy risk, so it’s hard to explain them clearly and quickly. Babies at highest risk – as judged by having severe eczema, egg allergy, or both – should get peanut IgE blood testing and, if negative, begin regular consumption of peanut by 4-6 months. Intermediate-risk babies who have mild-to-moderate eczema are recommended to start peanut-containing foods by 6 months. And for low-risk babies with no eczema or known food allergies, the guidance is simply to introduce peanut-containing foods “in accordance with family preferences and cultural practices.”

As for pediatricians who say it’s hard to distinguish mild-to-moderate from severe eczema, “any eczema puts you at some risk,” Dr. Gupta told this news organization. “If they’ve required steroid creams to clear up their skin, or if you look at their skin, and you think it’s severe, don’t hesitate. Go ahead and draw the IgE and send them to an allergist.”

Australia, which has the highest rate of confirmed food allergy, has had more success implementing early feeding guidelines, said Dr. Swanson. Unlike the United States’ tiered approach, she said, they “had a national guideline that very crisply, years ago, told parents what to do.” Australia also has nurse educators that follow up with new moms to make sure they understand and follow the recommendations.

Dr. Gupta receives research support from the National Institutes of Health, Food Allergy Research and Education, the Melchiorre Family Foundation, the Sunshine Charitable Foundation, the Walder Foundation, the UnitedHealth Group, Thermo Fisher Scientific, and Genentech. She serves as a medical consultant/advisor for Genentech, Novartis, and Food Allergy Research and Education. Dr. Swanson serves as chief medical officer for SpoonfulONE.

A version of this article first appeared on Medscape.com.

Four years after new infant feeding guidelines were issued to prevent allergies to peanut and other foods, 70% of surveyed parents and caregivers in the United States said they had never heard about the new recommendation.

Food allergies in developed countries have doubled in each of the last decades and now affect 7.6% of U.S. children. About 1 in 50 are allergic to peanut. Data from the 2015 LEAP study and other research has convincingly shown that early, sustained feeding of peanuts, eggs, and other allergens can prevent babies from developing allergies to these foods.

Based on those findings, the National Institute of Allergy and Infectious Diseases (NIAID) updated its feeding guidelines in 2017, urging parents to introduce these foods to babies around 4-6 months of age rather than wait until 1-3 years of age, as previously recommended. The American Academy of Pediatrics approved those guidelines too, and in 2019 changed its own feeding recommendations.

To assess awareness of this new guidance and to what extent these recommendations are being translated into clinical practice, researchers surveyed a demographically representative U.S. sample of 3,062 parents and caregivers with children between 7 months and 3½ years old. The survey was conducted in English and Spanish over the web or by phone.

More than one-third reported that their child’s primary care physician never discussed when to start feeding peanut-containing foods. And among those whose doctors did offer guidance, fewer than 1 in 4 specifically recommended introducing peanut by 6 months of age.

These data show that “despite strong evidence that early introduction of peanut within the first year of life can prevent the development of peanut allergy, this evidence is simply not making its way to parents of infants,” said Christopher Warren, PhD, assistant professor of preventive medicine at the Northwestern University Feinberg School of Medicine, Chicago. Dr. Warren led the study and presented the findings on a poster at this year’s American College of Allergy, Asthma & Immunology annual meeting in New Orleans.

In addition to caregivers, the Northwestern team surveyed U.S. allergists and pediatricians about the new feeding guidelines. Uptake was fairly good among allergists, with 65% reporting full implementation. On the other hand, while most pediatricians seemed familiar with the 2017 recommendations, fewer than one-third said they were following them.

“What’s unique about this challenge is that it’s not just a guideline change – it’s a guideline reversal,” said Wendy Sue Swanson, MD, chief medical officer for SpoonfulONE, a company that makes mix-ins and other products for multi-allergen feeding. After telling families for years to avoid these allergens in early life because food allergies were rising, “it’s harder advice to say, actually, we were wrong. Not only should you not wait, you should get peanut in while your baby’s immune system has this critical moment to learn and develop, and you should keep getting it in,” Dr. Swanson said in an interview.

Making matters worse, pediatricians are time pressed. Typically, at 4- to 6-month-old well-check visits, “they’re talking about sleep and development and feeding and milestones,” said Ruchi Gupta, MD, MPH, professor of pediatrics and medicine at Northwestern Feinberg, who led the allergist and pediatrician analyses.

Another challenge: Guidelines differ depending on the child’s level of food allergy risk, so it’s hard to explain them clearly and quickly. Babies at highest risk – as judged by having severe eczema, egg allergy, or both – should get peanut IgE blood testing and, if negative, begin regular consumption of peanut by 4-6 months. Intermediate-risk babies who have mild-to-moderate eczema are recommended to start peanut-containing foods by 6 months. And for low-risk babies with no eczema or known food allergies, the guidance is simply to introduce peanut-containing foods “in accordance with family preferences and cultural practices.”

As for pediatricians who say it’s hard to distinguish mild-to-moderate from severe eczema, “any eczema puts you at some risk,” Dr. Gupta told this news organization. “If they’ve required steroid creams to clear up their skin, or if you look at their skin, and you think it’s severe, don’t hesitate. Go ahead and draw the IgE and send them to an allergist.”

Australia, which has the highest rate of confirmed food allergy, has had more success implementing early feeding guidelines, said Dr. Swanson. Unlike the United States’ tiered approach, she said, they “had a national guideline that very crisply, years ago, told parents what to do.” Australia also has nurse educators that follow up with new moms to make sure they understand and follow the recommendations.

Dr. Gupta receives research support from the National Institutes of Health, Food Allergy Research and Education, the Melchiorre Family Foundation, the Sunshine Charitable Foundation, the Walder Foundation, the UnitedHealth Group, Thermo Fisher Scientific, and Genentech. She serves as a medical consultant/advisor for Genentech, Novartis, and Food Allergy Research and Education. Dr. Swanson serves as chief medical officer for SpoonfulONE.

A version of this article first appeared on Medscape.com.

Four years after new infant feeding guidelines were issued to prevent allergies to peanut and other foods, 70% of surveyed parents and caregivers in the United States said they had never heard about the new recommendation.

Food allergies in developed countries have doubled in each of the last decades and now affect 7.6% of U.S. children. About 1 in 50 are allergic to peanut. Data from the 2015 LEAP study and other research has convincingly shown that early, sustained feeding of peanuts, eggs, and other allergens can prevent babies from developing allergies to these foods.

Based on those findings, the National Institute of Allergy and Infectious Diseases (NIAID) updated its feeding guidelines in 2017, urging parents to introduce these foods to babies around 4-6 months of age rather than wait until 1-3 years of age, as previously recommended. The American Academy of Pediatrics approved those guidelines too, and in 2019 changed its own feeding recommendations.

To assess awareness of this new guidance and to what extent these recommendations are being translated into clinical practice, researchers surveyed a demographically representative U.S. sample of 3,062 parents and caregivers with children between 7 months and 3½ years old. The survey was conducted in English and Spanish over the web or by phone.

More than one-third reported that their child’s primary care physician never discussed when to start feeding peanut-containing foods. And among those whose doctors did offer guidance, fewer than 1 in 4 specifically recommended introducing peanut by 6 months of age.

These data show that “despite strong evidence that early introduction of peanut within the first year of life can prevent the development of peanut allergy, this evidence is simply not making its way to parents of infants,” said Christopher Warren, PhD, assistant professor of preventive medicine at the Northwestern University Feinberg School of Medicine, Chicago. Dr. Warren led the study and presented the findings on a poster at this year’s American College of Allergy, Asthma & Immunology annual meeting in New Orleans.

In addition to caregivers, the Northwestern team surveyed U.S. allergists and pediatricians about the new feeding guidelines. Uptake was fairly good among allergists, with 65% reporting full implementation. On the other hand, while most pediatricians seemed familiar with the 2017 recommendations, fewer than one-third said they were following them.

“What’s unique about this challenge is that it’s not just a guideline change – it’s a guideline reversal,” said Wendy Sue Swanson, MD, chief medical officer for SpoonfulONE, a company that makes mix-ins and other products for multi-allergen feeding. After telling families for years to avoid these allergens in early life because food allergies were rising, “it’s harder advice to say, actually, we were wrong. Not only should you not wait, you should get peanut in while your baby’s immune system has this critical moment to learn and develop, and you should keep getting it in,” Dr. Swanson said in an interview.

Making matters worse, pediatricians are time pressed. Typically, at 4- to 6-month-old well-check visits, “they’re talking about sleep and development and feeding and milestones,” said Ruchi Gupta, MD, MPH, professor of pediatrics and medicine at Northwestern Feinberg, who led the allergist and pediatrician analyses.

Another challenge: Guidelines differ depending on the child’s level of food allergy risk, so it’s hard to explain them clearly and quickly. Babies at highest risk – as judged by having severe eczema, egg allergy, or both – should get peanut IgE blood testing and, if negative, begin regular consumption of peanut by 4-6 months. Intermediate-risk babies who have mild-to-moderate eczema are recommended to start peanut-containing foods by 6 months. And for low-risk babies with no eczema or known food allergies, the guidance is simply to introduce peanut-containing foods “in accordance with family preferences and cultural practices.”

