Commentary

In 2024, a record number of people are celebrating their 65th birthdays. Increasing age is associated with a higher risk for falls, fractures, and other injuries that may require hospitalization. 

In older adults with type 1 and type 2 diabetes, the risk for falls is double that seen in older people without these conditions. Increased clinician awareness of the many factors that result in this higher risk in people with diabetes, and timely implementation of strategies to prevent falls, are essential.

The annual incidence of falls in people with diabetes older than 65 years is about 39%, compared with 19% among those without diabetes. People with diabetes on insulin face an even greater increased risk for falls compared with those who are not using insulin (94% vs 27% increased risk).

Many well-known aspects of diabetes contribute to this greater risk. These include decreased sensorimotor function, musculoskeletal and neuromuscular deficits, foot and body pain, poor vision, hypoglycemic episodes, pharmacologic complications, and problems with hearing and balance. 

Optimal management of diabetes and its complications is essential, and the American Diabetes Association has developed clear guidelines for clinicians to follow to reduce the risk for diabetes related complications and manage these conditions.

The prevalence of diabetic peripheral neuropathy increases with age and duration of diabetes. People with diabetic peripheral neuropathy and diminished sensation on their feet are at increased risk for loss of postural control. Loss of proprioceptive feedback (the ability to sense movement, action and location) during standing and walking leads increases the risk for falls.

In addition, less physical activity, impaired muscle strength, and suboptimal postural control all influence gait patterns and increase the risk for falling. Adults with diabetes have a two to three times higher risk for sarcopenia (decreased muscle strength and muscle mass). They also have low plantar flexion strength, causing increased displacement of their center of gravity, which in turn reduces their maximum forward stride and may result in falls and injury.

Many people with diabetes experience neuropathic foot and body pain, requiring psychotropic and other medications that may exacerbate the risk, such as amitriptyline and duloxetine. Furthermore, older adults with diabetes are more likely to take more prescription medications and may be more sensitive to effects of multiple medications than are individuals without diabetes.

A hazard of managing diabetes, particularly with insulin, is the increased risk for unexpected low blood glucose levels. These episodes can also occur in patients taking certain kinds of oral diabetes medications, but they are more common in those on insulin. Low blood glucose can cause dizziness, confusion, and postural instability, increasing the risk for falling.

Diabetic eye complications include retinopathy, macular edema, cataracts, and glaucoma. In a study of close to 10,000 middle-aged and older adults with diabetes, those with moderate eye complications had almost double the risk of falls as those without eye complications.

Another concern with diabetes is its effect on nerves and blood vessels in the inner ear, leading to a negative effect on balance and hearing loss, both of which are also associated with a higher risk for falling and injury.

Clinicians can reduce the risk for falls in patients by taking measures to improve diabetes control and reduce the risk for microvascular disease affecting the nerves, eyes, and ears. 

In addition, exercises that optimize muscle mass, bone strength, gait, and balance, and use of specialized footwear in people with neuropathy, may reduce fall risk. Chair yoga and tai chi have also been shown to be helpful. Clinicians can also advise patients on commonsense strategies to implement in their homes, such as ensuring proper lighting, reducing, clutter and minimizing the use of floor rugs.

The risk for falls and the associated risk for fracture and possible hospitalization are of significant concern in older adults — particularly those with diabetes, and even more so in those with diabetes who are on insulin. It is our responsibility as clinicians to implement strategies to optimize diabetes control in our patients and monitor them for microvascular and other complications that may increase this risk, and manage them appropriately if and when these complications occur.

Madhusmita Misra, Professor, Chair, Physician-in-Chief, Department of Pediatrics, University of Virginia and UVA Health Children’s, Charlottesville, has disclosed being a key opinion leader for Lumos Pharma. Sidhartha Pani, Assistant Professor, Department of Internal Medicine, UVA School of Medicine; Medical Director, Department of General Medicine, Same Day Care Clinic, Charlottesville, disclosed no relevant financial relationships.

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

In 2024, a record number of people are celebrating their 65th birthdays. Increasing age is associated with a higher risk for falls, fractures, and other injuries that may require hospitalization. 

In older adults with type 1 and type 2 diabetes, the risk for falls is double that seen in older people without these conditions. Increased clinician awareness of the many factors that result in this higher risk in people with diabetes, and timely implementation of strategies to prevent falls, are essential.

The annual incidence of falls in people with diabetes older than 65 years is about 39%, compared with 19% among those without diabetes. People with diabetes on insulin face an even greater increased risk for falls compared with those who are not using insulin (94% vs 27% increased risk).

Many well-known aspects of diabetes contribute to this greater risk. These include decreased sensorimotor function, musculoskeletal and neuromuscular deficits, foot and body pain, poor vision, hypoglycemic episodes, pharmacologic complications, and problems with hearing and balance. 

Optimal management of diabetes and its complications is essential, and the American Diabetes Association has developed clear guidelines for clinicians to follow to reduce the risk for diabetes related complications and manage these conditions.

The prevalence of diabetic peripheral neuropathy increases with age and duration of diabetes. People with diabetic peripheral neuropathy and diminished sensation on their feet are at increased risk for loss of postural control. Loss of proprioceptive feedback (the ability to sense movement, action and location) during standing and walking leads increases the risk for falls.

In addition, less physical activity, impaired muscle strength, and suboptimal postural control all influence gait patterns and increase the risk for falling. Adults with diabetes have a two to three times higher risk for sarcopenia (decreased muscle strength and muscle mass). They also have low plantar flexion strength, causing increased displacement of their center of gravity, which in turn reduces their maximum forward stride and may result in falls and injury.

Many people with diabetes experience neuropathic foot and body pain, requiring psychotropic and other medications that may exacerbate the risk, such as amitriptyline and duloxetine. Furthermore, older adults with diabetes are more likely to take more prescription medications and may be more sensitive to effects of multiple medications than are individuals without diabetes.

A hazard of managing diabetes, particularly with insulin, is the increased risk for unexpected low blood glucose levels. These episodes can also occur in patients taking certain kinds of oral diabetes medications, but they are more common in those on insulin. Low blood glucose can cause dizziness, confusion, and postural instability, increasing the risk for falling.

Diabetic eye complications include retinopathy, macular edema, cataracts, and glaucoma. In a study of close to 10,000 middle-aged and older adults with diabetes, those with moderate eye complications had almost double the risk of falls as those without eye complications.

Another concern with diabetes is its effect on nerves and blood vessels in the inner ear, leading to a negative effect on balance and hearing loss, both of which are also associated with a higher risk for falling and injury.

Clinicians can reduce the risk for falls in patients by taking measures to improve diabetes control and reduce the risk for microvascular disease affecting the nerves, eyes, and ears. 

In addition, exercises that optimize muscle mass, bone strength, gait, and balance, and use of specialized footwear in people with neuropathy, may reduce fall risk. Chair yoga and tai chi have also been shown to be helpful. Clinicians can also advise patients on commonsense strategies to implement in their homes, such as ensuring proper lighting, reducing, clutter and minimizing the use of floor rugs.

The risk for falls and the associated risk for fracture and possible hospitalization are of significant concern in older adults — particularly those with diabetes, and even more so in those with diabetes who are on insulin. It is our responsibility as clinicians to implement strategies to optimize diabetes control in our patients and monitor them for microvascular and other complications that may increase this risk, and manage them appropriately if and when these complications occur.

Madhusmita Misra, Professor, Chair, Physician-in-Chief, Department of Pediatrics, University of Virginia and UVA Health Children’s, Charlottesville, has disclosed being a key opinion leader for Lumos Pharma. Sidhartha Pani, Assistant Professor, Department of Internal Medicine, UVA School of Medicine; Medical Director, Department of General Medicine, Same Day Care Clinic, Charlottesville, disclosed no relevant financial relationships.

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

In 2024, a record number of people are celebrating their 65th birthdays. Increasing age is associated with a higher risk for falls, fractures, and other injuries that may require hospitalization. 

In older adults with type 1 and type 2 diabetes, the risk for falls is double that seen in older people without these conditions. Increased clinician awareness of the many factors that result in this higher risk in people with diabetes, and timely implementation of strategies to prevent falls, are essential.

The annual incidence of falls in people with diabetes older than 65 years is about 39%, compared with 19% among those without diabetes. People with diabetes on insulin face an even greater increased risk for falls compared with those who are not using insulin (94% vs 27% increased risk).

Many well-known aspects of diabetes contribute to this greater risk. These include decreased sensorimotor function, musculoskeletal and neuromuscular deficits, foot and body pain, poor vision, hypoglycemic episodes, pharmacologic complications, and problems with hearing and balance. 

Optimal management of diabetes and its complications is essential, and the American Diabetes Association has developed clear guidelines for clinicians to follow to reduce the risk for diabetes related complications and manage these conditions.

The prevalence of diabetic peripheral neuropathy increases with age and duration of diabetes. People with diabetic peripheral neuropathy and diminished sensation on their feet are at increased risk for loss of postural control. Loss of proprioceptive feedback (the ability to sense movement, action and location) during standing and walking leads increases the risk for falls.

In addition, less physical activity, impaired muscle strength, and suboptimal postural control all influence gait patterns and increase the risk for falling. Adults with diabetes have a two to three times higher risk for sarcopenia (decreased muscle strength and muscle mass). They also have low plantar flexion strength, causing increased displacement of their center of gravity, which in turn reduces their maximum forward stride and may result in falls and injury.

Many people with diabetes experience neuropathic foot and body pain, requiring psychotropic and other medications that may exacerbate the risk, such as amitriptyline and duloxetine. Furthermore, older adults with diabetes are more likely to take more prescription medications and may be more sensitive to effects of multiple medications than are individuals without diabetes.

A hazard of managing diabetes, particularly with insulin, is the increased risk for unexpected low blood glucose levels. These episodes can also occur in patients taking certain kinds of oral diabetes medications, but they are more common in those on insulin. Low blood glucose can cause dizziness, confusion, and postural instability, increasing the risk for falling.

Diabetic eye complications include retinopathy, macular edema, cataracts, and glaucoma. In a study of close to 10,000 middle-aged and older adults with diabetes, those with moderate eye complications had almost double the risk of falls as those without eye complications.

Another concern with diabetes is its effect on nerves and blood vessels in the inner ear, leading to a negative effect on balance and hearing loss, both of which are also associated with a higher risk for falling and injury.

Clinicians can reduce the risk for falls in patients by taking measures to improve diabetes control and reduce the risk for microvascular disease affecting the nerves, eyes, and ears. 

In addition, exercises that optimize muscle mass, bone strength, gait, and balance, and use of specialized footwear in people with neuropathy, may reduce fall risk. Chair yoga and tai chi have also been shown to be helpful. Clinicians can also advise patients on commonsense strategies to implement in their homes, such as ensuring proper lighting, reducing, clutter and minimizing the use of floor rugs.

The risk for falls and the associated risk for fracture and possible hospitalization are of significant concern in older adults — particularly those with diabetes, and even more so in those with diabetes who are on insulin. It is our responsibility as clinicians to implement strategies to optimize diabetes control in our patients and monitor them for microvascular and other complications that may increase this risk, and manage them appropriately if and when these complications occur.

Madhusmita Misra, Professor, Chair, Physician-in-Chief, Department of Pediatrics, University of Virginia and UVA Health Children’s, Charlottesville, has disclosed being a key opinion leader for Lumos Pharma. Sidhartha Pani, Assistant Professor, Department of Internal Medicine, UVA School of Medicine; Medical Director, Department of General Medicine, Same Day Care Clinic, Charlottesville, disclosed no relevant financial relationships.

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

Vitiligo, the most common skin pigmentation disorder, has affected patients for thousands of years.¹ The psychological and social impacts on patients include sleep and sexual disorders, low self-esteem, low quality of life, anxiety, and depression when compared to those without vitiligo.^2,3 There have been substantial therapeutic advancements in the treatment of vitiligo, with the recent approval of ruxolitinib cream 1.5% by the US Food and Drug Administration (FDA) in 2022 and by the European Medicines Agency in 2023.⁴ Ruxolitinib is the first topical Janus kinase (JAK) inhibitor approved by the FDA for the treatment of nonsegmental vitiligo in patients 12 years and older, ushering in the era of JAK inhibitors for patients affected by vitiligo. The efficacy and safety of ruxolitinib was supported by 2 randomized clinical trials.⁴ It also is FDA approved for the intermittent and short-term treatment of mild to moderate atopic dermatitis in nonimmunocompromised patients 12 years and older whose disease is not adequately controlled with other topical medications.⁵

Vitiligo is characterized by an important inflammatory component, with the JAK/STAT (signal transducer and activator of transcription) pathway playing a crucial role in transmitting signals of inflammatory cytokines. In particular, IFN-γ and chemokines CXCL9 and CXCL10 are major contributors to the development of vitiligo, acting through the JAK/STAT pathway in local keratinocytes. Inhibiting JAK activity helps mitigate the effects of IFN-γ and downstream chemokines.⁶

Currently, baricitinib is not FDA approved for the treatment of vitiligo; it is FDA approved for moderate to severe active rheumatoid arthritis, severe alopecia areata, and in specific cases for COVID-19.⁷ Mumford et al⁸ first reported the use of oral baricitinib for the treatment of nonsegmental vitiligo. This patient experienced poor improvement using the oral JAK inhibitor tofacitinib for 5 months but achieved near-complete repigmentation after switching to baricitinib for 8 months (4 mg daily).⁸ Furthermore, a recent study found that in vitro baricitinib could increase tyrosinase activity and melanin content as well as stimulate the expression of genes related to tyrosinase in damaged melanocytes.⁹

A recent study by Li et al¹⁰ has shown satisfactory repigmentation and good tolerance in 2 cases of vitiligo treated with oral baricitinib in combination with narrowband UVB (NB-UVB) phototherapy. These findings are supported by a prior study of oral tofacitinib and NB-UVB phototherapy in 10 cases; the JAK inhibitor treatment demonstrated enhanced effectiveness when combined with light exposure.¹¹

Large-scale randomized clinical trials are needed to evaluate the efficacy and safety of oral baricitinib for vitiligo treatment. Currently, a clinical trial is underway (recruiting phase) to compare the efficacy and safety of combining baricitinib and excimer lamp phototherapy vs phototherapy alone.¹² The results of this trial can provide valuable information about whether baricitinib is promising as part of the therapeutic arsenal for vitiligo treatment in the future. A recently completed multicenter, randomized, double-blind clinical trial assessed the efficacy and tolerability of oral baricitinib in combination with NB-UVB phototherapy for the treatment of vitiligo. The trial included 49 patients and may provide valuable insights for the potential future application of baricitinib in the treatment of vitiligo.¹³ If the results of these clinical trials are favorable, approval of the first orally administered JAK inhibitor for repigmentation treatment in patients with vitiligo could follow, which would be a major breakthrough.

The off-label use of baricitinib—alone or in combination with phototherapy—appears to be promising in studies with a small sample size (an important limitation). The results of clinical trials will help us elucidate the efficacy and safety of baricitinib for vitiligo treatment, which could be a subject of debate. Recently, the FDA issued a warning due to findings showing that the use of tofacitinib has been associated with an increased risk of serious heart-related events, such heart attack, stroke, cancer, blood clots, and death.¹⁴ In response, the FDA issued warnings for 2 other JAK inhibitors—baricitinib and upadacitinib. Unlike tofacitinib, baricitinib and upadacitinib have not been studied in large safety clinical trials, and as a result, their risks have not been adequately evaluated. However, due to the shared mechanisms of action of these drugs, the FDA believes that these medications may pose similar risks as those observed in the tofacitinib safety trial.¹⁴

Disadvantages of JAK inhibitors include the high cost, immune-related side effects, potential cardiovascular adverse effects, and limited availability worldwide. If current and future clinical trials obtain objective evidence with a large sample size that yields positive outcomes with tolerable or acceptable side effects, and if the drug is affordable for hospitals and patients, the use of oral or topical baricitinib will be embraced and may be approved for vitiligo.

Vitiligo, the most common skin pigmentation disorder, has affected patients for thousands of years.¹ The psychological and social impacts on patients include sleep and sexual disorders, low self-esteem, low quality of life, anxiety, and depression when compared to those without vitiligo.^2,3 There have been substantial therapeutic advancements in the treatment of vitiligo, with the recent approval of ruxolitinib cream 1.5% by the US Food and Drug Administration (FDA) in 2022 and by the European Medicines Agency in 2023.⁴ Ruxolitinib is the first topical Janus kinase (JAK) inhibitor approved by the FDA for the treatment of nonsegmental vitiligo in patients 12 years and older, ushering in the era of JAK inhibitors for patients affected by vitiligo. The efficacy and safety of ruxolitinib was supported by 2 randomized clinical trials.⁴ It also is FDA approved for the intermittent and short-term treatment of mild to moderate atopic dermatitis in nonimmunocompromised patients 12 years and older whose disease is not adequately controlled with other topical medications.⁵

Vitiligo is characterized by an important inflammatory component, with the JAK/STAT (signal transducer and activator of transcription) pathway playing a crucial role in transmitting signals of inflammatory cytokines. In particular, IFN-γ and chemokines CXCL9 and CXCL10 are major contributors to the development of vitiligo, acting through the JAK/STAT pathway in local keratinocytes. Inhibiting JAK activity helps mitigate the effects of IFN-γ and downstream chemokines.⁶

Currently, baricitinib is not FDA approved for the treatment of vitiligo; it is FDA approved for moderate to severe active rheumatoid arthritis, severe alopecia areata, and in specific cases for COVID-19.⁷ Mumford et al⁸ first reported the use of oral baricitinib for the treatment of nonsegmental vitiligo. This patient experienced poor improvement using the oral JAK inhibitor tofacitinib for 5 months but achieved near-complete repigmentation after switching to baricitinib for 8 months (4 mg daily).⁸ Furthermore, a recent study found that in vitro baricitinib could increase tyrosinase activity and melanin content as well as stimulate the expression of genes related to tyrosinase in damaged melanocytes.⁹

A recent study by Li et al¹⁰ has shown satisfactory repigmentation and good tolerance in 2 cases of vitiligo treated with oral baricitinib in combination with narrowband UVB (NB-UVB) phototherapy. These findings are supported by a prior study of oral tofacitinib and NB-UVB phototherapy in 10 cases; the JAK inhibitor treatment demonstrated enhanced effectiveness when combined with light exposure.¹¹

Large-scale randomized clinical trials are needed to evaluate the efficacy and safety of oral baricitinib for vitiligo treatment. Currently, a clinical trial is underway (recruiting phase) to compare the efficacy and safety of combining baricitinib and excimer lamp phototherapy vs phototherapy alone.¹² The results of this trial can provide valuable information about whether baricitinib is promising as part of the therapeutic arsenal for vitiligo treatment in the future. A recently completed multicenter, randomized, double-blind clinical trial assessed the efficacy and tolerability of oral baricitinib in combination with NB-UVB phototherapy for the treatment of vitiligo. The trial included 49 patients and may provide valuable insights for the potential future application of baricitinib in the treatment of vitiligo.¹³ If the results of these clinical trials are favorable, approval of the first orally administered JAK inhibitor for repigmentation treatment in patients with vitiligo could follow, which would be a major breakthrough.

The off-label use of baricitinib—alone or in combination with phototherapy—appears to be promising in studies with a small sample size (an important limitation). The results of clinical trials will help us elucidate the efficacy and safety of baricitinib for vitiligo treatment, which could be a subject of debate. Recently, the FDA issued a warning due to findings showing that the use of tofacitinib has been associated with an increased risk of serious heart-related events, such heart attack, stroke, cancer, blood clots, and death.¹⁴ In response, the FDA issued warnings for 2 other JAK inhibitors—baricitinib and upadacitinib. Unlike tofacitinib, baricitinib and upadacitinib have not been studied in large safety clinical trials, and as a result, their risks have not been adequately evaluated. However, due to the shared mechanisms of action of these drugs, the FDA believes that these medications may pose similar risks as those observed in the tofacitinib safety trial.¹⁴

Disadvantages of JAK inhibitors include the high cost, immune-related side effects, potential cardiovascular adverse effects, and limited availability worldwide. If current and future clinical trials obtain objective evidence with a large sample size that yields positive outcomes with tolerable or acceptable side effects, and if the drug is affordable for hospitals and patients, the use of oral or topical baricitinib will be embraced and may be approved for vitiligo.

Vitiligo, the most common skin pigmentation disorder, has affected patients for thousands of years.¹ The psychological and social impacts on patients include sleep and sexual disorders, low self-esteem, low quality of life, anxiety, and depression when compared to those without vitiligo.^2,3 There have been substantial therapeutic advancements in the treatment of vitiligo, with the recent approval of ruxolitinib cream 1.5% by the US Food and Drug Administration (FDA) in 2022 and by the European Medicines Agency in 2023.⁴ Ruxolitinib is the first topical Janus kinase (JAK) inhibitor approved by the FDA for the treatment of nonsegmental vitiligo in patients 12 years and older, ushering in the era of JAK inhibitors for patients affected by vitiligo. The efficacy and safety of ruxolitinib was supported by 2 randomized clinical trials.⁴ It also is FDA approved for the intermittent and short-term treatment of mild to moderate atopic dermatitis in nonimmunocompromised patients 12 years and older whose disease is not adequately controlled with other topical medications.⁵

Vitiligo is characterized by an important inflammatory component, with the JAK/STAT (signal transducer and activator of transcription) pathway playing a crucial role in transmitting signals of inflammatory cytokines. In particular, IFN-γ and chemokines CXCL9 and CXCL10 are major contributors to the development of vitiligo, acting through the JAK/STAT pathway in local keratinocytes. Inhibiting JAK activity helps mitigate the effects of IFN-γ and downstream chemokines.⁶

Currently, baricitinib is not FDA approved for the treatment of vitiligo; it is FDA approved for moderate to severe active rheumatoid arthritis, severe alopecia areata, and in specific cases for COVID-19.⁷ Mumford et al⁸ first reported the use of oral baricitinib for the treatment of nonsegmental vitiligo. This patient experienced poor improvement using the oral JAK inhibitor tofacitinib for 5 months but achieved near-complete repigmentation after switching to baricitinib for 8 months (4 mg daily).⁸ Furthermore, a recent study found that in vitro baricitinib could increase tyrosinase activity and melanin content as well as stimulate the expression of genes related to tyrosinase in damaged melanocytes.⁹

A recent study by Li et al¹⁰ has shown satisfactory repigmentation and good tolerance in 2 cases of vitiligo treated with oral baricitinib in combination with narrowband UVB (NB-UVB) phototherapy. These findings are supported by a prior study of oral tofacitinib and NB-UVB phototherapy in 10 cases; the JAK inhibitor treatment demonstrated enhanced effectiveness when combined with light exposure.¹¹

Large-scale randomized clinical trials are needed to evaluate the efficacy and safety of oral baricitinib for vitiligo treatment. Currently, a clinical trial is underway (recruiting phase) to compare the efficacy and safety of combining baricitinib and excimer lamp phototherapy vs phototherapy alone.¹² The results of this trial can provide valuable information about whether baricitinib is promising as part of the therapeutic arsenal for vitiligo treatment in the future. A recently completed multicenter, randomized, double-blind clinical trial assessed the efficacy and tolerability of oral baricitinib in combination with NB-UVB phototherapy for the treatment of vitiligo. The trial included 49 patients and may provide valuable insights for the potential future application of baricitinib in the treatment of vitiligo.¹³ If the results of these clinical trials are favorable, approval of the first orally administered JAK inhibitor for repigmentation treatment in patients with vitiligo could follow, which would be a major breakthrough.

