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Guidance for Practicing Primary Care: Updated Clinical Guidelines Regarding Dry Eye Syndrome
On February 11, 2024, the American Academy of Ophthalmology (AAO) issued new guidelines regarding dry eye syndrome or keratoconjunctivitis sicca. According to the National Eye Institute, dry eye affects approximately 16 million Americans. Dry eye is a multifactorial disease with causes including excessive screen time and refractive surgery. While it may seem that dry eye is a nuisance disease, it can actually damage the cornea if not treated appropriately.
The guidelines state that dry eye can affect the quality of life as well as the outcomes of ocular surgeries such as cataract surgery. It is imperative that we discuss this potential complication before our patients undergo these procedures. As primary care physicians, we have seen that patients may not be well educated on their health conditions by other doctors. We may not be the one performing the surgery but it is likely the patient will seek our advice if any complication arises.
The guidelines say that clinical examination is the gold standard for diagnosing this disease. We need to be proficient at doing eye exams and refer to a specialist when appropriate. The treatment can likely be undertaken in the primary care office unless there are other symptoms such as loss of visual acuity. The guidelines suggest several diagnostic tests, such as the Schirmer test and tear osmolarity test, which may be outside the scope of the primary care setting. Often, clinical history will guide the diagnosis.
Treatments include several Food and Drug Administration–approved eye drops. We need to know what they are and when to prescribe them. We know they will not cure the disease but can keep it under control and improve the patient’s quality of life.
Dry eye may seem a trivial complaint in the sea of diseases we treat on a daily basis. However, it is not trivial to the patient. It can affect their vision and make their life miserable. We need to pay attention when our patients bring this to our attention. We are not just making them comfortable but protecting their corneas. This can be done in conjunction with routine ophthalmologic visits.
According to the authors of these guidelines, approximately 10% of patients with significantly dry eyes and mouth will have Sj
These guidelines also suggest a classification for dry eye including mild, moderate, and severe. Since the treatment varies depending on classification, we need to learn this classification system. They also stress follow-up visits. It is not enough just to diagnose the disease and start treatment, we need to see the patients back for follow-up.
Currently, most people work and play on electronic devices. Dry eye syndrome can make this more difficult and vice versa. While it is typically not a vision-threatening disease, it can be a life-altering one. Ocular symptoms are something we see frequently in our practices, from allergic conjunctivitis to glaucoma. Often, the patient starts seeking help in our office.
Yes, our patients may have more life-threatening diseases. Our job is not just to save lives but to help our patients live healthy lives. If their lives are being affected by any disease, we must step in and do something. Dry eye is not just an inconvenience but something that causes great suffering. Eventually we may end up referring the patient to the ophthalmologist, but if we can do something to ease their discomfort while they are waiting, we would be changing their lives. We must educate ourselves on this disease and appropriate treatments to be prescribed depending on the classification of disease.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, NJ. She has no conflicts of interest.
On February 11, 2024, the American Academy of Ophthalmology (AAO) issued new guidelines regarding dry eye syndrome or keratoconjunctivitis sicca. According to the National Eye Institute, dry eye affects approximately 16 million Americans. Dry eye is a multifactorial disease with causes including excessive screen time and refractive surgery. While it may seem that dry eye is a nuisance disease, it can actually damage the cornea if not treated appropriately.
The guidelines state that dry eye can affect the quality of life as well as the outcomes of ocular surgeries such as cataract surgery. It is imperative that we discuss this potential complication before our patients undergo these procedures. As primary care physicians, we have seen that patients may not be well educated on their health conditions by other doctors. We may not be the one performing the surgery but it is likely the patient will seek our advice if any complication arises.
The guidelines say that clinical examination is the gold standard for diagnosing this disease. We need to be proficient at doing eye exams and refer to a specialist when appropriate. The treatment can likely be undertaken in the primary care office unless there are other symptoms such as loss of visual acuity. The guidelines suggest several diagnostic tests, such as the Schirmer test and tear osmolarity test, which may be outside the scope of the primary care setting. Often, clinical history will guide the diagnosis.
Treatments include several Food and Drug Administration–approved eye drops. We need to know what they are and when to prescribe them. We know they will not cure the disease but can keep it under control and improve the patient’s quality of life.
Dry eye may seem a trivial complaint in the sea of diseases we treat on a daily basis. However, it is not trivial to the patient. It can affect their vision and make their life miserable. We need to pay attention when our patients bring this to our attention. We are not just making them comfortable but protecting their corneas. This can be done in conjunction with routine ophthalmologic visits.
According to the authors of these guidelines, approximately 10% of patients with significantly dry eyes and mouth will have Sj
These guidelines also suggest a classification for dry eye including mild, moderate, and severe. Since the treatment varies depending on classification, we need to learn this classification system. They also stress follow-up visits. It is not enough just to diagnose the disease and start treatment, we need to see the patients back for follow-up.
Currently, most people work and play on electronic devices. Dry eye syndrome can make this more difficult and vice versa. While it is typically not a vision-threatening disease, it can be a life-altering one. Ocular symptoms are something we see frequently in our practices, from allergic conjunctivitis to glaucoma. Often, the patient starts seeking help in our office.
Yes, our patients may have more life-threatening diseases. Our job is not just to save lives but to help our patients live healthy lives. If their lives are being affected by any disease, we must step in and do something. Dry eye is not just an inconvenience but something that causes great suffering. Eventually we may end up referring the patient to the ophthalmologist, but if we can do something to ease their discomfort while they are waiting, we would be changing their lives. We must educate ourselves on this disease and appropriate treatments to be prescribed depending on the classification of disease.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, NJ. She has no conflicts of interest.
On February 11, 2024, the American Academy of Ophthalmology (AAO) issued new guidelines regarding dry eye syndrome or keratoconjunctivitis sicca. According to the National Eye Institute, dry eye affects approximately 16 million Americans. Dry eye is a multifactorial disease with causes including excessive screen time and refractive surgery. While it may seem that dry eye is a nuisance disease, it can actually damage the cornea if not treated appropriately.
The guidelines state that dry eye can affect the quality of life as well as the outcomes of ocular surgeries such as cataract surgery. It is imperative that we discuss this potential complication before our patients undergo these procedures. As primary care physicians, we have seen that patients may not be well educated on their health conditions by other doctors. We may not be the one performing the surgery but it is likely the patient will seek our advice if any complication arises.
The guidelines say that clinical examination is the gold standard for diagnosing this disease. We need to be proficient at doing eye exams and refer to a specialist when appropriate. The treatment can likely be undertaken in the primary care office unless there are other symptoms such as loss of visual acuity. The guidelines suggest several diagnostic tests, such as the Schirmer test and tear osmolarity test, which may be outside the scope of the primary care setting. Often, clinical history will guide the diagnosis.
Treatments include several Food and Drug Administration–approved eye drops. We need to know what they are and when to prescribe them. We know they will not cure the disease but can keep it under control and improve the patient’s quality of life.
Dry eye may seem a trivial complaint in the sea of diseases we treat on a daily basis. However, it is not trivial to the patient. It can affect their vision and make their life miserable. We need to pay attention when our patients bring this to our attention. We are not just making them comfortable but protecting their corneas. This can be done in conjunction with routine ophthalmologic visits.
According to the authors of these guidelines, approximately 10% of patients with significantly dry eyes and mouth will have Sj
These guidelines also suggest a classification for dry eye including mild, moderate, and severe. Since the treatment varies depending on classification, we need to learn this classification system. They also stress follow-up visits. It is not enough just to diagnose the disease and start treatment, we need to see the patients back for follow-up.
Currently, most people work and play on electronic devices. Dry eye syndrome can make this more difficult and vice versa. While it is typically not a vision-threatening disease, it can be a life-altering one. Ocular symptoms are something we see frequently in our practices, from allergic conjunctivitis to glaucoma. Often, the patient starts seeking help in our office.
Yes, our patients may have more life-threatening diseases. Our job is not just to save lives but to help our patients live healthy lives. If their lives are being affected by any disease, we must step in and do something. Dry eye is not just an inconvenience but something that causes great suffering. Eventually we may end up referring the patient to the ophthalmologist, but if we can do something to ease their discomfort while they are waiting, we would be changing their lives. We must educate ourselves on this disease and appropriate treatments to be prescribed depending on the classification of disease.
Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Robert Wood Johnson Medical School, New Brunswick, NJ. She has no conflicts of interest.
Macadamia and Sapucaia Extracts and the Skin
Macadamia (Macadamia tetraphylla) is endemic to Australia and is now commercially cultivated worldwide.1 It is closely related genetically to the other macadamia plants, including the other main one, M. integrifolia, cultivated for macadamia nuts. Known in Brazil as sapucaia or castanha-de-sapucaia, Lecythis pisonis (also referred to as “cream nut” or “monkey pot”) is a large, deciduous tropical tree and member of the Brazil nut family, Lecythidaceae.2 Various parts of both of these plants have been associated with medicinal properties, including the potential for dermatologic activity. Notably, the leaves of L. pisonis have been used in traditional medicine to treat pruritus.2.
Macadamia
Extraction to Harness Antioxidant Activity
In 2015, Dailey and Vuong developed an aqueous extraction process to recover the phenolic content and antioxidant functionality from the skin waste of M. tetraphylla using response surface methodology. As an environmentally suitable solvent that is also cheap and safe, water was chosen to maximize the extraction scenario. They identified the proper conditions (90° C, a time of 20 min, and a sample-to-solvent ratio of 5 g/100 mL) to obtain sufficient phenolic compounds, proanthocyanidins, and flavonoids to render robust antioxidant function.1
Early in 2023, Somwongin et al. investigated various green extraction methods for viability in harnessing the cosmetic/cosmeceutical ingredients of M. integrifolia pericarps. Extracts were assessed for total phenolic content as well as antioxidant and anti–skin aging functions. They found that among the green extraction methods (ultrasound, micellar, microwave, and pulsed electric field extraction with water used as a clean solvent), the ultrasound-assisted extraction method netted the greatest yield and total phenolic content. It was also associated with the most robust antioxidant and anti–skin aging activities. Indeed, the researchers reported that its antioxidant activities were comparable to ascorbic acid and Trolox and its anti–skin aging potency on a par with epigallocatechin-3-gallate and oleanolic acid. The ultrasound-assisted extract was also deemed safe as it did not provoke irritation. The authors concluded that this environmentally suitable extraction method for M. integrifolia is appropriate for obtaining effective macadamia extracts for use in cosmetics and cosmeceuticals.3
Anti-Aging Activity
In 2017, Addy et al. set out to characterize skin surface lipid composition and differences in an age- and sex-controlled population as a foundation for developing a botanically derived skin surface lipid mimetic agent. They noted that fatty acids, triglycerides, cholesterol, steryl esters, wax esters, and squalene are the main constituents of skin surface lipids. The investigators obtained skin surface lipid samples from the foreheads of 59 healthy 22-year-old women, analyzed them, and used the raw components of M. integrifolia, Simmondsia chinensis, and Olea europaea to engineer a mimetic product. They reported that the esterification reactions of jojoba, macadamia, and tall oils, combined with squalene derived from O. europaea, yielded an appropriate skin surface lipid mimetic, which, when applied to delipidized skin, assisted in recovering barrier function, enhancing skin hydration, and improving elasticity as well as firmness in aged skin. The researchers concluded that this skin surface lipid mimetic could serve as an effective supplement to human skin surface lipids in aged skin and for conditions in which the stratum corneum is impaired.4
Two years later, Hanum et al. compared the effects of macadamia nut oil nanocream and conventional cream for treating cutaneous aging over a 4-week period. The macadamia nut oil nanocream, which contained macadamia nut oil 10%, tween 80, propylene glycol, cetyl alcohol, methylparaben, propylparaben, and distilled water, was compared with the conventional cream based on effects on moisture, evenness, pore size, melanin, and wrinkling. The macadamia nut oil was found to yield superior anti-aging activity along each parameter as compared with the conventional cream. The researchers concluded that the macadamia nut oil in nanocream can be an effective formulation for providing benefits in addressing cutaneous aging.5
Macadamia nut oil has also been used in an anti-aging emulsion that was evaluated in a small study with 11 volunteers in 2008. Akhtar et al. prepared multiple emulsions of vitamin C and wheat protein using macadamia oil for its abundant supply of palmitoleic acid. Over 4 weeks, the emulsion was found to increase skin moisture without affecting other skin parameters, such as elasticity, erythema, melanin, pH, or sebum levels.6
Sapucaia (L. pisonis), an ornamental tree that is used for timber, produces edible, nutritious nuts that are rich in tocopherols, polyphenols, and fatty acids.7,8 In 2018, Demoliner et al. identified and characterized the phenolic substances present in sapucaia nut extract and its shell. Antioxidant activity conferred by the extract was attributed to the copious supply of catechin, epicatechin, and myricetin, as well as ellagic and ferulic acids, among the 14 phenolic constituents. The shell included 22 phenolic substances along with a significant level of condensed tannins and marked antioxidant function. The authors correlated the substantial activity imparted by the shell with its higher phenolic content, and suggested this robust source of natural antioxidants could be well suited to use in cosmetic products.9
Antifungal Activity
In 2015, Vieira et al. characterized 12 fractions enriched in peptides derived from L. pisonis seeds to determine inhibitory activity against Candida albicans. The fraction that exerted the strongest activity at 10 μg/mL, suppressing C. albicans growth by 38.5% and inducing a 69.3% loss of viability, was identified as similar to plant defensins and thus dubbed “L. pisonis defensin 1 (Lp-Def1).” The investigators concluded that Lp-Def1 acts on C. albicans by slightly elevating the induction of reactive oxygen species and causing a significant reduction in mitochondrial activity. They suggested that their findings support the use of plant defensins, particularly Lp-Def1, in the formulation of antifungal products, especially to address C. albicans.10
Pruritus
In 2012, Silva et al. studied the antipruritic impact of L. pisonis leaf extracts in mice and rats. Pretreatment with the various fractions of L. pisonis as well as constituent mixed triterpenes (ursolic and oleanolic acids) significantly blocked scratching behavior provoked by compound 48/80. The degranulation of rat peritoneal mast cells caused by compound 48/80 was also substantially decreased from pretreatment with the ethanol extract of L. pisonis, ether-L. pisonis fraction, and mixed triterpenes. The L. pisonis ether fraction suppressed edema induced by carrageenan administration and the ethanol extract displayed no toxicity up to an oral dose of 2g/kg. The investigators concluded that their results strongly support the antipruritic effects of L. pisonis leaves as well as the traditional use of the plant to treat pruritus.2
Stability for Cosmetic Creams
In 2020, Rampazzo et al. assessed the stability and cytotoxicity of a cosmetic cream containing sapucaia nut oil. All three tested concentrations (1%, 5%, and 10%) of the cream were found to be stable, with an effective preservative system, and deemed safe for use on human skin. To maintain a pH appropriate for a body cream, the formulation requires a stabilizing agent. The cream with 5% nut oil was identified as the most stable and satisfying for use on the skin.7
More recently, Hertel Pereira et al. investigated the benefits of using L. pisonis pericarp extract, known to exhibit abundant antioxidants, in an all-natural skin cream. They found that formulation instability increased proportionally with the concentration of the extract, but the use of the outer pericarp of L. pisonis was well suited for the cream formulation, with physical-chemical and organoleptic qualities unchanged after the stability test.11
Conclusion
The available literature on the medical applications of macadamia and sapucaia plants is sparse. Some recent findings are promising regarding possible uses in skin health. However, much more research is necessary before considering macadamia and sapucaia as viable sources of botanical agents capable of delivering significant cutaneous benefits.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., an SaaS company used to generate skin care routines in office and as an e-commerce solution. Write to her at [email protected].
References
1. Dailey A and Vuong QV. Antioxidants (Basel). 2015 Nov 12;4(4):699-718.
2. Silva LL et al. J Ethnopharmacol. 2012 Jan 6;139(1):90-97.
3. Somwongin S et al. Ultrason Sonochem. 2023 Jan;92:106266.
4. Addy J et al. J Cosmet Sci. 2017 Jan/Feb;68(1):59-67.
5. Hanum TI et al. Open Access Maced J Med Sci. 2019 Nov 14;7(22):3917-3920.
6. Akhtar N and Yazan Y. Pak J Pharm Sci. 2008 Jan;21(1):45-50.
7. Rampazzo APS et al. J Cosmet Sci. 2020 Sep/Oct;71(5):239-250.
8. Rosa TLM et al. Food Res Int. 2020 Nov;137:109383.
9. Demoliner F et al. Food Res Int. 2018 Oct;112:434-442.
10. Vieira ME et al. Acta Biochim Biophys Sin (Shanghai). 2015 Sep;47(9):716-729.
11. Hertel Pereira AC et al. J Cosmet Sci. 2021 Mar-Apr;72(2):155-162.
Macadamia (Macadamia tetraphylla) is endemic to Australia and is now commercially cultivated worldwide.1 It is closely related genetically to the other macadamia plants, including the other main one, M. integrifolia, cultivated for macadamia nuts. Known in Brazil as sapucaia or castanha-de-sapucaia, Lecythis pisonis (also referred to as “cream nut” or “monkey pot”) is a large, deciduous tropical tree and member of the Brazil nut family, Lecythidaceae.2 Various parts of both of these plants have been associated with medicinal properties, including the potential for dermatologic activity. Notably, the leaves of L. pisonis have been used in traditional medicine to treat pruritus.2.