As for pediatricians who say it’s hard to distinguish mild-to-moderate from severe eczema, “any eczema puts you at some risk,” Dr. Gupta told this news organization. “If they’ve required steroid creams to clear up their skin, or if you look at their skin, and you think it’s severe, don’t hesitate. Go ahead and draw the IgE and send them to an allergist.”

Australia, which has the highest rate of confirmed food allergy, has had more success implementing early feeding guidelines, said Dr. Swanson. Unlike the United States’ tiered approach, she said, they “had a national guideline that very crisply, years ago, told parents what to do.” Australia also has nurse educators that follow up with new moms to make sure they understand and follow the recommendations.

Dr. Gupta receives research support from the National Institutes of Health, Food Allergy Research and Education, the Melchiorre Family Foundation, the Sunshine Charitable Foundation, the Walder Foundation, the UnitedHealth Group, Thermo Fisher Scientific, and Genentech. She serves as a medical consultant/advisor for Genentech, Novartis, and Food Allergy Research and Education. Dr. Swanson serves as chief medical officer for SpoonfulONE.

A version of this article first appeared on Medscape.com.

Percutaneous coronary intervention (PCI) guided by quantitative flow ratio (QFR) lesion assessment provided better clinical outcomes than visual assessment of the angiogram in the sham-controlled FAVOR III China study.

PCI success rates were about 95% with both strategies; however, QFR guidance was associated with fewer major adverse cardiac events (MACE) at 1 year, use of fewer stents, less contrast medium exposure, and fewer procedural complications.

“The simplicity and safety of QFR compared with wire-based physiologic measurements should facilitate the adoption of physiologic lesion assessment into routine clinical practice,” co–primary investigator Bo Xu, MBBS, Fuwai Hospital, Beijing, said.

The results were presented at Transcatheter Cardiovascular Therapeutics (TCT) 2021, held online and in Orlando, and published simultaneously in The Lancet.

Although pressure wire–based physiological assessment with fractional flow reserve (FFR) and instantaneous wave-free ratio (IFR) more accurately identify flow-limiting lesions than standard angiography and have been shown to improve outcomes after PCI, the authors note that it’s underused in practice because of prolonged procedural time, potential pressure wire complications, and side effects from hyperemic agents.

QFR, however, is derived from 3-dimensional coronary artery reconstruction and computational fluid dynamics from the angiogram, so FFR can be estimated without the need for a pressure wire or hyperemic drugs.

FAVOR III China was designed statistically for superiority and enrolled 3,847 patients with stable or unstable angina or a myocardial infarction (MI) at least 72 hours before screening if they had at least one coronary lesion with a diameter stenosis of 50% to 90% and a reference vessel diameter of at least 2.5 mm. The intention-to-treat population included 3,825 patients (mean age, 62.7 years; 29.4% female).

In the QFR group, QFR was measured in all coronary arteries with a lesion but PCI performed only in lesions with a QFR of at least 0.80 or diameter stenosis greater than 90%. Two angiographic imaging runs were taken and the data transmitted to the AngioPlus system (Pulse Medical Imaging Technology) by a local network of sites for QFR calculation.

PCI in the angiography-guided group was performed on the basis of visual angiographic assessment only. A 10-minute delay was used in both groups to preserve masking.

The primary endpoint of 1-year MACE, a composite of all-cause death, MI, or ischemia-driven revascularization, occurred in 5.8% of the QFR-guided group and 8.8% of the angiography-guided group (hazard ratio, 0.65; 95% CI, 0.51-0.83; P = .0004).

The curves separated within 48 hours, driven largely by fewer MIs (3.4% vs. 5.7%; P = .0008) and ischemia-driven revascularizations (2.0% vs. 3.1%; P = .0078) in the QFR-guided group, Mr. Xu said.

The major secondary endpoint of MACE excluding periprocedural MI occurred in 3.1% of QFR-guided patients and 4.8% of angiography-guided patients (HR, 0.64; 95% CI, 0.46-0.89; P = .0073).

The prerandomization revascularization plan was changed in 23.3% of patients with QFR and only 6.2% in the angiography group (P < .0001), mainly due to deferral of treatment of at least one vessel originally planned for PCI (19.6% vs. 5.2%; P < .0001).

“I think in the next guideline they will change the recommendation, not just to include FFR and IFR, but also to include QFR,” Giuseppe Tarantini, MD, PhD, University of Padua, Italy, said during a press briefing on the study.

“This is a milestone in our community, not only because it is easier to use compared to the other lesion-specific indexes like FFR, IFR, but also for the need to expand the use of physiology in the setting of interventional cardiology,” he added.

In an accompanying commentary, Robert A. Byrne, MBBCh, PhD, and Laurna McGovern, MBBCh, both from the Cardiovascular Research Institute Dublin, say the results are “relevant for cardiovascular disease researchers and clinicians and an important step forward for the field of angiography-derived flow measurements for guidance of PCI.”

They point out, however, that the control group did not receive pressure wire–guided PCI, which is the standard of care in contemporary practice and out of step with clinical practice guidelines, thus limiting external validity.

They also note that experiences to date suggest that up to 20% of patients may be unsuitable for the algorithm analysis because of coronary anatomy, presence of overlapping vessels, and insufficient image quality.

Commenting for this news organization, David E. Kandzari, MD, chief of the Piedmont Heart Institute, Atlanta, said “the technology isn’t readily available in catheterization labs today. Could it be assimilated into the cath labs at one point in the near term? I think absolutely, and that would be a welcome addition to expedite the procedure itself.”

Nevertheless, he said the results “need to be externally validated too, with what is the gold standard today of FFR in a larger experience.”

Session moderator Gregg W. Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said FAVOR III China has “advanced our knowledge” but pointed out that the ongoing randomized FAVOR III Europe Japan study is directly comparing QFR with invasive pressure-wire assessed FFR. The estimated primary completion date for that study is Dec. 31.

The study was supported by grants from the Beijing Municipal Science and Technology Commission, Chinese Academy of Medical Sciences, and the National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital. Dr. Byrne reported institutional research or educational funding from Abbott Vascular, Biosensors, Biotronik, and Boston Scientific. Ms. McGovern has disclosed no relevant financial relationships. Dr. Kandzari reported minor consulting honoraria from the interventional device industry and institutional research grant support.

A version of this article first appeared on Medscape.com.

Percutaneous coronary intervention (PCI) guided by quantitative flow ratio (QFR) lesion assessment provided better clinical outcomes than visual assessment of the angiogram in the sham-controlled FAVOR III China study.

PCI success rates were about 95% with both strategies; however, QFR guidance was associated with fewer major adverse cardiac events (MACE) at 1 year, use of fewer stents, less contrast medium exposure, and fewer procedural complications.

“The simplicity and safety of QFR compared with wire-based physiologic measurements should facilitate the adoption of physiologic lesion assessment into routine clinical practice,” co–primary investigator Bo Xu, MBBS, Fuwai Hospital, Beijing, said.

The results were presented at Transcatheter Cardiovascular Therapeutics (TCT) 2021, held online and in Orlando, and published simultaneously in The Lancet.

Although pressure wire–based physiological assessment with fractional flow reserve (FFR) and instantaneous wave-free ratio (IFR) more accurately identify flow-limiting lesions than standard angiography and have been shown to improve outcomes after PCI, the authors note that it’s underused in practice because of prolonged procedural time, potential pressure wire complications, and side effects from hyperemic agents.

QFR, however, is derived from 3-dimensional coronary artery reconstruction and computational fluid dynamics from the angiogram, so FFR can be estimated without the need for a pressure wire or hyperemic drugs.

FAVOR III China was designed statistically for superiority and enrolled 3,847 patients with stable or unstable angina or a myocardial infarction (MI) at least 72 hours before screening if they had at least one coronary lesion with a diameter stenosis of 50% to 90% and a reference vessel diameter of at least 2.5 mm. The intention-to-treat population included 3,825 patients (mean age, 62.7 years; 29.4% female).

In the QFR group, QFR was measured in all coronary arteries with a lesion but PCI performed only in lesions with a QFR of at least 0.80 or diameter stenosis greater than 90%. Two angiographic imaging runs were taken and the data transmitted to the AngioPlus system (Pulse Medical Imaging Technology) by a local network of sites for QFR calculation.

PCI in the angiography-guided group was performed on the basis of visual angiographic assessment only. A 10-minute delay was used in both groups to preserve masking.

The primary endpoint of 1-year MACE, a composite of all-cause death, MI, or ischemia-driven revascularization, occurred in 5.8% of the QFR-guided group and 8.8% of the angiography-guided group (hazard ratio, 0.65; 95% CI, 0.51-0.83; P = .0004).

The curves separated within 48 hours, driven largely by fewer MIs (3.4% vs. 5.7%; P = .0008) and ischemia-driven revascularizations (2.0% vs. 3.1%; P = .0078) in the QFR-guided group, Mr. Xu said.

The major secondary endpoint of MACE excluding periprocedural MI occurred in 3.1% of QFR-guided patients and 4.8% of angiography-guided patients (HR, 0.64; 95% CI, 0.46-0.89; P = .0073).

The prerandomization revascularization plan was changed in 23.3% of patients with QFR and only 6.2% in the angiography group (P < .0001), mainly due to deferral of treatment of at least one vessel originally planned for PCI (19.6% vs. 5.2%; P < .0001).

“I think in the next guideline they will change the recommendation, not just to include FFR and IFR, but also to include QFR,” Giuseppe Tarantini, MD, PhD, University of Padua, Italy, said during a press briefing on the study.