The off-label use of baricitinib—alone or in combination with phototherapy—appears to be promising in studies with a small sample size (an important limitation). The results of clinical trials will help us elucidate the efficacy and safety of baricitinib for vitiligo treatment, which could be a subject of debate. Recently, the FDA issued a warning due to findings showing that the use of tofacitinib has been associated with an increased risk of serious heart-related events, such heart attack, stroke, cancer, blood clots, and death.¹⁴ In response, the FDA issued warnings for 2 other JAK inhibitors—baricitinib and upadacitinib. Unlike tofacitinib, baricitinib and upadacitinib have not been studied in large safety clinical trials, and as a result, their risks have not been adequately evaluated. However, due to the shared mechanisms of action of these drugs, the FDA believes that these medications may pose similar risks as those observed in the tofacitinib safety trial.¹⁴

Disadvantages of JAK inhibitors include the high cost, immune-related side effects, potential cardiovascular adverse effects, and limited availability worldwide. If current and future clinical trials obtain objective evidence with a large sample size that yields positive outcomes with tolerable or acceptable side effects, and if the drug is affordable for hospitals and patients, the use of oral or topical baricitinib will be embraced and may be approved for vitiligo.

Frontal fibrosing alopecia (FFA) has become increasingly common since it was first described in 1994.¹ A positive correlation between FFA and the use of sunscreens was reported in an observational study.² The geographic distribution of this association has spanned the United Kingdom (UK), Europe, and Asia, though data from the United States are lacking. Various international studies have demonstrated an association between FFA and sunscreen use, further exemplifying this stark contrast.

In the United Kingdom (UK), Aldoori et al² found that women who used sunscreen at least twice weekly had 2 times the likelihood of developing FFA compared with women who did not use sunscreen regularly. Kidambi et al³ found similar results in UK men with FFA who had higher rates of primary sunscreen use and higher rates of at least twice-weekly use of facial moisturizer with unspecified sunscreen content.

These associations between FFA and sunscreen use are not unique to the UK. A study conducted in Spain identified a statistical association between FFA and use of facial sunscreen in women (odds ratio, 1.6 [95% CI, 1.06-2.41]) and men (odds ratio, 1.84 [95% CI, 1.04-3.23]).⁴ In Thailand, FFA was nearly twice as likely to be present in patients with regular sunscreen use compared to controls who did not apply sunscreen regularly.⁵ Interestingly, a Brazilian study showed no connection between sunscreen use and FFA. Instead, FFA was associated with hair straightening with formalin or use of facial soap orfacial moisturizer.⁶ An international systematic review of 1248 patients with FFA and 1459 controls determined that sunscreen users were 2.21 times more likely to develop FFA than their counterparts who did not use sunscreen regularly.⁷

Quite glaring is the lack of data from the United States, which could be used to compare FFA and sunscreen associations to other nations. It is possible that certain regions of the world such as the United States may not have an increased risk for FFA in sunscreen users due to other environmental factors, differing sunscreen application practices, or differing chemical ingredients. At the same time, many other countries cannot afford or lack access to sunscreens or facial moisturizers, which is an additional variable that may complicate this association. These populations need to be studied to determine whether they are as susceptible to FFA as those who use sunscreen regularly around the world.

Another underlying factor supporting this association is the inherent need for sunscreen use. For instance, research has shown that patients with FFA had higher rates of actinic skin damage, which could explain increased sunscreen use.⁸

To make more clear and distinct claims, further studies are needed in regions that are known to use sunscreen extensively (eg, United States) to compare with their European, Asian, and South American counterparts. Moreover, it also is important to study regions where sunscreen access is limited and whether there is FFA development in these populations.

Given the potential association between sunscreen use and FFA, dermatologists can take a cautious approach tailored to the patient by recommending noncomedogenic mineral sunscreens with zinc or titanium oxide, which are less irritating than chemical sunscreens. Avoidance of sunscreen application to the hairline and use of additional sun-protection methods such as broad-brimmed hats also should be emphasized.

Frontal fibrosing alopecia (FFA) has become increasingly common since it was first described in 1994.¹ A positive correlation between FFA and the use of sunscreens was reported in an observational study.² The geographic distribution of this association has spanned the United Kingdom (UK), Europe, and Asia, though data from the United States are lacking. Various international studies have demonstrated an association between FFA and sunscreen use, further exemplifying this stark contrast.

In the United Kingdom (UK), Aldoori et al² found that women who used sunscreen at least twice weekly had 2 times the likelihood of developing FFA compared with women who did not use sunscreen regularly. Kidambi et al³ found similar results in UK men with FFA who had higher rates of primary sunscreen use and higher rates of at least twice-weekly use of facial moisturizer with unspecified sunscreen content.

These associations between FFA and sunscreen use are not unique to the UK. A study conducted in Spain identified a statistical association between FFA and use of facial sunscreen in women (odds ratio, 1.6 [95% CI, 1.06-2.41]) and men (odds ratio, 1.84 [95% CI, 1.04-3.23]).⁴ In Thailand, FFA was nearly twice as likely to be present in patients with regular sunscreen use compared to controls who did not apply sunscreen regularly.⁵ Interestingly, a Brazilian study showed no connection between sunscreen use and FFA. Instead, FFA was associated with hair straightening with formalin or use of facial soap orfacial moisturizer.⁶ An international systematic review of 1248 patients with FFA and 1459 controls determined that sunscreen users were 2.21 times more likely to develop FFA than their counterparts who did not use sunscreen regularly.⁷

Quite glaring is the lack of data from the United States, which could be used to compare FFA and sunscreen associations to other nations. It is possible that certain regions of the world such as the United States may not have an increased risk for FFA in sunscreen users due to other environmental factors, differing sunscreen application practices, or differing chemical ingredients. At the same time, many other countries cannot afford or lack access to sunscreens or facial moisturizers, which is an additional variable that may complicate this association. These populations need to be studied to determine whether they are as susceptible to FFA as those who use sunscreen regularly around the world.

Another underlying factor supporting this association is the inherent need for sunscreen use. For instance, research has shown that patients with FFA had higher rates of actinic skin damage, which could explain increased sunscreen use.⁸

To make more clear and distinct claims, further studies are needed in regions that are known to use sunscreen extensively (eg, United States) to compare with their European, Asian, and South American counterparts. Moreover, it also is important to study regions where sunscreen access is limited and whether there is FFA development in these populations.

Given the potential association between sunscreen use and FFA, dermatologists can take a cautious approach tailored to the patient by recommending noncomedogenic mineral sunscreens with zinc or titanium oxide, which are less irritating than chemical sunscreens. Avoidance of sunscreen application to the hairline and use of additional sun-protection methods such as broad-brimmed hats also should be emphasized.

Frontal fibrosing alopecia (FFA) has become increasingly common since it was first described in 1994.¹ A positive correlation between FFA and the use of sunscreens was reported in an observational study.² The geographic distribution of this association has spanned the United Kingdom (UK), Europe, and Asia, though data from the United States are lacking. Various international studies have demonstrated an association between FFA and sunscreen use, further exemplifying this stark contrast.

In the United Kingdom (UK), Aldoori et al² found that women who used sunscreen at least twice weekly had 2 times the likelihood of developing FFA compared with women who did not use sunscreen regularly. Kidambi et al³ found similar results in UK men with FFA who had higher rates of primary sunscreen use and higher rates of at least twice-weekly use of facial moisturizer with unspecified sunscreen content.

These associations between FFA and sunscreen use are not unique to the UK. A study conducted in Spain identified a statistical association between FFA and use of facial sunscreen in women (odds ratio, 1.6 [95% CI, 1.06-2.41]) and men (odds ratio, 1.84 [95% CI, 1.04-3.23]).⁴ In Thailand, FFA was nearly twice as likely to be present in patients with regular sunscreen use compared to controls who did not apply sunscreen regularly.⁵ Interestingly, a Brazilian study showed no connection between sunscreen use and FFA. Instead, FFA was associated with hair straightening with formalin or use of facial soap orfacial moisturizer.⁶ An international systematic review of 1248 patients with FFA and 1459 controls determined that sunscreen users were 2.21 times more likely to develop FFA than their counterparts who did not use sunscreen regularly.⁷

Quite glaring is the lack of data from the United States, which could be used to compare FFA and sunscreen associations to other nations. It is possible that certain regions of the world such as the United States may not have an increased risk for FFA in sunscreen users due to other environmental factors, differing sunscreen application practices, or differing chemical ingredients. At the same time, many other countries cannot afford or lack access to sunscreens or facial moisturizers, which is an additional variable that may complicate this association. These populations need to be studied to determine whether they are as susceptible to FFA as those who use sunscreen regularly around the world.

Another underlying factor supporting this association is the inherent need for sunscreen use. For instance, research has shown that patients with FFA had higher rates of actinic skin damage, which could explain increased sunscreen use.⁸

To make more clear and distinct claims, further studies are needed in regions that are known to use sunscreen extensively (eg, United States) to compare with their European, Asian, and South American counterparts. Moreover, it also is important to study regions where sunscreen access is limited and whether there is FFA development in these populations.

Given the potential association between sunscreen use and FFA, dermatologists can take a cautious approach tailored to the patient by recommending noncomedogenic mineral sunscreens with zinc or titanium oxide, which are less irritating than chemical sunscreens. Avoidance of sunscreen application to the hairline and use of additional sun-protection methods such as broad-brimmed hats also should be emphasized.

To the Editor:

We read with interest the case reported by Yanovsky et al¹ (Cutis. 2023;112:E23-E25). We thank the authors for updating our knowledge about atopic dermatitis (AD) and omalizumab and improving our understanding of the various wanted and unwanted effects that may manifest with omalizumab. We wish to clarify a few points on omalizumab use.

First, Yanovsky et al¹ reported that their patient’s AD flares occurred within a few days after omalizumab injections to control asthma, possibly because omalizumab may have caused a paradoxical increase in sensitivity to other cytokines such as IL-33 in basophils and increased IL-4/IL-13 production in the skin. The authors cited Imai² to explain that IL-33 plays a role in the pathogenesis of AD, increases itching, and disrupts the skin barrier. However, Imai² did not discuss a relationship with omalizumab. As a recombinant humanized IgG1 monoclonal anti-IgE antibody, omalizumab works by interacting with the high-affinity receptor Fc epsilon RI that typically is found on eosinophils, mast cells, and basophils and plays a critical role in preventing the allergic cascade.³ We could not find any studies in the literature regarding omalizumab having a specific effect on the skin, causing cytokine imbalance, or increasing IL-4/IL-13 levels.

Second, the case report indicated that AD lesions improved with the biologic dupilumab,¹ which seems amazing. Dupilumab is a monoclonal antibody used in patients with moderate to severe AD that blocks IL-4/IL-13 signaling and thus inhibits receptor signaling downstream of the Janus kinase signal transducer and activator of transcription protein pathway.⁴ It also has been shown to be beneficial in children with moderate to severe uncontrolled asthma.⁵ In vivo studies are needed to learn about the effects of these biologics on asthma and AD, whose complex immunologic effects are increasingly well understood by real patient experience.

Third, omalizumab has been found to relieve AD, not exacerbate it, in our own experience with 7 patients (unpublished data, 2024) and randomized controlled trials.⁶

Fourth, Yanovsky et al¹ reported that the patient’s lesions flared up within a few days after taking omalizumab, which suggests a non-IgE delayed reaction. Could this reaction be related to polysorbate 20 used as an excipient in the commercial preparation? When we examined both preparations, the presence of polysorbate 80 in dupilumab was noteworthy,⁷ unlike omalizumab. We suggest the authors perform a patch test including polysorbate 20 and polysorbate 80.

Finally, the authors mentioned that omalizumab may cause a paradoxical exacerbation of AD in certain patients, as in tumor necrosis factor α inhibitor–induced psoriasis.⁸ This has been reported,⁸ but tumor necrosis factor α inhibitors are cytokine inhibitors and can lead to cytokine imbalance, while omalizumab is an IgE inhibitor.

Yanovsky et al¹ described AD flares as “triggered by omalizumab,” which we believe was not the case. Because this patient had chronic AD, other causes of AD exacerbation in this patient could include stress or infection. Also, when they say that AD is triggered or induced, it implies that they are attributing the occurrence/development of AD in this patient to omalizumab. Of course, this also is not true.

Author’s Response

Thank you for your thoughtful comments. Although we agree that we cannot prove omalizumab was the cause of our patient’s AD flares, the new onset of severely worsening disease that was exacerbated by each dose of omalizumab as well as subsequent resolution upon switching to dupilumab was highly suggestive for a causal relationship. Our goal was to alert physicians to the possibility of this phenomenon and to encourage further study.

Karen A. Chernoff, MD
From the Department of Dermatology, Weill Cornell Medical College, New York, New York.
The author has no relevant financial disclosures to report.

To the Editor:

We read with interest the case reported by Yanovsky et al¹ (Cutis. 2023;112:E23-E25). We thank the authors for updating our knowledge about atopic dermatitis (AD) and omalizumab and improving our understanding of the various wanted and unwanted effects that may manifest with omalizumab. We wish to clarify a few points on omalizumab use.

First, Yanovsky et al¹ reported that their patient’s AD flares occurred within a few days after omalizumab injections to control asthma, possibly because omalizumab may have caused a paradoxical increase in sensitivity to other cytokines such as IL-33 in basophils and increased IL-4/IL-13 production in the skin. The authors cited Imai² to explain that IL-33 plays a role in the pathogenesis of AD, increases itching, and disrupts the skin barrier. However, Imai² did not discuss a relationship with omalizumab. As a recombinant humanized IgG1 monoclonal anti-IgE antibody, omalizumab works by interacting with the high-affinity receptor Fc epsilon RI that typically is found on eosinophils, mast cells, and basophils and plays a critical role in preventing the allergic cascade.³ We could not find any studies in the literature regarding omalizumab having a specific effect on the skin, causing cytokine imbalance, or increasing IL-4/IL-13 levels.

Second, the case report indicated that AD lesions improved with the biologic dupilumab,¹ which seems amazing. Dupilumab is a monoclonal antibody used in patients with moderate to severe AD that blocks IL-4/IL-13 signaling and thus inhibits receptor signaling downstream of the Janus kinase signal transducer and activator of transcription protein pathway.⁴ It also has been shown to be beneficial in children with moderate to severe uncontrolled asthma.⁵ In vivo studies are needed to learn about the effects of these biologics on asthma and AD, whose complex immunologic effects are increasingly well understood by real patient experience.

Third, omalizumab has been found to relieve AD, not exacerbate it, in our own experience with 7 patients (unpublished data, 2024) and randomized controlled trials.⁶

Fourth, Yanovsky et al¹ reported that the patient’s lesions flared up within a few days after taking omalizumab, which suggests a non-IgE delayed reaction. Could this reaction be related to polysorbate 20 used as an excipient in the commercial preparation? When we examined both preparations, the presence of polysorbate 80 in dupilumab was noteworthy,⁷ unlike omalizumab. We suggest the authors perform a patch test including polysorbate 20 and polysorbate 80.

Finally, the authors mentioned that omalizumab may cause a paradoxical exacerbation of AD in certain patients, as in tumor necrosis factor α inhibitor–induced psoriasis.⁸ This has been reported,⁸ but tumor necrosis factor α inhibitors are cytokine inhibitors and can lead to cytokine imbalance, while omalizumab is an IgE inhibitor.

Yanovsky et al¹ described AD flares as “triggered by omalizumab,” which we believe was not the case. Because this patient had chronic AD, other causes of AD exacerbation in this patient could include stress or infection. Also, when they say that AD is triggered or induced, it implies that they are attributing the occurrence/development of AD in this patient to omalizumab. Of course, this also is not true.

Author’s Response

Thank you for your thoughtful comments. Although we agree that we cannot prove omalizumab was the cause of our patient’s AD flares, the new onset of severely worsening disease that was exacerbated by each dose of omalizumab as well as subsequent resolution upon switching to dupilumab was highly suggestive for a causal relationship. Our goal was to alert physicians to the possibility of this phenomenon and to encourage further study.

Karen A. Chernoff, MD
From the Department of Dermatology, Weill Cornell Medical College, New York, New York.
The author has no relevant financial disclosures to report.

To the Editor:

We read with interest the case reported by Yanovsky et al¹ (Cutis. 2023;112:E23-E25). We thank the authors for updating our knowledge about atopic dermatitis (AD) and omalizumab and improving our understanding of the various wanted and unwanted effects that may manifest with omalizumab. We wish to clarify a few points on omalizumab use.

First, Yanovsky et al¹ reported that their patient’s AD flares occurred within a few days after omalizumab injections to control asthma, possibly because omalizumab may have caused a paradoxical increase in sensitivity to other cytokines such as IL-33 in basophils and increased IL-4/IL-13 production in the skin. The authors cited Imai² to explain that IL-33 plays a role in the pathogenesis of AD, increases itching, and disrupts the skin barrier. However, Imai² did not discuss a relationship with omalizumab. As a recombinant humanized IgG1 monoclonal anti-IgE antibody, omalizumab works by interacting with the high-affinity receptor Fc epsilon RI that typically is found on eosinophils, mast cells, and basophils and plays a critical role in preventing the allergic cascade.³ We could not find any studies in the literature regarding omalizumab having a specific effect on the skin, causing cytokine imbalance, or increasing IL-4/IL-13 levels.

Second, the case report indicated that AD lesions improved with the biologic dupilumab,¹ which seems amazing. Dupilumab is a monoclonal antibody used in patients with moderate to severe AD that blocks IL-4/IL-13 signaling and thus inhibits receptor signaling downstream of the Janus kinase signal transducer and activator of transcription protein pathway.⁴ It also has been shown to be beneficial in children with moderate to severe uncontrolled asthma.⁵ In vivo studies are needed to learn about the effects of these biologics on asthma and AD, whose complex immunologic effects are increasingly well understood by real patient experience.

Third, omalizumab has been found to relieve AD, not exacerbate it, in our own experience with 7 patients (unpublished data, 2024) and randomized controlled trials.⁶

Fourth, Yanovsky et al¹ reported that the patient’s lesions flared up within a few days after taking omalizumab, which suggests a non-IgE delayed reaction. Could this reaction be related to polysorbate 20 used as an excipient in the commercial preparation? When we examined both preparations, the presence of polysorbate 80 in dupilumab was noteworthy,⁷ unlike omalizumab. We suggest the authors perform a patch test including polysorbate 20 and polysorbate 80.

Finally, the authors mentioned that omalizumab may cause a paradoxical exacerbation of AD in certain patients, as in tumor necrosis factor α inhibitor–induced psoriasis.⁸ This has been reported,⁸ but tumor necrosis factor α inhibitors are cytokine inhibitors and can lead to cytokine imbalance, while omalizumab is an IgE inhibitor.

Yanovsky et al¹ described AD flares as “triggered by omalizumab,” which we believe was not the case. Because this patient had chronic AD, other causes of AD exacerbation in this patient could include stress or infection. Also, when they say that AD is triggered or induced, it implies that they are attributing the occurrence/development of AD in this patient to omalizumab. Of course, this also is not true.

Author’s Response

Thank you for your thoughtful comments. Although we agree that we cannot prove omalizumab was the cause of our patient’s AD flares, the new onset of severely worsening disease that was exacerbated by each dose of omalizumab as well as subsequent resolution upon switching to dupilumab was highly suggestive for a causal relationship. Our goal was to alert physicians to the possibility of this phenomenon and to encourage further study.

Karen A. Chernoff, MD
From the Department of Dermatology, Weill Cornell Medical College, New York, New York.
The author has no relevant financial disclosures to report.

There is a well-established connection between the mind and the skin, and it is clear that this relationship is bidirectional—not only does skin disease increase the risk for depression, anxiety, sleep disturbance, and suicidality, but psychologic stress actually can worsen skin disease through multiple mechanisms, including direct damage to the skin barrier.^1,2 Psychologic stress also impacts the microbiome, another critical driver of skin disease.^3,4 The concept of the itch-scratch cycle vividly illustrates the vicious interplay between the mind and body in atopic dermatitis (AD).

However, patients with AD are not the only ones impacted—caregivers also experience psychologic stress. Remarkably, one study of patients with AD and their caregivers found that the caregivers actually reported significantly worse mental health and anxiety (P=.01 and P=.03, respectively) than patients themselves, even when controlling for the severity of disease.⁵

Thus, it would seem obvious for mental health to be a central component of AD care—to improve patient and caregiver quality of life while also improving symptoms. Research has actually borne this out, with one systematic review and meta-analysis concluding that psychological intervention has a beneficial effect on AD,⁶ and another that the addition of psychological and educational interventions to conventional treatment provided better therapeutic results in alleviating eczema severity and psychological symptoms.⁷ One study demonstrated that patients with AD who received cognitive behavioral therapy via the internet displayed a statistically significant improvement in their disease (P<.001) as measured by the Patient-Oriented Eczema Measure compared with those in the control group who received standard care alone. They also reported improvements in perceived stress, sleep problems, and depression in the intervention group that were sustained at 1-year follow-up.⁸ These findings are particularly impactful because clinical results were achieved while leveraging an internet-based approach to therapy.

Regrettably, despite the preponderance of evidence supporting the connection between mental health and AD, there remain considerable unmet needs. A recent cross-sectional survey of 954 adults with AD and caregivers of children with AD (N=954) conducted by the National Eczema Association found that half of patients were never asked about mental health during any of their visits, and of those referred for mental health resources, only 57% utilized the recommended services.⁹ Importantly, patients aged 18 to 34 years reported wanting to be asked about mental health. Of those who did receive referrals, most were for counseling services (23%), followed by alternative mental health therapy such as music or art therapy (15%), cognitive behavioral therapy (13%), or peer/social support groups (12%). Approximately 10% reported receiving a pamphlet or a brochure only.⁹

Physicians who treat patients with AD can and must do better, but first we must explore why these referral rates are so low. As with many complex problems, there is unlikely to be one simple unifying reason. As expected, the answer is nuanced and multifaceted, and—most importantly—staggeringly incomplete.

For starters, mental health interventions rarely are as easy as applying a cream or taking a pill. Hedman-Lagerlöf et al⁸ specifically pointed out that although their approach—using internet-based cognitive behavioral therapy—was explicitly designed to be more accessible with fewer resources, it required approximately 35 hours of treatment over 12 weeks, requiring both substantial time and commitment from patients who often are already burned out and exhausted due to AD. They even underscored that the most commonly reported adverse effect of therapy was increased stress or worry, making it a difficult sell.⁸

Even before most patients have a chance to consider the time required and the potential adverse effects of mental health interventions for AD, greater hurdles exist. Finances, medical insurance, and wait times were highlighted as barriers to care in a systematic review.¹⁰ These are deep-seated problems in the United States; while they may be surmountable in certain geo­graphic areas, the frequency with which these concerns arise means that it does not take too many failed attempts at referring patients for mental health services before clinicians just give up—similar to any form of operant conditioning.