Macadamia
Extraction to Harness Antioxidant Activity
In 2015, Dailey and Vuong developed an aqueous extraction process to recover the phenolic content and antioxidant functionality from the skin waste of M. tetraphylla using response surface methodology. As an environmentally suitable solvent that is also cheap and safe, water was chosen to maximize the extraction scenario. They identified the proper conditions (90° C, a time of 20 min, and a sample-to-solvent ratio of 5 g/100 mL) to obtain sufficient phenolic compounds, proanthocyanidins, and flavonoids to render robust antioxidant function.1
Early in 2023, Somwongin et al. investigated various green extraction methods for viability in harnessing the cosmetic/cosmeceutical ingredients of M. integrifolia pericarps. Extracts were assessed for total phenolic content as well as antioxidant and anti–skin aging functions. They found that among the green extraction methods (ultrasound, micellar, microwave, and pulsed electric field extraction with water used as a clean solvent), the ultrasound-assisted extraction method netted the greatest yield and total phenolic content. It was also associated with the most robust antioxidant and anti–skin aging activities. Indeed, the researchers reported that its antioxidant activities were comparable to ascorbic acid and Trolox and its anti–skin aging potency on a par with epigallocatechin-3-gallate and oleanolic acid. The ultrasound-assisted extract was also deemed safe as it did not provoke irritation. The authors concluded that this environmentally suitable extraction method for M. integrifolia is appropriate for obtaining effective macadamia extracts for use in cosmetics and cosmeceuticals.3
Anti-Aging Activity
In 2017, Addy et al. set out to characterize skin surface lipid composition and differences in an age- and sex-controlled population as a foundation for developing a botanically derived skin surface lipid mimetic agent. They noted that fatty acids, triglycerides, cholesterol, steryl esters, wax esters, and squalene are the main constituents of skin surface lipids. The investigators obtained skin surface lipid samples from the foreheads of 59 healthy 22-year-old women, analyzed them, and used the raw components of M. integrifolia, Simmondsia chinensis, and Olea europaea to engineer a mimetic product. They reported that the esterification reactions of jojoba, macadamia, and tall oils, combined with squalene derived from O. europaea, yielded an appropriate skin surface lipid mimetic, which, when applied to delipidized skin, assisted in recovering barrier function, enhancing skin hydration, and improving elasticity as well as firmness in aged skin. The researchers concluded that this skin surface lipid mimetic could serve as an effective supplement to human skin surface lipids in aged skin and for conditions in which the stratum corneum is impaired.4
Two years later, Hanum et al. compared the effects of macadamia nut oil nanocream and conventional cream for treating cutaneous aging over a 4-week period. The macadamia nut oil nanocream, which contained macadamia nut oil 10%, tween 80, propylene glycol, cetyl alcohol, methylparaben, propylparaben, and distilled water, was compared with the conventional cream based on effects on moisture, evenness, pore size, melanin, and wrinkling. The macadamia nut oil was found to yield superior anti-aging activity along each parameter as compared with the conventional cream. The researchers concluded that the macadamia nut oil in nanocream can be an effective formulation for providing benefits in addressing cutaneous aging.5
Macadamia nut oil has also been used in an anti-aging emulsion that was evaluated in a small study with 11 volunteers in 2008. Akhtar et al. prepared multiple emulsions of vitamin C and wheat protein using macadamia oil for its abundant supply of palmitoleic acid. Over 4 weeks, the emulsion was found to increase skin moisture without affecting other skin parameters, such as elasticity, erythema, melanin, pH, or sebum levels.6
Sapucaia (L. pisonis), an ornamental tree that is used for timber, produces edible, nutritious nuts that are rich in tocopherols, polyphenols, and fatty acids.7,8 In 2018, Demoliner et al. identified and characterized the phenolic substances present in sapucaia nut extract and its shell. Antioxidant activity conferred by the extract was attributed to the copious supply of catechin, epicatechin, and myricetin, as well as ellagic and ferulic acids, among the 14 phenolic constituents. The shell included 22 phenolic substances along with a significant level of condensed tannins and marked antioxidant function. The authors correlated the substantial activity imparted by the shell with its higher phenolic content, and suggested this robust source of natural antioxidants could be well suited to use in cosmetic products.9
Antifungal Activity
In 2015, Vieira et al. characterized 12 fractions enriched in peptides derived from L. pisonis seeds to determine inhibitory activity against Candida albicans. The fraction that exerted the strongest activity at 10 μg/mL, suppressing C. albicans growth by 38.5% and inducing a 69.3% loss of viability, was identified as similar to plant defensins and thus dubbed “L. pisonis defensin 1 (Lp-Def1).” The investigators concluded that Lp-Def1 acts on C. albicans by slightly elevating the induction of reactive oxygen species and causing a significant reduction in mitochondrial activity. They suggested that their findings support the use of plant defensins, particularly Lp-Def1, in the formulation of antifungal products, especially to address C. albicans.10
Pruritus
In 2012, Silva et al. studied the antipruritic impact of L. pisonis leaf extracts in mice and rats. Pretreatment with the various fractions of L. pisonis as well as constituent mixed triterpenes (ursolic and oleanolic acids) significantly blocked scratching behavior provoked by compound 48/80. The degranulation of rat peritoneal mast cells caused by compound 48/80 was also substantially decreased from pretreatment with the ethanol extract of L. pisonis, ether-L. pisonis fraction, and mixed triterpenes. The L. pisonis ether fraction suppressed edema induced by carrageenan administration and the ethanol extract displayed no toxicity up to an oral dose of 2g/kg. The investigators concluded that their results strongly support the antipruritic effects of L. pisonis leaves as well as the traditional use of the plant to treat pruritus.2
Stability for Cosmetic Creams
In 2020, Rampazzo et al. assessed the stability and cytotoxicity of a cosmetic cream containing sapucaia nut oil. All three tested concentrations (1%, 5%, and 10%) of the cream were found to be stable, with an effective preservative system, and deemed safe for use on human skin. To maintain a pH appropriate for a body cream, the formulation requires a stabilizing agent. The cream with 5% nut oil was identified as the most stable and satisfying for use on the skin.7
More recently, Hertel Pereira et al. investigated the benefits of using L. pisonis pericarp extract, known to exhibit abundant antioxidants, in an all-natural skin cream. They found that formulation instability increased proportionally with the concentration of the extract, but the use of the outer pericarp of L. pisonis was well suited for the cream formulation, with physical-chemical and organoleptic qualities unchanged after the stability test.11
Conclusion
The available literature on the medical applications of macadamia and sapucaia plants is sparse. Some recent findings are promising regarding possible uses in skin health. However, much more research is necessary before considering macadamia and sapucaia as viable sources of botanical agents capable of delivering significant cutaneous benefits.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., an SaaS company used to generate skin care routines in office and as an e-commerce solution. Write to her at [email protected].
References
1. Dailey A and Vuong QV. Antioxidants (Basel). 2015 Nov 12;4(4):699-718.
2. Silva LL et al. J Ethnopharmacol. 2012 Jan 6;139(1):90-97.
3. Somwongin S et al. Ultrason Sonochem. 2023 Jan;92:106266.
4. Addy J et al. J Cosmet Sci. 2017 Jan/Feb;68(1):59-67.
5. Hanum TI et al. Open Access Maced J Med Sci. 2019 Nov 14;7(22):3917-3920.
6. Akhtar N and Yazan Y. Pak J Pharm Sci. 2008 Jan;21(1):45-50.
7. Rampazzo APS et al. J Cosmet Sci. 2020 Sep/Oct;71(5):239-250.
8. Rosa TLM et al. Food Res Int. 2020 Nov;137:109383.
9. Demoliner F et al. Food Res Int. 2018 Oct;112:434-442.
10. Vieira ME et al. Acta Biochim Biophys Sin (Shanghai). 2015 Sep;47(9):716-729.
11. Hertel Pereira AC et al. J Cosmet Sci. 2021 Mar-Apr;72(2):155-162.
Macadamia (Macadamia tetraphylla) is endemic to Australia and is now commercially cultivated worldwide.1 It is closely related genetically to the other macadamia plants, including the other main one, M. integrifolia, cultivated for macadamia nuts. Known in Brazil as sapucaia or castanha-de-sapucaia, Lecythis pisonis (also referred to as “cream nut” or “monkey pot”) is a large, deciduous tropical tree and member of the Brazil nut family, Lecythidaceae.2 Various parts of both of these plants have been associated with medicinal properties, including the potential for dermatologic activity. Notably, the leaves of L. pisonis have been used in traditional medicine to treat pruritus.2.
Macadamia
Extraction to Harness Antioxidant Activity
In 2015, Dailey and Vuong developed an aqueous extraction process to recover the phenolic content and antioxidant functionality from the skin waste of M. tetraphylla using response surface methodology. As an environmentally suitable solvent that is also cheap and safe, water was chosen to maximize the extraction scenario. They identified the proper conditions (90° C, a time of 20 min, and a sample-to-solvent ratio of 5 g/100 mL) to obtain sufficient phenolic compounds, proanthocyanidins, and flavonoids to render robust antioxidant function.1
Early in 2023, Somwongin et al. investigated various green extraction methods for viability in harnessing the cosmetic/cosmeceutical ingredients of M. integrifolia pericarps. Extracts were assessed for total phenolic content as well as antioxidant and anti–skin aging functions. They found that among the green extraction methods (ultrasound, micellar, microwave, and pulsed electric field extraction with water used as a clean solvent), the ultrasound-assisted extraction method netted the greatest yield and total phenolic content. It was also associated with the most robust antioxidant and anti–skin aging activities. Indeed, the researchers reported that its antioxidant activities were comparable to ascorbic acid and Trolox and its anti–skin aging potency on a par with epigallocatechin-3-gallate and oleanolic acid. The ultrasound-assisted extract was also deemed safe as it did not provoke irritation. The authors concluded that this environmentally suitable extraction method for M. integrifolia is appropriate for obtaining effective macadamia extracts for use in cosmetics and cosmeceuticals.3
Anti-Aging Activity
In 2017, Addy et al. set out to characterize skin surface lipid composition and differences in an age- and sex-controlled population as a foundation for developing a botanically derived skin surface lipid mimetic agent. They noted that fatty acids, triglycerides, cholesterol, steryl esters, wax esters, and squalene are the main constituents of skin surface lipids. The investigators obtained skin surface lipid samples from the foreheads of 59 healthy 22-year-old women, analyzed them, and used the raw components of M. integrifolia, Simmondsia chinensis, and Olea europaea to engineer a mimetic product. They reported that the esterification reactions of jojoba, macadamia, and tall oils, combined with squalene derived from O. europaea, yielded an appropriate skin surface lipid mimetic, which, when applied to delipidized skin, assisted in recovering barrier function, enhancing skin hydration, and improving elasticity as well as firmness in aged skin. The researchers concluded that this skin surface lipid mimetic could serve as an effective supplement to human skin surface lipids in aged skin and for conditions in which the stratum corneum is impaired.4
Two years later, Hanum et al. compared the effects of macadamia nut oil nanocream and conventional cream for treating cutaneous aging over a 4-week period. The macadamia nut oil nanocream, which contained macadamia nut oil 10%, tween 80, propylene glycol, cetyl alcohol, methylparaben, propylparaben, and distilled water, was compared with the conventional cream based on effects on moisture, evenness, pore size, melanin, and wrinkling. The macadamia nut oil was found to yield superior anti-aging activity along each parameter as compared with the conventional cream. The researchers concluded that the macadamia nut oil in nanocream can be an effective formulation for providing benefits in addressing cutaneous aging.5
Macadamia nut oil has also been used in an anti-aging emulsion that was evaluated in a small study with 11 volunteers in 2008. Akhtar et al. prepared multiple emulsions of vitamin C and wheat protein using macadamia oil for its abundant supply of palmitoleic acid. Over 4 weeks, the emulsion was found to increase skin moisture without affecting other skin parameters, such as elasticity, erythema, melanin, pH, or sebum levels.6
Sapucaia (L. pisonis), an ornamental tree that is used for timber, produces edible, nutritious nuts that are rich in tocopherols, polyphenols, and fatty acids.7,8 In 2018, Demoliner et al. identified and characterized the phenolic substances present in sapucaia nut extract and its shell. Antioxidant activity conferred by the extract was attributed to the copious supply of catechin, epicatechin, and myricetin, as well as ellagic and ferulic acids, among the 14 phenolic constituents. The shell included 22 phenolic substances along with a significant level of condensed tannins and marked antioxidant function. The authors correlated the substantial activity imparted by the shell with its higher phenolic content, and suggested this robust source of natural antioxidants could be well suited to use in cosmetic products.9
Antifungal Activity
In 2015, Vieira et al. characterized 12 fractions enriched in peptides derived from L. pisonis seeds to determine inhibitory activity against Candida albicans. The fraction that exerted the strongest activity at 10 μg/mL, suppressing C. albicans growth by 38.5% and inducing a 69.3% loss of viability, was identified as similar to plant defensins and thus dubbed “L. pisonis defensin 1 (Lp-Def1).” The investigators concluded that Lp-Def1 acts on C. albicans by slightly elevating the induction of reactive oxygen species and causing a significant reduction in mitochondrial activity. They suggested that their findings support the use of plant defensins, particularly Lp-Def1, in the formulation of antifungal products, especially to address C. albicans.10
Pruritus
In 2012, Silva et al. studied the antipruritic impact of L. pisonis leaf extracts in mice and rats. Pretreatment with the various fractions of L. pisonis as well as constituent mixed triterpenes (ursolic and oleanolic acids) significantly blocked scratching behavior provoked by compound 48/80. The degranulation of rat peritoneal mast cells caused by compound 48/80 was also substantially decreased from pretreatment with the ethanol extract of L. pisonis, ether-L. pisonis fraction, and mixed triterpenes. The L. pisonis ether fraction suppressed edema induced by carrageenan administration and the ethanol extract displayed no toxicity up to an oral dose of 2g/kg. The investigators concluded that their results strongly support the antipruritic effects of L. pisonis leaves as well as the traditional use of the plant to treat pruritus.2
Stability for Cosmetic Creams
In 2020, Rampazzo et al. assessed the stability and cytotoxicity of a cosmetic cream containing sapucaia nut oil. All three tested concentrations (1%, 5%, and 10%) of the cream were found to be stable, with an effective preservative system, and deemed safe for use on human skin. To maintain a pH appropriate for a body cream, the formulation requires a stabilizing agent. The cream with 5% nut oil was identified as the most stable and satisfying for use on the skin.7
More recently, Hertel Pereira et al. investigated the benefits of using L. pisonis pericarp extract, known to exhibit abundant antioxidants, in an all-natural skin cream. They found that formulation instability increased proportionally with the concentration of the extract, but the use of the outer pericarp of L. pisonis was well suited for the cream formulation, with physical-chemical and organoleptic qualities unchanged after the stability test.11
Conclusion
The available literature on the medical applications of macadamia and sapucaia plants is sparse. Some recent findings are promising regarding possible uses in skin health. However, much more research is necessary before considering macadamia and sapucaia as viable sources of botanical agents capable of delivering significant cutaneous benefits.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., an SaaS company used to generate skin care routines in office and as an e-commerce solution. Write to her at [email protected].
References
1. Dailey A and Vuong QV. Antioxidants (Basel). 2015 Nov 12;4(4):699-718.
2. Silva LL et al. J Ethnopharmacol. 2012 Jan 6;139(1):90-97.
3. Somwongin S et al. Ultrason Sonochem. 2023 Jan;92:106266.
4. Addy J et al. J Cosmet Sci. 2017 Jan/Feb;68(1):59-67.
5. Hanum TI et al. Open Access Maced J Med Sci. 2019 Nov 14;7(22):3917-3920.
6. Akhtar N and Yazan Y. Pak J Pharm Sci. 2008 Jan;21(1):45-50.
7. Rampazzo APS et al. J Cosmet Sci. 2020 Sep/Oct;71(5):239-250.
8. Rosa TLM et al. Food Res Int. 2020 Nov;137:109383.
9. Demoliner F et al. Food Res Int. 2018 Oct;112:434-442.
10. Vieira ME et al. Acta Biochim Biophys Sin (Shanghai). 2015 Sep;47(9):716-729.
11. Hertel Pereira AC et al. J Cosmet Sci. 2021 Mar-Apr;72(2):155-162.
Alcohol to Blame: Weight Regain After Bariatric Surgery
A 50-year-old woman with a history of class 3 obesity, gastroesophageal reflux disease, prediabetes, metabolic dysfunction–associated steatotic liver disease, asthma, and depression returns to our weight management clinic with weight regain 4 years after Roux-en-Y gastric bypass.