“This is a milestone in our community, not only because it is easier to use compared to the other lesion-specific indexes like FFR, IFR, but also for the need to expand the use of physiology in the setting of interventional cardiology,” he added.

In an accompanying commentary, Robert A. Byrne, MBBCh, PhD, and Laurna McGovern, MBBCh, both from the Cardiovascular Research Institute Dublin, say the results are “relevant for cardiovascular disease researchers and clinicians and an important step forward for the field of angiography-derived flow measurements for guidance of PCI.”

They point out, however, that the control group did not receive pressure wire–guided PCI, which is the standard of care in contemporary practice and out of step with clinical practice guidelines, thus limiting external validity.

They also note that experiences to date suggest that up to 20% of patients may be unsuitable for the algorithm analysis because of coronary anatomy, presence of overlapping vessels, and insufficient image quality.

Commenting for this news organization, David E. Kandzari, MD, chief of the Piedmont Heart Institute, Atlanta, said “the technology isn’t readily available in catheterization labs today. Could it be assimilated into the cath labs at one point in the near term? I think absolutely, and that would be a welcome addition to expedite the procedure itself.”

Nevertheless, he said the results “need to be externally validated too, with what is the gold standard today of FFR in a larger experience.”

Session moderator Gregg W. Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said FAVOR III China has “advanced our knowledge” but pointed out that the ongoing randomized FAVOR III Europe Japan study is directly comparing QFR with invasive pressure-wire assessed FFR. The estimated primary completion date for that study is Dec. 31.

The study was supported by grants from the Beijing Municipal Science and Technology Commission, Chinese Academy of Medical Sciences, and the National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital. Dr. Byrne reported institutional research or educational funding from Abbott Vascular, Biosensors, Biotronik, and Boston Scientific. Ms. McGovern has disclosed no relevant financial relationships. Dr. Kandzari reported minor consulting honoraria from the interventional device industry and institutional research grant support.

A version of this article first appeared on Medscape.com.

Percutaneous coronary intervention (PCI) guided by quantitative flow ratio (QFR) lesion assessment provided better clinical outcomes than visual assessment of the angiogram in the sham-controlled FAVOR III China study.

PCI success rates were about 95% with both strategies; however, QFR guidance was associated with fewer major adverse cardiac events (MACE) at 1 year, use of fewer stents, less contrast medium exposure, and fewer procedural complications.

“The simplicity and safety of QFR compared with wire-based physiologic measurements should facilitate the adoption of physiologic lesion assessment into routine clinical practice,” co–primary investigator Bo Xu, MBBS, Fuwai Hospital, Beijing, said.

The results were presented at Transcatheter Cardiovascular Therapeutics (TCT) 2021, held online and in Orlando, and published simultaneously in The Lancet.

Although pressure wire–based physiological assessment with fractional flow reserve (FFR) and instantaneous wave-free ratio (IFR) more accurately identify flow-limiting lesions than standard angiography and have been shown to improve outcomes after PCI, the authors note that it’s underused in practice because of prolonged procedural time, potential pressure wire complications, and side effects from hyperemic agents.

QFR, however, is derived from 3-dimensional coronary artery reconstruction and computational fluid dynamics from the angiogram, so FFR can be estimated without the need for a pressure wire or hyperemic drugs.

FAVOR III China was designed statistically for superiority and enrolled 3,847 patients with stable or unstable angina or a myocardial infarction (MI) at least 72 hours before screening if they had at least one coronary lesion with a diameter stenosis of 50% to 90% and a reference vessel diameter of at least 2.5 mm. The intention-to-treat population included 3,825 patients (mean age, 62.7 years; 29.4% female).

In the QFR group, QFR was measured in all coronary arteries with a lesion but PCI performed only in lesions with a QFR of at least 0.80 or diameter stenosis greater than 90%. Two angiographic imaging runs were taken and the data transmitted to the AngioPlus system (Pulse Medical Imaging Technology) by a local network of sites for QFR calculation.

PCI in the angiography-guided group was performed on the basis of visual angiographic assessment only. A 10-minute delay was used in both groups to preserve masking.

The primary endpoint of 1-year MACE, a composite of all-cause death, MI, or ischemia-driven revascularization, occurred in 5.8% of the QFR-guided group and 8.8% of the angiography-guided group (hazard ratio, 0.65; 95% CI, 0.51-0.83; P = .0004).

The curves separated within 48 hours, driven largely by fewer MIs (3.4% vs. 5.7%; P = .0008) and ischemia-driven revascularizations (2.0% vs. 3.1%; P = .0078) in the QFR-guided group, Mr. Xu said.

The major secondary endpoint of MACE excluding periprocedural MI occurred in 3.1% of QFR-guided patients and 4.8% of angiography-guided patients (HR, 0.64; 95% CI, 0.46-0.89; P = .0073).

The prerandomization revascularization plan was changed in 23.3% of patients with QFR and only 6.2% in the angiography group (P < .0001), mainly due to deferral of treatment of at least one vessel originally planned for PCI (19.6% vs. 5.2%; P < .0001).

“I think in the next guideline they will change the recommendation, not just to include FFR and IFR, but also to include QFR,” Giuseppe Tarantini, MD, PhD, University of Padua, Italy, said during a press briefing on the study.

“This is a milestone in our community, not only because it is easier to use compared to the other lesion-specific indexes like FFR, IFR, but also for the need to expand the use of physiology in the setting of interventional cardiology,” he added.

In an accompanying commentary, Robert A. Byrne, MBBCh, PhD, and Laurna McGovern, MBBCh, both from the Cardiovascular Research Institute Dublin, say the results are “relevant for cardiovascular disease researchers and clinicians and an important step forward for the field of angiography-derived flow measurements for guidance of PCI.”

They point out, however, that the control group did not receive pressure wire–guided PCI, which is the standard of care in contemporary practice and out of step with clinical practice guidelines, thus limiting external validity.

They also note that experiences to date suggest that up to 20% of patients may be unsuitable for the algorithm analysis because of coronary anatomy, presence of overlapping vessels, and insufficient image quality.

Commenting for this news organization, David E. Kandzari, MD, chief of the Piedmont Heart Institute, Atlanta, said “the technology isn’t readily available in catheterization labs today. Could it be assimilated into the cath labs at one point in the near term? I think absolutely, and that would be a welcome addition to expedite the procedure itself.”

Nevertheless, he said the results “need to be externally validated too, with what is the gold standard today of FFR in a larger experience.”

Session moderator Gregg W. Stone, MD, Icahn School of Medicine at Mount Sinai, New York, said FAVOR III China has “advanced our knowledge” but pointed out that the ongoing randomized FAVOR III Europe Japan study is directly comparing QFR with invasive pressure-wire assessed FFR. The estimated primary completion date for that study is Dec. 31.

The study was supported by grants from the Beijing Municipal Science and Technology Commission, Chinese Academy of Medical Sciences, and the National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital. Dr. Byrne reported institutional research or educational funding from Abbott Vascular, Biosensors, Biotronik, and Boston Scientific. Ms. McGovern has disclosed no relevant financial relationships. Dr. Kandzari reported minor consulting honoraria from the interventional device industry and institutional research grant support.

A version of this article first appeared on Medscape.com.

Tolerance doesn’t seem to be the reason why adolescents and young adults don’t do as well as children on intensive treatment protocols for acute lymphocytic leukemia (ALL), according to a recent Australian investigation.

The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney

It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.

To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).

Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).

About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.

The investigators also found that a body mass index at or above 30 kg/m² and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.

They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”

Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.

The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.

[email protected]

Tolerance doesn’t seem to be the reason why adolescents and young adults don’t do as well as children on intensive treatment protocols for acute lymphocytic leukemia (ALL), according to a recent Australian investigation.

The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney

It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.

To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).

Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).

About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.

The investigators also found that a body mass index at or above 30 kg/m² and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.

They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”

Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.

The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.

[email protected]

Tolerance doesn’t seem to be the reason why adolescents and young adults don’t do as well as children on intensive treatment protocols for acute lymphocytic leukemia (ALL), according to a recent Australian investigation.

The study team found that “an intensive pediatric ALL induction protocol can be delivered in an AYA [adolescent and young adult] cohort in a similar time frame to a pediatric population, suggesting that the inferior outcomes seen in AYA patients are more likely related to the biology of AYA ALL rather than intolerance of more intensive therapy,” said investigators led by Matthew Greenwood, MBBS, director of the stem cell transplant at the Royal North Shore Hospital, outside of Sydney

It’s been a long-standing question why intensive ALL regimens, which can be curative in children, don’t work as well in adolescents and young adults.

To see if tolerability and lack of adherence were issues, the investigators compared the treatment time lines of 82 AYA subjects with a median age of 22 years to the time lines of 608 children aged 1-17 years who were treated with the same intensive regimen (the ANZCHOG Study 8 protocol).

Induction/consolidation was equally deliverable in both populations. In the AYA group, 41.5% of subjects started the next phase of treatment – protocol M or high-risk (HR) therapy based on minimal residual disease (MRD) response to initial treatment – by day 94 versus 39.3% in the previous pediatric study (P = 0.77). The median time to protocol M/HR treatment was 96 days in AYAs and 98 days in children (P = .80).

About 52% of AYA subjects proceeded to HR therapy following induction/consolidation, versus just 10.7% in the pediatric study.