A more elusive concept is stigmatization. Although it may not be quantifiable, the idea is that patients may encounter additional challenges when seeking mental health care, either because the interactions themselves may worsen their symptoms (eg, increased anxiety) or they may be more likely to have a negative perception of the experience.¹¹ A 2020 systematic review of barriers to addressing common mental health problems found that stigma was the most prominent barrier in adolescents, with the second most prominent being negative attitudes and beliefs about mental health services and professionals.¹² As a clinician, I can attest that I have sometimes detected skepticism when I have suggested mental health services to patients and have even been asked outright if I thought the problem was all in their head. My patients with AD generally have been much more open to the idea of mental health support, especially after I explain the powerful mind-body connection, than patients with other conditions—most notably delusions of parasitosis—who have been much more dismissive of such overtures. An oft-cited paper from 1976 frames the problem perfectly, describing what can happen after a referral for mental health services.¹³ The authors stated that the suggestion of mental health makes patients feel that the dermatologist does not believe them in the first place. Beyond this, the authors pointed out that referring the patient elsewhere reduces their hopes for dermatologic treatment.¹³

Knowing now—perhaps more than ever before—that the mind and skin are intimately connected compels us to solve these problems and find ways around these obstacles. Selecting the optimal forms of mental health services for each patient, having the structural support of the health care system, and winning the trust of patients and caregivers while combating stigma are undoubtedly tall orders; however, understanding the stakes for patients with AD, their caregivers, and society as a whole should inspire us to keep pushing forward.

There is a well-established connection between the mind and the skin, and it is clear that this relationship is bidirectional—not only does skin disease increase the risk for depression, anxiety, sleep disturbance, and suicidality, but psychologic stress actually can worsen skin disease through multiple mechanisms, including direct damage to the skin barrier.^1,2 Psychologic stress also impacts the microbiome, another critical driver of skin disease.^3,4 The concept of the itch-scratch cycle vividly illustrates the vicious interplay between the mind and body in atopic dermatitis (AD).

However, patients with AD are not the only ones impacted—caregivers also experience psychologic stress. Remarkably, one study of patients with AD and their caregivers found that the caregivers actually reported significantly worse mental health and anxiety (P=.01 and P=.03, respectively) than patients themselves, even when controlling for the severity of disease.⁵

Thus, it would seem obvious for mental health to be a central component of AD care—to improve patient and caregiver quality of life while also improving symptoms. Research has actually borne this out, with one systematic review and meta-analysis concluding that psychological intervention has a beneficial effect on AD,⁶ and another that the addition of psychological and educational interventions to conventional treatment provided better therapeutic results in alleviating eczema severity and psychological symptoms.⁷ One study demonstrated that patients with AD who received cognitive behavioral therapy via the internet displayed a statistically significant improvement in their disease (P<.001) as measured by the Patient-Oriented Eczema Measure compared with those in the control group who received standard care alone. They also reported improvements in perceived stress, sleep problems, and depression in the intervention group that were sustained at 1-year follow-up.⁸ These findings are particularly impactful because clinical results were achieved while leveraging an internet-based approach to therapy.

Regrettably, despite the preponderance of evidence supporting the connection between mental health and AD, there remain considerable unmet needs. A recent cross-sectional survey of 954 adults with AD and caregivers of children with AD (N=954) conducted by the National Eczema Association found that half of patients were never asked about mental health during any of their visits, and of those referred for mental health resources, only 57% utilized the recommended services.⁹ Importantly, patients aged 18 to 34 years reported wanting to be asked about mental health. Of those who did receive referrals, most were for counseling services (23%), followed by alternative mental health therapy such as music or art therapy (15%), cognitive behavioral therapy (13%), or peer/social support groups (12%). Approximately 10% reported receiving a pamphlet or a brochure only.⁹

Physicians who treat patients with AD can and must do better, but first we must explore why these referral rates are so low. As with many complex problems, there is unlikely to be one simple unifying reason. As expected, the answer is nuanced and multifaceted, and—most importantly—staggeringly incomplete.

For starters, mental health interventions rarely are as easy as applying a cream or taking a pill. Hedman-Lagerlöf et al⁸ specifically pointed out that although their approach—using internet-based cognitive behavioral therapy—was explicitly designed to be more accessible with fewer resources, it required approximately 35 hours of treatment over 12 weeks, requiring both substantial time and commitment from patients who often are already burned out and exhausted due to AD. They even underscored that the most commonly reported adverse effect of therapy was increased stress or worry, making it a difficult sell.⁸

Even before most patients have a chance to consider the time required and the potential adverse effects of mental health interventions for AD, greater hurdles exist. Finances, medical insurance, and wait times were highlighted as barriers to care in a systematic review.¹⁰ These are deep-seated problems in the United States; while they may be surmountable in certain geo­graphic areas, the frequency with which these concerns arise means that it does not take too many failed attempts at referring patients for mental health services before clinicians just give up—similar to any form of operant conditioning.

A more elusive concept is stigmatization. Although it may not be quantifiable, the idea is that patients may encounter additional challenges when seeking mental health care, either because the interactions themselves may worsen their symptoms (eg, increased anxiety) or they may be more likely to have a negative perception of the experience.¹¹ A 2020 systematic review of barriers to addressing common mental health problems found that stigma was the most prominent barrier in adolescents, with the second most prominent being negative attitudes and beliefs about mental health services and professionals.¹² As a clinician, I can attest that I have sometimes detected skepticism when I have suggested mental health services to patients and have even been asked outright if I thought the problem was all in their head. My patients with AD generally have been much more open to the idea of mental health support, especially after I explain the powerful mind-body connection, than patients with other conditions—most notably delusions of parasitosis—who have been much more dismissive of such overtures. An oft-cited paper from 1976 frames the problem perfectly, describing what can happen after a referral for mental health services.¹³ The authors stated that the suggestion of mental health makes patients feel that the dermatologist does not believe them in the first place. Beyond this, the authors pointed out that referring the patient elsewhere reduces their hopes for dermatologic treatment.¹³

Knowing now—perhaps more than ever before—that the mind and skin are intimately connected compels us to solve these problems and find ways around these obstacles. Selecting the optimal forms of mental health services for each patient, having the structural support of the health care system, and winning the trust of patients and caregivers while combating stigma are undoubtedly tall orders; however, understanding the stakes for patients with AD, their caregivers, and society as a whole should inspire us to keep pushing forward.

There is a well-established connection between the mind and the skin, and it is clear that this relationship is bidirectional—not only does skin disease increase the risk for depression, anxiety, sleep disturbance, and suicidality, but psychologic stress actually can worsen skin disease through multiple mechanisms, including direct damage to the skin barrier.^1,2 Psychologic stress also impacts the microbiome, another critical driver of skin disease.^3,4 The concept of the itch-scratch cycle vividly illustrates the vicious interplay between the mind and body in atopic dermatitis (AD).

However, patients with AD are not the only ones impacted—caregivers also experience psychologic stress. Remarkably, one study of patients with AD and their caregivers found that the caregivers actually reported significantly worse mental health and anxiety (P=.01 and P=.03, respectively) than patients themselves, even when controlling for the severity of disease.⁵

Thus, it would seem obvious for mental health to be a central component of AD care—to improve patient and caregiver quality of life while also improving symptoms. Research has actually borne this out, with one systematic review and meta-analysis concluding that psychological intervention has a beneficial effect on AD,⁶ and another that the addition of psychological and educational interventions to conventional treatment provided better therapeutic results in alleviating eczema severity and psychological symptoms.⁷ One study demonstrated that patients with AD who received cognitive behavioral therapy via the internet displayed a statistically significant improvement in their disease (P<.001) as measured by the Patient-Oriented Eczema Measure compared with those in the control group who received standard care alone. They also reported improvements in perceived stress, sleep problems, and depression in the intervention group that were sustained at 1-year follow-up.⁸ These findings are particularly impactful because clinical results were achieved while leveraging an internet-based approach to therapy.

Regrettably, despite the preponderance of evidence supporting the connection between mental health and AD, there remain considerable unmet needs. A recent cross-sectional survey of 954 adults with AD and caregivers of children with AD (N=954) conducted by the National Eczema Association found that half of patients were never asked about mental health during any of their visits, and of those referred for mental health resources, only 57% utilized the recommended services.⁹ Importantly, patients aged 18 to 34 years reported wanting to be asked about mental health. Of those who did receive referrals, most were for counseling services (23%), followed by alternative mental health therapy such as music or art therapy (15%), cognitive behavioral therapy (13%), or peer/social support groups (12%). Approximately 10% reported receiving a pamphlet or a brochure only.⁹

Physicians who treat patients with AD can and must do better, but first we must explore why these referral rates are so low. As with many complex problems, there is unlikely to be one simple unifying reason. As expected, the answer is nuanced and multifaceted, and—most importantly—staggeringly incomplete.

For starters, mental health interventions rarely are as easy as applying a cream or taking a pill. Hedman-Lagerlöf et al⁸ specifically pointed out that although their approach—using internet-based cognitive behavioral therapy—was explicitly designed to be more accessible with fewer resources, it required approximately 35 hours of treatment over 12 weeks, requiring both substantial time and commitment from patients who often are already burned out and exhausted due to AD. They even underscored that the most commonly reported adverse effect of therapy was increased stress or worry, making it a difficult sell.⁸

Even before most patients have a chance to consider the time required and the potential adverse effects of mental health interventions for AD, greater hurdles exist. Finances, medical insurance, and wait times were highlighted as barriers to care in a systematic review.¹⁰ These are deep-seated problems in the United States; while they may be surmountable in certain geo­graphic areas, the frequency with which these concerns arise means that it does not take too many failed attempts at referring patients for mental health services before clinicians just give up—similar to any form of operant conditioning.

A more elusive concept is stigmatization. Although it may not be quantifiable, the idea is that patients may encounter additional challenges when seeking mental health care, either because the interactions themselves may worsen their symptoms (eg, increased anxiety) or they may be more likely to have a negative perception of the experience.¹¹ A 2020 systematic review of barriers to addressing common mental health problems found that stigma was the most prominent barrier in adolescents, with the second most prominent being negative attitudes and beliefs about mental health services and professionals.¹² As a clinician, I can attest that I have sometimes detected skepticism when I have suggested mental health services to patients and have even been asked outright if I thought the problem was all in their head. My patients with AD generally have been much more open to the idea of mental health support, especially after I explain the powerful mind-body connection, than patients with other conditions—most notably delusions of parasitosis—who have been much more dismissive of such overtures. An oft-cited paper from 1976 frames the problem perfectly, describing what can happen after a referral for mental health services.¹³ The authors stated that the suggestion of mental health makes patients feel that the dermatologist does not believe them in the first place. Beyond this, the authors pointed out that referring the patient elsewhere reduces their hopes for dermatologic treatment.¹³

Knowing now—perhaps more than ever before—that the mind and skin are intimately connected compels us to solve these problems and find ways around these obstacles. Selecting the optimal forms of mental health services for each patient, having the structural support of the health care system, and winning the trust of patients and caregivers while combating stigma are undoubtedly tall orders; however, understanding the stakes for patients with AD, their caregivers, and society as a whole should inspire us to keep pushing forward.

This transcript has been edited for clarity. 

I’d like to talk about a very different topic from what I normally discuss, which is probably relatively rarely addressed in clinical conversations among clinicians. There was a very provocative commentary that appeared in JCO Oncology Practice, titled “Hollywood’s Take on Oncology: Portrayal of Cancer in Movies, 2010-2020.”

All of us, as we grow up — as kids, adolescents, young adults, adults, and older individuals — watch television and movies. The older of us know that the doctor in everybody’s home that we all wanted was Marcus Welby. Of course, there was Dr. Kildare, ER, Grey’s Anatomy, and St. Elsewhere. There was Love Story and Brian’s Song. We all know about these. 

This particular review was fascinating. The authors looked at 100 English-language movies that had cancer included in the storyline over the past decade. They asked some relatively simple questions: How did they discuss it? What were the tumor types they discussed? What were the outcomes? 

The question is, what is the public seeing? If you watch these movies and you don’t have family experience or personal experience with cancer, what do you think about cancer? Maybe this is what you know about it. Despite what the National Cancer Institute or the American Society of Clinical Oncology tells you, this may be what you know.

What they showed was really quite interesting. Only one third of the movies even said the cancer type, so in two thirds, you just knew they had “cancer.”

There is another very interesting phenomenon. What do you think was the most common cancer type when they did define the cancer? It was brain tumors, even though we know that brain tumors are certainly not even within the top 10. They’re obviously very serious cancers, but if you’re talking about common cancers, brain cancer doesn’t rank in the top 10, and it was the most common cancer on these shows.

The authors of this paper made the point of whether this would be an opportunity for filmmakers. Again, with the storyline, they’re trying to sell a product here, but wouldn’t this be the opportunity to provide some information about the reality of cancer? They could emphasize the fact that smokers get lung cancer. In my opinion, they could discuss cervical cancer and comment that if HPV vaccination had been done, maybe this would not have happened.

They noted that the majority of cancers in these movies were incurable, and they commented that that’s not the reality today. Today, obviously, many of our cancers that weren’t curable have become quite curable for a percentage of patients, in addition to which, obviously, with early detection, we have a very high cure rate. How about trying to get that message out, too, that we’ve actually had increasing success?

They commented that there was very rarely, if ever, a conversation about multidisciplinary care, that somehow there are multiple doctors with multiple specialties involved. They noted that this is potentially a very important message to give out. They commented that in 12 of these movies, the patient refused cancer care. Again, that happens, but it’s clearly a rare event today. Maybe this is not really a very accurate depiction of what’s going on.

They commented on the fact that, obviously, we’re going back through the past 10 years, so there were no patients who received immunotherapy or targeted therapy. Again, the goal here is not to sell oncology care but to be accurate, or more accurate, about the state of treatment to the extent you can.

They noted that, in fact, there was essentially very little, if any, comment on palliative care or hospice care. The final point they made is that there was very little conversation in these movies about what we now recognize as financial distress in many of our patients. That’s an unfortunate reality and perhaps that might come in the future.

Again, the point of this was not to tell Hollywood how to make their movies but to have the oncology community recognize that if their patients or the families of their patients are seeing these movies, they are not getting a very accurate picture of what is happening in the oncology world today and that some education may very well be required.

Maurie Markman is Professor, Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California, and President of Medicine & Science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed the following relevant financial relationships: income in an amount equal to or greater than $250 from: GlaxoSmithKline; AstraZeneca.

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

This transcript has been edited for clarity. 

I’d like to talk about a very different topic from what I normally discuss, which is probably relatively rarely addressed in clinical conversations among clinicians. There was a very provocative commentary that appeared in JCO Oncology Practice, titled “Hollywood’s Take on Oncology: Portrayal of Cancer in Movies, 2010-2020.”

All of us, as we grow up — as kids, adolescents, young adults, adults, and older individuals — watch television and movies. The older of us know that the doctor in everybody’s home that we all wanted was Marcus Welby. Of course, there was Dr. Kildare, ER, Grey’s Anatomy, and St. Elsewhere. There was Love Story and Brian’s Song. We all know about these. 

This particular review was fascinating. The authors looked at 100 English-language movies that had cancer included in the storyline over the past decade. They asked some relatively simple questions: How did they discuss it? What were the tumor types they discussed? What were the outcomes? 

The question is, what is the public seeing? If you watch these movies and you don’t have family experience or personal experience with cancer, what do you think about cancer? Maybe this is what you know about it. Despite what the National Cancer Institute or the American Society of Clinical Oncology tells you, this may be what you know.

What they showed was really quite interesting. Only one third of the movies even said the cancer type, so in two thirds, you just knew they had “cancer.”

There is another very interesting phenomenon. What do you think was the most common cancer type when they did define the cancer? It was brain tumors, even though we know that brain tumors are certainly not even within the top 10. They’re obviously very serious cancers, but if you’re talking about common cancers, brain cancer doesn’t rank in the top 10, and it was the most common cancer on these shows.

The authors of this paper made the point of whether this would be an opportunity for filmmakers. Again, with the storyline, they’re trying to sell a product here, but wouldn’t this be the opportunity to provide some information about the reality of cancer? They could emphasize the fact that smokers get lung cancer. In my opinion, they could discuss cervical cancer and comment that if HPV vaccination had been done, maybe this would not have happened.

They noted that the majority of cancers in these movies were incurable, and they commented that that’s not the reality today. Today, obviously, many of our cancers that weren’t curable have become quite curable for a percentage of patients, in addition to which, obviously, with early detection, we have a very high cure rate. How about trying to get that message out, too, that we’ve actually had increasing success?

They commented that there was very rarely, if ever, a conversation about multidisciplinary care, that somehow there are multiple doctors with multiple specialties involved. They noted that this is potentially a very important message to give out. They commented that in 12 of these movies, the patient refused cancer care. Again, that happens, but it’s clearly a rare event today. Maybe this is not really a very accurate depiction of what’s going on.

They commented on the fact that, obviously, we’re going back through the past 10 years, so there were no patients who received immunotherapy or targeted therapy. Again, the goal here is not to sell oncology care but to be accurate, or more accurate, about the state of treatment to the extent you can.

They noted that, in fact, there was essentially very little, if any, comment on palliative care or hospice care. The final point they made is that there was very little conversation in these movies about what we now recognize as financial distress in many of our patients. That’s an unfortunate reality and perhaps that might come in the future.

Again, the point of this was not to tell Hollywood how to make their movies but to have the oncology community recognize that if their patients or the families of their patients are seeing these movies, they are not getting a very accurate picture of what is happening in the oncology world today and that some education may very well be required.

Maurie Markman is Professor, Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California, and President of Medicine & Science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed the following relevant financial relationships: income in an amount equal to or greater than $250 from: GlaxoSmithKline; AstraZeneca.

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

This transcript has been edited for clarity. 

I’d like to talk about a very different topic from what I normally discuss, which is probably relatively rarely addressed in clinical conversations among clinicians. There was a very provocative commentary that appeared in JCO Oncology Practice, titled “Hollywood’s Take on Oncology: Portrayal of Cancer in Movies, 2010-2020.”

All of us, as we grow up — as kids, adolescents, young adults, adults, and older individuals — watch television and movies. The older of us know that the doctor in everybody’s home that we all wanted was Marcus Welby. Of course, there was Dr. Kildare, ER, Grey’s Anatomy, and St. Elsewhere. There was Love Story and Brian’s Song. We all know about these. 

This particular review was fascinating. The authors looked at 100 English-language movies that had cancer included in the storyline over the past decade. They asked some relatively simple questions: How did they discuss it? What were the tumor types they discussed? What were the outcomes? 

The question is, what is the public seeing? If you watch these movies and you don’t have family experience or personal experience with cancer, what do you think about cancer? Maybe this is what you know about it. Despite what the National Cancer Institute or the American Society of Clinical Oncology tells you, this may be what you know.

What they showed was really quite interesting. Only one third of the movies even said the cancer type, so in two thirds, you just knew they had “cancer.”

There is another very interesting phenomenon. What do you think was the most common cancer type when they did define the cancer? It was brain tumors, even though we know that brain tumors are certainly not even within the top 10. They’re obviously very serious cancers, but if you’re talking about common cancers, brain cancer doesn’t rank in the top 10, and it was the most common cancer on these shows.

The authors of this paper made the point of whether this would be an opportunity for filmmakers. Again, with the storyline, they’re trying to sell a product here, but wouldn’t this be the opportunity to provide some information about the reality of cancer? They could emphasize the fact that smokers get lung cancer. In my opinion, they could discuss cervical cancer and comment that if HPV vaccination had been done, maybe this would not have happened.

They noted that the majority of cancers in these movies were incurable, and they commented that that’s not the reality today. Today, obviously, many of our cancers that weren’t curable have become quite curable for a percentage of patients, in addition to which, obviously, with early detection, we have a very high cure rate. How about trying to get that message out, too, that we’ve actually had increasing success?

They commented that there was very rarely, if ever, a conversation about multidisciplinary care, that somehow there are multiple doctors with multiple specialties involved. They noted that this is potentially a very important message to give out. They commented that in 12 of these movies, the patient refused cancer care. Again, that happens, but it’s clearly a rare event today. Maybe this is not really a very accurate depiction of what’s going on.

They commented on the fact that, obviously, we’re going back through the past 10 years, so there were no patients who received immunotherapy or targeted therapy. Again, the goal here is not to sell oncology care but to be accurate, or more accurate, about the state of treatment to the extent you can.

They noted that, in fact, there was essentially very little, if any, comment on palliative care or hospice care. The final point they made is that there was very little conversation in these movies about what we now recognize as financial distress in many of our patients. That’s an unfortunate reality and perhaps that might come in the future.

Again, the point of this was not to tell Hollywood how to make their movies but to have the oncology community recognize that if their patients or the families of their patients are seeing these movies, they are not getting a very accurate picture of what is happening in the oncology world today and that some education may very well be required.

Maurie Markman is Professor, Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California, and President of Medicine & Science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed the following relevant financial relationships: income in an amount equal to or greater than $250 from: GlaxoSmithKline; AstraZeneca.

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

Ryan Forbess, MD: I live at the beach in Orange Beach, Alabama. I’ve lived in Hawaii, the Caymans, and other beach areas for years. I’ve seen a lot of sharks but never a shark attack. Not until now.

Mohammad Ali, MD: Ryan and I have been friends for 20 years. Every year, my family goes to 30A in Florida (a popular resort stretch of highway) to celebrate my wife’s birthday, and the Forbesses always meet us there. This year we had a group of about 18 people.

On Friday, it was beautiful, and we decided to make it a beach day. We had nine kids with us. So by the time we rounded them up and got there, it was noon, and there was nowhere to sit. We almost turned around and went to the pool. But my wife finally found a spot for an umbrella.

Dr. Forbess: We were in the water boogie boarding. I was with my 8-year-old son, and Mo was with his daughter who is the same age. Suddenly, we noticed a lot of commotion just to the left of us. My first thought was: Someone saw a shark, not an attack. They’re so rare. But seeing one would scare people.

We grabbed our kids and started running out of the water. As we got closer to the shore, I looked back to the left. And I saw it: Blood. Waves of blood.

We handed the kids off and started running down the beach.

Dr. Ali: It was mass panic. People were screaming and running out of the water. Other people were running in and grabbing their kids. Everyone just looked frantic.

We saw two men dragging this poor girl out of the water. It was surreal. The majority of her right leg was severed, her femur bone visible and stark white; it didn’t look real. I kept telling myself I was in a dream and now I’d wake up.

A young EMT who was there had put an informal tourniquet on her leg, but she was still bleeding. So I compressed the femoral artery as hard as I could, something I’m very familiar with doing.

Dr. Forbess: People asked me later what we used for a tourniquet. I said, “Mo’s big hands.” I tease him because most doctors play golf or go fishing; Mo lives in the gym. He was just holding pressure.

The girl’s left hand was also severed off at the wrist. There were two nurses there, and they helped with holding tourniquets on her arm.

Lulu (the girl’s name) was 15 years old. She was in and out of consciousness. At one point, her face started getting really pale, so we tried to lift her extremities up to keep the blood flow to the heart. With such severe blood loss, I thought she might go into cardiovascular shock, and we would have to start compressions. But she had a pulse, and she was breathing.

Dr. Ali: The beach was very crowded, and a lot of people had gathered around. Everyone was emotional, shocked, really shaken up. But they gave us space to work.

Dr. Forbess: People were handing us things — towels, a ratchet strap to use as a tourniquet. There was even an anesthesiologist there who said, “If you need an airway, let me know.” It was like we had a trauma team.

Dr. Ali: Lulu’s mom had been having lunch with friends. When she saw all the commotion, she ran down to the beach to look for her daughter. It was heartbreaking to hear her screams when she saw Lulu. But I was able to tune it out because we had to just concentrate on decreasing the loss of blood.

Dr. Forbess: Another girl came over and said, “That’s my sister.” Lulu has a twin. So she sat there holding Lulu’s hand and being with her the whole time.

Waiting for the EMTs to get there, the seconds were like hours. It seemed like it took forever. Finally, they came, and we were able to get the real tourniquets on, get her boarded and off the beach.

After that, they closed the beach. We got all our stuff and got on the little trolley that would take us back to the house. The lady who was driving asked us, “Did y’all hear about the shark attack?” My wife said, “Yeah, we were there.” And she said, “No, there was one an hour and a half ago.”