Her initial body weight was 389 lb (176.8 kg; body mass index [BMI], 65), and her nadir weight after surgery was 183 lb (83.2 kg; BMI, 30.5), representing a total weight loss of 53%. During the initial 2 years after surgery, she experienced multiple life stressors and was treated with venlafaxine for mild depression. She regained 25 lb (11.4 kg). Over the next 2 years, she gained another 20 lb (9.1 kg), for a total of 45 lb (20.5 kg) above nadir.
The patient reported increased nighttime consumption of alcohol including vodka, wine, and beer of over 20 drinks per week for the past 2 years. Her laboratory profile showed an elevated fasting glucose level (106 mg/dL, formerly 98 mg/dL), an elevated gamma-glutamyl transferase (GGT) level, and iron deficiency anemia. She admitted to regularly missing doses of postbariatric vitamins and minerals.
Ask Patients About Alcohol Use
It’s important to ask patients with significant weight regain after metabolic and bariatric surgery (MBS) about alcohol intake, because patients who have MBS are at an increased risk of developing alcohol use disorder (AUD).
The American Society for Metabolic and Bariatric Surgery recommends screening for alcohol intake both before and after MBS. Underreporting of alcohol consumption is common, but an elevated GGT level or elevated liver enzyme levels can indicate alcohol use. Depression and anxiety exacerbated by life stressors often accompany excessive alcohol intake.
Some antiobesity medications that regulate appetite may also help limit excessive alcohol intake. Naltrexone is used both for the treatment of AUD and for weight management, often in combination with bupropion). In a patient with weight regain and AUD, naltrexone alone would be a reasonable treatment option, although weight loss would probably be modest. The addition of bupropion to naltrexone would probably produce more weight loss; average total body weight loss with bupropion-naltrexone in clinical trials was about 6%. One cautionary note on bupropion: A patient’s seizure history should be elicited, because people with AUD are at increased risk for seizures in the withdrawal stage and bupropion can make those seizures more likely.
Glucagon-like peptide 1 (GLP-1) receptor agonists (eg, liraglutide and semaglutide) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide receptor agonists) (eg, tirzepatide) are second-generation antiobesity medications that produce more weight loss than first-generation agents such as bupropion/naltrexone. Of note, prior bariatric surgery was an exclusion criterion in the clinical trials assessing the efficacy of these agents for weight loss. The use of GLP-1 receptor agonists after MBS in people with inadequate weight loss or weight regain has been an area of active research. The BARI-OPTIMISE randomized clinical trial published in 2023 assessed the safety and efficacy of liraglutide 3.0 mg daily in patients with inadequate weight loss after MBS. The mean body weight reduction was 8.82% in the liraglutide group vs 0.54% in the placebo group.
There is also emerging interest in the potential of GLP-1 receptor agonists in AUD. These medications act on the central nervous system to influence reward pathways. In rodents, studies have shown that GLP-1 receptor agonist administration reduces alcohol intake, although most studies have focused on short-term effects.
A series of experiments assessed the effects of semaglutide on alcohol intake in rodents. The authors found that semaglutide lowered the alcohol-induced release of dopamine and enhanced dopamine metabolism within the nucleus accumbens.
Evidence in humans is still limited, with only one published randomized controlled trial to date. In the 26-week study, weekly exenatide was not superior to placebo in reducing the number of heavy drinking days in patients with AUD who also received cognitive-behavioral therapy. An exploratory analysis in a subgroup of patients with obesity and AUD showed that exenatide reduced alcohol consumption. Of note, exenatide is rarely used in clinical practice because it does not produce substantial weight loss.
Liraglutide was chosen for this patient because of the established efficacy for this agent in patients with a history of MBS. In addition, patients often anecdotally report reduced desire for alcohol while taking a GLP-1 receptor agonist. Although GLP-1 receptor agonists have been shown to reduce alcohol intake in animal studies, their efficacy and safety in humans with AUD are not yet well established.
Back to Our Patient:
Given the patient’s weight regain, an upper gastrointestinal series was performed to rule out gastro-gastric fistula or other anatomic abnormalities. After fistula was ruled out, she was prescribed liraglutide for weight management, which was titrated from 0.6 mg/d to 3 mg/d per the prescribing guidelines.
With the use of liraglutide over the next year, the patient maintained a stable weight of 200 lb (90.9 kg) and noted that along with reduced appetite, her cravings for alcohol had diminished and she no longer felt the urge to drink alcohol at night. Her fasting glucose and GGT levels normalized. She began to see a nutritionist regularly and was planning to rejoin a bariatric support group.
Dr. Schmitz is an instructor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York. She has disclosed no relevant financial relationships. Dr. Kashyap is a assistant chief of clinical affairs, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell New York Presbyterian, New York. She disclosed ties to GI Dynamics.
A version of this article appeared on Medscape.com.
A 50-year-old woman with a history of class 3 obesity, gastroesophageal reflux disease, prediabetes, metabolic dysfunction–associated steatotic liver disease, asthma, and depression returns to our weight management clinic with weight regain 4 years after Roux-en-Y gastric bypass.
Her initial body weight was 389 lb (176.8 kg; body mass index [BMI], 65), and her nadir weight after surgery was 183 lb (83.2 kg; BMI, 30.5), representing a total weight loss of 53%. During the initial 2 years after surgery, she experienced multiple life stressors and was treated with venlafaxine for mild depression. She regained 25 lb (11.4 kg). Over the next 2 years, she gained another 20 lb (9.1 kg), for a total of 45 lb (20.5 kg) above nadir.
The patient reported increased nighttime consumption of alcohol including vodka, wine, and beer of over 20 drinks per week for the past 2 years. Her laboratory profile showed an elevated fasting glucose level (106 mg/dL, formerly 98 mg/dL), an elevated gamma-glutamyl transferase (GGT) level, and iron deficiency anemia. She admitted to regularly missing doses of postbariatric vitamins and minerals.
Ask Patients About Alcohol Use
It’s important to ask patients with significant weight regain after metabolic and bariatric surgery (MBS) about alcohol intake, because patients who have MBS are at an increased risk of developing alcohol use disorder (AUD).
The American Society for Metabolic and Bariatric Surgery recommends screening for alcohol intake both before and after MBS. Underreporting of alcohol consumption is common, but an elevated GGT level or elevated liver enzyme levels can indicate alcohol use. Depression and anxiety exacerbated by life stressors often accompany excessive alcohol intake.
Some antiobesity medications that regulate appetite may also help limit excessive alcohol intake. Naltrexone is used both for the treatment of AUD and for weight management, often in combination with bupropion). In a patient with weight regain and AUD, naltrexone alone would be a reasonable treatment option, although weight loss would probably be modest. The addition of bupropion to naltrexone would probably produce more weight loss; average total body weight loss with bupropion-naltrexone in clinical trials was about 6%. One cautionary note on bupropion: A patient’s seizure history should be elicited, because people with AUD are at increased risk for seizures in the withdrawal stage and bupropion can make those seizures more likely.
Glucagon-like peptide 1 (GLP-1) receptor agonists (eg, liraglutide and semaglutide) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide receptor agonists) (eg, tirzepatide) are second-generation antiobesity medications that produce more weight loss than first-generation agents such as bupropion/naltrexone. Of note, prior bariatric surgery was an exclusion criterion in the clinical trials assessing the efficacy of these agents for weight loss. The use of GLP-1 receptor agonists after MBS in people with inadequate weight loss or weight regain has been an area of active research. The BARI-OPTIMISE randomized clinical trial published in 2023 assessed the safety and efficacy of liraglutide 3.0 mg daily in patients with inadequate weight loss after MBS. The mean body weight reduction was 8.82% in the liraglutide group vs 0.54% in the placebo group.
There is also emerging interest in the potential of GLP-1 receptor agonists in AUD. These medications act on the central nervous system to influence reward pathways. In rodents, studies have shown that GLP-1 receptor agonist administration reduces alcohol intake, although most studies have focused on short-term effects.
A series of experiments assessed the effects of semaglutide on alcohol intake in rodents. The authors found that semaglutide lowered the alcohol-induced release of dopamine and enhanced dopamine metabolism within the nucleus accumbens.
Evidence in humans is still limited, with only one published randomized controlled trial to date. In the 26-week study, weekly exenatide was not superior to placebo in reducing the number of heavy drinking days in patients with AUD who also received cognitive-behavioral therapy. An exploratory analysis in a subgroup of patients with obesity and AUD showed that exenatide reduced alcohol consumption. Of note, exenatide is rarely used in clinical practice because it does not produce substantial weight loss.
Liraglutide was chosen for this patient because of the established efficacy for this agent in patients with a history of MBS. In addition, patients often anecdotally report reduced desire for alcohol while taking a GLP-1 receptor agonist. Although GLP-1 receptor agonists have been shown to reduce alcohol intake in animal studies, their efficacy and safety in humans with AUD are not yet well established.
Back to Our Patient:
Given the patient’s weight regain, an upper gastrointestinal series was performed to rule out gastro-gastric fistula or other anatomic abnormalities. After fistula was ruled out, she was prescribed liraglutide for weight management, which was titrated from 0.6 mg/d to 3 mg/d per the prescribing guidelines.
With the use of liraglutide over the next year, the patient maintained a stable weight of 200 lb (90.9 kg) and noted that along with reduced appetite, her cravings for alcohol had diminished and she no longer felt the urge to drink alcohol at night. Her fasting glucose and GGT levels normalized. She began to see a nutritionist regularly and was planning to rejoin a bariatric support group.
Dr. Schmitz is an instructor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York. She has disclosed no relevant financial relationships. Dr. Kashyap is a assistant chief of clinical affairs, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell New York Presbyterian, New York. She disclosed ties to GI Dynamics.
A version of this article appeared on Medscape.com.
A 50-year-old woman with a history of class 3 obesity, gastroesophageal reflux disease, prediabetes, metabolic dysfunction–associated steatotic liver disease, asthma, and depression returns to our weight management clinic with weight regain 4 years after Roux-en-Y gastric bypass.
Her initial body weight was 389 lb (176.8 kg; body mass index [BMI], 65), and her nadir weight after surgery was 183 lb (83.2 kg; BMI, 30.5), representing a total weight loss of 53%. During the initial 2 years after surgery, she experienced multiple life stressors and was treated with venlafaxine for mild depression. She regained 25 lb (11.4 kg). Over the next 2 years, she gained another 20 lb (9.1 kg), for a total of 45 lb (20.5 kg) above nadir.
The patient reported increased nighttime consumption of alcohol including vodka, wine, and beer of over 20 drinks per week for the past 2 years. Her laboratory profile showed an elevated fasting glucose level (106 mg/dL, formerly 98 mg/dL), an elevated gamma-glutamyl transferase (GGT) level, and iron deficiency anemia. She admitted to regularly missing doses of postbariatric vitamins and minerals.
Ask Patients About Alcohol Use
It’s important to ask patients with significant weight regain after metabolic and bariatric surgery (MBS) about alcohol intake, because patients who have MBS are at an increased risk of developing alcohol use disorder (AUD).
The American Society for Metabolic and Bariatric Surgery recommends screening for alcohol intake both before and after MBS. Underreporting of alcohol consumption is common, but an elevated GGT level or elevated liver enzyme levels can indicate alcohol use. Depression and anxiety exacerbated by life stressors often accompany excessive alcohol intake.
Some antiobesity medications that regulate appetite may also help limit excessive alcohol intake. Naltrexone is used both for the treatment of AUD and for weight management, often in combination with bupropion). In a patient with weight regain and AUD, naltrexone alone would be a reasonable treatment option, although weight loss would probably be modest. The addition of bupropion to naltrexone would probably produce more weight loss; average total body weight loss with bupropion-naltrexone in clinical trials was about 6%. One cautionary note on bupropion: A patient’s seizure history should be elicited, because people with AUD are at increased risk for seizures in the withdrawal stage and bupropion can make those seizures more likely.
Glucagon-like peptide 1 (GLP-1) receptor agonists (eg, liraglutide and semaglutide) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide receptor agonists) (eg, tirzepatide) are second-generation antiobesity medications that produce more weight loss than first-generation agents such as bupropion/naltrexone. Of note, prior bariatric surgery was an exclusion criterion in the clinical trials assessing the efficacy of these agents for weight loss. The use of GLP-1 receptor agonists after MBS in people with inadequate weight loss or weight regain has been an area of active research. The BARI-OPTIMISE randomized clinical trial published in 2023 assessed the safety and efficacy of liraglutide 3.0 mg daily in patients with inadequate weight loss after MBS. The mean body weight reduction was 8.82% in the liraglutide group vs 0.54% in the placebo group.
There is also emerging interest in the potential of GLP-1 receptor agonists in AUD. These medications act on the central nervous system to influence reward pathways. In rodents, studies have shown that GLP-1 receptor agonist administration reduces alcohol intake, although most studies have focused on short-term effects.
A series of experiments assessed the effects of semaglutide on alcohol intake in rodents. The authors found that semaglutide lowered the alcohol-induced release of dopamine and enhanced dopamine metabolism within the nucleus accumbens.
Evidence in humans is still limited, with only one published randomized controlled trial to date. In the 26-week study, weekly exenatide was not superior to placebo in reducing the number of heavy drinking days in patients with AUD who also received cognitive-behavioral therapy. An exploratory analysis in a subgroup of patients with obesity and AUD showed that exenatide reduced alcohol consumption. Of note, exenatide is rarely used in clinical practice because it does not produce substantial weight loss.
Liraglutide was chosen for this patient because of the established efficacy for this agent in patients with a history of MBS. In addition, patients often anecdotally report reduced desire for alcohol while taking a GLP-1 receptor agonist. Although GLP-1 receptor agonists have been shown to reduce alcohol intake in animal studies, their efficacy and safety in humans with AUD are not yet well established.
Back to Our Patient:
Given the patient’s weight regain, an upper gastrointestinal series was performed to rule out gastro-gastric fistula or other anatomic abnormalities. After fistula was ruled out, she was prescribed liraglutide for weight management, which was titrated from 0.6 mg/d to 3 mg/d per the prescribing guidelines.
With the use of liraglutide over the next year, the patient maintained a stable weight of 200 lb (90.9 kg) and noted that along with reduced appetite, her cravings for alcohol had diminished and she no longer felt the urge to drink alcohol at night. Her fasting glucose and GGT levels normalized. She began to see a nutritionist regularly and was planning to rejoin a bariatric support group.
Dr. Schmitz is an instructor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York. She has disclosed no relevant financial relationships. Dr. Kashyap is a assistant chief of clinical affairs, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell New York Presbyterian, New York. She disclosed ties to GI Dynamics.
A version of this article appeared on Medscape.com.
Specialists Are ‘Underwater’ With Some Insurance-Preferred Biosimilars
Editor’s note: This article is adapted from an explanatory statement that Dr. Feldman wrote for the Coalition of State Rheumatology Organizations (CSRO).
According to the Guinness Book of World records, the longest time someone has held their breath underwater voluntarily is 24 minutes and 37.36 seconds. While certainly an amazing feat, UnitedHealthcare, many of the Blues, and other national “payers” are expecting rheumatologists and other specialists to live “underwater” in order to take care of their patients. In other words, these insurance companies are mandating that specialists use certain provider-administered biosimilars whose acquisition cost is higher than what the insurance company is willing to reimburse them. Essentially, the insurance companies expect the rheumatologists to pay them to take care of their patients. Because of the substantial and destabilizing financial losses incurred, many practices and free-standing infusion centers have been forced to cease offering these biosimilars. Most rheumatologists will provide patients with appropriate alternatives when available and permitted by the insurer; otherwise, they must refer patients to hospital-based infusion centers. That results in delayed care and increased costs for patients and the system, because hospital-based infusion typically costs more than twice what office-based infusion costs.
Quantifying the Problem
To help quantify the magnitude of this issue, the Coalition of State Rheumatology Organizations (CSRO) recently conducted a survey of its membership. A shocking 97% of respondents reported that their practice had been affected by reimbursement rates for some biosimilars being lower than acquisition costs, with 91% of respondents stating that this issue is more pronounced for certain biosimilars than others. Across the board, respondents most frequently identified Inflectra (infliximab-dyyb) and Avsola (infliximab-axxq) as being especially affected: Over 88% and over 85% of respondents identified these two products, respectively, as being underwater. These results support the ongoing anecdotal reports CSRO continues to receive from rheumatology practices.
However, the survey results indicated that this issue is by no means confined to those two biosimilars. Truxima (rituximab-abbs) — a biosimilar for Rituxan — was frequently mentioned as well. Notably, respondents almost uniformly identified biosimilars in the infliximab and rituximab families, which illustrates that this issue is no longer confined to one or two early-to-market biosimilars but has almost become a hallmark of this particular biosimilars market. Remarkably, one respondent commented that the brand products are now cheaper to acquire than the biosimilars. Furthermore, the survey included respondents from across the country, indicating that this issue is not confined to a particular region.