The investigators also found that a body mass index at or above 30 kg/m² and the presence of MRD were both associated with worse disease-free and overall survival. “By addressing the factors predicting poorer outcomes from this study, we hope to significantly improve the outcomes for patients,” they said.

They noted that their work is the first to “report of the safety and efficacy of an MRD-stratified approach utilizing [Berlin-Frankfurt-Munich] HR therapy in an AYA cohort and show that this is a moderately efficacious strategy in patients who would otherwise be considered at high risk of relapse and death.”

Over a median follow-up of 44 months, estimated 3-year disease-free survival was 72.8% and estimated 3-year overall survival 74.9% in the AYA population.

The work was funded by the Australasian Leukaemia and Lymphoma Group. Several investigators had industry ties, including Dr. Greenwood, an adviser and/or researcher for Amgen, Pfizer, Servier, and Jazz.

[email protected]

More than half of people living with HIV and suppressed viral loads nonetheless had imaging-confirmed coronary artery disease – and despite longtime use of HIV drugs that have been associated with cardiovascular trouble, none of those drugs were implicated in disease risk in this study.

“Traditional risk factors and duration of HIV infection were associated with severe coronary artery disease,” said Andreas Knudsen, MD, PhD, an infectious disease provider at Copenhagen University Hospital, Hvidovre, Denmark, during his presentation at the 18th European AIDS Conference. “When we adjusted for time since diagnosis of HIV, none of the drugs remained associated with the severity of coronary artery disease.”

Notably, that included abacavir, which was found in another EACS presentation and in past research to be associated with increased rates of heart attacks. Abacavir is sold individually as a generic as well as a component of Epzicom (abacavir/lamivudine) and the single-drug regimen Triumeq (dolutegravir/abacavir/lamivudine).

The Copenhagen Comorbidity in HIV Infection (COCOMO) study enrolled 1,099 people living with HIV in the Danish capital beginning in 2015, and 705 of them had angiographies via CT available to include in the results. The participants were almost all male (89%), at a healthy weight (BMI of 25), and 96% had undetectable viral loads.

Large minorities of participants also had traditional risk factors for coronary artery disease. More than one in four smoked, one in five had high cholesterol, and 42% had high blood pressure. In addition, many had used drugs that have been associated with cardiovascular trouble, including abacavir, which 26% of participants had used; indinavir, used by 17% of participants; zidovudine/AZT, used by 47%; and didanosine, which 14% used. (While abacavir is still in use, the other three drugs are considered legacy drugs and are not in current use.)

In addition, nearly one in three (29%) were currently using a protease inhibitor, which has been associated with heart failure.

When the investigators looked at participants’ CTs, they found that, by the Coronary Artery Disease-Reporting and Data Systems (CAD-RAMS) scoring system, close to half (46%) had clear arteries with no signs of coronary artery disease. But that also meant that 54% had some blockage or stiffening of the arteries. The good news is that 27% of those people had minimal or mild coronary artery disease.

But a full 17% had confirmed obstructive coronary artery disease, and another 1 in 10 participants had the highest level of blockages. When they broke the data down by traditional and HIV medication–related risk factors for coronary artery disease, they found something interesting. Although obesity was associated with the presence of atherosclerosis, it wasn’t associated with severe disease. But diabetes was the reverse of that: It wasn’t associated with the presence of the disease, but it was associated with more severe disease.

And when they looked at abacavir, they found no relationship between the drug and atherosclerosis. “Abacavir was not associated with the presence of atherosclerosis and was also not associated with severity of disease,” said Dr. Knudsen.

Although past use of AZT, indinavir, and didanosine were associated with severity of atherosclerosis, that association went away when Dr. Knudsen and team adjusted the findings for time since diagnosis. What was associated atherosclerosis was length of time living with HIV itself. For every 5 years a person lived with HIV, the study found the risk of having any atherosclerosis increased 20% and severity increased 23%. In addition, being a man was associated with a nearly 2.5-times increased risk of having any atherosclerosis and a 96% increased chance of having more severe atherosclerosis. Having diabetes was associated with a nearly threefold increased risk of atherosclerosis, as was every additional decade of life for a person who was living with HIV.

The findings confirm the baseline data of the REPRIEVE trial, which recently released data showing similarly high rates of atherosclerotic plaque in people living with HIV who didn’t register as “at risk” for cardiovascular disease using traditional scoring methods.

“It’s important in that it’s a huge study that’s confirmatory [of] what we know, which is that there are high levels of subclinical coronary artery disease in people living with HIV,” said Steven Grinspoon, MD, professor at Harvard Medical School in Boston, Massachusetts, and principal investigator of REPRIEVE.

As for the lack of association between abacavir and cardiovascular risk, he said he’s taking the findings with a grain of salt.

“It’s hard to make a lot out of that,” he said. “It’s hard to know in a cross-sectional study. People put people on different things.”

In Spain, where Jose Ignacio Bernardino, MD, treats people living with HIV at La Paz University Hospital in Madrid, abacavir is mostly a moot point, as clinicians have long since moved away from maintaining people living with HIV on any abacavir-containing regimens. What’s more important in the study, he told this news organization, is that “worrisome” high level of risk. REPRIEVE will test whether statins can reduce heart disease events in people living with HIV. But in the meantime, he said the take-away for clinicians from the study is the primary importance of traditional cardiovascular risk factors.

“We have to acknowledge that the major cardiovascular risk factor is age,” he said. “When patients are approaching their 50s, I usually try to stress a lot about cardiovascular risk factors in general. I stress healthy lifestyle – get physical exercise, hypertension, glucose, lipids – in every single patient.”

Dr. Knudsen and Dr. Bernardino have disclosed no relevant financial relationships. Dr. Grinspoon reports receiving personal and consulting fees from Theratechnologies and ViiV Healthcare.

A version of this article first appeared on Medscape.com.

More than half of people living with HIV and suppressed viral loads nonetheless had imaging-confirmed coronary artery disease – and despite longtime use of HIV drugs that have been associated with cardiovascular trouble, none of those drugs were implicated in disease risk in this study.

“Traditional risk factors and duration of HIV infection were associated with severe coronary artery disease,” said Andreas Knudsen, MD, PhD, an infectious disease provider at Copenhagen University Hospital, Hvidovre, Denmark, during his presentation at the 18th European AIDS Conference. “When we adjusted for time since diagnosis of HIV, none of the drugs remained associated with the severity of coronary artery disease.”

Notably, that included abacavir, which was found in another EACS presentation and in past research to be associated with increased rates of heart attacks. Abacavir is sold individually as a generic as well as a component of Epzicom (abacavir/lamivudine) and the single-drug regimen Triumeq (dolutegravir/abacavir/lamivudine).

The Copenhagen Comorbidity in HIV Infection (COCOMO) study enrolled 1,099 people living with HIV in the Danish capital beginning in 2015, and 705 of them had angiographies via CT available to include in the results. The participants were almost all male (89%), at a healthy weight (BMI of 25), and 96% had undetectable viral loads.

Large minorities of participants also had traditional risk factors for coronary artery disease. More than one in four smoked, one in five had high cholesterol, and 42% had high blood pressure. In addition, many had used drugs that have been associated with cardiovascular trouble, including abacavir, which 26% of participants had used; indinavir, used by 17% of participants; zidovudine/AZT, used by 47%; and didanosine, which 14% used. (While abacavir is still in use, the other three drugs are considered legacy drugs and are not in current use.)

In addition, nearly one in three (29%) were currently using a protease inhibitor, which has been associated with heart failure.

When the investigators looked at participants’ CTs, they found that, by the Coronary Artery Disease-Reporting and Data Systems (CAD-RAMS) scoring system, close to half (46%) had clear arteries with no signs of coronary artery disease. But that also meant that 54% had some blockage or stiffening of the arteries. The good news is that 27% of those people had minimal or mild coronary artery disease.

But a full 17% had confirmed obstructive coronary artery disease, and another 1 in 10 participants had the highest level of blockages. When they broke the data down by traditional and HIV medication–related risk factors for coronary artery disease, they found something interesting. Although obesity was associated with the presence of atherosclerosis, it wasn’t associated with severe disease. But diabetes was the reverse of that: It wasn’t associated with the presence of the disease, but it was associated with more severe disease.

And when they looked at abacavir, they found no relationship between the drug and atherosclerosis. “Abacavir was not associated with the presence of atherosclerosis and was also not associated with severity of disease,” said Dr. Knudsen.

Although past use of AZT, indinavir, and didanosine were associated with severity of atherosclerosis, that association went away when Dr. Knudsen and team adjusted the findings for time since diagnosis. What was associated atherosclerosis was length of time living with HIV itself. For every 5 years a person lived with HIV, the study found the risk of having any atherosclerosis increased 20% and severity increased 23%. In addition, being a man was associated with a nearly 2.5-times increased risk of having any atherosclerosis and a 96% increased chance of having more severe atherosclerosis. Having diabetes was associated with a nearly threefold increased risk of atherosclerosis, as was every additional decade of life for a person who was living with HIV.

The findings confirm the baseline data of the REPRIEVE trial, which recently released data showing similarly high rates of atherosclerotic plaque in people living with HIV who didn’t register as “at risk” for cardiovascular disease using traditional scoring methods.