Dr. Ali: What we didn’t know was there had been two other attacks that day. Around the same time, one of Lulu’s friends was bitten and got a flesh wound on her heel. And before that, about 4 miles away, there was a serious injury: A lady in her 40s lost her hand and forearm and was bitten in the pelvis.

Dr. Forbess: At that point, my wife leaned back to me and said, “You know we’re never going to the beach again, right? We’re never ever going to the beach.”

If we had known about those attacks, we definitely wouldn’t have been in the water.

Dr. Ali: My wife has never liked going in the water. The evening before, we had debated about taking our daughters in the ocean because she was worried about sharks. I had given her this condescending speech about waist-deep water and the statistical probabilities of ever witnessing a shark attack. I was in trouble.

Dr. Forbess: We didn’t know if Lulu would make it. I’ve done rural family medicine in Oklahoma, so I’ve seen my fair share of injuries — guys on oil rigs, this and that. But I had never seen anything like this kind of trauma and blood loss.

Later that day, I called my office manager to catch up with her and told her what happened. She was actually in Pensacola having dinner across the street from Sacred Heart Hospital where they had taken Lulu. She went over to the emergency room to try to find out Lulu’s status — she was alive.

My office manager was able to go upstairs and talk to Lulu’s mom. Then she called, and we talked to her mom on the phone. She just said, “Thank you for helping my daughter.” It was an emotional moment.

Dr. Ali: It was such a relief. We had no idea how things would turn out. Even if Lulu did survive, was she going to be neurologically sound? But thank God she was. We were so relieved to hear her mom say that it was looking good. We still didn’t know for sure. But at least she was alive and seemed to be functioning.

Dr. Forbess: A few days later, my wife and I went to go visit her at the hospital. Her mom and her grandma were there. They were giving us hugs. We FaceTimed Mo because he was back in Jackson. It was really amazing.

What are the odds? The chances of a shark attack are about one in 12 million. And to have two physicians trained in trauma, a trauma nurse, another nurse, and an anesthesiologist less than 20 yards away when it happened? It’s crazy to think about.

Dr. Ali: And we almost weren’t there. We could have turned away.

Dr. Forbess: Humans are on top of the food chain. Or we think we are. But water really isn’t our element. Against a 12-foot bull shark, we don’t stand a chance. Lulu is here though. It’s unbelievable.

Her mom told me that when Lulu woke up, she just said, “I made it!” That girl is meant to be here. She is a tough girl with a great personality. She has these new prosthetics now that she can move with her mind; it’s like Star Wars. She says she wants to be a physician someday. So she’ll probably cure cancer.

Dr. Forbess is a family medicine physician at Orange Beach Family Medicine in Orange Beach, Alabama. Dr. Ali is an interventional radiologist with Baptist Memorial Health in Jackson, Mississippi.

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

Ryan Forbess, MD: I live at the beach in Orange Beach, Alabama. I’ve lived in Hawaii, the Caymans, and other beach areas for years. I’ve seen a lot of sharks but never a shark attack. Not until now.

Mohammad Ali, MD: Ryan and I have been friends for 20 years. Every year, my family goes to 30A in Florida (a popular resort stretch of highway) to celebrate my wife’s birthday, and the Forbesses always meet us there. This year we had a group of about 18 people.

On Friday, it was beautiful, and we decided to make it a beach day. We had nine kids with us. So by the time we rounded them up and got there, it was noon, and there was nowhere to sit. We almost turned around and went to the pool. But my wife finally found a spot for an umbrella.

Dr. Forbess: We were in the water boogie boarding. I was with my 8-year-old son, and Mo was with his daughter who is the same age. Suddenly, we noticed a lot of commotion just to the left of us. My first thought was: Someone saw a shark, not an attack. They’re so rare. But seeing one would scare people.

We grabbed our kids and started running out of the water. As we got closer to the shore, I looked back to the left. And I saw it: Blood. Waves of blood.

We handed the kids off and started running down the beach.

Dr. Ali: It was mass panic. People were screaming and running out of the water. Other people were running in and grabbing their kids. Everyone just looked frantic.

We saw two men dragging this poor girl out of the water. It was surreal. The majority of her right leg was severed, her femur bone visible and stark white; it didn’t look real. I kept telling myself I was in a dream and now I’d wake up.

A young EMT who was there had put an informal tourniquet on her leg, but she was still bleeding. So I compressed the femoral artery as hard as I could, something I’m very familiar with doing.

Dr. Forbess: People asked me later what we used for a tourniquet. I said, “Mo’s big hands.” I tease him because most doctors play golf or go fishing; Mo lives in the gym. He was just holding pressure.

The girl’s left hand was also severed off at the wrist. There were two nurses there, and they helped with holding tourniquets on her arm.

Lulu (the girl’s name) was 15 years old. She was in and out of consciousness. At one point, her face started getting really pale, so we tried to lift her extremities up to keep the blood flow to the heart. With such severe blood loss, I thought she might go into cardiovascular shock, and we would have to start compressions. But she had a pulse, and she was breathing.

Dr. Ali: The beach was very crowded, and a lot of people had gathered around. Everyone was emotional, shocked, really shaken up. But they gave us space to work.

Dr. Forbess: People were handing us things — towels, a ratchet strap to use as a tourniquet. There was even an anesthesiologist there who said, “If you need an airway, let me know.” It was like we had a trauma team.

Dr. Ali: Lulu’s mom had been having lunch with friends. When she saw all the commotion, she ran down to the beach to look for her daughter. It was heartbreaking to hear her screams when she saw Lulu. But I was able to tune it out because we had to just concentrate on decreasing the loss of blood.

Dr. Forbess: Another girl came over and said, “That’s my sister.” Lulu has a twin. So she sat there holding Lulu’s hand and being with her the whole time.

Waiting for the EMTs to get there, the seconds were like hours. It seemed like it took forever. Finally, they came, and we were able to get the real tourniquets on, get her boarded and off the beach.

After that, they closed the beach. We got all our stuff and got on the little trolley that would take us back to the house. The lady who was driving asked us, “Did y’all hear about the shark attack?” My wife said, “Yeah, we were there.” And she said, “No, there was one an hour and a half ago.”

Dr. Ali: What we didn’t know was there had been two other attacks that day. Around the same time, one of Lulu’s friends was bitten and got a flesh wound on her heel. And before that, about 4 miles away, there was a serious injury: A lady in her 40s lost her hand and forearm and was bitten in the pelvis.

Dr. Forbess: At that point, my wife leaned back to me and said, “You know we’re never going to the beach again, right? We’re never ever going to the beach.”

If we had known about those attacks, we definitely wouldn’t have been in the water.

Dr. Ali: My wife has never liked going in the water. The evening before, we had debated about taking our daughters in the ocean because she was worried about sharks. I had given her this condescending speech about waist-deep water and the statistical probabilities of ever witnessing a shark attack. I was in trouble.

Dr. Forbess: We didn’t know if Lulu would make it. I’ve done rural family medicine in Oklahoma, so I’ve seen my fair share of injuries — guys on oil rigs, this and that. But I had never seen anything like this kind of trauma and blood loss.

Later that day, I called my office manager to catch up with her and told her what happened. She was actually in Pensacola having dinner across the street from Sacred Heart Hospital where they had taken Lulu. She went over to the emergency room to try to find out Lulu’s status — she was alive.

My office manager was able to go upstairs and talk to Lulu’s mom. Then she called, and we talked to her mom on the phone. She just said, “Thank you for helping my daughter.” It was an emotional moment.

Dr. Ali: It was such a relief. We had no idea how things would turn out. Even if Lulu did survive, was she going to be neurologically sound? But thank God she was. We were so relieved to hear her mom say that it was looking good. We still didn’t know for sure. But at least she was alive and seemed to be functioning.

Dr. Forbess: A few days later, my wife and I went to go visit her at the hospital. Her mom and her grandma were there. They were giving us hugs. We FaceTimed Mo because he was back in Jackson. It was really amazing.

What are the odds? The chances of a shark attack are about one in 12 million. And to have two physicians trained in trauma, a trauma nurse, another nurse, and an anesthesiologist less than 20 yards away when it happened? It’s crazy to think about.

Dr. Ali: And we almost weren’t there. We could have turned away.

Dr. Forbess: Humans are on top of the food chain. Or we think we are. But water really isn’t our element. Against a 12-foot bull shark, we don’t stand a chance. Lulu is here though. It’s unbelievable.

Her mom told me that when Lulu woke up, she just said, “I made it!” That girl is meant to be here. She is a tough girl with a great personality. She has these new prosthetics now that she can move with her mind; it’s like Star Wars. She says she wants to be a physician someday. So she’ll probably cure cancer.

Dr. Forbess is a family medicine physician at Orange Beach Family Medicine in Orange Beach, Alabama. Dr. Ali is an interventional radiologist with Baptist Memorial Health in Jackson, Mississippi.

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

Ryan Forbess, MD: I live at the beach in Orange Beach, Alabama. I’ve lived in Hawaii, the Caymans, and other beach areas for years. I’ve seen a lot of sharks but never a shark attack. Not until now.

Mohammad Ali, MD: Ryan and I have been friends for 20 years. Every year, my family goes to 30A in Florida (a popular resort stretch of highway) to celebrate my wife’s birthday, and the Forbesses always meet us there. This year we had a group of about 18 people.

On Friday, it was beautiful, and we decided to make it a beach day. We had nine kids with us. So by the time we rounded them up and got there, it was noon, and there was nowhere to sit. We almost turned around and went to the pool. But my wife finally found a spot for an umbrella.

Dr. Forbess: We were in the water boogie boarding. I was with my 8-year-old son, and Mo was with his daughter who is the same age. Suddenly, we noticed a lot of commotion just to the left of us. My first thought was: Someone saw a shark, not an attack. They’re so rare. But seeing one would scare people.

We grabbed our kids and started running out of the water. As we got closer to the shore, I looked back to the left. And I saw it: Blood. Waves of blood.

We handed the kids off and started running down the beach.

Dr. Ali: It was mass panic. People were screaming and running out of the water. Other people were running in and grabbing their kids. Everyone just looked frantic.

We saw two men dragging this poor girl out of the water. It was surreal. The majority of her right leg was severed, her femur bone visible and stark white; it didn’t look real. I kept telling myself I was in a dream and now I’d wake up.

A young EMT who was there had put an informal tourniquet on her leg, but she was still bleeding. So I compressed the femoral artery as hard as I could, something I’m very familiar with doing.

Dr. Forbess: People asked me later what we used for a tourniquet. I said, “Mo’s big hands.” I tease him because most doctors play golf or go fishing; Mo lives in the gym. He was just holding pressure.

The girl’s left hand was also severed off at the wrist. There were two nurses there, and they helped with holding tourniquets on her arm.

Lulu (the girl’s name) was 15 years old. She was in and out of consciousness. At one point, her face started getting really pale, so we tried to lift her extremities up to keep the blood flow to the heart. With such severe blood loss, I thought she might go into cardiovascular shock, and we would have to start compressions. But she had a pulse, and she was breathing.

Dr. Ali: The beach was very crowded, and a lot of people had gathered around. Everyone was emotional, shocked, really shaken up. But they gave us space to work.

Dr. Forbess: People were handing us things — towels, a ratchet strap to use as a tourniquet. There was even an anesthesiologist there who said, “If you need an airway, let me know.” It was like we had a trauma team.

Dr. Ali: Lulu’s mom had been having lunch with friends. When she saw all the commotion, she ran down to the beach to look for her daughter. It was heartbreaking to hear her screams when she saw Lulu. But I was able to tune it out because we had to just concentrate on decreasing the loss of blood.

Dr. Forbess: Another girl came over and said, “That’s my sister.” Lulu has a twin. So she sat there holding Lulu’s hand and being with her the whole time.

Waiting for the EMTs to get there, the seconds were like hours. It seemed like it took forever. Finally, they came, and we were able to get the real tourniquets on, get her boarded and off the beach.

After that, they closed the beach. We got all our stuff and got on the little trolley that would take us back to the house. The lady who was driving asked us, “Did y’all hear about the shark attack?” My wife said, “Yeah, we were there.” And she said, “No, there was one an hour and a half ago.”

Dr. Ali: What we didn’t know was there had been two other attacks that day. Around the same time, one of Lulu’s friends was bitten and got a flesh wound on her heel. And before that, about 4 miles away, there was a serious injury: A lady in her 40s lost her hand and forearm and was bitten in the pelvis.

Dr. Forbess: At that point, my wife leaned back to me and said, “You know we’re never going to the beach again, right? We’re never ever going to the beach.”

If we had known about those attacks, we definitely wouldn’t have been in the water.

Dr. Ali: My wife has never liked going in the water. The evening before, we had debated about taking our daughters in the ocean because she was worried about sharks. I had given her this condescending speech about waist-deep water and the statistical probabilities of ever witnessing a shark attack. I was in trouble.

Dr. Forbess: We didn’t know if Lulu would make it. I’ve done rural family medicine in Oklahoma, so I’ve seen my fair share of injuries — guys on oil rigs, this and that. But I had never seen anything like this kind of trauma and blood loss.

Later that day, I called my office manager to catch up with her and told her what happened. She was actually in Pensacola having dinner across the street from Sacred Heart Hospital where they had taken Lulu. She went over to the emergency room to try to find out Lulu’s status — she was alive.

My office manager was able to go upstairs and talk to Lulu’s mom. Then she called, and we talked to her mom on the phone. She just said, “Thank you for helping my daughter.” It was an emotional moment.

Dr. Ali: It was such a relief. We had no idea how things would turn out. Even if Lulu did survive, was she going to be neurologically sound? But thank God she was. We were so relieved to hear her mom say that it was looking good. We still didn’t know for sure. But at least she was alive and seemed to be functioning.

Dr. Forbess: A few days later, my wife and I went to go visit her at the hospital. Her mom and her grandma were there. They were giving us hugs. We FaceTimed Mo because he was back in Jackson. It was really amazing.

What are the odds? The chances of a shark attack are about one in 12 million. And to have two physicians trained in trauma, a trauma nurse, another nurse, and an anesthesiologist less than 20 yards away when it happened? It’s crazy to think about.

Dr. Ali: And we almost weren’t there. We could have turned away.

Dr. Forbess: Humans are on top of the food chain. Or we think we are. But water really isn’t our element. Against a 12-foot bull shark, we don’t stand a chance. Lulu is here though. It’s unbelievable.

Her mom told me that when Lulu woke up, she just said, “I made it!” That girl is meant to be here. She is a tough girl with a great personality. She has these new prosthetics now that she can move with her mind; it’s like Star Wars. She says she wants to be a physician someday. So she’ll probably cure cancer.

Dr. Forbess is a family medicine physician at Orange Beach Family Medicine in Orange Beach, Alabama. Dr. Ali is an interventional radiologist with Baptist Memorial Health in Jackson, Mississippi.

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

This discussion was recorded on August 2, 2024. This transcript has been edited for clarity. 

Robert D. Glatter, MD: Today, we’ll be discussing the results of a new study published in The Journal of Emergency Medicine, looking at the incidence of delayed intracranial hemorrhage among older patients taking preinjury anticoagulants who present to the emergency department (ED) with blunt head trauma.

Joining me today is the lead author of the study, Dr. Richard Shih, professor of emergency medicine at Florida Atlantic University. Also joining me is Dr. Christina Shenvi, associate professor of emergency medicine at the University of North Carolina (UNC) Chapel Hill, with fellowship training in geriatric emergency medicine. 

Welcome to both of you.

Richard D. Shih, MD: Thanks, Rob. 

Christina L. Shenvi, MD, PhD, MBA: Thanks. Pleasure to be here. 
 

ICH Study Methodology

Dr. Glatter: It’s a pleasure to have you. Rich, this is a great study and targeted toward a population we see daily in the emergency department. I want you to describe your methodology, patient selection, and how you went about organizing your study to look at this important finding of delayed intracranial hemorrhage, especially in those on anticoagulants.

Dr. Shih: This all started for our research team when we first read the 2012 Annals of Emergency Medicine paper. The first author was Vincenzo Menditto, and he looked at a group of patients that had minor head injury, were anticoagulated, and had negative initial head CTs. 

There were about 100 patients, of which about 10 of them did not consent, but they hospitalized all these patients. These were anticoagulated, negative-first head CTs. They hospitalized the patients and then did a routine second CT at about 24 hours. They also followed them for a week, and it turned out a little over 7% of them had delayed head CT. 

We were wondering how many delayed intracranial hemorrhages we had missed because current practice for us was that, if patients had a good physical exam, their head CT was normal, and everything looked good, we would send them home.

Because of that, a number of people across the country wanted to verify those findings from the Menditto study. We tried to design a good study to answer that question. We happen to have a very large geriatric population in Florida, and our ED census is very high for age over 65, at nearly 60%. 

There are two Level I trauma centers in Palm Beach County. We included a second multicenter hospital, and we prospectively enrolled patients. We know the current state of practice is not to routinely do second CTs, so we followed these patients over time and followed their medical records to try to identify delayed bleeding. That’s how we set up our methodology.
 

Is It Safe to Discharge Patients With Trauma After 24 Hours?

Dr. Glatter: For the bulk of these patients with negative head CTs, it’s been my practice that when they’re stable and they look fine and there’s no other apparent, distracting painful trauma, injuries and so forth, they’re safe to discharge. 

The secondary outcome in your study is interesting: the need for neurosurgical intervention in terms of those with delayed intracranial hemorrhage.

Dr. Shih: I do believe that it’s certainly not the problem that Menditto described, which is 7%. There are two other prospective studies that have looked at this issue with delayed bleeding on anticoagulants. Both of these also showed a relatively low rate of delayed bleeding, which is between like 0.2% and 1.0%. In our study, it was 0.4%. 

The difference in the studies is that Menditto and colleagues routinely did 24-hour head CTs. They admitted everybody. For these other studies, routine head CT was not part of it. My bet is that there is a rate of delayed bleeding somewhere in between that seen in the Menditto study and that in all the other studies.

However, talking about significant intracranial hemorrhage, ones that perhaps need neurosurgery, I believe most of them are not significant. There’s some number that do occur, but the vast majority of those probably don’t need neurosurgery. We had 14 delayed bleeds out of 6000 patients with head trauma. One of them ended up requiring neurosurgery, so the answer is not zero, but I don’t think it’s 7% either. 

Dr. Glatter: Dr. Shenvi, I want to bring you into the conversation to talk about your experience at UNC, and how you run things in terms of older patients with blunt head trauma on preinjury anticoagulants.

Dr. Shenvi: Thanks, Rob. I remember when this paper came out showing this 7% rate of delayed bleeding and the question was, “Should we be admitting all these people?” Partly just from an overwhelming need for capacity that that would bring, it just wasn’t practical to say, “We’re going to admit every patient with a negative head CT to the hospital and rescan them.” That would be hundreds or thousands of patients each year in any given facility. 

The other thing is that delayed bleeds don’t always happen just in the first 24 hours. It’s not even a matter of bringing patients into observation for 24 hours, watching them, and rescanning them if they have symptoms. It can occur several days out. That never, in almost any institution that I know of, became standard practice. 

The way that it did change my care was to give good return precautions to patients, to make sure they have somebody with them to say, “Hey, sometimes you can have bleeding several days out after a fall, even though your CT scan here today looks perfect,” and to alert them that if they start having severe headaches, vomiting, or other symptoms of intracranial hemorrhage, that they should come back. 

I don’t think it ever became standard practice, and for good reason, because that was one study. The subsequent studies that Richard mentioned, pretty quickly on the heels of that initial one, showed a much lower rate of delayed ICH with the caveats that the methodology was different. 
 

Shift in Anticoagulants

Dr. Shenvi: One other big change from that original study, and now to Richard’s study, is the shift in anticoagulants. Back in the initial study you mentioned, it was all warfarin. We know from other studies looking at warfarin vs the direct oral anticoagulants (DOACs) that DOACs have lower rates of ICH after a head injury, lower rates of need for neurosurgical intervention, and lower rates of discharge to a skilled nursing facility after an intracranial hemorrhage.

Across the board, we know that the DOACs tend to do better. It’s difficult to compare newer studies because it’s a different medication. It did inform my practice to have an awareness of delayed intracranial hemorrhage so that I warn patients more proactively. 

Dr. Glatter: I haven’t seen a patient on warfarin in years. I don’t know if either of you have, but it’s all DOACs now unless there’s some other reason. That shift is quite apparent.

Dr. Shih: The problem with looking at delayed bleeding for DOACs vs warfarin is the numbers were so low. I think we had 13 people, and seven were in the no-anticoagulant group. The numbers are even lower, so it’s hard to say. 

I just wanted to comment on something that Dr. Shenvi said, and I pretty much agree with everything that she said. Anticoagulants and warfarin, and that Menditto study, have a carryover effect. People group DOACs with warfarin similarly. When a patient is brought in, the first thing they talk about with head trauma is, “Oh, they’re on an anticoagulant” or “They’re not on an anticoagulant.” It’s so ingrained.

I believe that, in emergency medicine, we’re pressed for space and time and we’re not as affected by that 24-hour observation. Maybe many of our surgeons will automatically admit those patients. 

I haven’t seen a guideline from the United States, but there are two international guidelines. One is from Austria from 2019, and one is from Scandinavia. Both recommended 24-hour observation if you’re on an anticoagulant.

There is a bit of controversy left over with that. Hopefully, as more and more of information, like in our study, comes out, people will be a little bit more clear about it. I don’t think there’s a need to routinely admit them. 

I do want to mention that the Menditto study had such a massive impact on everybody. They pointed out one subgroup (and it’s such a small number of patients). They had seven cases of delayed bleeding; four or five of them were within that 24 hours, and a couple were diagnosed later over the next couple days.

Of those seven people, four of them had international normalized ratios (INRs) greater than 3. Of those four patients, I’ve heard people talk about this and recommend, “Okay, that’s the subgroup I would admit.” There’s a toss-up with what to do with DOAC because it’s very hard to tell whether there’s an issue, whether there are problems with their dosing, and whatever. 

We actually recently looked at that. We have a much larger sample than four: close to 300 patients who were on warfarin. We looked at patients who had INRs below 3 and above 3, and we didn’t show a difference. We still don’t believe that warfarin is a big issue with delayed bleeding.
 

Should We Be Asking: ‘Are They on Blood Thinners?’

Dr. Shenvi: One of the interesting trends related to warfarin and the DOACs vs no anticoagulant is that as you mentioned, Dr Shih, the first question out of people’s mouths or the first piece of information emergency medical services gives you when they come in with a patient who’s had a head injury is, “Are they on blood thinners or not?”

Yet, the paradigm is shifting to say it’s not actually the blood thinners themselves that are giving older patients the higher risk for bleeding; it’s age and other comorbidities.

Certainly, if you’re on an anticoagulant and you start to bleed, your prognosis is much worse because the bleeding doesn’t stop. In terms of who has a bleeding event, there’s much less impact of anticoagulation than we used to think. That, in part, may be due to the change from warfarin to other medications.

Some of the experts I’ve talked to who have done the research on this have said, “Well, actually, warfarin was more of a marker for being much older and more frail, because it was primarily prescribed to older patients who have significant heart disease, atrial fibrillation, and so on.” It was more a marker for somebody who is at risk for an intracranial hemorrhage. There are many changes that have happened in the past 10 years with medications and also our understanding. 
 