How Did This Happen?
Biosimilars held promise for increasing availability and decreasing biologic costs for patients but, thus far, no patients have seen their cost go down. It appears that the only biosimilars that have made it to “preferred” status on the formulary are the ones that have made more money for the middlemen in the drug supply chain, particularly those that construct formularies. Now, we have provider-administered biosimilars whose acquisition cost exceeds the reimbursement for these drugs. This disparity was ultimately created by biosimilar manufacturers “over-rebating” their drugs to health insurance companies to gain “fail-first” status on the formulary.
For example, the manufacturer of Inflectra offered substantial rebates to health insurers for preferred formulary placement. These rebates are factored into the sales price of the medication, which then results in a rapidly declining average sales price (ASP) for the biosimilar. Unfortunately, the acquisition cost for the drug does not experience commensurate reductions, resulting in physicians being reimbursed far less for the drug than it costs to acquire. The financial losses for physicians put them underwater as a result of the acquisition costs for the preferred drugs far surpassing the reimbursement from the health insurance company that constructed the formulary.
While various factors affect ASPs and acquisition costs, this particular consequence of formulary placement based on price concessions is a major driver of the underwater situation in which physicians have found themselves with many biosimilars. Not only does that lead to a lower uptake of biosimilars, but it also results in patients being referred to the hospital outpatient infusion sites to receive this care, as freestanding infusion centers cannot treat these patients either. Hospitals incur higher costs because of facility fees and elevated rates, and this makes private rheumatology in-office infusion centers a much lower-cost option. Similarly, home infusion services, while convenient, are marginally more expensive than private practices and, in cases of biologic infusions, it is important to note that physicians’ offices have a greater safety profile than home infusion of biologics. The overall result of these “fail-first underwater drugs” is delayed and more costly care for the patient and the “system,” particularly self-insured employers.
What Is Being Done to Correct This?
Since ASPs are updated quarterly, it is possible that acquisition costs and reimbursements might stabilize over time, making the drugs affordable again to practices. However, that does not appear to be happening in the near future, so that possibility does not offer immediate relief to struggling practices. It doesn’t promise a favorable outlook for future biosimilar entries of provider-administered medications if formularies continue to prefer the highest-rebated medication.
This dynamic between ASP and acquisition cost does not happen on the pharmacy side because the price concessions on specific drug rebates and fees are proprietary. There appears to be no equivalent to a publicly known ASP on the pharmacy side, which has led to myriad pricing definitions and manipulation on the pharmacy benefit side of medications. In any event, the savings from rebates and other manufacturer price concessions on pharmacy drugs do not influence ASPs of medical benefit drugs.
The Inflation Reduction Act provided a temporary increase in the add-on payment for biosimilars from ASP+6% to ASP+8%, but as long as the biosimilar’s ASP is lower than the reference brand’s ASP, that temporary increase does not appear to make up for the large differential between ASP and acquisition cost. It should be noted that any federal attempt to artificially lower the ASP of a provider-administered drug without a pathway assuring that the acquisition cost for the provider is less than the reimbursement is going to result in loss of access for patients to those medications and/or higher hospital site of care costs.
A Few Partial Fixes, But Most Complaints Go Ignored
Considering the higher costs of hospital-based infusion, insurers should be motivated to keep patients within private practices. Perhaps through insurers’ recognition of that fact, some practices have successfully negotiated exceptions for specific patients by discussing this situation with insurers. From the feedback that CSRO has received from rheumatology practices, it appears that most insurers have been ignoring the complaints from physicians. The few who have responded have resulted in only partial fixes, with some of the biosimilars still left underwater.
Ultimate Solution?
This issue is a direct result of the “rebate game,” whereby price concessions from drug manufacturers drive formulary placement. For provider-administered medications, this results in an artificially lowered ASP, not as a consequence of free-market incentives that benefit the patient, but as a result of misaligned incentives created by Safe Harbor–protected “kickbacks,” distorting the free market and paradoxically reducing access to these medications, delaying care, and increasing prices for patients and the healthcare system.
While federal and state governments are not likely to address this particular situation in the biosimilars market, CSRO is highlighting this issue as a prime example of why the current formulary construction system urgently requires federal reform. At this time, the biosimilars most affected are Inflectra and Avsola, but if nothing changes, more and more biosimilars will fall victim to the short-sighted pricing strategy of aggressive rebating to gain formulary position, with physician purchasers and patients left to navigate the aftermath. The existing system, which necessitates drug companies purchasing formulary access from pharmacy benefit managers, has led to delayed and even denied patient access to certain provider-administered drugs. Moreover, it now appears to be hindering the adoption of biosimilars.
To address this, a multifaceted approach is required. It not only involves reevaluating the rebate system and its impact on formulary construction and ASP, but also ensuring that acquisition costs for providers are aligned with reimbursement rates. Insurers must recognize the economic and clinical value of maintaining infusions within private practices and immediately update their policies to ensure that physician in-office infusion is financially feasible for these “fail-first” biosimilars.
Ultimately, the goal should be to create a sustainable model that promotes the use of affordable biosimilars, enhances patient access to affordable care, and supports the financial viability of medical practices. Concerted efforts to reform the current formulary construction system are required to achieve a healthcare environment that is both cost effective and patient centric.
Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].
Editor’s note: This article is adapted from an explanatory statement that Dr. Feldman wrote for the Coalition of State Rheumatology Organizations (CSRO).
According to the Guinness Book of World records, the longest time someone has held their breath underwater voluntarily is 24 minutes and 37.36 seconds. While certainly an amazing feat, UnitedHealthcare, many of the Blues, and other national “payers” are expecting rheumatologists and other specialists to live “underwater” in order to take care of their patients. In other words, these insurance companies are mandating that specialists use certain provider-administered biosimilars whose acquisition cost is higher than what the insurance company is willing to reimburse them. Essentially, the insurance companies expect the rheumatologists to pay them to take care of their patients. Because of the substantial and destabilizing financial losses incurred, many practices and free-standing infusion centers have been forced to cease offering these biosimilars. Most rheumatologists will provide patients with appropriate alternatives when available and permitted by the insurer; otherwise, they must refer patients to hospital-based infusion centers. That results in delayed care and increased costs for patients and the system, because hospital-based infusion typically costs more than twice what office-based infusion costs.
Quantifying the Problem
To help quantify the magnitude of this issue, the Coalition of State Rheumatology Organizations (CSRO) recently conducted a survey of its membership. A shocking 97% of respondents reported that their practice had been affected by reimbursement rates for some biosimilars being lower than acquisition costs, with 91% of respondents stating that this issue is more pronounced for certain biosimilars than others. Across the board, respondents most frequently identified Inflectra (infliximab-dyyb) and Avsola (infliximab-axxq) as being especially affected: Over 88% and over 85% of respondents identified these two products, respectively, as being underwater. These results support the ongoing anecdotal reports CSRO continues to receive from rheumatology practices.
However, the survey results indicated that this issue is by no means confined to those two biosimilars. Truxima (rituximab-abbs) — a biosimilar for Rituxan — was frequently mentioned as well. Notably, respondents almost uniformly identified biosimilars in the infliximab and rituximab families, which illustrates that this issue is no longer confined to one or two early-to-market biosimilars but has almost become a hallmark of this particular biosimilars market. Remarkably, one respondent commented that the brand products are now cheaper to acquire than the biosimilars. Furthermore, the survey included respondents from across the country, indicating that this issue is not confined to a particular region.
How Did This Happen?
Biosimilars held promise for increasing availability and decreasing biologic costs for patients but, thus far, no patients have seen their cost go down. It appears that the only biosimilars that have made it to “preferred” status on the formulary are the ones that have made more money for the middlemen in the drug supply chain, particularly those that construct formularies. Now, we have provider-administered biosimilars whose acquisition cost exceeds the reimbursement for these drugs. This disparity was ultimately created by biosimilar manufacturers “over-rebating” their drugs to health insurance companies to gain “fail-first” status on the formulary.
For example, the manufacturer of Inflectra offered substantial rebates to health insurers for preferred formulary placement. These rebates are factored into the sales price of the medication, which then results in a rapidly declining average sales price (ASP) for the biosimilar. Unfortunately, the acquisition cost for the drug does not experience commensurate reductions, resulting in physicians being reimbursed far less for the drug than it costs to acquire. The financial losses for physicians put them underwater as a result of the acquisition costs for the preferred drugs far surpassing the reimbursement from the health insurance company that constructed the formulary.
While various factors affect ASPs and acquisition costs, this particular consequence of formulary placement based on price concessions is a major driver of the underwater situation in which physicians have found themselves with many biosimilars. Not only does that lead to a lower uptake of biosimilars, but it also results in patients being referred to the hospital outpatient infusion sites to receive this care, as freestanding infusion centers cannot treat these patients either. Hospitals incur higher costs because of facility fees and elevated rates, and this makes private rheumatology in-office infusion centers a much lower-cost option. Similarly, home infusion services, while convenient, are marginally more expensive than private practices and, in cases of biologic infusions, it is important to note that physicians’ offices have a greater safety profile than home infusion of biologics. The overall result of these “fail-first underwater drugs” is delayed and more costly care for the patient and the “system,” particularly self-insured employers.
What Is Being Done to Correct This?
Since ASPs are updated quarterly, it is possible that acquisition costs and reimbursements might stabilize over time, making the drugs affordable again to practices. However, that does not appear to be happening in the near future, so that possibility does not offer immediate relief to struggling practices. It doesn’t promise a favorable outlook for future biosimilar entries of provider-administered medications if formularies continue to prefer the highest-rebated medication.
This dynamic between ASP and acquisition cost does not happen on the pharmacy side because the price concessions on specific drug rebates and fees are proprietary. There appears to be no equivalent to a publicly known ASP on the pharmacy side, which has led to myriad pricing definitions and manipulation on the pharmacy benefit side of medications. In any event, the savings from rebates and other manufacturer price concessions on pharmacy drugs do not influence ASPs of medical benefit drugs.
The Inflation Reduction Act provided a temporary increase in the add-on payment for biosimilars from ASP+6% to ASP+8%, but as long as the biosimilar’s ASP is lower than the reference brand’s ASP, that temporary increase does not appear to make up for the large differential between ASP and acquisition cost. It should be noted that any federal attempt to artificially lower the ASP of a provider-administered drug without a pathway assuring that the acquisition cost for the provider is less than the reimbursement is going to result in loss of access for patients to those medications and/or higher hospital site of care costs.
A Few Partial Fixes, But Most Complaints Go Ignored
Considering the higher costs of hospital-based infusion, insurers should be motivated to keep patients within private practices. Perhaps through insurers’ recognition of that fact, some practices have successfully negotiated exceptions for specific patients by discussing this situation with insurers. From the feedback that CSRO has received from rheumatology practices, it appears that most insurers have been ignoring the complaints from physicians. The few who have responded have resulted in only partial fixes, with some of the biosimilars still left underwater.
Ultimate Solution?
This issue is a direct result of the “rebate game,” whereby price concessions from drug manufacturers drive formulary placement. For provider-administered medications, this results in an artificially lowered ASP, not as a consequence of free-market incentives that benefit the patient, but as a result of misaligned incentives created by Safe Harbor–protected “kickbacks,” distorting the free market and paradoxically reducing access to these medications, delaying care, and increasing prices for patients and the healthcare system.
While federal and state governments are not likely to address this particular situation in the biosimilars market, CSRO is highlighting this issue as a prime example of why the current formulary construction system urgently requires federal reform. At this time, the biosimilars most affected are Inflectra and Avsola, but if nothing changes, more and more biosimilars will fall victim to the short-sighted pricing strategy of aggressive rebating to gain formulary position, with physician purchasers and patients left to navigate the aftermath. The existing system, which necessitates drug companies purchasing formulary access from pharmacy benefit managers, has led to delayed and even denied patient access to certain provider-administered drugs. Moreover, it now appears to be hindering the adoption of biosimilars.
To address this, a multifaceted approach is required. It not only involves reevaluating the rebate system and its impact on formulary construction and ASP, but also ensuring that acquisition costs for providers are aligned with reimbursement rates. Insurers must recognize the economic and clinical value of maintaining infusions within private practices and immediately update their policies to ensure that physician in-office infusion is financially feasible for these “fail-first” biosimilars.
Ultimately, the goal should be to create a sustainable model that promotes the use of affordable biosimilars, enhances patient access to affordable care, and supports the financial viability of medical practices. Concerted efforts to reform the current formulary construction system are required to achieve a healthcare environment that is both cost effective and patient centric.
Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].
Editor’s note: This article is adapted from an explanatory statement that Dr. Feldman wrote for the Coalition of State Rheumatology Organizations (CSRO).
According to the Guinness Book of World records, the longest time someone has held their breath underwater voluntarily is 24 minutes and 37.36 seconds. While certainly an amazing feat, UnitedHealthcare, many of the Blues, and other national “payers” are expecting rheumatologists and other specialists to live “underwater” in order to take care of their patients. In other words, these insurance companies are mandating that specialists use certain provider-administered biosimilars whose acquisition cost is higher than what the insurance company is willing to reimburse them. Essentially, the insurance companies expect the rheumatologists to pay them to take care of their patients. Because of the substantial and destabilizing financial losses incurred, many practices and free-standing infusion centers have been forced to cease offering these biosimilars. Most rheumatologists will provide patients with appropriate alternatives when available and permitted by the insurer; otherwise, they must refer patients to hospital-based infusion centers. That results in delayed care and increased costs for patients and the system, because hospital-based infusion typically costs more than twice what office-based infusion costs.
Quantifying the Problem
To help quantify the magnitude of this issue, the Coalition of State Rheumatology Organizations (CSRO) recently conducted a survey of its membership. A shocking 97% of respondents reported that their practice had been affected by reimbursement rates for some biosimilars being lower than acquisition costs, with 91% of respondents stating that this issue is more pronounced for certain biosimilars than others. Across the board, respondents most frequently identified Inflectra (infliximab-dyyb) and Avsola (infliximab-axxq) as being especially affected: Over 88% and over 85% of respondents identified these two products, respectively, as being underwater. These results support the ongoing anecdotal reports CSRO continues to receive from rheumatology practices.
However, the survey results indicated that this issue is by no means confined to those two biosimilars. Truxima (rituximab-abbs) — a biosimilar for Rituxan — was frequently mentioned as well. Notably, respondents almost uniformly identified biosimilars in the infliximab and rituximab families, which illustrates that this issue is no longer confined to one or two early-to-market biosimilars but has almost become a hallmark of this particular biosimilars market. Remarkably, one respondent commented that the brand products are now cheaper to acquire than the biosimilars. Furthermore, the survey included respondents from across the country, indicating that this issue is not confined to a particular region.
How Did This Happen?
Biosimilars held promise for increasing availability and decreasing biologic costs for patients but, thus far, no patients have seen their cost go down. It appears that the only biosimilars that have made it to “preferred” status on the formulary are the ones that have made more money for the middlemen in the drug supply chain, particularly those that construct formularies. Now, we have provider-administered biosimilars whose acquisition cost exceeds the reimbursement for these drugs. This disparity was ultimately created by biosimilar manufacturers “over-rebating” their drugs to health insurance companies to gain “fail-first” status on the formulary.
For example, the manufacturer of Inflectra offered substantial rebates to health insurers for preferred formulary placement. These rebates are factored into the sales price of the medication, which then results in a rapidly declining average sales price (ASP) for the biosimilar. Unfortunately, the acquisition cost for the drug does not experience commensurate reductions, resulting in physicians being reimbursed far less for the drug than it costs to acquire. The financial losses for physicians put them underwater as a result of the acquisition costs for the preferred drugs far surpassing the reimbursement from the health insurance company that constructed the formulary.
While various factors affect ASPs and acquisition costs, this particular consequence of formulary placement based on price concessions is a major driver of the underwater situation in which physicians have found themselves with many biosimilars. Not only does that lead to a lower uptake of biosimilars, but it also results in patients being referred to the hospital outpatient infusion sites to receive this care, as freestanding infusion centers cannot treat these patients either. Hospitals incur higher costs because of facility fees and elevated rates, and this makes private rheumatology in-office infusion centers a much lower-cost option. Similarly, home infusion services, while convenient, are marginally more expensive than private practices and, in cases of biologic infusions, it is important to note that physicians’ offices have a greater safety profile than home infusion of biologics. The overall result of these “fail-first underwater drugs” is delayed and more costly care for the patient and the “system,” particularly self-insured employers.
What Is Being Done to Correct This?
Since ASPs are updated quarterly, it is possible that acquisition costs and reimbursements might stabilize over time, making the drugs affordable again to practices. However, that does not appear to be happening in the near future, so that possibility does not offer immediate relief to struggling practices. It doesn’t promise a favorable outlook for future biosimilar entries of provider-administered medications if formularies continue to prefer the highest-rebated medication.