“It’s important in that it’s a huge study that’s confirmatory [of] what we know, which is that there are high levels of subclinical coronary artery disease in people living with HIV,” said Steven Grinspoon, MD, professor at Harvard Medical School in Boston, Massachusetts, and principal investigator of REPRIEVE.

As for the lack of association between abacavir and cardiovascular risk, he said he’s taking the findings with a grain of salt.

“It’s hard to make a lot out of that,” he said. “It’s hard to know in a cross-sectional study. People put people on different things.”

In Spain, where Jose Ignacio Bernardino, MD, treats people living with HIV at La Paz University Hospital in Madrid, abacavir is mostly a moot point, as clinicians have long since moved away from maintaining people living with HIV on any abacavir-containing regimens. What’s more important in the study, he told this news organization, is that “worrisome” high level of risk. REPRIEVE will test whether statins can reduce heart disease events in people living with HIV. But in the meantime, he said the take-away for clinicians from the study is the primary importance of traditional cardiovascular risk factors.

“We have to acknowledge that the major cardiovascular risk factor is age,” he said. “When patients are approaching their 50s, I usually try to stress a lot about cardiovascular risk factors in general. I stress healthy lifestyle – get physical exercise, hypertension, glucose, lipids – in every single patient.”

Dr. Knudsen and Dr. Bernardino have disclosed no relevant financial relationships. Dr. Grinspoon reports receiving personal and consulting fees from Theratechnologies and ViiV Healthcare.

A version of this article first appeared on Medscape.com.

More than half of people living with HIV and suppressed viral loads nonetheless had imaging-confirmed coronary artery disease – and despite longtime use of HIV drugs that have been associated with cardiovascular trouble, none of those drugs were implicated in disease risk in this study.

“Traditional risk factors and duration of HIV infection were associated with severe coronary artery disease,” said Andreas Knudsen, MD, PhD, an infectious disease provider at Copenhagen University Hospital, Hvidovre, Denmark, during his presentation at the 18th European AIDS Conference. “When we adjusted for time since diagnosis of HIV, none of the drugs remained associated with the severity of coronary artery disease.”

Notably, that included abacavir, which was found in another EACS presentation and in past research to be associated with increased rates of heart attacks. Abacavir is sold individually as a generic as well as a component of Epzicom (abacavir/lamivudine) and the single-drug regimen Triumeq (dolutegravir/abacavir/lamivudine).

The Copenhagen Comorbidity in HIV Infection (COCOMO) study enrolled 1,099 people living with HIV in the Danish capital beginning in 2015, and 705 of them had angiographies via CT available to include in the results. The participants were almost all male (89%), at a healthy weight (BMI of 25), and 96% had undetectable viral loads.

Large minorities of participants also had traditional risk factors for coronary artery disease. More than one in four smoked, one in five had high cholesterol, and 42% had high blood pressure. In addition, many had used drugs that have been associated with cardiovascular trouble, including abacavir, which 26% of participants had used; indinavir, used by 17% of participants; zidovudine/AZT, used by 47%; and didanosine, which 14% used. (While abacavir is still in use, the other three drugs are considered legacy drugs and are not in current use.)

In addition, nearly one in three (29%) were currently using a protease inhibitor, which has been associated with heart failure.

When the investigators looked at participants’ CTs, they found that, by the Coronary Artery Disease-Reporting and Data Systems (CAD-RAMS) scoring system, close to half (46%) had clear arteries with no signs of coronary artery disease. But that also meant that 54% had some blockage or stiffening of the arteries. The good news is that 27% of those people had minimal or mild coronary artery disease.

But a full 17% had confirmed obstructive coronary artery disease, and another 1 in 10 participants had the highest level of blockages. When they broke the data down by traditional and HIV medication–related risk factors for coronary artery disease, they found something interesting. Although obesity was associated with the presence of atherosclerosis, it wasn’t associated with severe disease. But diabetes was the reverse of that: It wasn’t associated with the presence of the disease, but it was associated with more severe disease.

And when they looked at abacavir, they found no relationship between the drug and atherosclerosis. “Abacavir was not associated with the presence of atherosclerosis and was also not associated with severity of disease,” said Dr. Knudsen.

Although past use of AZT, indinavir, and didanosine were associated with severity of atherosclerosis, that association went away when Dr. Knudsen and team adjusted the findings for time since diagnosis. What was associated atherosclerosis was length of time living with HIV itself. For every 5 years a person lived with HIV, the study found the risk of having any atherosclerosis increased 20% and severity increased 23%. In addition, being a man was associated with a nearly 2.5-times increased risk of having any atherosclerosis and a 96% increased chance of having more severe atherosclerosis. Having diabetes was associated with a nearly threefold increased risk of atherosclerosis, as was every additional decade of life for a person who was living with HIV.

The findings confirm the baseline data of the REPRIEVE trial, which recently released data showing similarly high rates of atherosclerotic plaque in people living with HIV who didn’t register as “at risk” for cardiovascular disease using traditional scoring methods.

“It’s important in that it’s a huge study that’s confirmatory [of] what we know, which is that there are high levels of subclinical coronary artery disease in people living with HIV,” said Steven Grinspoon, MD, professor at Harvard Medical School in Boston, Massachusetts, and principal investigator of REPRIEVE.

As for the lack of association between abacavir and cardiovascular risk, he said he’s taking the findings with a grain of salt.

“It’s hard to make a lot out of that,” he said. “It’s hard to know in a cross-sectional study. People put people on different things.”

In Spain, where Jose Ignacio Bernardino, MD, treats people living with HIV at La Paz University Hospital in Madrid, abacavir is mostly a moot point, as clinicians have long since moved away from maintaining people living with HIV on any abacavir-containing regimens. What’s more important in the study, he told this news organization, is that “worrisome” high level of risk. REPRIEVE will test whether statins can reduce heart disease events in people living with HIV. But in the meantime, he said the take-away for clinicians from the study is the primary importance of traditional cardiovascular risk factors.

“We have to acknowledge that the major cardiovascular risk factor is age,” he said. “When patients are approaching their 50s, I usually try to stress a lot about cardiovascular risk factors in general. I stress healthy lifestyle – get physical exercise, hypertension, glucose, lipids – in every single patient.”

Dr. Knudsen and Dr. Bernardino have disclosed no relevant financial relationships. Dr. Grinspoon reports receiving personal and consulting fees from Theratechnologies and ViiV Healthcare.

A version of this article first appeared on Medscape.com.

Stereotactic body radiation therapy (SBRT) directed at progressive lesions in patients with oligoprogressive metastatic non–small cell lung cancer (NSCLC) was beneficial and significantly improved progression-free survival (PFS), suggest clinical trial results presented this week.

Patients treated with SBRT had a median PFS of 44 weeks, compared with 9 weeks for those who received standard care.

However, no benefit was observed in patients with metastatic breast cancer. There was no significant difference in PFS between the two groups (18 weeks with SBRT vs. 19 weeks with standard care).

“In this preplanned interim analysis, we demonstrated the benefit of SBRT to sites of oligoprogression on overall progression-free survival, which was the primary endpoint,” said lead author C. Jillian Tsai, MD, PhD, a radiation oncologist and director of metastatic disease radiation oncology research at Memorial Sloan Kettering Cancer Center in New York. “The difference was driven by the substantial response in [this] NSCLC cohort.”

There was no benefit of SBRT seen in the breast cohort, she noted, and most breast patients developed new lesions upon further progression.

Dr. Tsai and colleagues are planning to close the trial early, after the interim analysis established the benefit of SBRT. They are now investigating why SBRT was beneficial in NSCLC but not in breast cancer.

The findings were presented at the American Society for Radiation Oncology (ASTRO) annual meeting.

Dr. Tsai explained that the current standard of care for patients with oligoprogressive metastatic NSCLC is to switch to a different targeted therapy or chemotherapy following progression, but options may be limited. Efficacy for second-line therapy can be poor, with PFS ranging from about 4 months to 10 months for NSCLC, “and after second line, efficacy for third and fourth lines is even poorer,” she said.

Similarly, for breast cancer, PFS ranges from about 9 months to 20 months for estrogen-receptor positive patients. “But for triple negative patients, there really is no standard of care and PFS is poor,” Dr. Tsai said.
 

SBRT superior to standard of care

The authors hypothesized that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved by applying local therapy to progressive lesions only.

The cohort included 102 patients with metastatic NSCLC or breast cancer who had received one or more lines of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of nonprogressive lesions.

Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤5 individual lesions.

Patients were randomly assigned to receive either SBRT to all progressive sites plus palliative standard of care or systemic SOC only. Systemic therapy was per physician’s discretion.

There were 58 patients with NSCLC (30 in the SBRT group) and 44 patients with breast cancer (22 in each group).

Most patients (75%) had more than one site of oligoprogression and 47% had more than 5 total metastatic lesions. About half of patients (54%) had received immunotherapy and the majority of those with NSCLC (86%) did not harbor an actionable driver mutation. About one-third (32%) of the breast cancer cohort were triple negative.

Patients were followed for a median of 45 weeks (58 weeks for living patients), by which time 78 (74%) had experienced further tumor progression and 39 (37%) had died.

Median progression-free survival for the entire cohort was 31 weeks for SBRT and 11 weeks for palliative SOC (P = .002).

In multivariable analysis that stratified for factors including age, sex, lines of systemic therapy, and change of systemic therapy, the progression-free survival benefit of SBRT continued to remain substantial in the NSCLC cohort (hazard ratio: 0.38; P = .007).