Challenges in Patient Follow-up

Dr. Glatter: That’s a great point. One thing, Rich, I want to ask you about is in terms of your proxy outcome assessment. When you use that at 14 and 60 days with telephone follow-up and then chart review at 60 and 90 days (because, obviously, everyone can’t get another head CT or it’s difficult to follow patients up), did you find that worked out well in your prospective cohort study, in terms of using that as a proxy, so to speak? 

Dr. Shih: I would say to a certain extent. Unfortunately, we don’t have access to the patients to come back to follow up all of them, and there was obviously a large number of patients in our study. 

The next best thing was that we had dedicated research assistants calling all of the patients at 14 days and 60 days. I’ve certainly read research studies where, when they call them, they get 80%-90% follow-up, but we did not achieve that.

I don’t know if people are more inundated with spam phone calls now, or the older people are just afraid of picking up their phone sometimes with all the scams and so forth. I totally understand, but in all honesty, we only had about a 30%-35% follow-up using that follow-up pathway. 

Then the proxy pathway was to look at their charts at 60 and 90 days. Also, we looked at the Florida death registry, which is pretty good, and then finally, we had both Level I trauma centers in the county that we were in participating. It’s standard practice that if you have an intracranial hemorrhage at a non–Level I trauma center, you would be transferred to a Level I trauma center. That’s the protocol. I know that’s not followed 100% of the time, but that’s part of the proxy follow-up. You could criticize the study for not having closer to 90% actual contact, but that’s the best we could do. 

Dr. Glatter: I think that’s admirable. Using that paradigm of what you described certainly allows the reader to understand the difficulty in assessing patients that don’t get follow-up head CT, and hardly anyone does that, as we know.

To your point of having both Level I trauma centers in the county, that makes it pretty secure. If we’re going to do a study encompassing a similar type of regional aspect, it would be similar.

Dr. Shenvi: I think your proxies, to your credit, were as good as you can get. You can never get a 100% follow-up, but you really looked at all the different avenues by which patients might present, either in the death registry or a Level I center. Well done on that aspect.

 

Determining When to Admit Patients for Observation

Dr. Glatter: In terms of admissions: You admit a patient, then you hear back that this patient should not have been admitted because they had a negative head CT, but you put them in anyway in the sense of delayed bleeding happening or not happening.

It’s interesting. Maybe the insurers will start looking at this in some capacity, based on your study, that because it’s so infrequent that you see delayed bleeding, that admitting someone for any reason whatsoever would be declined. Do you see that being an issue? In other words, [do you see] this leading to a pattern in terms of the payers?

Dr. Shih: Certainly, you could interpret it that way, and that would be unfortunate. The [incidence of] delayed bleeding is definitely not zero. That’s the first thing. 

The second thing is that when you’re dealing with an older population, having some sense that they’re not doing well is an important contributor to trying to fully assess what’s going on — whether or not they have a bleed or whether they’re at risk for falling again and then hitting their head and causing a second bleed, and making sure they can do the activities of daily life. There really should be some room for a physician to say, “They just got here, and we don’t know him that well. There’s something that bothers me about this person” and have the ability to watch them for at least another 24 hours. That’s how I feel. 

Dr. Shenvi: In my location, it would be difficult to try to admit somebody purely for observation for delayed bleeding. I think we would get a lot of pushback on that. The reasons I might admit a patient after a fall with a negative head CT, though, are all the things that, Rob, you alluded to earlier — which are, what made them fall in the first place and were they unable to get up? 

I had this happen just this week. A patient who fell couldn’t get off the ground for 12 hours, and so now she’s dehydrated and delirious with slight rhabdomyolysis. Then you’re admitting them either for the sequelae of the fall that are not related to the intracranial hemorrhage, or the fact that they are so debilitated and deconditioned that they cannot take care of themselves. They need physical therapy. Often, we will have physical and occupational therapists come see them in the ED during business hours and help make an assessment of whether they are safe to go home or whether they fall again. That can give more evidence for the need for admission.

Dr. Glatter: To bring artificial intelligence into this discussion, algorithms that are out there that say, “Push a button and the patient’s safe for discharge.” Well, this argues for a clinical gestalt and a human being to make an assessment because you can use these predictive models, which are coming and they’re going to be here soon, and they already are in some sense. Again, we have to use clinical human judgment. 

Dr. Shih: I agree. 
 

Advice for Primary Care Physicians

Dr. Glatter: What return precautions do you discuss with patients who’ve had blunt head trauma that maybe had a head CT, or even didn’t? What are the main things we’re looking for?

Dr. Shenvi: What I usually tell people is if you start to have a worse headache, nausea or vomiting, any weakness in one area of your body, or vision changes, and if there’s a family member or friend there, I’ll say, “If you notice that they’re acting differently or seem confused, come back.”

Dr. Shih: I agree with what she said, and I’m also going to add one thing. The most important part is they are trying to prevent a subsequent fall. We know that when they’ve fallen and they present to the ED, they’re at even higher risk for falling and reinjuring themselves, and that’s a population that’s already at risk.

One of the secondary studies that we published out of this project was looking at follow-up with their primary care physicians, and there were two things that we wanted to address. The first was, how often did they do it? Then, when they did do it, did their primary care physicians try to address and prevent subsequent falls?

Both the answers are actually bad. Amazingly, just over like 60% followed up. 

In some of our subsequent research, because we’re in the midst of a randomized, controlled trial where we do a home visit, when we initially see these individuals that have fallen, they’ll schedule a home visit for us. Then a week or two later, when we schedule the home visit, many of them cancel because they think, Oh, that was a one-off and it’s not going to happen again. Part of the problem is the patients, because many of them believe that they just slipped and fell and it’s not going to happen again, or they’re not prone to it.

The second issue was when patients did go to a primary care physician, we have found that some primary care physicians believe that falling and injuring themselves is just part of the normal aging process. A percentage of them don’t go over assessment for fall risk or even initiate fall prevention treatments or programs. 

I try to take that time to tell them that this is very common in their age group, and believe it or not, a fall from standing is the way people really injure themselves, and there may be ways to prevent subsequent falls and injuries. 

Dr. Glatter: Absolutely. Do you find that their medications are a contributor in some sense? Say they’re antihypertensive, have issues of orthostasis, or a new medication was added in the last week. 

Dr. Shenvi: It’s all of the above. Sometimes it’s one thing, like they just started tamsulosin for their kidney stone, they stood up, they felt lightheaded, and they fell. Usually, it’s multifactorial with some changes in their gait, vision, balance, reflex time, and strength, plus the medications or the need for assistive devices. Maybe they can’t take care of their home as well as they used to and there are things on the floor. It’s really all of the above.
 

‘Harder to Unlearn Something Than to Learn It’

Dr. Glatter: Would either of you like to add any additional points to the discussion or add a few pearls? 

Dr. Shenvi: This just highlights the challenge of how it’s harder to unlearn something than to learn it, where one study that maybe wasn’t quite looking at what we needed to, or practice and prescribing patterns have changed, so it’s no longer really relevant. 

The things that we learned from that, or the fears that we instilled in our minds of, Uh oh, they could go home and have delayed bleeding, are much harder to unlearn, and it takes more studies to unlearn that idea than it did to actually put it into place. 

I’m glad that your team has done this much larger, prospective study and hopefully will reduce the concern about this entity. 

Dr. Shih: I appreciate that segue. It is amazing that, for paramedics and medical students, the first thing out of their mouth is, “Are they on an anticoagulant?”

In terms of the risk of developing an intracranial hemorrhage, I think it’s much less than the weight we’ve put on it before. However, I believe if they have a bleed, the bleeds are worse. It’s kind of a double-edged sword. It’s still an important factor, but it doesn’t come with the Oh my gosh, they’re on an anticoagulant that everybody thinks about.
 

No. 1 Cause of Traumatic Injury Is a Fall from Standing

Dr. Glatter: These are obviously ground-level falls in most patients and not motor vehicle crashes. That’s an important part in the population that you looked at that should be mentioned clearly. 

Dr. Shih: It’s astonishing. I’ve been a program director for over 20 years, and geriatrics is not well taught in the curriculum. It’s astonishing for many of our trainees and emergency physicians in general that the number-one cause for traumatic injury is a fall from standing.

Certainly, we get patients coming in the trauma center like a 95-year-old person who’s on a ladder putting up his Christmas lights. I’m like, oh my God. 

For the vast majority, it’s closer to 90%, but in our study, for the patients we looked at, it was 80% that fall from standing. That’s the mechanism that causes these bleeds and these major injuries. 

Dr. Shenvi: That’s reflective of what we see, so it’s good that that’s what you looked at also. 

Dr. Glatter: Absolutely. Well, thank you both. This has been a very informative discussion. I appreciate your time, and our readers will certainly benefit from your knowledge and expertise. Thank you again.

Dr. Glatter, assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, is a medical adviser for this news organization. He disclosed having no relevant financial conflicts. Dr. Shih is professor of emergency medicine at the Charles E. Schmidt College of Medicine at Florida Atlantic University, Boca Raton. His current grant funding and area of research interest involves geriatric emergency department patients with head injury and fall-related injury. He disclosed receiving a research grant from The Florida Medical Malpractice Joint Underwriting Association Grant for Safety of Health Care Services). Dr. Shenvi, associate professor of emergency medicine at the University of North Carolina at Chapel Hill, disclosed ties with the American College of Emergency Physicians, Institute for Healthcare Improvement, AstraZeneca, and CurvaFix.

A version of this article appeared on Medscape.com.

This discussion was recorded on August 2, 2024. This transcript has been edited for clarity. 

Robert D. Glatter, MD: Today, we’ll be discussing the results of a new study published in The Journal of Emergency Medicine, looking at the incidence of delayed intracranial hemorrhage among older patients taking preinjury anticoagulants who present to the emergency department (ED) with blunt head trauma.

Joining me today is the lead author of the study, Dr. Richard Shih, professor of emergency medicine at Florida Atlantic University. Also joining me is Dr. Christina Shenvi, associate professor of emergency medicine at the University of North Carolina (UNC) Chapel Hill, with fellowship training in geriatric emergency medicine. 

Welcome to both of you.

Richard D. Shih, MD: Thanks, Rob. 

Christina L. Shenvi, MD, PhD, MBA: Thanks. Pleasure to be here. 
 

ICH Study Methodology

Dr. Glatter: It’s a pleasure to have you. Rich, this is a great study and targeted toward a population we see daily in the emergency department. I want you to describe your methodology, patient selection, and how you went about organizing your study to look at this important finding of delayed intracranial hemorrhage, especially in those on anticoagulants.

Dr. Shih: This all started for our research team when we first read the 2012 Annals of Emergency Medicine paper. The first author was Vincenzo Menditto, and he looked at a group of patients that had minor head injury, were anticoagulated, and had negative initial head CTs. 

There were about 100 patients, of which about 10 of them did not consent, but they hospitalized all these patients. These were anticoagulated, negative-first head CTs. They hospitalized the patients and then did a routine second CT at about 24 hours. They also followed them for a week, and it turned out a little over 7% of them had delayed head CT. 

We were wondering how many delayed intracranial hemorrhages we had missed because current practice for us was that, if patients had a good physical exam, their head CT was normal, and everything looked good, we would send them home.

Because of that, a number of people across the country wanted to verify those findings from the Menditto study. We tried to design a good study to answer that question. We happen to have a very large geriatric population in Florida, and our ED census is very high for age over 65, at nearly 60%. 

There are two Level I trauma centers in Palm Beach County. We included a second multicenter hospital, and we prospectively enrolled patients. We know the current state of practice is not to routinely do second CTs, so we followed these patients over time and followed their medical records to try to identify delayed bleeding. That’s how we set up our methodology.
 

Is It Safe to Discharge Patients With Trauma After 24 Hours?

Dr. Glatter: For the bulk of these patients with negative head CTs, it’s been my practice that when they’re stable and they look fine and there’s no other apparent, distracting painful trauma, injuries and so forth, they’re safe to discharge. 

The secondary outcome in your study is interesting: the need for neurosurgical intervention in terms of those with delayed intracranial hemorrhage.

Dr. Shih: I do believe that it’s certainly not the problem that Menditto described, which is 7%. There are two other prospective studies that have looked at this issue with delayed bleeding on anticoagulants. Both of these also showed a relatively low rate of delayed bleeding, which is between like 0.2% and 1.0%. In our study, it was 0.4%. 

The difference in the studies is that Menditto and colleagues routinely did 24-hour head CTs. They admitted everybody. For these other studies, routine head CT was not part of it. My bet is that there is a rate of delayed bleeding somewhere in between that seen in the Menditto study and that in all the other studies.

However, talking about significant intracranial hemorrhage, ones that perhaps need neurosurgery, I believe most of them are not significant. There’s some number that do occur, but the vast majority of those probably don’t need neurosurgery. We had 14 delayed bleeds out of 6000 patients with head trauma. One of them ended up requiring neurosurgery, so the answer is not zero, but I don’t think it’s 7% either. 

Dr. Glatter: Dr. Shenvi, I want to bring you into the conversation to talk about your experience at UNC, and how you run things in terms of older patients with blunt head trauma on preinjury anticoagulants.

Dr. Shenvi: Thanks, Rob. I remember when this paper came out showing this 7% rate of delayed bleeding and the question was, “Should we be admitting all these people?” Partly just from an overwhelming need for capacity that that would bring, it just wasn’t practical to say, “We’re going to admit every patient with a negative head CT to the hospital and rescan them.” That would be hundreds or thousands of patients each year in any given facility. 

The other thing is that delayed bleeds don’t always happen just in the first 24 hours. It’s not even a matter of bringing patients into observation for 24 hours, watching them, and rescanning them if they have symptoms. It can occur several days out. That never, in almost any institution that I know of, became standard practice. 

The way that it did change my care was to give good return precautions to patients, to make sure they have somebody with them to say, “Hey, sometimes you can have bleeding several days out after a fall, even though your CT scan here today looks perfect,” and to alert them that if they start having severe headaches, vomiting, or other symptoms of intracranial hemorrhage, that they should come back. 

I don’t think it ever became standard practice, and for good reason, because that was one study. The subsequent studies that Richard mentioned, pretty quickly on the heels of that initial one, showed a much lower rate of delayed ICH with the caveats that the methodology was different. 
 

Shift in Anticoagulants

Dr. Shenvi: One other big change from that original study, and now to Richard’s study, is the shift in anticoagulants. Back in the initial study you mentioned, it was all warfarin. We know from other studies looking at warfarin vs the direct oral anticoagulants (DOACs) that DOACs have lower rates of ICH after a head injury, lower rates of need for neurosurgical intervention, and lower rates of discharge to a skilled nursing facility after an intracranial hemorrhage.

Across the board, we know that the DOACs tend to do better. It’s difficult to compare newer studies because it’s a different medication. It did inform my practice to have an awareness of delayed intracranial hemorrhage so that I warn patients more proactively. 

Dr. Glatter: I haven’t seen a patient on warfarin in years. I don’t know if either of you have, but it’s all DOACs now unless there’s some other reason. That shift is quite apparent.

Dr. Shih: The problem with looking at delayed bleeding for DOACs vs warfarin is the numbers were so low. I think we had 13 people, and seven were in the no-anticoagulant group. The numbers are even lower, so it’s hard to say. 

I just wanted to comment on something that Dr. Shenvi said, and I pretty much agree with everything that she said. Anticoagulants and warfarin, and that Menditto study, have a carryover effect. People group DOACs with warfarin similarly. When a patient is brought in, the first thing they talk about with head trauma is, “Oh, they’re on an anticoagulant” or “They’re not on an anticoagulant.” It’s so ingrained.

I believe that, in emergency medicine, we’re pressed for space and time and we’re not as affected by that 24-hour observation. Maybe many of our surgeons will automatically admit those patients. 

I haven’t seen a guideline from the United States, but there are two international guidelines. One is from Austria from 2019, and one is from Scandinavia. Both recommended 24-hour observation if you’re on an anticoagulant.

There is a bit of controversy left over with that. Hopefully, as more and more of information, like in our study, comes out, people will be a little bit more clear about it. I don’t think there’s a need to routinely admit them. 

I do want to mention that the Menditto study had such a massive impact on everybody. They pointed out one subgroup (and it’s such a small number of patients). They had seven cases of delayed bleeding; four or five of them were within that 24 hours, and a couple were diagnosed later over the next couple days.

Of those seven people, four of them had international normalized ratios (INRs) greater than 3. Of those four patients, I’ve heard people talk about this and recommend, “Okay, that’s the subgroup I would admit.” There’s a toss-up with what to do with DOAC because it’s very hard to tell whether there’s an issue, whether there are problems with their dosing, and whatever. 

We actually recently looked at that. We have a much larger sample than four: close to 300 patients who were on warfarin. We looked at patients who had INRs below 3 and above 3, and we didn’t show a difference. We still don’t believe that warfarin is a big issue with delayed bleeding.
 

Should We Be Asking: ‘Are They on Blood Thinners?’

Dr. Shenvi: One of the interesting trends related to warfarin and the DOACs vs no anticoagulant is that as you mentioned, Dr Shih, the first question out of people’s mouths or the first piece of information emergency medical services gives you when they come in with a patient who’s had a head injury is, “Are they on blood thinners or not?”

Yet, the paradigm is shifting to say it’s not actually the blood thinners themselves that are giving older patients the higher risk for bleeding; it’s age and other comorbidities.

Certainly, if you’re on an anticoagulant and you start to bleed, your prognosis is much worse because the bleeding doesn’t stop. In terms of who has a bleeding event, there’s much less impact of anticoagulation than we used to think. That, in part, may be due to the change from warfarin to other medications.

Some of the experts I’ve talked to who have done the research on this have said, “Well, actually, warfarin was more of a marker for being much older and more frail, because it was primarily prescribed to older patients who have significant heart disease, atrial fibrillation, and so on.” It was more a marker for somebody who is at risk for an intracranial hemorrhage. There are many changes that have happened in the past 10 years with medications and also our understanding. 
 

Challenges in Patient Follow-up

Dr. Glatter: That’s a great point. One thing, Rich, I want to ask you about is in terms of your proxy outcome assessment. When you use that at 14 and 60 days with telephone follow-up and then chart review at 60 and 90 days (because, obviously, everyone can’t get another head CT or it’s difficult to follow patients up), did you find that worked out well in your prospective cohort study, in terms of using that as a proxy, so to speak? 

Dr. Shih: I would say to a certain extent. Unfortunately, we don’t have access to the patients to come back to follow up all of them, and there was obviously a large number of patients in our study. 

The next best thing was that we had dedicated research assistants calling all of the patients at 14 days and 60 days. I’ve certainly read research studies where, when they call them, they get 80%-90% follow-up, but we did not achieve that.

I don’t know if people are more inundated with spam phone calls now, or the older people are just afraid of picking up their phone sometimes with all the scams and so forth. I totally understand, but in all honesty, we only had about a 30%-35% follow-up using that follow-up pathway. 

Then the proxy pathway was to look at their charts at 60 and 90 days. Also, we looked at the Florida death registry, which is pretty good, and then finally, we had both Level I trauma centers in the county that we were in participating. It’s standard practice that if you have an intracranial hemorrhage at a non–Level I trauma center, you would be transferred to a Level I trauma center. That’s the protocol. I know that’s not followed 100% of the time, but that’s part of the proxy follow-up. You could criticize the study for not having closer to 90% actual contact, but that’s the best we could do. 

Dr. Glatter: I think that’s admirable. Using that paradigm of what you described certainly allows the reader to understand the difficulty in assessing patients that don’t get follow-up head CT, and hardly anyone does that, as we know.

To your point of having both Level I trauma centers in the county, that makes it pretty secure. If we’re going to do a study encompassing a similar type of regional aspect, it would be similar.

Dr. Shenvi: I think your proxies, to your credit, were as good as you can get. You can never get a 100% follow-up, but you really looked at all the different avenues by which patients might present, either in the death registry or a Level I center. Well done on that aspect.

 

Determining When to Admit Patients for Observation

Dr. Glatter: In terms of admissions: You admit a patient, then you hear back that this patient should not have been admitted because they had a negative head CT, but you put them in anyway in the sense of delayed bleeding happening or not happening.

It’s interesting. Maybe the insurers will start looking at this in some capacity, based on your study, that because it’s so infrequent that you see delayed bleeding, that admitting someone for any reason whatsoever would be declined. Do you see that being an issue? In other words, [do you see] this leading to a pattern in terms of the payers?

Dr. Shih: Certainly, you could interpret it that way, and that would be unfortunate. The [incidence of] delayed bleeding is definitely not zero. That’s the first thing. 

The second thing is that when you’re dealing with an older population, having some sense that they’re not doing well is an important contributor to trying to fully assess what’s going on — whether or not they have a bleed or whether they’re at risk for falling again and then hitting their head and causing a second bleed, and making sure they can do the activities of daily life. There really should be some room for a physician to say, “They just got here, and we don’t know him that well. There’s something that bothers me about this person” and have the ability to watch them for at least another 24 hours. That’s how I feel. 

Dr. Shenvi: In my location, it would be difficult to try to admit somebody purely for observation for delayed bleeding. I think we would get a lot of pushback on that. The reasons I might admit a patient after a fall with a negative head CT, though, are all the things that, Rob, you alluded to earlier — which are, what made them fall in the first place and were they unable to get up? 

I had this happen just this week. A patient who fell couldn’t get off the ground for 12 hours, and so now she’s dehydrated and delirious with slight rhabdomyolysis. Then you’re admitting them either for the sequelae of the fall that are not related to the intracranial hemorrhage, or the fact that they are so debilitated and deconditioned that they cannot take care of themselves. They need physical therapy. Often, we will have physical and occupational therapists come see them in the ED during business hours and help make an assessment of whether they are safe to go home or whether they fall again. That can give more evidence for the need for admission.

Dr. Glatter: To bring artificial intelligence into this discussion, algorithms that are out there that say, “Push a button and the patient’s safe for discharge.” Well, this argues for a clinical gestalt and a human being to make an assessment because you can use these predictive models, which are coming and they’re going to be here soon, and they already are in some sense. Again, we have to use clinical human judgment. 

Dr. Shih: I agree. 
 

Advice for Primary Care Physicians

Dr. Glatter: What return precautions do you discuss with patients who’ve had blunt head trauma that maybe had a head CT, or even didn’t? What are the main things we’re looking for?

Dr. Shenvi: What I usually tell people is if you start to have a worse headache, nausea or vomiting, any weakness in one area of your body, or vision changes, and if there’s a family member or friend there, I’ll say, “If you notice that they’re acting differently or seem confused, come back.”

Dr. Shih: I agree with what she said, and I’m also going to add one thing. The most important part is they are trying to prevent a subsequent fall. We know that when they’ve fallen and they present to the ED, they’re at even higher risk for falling and reinjuring themselves, and that’s a population that’s already at risk.

One of the secondary studies that we published out of this project was looking at follow-up with their primary care physicians, and there were two things that we wanted to address. The first was, how often did they do it? Then, when they did do it, did their primary care physicians try to address and prevent subsequent falls?

Both the answers are actually bad. Amazingly, just over like 60% followed up. 

In some of our subsequent research, because we’re in the midst of a randomized, controlled trial where we do a home visit, when we initially see these individuals that have fallen, they’ll schedule a home visit for us. Then a week or two later, when we schedule the home visit, many of them cancel because they think, Oh, that was a one-off and it’s not going to happen again. Part of the problem is the patients, because many of them believe that they just slipped and fell and it’s not going to happen again, or they’re not prone to it.

The second issue was when patients did go to a primary care physician, we have found that some primary care physicians believe that falling and injuring themselves is just part of the normal aging process. A percentage of them don’t go over assessment for fall risk or even initiate fall prevention treatments or programs. 