This dynamic between ASP and acquisition cost does not happen on the pharmacy side because the price concessions on specific drug rebates and fees are proprietary. There appears to be no equivalent to a publicly known ASP on the pharmacy side, which has led to myriad pricing definitions and manipulation on the pharmacy benefit side of medications. In any event, the savings from rebates and other manufacturer price concessions on pharmacy drugs do not influence ASPs of medical benefit drugs.
The Inflation Reduction Act provided a temporary increase in the add-on payment for biosimilars from ASP+6% to ASP+8%, but as long as the biosimilar’s ASP is lower than the reference brand’s ASP, that temporary increase does not appear to make up for the large differential between ASP and acquisition cost. It should be noted that any federal attempt to artificially lower the ASP of a provider-administered drug without a pathway assuring that the acquisition cost for the provider is less than the reimbursement is going to result in loss of access for patients to those medications and/or higher hospital site of care costs.
A Few Partial Fixes, But Most Complaints Go Ignored
Considering the higher costs of hospital-based infusion, insurers should be motivated to keep patients within private practices. Perhaps through insurers’ recognition of that fact, some practices have successfully negotiated exceptions for specific patients by discussing this situation with insurers. From the feedback that CSRO has received from rheumatology practices, it appears that most insurers have been ignoring the complaints from physicians. The few who have responded have resulted in only partial fixes, with some of the biosimilars still left underwater.
Ultimate Solution?
This issue is a direct result of the “rebate game,” whereby price concessions from drug manufacturers drive formulary placement. For provider-administered medications, this results in an artificially lowered ASP, not as a consequence of free-market incentives that benefit the patient, but as a result of misaligned incentives created by Safe Harbor–protected “kickbacks,” distorting the free market and paradoxically reducing access to these medications, delaying care, and increasing prices for patients and the healthcare system.
While federal and state governments are not likely to address this particular situation in the biosimilars market, CSRO is highlighting this issue as a prime example of why the current formulary construction system urgently requires federal reform. At this time, the biosimilars most affected are Inflectra and Avsola, but if nothing changes, more and more biosimilars will fall victim to the short-sighted pricing strategy of aggressive rebating to gain formulary position, with physician purchasers and patients left to navigate the aftermath. The existing system, which necessitates drug companies purchasing formulary access from pharmacy benefit managers, has led to delayed and even denied patient access to certain provider-administered drugs. Moreover, it now appears to be hindering the adoption of biosimilars.
To address this, a multifaceted approach is required. It not only involves reevaluating the rebate system and its impact on formulary construction and ASP, but also ensuring that acquisition costs for providers are aligned with reimbursement rates. Insurers must recognize the economic and clinical value of maintaining infusions within private practices and immediately update their policies to ensure that physician in-office infusion is financially feasible for these “fail-first” biosimilars.
Ultimately, the goal should be to create a sustainable model that promotes the use of affordable biosimilars, enhances patient access to affordable care, and supports the financial viability of medical practices. Concerted efforts to reform the current formulary construction system are required to achieve a healthcare environment that is both cost effective and patient centric.
Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].
CPAP Underperforms: The Sequel
A few months ago, I posted a column on continuous positive airway pressure (CPAP) with the title, “CPAP Oversells and Underperforms.” To date, it has 299 likes and 90 comments, which are almost all negative. I’m glad to see that it’s generated interest, and I’d like to address some of the themes expressed in the posts.
Most comments were personal testimonies to the miracles of CPAP. These are important, and the point deserves emphasis. CPAP can provide significant improvements in daytime sleepiness and quality of life. I closed the original piece by acknowledging this important fact. Readers can be forgiven for missing it given that the title and text were otherwise disparaging of CPAP.
But several comments warrant a more in-depth discussion. The original piece focuses on CPAP and cardiovascular (CV) outcomes but made no mention of atrial fibrillation (AF) or ejection fraction (EF). The effects of CPAP on each are touted by cardiologists and PAP-pushers alike and are drivers of frequent referrals. It›s my fault for omitting them from the discussion.
AF is easy. The data is identical to all other things CPAP and CV. Based on biologic plausibility alone, the likelihood of a relationship between AF and obstructive sleep apnea (OSA) is similar to the odds that the Celtics raise an 18th banner come June. There’s hypoxia, intrathoracic pressure swings, sympathetic surges, and sleep state disruptions. It’s easy to get from there to arrhythmogenesis. There’s lots of observational noise, too, but no randomized proof that CPAP alters this relationship.
I found four randomized controlled trials (RCTs) that tested CPAP’s effect on AF. I’ll save you the suspense; they were all negative. One even found a signal for more adverse events in the CPAP group. These studies have several positive qualities: They enrolled patients with moderate to severe sleep apnea and high oxygen desaturation indices, adherence averaged more than 4 hours across all groups in all trials, and the methods for assessing the AF outcomes differed slightly. There’s also a lot not to like: The sample sizes were small, only one trial enrolled “sleepy” patients (as assessed by the Epworth Sleepiness Score), and follow-up was short.
To paraphrase Carl Sagan, “absence of evidence does not equal evidence of absence.” As a statistician would say, type II error cannot be excluded by these RCTs. In medicine, however, the burden of proof falls on demonstrating efficacy. If we treat before concluding that a therapy works, we risk wasting time, money, medical resources, and the most precious of patient commodities: the energy required for behavior change. In their response to letters to the editor, the authors of the third RCT summarize the CPAP, AF, and CV disease data far better than I ever could. They sound the same words of caution and come out against screening patients with AF for OSA.
The story for CPAP’s effects on EF is similar though muddier. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for heart failure cite a meta-analysis showing that CPAP improves left ventricular EF. In 2019, the American Academy of Sleep Medicine (AASM) CPAP guidelines included a systematic review and meta-analysis that found that CPAP has no effect on left ventricular EF in patients with or without heart failure.
There are a million reasons why two systematic reviews on the same topic might come to different conclusions. In this case, the included studies only partially overlap, and broadly speaking, it appears the authors made trade-offs. The review cited by the ACC/AHA had broader inclusion and significantly more patients and paid for it in heterogeneity (I2 in the 80%-90% range). The AASM analysis achieved 0% heterogeneity but limited inclusion to fewer than 100 patients. Across both, the improvement in EF was 2%- 5% at a minimally clinically important difference of 4%. Hardly convincing.
In summary, the road to negative trials and patient harm has always been paved with observational signal and biologic plausibility. Throw in some intellectual and academic bias, and you’ve created the perfect storm of therapeutic overconfidence.
Dr. Holley is a professor in the department of medicine, Uniformed Services University, Bethesda, Maryland, and a physician at Pulmonary/Sleep and Critical Care Medicine, MedStar Washington Hospital Center, Washington. He disclosed ties to Metapharm Inc., CHEST College, and WebMD.
A version of this article appeared on Medscape.com .
A few months ago, I posted a column on continuous positive airway pressure (CPAP) with the title, “CPAP Oversells and Underperforms.” To date, it has 299 likes and 90 comments, which are almost all negative. I’m glad to see that it’s generated interest, and I’d like to address some of the themes expressed in the posts.
Most comments were personal testimonies to the miracles of CPAP. These are important, and the point deserves emphasis. CPAP can provide significant improvements in daytime sleepiness and quality of life. I closed the original piece by acknowledging this important fact. Readers can be forgiven for missing it given that the title and text were otherwise disparaging of CPAP.
But several comments warrant a more in-depth discussion. The original piece focuses on CPAP and cardiovascular (CV) outcomes but made no mention of atrial fibrillation (AF) or ejection fraction (EF). The effects of CPAP on each are touted by cardiologists and PAP-pushers alike and are drivers of frequent referrals. It›s my fault for omitting them from the discussion.
AF is easy. The data is identical to all other things CPAP and CV. Based on biologic plausibility alone, the likelihood of a relationship between AF and obstructive sleep apnea (OSA) is similar to the odds that the Celtics raise an 18th banner come June. There’s hypoxia, intrathoracic pressure swings, sympathetic surges, and sleep state disruptions. It’s easy to get from there to arrhythmogenesis. There’s lots of observational noise, too, but no randomized proof that CPAP alters this relationship.
I found four randomized controlled trials (RCTs) that tested CPAP’s effect on AF. I’ll save you the suspense; they were all negative. One even found a signal for more adverse events in the CPAP group. These studies have several positive qualities: They enrolled patients with moderate to severe sleep apnea and high oxygen desaturation indices, adherence averaged more than 4 hours across all groups in all trials, and the methods for assessing the AF outcomes differed slightly. There’s also a lot not to like: The sample sizes were small, only one trial enrolled “sleepy” patients (as assessed by the Epworth Sleepiness Score), and follow-up was short.
To paraphrase Carl Sagan, “absence of evidence does not equal evidence of absence.” As a statistician would say, type II error cannot be excluded by these RCTs. In medicine, however, the burden of proof falls on demonstrating efficacy. If we treat before concluding that a therapy works, we risk wasting time, money, medical resources, and the most precious of patient commodities: the energy required for behavior change. In their response to letters to the editor, the authors of the third RCT summarize the CPAP, AF, and CV disease data far better than I ever could. They sound the same words of caution and come out against screening patients with AF for OSA.
The story for CPAP’s effects on EF is similar though muddier. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for heart failure cite a meta-analysis showing that CPAP improves left ventricular EF. In 2019, the American Academy of Sleep Medicine (AASM) CPAP guidelines included a systematic review and meta-analysis that found that CPAP has no effect on left ventricular EF in patients with or without heart failure.
There are a million reasons why two systematic reviews on the same topic might come to different conclusions. In this case, the included studies only partially overlap, and broadly speaking, it appears the authors made trade-offs. The review cited by the ACC/AHA had broader inclusion and significantly more patients and paid for it in heterogeneity (I2 in the 80%-90% range). The AASM analysis achieved 0% heterogeneity but limited inclusion to fewer than 100 patients. Across both, the improvement in EF was 2%- 5% at a minimally clinically important difference of 4%. Hardly convincing.
In summary, the road to negative trials and patient harm has always been paved with observational signal and biologic plausibility. Throw in some intellectual and academic bias, and you’ve created the perfect storm of therapeutic overconfidence.
Dr. Holley is a professor in the department of medicine, Uniformed Services University, Bethesda, Maryland, and a physician at Pulmonary/Sleep and Critical Care Medicine, MedStar Washington Hospital Center, Washington. He disclosed ties to Metapharm Inc., CHEST College, and WebMD.
A version of this article appeared on Medscape.com .
A few months ago, I posted a column on continuous positive airway pressure (CPAP) with the title, “CPAP Oversells and Underperforms.” To date, it has 299 likes and 90 comments, which are almost all negative. I’m glad to see that it’s generated interest, and I’d like to address some of the themes expressed in the posts.
Most comments were personal testimonies to the miracles of CPAP. These are important, and the point deserves emphasis. CPAP can provide significant improvements in daytime sleepiness and quality of life. I closed the original piece by acknowledging this important fact. Readers can be forgiven for missing it given that the title and text were otherwise disparaging of CPAP.
But several comments warrant a more in-depth discussion. The original piece focuses on CPAP and cardiovascular (CV) outcomes but made no mention of atrial fibrillation (AF) or ejection fraction (EF). The effects of CPAP on each are touted by cardiologists and PAP-pushers alike and are drivers of frequent referrals. It›s my fault for omitting them from the discussion.
AF is easy. The data is identical to all other things CPAP and CV. Based on biologic plausibility alone, the likelihood of a relationship between AF and obstructive sleep apnea (OSA) is similar to the odds that the Celtics raise an 18th banner come June. There’s hypoxia, intrathoracic pressure swings, sympathetic surges, and sleep state disruptions. It’s easy to get from there to arrhythmogenesis. There’s lots of observational noise, too, but no randomized proof that CPAP alters this relationship.
I found four randomized controlled trials (RCTs) that tested CPAP’s effect on AF. I’ll save you the suspense; they were all negative. One even found a signal for more adverse events in the CPAP group. These studies have several positive qualities: They enrolled patients with moderate to severe sleep apnea and high oxygen desaturation indices, adherence averaged more than 4 hours across all groups in all trials, and the methods for assessing the AF outcomes differed slightly. There’s also a lot not to like: The sample sizes were small, only one trial enrolled “sleepy” patients (as assessed by the Epworth Sleepiness Score), and follow-up was short.
To paraphrase Carl Sagan, “absence of evidence does not equal evidence of absence.” As a statistician would say, type II error cannot be excluded by these RCTs. In medicine, however, the burden of proof falls on demonstrating efficacy. If we treat before concluding that a therapy works, we risk wasting time, money, medical resources, and the most precious of patient commodities: the energy required for behavior change. In their response to letters to the editor, the authors of the third RCT summarize the CPAP, AF, and CV disease data far better than I ever could. They sound the same words of caution and come out against screening patients with AF for OSA.
The story for CPAP’s effects on EF is similar though muddier. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for heart failure cite a meta-analysis showing that CPAP improves left ventricular EF. In 2019, the American Academy of Sleep Medicine (AASM) CPAP guidelines included a systematic review and meta-analysis that found that CPAP has no effect on left ventricular EF in patients with or without heart failure.
There are a million reasons why two systematic reviews on the same topic might come to different conclusions. In this case, the included studies only partially overlap, and broadly speaking, it appears the authors made trade-offs. The review cited by the ACC/AHA had broader inclusion and significantly more patients and paid for it in heterogeneity (I2 in the 80%-90% range). The AASM analysis achieved 0% heterogeneity but limited inclusion to fewer than 100 patients. Across both, the improvement in EF was 2%- 5% at a minimally clinically important difference of 4%. Hardly convincing.
In summary, the road to negative trials and patient harm has always been paved with observational signal and biologic plausibility. Throw in some intellectual and academic bias, and you’ve created the perfect storm of therapeutic overconfidence.
Dr. Holley is a professor in the department of medicine, Uniformed Services University, Bethesda, Maryland, and a physician at Pulmonary/Sleep and Critical Care Medicine, MedStar Washington Hospital Center, Washington. He disclosed ties to Metapharm Inc., CHEST College, and WebMD.
A version of this article appeared on Medscape.com .
Unplanned Pregnancy With Weight Loss Drugs: Fact or Fiction?
Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.
At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue.
About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.
She had three pressing questions for me:
Q: How had this happened while she had taken the birth control pills faithfully?
A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold:
- Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
- The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
- Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.
Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?
A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.
Q: What would happen to her weight loss efforts?
A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy.
After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful.
*Patient’s name changed.
A version of this article appeared on Medscape.com.
Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.
At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue.
About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.
She had three pressing questions for me:
Q: How had this happened while she had taken the birth control pills faithfully?
A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold:
- Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
- The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
- Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.
Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?
A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.
Q: What would happen to her weight loss efforts?
A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy.
After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful.
*Patient’s name changed.
A version of this article appeared on Medscape.com.
Claudia* was a charming 27-year-old newlywed. She and her husband wanted to start a family — with one small catch. She had recently gained 30 pounds. During COVID, she and her husband spent 18 months camped out in her parents’ guest room in upstate New York and had eaten their emotions with abandon. They ate when they were happy and ate more when they were sad. They ate when they felt isolated and again when they felt anxious. It didn’t help that her mother was a Culinary Institute–trained amateur chef. They both worked from home and logged long hours on Zoom calls. Because there was no home gym, they replaced their usual fitness club workouts in the city with leisurely strolls around the local lake. When I met her, Claudia categorically refused to entertain the notion of pregnancy until she reached her pre-COVID weight.
At the time, this all seemed quite reasonable to me. We outlined a plan including semaglutide (Wegovy) until she reached her target weight and then a minimum of 2 months off Wegovy prior to conception. We also lined up sessions with a dietitian and trainer and renewed her birth control pill. There was one detail I failed to mention to her: Birth control pills are less effective while on incretin hormones like semaglutide. The reason for my omission is that the medical community at large wasn’t yet aware of this issue.
About 12 weeks into treatment, Claudia had lost 20 of the 30 pounds. She had canceled several appointments with the trainer and dietitian due to work conflicts. She messaged me over the weekend in a panic. Her period was late, and her pregnancy test was positive.
She had three pressing questions for me:
Q: How had this happened while she had taken the birth control pills faithfully?
A: I answered that the scientific reasons for the decrease in efficacy of birth control pills while on semaglutide medications are threefold:
- Weight loss can improve menstrual cycle irregularities and improve fertility. In fact, I have been using semaglutide-like medications to treat polycystic ovary syndrome for decades, well before these medications became mainstream.
- The delayed gastric emptying inherent to incretins leads to decreased absorption of birth control pills.
- Finally, while this did not apply to Claudia, no medicine is particularly efficacious if vomited up shortly after taking. Wegovy is known to cause nausea and vomiting in a sizable percentage of patients.
Q: Would she have a healthy pregnancy given the lingering effects of Wegovy?