Adverse events were higher in the SBRT group. Grade 2 or higher adverse events occurred in 23 (61%) of SBRT patients, and 15 (40%) of SOC patients (P = .13).
 

Hoped-for results, with a few caveats

Approached for comment on the new findings, Clifford Robinson, MD, professor of radiation oncology, chief of SBRT service, and director of clinical trials and informatics at Washington University, St. Louis, said the results tie in with previous findings.

There are multiple published or presented prospective randomized phase 2 and 3 trials in various disease sites that have explored the role of local therapy, including SBRT, for patients who present with oligometastatic disease.

“These studies have nearly uniformly shown improvements in progression-free and/or overall survival with the inclusion of local therapy,” he told this news organization. Dr. Robinson was not involved with the study.

He explained that relatively few patients present with oligometastatic disease. However, many patients present with more advanced disease, but after an initial course of systemic therapy, develop oligoprogression.

“There is tremendous appeal to using local therapy at the time of oligoprogression in lieu of switching systemic therapy,” said Dr. Robinson. “It allows patients to stay on systemic therapy that is otherwise effective for the remainder of their disease.”

First-line systemic therapies are the most effective and the most tolerable, he continued, and switching systemic therapy introduces the potential for more toxicity and less efficacy. Therefore, it has become increasingly popular to offer SBRT to one or a few sites of oligoprogressive disease based on the results of oligometastatic disease.

“However, there is no established prospective data to guide this practice,” he said. “This trial is the first to examine this carefully in lung and breast cancer patients, and this trial shows what we hoped to see – that use of SBRT after oligoprogression results in improved progression-free survival as compared with standard of care alone. And this was accomplished with limited toxicity.”

There are a few caveats, though, he pointed out. “Progression-free survival is defined as time to first progression or death,” he said. “Since we don’t know what the overall survival is in this abstract, it’s entirely possible that patients live for the same length of time, but just take longer to progress.”

Another caveat is that this was a planned interim analysis. “Typically, planned interim analyses occur to see if the trial should be stopped or to adjust the study based on results,” he said. “It’s unclear what the investigators will do with this information.”

“But overall, these are very exciting data and lend support to the increasingly common practice of treating oligoprogressive disease,” Dr. Robinson added. “Since most of the serious adverse events of SBRT occur later, longer follow-up is needed, although the median survival of patients may not reach that timepoint.”

“For now, practice should not be altered based on these interim results,” he added.

Dr. Tsai reported acting as a consultant/advisor for Varian and Galera and also receiving research funding from Varian. Dr. Robinson reports stock/ownership in Radialogica, acting as a consultant/advisor for Varian, AstraZeneca, EMD Serono, Quantitative Radiology Solutions, research funding from Varian and Merck, and owning patents on systems for cardiac arrhythmias and ablation.

A version of this article first appeared on Medscape.com.

Stereotactic body radiation therapy (SBRT) directed at progressive lesions in patients with oligoprogressive metastatic non–small cell lung cancer (NSCLC) was beneficial and significantly improved progression-free survival (PFS), suggest clinical trial results presented this week.

Patients treated with SBRT had a median PFS of 44 weeks, compared with 9 weeks for those who received standard care.

However, no benefit was observed in patients with metastatic breast cancer. There was no significant difference in PFS between the two groups (18 weeks with SBRT vs. 19 weeks with standard care).

“In this preplanned interim analysis, we demonstrated the benefit of SBRT to sites of oligoprogression on overall progression-free survival, which was the primary endpoint,” said lead author C. Jillian Tsai, MD, PhD, a radiation oncologist and director of metastatic disease radiation oncology research at Memorial Sloan Kettering Cancer Center in New York. “The difference was driven by the substantial response in [this] NSCLC cohort.”

There was no benefit of SBRT seen in the breast cohort, she noted, and most breast patients developed new lesions upon further progression.

Dr. Tsai and colleagues are planning to close the trial early, after the interim analysis established the benefit of SBRT. They are now investigating why SBRT was beneficial in NSCLC but not in breast cancer.

The findings were presented at the American Society for Radiation Oncology (ASTRO) annual meeting.

Dr. Tsai explained that the current standard of care for patients with oligoprogressive metastatic NSCLC is to switch to a different targeted therapy or chemotherapy following progression, but options may be limited. Efficacy for second-line therapy can be poor, with PFS ranging from about 4 months to 10 months for NSCLC, “and after second line, efficacy for third and fourth lines is even poorer,” she said.

Similarly, for breast cancer, PFS ranges from about 9 months to 20 months for estrogen-receptor positive patients. “But for triple negative patients, there really is no standard of care and PFS is poor,” Dr. Tsai said.
 

SBRT superior to standard of care

The authors hypothesized that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved by applying local therapy to progressive lesions only.

The cohort included 102 patients with metastatic NSCLC or breast cancer who had received one or more lines of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of nonprogressive lesions.

Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤5 individual lesions.

Patients were randomly assigned to receive either SBRT to all progressive sites plus palliative standard of care or systemic SOC only. Systemic therapy was per physician’s discretion.

There were 58 patients with NSCLC (30 in the SBRT group) and 44 patients with breast cancer (22 in each group).

Most patients (75%) had more than one site of oligoprogression and 47% had more than 5 total metastatic lesions. About half of patients (54%) had received immunotherapy and the majority of those with NSCLC (86%) did not harbor an actionable driver mutation. About one-third (32%) of the breast cancer cohort were triple negative.

Patients were followed for a median of 45 weeks (58 weeks for living patients), by which time 78 (74%) had experienced further tumor progression and 39 (37%) had died.

Median progression-free survival for the entire cohort was 31 weeks for SBRT and 11 weeks for palliative SOC (P = .002).

In multivariable analysis that stratified for factors including age, sex, lines of systemic therapy, and change of systemic therapy, the progression-free survival benefit of SBRT continued to remain substantial in the NSCLC cohort (hazard ratio: 0.38; P = .007).

Adverse events were higher in the SBRT group. Grade 2 or higher adverse events occurred in 23 (61%) of SBRT patients, and 15 (40%) of SOC patients (P = .13).
 

Hoped-for results, with a few caveats

Approached for comment on the new findings, Clifford Robinson, MD, professor of radiation oncology, chief of SBRT service, and director of clinical trials and informatics at Washington University, St. Louis, said the results tie in with previous findings.

There are multiple published or presented prospective randomized phase 2 and 3 trials in various disease sites that have explored the role of local therapy, including SBRT, for patients who present with oligometastatic disease.

“These studies have nearly uniformly shown improvements in progression-free and/or overall survival with the inclusion of local therapy,” he told this news organization. Dr. Robinson was not involved with the study.

He explained that relatively few patients present with oligometastatic disease. However, many patients present with more advanced disease, but after an initial course of systemic therapy, develop oligoprogression.

“There is tremendous appeal to using local therapy at the time of oligoprogression in lieu of switching systemic therapy,” said Dr. Robinson. “It allows patients to stay on systemic therapy that is otherwise effective for the remainder of their disease.”

First-line systemic therapies are the most effective and the most tolerable, he continued, and switching systemic therapy introduces the potential for more toxicity and less efficacy. Therefore, it has become increasingly popular to offer SBRT to one or a few sites of oligoprogressive disease based on the results of oligometastatic disease.

“However, there is no established prospective data to guide this practice,” he said. “This trial is the first to examine this carefully in lung and breast cancer patients, and this trial shows what we hoped to see – that use of SBRT after oligoprogression results in improved progression-free survival as compared with standard of care alone. And this was accomplished with limited toxicity.”

There are a few caveats, though, he pointed out. “Progression-free survival is defined as time to first progression or death,” he said. “Since we don’t know what the overall survival is in this abstract, it’s entirely possible that patients live for the same length of time, but just take longer to progress.”

Another caveat is that this was a planned interim analysis. “Typically, planned interim analyses occur to see if the trial should be stopped or to adjust the study based on results,” he said. “It’s unclear what the investigators will do with this information.”

“But overall, these are very exciting data and lend support to the increasingly common practice of treating oligoprogressive disease,” Dr. Robinson added. “Since most of the serious adverse events of SBRT occur later, longer follow-up is needed, although the median survival of patients may not reach that timepoint.”

“For now, practice should not be altered based on these interim results,” he added.

Dr. Tsai reported acting as a consultant/advisor for Varian and Galera and also receiving research funding from Varian. Dr. Robinson reports stock/ownership in Radialogica, acting as a consultant/advisor for Varian, AstraZeneca, EMD Serono, Quantitative Radiology Solutions, research funding from Varian and Merck, and owning patents on systems for cardiac arrhythmias and ablation.

A version of this article first appeared on Medscape.com.

Stereotactic body radiation therapy (SBRT) directed at progressive lesions in patients with oligoprogressive metastatic non–small cell lung cancer (NSCLC) was beneficial and significantly improved progression-free survival (PFS), suggest clinical trial results presented this week.

Patients treated with SBRT had a median PFS of 44 weeks, compared with 9 weeks for those who received standard care.

However, no benefit was observed in patients with metastatic breast cancer. There was no significant difference in PFS between the two groups (18 weeks with SBRT vs. 19 weeks with standard care).