I try to take that time to tell them that this is very common in their age group, and believe it or not, a fall from standing is the way people really injure themselves, and there may be ways to prevent subsequent falls and injuries. 

Dr. Glatter: Absolutely. Do you find that their medications are a contributor in some sense? Say they’re antihypertensive, have issues of orthostasis, or a new medication was added in the last week. 

Dr. Shenvi: It’s all of the above. Sometimes it’s one thing, like they just started tamsulosin for their kidney stone, they stood up, they felt lightheaded, and they fell. Usually, it’s multifactorial with some changes in their gait, vision, balance, reflex time, and strength, plus the medications or the need for assistive devices. Maybe they can’t take care of their home as well as they used to and there are things on the floor. It’s really all of the above.
 

‘Harder to Unlearn Something Than to Learn It’

Dr. Glatter: Would either of you like to add any additional points to the discussion or add a few pearls? 

Dr. Shenvi: This just highlights the challenge of how it’s harder to unlearn something than to learn it, where one study that maybe wasn’t quite looking at what we needed to, or practice and prescribing patterns have changed, so it’s no longer really relevant. 

The things that we learned from that, or the fears that we instilled in our minds of, Uh oh, they could go home and have delayed bleeding, are much harder to unlearn, and it takes more studies to unlearn that idea than it did to actually put it into place. 

I’m glad that your team has done this much larger, prospective study and hopefully will reduce the concern about this entity. 

Dr. Shih: I appreciate that segue. It is amazing that, for paramedics and medical students, the first thing out of their mouth is, “Are they on an anticoagulant?”

In terms of the risk of developing an intracranial hemorrhage, I think it’s much less than the weight we’ve put on it before. However, I believe if they have a bleed, the bleeds are worse. It’s kind of a double-edged sword. It’s still an important factor, but it doesn’t come with the Oh my gosh, they’re on an anticoagulant that everybody thinks about.
 

No. 1 Cause of Traumatic Injury Is a Fall from Standing

Dr. Glatter: These are obviously ground-level falls in most patients and not motor vehicle crashes. That’s an important part in the population that you looked at that should be mentioned clearly. 

Dr. Shih: It’s astonishing. I’ve been a program director for over 20 years, and geriatrics is not well taught in the curriculum. It’s astonishing for many of our trainees and emergency physicians in general that the number-one cause for traumatic injury is a fall from standing.

Certainly, we get patients coming in the trauma center like a 95-year-old person who’s on a ladder putting up his Christmas lights. I’m like, oh my God. 

For the vast majority, it’s closer to 90%, but in our study, for the patients we looked at, it was 80% that fall from standing. That’s the mechanism that causes these bleeds and these major injuries. 

Dr. Shenvi: That’s reflective of what we see, so it’s good that that’s what you looked at also. 

Dr. Glatter: Absolutely. Well, thank you both. This has been a very informative discussion. I appreciate your time, and our readers will certainly benefit from your knowledge and expertise. Thank you again.

Dr. Glatter, assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, is a medical adviser for this news organization. He disclosed having no relevant financial conflicts. Dr. Shih is professor of emergency medicine at the Charles E. Schmidt College of Medicine at Florida Atlantic University, Boca Raton. His current grant funding and area of research interest involves geriatric emergency department patients with head injury and fall-related injury. He disclosed receiving a research grant from The Florida Medical Malpractice Joint Underwriting Association Grant for Safety of Health Care Services). Dr. Shenvi, associate professor of emergency medicine at the University of North Carolina at Chapel Hill, disclosed ties with the American College of Emergency Physicians, Institute for Healthcare Improvement, AstraZeneca, and CurvaFix.

A version of this article appeared on Medscape.com.

This discussion was recorded on August 2, 2024. This transcript has been edited for clarity. 

Robert D. Glatter, MD: Today, we’ll be discussing the results of a new study published in The Journal of Emergency Medicine, looking at the incidence of delayed intracranial hemorrhage among older patients taking preinjury anticoagulants who present to the emergency department (ED) with blunt head trauma.

Joining me today is the lead author of the study, Dr. Richard Shih, professor of emergency medicine at Florida Atlantic University. Also joining me is Dr. Christina Shenvi, associate professor of emergency medicine at the University of North Carolina (UNC) Chapel Hill, with fellowship training in geriatric emergency medicine. 

Welcome to both of you.

Richard D. Shih, MD: Thanks, Rob. 

Christina L. Shenvi, MD, PhD, MBA: Thanks. Pleasure to be here. 
 

ICH Study Methodology

Dr. Glatter: It’s a pleasure to have you. Rich, this is a great study and targeted toward a population we see daily in the emergency department. I want you to describe your methodology, patient selection, and how you went about organizing your study to look at this important finding of delayed intracranial hemorrhage, especially in those on anticoagulants.

Dr. Shih: This all started for our research team when we first read the 2012 Annals of Emergency Medicine paper. The first author was Vincenzo Menditto, and he looked at a group of patients that had minor head injury, were anticoagulated, and had negative initial head CTs. 

There were about 100 patients, of which about 10 of them did not consent, but they hospitalized all these patients. These were anticoagulated, negative-first head CTs. They hospitalized the patients and then did a routine second CT at about 24 hours. They also followed them for a week, and it turned out a little over 7% of them had delayed head CT. 

We were wondering how many delayed intracranial hemorrhages we had missed because current practice for us was that, if patients had a good physical exam, their head CT was normal, and everything looked good, we would send them home.

Because of that, a number of people across the country wanted to verify those findings from the Menditto study. We tried to design a good study to answer that question. We happen to have a very large geriatric population in Florida, and our ED census is very high for age over 65, at nearly 60%. 

There are two Level I trauma centers in Palm Beach County. We included a second multicenter hospital, and we prospectively enrolled patients. We know the current state of practice is not to routinely do second CTs, so we followed these patients over time and followed their medical records to try to identify delayed bleeding. That’s how we set up our methodology.
 

Is It Safe to Discharge Patients With Trauma After 24 Hours?

Dr. Glatter: For the bulk of these patients with negative head CTs, it’s been my practice that when they’re stable and they look fine and there’s no other apparent, distracting painful trauma, injuries and so forth, they’re safe to discharge. 

The secondary outcome in your study is interesting: the need for neurosurgical intervention in terms of those with delayed intracranial hemorrhage.

Dr. Shih: I do believe that it’s certainly not the problem that Menditto described, which is 7%. There are two other prospective studies that have looked at this issue with delayed bleeding on anticoagulants. Both of these also showed a relatively low rate of delayed bleeding, which is between like 0.2% and 1.0%. In our study, it was 0.4%. 

The difference in the studies is that Menditto and colleagues routinely did 24-hour head CTs. They admitted everybody. For these other studies, routine head CT was not part of it. My bet is that there is a rate of delayed bleeding somewhere in between that seen in the Menditto study and that in all the other studies.

However, talking about significant intracranial hemorrhage, ones that perhaps need neurosurgery, I believe most of them are not significant. There’s some number that do occur, but the vast majority of those probably don’t need neurosurgery. We had 14 delayed bleeds out of 6000 patients with head trauma. One of them ended up requiring neurosurgery, so the answer is not zero, but I don’t think it’s 7% either. 

Dr. Glatter: Dr. Shenvi, I want to bring you into the conversation to talk about your experience at UNC, and how you run things in terms of older patients with blunt head trauma on preinjury anticoagulants.

Dr. Shenvi: Thanks, Rob. I remember when this paper came out showing this 7% rate of delayed bleeding and the question was, “Should we be admitting all these people?” Partly just from an overwhelming need for capacity that that would bring, it just wasn’t practical to say, “We’re going to admit every patient with a negative head CT to the hospital and rescan them.” That would be hundreds or thousands of patients each year in any given facility. 

The other thing is that delayed bleeds don’t always happen just in the first 24 hours. It’s not even a matter of bringing patients into observation for 24 hours, watching them, and rescanning them if they have symptoms. It can occur several days out. That never, in almost any institution that I know of, became standard practice. 

The way that it did change my care was to give good return precautions to patients, to make sure they have somebody with them to say, “Hey, sometimes you can have bleeding several days out after a fall, even though your CT scan here today looks perfect,” and to alert them that if they start having severe headaches, vomiting, or other symptoms of intracranial hemorrhage, that they should come back. 

I don’t think it ever became standard practice, and for good reason, because that was one study. The subsequent studies that Richard mentioned, pretty quickly on the heels of that initial one, showed a much lower rate of delayed ICH with the caveats that the methodology was different. 
 

Shift in Anticoagulants

Dr. Shenvi: One other big change from that original study, and now to Richard’s study, is the shift in anticoagulants. Back in the initial study you mentioned, it was all warfarin. We know from other studies looking at warfarin vs the direct oral anticoagulants (DOACs) that DOACs have lower rates of ICH after a head injury, lower rates of need for neurosurgical intervention, and lower rates of discharge to a skilled nursing facility after an intracranial hemorrhage.

Across the board, we know that the DOACs tend to do better. It’s difficult to compare newer studies because it’s a different medication. It did inform my practice to have an awareness of delayed intracranial hemorrhage so that I warn patients more proactively. 

Dr. Glatter: I haven’t seen a patient on warfarin in years. I don’t know if either of you have, but it’s all DOACs now unless there’s some other reason. That shift is quite apparent.

Dr. Shih: The problem with looking at delayed bleeding for DOACs vs warfarin is the numbers were so low. I think we had 13 people, and seven were in the no-anticoagulant group. The numbers are even lower, so it’s hard to say. 

I just wanted to comment on something that Dr. Shenvi said, and I pretty much agree with everything that she said. Anticoagulants and warfarin, and that Menditto study, have a carryover effect. People group DOACs with warfarin similarly. When a patient is brought in, the first thing they talk about with head trauma is, “Oh, they’re on an anticoagulant” or “They’re not on an anticoagulant.” It’s so ingrained.

I believe that, in emergency medicine, we’re pressed for space and time and we’re not as affected by that 24-hour observation. Maybe many of our surgeons will automatically admit those patients. 

I haven’t seen a guideline from the United States, but there are two international guidelines. One is from Austria from 2019, and one is from Scandinavia. Both recommended 24-hour observation if you’re on an anticoagulant.

There is a bit of controversy left over with that. Hopefully, as more and more of information, like in our study, comes out, people will be a little bit more clear about it. I don’t think there’s a need to routinely admit them. 

I do want to mention that the Menditto study had such a massive impact on everybody. They pointed out one subgroup (and it’s such a small number of patients). They had seven cases of delayed bleeding; four or five of them were within that 24 hours, and a couple were diagnosed later over the next couple days.

Of those seven people, four of them had international normalized ratios (INRs) greater than 3. Of those four patients, I’ve heard people talk about this and recommend, “Okay, that’s the subgroup I would admit.” There’s a toss-up with what to do with DOAC because it’s very hard to tell whether there’s an issue, whether there are problems with their dosing, and whatever. 

We actually recently looked at that. We have a much larger sample than four: close to 300 patients who were on warfarin. We looked at patients who had INRs below 3 and above 3, and we didn’t show a difference. We still don’t believe that warfarin is a big issue with delayed bleeding.
 

Should We Be Asking: ‘Are They on Blood Thinners?’

Dr. Shenvi: One of the interesting trends related to warfarin and the DOACs vs no anticoagulant is that as you mentioned, Dr Shih, the first question out of people’s mouths or the first piece of information emergency medical services gives you when they come in with a patient who’s had a head injury is, “Are they on blood thinners or not?”

Yet, the paradigm is shifting to say it’s not actually the blood thinners themselves that are giving older patients the higher risk for bleeding; it’s age and other comorbidities.

Certainly, if you’re on an anticoagulant and you start to bleed, your prognosis is much worse because the bleeding doesn’t stop. In terms of who has a bleeding event, there’s much less impact of anticoagulation than we used to think. That, in part, may be due to the change from warfarin to other medications.

Some of the experts I’ve talked to who have done the research on this have said, “Well, actually, warfarin was more of a marker for being much older and more frail, because it was primarily prescribed to older patients who have significant heart disease, atrial fibrillation, and so on.” It was more a marker for somebody who is at risk for an intracranial hemorrhage. There are many changes that have happened in the past 10 years with medications and also our understanding. 
 

Challenges in Patient Follow-up

Dr. Glatter: That’s a great point. One thing, Rich, I want to ask you about is in terms of your proxy outcome assessment. When you use that at 14 and 60 days with telephone follow-up and then chart review at 60 and 90 days (because, obviously, everyone can’t get another head CT or it’s difficult to follow patients up), did you find that worked out well in your prospective cohort study, in terms of using that as a proxy, so to speak? 

Dr. Shih: I would say to a certain extent. Unfortunately, we don’t have access to the patients to come back to follow up all of them, and there was obviously a large number of patients in our study. 

The next best thing was that we had dedicated research assistants calling all of the patients at 14 days and 60 days. I’ve certainly read research studies where, when they call them, they get 80%-90% follow-up, but we did not achieve that.

I don’t know if people are more inundated with spam phone calls now, or the older people are just afraid of picking up their phone sometimes with all the scams and so forth. I totally understand, but in all honesty, we only had about a 30%-35% follow-up using that follow-up pathway. 

Then the proxy pathway was to look at their charts at 60 and 90 days. Also, we looked at the Florida death registry, which is pretty good, and then finally, we had both Level I trauma centers in the county that we were in participating. It’s standard practice that if you have an intracranial hemorrhage at a non–Level I trauma center, you would be transferred to a Level I trauma center. That’s the protocol. I know that’s not followed 100% of the time, but that’s part of the proxy follow-up. You could criticize the study for not having closer to 90% actual contact, but that’s the best we could do. 

Dr. Glatter: I think that’s admirable. Using that paradigm of what you described certainly allows the reader to understand the difficulty in assessing patients that don’t get follow-up head CT, and hardly anyone does that, as we know.

To your point of having both Level I trauma centers in the county, that makes it pretty secure. If we’re going to do a study encompassing a similar type of regional aspect, it would be similar.

Dr. Shenvi: I think your proxies, to your credit, were as good as you can get. You can never get a 100% follow-up, but you really looked at all the different avenues by which patients might present, either in the death registry or a Level I center. Well done on that aspect.

 

Determining When to Admit Patients for Observation

Dr. Glatter: In terms of admissions: You admit a patient, then you hear back that this patient should not have been admitted because they had a negative head CT, but you put them in anyway in the sense of delayed bleeding happening or not happening.

It’s interesting. Maybe the insurers will start looking at this in some capacity, based on your study, that because it’s so infrequent that you see delayed bleeding, that admitting someone for any reason whatsoever would be declined. Do you see that being an issue? In other words, [do you see] this leading to a pattern in terms of the payers?

Dr. Shih: Certainly, you could interpret it that way, and that would be unfortunate. The [incidence of] delayed bleeding is definitely not zero. That’s the first thing. 

The second thing is that when you’re dealing with an older population, having some sense that they’re not doing well is an important contributor to trying to fully assess what’s going on — whether or not they have a bleed or whether they’re at risk for falling again and then hitting their head and causing a second bleed, and making sure they can do the activities of daily life. There really should be some room for a physician to say, “They just got here, and we don’t know him that well. There’s something that bothers me about this person” and have the ability to watch them for at least another 24 hours. That’s how I feel. 

Dr. Shenvi: In my location, it would be difficult to try to admit somebody purely for observation for delayed bleeding. I think we would get a lot of pushback on that. The reasons I might admit a patient after a fall with a negative head CT, though, are all the things that, Rob, you alluded to earlier — which are, what made them fall in the first place and were they unable to get up? 

I had this happen just this week. A patient who fell couldn’t get off the ground for 12 hours, and so now she’s dehydrated and delirious with slight rhabdomyolysis. Then you’re admitting them either for the sequelae of the fall that are not related to the intracranial hemorrhage, or the fact that they are so debilitated and deconditioned that they cannot take care of themselves. They need physical therapy. Often, we will have physical and occupational therapists come see them in the ED during business hours and help make an assessment of whether they are safe to go home or whether they fall again. That can give more evidence for the need for admission.

Dr. Glatter: To bring artificial intelligence into this discussion, algorithms that are out there that say, “Push a button and the patient’s safe for discharge.” Well, this argues for a clinical gestalt and a human being to make an assessment because you can use these predictive models, which are coming and they’re going to be here soon, and they already are in some sense. Again, we have to use clinical human judgment. 

Dr. Shih: I agree. 
 

Advice for Primary Care Physicians

Dr. Glatter: What return precautions do you discuss with patients who’ve had blunt head trauma that maybe had a head CT, or even didn’t? What are the main things we’re looking for?

Dr. Shenvi: What I usually tell people is if you start to have a worse headache, nausea or vomiting, any weakness in one area of your body, or vision changes, and if there’s a family member or friend there, I’ll say, “If you notice that they’re acting differently or seem confused, come back.”

Dr. Shih: I agree with what she said, and I’m also going to add one thing. The most important part is they are trying to prevent a subsequent fall. We know that when they’ve fallen and they present to the ED, they’re at even higher risk for falling and reinjuring themselves, and that’s a population that’s already at risk.

One of the secondary studies that we published out of this project was looking at follow-up with their primary care physicians, and there were two things that we wanted to address. The first was, how often did they do it? Then, when they did do it, did their primary care physicians try to address and prevent subsequent falls?

Both the answers are actually bad. Amazingly, just over like 60% followed up. 

In some of our subsequent research, because we’re in the midst of a randomized, controlled trial where we do a home visit, when we initially see these individuals that have fallen, they’ll schedule a home visit for us. Then a week or two later, when we schedule the home visit, many of them cancel because they think, Oh, that was a one-off and it’s not going to happen again. Part of the problem is the patients, because many of them believe that they just slipped and fell and it’s not going to happen again, or they’re not prone to it.

The second issue was when patients did go to a primary care physician, we have found that some primary care physicians believe that falling and injuring themselves is just part of the normal aging process. A percentage of them don’t go over assessment for fall risk or even initiate fall prevention treatments or programs. 

I try to take that time to tell them that this is very common in their age group, and believe it or not, a fall from standing is the way people really injure themselves, and there may be ways to prevent subsequent falls and injuries. 

Dr. Glatter: Absolutely. Do you find that their medications are a contributor in some sense? Say they’re antihypertensive, have issues of orthostasis, or a new medication was added in the last week. 

Dr. Shenvi: It’s all of the above. Sometimes it’s one thing, like they just started tamsulosin for their kidney stone, they stood up, they felt lightheaded, and they fell. Usually, it’s multifactorial with some changes in their gait, vision, balance, reflex time, and strength, plus the medications or the need for assistive devices. Maybe they can’t take care of their home as well as they used to and there are things on the floor. It’s really all of the above.
 

‘Harder to Unlearn Something Than to Learn It’

Dr. Glatter: Would either of you like to add any additional points to the discussion or add a few pearls? 

Dr. Shenvi: This just highlights the challenge of how it’s harder to unlearn something than to learn it, where one study that maybe wasn’t quite looking at what we needed to, or practice and prescribing patterns have changed, so it’s no longer really relevant. 

The things that we learned from that, or the fears that we instilled in our minds of, Uh oh, they could go home and have delayed bleeding, are much harder to unlearn, and it takes more studies to unlearn that idea than it did to actually put it into place. 

I’m glad that your team has done this much larger, prospective study and hopefully will reduce the concern about this entity. 

Dr. Shih: I appreciate that segue. It is amazing that, for paramedics and medical students, the first thing out of their mouth is, “Are they on an anticoagulant?”

In terms of the risk of developing an intracranial hemorrhage, I think it’s much less than the weight we’ve put on it before. However, I believe if they have a bleed, the bleeds are worse. It’s kind of a double-edged sword. It’s still an important factor, but it doesn’t come with the Oh my gosh, they’re on an anticoagulant that everybody thinks about.
 

No. 1 Cause of Traumatic Injury Is a Fall from Standing

Dr. Glatter: These are obviously ground-level falls in most patients and not motor vehicle crashes. That’s an important part in the population that you looked at that should be mentioned clearly. 

Dr. Shih: It’s astonishing. I’ve been a program director for over 20 years, and geriatrics is not well taught in the curriculum. It’s astonishing for many of our trainees and emergency physicians in general that the number-one cause for traumatic injury is a fall from standing.

Certainly, we get patients coming in the trauma center like a 95-year-old person who’s on a ladder putting up his Christmas lights. I’m like, oh my God. 

For the vast majority, it’s closer to 90%, but in our study, for the patients we looked at, it was 80% that fall from standing. That’s the mechanism that causes these bleeds and these major injuries. 

Dr. Shenvi: That’s reflective of what we see, so it’s good that that’s what you looked at also. 

Dr. Glatter: Absolutely. Well, thank you both. This has been a very informative discussion. I appreciate your time, and our readers will certainly benefit from your knowledge and expertise. Thank you again.

Dr. Glatter, assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, is a medical adviser for this news organization. He disclosed having no relevant financial conflicts. Dr. Shih is professor of emergency medicine at the Charles E. Schmidt College of Medicine at Florida Atlantic University, Boca Raton. His current grant funding and area of research interest involves geriatric emergency department patients with head injury and fall-related injury. He disclosed receiving a research grant from The Florida Medical Malpractice Joint Underwriting Association Grant for Safety of Health Care Services). Dr. Shenvi, associate professor of emergency medicine at the University of North Carolina at Chapel Hill, disclosed ties with the American College of Emergency Physicians, Institute for Healthcare Improvement, AstraZeneca, and CurvaFix.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.
 

Benjamin L. Schlechter, MD: Today we’re discussing liver transplant for metastatic colorectal cancer with our guest, Dr. Martin Dib. Dr. Dib is the director of the Hepatobiliary Surgery and Living Donor Program at Beth Israel Deaconess Medical Center here in Boston, and a Harvard Medical School faculty member.

He was previously at the Pontificia Universidad Católica de Chile, a leading international institution investigating the role of liver transplant in colorectal cancer, among other diseases. Dr. Dib, before we move to our discussion, I’d like to hear a bit about your pathway to becoming a transplant surgeon. How did you end up working on colorectal cancer and liver transplants in this field?

Martin J. Dib, MD: Thank you so much, Dr. Schlechter. I am originally from Chile. I had an opportunity to come to Beth Israel Deaconess Medical Center after medical school and I did liver regeneration research at the transplant center. After that, I was lucky enough to match as a general surgery resident at Beth Israel Deaconess.

This is my alma mater and I was able to graduate as a surgeon here. You and I had some paths together. After graduating from Harvard as a surgeon, I was trained in liver transplant, abdominal transplant, surgical oncology, and hepatobiliary surgery at the University of Toronto.

I have been developing this passion for being able to transplant cancer patients and use organ transplant techniques to be able to do complex resections for cancer.

Dr. Schlechter: Let’s talk about the topic for today, which is liver transplant and colorectal cancer. I’ll be honest — this is not a very familiar topic for a lot of oncologists. There are a lot of details that I think are new to us as oncologists. We need to expand this conversation to get access to patients for this.

First and foremost, can you talk about some of the parameters for a resectable liver metastasis vs unresectable disease that would be an indication for a liver transplant?

Dr. Dib: I think this is a very interesting topic because liver transplantation for cancer is not new. Liver transplantation started in the 1960s when people started doing liver transplants for advanced liver tumors. The problem is that they were selecting patients who had very advanced — and poor tumor biology — tumors. The outcomes were not good.

It was only in 1996 when the Milan criteria started. Mazzaferro and colleagues, using strict patient selection, were able to do liver transplant for selected hepatocellular carcinoma patients. Having those excellent outcomes in selecting patients opened the field for what we now call transplant oncology, which is using selection criteria and using other methods to be able to select which patients will do well after transplantation, even with immunosuppression.