A: The short answer is: most likely yes. A review of the package insert revealed something fascinating. It was not strictly contraindicated. It advised doctors to weigh the risks and benefits of the medication during pregnancy. Animal studies have shown that semaglutide increases the risk for fetal death, birth defects, and growth issues, but this is probably due to restrictive eating patterns rather than a direct effect of the medication. A recent study of health records of more than 50,000 women with diabetes who had been inadvertently taking these medications in early pregnancy showed no increase in birth defects when compared with women who took insulin.
Q: What would happen to her weight loss efforts?
A: To address her third concern, I tried to offset the risk for rebound weight gain by stopping Wegovy and giving her metformin in the second and third trimesters. Considered a safe medication in pregnancy, metformin is thought to support weight loss, but it proved to be ineffective against the rebound weight gain from stopping Wegovy. Claudia had not resumed regular exercise and quickly fell into the age-old eating-for-two trap. She gained nearly 50 pounds over the course of her pregnancy.
After a short and unfulfilling attempt at nursing, Claudia restarted Wegovy, this time in conjunction with a Mediterranean meal plan and regular sessions at a fitness club. After losing the pregnancy weight, she has been able to successfully maintain her ideal body weight for the past year, and her baby is perfectly healthy and beautiful.
*Patient’s name changed.
A version of this article appeared on Medscape.com.
Why Cardiac Biomarkers Don’t Help Predict Heart Disease
This transcript has been edited for clarity.
It’s the counterintuitive stuff in epidemiology that always really interests me. One intuition many of us have is that if a risk factor is significantly associated with an outcome, knowledge of that risk factor would help to predict that outcome. Makes sense. Feels right.
But it’s not right. Not always.
Here’s a fake example to illustrate my point. Let’s say we have 10,000 individuals who we follow for 10 years and 2000 of them die. (It’s been a rough decade.) At baseline, I measured a novel biomarker, the Perry Factor, in everyone. To keep it simple, the Perry Factor has only two values: 0 or 1.
I then do a standard associational analysis and find that individuals who are positive for the Perry Factor have a 40-fold higher odds of death than those who are negative for it. I am beginning to reconsider ascribing my good name to this biomarker. This is a highly statistically significant result — a P value <.001.
Clearly, knowledge of the Perry Factor should help me predict who will die in the cohort. I evaluate predictive power using a metric called the area under the receiver operating characteristic curve (AUC, referred to as the C-statistic in time-to-event studies). It tells you, given two people — one who dies and one who doesn’t — how frequently you “pick” the right person, given the knowledge of their Perry Factor.
A C-statistic of 0.5, or 50%, would mean the Perry Factor gives you no better results than a coin flip; it’s chance. A C-statistic of 1 is perfect prediction. So, what will the C-statistic be, given the incredibly strong association of the Perry Factor with outcomes? 0.9? 0.95?
0.5024. Almost useless.
Let’s figure out why strength of association and usefulness for prediction are not always the same thing.
I constructed my fake Perry Factor dataset quite carefully to illustrate this point. Let me show you what happened. What you see here is a breakdown of the patients in my fake study. You can see that just 11 of them were Perry Factor positive, but 10 of those 11 ended up dying.
That’s quite unlikely by chance alone. It really does appear that if you have Perry Factor, your risk for death is much higher. But the reason that Perry Factor is a bad predictor is because it is so rare in the population. Sure, you can use it to correctly predict the outcome of 10 of the 11 people who have it, but the vast majority of people don’t have Perry Factor. It’s useless to distinguish who will die vs who will live in that population.
Why have I spent so much time trying to reverse our intuition that strength of association and strength of predictive power must be related? Because it helps to explain this paper, “Prognostic Value of Cardiovascular Biomarkers in the Population,” appearing in JAMA, which is a very nice piece of work trying to help us better predict cardiovascular disease.
I don’t need to tell you that cardiovascular disease is the number-one killer in this country and most of the world. I don’t need to tell you that we have really good preventive therapies and lifestyle interventions that can reduce the risk. But it would be nice to know in whom, specifically, we should use those interventions.
Cardiovascular risk scores, to date, are pretty simple. The most common one in use in the United States, the pooled cohort risk equation, has nine variables, two of which require a cholesterol panel and one a blood pressure test. It’s easy and it’s pretty accurate.
Using the score from the pooled cohort risk calculator, you get a C-statistic as high as 0.82 when applied to Black women, a low of 0.71 when applied to Black men. Non-Black individuals are in the middle. Not bad. But, clearly, not perfect.
And aren’t we in the era of big data, the era of personalized medicine? We have dozens, maybe hundreds, of quantifiable biomarkers that are associated with subsequent heart disease. Surely, by adding these biomarkers into the risk equation, we can improve prediction. Right?
The JAMA study includes 164,054 patients pooled from 28 cohort studies from 12 countries. All the studies measured various key biomarkers at baseline and followed their participants for cardiovascular events like heart attack, stroke, coronary revascularization, and so on.
The biomarkers in question are really the big guns in this space: troponin, a marker of stress on the heart muscle; NT-proBNP, a marker of stretch on the heart muscle; and C-reactive protein, a marker of inflammation. In every case, higher levels of these markers at baseline were associated with a higher risk for cardiovascular disease in the future.
Troponin T, shown here, has a basically linear risk with subsequent cardiovascular disease.
BNP seems to demonstrate more of a threshold effect, where levels above 60 start to associate with problems.
And CRP does a similar thing, with levels above 1.
All of these findings were statistically significant. If you have higher levels of one or more of these biomarkers, you are more likely to have cardiovascular disease in the future.
Of course, our old friend the pooled cohort risk equation is still here — in the background — requiring just that one blood test and measurement of blood pressure. Let’s talk about predictive power.
The pooled cohort risk equation score, in this study, had a C-statistic of 0.812.
By adding troponin, BNP, and CRP to the equation, the new C-statistic is 0.819. Barely any change.
Now, the authors looked at different types of prediction here. The greatest improvement in the AUC was seen when they tried to predict heart failure within 1 year of measurement; there the AUC improved by 0.04. But the presence of BNP as a biomarker and the short time window of 1 year makes me wonder whether this is really prediction at all or whether they were essentially just diagnosing people with existing heart failure.
Why does this happen? Why do these promising biomarkers, clearly associated with bad outcomes, fail to improve our ability to predict the future? I already gave one example, which has to do with how the markers are distributed in the population. But even more relevant here is that the new markers will only improve prediction insofar as they are not already represented in the old predictive model.
Of course, BNP, for example, wasn’t in the old model. But smoking was. Diabetes was. Blood pressure was. All of that data might actually tell you something about the patient’s BNP through their mutual correlation. And improvement in prediction requires new information.
This is actually why I consider this a really successful study. We need to do studies like this to help us find what those new sources of information might be.
We will never get to a C-statistic of 1. Perfect prediction is the domain of palm readers and astrophysicists. But better prediction is always possible through data. The big question, of course, is which data?
Dr. Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
It’s the counterintuitive stuff in epidemiology that always really interests me. One intuition many of us have is that if a risk factor is significantly associated with an outcome, knowledge of that risk factor would help to predict that outcome. Makes sense. Feels right.
But it’s not right. Not always.
Here’s a fake example to illustrate my point. Let’s say we have 10,000 individuals who we follow for 10 years and 2000 of them die. (It’s been a rough decade.) At baseline, I measured a novel biomarker, the Perry Factor, in everyone. To keep it simple, the Perry Factor has only two values: 0 or 1.
I then do a standard associational analysis and find that individuals who are positive for the Perry Factor have a 40-fold higher odds of death than those who are negative for it. I am beginning to reconsider ascribing my good name to this biomarker. This is a highly statistically significant result — a P value <.001.
Clearly, knowledge of the Perry Factor should help me predict who will die in the cohort. I evaluate predictive power using a metric called the area under the receiver operating characteristic curve (AUC, referred to as the C-statistic in time-to-event studies). It tells you, given two people — one who dies and one who doesn’t — how frequently you “pick” the right person, given the knowledge of their Perry Factor.
A C-statistic of 0.5, or 50%, would mean the Perry Factor gives you no better results than a coin flip; it’s chance. A C-statistic of 1 is perfect prediction. So, what will the C-statistic be, given the incredibly strong association of the Perry Factor with outcomes? 0.9? 0.95?
0.5024. Almost useless.
Let’s figure out why strength of association and usefulness for prediction are not always the same thing.
I constructed my fake Perry Factor dataset quite carefully to illustrate this point. Let me show you what happened. What you see here is a breakdown of the patients in my fake study. You can see that just 11 of them were Perry Factor positive, but 10 of those 11 ended up dying.
That’s quite unlikely by chance alone. It really does appear that if you have Perry Factor, your risk for death is much higher. But the reason that Perry Factor is a bad predictor is because it is so rare in the population. Sure, you can use it to correctly predict the outcome of 10 of the 11 people who have it, but the vast majority of people don’t have Perry Factor. It’s useless to distinguish who will die vs who will live in that population.
Why have I spent so much time trying to reverse our intuition that strength of association and strength of predictive power must be related? Because it helps to explain this paper, “Prognostic Value of Cardiovascular Biomarkers in the Population,” appearing in JAMA, which is a very nice piece of work trying to help us better predict cardiovascular disease.
I don’t need to tell you that cardiovascular disease is the number-one killer in this country and most of the world. I don’t need to tell you that we have really good preventive therapies and lifestyle interventions that can reduce the risk. But it would be nice to know in whom, specifically, we should use those interventions.
Cardiovascular risk scores, to date, are pretty simple. The most common one in use in the United States, the pooled cohort risk equation, has nine variables, two of which require a cholesterol panel and one a blood pressure test. It’s easy and it’s pretty accurate.
Using the score from the pooled cohort risk calculator, you get a C-statistic as high as 0.82 when applied to Black women, a low of 0.71 when applied to Black men. Non-Black individuals are in the middle. Not bad. But, clearly, not perfect.
And aren’t we in the era of big data, the era of personalized medicine? We have dozens, maybe hundreds, of quantifiable biomarkers that are associated with subsequent heart disease. Surely, by adding these biomarkers into the risk equation, we can improve prediction. Right?
The JAMA study includes 164,054 patients pooled from 28 cohort studies from 12 countries. All the studies measured various key biomarkers at baseline and followed their participants for cardiovascular events like heart attack, stroke, coronary revascularization, and so on.
The biomarkers in question are really the big guns in this space: troponin, a marker of stress on the heart muscle; NT-proBNP, a marker of stretch on the heart muscle; and C-reactive protein, a marker of inflammation. In every case, higher levels of these markers at baseline were associated with a higher risk for cardiovascular disease in the future.
Troponin T, shown here, has a basically linear risk with subsequent cardiovascular disease.
BNP seems to demonstrate more of a threshold effect, where levels above 60 start to associate with problems.
And CRP does a similar thing, with levels above 1.
All of these findings were statistically significant. If you have higher levels of one or more of these biomarkers, you are more likely to have cardiovascular disease in the future.
Of course, our old friend the pooled cohort risk equation is still here — in the background — requiring just that one blood test and measurement of blood pressure. Let’s talk about predictive power.
The pooled cohort risk equation score, in this study, had a C-statistic of 0.812.
By adding troponin, BNP, and CRP to the equation, the new C-statistic is 0.819. Barely any change.
Now, the authors looked at different types of prediction here. The greatest improvement in the AUC was seen when they tried to predict heart failure within 1 year of measurement; there the AUC improved by 0.04. But the presence of BNP as a biomarker and the short time window of 1 year makes me wonder whether this is really prediction at all or whether they were essentially just diagnosing people with existing heart failure.
Why does this happen? Why do these promising biomarkers, clearly associated with bad outcomes, fail to improve our ability to predict the future? I already gave one example, which has to do with how the markers are distributed in the population. But even more relevant here is that the new markers will only improve prediction insofar as they are not already represented in the old predictive model.
Of course, BNP, for example, wasn’t in the old model. But smoking was. Diabetes was. Blood pressure was. All of that data might actually tell you something about the patient’s BNP through their mutual correlation. And improvement in prediction requires new information.
This is actually why I consider this a really successful study. We need to do studies like this to help us find what those new sources of information might be.
We will never get to a C-statistic of 1. Perfect prediction is the domain of palm readers and astrophysicists. But better prediction is always possible through data. The big question, of course, is which data?
Dr. Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
It’s the counterintuitive stuff in epidemiology that always really interests me. One intuition many of us have is that if a risk factor is significantly associated with an outcome, knowledge of that risk factor would help to predict that outcome. Makes sense. Feels right.
But it’s not right. Not always.
Here’s a fake example to illustrate my point. Let’s say we have 10,000 individuals who we follow for 10 years and 2000 of them die. (It’s been a rough decade.) At baseline, I measured a novel biomarker, the Perry Factor, in everyone. To keep it simple, the Perry Factor has only two values: 0 or 1.
I then do a standard associational analysis and find that individuals who are positive for the Perry Factor have a 40-fold higher odds of death than those who are negative for it. I am beginning to reconsider ascribing my good name to this biomarker. This is a highly statistically significant result — a P value <.001.
Clearly, knowledge of the Perry Factor should help me predict who will die in the cohort. I evaluate predictive power using a metric called the area under the receiver operating characteristic curve (AUC, referred to as the C-statistic in time-to-event studies). It tells you, given two people — one who dies and one who doesn’t — how frequently you “pick” the right person, given the knowledge of their Perry Factor.
A C-statistic of 0.5, or 50%, would mean the Perry Factor gives you no better results than a coin flip; it’s chance. A C-statistic of 1 is perfect prediction. So, what will the C-statistic be, given the incredibly strong association of the Perry Factor with outcomes? 0.9? 0.95?
0.5024. Almost useless.
Let’s figure out why strength of association and usefulness for prediction are not always the same thing.
I constructed my fake Perry Factor dataset quite carefully to illustrate this point. Let me show you what happened. What you see here is a breakdown of the patients in my fake study. You can see that just 11 of them were Perry Factor positive, but 10 of those 11 ended up dying.
That’s quite unlikely by chance alone. It really does appear that if you have Perry Factor, your risk for death is much higher. But the reason that Perry Factor is a bad predictor is because it is so rare in the population. Sure, you can use it to correctly predict the outcome of 10 of the 11 people who have it, but the vast majority of people don’t have Perry Factor. It’s useless to distinguish who will die vs who will live in that population.
Why have I spent so much time trying to reverse our intuition that strength of association and strength of predictive power must be related? Because it helps to explain this paper, “Prognostic Value of Cardiovascular Biomarkers in the Population,” appearing in JAMA, which is a very nice piece of work trying to help us better predict cardiovascular disease.
I don’t need to tell you that cardiovascular disease is the number-one killer in this country and most of the world. I don’t need to tell you that we have really good preventive therapies and lifestyle interventions that can reduce the risk. But it would be nice to know in whom, specifically, we should use those interventions.
Cardiovascular risk scores, to date, are pretty simple. The most common one in use in the United States, the pooled cohort risk equation, has nine variables, two of which require a cholesterol panel and one a blood pressure test. It’s easy and it’s pretty accurate.
Using the score from the pooled cohort risk calculator, you get a C-statistic as high as 0.82 when applied to Black women, a low of 0.71 when applied to Black men. Non-Black individuals are in the middle. Not bad. But, clearly, not perfect.
And aren’t we in the era of big data, the era of personalized medicine? We have dozens, maybe hundreds, of quantifiable biomarkers that are associated with subsequent heart disease. Surely, by adding these biomarkers into the risk equation, we can improve prediction. Right?
The JAMA study includes 164,054 patients pooled from 28 cohort studies from 12 countries. All the studies measured various key biomarkers at baseline and followed their participants for cardiovascular events like heart attack, stroke, coronary revascularization, and so on.
The biomarkers in question are really the big guns in this space: troponin, a marker of stress on the heart muscle; NT-proBNP, a marker of stretch on the heart muscle; and C-reactive protein, a marker of inflammation. In every case, higher levels of these markers at baseline were associated with a higher risk for cardiovascular disease in the future.
Troponin T, shown here, has a basically linear risk with subsequent cardiovascular disease.
BNP seems to demonstrate more of a threshold effect, where levels above 60 start to associate with problems.
And CRP does a similar thing, with levels above 1.
All of these findings were statistically significant. If you have higher levels of one or more of these biomarkers, you are more likely to have cardiovascular disease in the future.
Of course, our old friend the pooled cohort risk equation is still here — in the background — requiring just that one blood test and measurement of blood pressure. Let’s talk about predictive power.
The pooled cohort risk equation score, in this study, had a C-statistic of 0.812.
By adding troponin, BNP, and CRP to the equation, the new C-statistic is 0.819. Barely any change.
Now, the authors looked at different types of prediction here. The greatest improvement in the AUC was seen when they tried to predict heart failure within 1 year of measurement; there the AUC improved by 0.04. But the presence of BNP as a biomarker and the short time window of 1 year makes me wonder whether this is really prediction at all or whether they were essentially just diagnosing people with existing heart failure.
Why does this happen? Why do these promising biomarkers, clearly associated with bad outcomes, fail to improve our ability to predict the future? I already gave one example, which has to do with how the markers are distributed in the population. But even more relevant here is that the new markers will only improve prediction insofar as they are not already represented in the old predictive model.