“In this preplanned interim analysis, we demonstrated the benefit of SBRT to sites of oligoprogression on overall progression-free survival, which was the primary endpoint,” said lead author C. Jillian Tsai, MD, PhD, a radiation oncologist and director of metastatic disease radiation oncology research at Memorial Sloan Kettering Cancer Center in New York. “The difference was driven by the substantial response in [this] NSCLC cohort.”

There was no benefit of SBRT seen in the breast cohort, she noted, and most breast patients developed new lesions upon further progression.

Dr. Tsai and colleagues are planning to close the trial early, after the interim analysis established the benefit of SBRT. They are now investigating why SBRT was beneficial in NSCLC but not in breast cancer.

The findings were presented at the American Society for Radiation Oncology (ASTRO) annual meeting.

Dr. Tsai explained that the current standard of care for patients with oligoprogressive metastatic NSCLC is to switch to a different targeted therapy or chemotherapy following progression, but options may be limited. Efficacy for second-line therapy can be poor, with PFS ranging from about 4 months to 10 months for NSCLC, “and after second line, efficacy for third and fourth lines is even poorer,” she said.

Similarly, for breast cancer, PFS ranges from about 9 months to 20 months for estrogen-receptor positive patients. “But for triple negative patients, there really is no standard of care and PFS is poor,” Dr. Tsai said.
 

SBRT superior to standard of care

The authors hypothesized that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved by applying local therapy to progressive lesions only.

The cohort included 102 patients with metastatic NSCLC or breast cancer who had received one or more lines of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of nonprogressive lesions.

Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤5 individual lesions.

Patients were randomly assigned to receive either SBRT to all progressive sites plus palliative standard of care or systemic SOC only. Systemic therapy was per physician’s discretion.

There were 58 patients with NSCLC (30 in the SBRT group) and 44 patients with breast cancer (22 in each group).

Most patients (75%) had more than one site of oligoprogression and 47% had more than 5 total metastatic lesions. About half of patients (54%) had received immunotherapy and the majority of those with NSCLC (86%) did not harbor an actionable driver mutation. About one-third (32%) of the breast cancer cohort were triple negative.

Patients were followed for a median of 45 weeks (58 weeks for living patients), by which time 78 (74%) had experienced further tumor progression and 39 (37%) had died.

Median progression-free survival for the entire cohort was 31 weeks for SBRT and 11 weeks for palliative SOC (P = .002).

In multivariable analysis that stratified for factors including age, sex, lines of systemic therapy, and change of systemic therapy, the progression-free survival benefit of SBRT continued to remain substantial in the NSCLC cohort (hazard ratio: 0.38; P = .007).

Adverse events were higher in the SBRT group. Grade 2 or higher adverse events occurred in 23 (61%) of SBRT patients, and 15 (40%) of SOC patients (P = .13).
 

Hoped-for results, with a few caveats

Approached for comment on the new findings, Clifford Robinson, MD, professor of radiation oncology, chief of SBRT service, and director of clinical trials and informatics at Washington University, St. Louis, said the results tie in with previous findings.

There are multiple published or presented prospective randomized phase 2 and 3 trials in various disease sites that have explored the role of local therapy, including SBRT, for patients who present with oligometastatic disease.

“These studies have nearly uniformly shown improvements in progression-free and/or overall survival with the inclusion of local therapy,” he told this news organization. Dr. Robinson was not involved with the study.

He explained that relatively few patients present with oligometastatic disease. However, many patients present with more advanced disease, but after an initial course of systemic therapy, develop oligoprogression.

“There is tremendous appeal to using local therapy at the time of oligoprogression in lieu of switching systemic therapy,” said Dr. Robinson. “It allows patients to stay on systemic therapy that is otherwise effective for the remainder of their disease.”

First-line systemic therapies are the most effective and the most tolerable, he continued, and switching systemic therapy introduces the potential for more toxicity and less efficacy. Therefore, it has become increasingly popular to offer SBRT to one or a few sites of oligoprogressive disease based on the results of oligometastatic disease.

“However, there is no established prospective data to guide this practice,” he said. “This trial is the first to examine this carefully in lung and breast cancer patients, and this trial shows what we hoped to see – that use of SBRT after oligoprogression results in improved progression-free survival as compared with standard of care alone. And this was accomplished with limited toxicity.”

There are a few caveats, though, he pointed out. “Progression-free survival is defined as time to first progression or death,” he said. “Since we don’t know what the overall survival is in this abstract, it’s entirely possible that patients live for the same length of time, but just take longer to progress.”

Another caveat is that this was a planned interim analysis. “Typically, planned interim analyses occur to see if the trial should be stopped or to adjust the study based on results,” he said. “It’s unclear what the investigators will do with this information.”

“But overall, these are very exciting data and lend support to the increasingly common practice of treating oligoprogressive disease,” Dr. Robinson added. “Since most of the serious adverse events of SBRT occur later, longer follow-up is needed, although the median survival of patients may not reach that timepoint.”

“For now, practice should not be altered based on these interim results,” he added.

Dr. Tsai reported acting as a consultant/advisor for Varian and Galera and also receiving research funding from Varian. Dr. Robinson reports stock/ownership in Radialogica, acting as a consultant/advisor for Varian, AstraZeneca, EMD Serono, Quantitative Radiology Solutions, research funding from Varian and Merck, and owning patents on systems for cardiac arrhythmias and ablation.

A version of this article first appeared on Medscape.com.

The largest-ever breast cancer screening trial in the United States, which is federally funded with costs expected to reach $100 million, is a “waste,” says prominent radiologist Daniel Kopans, MD, from Harvard Medical School, Boston. Funding for this trial is largely misspent money, it may produce misleading results, and it should be abandoned, he says.

Dr. Kopans has been an outspoken critic of the trial, describing it as a “huge waste of money” in comments made last year. Now he has set out his criticisms of the trial in an essay published in the October issue of Clinical Imaging, which outlines his objections and concerns for the first time in a peer-reviewed journal.

The Tomosynthesis Mammographic Imaging Screening Trial (TMIST) is comparing digital breast tomosynthesis (DBT), also known as 3-D mammography, with the older 2-D technology or full-field digital mammography (FFDM).

Dr. Kopans coined the term DBT and formerly held a now-expired patent on the first version of this technology.

“It could be argued that the imaging part of TMIST is a waste of valuable resources,” he writes in the essay.

The “imaging part” of the trial refers to the primary outcome measure and driving purpose of the trial, which is designed to learn which technology is better at finding – and reducing the rate of – potentially lethal “advanced” cancers.

These cancers include larger HER2-positive and triple-negative malignancies; those associated with positive nodes; and metastatic disease. These malignancies correlate with breast cancer mortality, TMIST’s principal investigator Etta Pisano, MD, of the American College of Radiology, has said in the past.

However, Dr. Kopans says that this surrogate endpoint is problematic. “TMIST will only investigate whether or not digital breast tomography results in a decline in advanced cancers, ignoring the fact that many women still die from cancers that are not advanced at the time of diagnosis,” he writes.

“Clearly reducing the rate of advanced cancers is not the only way that early detection saves lives. Lives are also saved by finding cancers at a smaller size within stages,” Dr. Kopans writes. He adds that DBT has been proven in observational cohort studies to find more smaller breast cancers than FFDM.

Dr. Kopans’ opinion that TMIST is largely a waste of resources is not shared by the National Cancer Institute. “We feel strongly that TMIST is a critical study,” an NCI spokesperson told this news organization.
 

Study power concerns

Another concern is that TMIST “may be underpowered,” Dr. Kopans writes. That concern arises in part from a recent review of TMIST by an advisory committee (that was prompted by low patient accrual rates), which proposed reducing the size of the trial. Dr. Kopans says this would result in “a reduction of the planned power of the trial.”  

The NCI says that reducing the study size has been discussed but has not yet been implemented. “Any reduction in size would, of course, have appropriate statistical considerations in mind,” according to the NCI spokesperson.

Dr. Kopans’ concern about statistical power extends beyond downsizing the trial. An advanced cancer in TMIST is counted “if it occurs at any time while the participant is on study,” according to the NCI. Dr. Kopans says that is a problem.

“Since DBT cannot have any effect on advanced cancers in the prevalence year (they are already there), data from the first year (prevalence cancers are likely the largest number) will be unusable, and if used will, inappropriately, dilute the results,” he writes.

Dr. Kopans hopes that the investigators address the statistical power issues with the trial because, if not, “its results may be grossly misleading.”
 

American radiology practice

Dr. Kopans praises one aspect of TMIST – the trial’s effort to create a repository of blood and oral swab specimens, along with participant genetic data. The goal, say TMIST investigators, is to individualize or optimize screening strategies by tying molecular data to clinical outcomes in the trial.

However, apart from that one aspect, Dr. Kopans is highly critical of the trial.

It is now too late to compare the two technologies, he suggests, as DBT is already replacing FFDM for breast cancer screening in the U.S.

He notes that 76% of mammography facilities in the United States have 3-D devices (as of April 2021). That percentage has climbed steadily in recent years. “By the time the TMIST study is completed, DBT will, almost certainly, have become the ‘standard of care,’” he asserts, echoing others who have commented on the trial, including some participating physicians.

The money being spent on TMIST “should not be used for looking backwards,” says Dr. Kopans.

The NCI responded to that criticism. “TMIST is looking to clarify the best screening for women based on the science and is not solely about access. We are seeking to determine which technology is better and [are] providing access to the trial across the country in diverse practices and populations,” the NCI said in an email.