Liver transplantation for colorectal metastasis was used at the very beginning of the era of liver transplantation, but with very poor outcomes. It was abandoned because of the outcomes. It is exciting to see that after 20 years of not doing it, there was a group in Norway that started again. They are doing liver transplants for colorectal metastases (mets), but with very selected patients.

In Norway, they had a very unusual setting where they had more liver donors than patients on the list waiting for liver transplant. So they can’t share these livers and we’re all jealous, right? Every single country in the West struggles because we don’t have enough livers for the rest of the list. And they had a lot of livers to be able to transplant people.

They decided to transplant some selected patients with colorectal mets that were unresectable. And the surprise was that they found that they were able to get a 60% survival at 5 years. And so that was new. After that, in Norway, they started showing this data to other centers in the world. It wasn’t until this year that we could see not only the long-term data and long-term outcomes of using liver transplantation for unresectable colorectal mets, but also we’re now having data from a prospective clinical trial from France.

It was three countries in the prospective clinical trial: France, Belgium, and Italy. We now see that we have a little stronger data to support the use of liver transplants for unresectable colorectal mets.

Dr. Schlechter: That’s the TRANSMET study you’re referencing that was presented at ASCO in the late-breaking abstract session in 2024, and then more recently in The Lancet’s eClinicalMedicine. Both of those papers were led by René Adam. That was a cool presentation to sit through. I was in the room, and I was taking a ton of notes and there was a lot of info that came out of that.

First of all, it showed that patients who had received chemotherapy and were responding could then go on to liver transplant in that population. Impressively, 81% of the patients who were randomized to transplant received it. Frankly, that’s a big number, especially compared with the West, as you said, and in particular the US and here in New England where livers are a very precious commodity.

And even accounting for that, if you look at the intention-to-treat analysis, the 5-year overall survival in that population was 57% compared with 13% with chemotherapy. And that feels like a real number for chemotherapy. If you look at the per-protocol analysis, frankly, the numbers are higher.

It’s always a challenging assessment. What was also interesting to me was the pattern of recurrence, which in general was that recurrences were extrahepatic. So not only were patients rendered disease-free, but in general, the liver remained disease-free and only 3% of patients had liver-only recurrence and 11% had widespread metastatic disease.

The biggest group was lung metastases, at about 40%. Ultimately, they reported a progression-free survival of 17. 4 months for transplant compared with 6. 4 months with chemotherapy. On every parameter, it looks like liver transplant wins for these people. Help me out. Who are these people? How do we find these people?

What are the inclusions and exclusions for this population?

Dr. Dib: I think that’s very important. This is not a therapy that will be for every patient. These are selected patients who have liver-only unresectable colorectal mets. These are patients that don’t have any extrahepatic disease and that either the primary has been taken out already or that they have the primary present, but the plan is to take the primary and then do a liver transplantation after 3 months, hopefully after 6 months, of removing the primary.

These are patients who meet all the criteria that we have seen in terms of the best outcomes — patients that have Oslo scores of less than three. The Oslo trial, which included the SECA (Secondary Cancer)-I and SECA-II trials, basically showed that patients with a maximal tumor diameter of less than 5.5 with a pretransplant CEA (carcinoembryonic antigen) of less than 80 that do not have progression on chemotherapy, among other variables, do better. But the concept is that this is a therapy that will apply only to selected patients. That way we can continue to have adequate overall survival post-transplant that would be comparable to other diseases that we do liver transplants for.

Dr. Schlechter: Were there other biomarkers, any mutations that were included or excluded?

Dr. Dib: Yes. If you look at SECA-I, SECA-II trial outcomes, and also TRANSMET, they all say patients with BRAF mutations shouldn’t be transplanted. There are other parameters, including, for example, the site of the primary tumor. Patients with a left-sided colon primary tumor do much better than patients who have a right-sided primary tumor.

That’s not a complete contraindication, but if you look at the most updated inclusion criteria of programs, like the ones that the one that we have here at Beth Israel Deaconess and many others, the inclusion criteria protocols include patients who have only hepatic disease.

So, if there are no extrahepatic mets, the resection of the primary has been done or will be done after a multidisciplinary discussion. We want to make sure they have the absence of BRAF mutation, and that they don’t have disease progression while on chemotherapy. So hopefully we have data from enough months to be able to make sure that there’s no intrahepatic or extrahepatic progression while on chemotherapy.

And that’s including CEA and also looking at the imaging.

Dr. Schlechter: When you’re seeing a patient, how much chemo do you think they should have? What’s a good run chemotherapy-wise for these patients? Let’s say, before I refer a patient to you, how much chemo should they have? And then what should I do? Do I get a PET scan? Do I get MRI? What’s the right scanning I should do to prove there’s no extrahepatic disease before sending a patient in for consideration?

Dr. Dib: First, we need to confirm unresectability. Referring patients early is always a good measure to make sure that we’re all in agreement that it’s an unresectable patient. Having a PET scan from the very beginning is helpful because it shows the disease before doing chemotherapy.

In terms of the lines of chemotherapy, ideally in the TRANSMET trial, for example, the idea was to show tumor control for at least 3 months, with less than three lines of chemotherapy. Some patients will do that with FOLFIRI. It depends on the case.

I think some of those evaluations will need a multidisciplinary discussion. In our case, we are connected to the Norway team. We frequently talk with the Oslo team and an international community of transplant centers to get opinions on particular cases.

But I think referring patients early is a good measure. If we don’t think that they qualify, we will let the team know. We’re strictly looking at patients who have unresectable liver mets that don’t have extrahepatic disease. The idea is to do a primary tumor resection, and then get to transplantation, hopefully after 6 months. In some cases that have some concerns in terms of tumor biology, we may even extend the time from diagnosis to transplant to over 1.5 years.

Dr. Schlechter: Excellent. And what’s the experience like for these patients? In training as a resident many years ago, I saw patients with cirrhosis who went on to have a liver transplant, and that was sort of trading one disease for another. What is the posttransplant, or the remission, experience of a liver transplant for colorectal cancer like for the patient?

Dr. Dib: That’s a very important point. I think that transplantation has gotten better and better, as has chemotherapy systemic therapy. The liver transplantation experience from 20 years ago has improved dramatically. I think the quality of life of liver transplant patients after transplantation has increased quite a bit.

At Beth Israel Deaconess, we have a liver transplant program that is doing over a 100 livers a year. And when you have a high-volume center, usually the experience gets better. The time in the hospital post-transplant decreases.

In general, when we’re doing liver transplants, patients are getting extubated in the OR 30% of the time. The vast majority of patients are going home within 1 or 2 weeks. They need to have immunosuppression for the rest of their lives. We have a very good program of transplant coordinators that will help the family and the patient to live with immunosuppression and live with a transplanted organ.

But I would say that we have many, many patients, especially these patients who are not patients with cirrhosis. Their health is not as deteriorated as patients who have low MELD (model for end-stage liver disease) scores. They don’t have liver disease. They have cancer. So usually patients like that, many of them can go back to work and live a quality of life that is fairly reasonable.

Dr. Schlechter: That’s good to hear. When we hear statements like liver transplant for colon cancer, a lot of us have this picture of a much sicker population, but it’s interesting and true that the colorectal cancer population as a candidate for liver transplant is a much healthier population than the population with cirrhosis.

Let’s talk about organs and donors. Largely in the TRANSMET study, for example, that was cadaveric donors. Those were not living donors and you’ve done a lot of work on living donors. If the answer in the United States, because of limited access to organs, is going to be living donors, who are those donors?

What is that like? How do you identify them?

Dr. Dib: There’s a lot of advantages to using living donors for these patients. In any type of patient that needs a liver transplant, cadaveric donors or deceased donors is the same concept. There are two types of deceased donors: the brain-dead donors and donors after cardiac death. Those are hard to come by.

We still have 15%-20% mortality on the waiting list in the United States. We’re already still struggling to get enough donors to transplant the patients that are on the list. Now, if you add a new indication, which is unresectable colorectal mets, we need to make sure that the outcomes are equivalent to the patients who are going to be transplanted for other reasons.

Right now, for example, the 5-year overall survival of a patient with cirrhosis, or a patient with hepatocellular carcinoma, is over 80% 5-year survival. In the SECA trials and TRANSMET trial, if we do a good selection, I think we can get to 70% 5-year survival. But until we have more data, I think it’s a cautious measure to, as a field, try to use living donors and not compete with the rest of the list of patients who are already dying on the list for liver transplants.

Once we get more data, it’s going to be something that, in the transplant community, we may be able to use deceased donors. Especially deceased donors with maybe extended criteria that are not going to be used for other patients. We can do living-unrelated or living-related donations. Family members or also friends or neighbors or part of the community, even altruistic donors, can donate to a potential recipient. And that enables us to not only time the transplant in an adequate manner, because we’re able to transplant the patient early, but also time it so we can give the number of chemotherapy cycles that we want to give.

That’s a huge advantage. You don’t compete for a liver with the cadaveric waiting list of patients that are waiting for other reasons, and you can select the tumor biology very well because you know exactly when the surgery is going to be. For instance, we can say, okay, this patient has KRAS mutation, left-sided colon cancer, and has been having good tumor biology with no progression. We will wait 6 months from the primary tumor to the transplant, which is going to be 1 year from diagnosis to transplant. And we can see during that time whether they continue to have good tumor biology.

But if you have a deceased donor liver transplant, sometimes you can’t time that well and schedule it. It becomes a bit more tricky in terms of patient selection and making sure that we do this for the people who are going to benefit.

Dr. Schlechter: And how does donor matching work? Is it HLA (human leukocyte antigen) matched or ABO-matched? Who can donate when you say a living-related? For example, when we think about bone marrow transplantation, which we’re all familiar with in the oncology population, it’s an incredibly complex match process. Is this the same challenge?

Dr. Dib: No, it’s a little bit simpler. Living donors for liver transplants need to be between the ages of 18 and 60. They need to be relatively healthy, relatively fit, with a BMI hopefully less than 30, definitely less than 35. The compatibility is ABO compatibility. So, if they’re ABO-compatible, relatively young, relatively healthy, they would be a potential donor and we will go ahead and do a CT scan.

If the CT scan shows that they have a good, adequate anatomy, more than 90% of those will be good donors. I would say that out of 100 people who want to be donors, 25 of them will be adequate. One out of four people who want to save their family member and want to have this operation are able to donate half of their liver to their family member or loved one.

Dr. Schlechter: Excellent. And it’s helpful to know that the matching process is simpler. During his discussion, René Adam unequivocally stated that liver transplants are a new standard of care for colorectal cancer. And I guess my question is, do you agree with this statement? How do we balance the demand for living donors and the demand for deceased donors? Especially in a time of increasing fatty liver disease and obesity, other indications for liver transplant, causes of cirrhosis, and also in an era of young-onset colorectal cancer. Patients are younger. Is this a new standard of care? Do you agree with that statement?

Dr. Dib: I do agree with that statement. I think it’s important to understand that not all patients with colorectal mets are the same. Of the number of patients in the United States who have colorectal cancer, let’s say 50% of them will have liver metastasis. Only 15%-20% of them will have liver-only metastasis.

This is only for patients who have liver-only metastasis without extrahepatic disease. And only maybe 15%-20% of them will meet all the criteria to be able to undergo liver transplantation. I think it’s for a very selective subset of patients who have very good tumor biology, generally young patients who don’t have any other alternative to having even a complex liver resection and are not able to get R0 resection. That is when we could think about doing liver transplantation.

It’s one more of the skills that we can have. It doesn’t mean that it will be the only skill, or the best skill, for all of the patients.

Dr. Schlechter: When a patient volunteers to be a living donor for a loved one or a family member, and they go through all the screening and they’re found to be a candidate, what is the surgical experience for that patient?

How long are they in the hospital? What sort of operation is that?

Dr. Dib: Living donors are very special patients. These are patients who do not need an operation. And the only reason they’re doing this is to save the life of their loved one. Donor safety is our priority number one, two, three, and four. The donor operation needs to be perfect.

And so we take good care of, first of all, selecting the living donors, making sure that they’re young and they don’t have any big contraindications. We also ensure that they are well informed of the process. The living donor surgery that we’re now doing is laparoscopic and minimally invasive. Here at Beth Israel Deaconess, we have done it laparoscopically with very good results.

I think that experience before and after the surgery gets so much better because of the better recovery. They’re able to go home, in general, within 4 or 5 days, and they get on with their normal life within 6-8 weeks. I think it’s important for them to know all the processes and the actual risks and benefits for the recipient.

Among those risks, I think it’s important for them to understand that this is a complex operation. Even if we do it laparoscopically or robotically, so that the scar is less, inside we’re still taking out half of the liver. That is a surgery that needs to be undertaken very meticulously, with a focus on minimizing any bleeding.

It’s a surgery that takes a long time. It takes about 6 hours. We do our best to try to minimize any risks.

Dr. Schlechter: Excellent. Thanks for that. Today we had Dr. Martin Dib joining us to discuss liver transplant for metastatic colorectal cancer. We discussed the various important criteria. We discussed that early referral to multidisciplinary centers that manage these is important to help get patients set up.

We discussed the fact that there are certain inclusion and exclusion criteria to consider. Obviously, unresectable disease is a critical determination that should be made by a liver surgeon. The absence of extrahepatic disease is important in staging with PET or other imaging. We discussed certain other biological exclusions.

There’s a relative contraindication of right-sided vs left-sided cancers, but right-sided cancers can be transplanted. We discussed that an elevated CEA greater than 80 is a contraindication, as are mutations in BRAF. We reviewed data from both the TRANSMET trial recently published in The Lancet and presented at ASCO in 2024, as well as the older Oslo criteria and Oslo trials and SECA trials.

And finally, we heard that donors can now come as living donors, a laparoscopic robotic surgery with a better safety profile, and greater access to organs that are ABO matched and not HLA matched because of the nature of the biology. Thank you again for joining us.


 

Benjamin L. Schlechter, MD, is senior physician, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts. He has disclosed no relevant financial relationships. Martin J. Dib, MD, is member of the faculty, Department of Surgery, Harvard Medical School; director of Hepatobiliary Surgery, Division of Transplantation, Beth Israel Deaconess Medical Center, Boston. He has disclosed no relevant financial relationships.

A version of this transcript appeared on Medscape.com.

This transcript has been edited for clarity.
 

Benjamin L. Schlechter, MD: Today we’re discussing liver transplant for metastatic colorectal cancer with our guest, Dr. Martin Dib. Dr. Dib is the director of the Hepatobiliary Surgery and Living Donor Program at Beth Israel Deaconess Medical Center here in Boston, and a Harvard Medical School faculty member.

He was previously at the Pontificia Universidad Católica de Chile, a leading international institution investigating the role of liver transplant in colorectal cancer, among other diseases. Dr. Dib, before we move to our discussion, I’d like to hear a bit about your pathway to becoming a transplant surgeon. How did you end up working on colorectal cancer and liver transplants in this field?

Martin J. Dib, MD: Thank you so much, Dr. Schlechter. I am originally from Chile. I had an opportunity to come to Beth Israel Deaconess Medical Center after medical school and I did liver regeneration research at the transplant center. After that, I was lucky enough to match as a general surgery resident at Beth Israel Deaconess.

This is my alma mater and I was able to graduate as a surgeon here. You and I had some paths together. After graduating from Harvard as a surgeon, I was trained in liver transplant, abdominal transplant, surgical oncology, and hepatobiliary surgery at the University of Toronto.

I have been developing this passion for being able to transplant cancer patients and use organ transplant techniques to be able to do complex resections for cancer.

Dr. Schlechter: Let’s talk about the topic for today, which is liver transplant and colorectal cancer. I’ll be honest — this is not a very familiar topic for a lot of oncologists. There are a lot of details that I think are new to us as oncologists. We need to expand this conversation to get access to patients for this.

First and foremost, can you talk about some of the parameters for a resectable liver metastasis vs unresectable disease that would be an indication for a liver transplant?

Dr. Dib: I think this is a very interesting topic because liver transplantation for cancer is not new. Liver transplantation started in the 1960s when people started doing liver transplants for advanced liver tumors. The problem is that they were selecting patients who had very advanced — and poor tumor biology — tumors. The outcomes were not good.

It was only in 1996 when the Milan criteria started. Mazzaferro and colleagues, using strict patient selection, were able to do liver transplant for selected hepatocellular carcinoma patients. Having those excellent outcomes in selecting patients opened the field for what we now call transplant oncology, which is using selection criteria and using other methods to be able to select which patients will do well after transplantation, even with immunosuppression.

Liver transplantation for colorectal metastasis was used at the very beginning of the era of liver transplantation, but with very poor outcomes. It was abandoned because of the outcomes. It is exciting to see that after 20 years of not doing it, there was a group in Norway that started again. They are doing liver transplants for colorectal metastases (mets), but with very selected patients.

In Norway, they had a very unusual setting where they had more liver donors than patients on the list waiting for liver transplant. So they can’t share these livers and we’re all jealous, right? Every single country in the West struggles because we don’t have enough livers for the rest of the list. And they had a lot of livers to be able to transplant people.

They decided to transplant some selected patients with colorectal mets that were unresectable. And the surprise was that they found that they were able to get a 60% survival at 5 years. And so that was new. After that, in Norway, they started showing this data to other centers in the world. It wasn’t until this year that we could see not only the long-term data and long-term outcomes of using liver transplantation for unresectable colorectal mets, but also we’re now having data from a prospective clinical trial from France.

It was three countries in the prospective clinical trial: France, Belgium, and Italy. We now see that we have a little stronger data to support the use of liver transplants for unresectable colorectal mets.

Dr. Schlechter: That’s the TRANSMET study you’re referencing that was presented at ASCO in the late-breaking abstract session in 2024, and then more recently in The Lancet’s eClinicalMedicine. Both of those papers were led by René Adam. That was a cool presentation to sit through. I was in the room, and I was taking a ton of notes and there was a lot of info that came out of that.

First of all, it showed that patients who had received chemotherapy and were responding could then go on to liver transplant in that population. Impressively, 81% of the patients who were randomized to transplant received it. Frankly, that’s a big number, especially compared with the West, as you said, and in particular the US and here in New England where livers are a very precious commodity.

And even accounting for that, if you look at the intention-to-treat analysis, the 5-year overall survival in that population was 57% compared with 13% with chemotherapy. And that feels like a real number for chemotherapy. If you look at the per-protocol analysis, frankly, the numbers are higher.

It’s always a challenging assessment. What was also interesting to me was the pattern of recurrence, which in general was that recurrences were extrahepatic. So not only were patients rendered disease-free, but in general, the liver remained disease-free and only 3% of patients had liver-only recurrence and 11% had widespread metastatic disease.

The biggest group was lung metastases, at about 40%. Ultimately, they reported a progression-free survival of 17. 4 months for transplant compared with 6. 4 months with chemotherapy. On every parameter, it looks like liver transplant wins for these people. Help me out. Who are these people? How do we find these people?

What are the inclusions and exclusions for this population?

Dr. Dib: I think that’s very important. This is not a therapy that will be for every patient. These are selected patients who have liver-only unresectable colorectal mets. These are patients that don’t have any extrahepatic disease and that either the primary has been taken out already or that they have the primary present, but the plan is to take the primary and then do a liver transplantation after 3 months, hopefully after 6 months, of removing the primary.

These are patients who meet all the criteria that we have seen in terms of the best outcomes — patients that have Oslo scores of less than three. The Oslo trial, which included the SECA (Secondary Cancer)-I and SECA-II trials, basically showed that patients with a maximal tumor diameter of less than 5.5 with a pretransplant CEA (carcinoembryonic antigen) of less than 80 that do not have progression on chemotherapy, among other variables, do better. But the concept is that this is a therapy that will apply only to selected patients. That way we can continue to have adequate overall survival post-transplant that would be comparable to other diseases that we do liver transplants for.

Dr. Schlechter: Were there other biomarkers, any mutations that were included or excluded?

Dr. Dib: Yes. If you look at SECA-I, SECA-II trial outcomes, and also TRANSMET, they all say patients with BRAF mutations shouldn’t be transplanted. There are other parameters, including, for example, the site of the primary tumor. Patients with a left-sided colon primary tumor do much better than patients who have a right-sided primary tumor.

That’s not a complete contraindication, but if you look at the most updated inclusion criteria of programs, like the ones that the one that we have here at Beth Israel Deaconess and many others, the inclusion criteria protocols include patients who have only hepatic disease.

So, if there are no extrahepatic mets, the resection of the primary has been done or will be done after a multidisciplinary discussion. We want to make sure they have the absence of BRAF mutation, and that they don’t have disease progression while on chemotherapy. So hopefully we have data from enough months to be able to make sure that there’s no intrahepatic or extrahepatic progression while on chemotherapy.

And that’s including CEA and also looking at the imaging.

Dr. Schlechter: When you’re seeing a patient, how much chemo do you think they should have? What’s a good run chemotherapy-wise for these patients? Let’s say, before I refer a patient to you, how much chemo should they have? And then what should I do? Do I get a PET scan? Do I get MRI? What’s the right scanning I should do to prove there’s no extrahepatic disease before sending a patient in for consideration?

Dr. Dib: First, we need to confirm unresectability. Referring patients early is always a good measure to make sure that we’re all in agreement that it’s an unresectable patient. Having a PET scan from the very beginning is helpful because it shows the disease before doing chemotherapy.

In terms of the lines of chemotherapy, ideally in the TRANSMET trial, for example, the idea was to show tumor control for at least 3 months, with less than three lines of chemotherapy. Some patients will do that with FOLFIRI. It depends on the case.

I think some of those evaluations will need a multidisciplinary discussion. In our case, we are connected to the Norway team. We frequently talk with the Oslo team and an international community of transplant centers to get opinions on particular cases.

But I think referring patients early is a good measure. If we don’t think that they qualify, we will let the team know. We’re strictly looking at patients who have unresectable liver mets that don’t have extrahepatic disease. The idea is to do a primary tumor resection, and then get to transplantation, hopefully after 6 months. In some cases that have some concerns in terms of tumor biology, we may even extend the time from diagnosis to transplant to over 1.5 years.

Dr. Schlechter: Excellent. And what’s the experience like for these patients? In training as a resident many years ago, I saw patients with cirrhosis who went on to have a liver transplant, and that was sort of trading one disease for another. What is the posttransplant, or the remission, experience of a liver transplant for colorectal cancer like for the patient?

Dr. Dib: That’s a very important point. I think that transplantation has gotten better and better, as has chemotherapy systemic therapy. The liver transplantation experience from 20 years ago has improved dramatically. I think the quality of life of liver transplant patients after transplantation has increased quite a bit.

At Beth Israel Deaconess, we have a liver transplant program that is doing over a 100 livers a year. And when you have a high-volume center, usually the experience gets better. The time in the hospital post-transplant decreases.

In general, when we’re doing liver transplants, patients are getting extubated in the OR 30% of the time. The vast majority of patients are going home within 1 or 2 weeks. They need to have immunosuppression for the rest of their lives. We have a very good program of transplant coordinators that will help the family and the patient to live with immunosuppression and live with a transplanted organ.

But I would say that we have many, many patients, especially these patients who are not patients with cirrhosis. Their health is not as deteriorated as patients who have low MELD (model for end-stage liver disease) scores. They don’t have liver disease. They have cancer. So usually patients like that, many of them can go back to work and live a quality of life that is fairly reasonable.

Dr. Schlechter: That’s good to hear. When we hear statements like liver transplant for colon cancer, a lot of us have this picture of a much sicker population, but it’s interesting and true that the colorectal cancer population as a candidate for liver transplant is a much healthier population than the population with cirrhosis.