Of course, BNP, for example, wasn’t in the old model. But smoking was. Diabetes was. Blood pressure was. All of that data might actually tell you something about the patient’s BNP through their mutual correlation. And improvement in prediction requires new information.
This is actually why I consider this a really successful study. We need to do studies like this to help us find what those new sources of information might be.
We will never get to a C-statistic of 1. Perfect prediction is the domain of palm readers and astrophysicists. But better prediction is always possible through data. The big question, of course, is which data?
Dr. Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Vacationing Doctors Fight to Revive a Drowned Child
Emergencies happen anywhere, anytime, and sometimes, medical professionals find themselves in situations where they are the only ones who can help. Is There a Doctor in the House? is a series telling these stories.
Jennifer Suders, DO: We were in Florida with our 1-year-old daughter visiting my parents. They moved to an area called Hallandale Beach and live in a high-rise community with a few different pools and spas.
Dan and I were in the spa area at the gym. He was getting me to hurry up because we were supposed to meet my parents who were with our daughter. I was sort of moseying and taking my time.
We were walking by one of the pool decks to get into the building when I heard what sounded like a slap. My first thought was that maybe somebody was choking and someone was hitting their back. Choking has always been my biggest fear with our daughter.
I turned and saw some people who seemed frantic. I looked at Dan and started to ask, “Do you think they need help?” I don’t even think I got the whole sentence out before this mom whipped her head around. I’ll never forget her dark brown hair flying. She screamed, “HELP!”
Dan and I just ran. I let go of my backpack and iPad and water bottle. They scattered across the pool deck. I instantly had my phone in my hand dialing 911.
Daniel Suders, DO: That’s what they teach us, to call 911 first. I didn’t think of it in the moment, but Jenny did.
Jennifer Suders:
Dan and I got down on either side of the boy and checked for a pulse. We couldn’t feel anything. Dan started chest compressions. I was talking to the 911 operator, and then I gave two rescue breaths. We did a sternal rub.
I was kind of yelling in the boy’s face, trying to get him to respond. I tried English and Russian because there’s a big Russian community there, and my family speaks Russian. The grandma asked us if we knew what we were doing.
Daniel Suders: I think she asked if Jenny was a nurse.
Jennifer Suders: Common misconception. Suddenly, the boy started vomiting, and so much water poured out. We turned him on his side, and he had two or three more episodes of spitting up the water. After that, we could see the color start to come back into his face. His eyes started fluttering.
We thought he was probably coming back. But we were too scared to say that in case we were wrong, and he went back under. So, we just held him steady. We didn’t know what had happened, if he might have hit his head, so we needed to keep him still.
Daniel Suders: It was amazing when those eyes opened, and he started to wake up.
Jennifer Suders: It felt like my heart had stopped while I was waiting for his to start.
Daniel Suders: He was clutching his chest like it hurt and started calling for his mom. He was crying and wanting to get in his mom’s arms. We had to keep him from standing up and walking.
Jennifer Suders: He was clearly scared. There were all these strange faces around him. I kept looking at my phone, anxiously waiting for EMS to come. They got there about 8 or 9 minutes later.
At some point, the father walked in with their daughter, a baby under a year old. He was in shock, not knowing what was going on. The grandma explained that the boy had been jumping into the pool over and over with his brother. All of a sudden, they looked over, and he was just lying there, floating, face down. They were right there; they were watching him. It was just that quick.
Daniel Suders: They pulled him out right away, and that was a big thing on his side that it was caught so quickly. He didn’t have to wait long to start resuscitation.
Jennifer Suders: Once EMS got there and assessed him, they put him and his mom on the stretcher. I remember watching them wheel it through the double doors to get to the elevator. As soon as they were gone, I just turned around and broke down. I had been in doctor mode if you will. Straight to the point. No nonsense. Suddenly, I went back into civilian mode, and my emotions just bubbled up.
After we left, we went to meet my parents who had our kid. Dan just beelined toward her and scooped her up and wouldn’t let her go.
For the rest of the day, it was all I could think about. It took me a while to fall asleep that night, and it was the first thing I thought when I woke up the next morning. We were hopeful that the boy was going to be okay, but you never know. We didn’t call the hospital because with HIPAA, I didn’t know if they could tell us anything.
And then the next day — there they were. The family was back at the pool. The little boy was running around like nothing had happened. We were a little surprised. But I would hate for him to be scared of the pool for the rest of his life. His family was watching him like a hawk.
They told us that the boy and his mom had stayed overnight in the ER, but only as a precaution. He didn’t have any more vomiting. He was absolutely fine. They were incredibly grateful.
We got their names and exchanged numbers and took a picture. That’s all I wanted — a photo to remember them.
A day or so later, we saw them again at a nearby park. The boy was climbing trees and seemed completely normal. It was the best outcome we could have hoped for.
Daniel Suders: My biggest worry was any harm to his chest from the resuscitation, or of course how long he was without oxygen. But everyone says that kids are really resilient. I work with adults, so I don’t have a lot of experience.
As a hospitalist, we don’t always see a lot of success with CPR. It’s often an elderly person who just doesn’t have much of a chance. That same week before our vacation, I had lost a 90-year-old in the hospital. It was such a juxtaposition — a 3-year-old with their whole life in front of them. We were able to preserve that, and it was incredible.
Jennifer Suders: I’m a nephrologist, so my field is pretty calm. No big emergencies. We have patients on the floor, but if a code gets called, there’s a team that comes in from the intensive care unit. I always kind of wondered what I would do if I was presented with a scenario like this.
Daniel Suders: We have a lot of friends that do ER medicine, and I felt like those were the guys that really understood when we told them the story. One friend said to me, “By the time they get to us, they’re either in bad shape or they’re better already.” A lot depends on what happens in the field.
Jennifer Suders: I’m even more vigilant about pool safety now. I want to make sure parents know that drowning doesn›t look like flailing theatrics. It can be soundless. Three adults were right next to this little boy and didn›t realize until they looked down and saw him.
If we hadn’t been there, I don’t know if anyone would’ve been able to step in. No one else was medically trained. But I think the message is — you don’t have to be. Anyone can take a CPR class.
When I told my parents, my dad said, “Oh my gosh, I would’ve laid right down there next to that kid and passed out.” Without any training, it’s petrifying to see something like that.
I think about how we could have stayed in the gym longer and been too late. Or we could have gotten on the elevator earlier and been gone. Two minutes, and it would’ve been a story we heard later, not one we were a part of. It feels like we were at a true crossroads in that moment where that boy could have lived or died. And the stars aligned perfectly.
We had no medicine, no monitors, nothing but our hands and our breaths. And we helped a family continue their vacation rather than plan a funeral.
Jennifer Suders, DO, is a nephrologist at West Virginia University Medicine Wheeling Clinic. Daniel Suders, DO, is a hospitalist at West Virginia University Medicine Reynolds Memorial Hospital.
A version of this article appeared on Medscape.com .
Emergencies happen anywhere, anytime, and sometimes, medical professionals find themselves in situations where they are the only ones who can help. Is There a Doctor in the House? is a series telling these stories.
Jennifer Suders, DO: We were in Florida with our 1-year-old daughter visiting my parents. They moved to an area called Hallandale Beach and live in a high-rise community with a few different pools and spas.
Dan and I were in the spa area at the gym. He was getting me to hurry up because we were supposed to meet my parents who were with our daughter. I was sort of moseying and taking my time.
We were walking by one of the pool decks to get into the building when I heard what sounded like a slap. My first thought was that maybe somebody was choking and someone was hitting their back. Choking has always been my biggest fear with our daughter.
I turned and saw some people who seemed frantic. I looked at Dan and started to ask, “Do you think they need help?” I don’t even think I got the whole sentence out before this mom whipped her head around. I’ll never forget her dark brown hair flying. She screamed, “HELP!”
Dan and I just ran. I let go of my backpack and iPad and water bottle. They scattered across the pool deck. I instantly had my phone in my hand dialing 911.
Daniel Suders, DO: That’s what they teach us, to call 911 first. I didn’t think of it in the moment, but Jenny did.
Jennifer Suders:
Dan and I got down on either side of the boy and checked for a pulse. We couldn’t feel anything. Dan started chest compressions. I was talking to the 911 operator, and then I gave two rescue breaths. We did a sternal rub.
I was kind of yelling in the boy’s face, trying to get him to respond. I tried English and Russian because there’s a big Russian community there, and my family speaks Russian. The grandma asked us if we knew what we were doing.
Daniel Suders: I think she asked if Jenny was a nurse.
Jennifer Suders: Common misconception. Suddenly, the boy started vomiting, and so much water poured out. We turned him on his side, and he had two or three more episodes of spitting up the water. After that, we could see the color start to come back into his face. His eyes started fluttering.
We thought he was probably coming back. But we were too scared to say that in case we were wrong, and he went back under. So, we just held him steady. We didn’t know what had happened, if he might have hit his head, so we needed to keep him still.
Daniel Suders: It was amazing when those eyes opened, and he started to wake up.
Jennifer Suders: It felt like my heart had stopped while I was waiting for his to start.
Daniel Suders: He was clutching his chest like it hurt and started calling for his mom. He was crying and wanting to get in his mom’s arms. We had to keep him from standing up and walking.
Jennifer Suders: He was clearly scared. There were all these strange faces around him. I kept looking at my phone, anxiously waiting for EMS to come. They got there about 8 or 9 minutes later.
At some point, the father walked in with their daughter, a baby under a year old. He was in shock, not knowing what was going on. The grandma explained that the boy had been jumping into the pool over and over with his brother. All of a sudden, they looked over, and he was just lying there, floating, face down. They were right there; they were watching him. It was just that quick.
Daniel Suders: They pulled him out right away, and that was a big thing on his side that it was caught so quickly. He didn’t have to wait long to start resuscitation.
Jennifer Suders: Once EMS got there and assessed him, they put him and his mom on the stretcher. I remember watching them wheel it through the double doors to get to the elevator. As soon as they were gone, I just turned around and broke down. I had been in doctor mode if you will. Straight to the point. No nonsense. Suddenly, I went back into civilian mode, and my emotions just bubbled up.
After we left, we went to meet my parents who had our kid. Dan just beelined toward her and scooped her up and wouldn’t let her go.
For the rest of the day, it was all I could think about. It took me a while to fall asleep that night, and it was the first thing I thought when I woke up the next morning. We were hopeful that the boy was going to be okay, but you never know. We didn’t call the hospital because with HIPAA, I didn’t know if they could tell us anything.
And then the next day — there they were. The family was back at the pool. The little boy was running around like nothing had happened. We were a little surprised. But I would hate for him to be scared of the pool for the rest of his life. His family was watching him like a hawk.
They told us that the boy and his mom had stayed overnight in the ER, but only as a precaution. He didn’t have any more vomiting. He was absolutely fine. They were incredibly grateful.
We got their names and exchanged numbers and took a picture. That’s all I wanted — a photo to remember them.
A day or so later, we saw them again at a nearby park. The boy was climbing trees and seemed completely normal. It was the best outcome we could have hoped for.
Daniel Suders: My biggest worry was any harm to his chest from the resuscitation, or of course how long he was without oxygen. But everyone says that kids are really resilient. I work with adults, so I don’t have a lot of experience.
As a hospitalist, we don’t always see a lot of success with CPR. It’s often an elderly person who just doesn’t have much of a chance. That same week before our vacation, I had lost a 90-year-old in the hospital. It was such a juxtaposition — a 3-year-old with their whole life in front of them. We were able to preserve that, and it was incredible.
Jennifer Suders: I’m a nephrologist, so my field is pretty calm. No big emergencies. We have patients on the floor, but if a code gets called, there’s a team that comes in from the intensive care unit. I always kind of wondered what I would do if I was presented with a scenario like this.
Daniel Suders: We have a lot of friends that do ER medicine, and I felt like those were the guys that really understood when we told them the story. One friend said to me, “By the time they get to us, they’re either in bad shape or they’re better already.” A lot depends on what happens in the field.
Jennifer Suders: I’m even more vigilant about pool safety now. I want to make sure parents know that drowning doesn›t look like flailing theatrics. It can be soundless. Three adults were right next to this little boy and didn›t realize until they looked down and saw him.
If we hadn’t been there, I don’t know if anyone would’ve been able to step in. No one else was medically trained. But I think the message is — you don’t have to be. Anyone can take a CPR class.
When I told my parents, my dad said, “Oh my gosh, I would’ve laid right down there next to that kid and passed out.” Without any training, it’s petrifying to see something like that.
I think about how we could have stayed in the gym longer and been too late. Or we could have gotten on the elevator earlier and been gone. Two minutes, and it would’ve been a story we heard later, not one we were a part of. It feels like we were at a true crossroads in that moment where that boy could have lived or died. And the stars aligned perfectly.
We had no medicine, no monitors, nothing but our hands and our breaths. And we helped a family continue their vacation rather than plan a funeral.
Jennifer Suders, DO, is a nephrologist at West Virginia University Medicine Wheeling Clinic. Daniel Suders, DO, is a hospitalist at West Virginia University Medicine Reynolds Memorial Hospital.
A version of this article appeared on Medscape.com .
Emergencies happen anywhere, anytime, and sometimes, medical professionals find themselves in situations where they are the only ones who can help. Is There a Doctor in the House? is a series telling these stories.
Jennifer Suders, DO: We were in Florida with our 1-year-old daughter visiting my parents. They moved to an area called Hallandale Beach and live in a high-rise community with a few different pools and spas.
Dan and I were in the spa area at the gym. He was getting me to hurry up because we were supposed to meet my parents who were with our daughter. I was sort of moseying and taking my time.
We were walking by one of the pool decks to get into the building when I heard what sounded like a slap. My first thought was that maybe somebody was choking and someone was hitting their back. Choking has always been my biggest fear with our daughter.
I turned and saw some people who seemed frantic. I looked at Dan and started to ask, “Do you think they need help?” I don’t even think I got the whole sentence out before this mom whipped her head around. I’ll never forget her dark brown hair flying. She screamed, “HELP!”
Dan and I just ran. I let go of my backpack and iPad and water bottle. They scattered across the pool deck. I instantly had my phone in my hand dialing 911.
Daniel Suders, DO: That’s what they teach us, to call 911 first. I didn’t think of it in the moment, but Jenny did.
Jennifer Suders:
Dan and I got down on either side of the boy and checked for a pulse. We couldn’t feel anything. Dan started chest compressions. I was talking to the 911 operator, and then I gave two rescue breaths. We did a sternal rub.
I was kind of yelling in the boy’s face, trying to get him to respond. I tried English and Russian because there’s a big Russian community there, and my family speaks Russian. The grandma asked us if we knew what we were doing.
Daniel Suders: I think she asked if Jenny was a nurse.
Jennifer Suders: Common misconception. Suddenly, the boy started vomiting, and so much water poured out. We turned him on his side, and he had two or three more episodes of spitting up the water. After that, we could see the color start to come back into his face. His eyes started fluttering.
We thought he was probably coming back. But we were too scared to say that in case we were wrong, and he went back under. So, we just held him steady. We didn’t know what had happened, if he might have hit his head, so we needed to keep him still.
Daniel Suders: It was amazing when those eyes opened, and he started to wake up.
Jennifer Suders: It felt like my heart had stopped while I was waiting for his to start.
Daniel Suders: He was clutching his chest like it hurt and started calling for his mom. He was crying and wanting to get in his mom’s arms. We had to keep him from standing up and walking.
Jennifer Suders: He was clearly scared. There were all these strange faces around him. I kept looking at my phone, anxiously waiting for EMS to come. They got there about 8 or 9 minutes later.
At some point, the father walked in with their daughter, a baby under a year old. He was in shock, not knowing what was going on. The grandma explained that the boy had been jumping into the pool over and over with his brother. All of a sudden, they looked over, and he was just lying there, floating, face down. They were right there; they were watching him. It was just that quick.
Daniel Suders: They pulled him out right away, and that was a big thing on his side that it was caught so quickly. He didn’t have to wait long to start resuscitation.
Jennifer Suders: Once EMS got there and assessed him, they put him and his mom on the stretcher. I remember watching them wheel it through the double doors to get to the elevator. As soon as they were gone, I just turned around and broke down. I had been in doctor mode if you will. Straight to the point. No nonsense. Suddenly, I went back into civilian mode, and my emotions just bubbled up.
After we left, we went to meet my parents who had our kid. Dan just beelined toward her and scooped her up and wouldn’t let her go.
For the rest of the day, it was all I could think about. It took me a while to fall asleep that night, and it was the first thing I thought when I woke up the next morning. We were hopeful that the boy was going to be okay, but you never know. We didn’t call the hospital because with HIPAA, I didn’t know if they could tell us anything.
And then the next day — there they were. The family was back at the pool. The little boy was running around like nothing had happened. We were a little surprised. But I would hate for him to be scared of the pool for the rest of his life. His family was watching him like a hawk.