In his essay, Dr. Kopans says it is time to stop TMIST and put the money into other pressing breast cancer issues and questions. “... it makes no sense to continue this flawed trial whose results will be obsolete by the time they become available,” he writes.

Dr. Kopans reports consulting with DART Imaging in China, which is developing a digital breast tomosynthesis machine.

A version of this article first appeared on Medscape.com.

The largest-ever breast cancer screening trial in the United States, which is federally funded with costs expected to reach $100 million, is a “waste,” says prominent radiologist Daniel Kopans, MD, from Harvard Medical School, Boston. Funding for this trial is largely misspent money, it may produce misleading results, and it should be abandoned, he says.

Dr. Kopans has been an outspoken critic of the trial, describing it as a “huge waste of money” in comments made last year. Now he has set out his criticisms of the trial in an essay published in the October issue of Clinical Imaging, which outlines his objections and concerns for the first time in a peer-reviewed journal.

The Tomosynthesis Mammographic Imaging Screening Trial (TMIST) is comparing digital breast tomosynthesis (DBT), also known as 3-D mammography, with the older 2-D technology or full-field digital mammography (FFDM).

Dr. Kopans coined the term DBT and formerly held a now-expired patent on the first version of this technology.

“It could be argued that the imaging part of TMIST is a waste of valuable resources,” he writes in the essay.

The “imaging part” of the trial refers to the primary outcome measure and driving purpose of the trial, which is designed to learn which technology is better at finding – and reducing the rate of – potentially lethal “advanced” cancers.

These cancers include larger HER2-positive and triple-negative malignancies; those associated with positive nodes; and metastatic disease. These malignancies correlate with breast cancer mortality, TMIST’s principal investigator Etta Pisano, MD, of the American College of Radiology, has said in the past.

However, Dr. Kopans says that this surrogate endpoint is problematic. “TMIST will only investigate whether or not digital breast tomography results in a decline in advanced cancers, ignoring the fact that many women still die from cancers that are not advanced at the time of diagnosis,” he writes.

“Clearly reducing the rate of advanced cancers is not the only way that early detection saves lives. Lives are also saved by finding cancers at a smaller size within stages,” Dr. Kopans writes. He adds that DBT has been proven in observational cohort studies to find more smaller breast cancers than FFDM.

Dr. Kopans’ opinion that TMIST is largely a waste of resources is not shared by the National Cancer Institute. “We feel strongly that TMIST is a critical study,” an NCI spokesperson told this news organization.
 

Study power concerns

Another concern is that TMIST “may be underpowered,” Dr. Kopans writes. That concern arises in part from a recent review of TMIST by an advisory committee (that was prompted by low patient accrual rates), which proposed reducing the size of the trial. Dr. Kopans says this would result in “a reduction of the planned power of the trial.”  

The NCI says that reducing the study size has been discussed but has not yet been implemented. “Any reduction in size would, of course, have appropriate statistical considerations in mind,” according to the NCI spokesperson.

Dr. Kopans’ concern about statistical power extends beyond downsizing the trial. An advanced cancer in TMIST is counted “if it occurs at any time while the participant is on study,” according to the NCI. Dr. Kopans says that is a problem.

“Since DBT cannot have any effect on advanced cancers in the prevalence year (they are already there), data from the first year (prevalence cancers are likely the largest number) will be unusable, and if used will, inappropriately, dilute the results,” he writes.

Dr. Kopans hopes that the investigators address the statistical power issues with the trial because, if not, “its results may be grossly misleading.”
 

American radiology practice

Dr. Kopans praises one aspect of TMIST – the trial’s effort to create a repository of blood and oral swab specimens, along with participant genetic data. The goal, say TMIST investigators, is to individualize or optimize screening strategies by tying molecular data to clinical outcomes in the trial.

However, apart from that one aspect, Dr. Kopans is highly critical of the trial.

It is now too late to compare the two technologies, he suggests, as DBT is already replacing FFDM for breast cancer screening in the U.S.

He notes that 76% of mammography facilities in the United States have 3-D devices (as of April 2021). That percentage has climbed steadily in recent years. “By the time the TMIST study is completed, DBT will, almost certainly, have become the ‘standard of care,’” he asserts, echoing others who have commented on the trial, including some participating physicians.

The money being spent on TMIST “should not be used for looking backwards,” says Dr. Kopans.

The NCI responded to that criticism. “TMIST is looking to clarify the best screening for women based on the science and is not solely about access. We are seeking to determine which technology is better and [are] providing access to the trial across the country in diverse practices and populations,” the NCI said in an email.

In his essay, Dr. Kopans says it is time to stop TMIST and put the money into other pressing breast cancer issues and questions. “... it makes no sense to continue this flawed trial whose results will be obsolete by the time they become available,” he writes.

Dr. Kopans reports consulting with DART Imaging in China, which is developing a digital breast tomosynthesis machine.

A version of this article first appeared on Medscape.com.

The largest-ever breast cancer screening trial in the United States, which is federally funded with costs expected to reach $100 million, is a “waste,” says prominent radiologist Daniel Kopans, MD, from Harvard Medical School, Boston. Funding for this trial is largely misspent money, it may produce misleading results, and it should be abandoned, he says.

Dr. Kopans has been an outspoken critic of the trial, describing it as a “huge waste of money” in comments made last year. Now he has set out his criticisms of the trial in an essay published in the October issue of Clinical Imaging, which outlines his objections and concerns for the first time in a peer-reviewed journal.

The Tomosynthesis Mammographic Imaging Screening Trial (TMIST) is comparing digital breast tomosynthesis (DBT), also known as 3-D mammography, with the older 2-D technology or full-field digital mammography (FFDM).

Dr. Kopans coined the term DBT and formerly held a now-expired patent on the first version of this technology.

“It could be argued that the imaging part of TMIST is a waste of valuable resources,” he writes in the essay.

The “imaging part” of the trial refers to the primary outcome measure and driving purpose of the trial, which is designed to learn which technology is better at finding – and reducing the rate of – potentially lethal “advanced” cancers.

These cancers include larger HER2-positive and triple-negative malignancies; those associated with positive nodes; and metastatic disease. These malignancies correlate with breast cancer mortality, TMIST’s principal investigator Etta Pisano, MD, of the American College of Radiology, has said in the past.

However, Dr. Kopans says that this surrogate endpoint is problematic. “TMIST will only investigate whether or not digital breast tomography results in a decline in advanced cancers, ignoring the fact that many women still die from cancers that are not advanced at the time of diagnosis,” he writes.

“Clearly reducing the rate of advanced cancers is not the only way that early detection saves lives. Lives are also saved by finding cancers at a smaller size within stages,” Dr. Kopans writes. He adds that DBT has been proven in observational cohort studies to find more smaller breast cancers than FFDM.

Dr. Kopans’ opinion that TMIST is largely a waste of resources is not shared by the National Cancer Institute. “We feel strongly that TMIST is a critical study,” an NCI spokesperson told this news organization.
 

Study power concerns

Another concern is that TMIST “may be underpowered,” Dr. Kopans writes. That concern arises in part from a recent review of TMIST by an advisory committee (that was prompted by low patient accrual rates), which proposed reducing the size of the trial. Dr. Kopans says this would result in “a reduction of the planned power of the trial.”  

The NCI says that reducing the study size has been discussed but has not yet been implemented. “Any reduction in size would, of course, have appropriate statistical considerations in mind,” according to the NCI spokesperson.

Dr. Kopans’ concern about statistical power extends beyond downsizing the trial. An advanced cancer in TMIST is counted “if it occurs at any time while the participant is on study,” according to the NCI. Dr. Kopans says that is a problem.

“Since DBT cannot have any effect on advanced cancers in the prevalence year (they are already there), data from the first year (prevalence cancers are likely the largest number) will be unusable, and if used will, inappropriately, dilute the results,” he writes.

Dr. Kopans hopes that the investigators address the statistical power issues with the trial because, if not, “its results may be grossly misleading.”
 

American radiology practice

Dr. Kopans praises one aspect of TMIST – the trial’s effort to create a repository of blood and oral swab specimens, along with participant genetic data. The goal, say TMIST investigators, is to individualize or optimize screening strategies by tying molecular data to clinical outcomes in the trial.

However, apart from that one aspect, Dr. Kopans is highly critical of the trial.

It is now too late to compare the two technologies, he suggests, as DBT is already replacing FFDM for breast cancer screening in the U.S.

He notes that 76% of mammography facilities in the United States have 3-D devices (as of April 2021). That percentage has climbed steadily in recent years. “By the time the TMIST study is completed, DBT will, almost certainly, have become the ‘standard of care,’” he asserts, echoing others who have commented on the trial, including some participating physicians.

The money being spent on TMIST “should not be used for looking backwards,” says Dr. Kopans.

The NCI responded to that criticism. “TMIST is looking to clarify the best screening for women based on the science and is not solely about access. We are seeking to determine which technology is better and [are] providing access to the trial across the country in diverse practices and populations,” the NCI said in an email.

In his essay, Dr. Kopans says it is time to stop TMIST and put the money into other pressing breast cancer issues and questions. “... it makes no sense to continue this flawed trial whose results will be obsolete by the time they become available,” he writes.

Dr. Kopans reports consulting with DART Imaging in China, which is developing a digital breast tomosynthesis machine.

A version of this article first appeared on Medscape.com.