Let’s talk about organs and donors. Largely in the TRANSMET study, for example, that was cadaveric donors. Those were not living donors and you’ve done a lot of work on living donors. If the answer in the United States, because of limited access to organs, is going to be living donors, who are those donors?

What is that like? How do you identify them?

Dr. Dib: There’s a lot of advantages to using living donors for these patients. In any type of patient that needs a liver transplant, cadaveric donors or deceased donors is the same concept. There are two types of deceased donors: the brain-dead donors and donors after cardiac death. Those are hard to come by.

We still have 15%-20% mortality on the waiting list in the United States. We’re already still struggling to get enough donors to transplant the patients that are on the list. Now, if you add a new indication, which is unresectable colorectal mets, we need to make sure that the outcomes are equivalent to the patients who are going to be transplanted for other reasons.

Right now, for example, the 5-year overall survival of a patient with cirrhosis, or a patient with hepatocellular carcinoma, is over 80% 5-year survival. In the SECA trials and TRANSMET trial, if we do a good selection, I think we can get to 70% 5-year survival. But until we have more data, I think it’s a cautious measure to, as a field, try to use living donors and not compete with the rest of the list of patients who are already dying on the list for liver transplants.

Once we get more data, it’s going to be something that, in the transplant community, we may be able to use deceased donors. Especially deceased donors with maybe extended criteria that are not going to be used for other patients. We can do living-unrelated or living-related donations. Family members or also friends or neighbors or part of the community, even altruistic donors, can donate to a potential recipient. And that enables us to not only time the transplant in an adequate manner, because we’re able to transplant the patient early, but also time it so we can give the number of chemotherapy cycles that we want to give.

That’s a huge advantage. You don’t compete for a liver with the cadaveric waiting list of patients that are waiting for other reasons, and you can select the tumor biology very well because you know exactly when the surgery is going to be. For instance, we can say, okay, this patient has KRAS mutation, left-sided colon cancer, and has been having good tumor biology with no progression. We will wait 6 months from the primary tumor to the transplant, which is going to be 1 year from diagnosis to transplant. And we can see during that time whether they continue to have good tumor biology.

But if you have a deceased donor liver transplant, sometimes you can’t time that well and schedule it. It becomes a bit more tricky in terms of patient selection and making sure that we do this for the people who are going to benefit.

Dr. Schlechter: And how does donor matching work? Is it HLA (human leukocyte antigen) matched or ABO-matched? Who can donate when you say a living-related? For example, when we think about bone marrow transplantation, which we’re all familiar with in the oncology population, it’s an incredibly complex match process. Is this the same challenge?

Dr. Dib: No, it’s a little bit simpler. Living donors for liver transplants need to be between the ages of 18 and 60. They need to be relatively healthy, relatively fit, with a BMI hopefully less than 30, definitely less than 35. The compatibility is ABO compatibility. So, if they’re ABO-compatible, relatively young, relatively healthy, they would be a potential donor and we will go ahead and do a CT scan.

If the CT scan shows that they have a good, adequate anatomy, more than 90% of those will be good donors. I would say that out of 100 people who want to be donors, 25 of them will be adequate. One out of four people who want to save their family member and want to have this operation are able to donate half of their liver to their family member or loved one.

Dr. Schlechter: Excellent. And it’s helpful to know that the matching process is simpler. During his discussion, René Adam unequivocally stated that liver transplants are a new standard of care for colorectal cancer. And I guess my question is, do you agree with this statement? How do we balance the demand for living donors and the demand for deceased donors? Especially in a time of increasing fatty liver disease and obesity, other indications for liver transplant, causes of cirrhosis, and also in an era of young-onset colorectal cancer. Patients are younger. Is this a new standard of care? Do you agree with that statement?

Dr. Dib: I do agree with that statement. I think it’s important to understand that not all patients with colorectal mets are the same. Of the number of patients in the United States who have colorectal cancer, let’s say 50% of them will have liver metastasis. Only 15%-20% of them will have liver-only metastasis.

This is only for patients who have liver-only metastasis without extrahepatic disease. And only maybe 15%-20% of them will meet all the criteria to be able to undergo liver transplantation. I think it’s for a very selective subset of patients who have very good tumor biology, generally young patients who don’t have any other alternative to having even a complex liver resection and are not able to get R0 resection. That is when we could think about doing liver transplantation.

It’s one more of the skills that we can have. It doesn’t mean that it will be the only skill, or the best skill, for all of the patients.

Dr. Schlechter: When a patient volunteers to be a living donor for a loved one or a family member, and they go through all the screening and they’re found to be a candidate, what is the surgical experience for that patient?

How long are they in the hospital? What sort of operation is that?

Dr. Dib: Living donors are very special patients. These are patients who do not need an operation. And the only reason they’re doing this is to save the life of their loved one. Donor safety is our priority number one, two, three, and four. The donor operation needs to be perfect.

And so we take good care of, first of all, selecting the living donors, making sure that they’re young and they don’t have any big contraindications. We also ensure that they are well informed of the process. The living donor surgery that we’re now doing is laparoscopic and minimally invasive. Here at Beth Israel Deaconess, we have done it laparoscopically with very good results.

I think that experience before and after the surgery gets so much better because of the better recovery. They’re able to go home, in general, within 4 or 5 days, and they get on with their normal life within 6-8 weeks. I think it’s important for them to know all the processes and the actual risks and benefits for the recipient.

Among those risks, I think it’s important for them to understand that this is a complex operation. Even if we do it laparoscopically or robotically, so that the scar is less, inside we’re still taking out half of the liver. That is a surgery that needs to be undertaken very meticulously, with a focus on minimizing any bleeding.

It’s a surgery that takes a long time. It takes about 6 hours. We do our best to try to minimize any risks.

Dr. Schlechter: Excellent. Thanks for that. Today we had Dr. Martin Dib joining us to discuss liver transplant for metastatic colorectal cancer. We discussed the various important criteria. We discussed that early referral to multidisciplinary centers that manage these is important to help get patients set up.

We discussed the fact that there are certain inclusion and exclusion criteria to consider. Obviously, unresectable disease is a critical determination that should be made by a liver surgeon. The absence of extrahepatic disease is important in staging with PET or other imaging. We discussed certain other biological exclusions.

There’s a relative contraindication of right-sided vs left-sided cancers, but right-sided cancers can be transplanted. We discussed that an elevated CEA greater than 80 is a contraindication, as are mutations in BRAF. We reviewed data from both the TRANSMET trial recently published in The Lancet and presented at ASCO in 2024, as well as the older Oslo criteria and Oslo trials and SECA trials.

And finally, we heard that donors can now come as living donors, a laparoscopic robotic surgery with a better safety profile, and greater access to organs that are ABO matched and not HLA matched because of the nature of the biology. Thank you again for joining us.


 

Benjamin L. Schlechter, MD, is senior physician, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts. He has disclosed no relevant financial relationships. Martin J. Dib, MD, is member of the faculty, Department of Surgery, Harvard Medical School; director of Hepatobiliary Surgery, Division of Transplantation, Beth Israel Deaconess Medical Center, Boston. He has disclosed no relevant financial relationships.

A version of this transcript appeared on Medscape.com.

This transcript has been edited for clarity.
 

Benjamin L. Schlechter, MD: Today we’re discussing liver transplant for metastatic colorectal cancer with our guest, Dr. Martin Dib. Dr. Dib is the director of the Hepatobiliary Surgery and Living Donor Program at Beth Israel Deaconess Medical Center here in Boston, and a Harvard Medical School faculty member.

He was previously at the Pontificia Universidad Católica de Chile, a leading international institution investigating the role of liver transplant in colorectal cancer, among other diseases. Dr. Dib, before we move to our discussion, I’d like to hear a bit about your pathway to becoming a transplant surgeon. How did you end up working on colorectal cancer and liver transplants in this field?

Martin J. Dib, MD: Thank you so much, Dr. Schlechter. I am originally from Chile. I had an opportunity to come to Beth Israel Deaconess Medical Center after medical school and I did liver regeneration research at the transplant center. After that, I was lucky enough to match as a general surgery resident at Beth Israel Deaconess.

This is my alma mater and I was able to graduate as a surgeon here. You and I had some paths together. After graduating from Harvard as a surgeon, I was trained in liver transplant, abdominal transplant, surgical oncology, and hepatobiliary surgery at the University of Toronto.

I have been developing this passion for being able to transplant cancer patients and use organ transplant techniques to be able to do complex resections for cancer.

Dr. Schlechter: Let’s talk about the topic for today, which is liver transplant and colorectal cancer. I’ll be honest — this is not a very familiar topic for a lot of oncologists. There are a lot of details that I think are new to us as oncologists. We need to expand this conversation to get access to patients for this.

First and foremost, can you talk about some of the parameters for a resectable liver metastasis vs unresectable disease that would be an indication for a liver transplant?

Dr. Dib: I think this is a very interesting topic because liver transplantation for cancer is not new. Liver transplantation started in the 1960s when people started doing liver transplants for advanced liver tumors. The problem is that they were selecting patients who had very advanced — and poor tumor biology — tumors. The outcomes were not good.

It was only in 1996 when the Milan criteria started. Mazzaferro and colleagues, using strict patient selection, were able to do liver transplant for selected hepatocellular carcinoma patients. Having those excellent outcomes in selecting patients opened the field for what we now call transplant oncology, which is using selection criteria and using other methods to be able to select which patients will do well after transplantation, even with immunosuppression.

Liver transplantation for colorectal metastasis was used at the very beginning of the era of liver transplantation, but with very poor outcomes. It was abandoned because of the outcomes. It is exciting to see that after 20 years of not doing it, there was a group in Norway that started again. They are doing liver transplants for colorectal metastases (mets), but with very selected patients.

In Norway, they had a very unusual setting where they had more liver donors than patients on the list waiting for liver transplant. So they can’t share these livers and we’re all jealous, right? Every single country in the West struggles because we don’t have enough livers for the rest of the list. And they had a lot of livers to be able to transplant people.

They decided to transplant some selected patients with colorectal mets that were unresectable. And the surprise was that they found that they were able to get a 60% survival at 5 years. And so that was new. After that, in Norway, they started showing this data to other centers in the world. It wasn’t until this year that we could see not only the long-term data and long-term outcomes of using liver transplantation for unresectable colorectal mets, but also we’re now having data from a prospective clinical trial from France.

It was three countries in the prospective clinical trial: France, Belgium, and Italy. We now see that we have a little stronger data to support the use of liver transplants for unresectable colorectal mets.

Dr. Schlechter: That’s the TRANSMET study you’re referencing that was presented at ASCO in the late-breaking abstract session in 2024, and then more recently in The Lancet’s eClinicalMedicine. Both of those papers were led by René Adam. That was a cool presentation to sit through. I was in the room, and I was taking a ton of notes and there was a lot of info that came out of that.

First of all, it showed that patients who had received chemotherapy and were responding could then go on to liver transplant in that population. Impressively, 81% of the patients who were randomized to transplant received it. Frankly, that’s a big number, especially compared with the West, as you said, and in particular the US and here in New England where livers are a very precious commodity.

And even accounting for that, if you look at the intention-to-treat analysis, the 5-year overall survival in that population was 57% compared with 13% with chemotherapy. And that feels like a real number for chemotherapy. If you look at the per-protocol analysis, frankly, the numbers are higher.

It’s always a challenging assessment. What was also interesting to me was the pattern of recurrence, which in general was that recurrences were extrahepatic. So not only were patients rendered disease-free, but in general, the liver remained disease-free and only 3% of patients had liver-only recurrence and 11% had widespread metastatic disease.

The biggest group was lung metastases, at about 40%. Ultimately, they reported a progression-free survival of 17. 4 months for transplant compared with 6. 4 months with chemotherapy. On every parameter, it looks like liver transplant wins for these people. Help me out. Who are these people? How do we find these people?

What are the inclusions and exclusions for this population?

Dr. Dib: I think that’s very important. This is not a therapy that will be for every patient. These are selected patients who have liver-only unresectable colorectal mets. These are patients that don’t have any extrahepatic disease and that either the primary has been taken out already or that they have the primary present, but the plan is to take the primary and then do a liver transplantation after 3 months, hopefully after 6 months, of removing the primary.

These are patients who meet all the criteria that we have seen in terms of the best outcomes — patients that have Oslo scores of less than three. The Oslo trial, which included the SECA (Secondary Cancer)-I and SECA-II trials, basically showed that patients with a maximal tumor diameter of less than 5.5 with a pretransplant CEA (carcinoembryonic antigen) of less than 80 that do not have progression on chemotherapy, among other variables, do better. But the concept is that this is a therapy that will apply only to selected patients. That way we can continue to have adequate overall survival post-transplant that would be comparable to other diseases that we do liver transplants for.

Dr. Schlechter: Were there other biomarkers, any mutations that were included or excluded?

Dr. Dib: Yes. If you look at SECA-I, SECA-II trial outcomes, and also TRANSMET, they all say patients with BRAF mutations shouldn’t be transplanted. There are other parameters, including, for example, the site of the primary tumor. Patients with a left-sided colon primary tumor do much better than patients who have a right-sided primary tumor.

That’s not a complete contraindication, but if you look at the most updated inclusion criteria of programs, like the ones that the one that we have here at Beth Israel Deaconess and many others, the inclusion criteria protocols include patients who have only hepatic disease.

So, if there are no extrahepatic mets, the resection of the primary has been done or will be done after a multidisciplinary discussion. We want to make sure they have the absence of BRAF mutation, and that they don’t have disease progression while on chemotherapy. So hopefully we have data from enough months to be able to make sure that there’s no intrahepatic or extrahepatic progression while on chemotherapy.

And that’s including CEA and also looking at the imaging.

Dr. Schlechter: When you’re seeing a patient, how much chemo do you think they should have? What’s a good run chemotherapy-wise for these patients? Let’s say, before I refer a patient to you, how much chemo should they have? And then what should I do? Do I get a PET scan? Do I get MRI? What’s the right scanning I should do to prove there’s no extrahepatic disease before sending a patient in for consideration?

Dr. Dib: First, we need to confirm unresectability. Referring patients early is always a good measure to make sure that we’re all in agreement that it’s an unresectable patient. Having a PET scan from the very beginning is helpful because it shows the disease before doing chemotherapy.

In terms of the lines of chemotherapy, ideally in the TRANSMET trial, for example, the idea was to show tumor control for at least 3 months, with less than three lines of chemotherapy. Some patients will do that with FOLFIRI. It depends on the case.

I think some of those evaluations will need a multidisciplinary discussion. In our case, we are connected to the Norway team. We frequently talk with the Oslo team and an international community of transplant centers to get opinions on particular cases.

But I think referring patients early is a good measure. If we don’t think that they qualify, we will let the team know. We’re strictly looking at patients who have unresectable liver mets that don’t have extrahepatic disease. The idea is to do a primary tumor resection, and then get to transplantation, hopefully after 6 months. In some cases that have some concerns in terms of tumor biology, we may even extend the time from diagnosis to transplant to over 1.5 years.

Dr. Schlechter: Excellent. And what’s the experience like for these patients? In training as a resident many years ago, I saw patients with cirrhosis who went on to have a liver transplant, and that was sort of trading one disease for another. What is the posttransplant, or the remission, experience of a liver transplant for colorectal cancer like for the patient?

Dr. Dib: That’s a very important point. I think that transplantation has gotten better and better, as has chemotherapy systemic therapy. The liver transplantation experience from 20 years ago has improved dramatically. I think the quality of life of liver transplant patients after transplantation has increased quite a bit.

At Beth Israel Deaconess, we have a liver transplant program that is doing over a 100 livers a year. And when you have a high-volume center, usually the experience gets better. The time in the hospital post-transplant decreases.

In general, when we’re doing liver transplants, patients are getting extubated in the OR 30% of the time. The vast majority of patients are going home within 1 or 2 weeks. They need to have immunosuppression for the rest of their lives. We have a very good program of transplant coordinators that will help the family and the patient to live with immunosuppression and live with a transplanted organ.

But I would say that we have many, many patients, especially these patients who are not patients with cirrhosis. Their health is not as deteriorated as patients who have low MELD (model for end-stage liver disease) scores. They don’t have liver disease. They have cancer. So usually patients like that, many of them can go back to work and live a quality of life that is fairly reasonable.

Dr. Schlechter: That’s good to hear. When we hear statements like liver transplant for colon cancer, a lot of us have this picture of a much sicker population, but it’s interesting and true that the colorectal cancer population as a candidate for liver transplant is a much healthier population than the population with cirrhosis.

Let’s talk about organs and donors. Largely in the TRANSMET study, for example, that was cadaveric donors. Those were not living donors and you’ve done a lot of work on living donors. If the answer in the United States, because of limited access to organs, is going to be living donors, who are those donors?

What is that like? How do you identify them?

Dr. Dib: There’s a lot of advantages to using living donors for these patients. In any type of patient that needs a liver transplant, cadaveric donors or deceased donors is the same concept. There are two types of deceased donors: the brain-dead donors and donors after cardiac death. Those are hard to come by.

We still have 15%-20% mortality on the waiting list in the United States. We’re already still struggling to get enough donors to transplant the patients that are on the list. Now, if you add a new indication, which is unresectable colorectal mets, we need to make sure that the outcomes are equivalent to the patients who are going to be transplanted for other reasons.

Right now, for example, the 5-year overall survival of a patient with cirrhosis, or a patient with hepatocellular carcinoma, is over 80% 5-year survival. In the SECA trials and TRANSMET trial, if we do a good selection, I think we can get to 70% 5-year survival. But until we have more data, I think it’s a cautious measure to, as a field, try to use living donors and not compete with the rest of the list of patients who are already dying on the list for liver transplants.

Once we get more data, it’s going to be something that, in the transplant community, we may be able to use deceased donors. Especially deceased donors with maybe extended criteria that are not going to be used for other patients. We can do living-unrelated or living-related donations. Family members or also friends or neighbors or part of the community, even altruistic donors, can donate to a potential recipient. And that enables us to not only time the transplant in an adequate manner, because we’re able to transplant the patient early, but also time it so we can give the number of chemotherapy cycles that we want to give.

That’s a huge advantage. You don’t compete for a liver with the cadaveric waiting list of patients that are waiting for other reasons, and you can select the tumor biology very well because you know exactly when the surgery is going to be. For instance, we can say, okay, this patient has KRAS mutation, left-sided colon cancer, and has been having good tumor biology with no progression. We will wait 6 months from the primary tumor to the transplant, which is going to be 1 year from diagnosis to transplant. And we can see during that time whether they continue to have good tumor biology.

But if you have a deceased donor liver transplant, sometimes you can’t time that well and schedule it. It becomes a bit more tricky in terms of patient selection and making sure that we do this for the people who are going to benefit.

Dr. Schlechter: And how does donor matching work? Is it HLA (human leukocyte antigen) matched or ABO-matched? Who can donate when you say a living-related? For example, when we think about bone marrow transplantation, which we’re all familiar with in the oncology population, it’s an incredibly complex match process. Is this the same challenge?

Dr. Dib: No, it’s a little bit simpler. Living donors for liver transplants need to be between the ages of 18 and 60. They need to be relatively healthy, relatively fit, with a BMI hopefully less than 30, definitely less than 35. The compatibility is ABO compatibility. So, if they’re ABO-compatible, relatively young, relatively healthy, they would be a potential donor and we will go ahead and do a CT scan.

If the CT scan shows that they have a good, adequate anatomy, more than 90% of those will be good donors. I would say that out of 100 people who want to be donors, 25 of them will be adequate. One out of four people who want to save their family member and want to have this operation are able to donate half of their liver to their family member or loved one.

Dr. Schlechter: Excellent. And it’s helpful to know that the matching process is simpler. During his discussion, René Adam unequivocally stated that liver transplants are a new standard of care for colorectal cancer. And I guess my question is, do you agree with this statement? How do we balance the demand for living donors and the demand for deceased donors? Especially in a time of increasing fatty liver disease and obesity, other indications for liver transplant, causes of cirrhosis, and also in an era of young-onset colorectal cancer. Patients are younger. Is this a new standard of care? Do you agree with that statement?

Dr. Dib: I do agree with that statement. I think it’s important to understand that not all patients with colorectal mets are the same. Of the number of patients in the United States who have colorectal cancer, let’s say 50% of them will have liver metastasis. Only 15%-20% of them will have liver-only metastasis.

This is only for patients who have liver-only metastasis without extrahepatic disease. And only maybe 15%-20% of them will meet all the criteria to be able to undergo liver transplantation. I think it’s for a very selective subset of patients who have very good tumor biology, generally young patients who don’t have any other alternative to having even a complex liver resection and are not able to get R0 resection. That is when we could think about doing liver transplantation.

It’s one more of the skills that we can have. It doesn’t mean that it will be the only skill, or the best skill, for all of the patients.

Dr. Schlechter: When a patient volunteers to be a living donor for a loved one or a family member, and they go through all the screening and they’re found to be a candidate, what is the surgical experience for that patient?

How long are they in the hospital? What sort of operation is that?

Dr. Dib: Living donors are very special patients. These are patients who do not need an operation. And the only reason they’re doing this is to save the life of their loved one. Donor safety is our priority number one, two, three, and four. The donor operation needs to be perfect.

And so we take good care of, first of all, selecting the living donors, making sure that they’re young and they don’t have any big contraindications. We also ensure that they are well informed of the process. The living donor surgery that we’re now doing is laparoscopic and minimally invasive. Here at Beth Israel Deaconess, we have done it laparoscopically with very good results.

I think that experience before and after the surgery gets so much better because of the better recovery. They’re able to go home, in general, within 4 or 5 days, and they get on with their normal life within 6-8 weeks. I think it’s important for them to know all the processes and the actual risks and benefits for the recipient.

Among those risks, I think it’s important for them to understand that this is a complex operation. Even if we do it laparoscopically or robotically, so that the scar is less, inside we’re still taking out half of the liver. That is a surgery that needs to be undertaken very meticulously, with a focus on minimizing any bleeding.

It’s a surgery that takes a long time. It takes about 6 hours. We do our best to try to minimize any risks.

Dr. Schlechter: Excellent. Thanks for that. Today we had Dr. Martin Dib joining us to discuss liver transplant for metastatic colorectal cancer. We discussed the various important criteria. We discussed that early referral to multidisciplinary centers that manage these is important to help get patients set up.

We discussed the fact that there are certain inclusion and exclusion criteria to consider. Obviously, unresectable disease is a critical determination that should be made by a liver surgeon. The absence of extrahepatic disease is important in staging with PET or other imaging. We discussed certain other biological exclusions.

There’s a relative contraindication of right-sided vs left-sided cancers, but right-sided cancers can be transplanted. We discussed that an elevated CEA greater than 80 is a contraindication, as are mutations in BRAF. We reviewed data from both the TRANSMET trial recently published in The Lancet and presented at ASCO in 2024, as well as the older Oslo criteria and Oslo trials and SECA trials.

And finally, we heard that donors can now come as living donors, a laparoscopic robotic surgery with a better safety profile, and greater access to organs that are ABO matched and not HLA matched because of the nature of the biology. Thank you again for joining us.


 

Benjamin L. Schlechter, MD, is senior physician, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts. He has disclosed no relevant financial relationships. Martin J. Dib, MD, is member of the faculty, Department of Surgery, Harvard Medical School; director of Hepatobiliary Surgery, Division of Transplantation, Beth Israel Deaconess Medical Center, Boston. He has disclosed no relevant financial relationships.

A version of this transcript appeared on Medscape.com.