They told us that the boy and his mom had stayed overnight in the ER, but only as a precaution. He didn’t have any more vomiting. He was absolutely fine. They were incredibly grateful.
We got their names and exchanged numbers and took a picture. That’s all I wanted — a photo to remember them.
A day or so later, we saw them again at a nearby park. The boy was climbing trees and seemed completely normal. It was the best outcome we could have hoped for.
Daniel Suders: My biggest worry was any harm to his chest from the resuscitation, or of course how long he was without oxygen. But everyone says that kids are really resilient. I work with adults, so I don’t have a lot of experience.
As a hospitalist, we don’t always see a lot of success with CPR. It’s often an elderly person who just doesn’t have much of a chance. That same week before our vacation, I had lost a 90-year-old in the hospital. It was such a juxtaposition — a 3-year-old with their whole life in front of them. We were able to preserve that, and it was incredible.
Jennifer Suders: I’m a nephrologist, so my field is pretty calm. No big emergencies. We have patients on the floor, but if a code gets called, there’s a team that comes in from the intensive care unit. I always kind of wondered what I would do if I was presented with a scenario like this.
Daniel Suders: We have a lot of friends that do ER medicine, and I felt like those were the guys that really understood when we told them the story. One friend said to me, “By the time they get to us, they’re either in bad shape or they’re better already.” A lot depends on what happens in the field.
Jennifer Suders: I’m even more vigilant about pool safety now. I want to make sure parents know that drowning doesn›t look like flailing theatrics. It can be soundless. Three adults were right next to this little boy and didn›t realize until they looked down and saw him.
If we hadn’t been there, I don’t know if anyone would’ve been able to step in. No one else was medically trained. But I think the message is — you don’t have to be. Anyone can take a CPR class.
When I told my parents, my dad said, “Oh my gosh, I would’ve laid right down there next to that kid and passed out.” Without any training, it’s petrifying to see something like that.
I think about how we could have stayed in the gym longer and been too late. Or we could have gotten on the elevator earlier and been gone. Two minutes, and it would’ve been a story we heard later, not one we were a part of. It feels like we were at a true crossroads in that moment where that boy could have lived or died. And the stars aligned perfectly.
We had no medicine, no monitors, nothing but our hands and our breaths. And we helped a family continue their vacation rather than plan a funeral.
Jennifer Suders, DO, is a nephrologist at West Virginia University Medicine Wheeling Clinic. Daniel Suders, DO, is a hospitalist at West Virginia University Medicine Reynolds Memorial Hospital.
A version of this article appeared on Medscape.com .
Nocturnal Hot Flashes and Alzheimer’s Risk
In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).
Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.
A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.
Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.
The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.
A version of this article appeared on Medscape.com.
In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).
Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.
A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.
Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.
The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.
A version of this article appeared on Medscape.com.
In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).
Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.
A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.
Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.
The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.
A version of this article appeared on Medscape.com.
Molecular Classification of Endometrial Carcinomas
Historically, endometrial cancer has been classified as type I or type II. Type I endometrial cancers are typically estrogen driven, low grade, with endometrioid histology, and have a more favorable prognosis. In contrast, type II endometrial cancers are typically high grade, have more aggressive histologies (eg, serous or clear cell), and have a poorer prognosis.1
While this system provides a helpful schema for understanding endometrial cancers, it fails to represent the immense variation of biologic behavior and outcomes in endometrial cancers and oversimplifies what has come to be understood as a complex and molecularly diverse disease.
In 2013, The Cancer Genome Atlas (TCGA) performed genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas. They identified four categories with distinct genetic profiles corresponding to clinical outcomes: 1) DNA polymerase epsilon (POLE) mutated; 2) mismatch repair deficient; 3) copy number high/p53 abnormal; and 4) copy number low/no specific molecular profile.2 By providing both predictive and prognostic information, these molecular features may be incorporated into treatment planning decisions in the future.
The POLE-mutated subtype are endometrial cancers with recurrent mutations in the POLE gene, which is involved in DNA replication and repair. POLE mutations occur in about 5%-10% of endometrial cancers. Despite some more aggressive histopathologic findings (eg, higher grade, deeper myometrial invasion, positive lymphovascular space invasion), recurrences rarely occur, and patients with POLE mutations have the best prognosis of the four molecular subtypes, with a 5-year recurrence-free survival of 92%-100%.3
The mismatch repair–deficient (MMRd) subtype are endometrial cancers with abnormalities in any of the mismatch repair proteins (MLH1, PMS2, MSH2, MSH6). These alterations may result from hereditary or somatic mutations in any of the MMR genes or epigenetic changes in the MLH1 promoter. Germ-line mutations are associated with Lynch syndrome; thus, patients found to have a germ-line mutation in any of the MMR genes necessitate a genetics referral. The MMRd subtype accounts for about 20%-30% of endometrial cancers, and patients with MMRd tumors have an intermediate prognosis, with a 5-year recurrence-free survival of about 70%.3. These tumors are more responsive to the use of immunotherapy checkpoint inhibitors. Two recent landmark trials showed improved outcomes in patients with advanced MMRd endometrial cancer treated with immune checkpoint inhibitors in addition to standard chemotherapy.4,5
The worst prognosis belongs to the copy number high subgroup, which accounts for approximately 10% of endometrial cancers. Five-year recurrence-free survival is ~50%.3 These tumors often contain TP53 mutations and are composed of aggressive histologies, such as serous, clear cell, high-grade endometrioid, and carcinosarcomas. Recent data suggests that human epidermal growth factor receptor 2 (HER2) amplification may also be prevalent in this subgroup.6
Endometrial cancers that lack any of the above alterations fall into the no specific molecular profile (NSMP) or copy number low subgroup. Mutations in other genes, such as PTEN, PIK3CA, CTNNB1, KRAS, and ARID1A, are often present in these tumors. As the most common subtype, this heterogeneous group accounts for about 50% of all endometrial cancers. These tumors frequently comprise endometrioid histology with estrogen and progesterone receptor positivity, high rates of response to hormonal therapy, and an overall intermediate to favorable prognosis, with a 5-year recurrence-free survival of ~75%.3
The use of whole-genome sequencing in TCGA limits the clinical applicability of testing because of the cost and complex methodologies involved. Multiple algorithms have been developed in the interim that approximate TCGA subtypes using relatively less expensive and more widely available testing methods, such as immunohistochemistry and next-generation sequencing. In the ProMisE algorithm, immunohistochemistry for p53 and MMR proteins is used as a surrogate for copy number high and MMRd tumors, respectively, and targeted sequencing is used to identify POLE mutations.7
Full molecular classification of endometrial tumors provides important prognostic information and allows for incorporation into treatment planning. To this end, the new 2023 International Federation of Gynecology and Obstetrics (FIGO) endometrial cancer staging incorporates an option for the addition of molecular subtype, with the stance that it allows for better prognostic prediction.8 While complete molecular classification is not required, it is encouraged. Furthermore, several clinical trials are currently investigating different treatment regimens based on these distinct molecular profiles.
Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.
References
1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecologic Oncology. 1983;15(1):10-17.
2. Kandoth C et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
3. León-Castillo A et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: Impact on prognosis and benefit from adjuvant therapy. J Clin Oncology. 2020;38(29):3388-3397.
4. Mirza MR et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158.
5. Eskander RN et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170.
6. Talia KL et al. The role of HER2 as a therapeutic biomarker in gynaecological malignancy: Potential for use beyond uterine serous carcinoma. Pathology. 2023;55(1):8-18.
7. Kommoss S et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Annals Oncology. 2018;29(5):1180-1188.
8. Berek JS et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet. 2023;162(2):383-394.
Historically, endometrial cancer has been classified as type I or type II. Type I endometrial cancers are typically estrogen driven, low grade, with endometrioid histology, and have a more favorable prognosis. In contrast, type II endometrial cancers are typically high grade, have more aggressive histologies (eg, serous or clear cell), and have a poorer prognosis.1
While this system provides a helpful schema for understanding endometrial cancers, it fails to represent the immense variation of biologic behavior and outcomes in endometrial cancers and oversimplifies what has come to be understood as a complex and molecularly diverse disease.
In 2013, The Cancer Genome Atlas (TCGA) performed genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas. They identified four categories with distinct genetic profiles corresponding to clinical outcomes: 1) DNA polymerase epsilon (POLE) mutated; 2) mismatch repair deficient; 3) copy number high/p53 abnormal; and 4) copy number low/no specific molecular profile.2 By providing both predictive and prognostic information, these molecular features may be incorporated into treatment planning decisions in the future.
The POLE-mutated subtype are endometrial cancers with recurrent mutations in the POLE gene, which is involved in DNA replication and repair. POLE mutations occur in about 5%-10% of endometrial cancers. Despite some more aggressive histopathologic findings (eg, higher grade, deeper myometrial invasion, positive lymphovascular space invasion), recurrences rarely occur, and patients with POLE mutations have the best prognosis of the four molecular subtypes, with a 5-year recurrence-free survival of 92%-100%.3
The mismatch repair–deficient (MMRd) subtype are endometrial cancers with abnormalities in any of the mismatch repair proteins (MLH1, PMS2, MSH2, MSH6). These alterations may result from hereditary or somatic mutations in any of the MMR genes or epigenetic changes in the MLH1 promoter. Germ-line mutations are associated with Lynch syndrome; thus, patients found to have a germ-line mutation in any of the MMR genes necessitate a genetics referral. The MMRd subtype accounts for about 20%-30% of endometrial cancers, and patients with MMRd tumors have an intermediate prognosis, with a 5-year recurrence-free survival of about 70%.3. These tumors are more responsive to the use of immunotherapy checkpoint inhibitors. Two recent landmark trials showed improved outcomes in patients with advanced MMRd endometrial cancer treated with immune checkpoint inhibitors in addition to standard chemotherapy.4,5
The worst prognosis belongs to the copy number high subgroup, which accounts for approximately 10% of endometrial cancers. Five-year recurrence-free survival is ~50%.3 These tumors often contain TP53 mutations and are composed of aggressive histologies, such as serous, clear cell, high-grade endometrioid, and carcinosarcomas. Recent data suggests that human epidermal growth factor receptor 2 (HER2) amplification may also be prevalent in this subgroup.6
Endometrial cancers that lack any of the above alterations fall into the no specific molecular profile (NSMP) or copy number low subgroup. Mutations in other genes, such as PTEN, PIK3CA, CTNNB1, KRAS, and ARID1A, are often present in these tumors. As the most common subtype, this heterogeneous group accounts for about 50% of all endometrial cancers. These tumors frequently comprise endometrioid histology with estrogen and progesterone receptor positivity, high rates of response to hormonal therapy, and an overall intermediate to favorable prognosis, with a 5-year recurrence-free survival of ~75%.3
The use of whole-genome sequencing in TCGA limits the clinical applicability of testing because of the cost and complex methodologies involved. Multiple algorithms have been developed in the interim that approximate TCGA subtypes using relatively less expensive and more widely available testing methods, such as immunohistochemistry and next-generation sequencing. In the ProMisE algorithm, immunohistochemistry for p53 and MMR proteins is used as a surrogate for copy number high and MMRd tumors, respectively, and targeted sequencing is used to identify POLE mutations.7
Full molecular classification of endometrial tumors provides important prognostic information and allows for incorporation into treatment planning. To this end, the new 2023 International Federation of Gynecology and Obstetrics (FIGO) endometrial cancer staging incorporates an option for the addition of molecular subtype, with the stance that it allows for better prognostic prediction.8 While complete molecular classification is not required, it is encouraged. Furthermore, several clinical trials are currently investigating different treatment regimens based on these distinct molecular profiles.
Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.
References
1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecologic Oncology. 1983;15(1):10-17.
2. Kandoth C et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
3. León-Castillo A et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: Impact on prognosis and benefit from adjuvant therapy. J Clin Oncology. 2020;38(29):3388-3397.
4. Mirza MR et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158.
5. Eskander RN et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170.
6. Talia KL et al. The role of HER2 as a therapeutic biomarker in gynaecological malignancy: Potential for use beyond uterine serous carcinoma. Pathology. 2023;55(1):8-18.
7. Kommoss S et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Annals Oncology. 2018;29(5):1180-1188.
8. Berek JS et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet. 2023;162(2):383-394.
Historically, endometrial cancer has been classified as type I or type II. Type I endometrial cancers are typically estrogen driven, low grade, with endometrioid histology, and have a more favorable prognosis. In contrast, type II endometrial cancers are typically high grade, have more aggressive histologies (eg, serous or clear cell), and have a poorer prognosis.1
While this system provides a helpful schema for understanding endometrial cancers, it fails to represent the immense variation of biologic behavior and outcomes in endometrial cancers and oversimplifies what has come to be understood as a complex and molecularly diverse disease.
In 2013, The Cancer Genome Atlas (TCGA) performed genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas. They identified four categories with distinct genetic profiles corresponding to clinical outcomes: 1) DNA polymerase epsilon (POLE) mutated; 2) mismatch repair deficient; 3) copy number high/p53 abnormal; and 4) copy number low/no specific molecular profile.2 By providing both predictive and prognostic information, these molecular features may be incorporated into treatment planning decisions in the future.
The POLE-mutated subtype are endometrial cancers with recurrent mutations in the POLE gene, which is involved in DNA replication and repair. POLE mutations occur in about 5%-10% of endometrial cancers. Despite some more aggressive histopathologic findings (eg, higher grade, deeper myometrial invasion, positive lymphovascular space invasion), recurrences rarely occur, and patients with POLE mutations have the best prognosis of the four molecular subtypes, with a 5-year recurrence-free survival of 92%-100%.3
The mismatch repair–deficient (MMRd) subtype are endometrial cancers with abnormalities in any of the mismatch repair proteins (MLH1, PMS2, MSH2, MSH6). These alterations may result from hereditary or somatic mutations in any of the MMR genes or epigenetic changes in the MLH1 promoter. Germ-line mutations are associated with Lynch syndrome; thus, patients found to have a germ-line mutation in any of the MMR genes necessitate a genetics referral. The MMRd subtype accounts for about 20%-30% of endometrial cancers, and patients with MMRd tumors have an intermediate prognosis, with a 5-year recurrence-free survival of about 70%.3. These tumors are more responsive to the use of immunotherapy checkpoint inhibitors. Two recent landmark trials showed improved outcomes in patients with advanced MMRd endometrial cancer treated with immune checkpoint inhibitors in addition to standard chemotherapy.4,5
The worst prognosis belongs to the copy number high subgroup, which accounts for approximately 10% of endometrial cancers. Five-year recurrence-free survival is ~50%.3 These tumors often contain TP53 mutations and are composed of aggressive histologies, such as serous, clear cell, high-grade endometrioid, and carcinosarcomas. Recent data suggests that human epidermal growth factor receptor 2 (HER2) amplification may also be prevalent in this subgroup.6
Endometrial cancers that lack any of the above alterations fall into the no specific molecular profile (NSMP) or copy number low subgroup. Mutations in other genes, such as PTEN, PIK3CA, CTNNB1, KRAS, and ARID1A, are often present in these tumors. As the most common subtype, this heterogeneous group accounts for about 50% of all endometrial cancers. These tumors frequently comprise endometrioid histology with estrogen and progesterone receptor positivity, high rates of response to hormonal therapy, and an overall intermediate to favorable prognosis, with a 5-year recurrence-free survival of ~75%.3
The use of whole-genome sequencing in TCGA limits the clinical applicability of testing because of the cost and complex methodologies involved. Multiple algorithms have been developed in the interim that approximate TCGA subtypes using relatively less expensive and more widely available testing methods, such as immunohistochemistry and next-generation sequencing. In the ProMisE algorithm, immunohistochemistry for p53 and MMR proteins is used as a surrogate for copy number high and MMRd tumors, respectively, and targeted sequencing is used to identify POLE mutations.7
Full molecular classification of endometrial tumors provides important prognostic information and allows for incorporation into treatment planning. To this end, the new 2023 International Federation of Gynecology and Obstetrics (FIGO) endometrial cancer staging incorporates an option for the addition of molecular subtype, with the stance that it allows for better prognostic prediction.8 While complete molecular classification is not required, it is encouraged. Furthermore, several clinical trials are currently investigating different treatment regimens based on these distinct molecular profiles.
Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.
References
1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecologic Oncology. 1983;15(1):10-17.
2. Kandoth C et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.
3. León-Castillo A et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: Impact on prognosis and benefit from adjuvant therapy. J Clin Oncology. 2020;38(29):3388-3397.
4. Mirza MR et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023;388(23):2145-2158.
5. Eskander RN et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N Engl J Med. 2023;388(23):2159-2170.
6. Talia KL et al. The role of HER2 as a therapeutic biomarker in gynaecological malignancy: Potential for use beyond uterine serous carcinoma. Pathology. 2023;55(1):8-18.
7. Kommoss S et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Annals Oncology. 2018;29(5):1180-1188.
8. Berek JS et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet. 2023;162(2):383-394.