Diversity in Medicine

FROM AAD 2024

SAN DIEGO — In separate studies evaluating treatments for severe forms of alopecia, inhibitors of Janus kinases (JAKs) produced clinically meaningful hair regrowth, according to late-breaking data presented at the annual meeting of  the American Academy of Dermatology.

In one study of brepocitinib, the target was cicatricial alopecia (CA), a form of hair loss for which there are no approved therapies. In the other, a subanalysis from phase 3 trials of ritlecitinib for alopecia areata (AA), hair regrowth was shown in the subset of patients who entered the study with alopecia totalis or alopecia universalis (AT/AU).

Reflecting comments from several experts, including one of the late-breaking session moderators, April W. Armstrong, MD, MPH, professor and chief of dermatology, University of California, Los Angeles, said that the CA study, which matched clinical response to changes in CA biomarkers, suggested that the results are a potential breakthrough.

“This is the first placebo-controlled study with an oral JAK inhibitor that not only shows that scarring alopecia can be reversible but also gives insights to the mechanism of action and which patients might respond best,” Emma Guttman-Yassky, MD, PhD, said in an interview. Dr. Guttman-Yassky, professor of Dermatology and Immunology, and director of the Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York City, was the study’s senior investigator.

Scarring Alopecia and Brepocitinib

For the study of scarring alopecia, 49 patients with CA were randomized in a 3:1 ratio to brepocitinib, a first-in-class inhibitor that targets both JAK1 and TYK2, or placebo. Because of the small size of the study, the primary endpoint was the change in CA biomarkers. The secondary outcome was clinical response, but because of a correlation between the two, these were mutually reinforcing.

Of the subtypes, nine patients enrolled in the study had frontal fibrosing alopecia (FFA), 16 had lichen planopilaris (LPP) alopecia, and 24 had central centrifugal cicatricial alopecia (CCCA). All of the forms of CA are more common in women overall and women of color specifically, particularly CCCA. For this analysis, the FFA and LPP subtypes were considered similar for assessing response and were combined.

The data included a comparison of response and safety during the 24-week randomization phase, as well as an additional follow-up conducted after another 24 weeks of open-label treatment. During the second phase, all patients on placebo were switched to active treatment.

Overall, there was a reduction in all four of the key scalp inflammatory biomarkers measured among those in the combined FFA/LLP group. In the placebo group, each of these markers — interferon gamma (IFN-gamma), CCLS, CXCL10, and STAT1 — increased over the same time period. In almost all cases, the differences were statistically significant.

In the CCCA subgroup, the same pattern (an increase among those on placebo but a decrease among those on brepocitinib) was observed for CCLS and CXCL10. For IFN-gamma and STAT1, a rise was observed among those on placebo and those on active treatment, although the rise was greater for placebo.

For clinical response, improvement on brepocitinib was observed on disease activity indexes, particularly among those in the FFA/LLP group, according to Marguerite Meariman, MD, a dermatology resident at Mount Sinai, who presented the results. She called the improvement in clinical activity scores at 48 weeks “dramatic.” Moreover, improvement was apparent within 4 weeks of starting therapy.

For CCCA, a more challenging condition to treat, Dr. Meariman said that no further progression might represent an acceptable response for many patients, but there were also cases of hair regrowth in this subset. Although improvement was not generally on the order seen among those with FFA/LLP, she suggested that there is promise even in these more difficult patients.

Further studies are planned, but Dr. Meariman said that it might be important to focus on early treatment regardless of CA subtype. She noted that patients with less than 5 years disease duration typically did better than those with longer durations.

Ritlecitinib for AT/AU

The analysis of patients with AT/AU was based on a subset analysis from the ALLEGRO phase 2b/3 study of ritlecitinib, which targets JAK3 and TEC kinases. The full results of the ALLEGRO trial were published last year in The Lancet. In the new late-breaker analysis, Severity of Alopecia Tool (SALT) scores were evaluated on an observed or last-observation-carried-forward basis. Generally, responses in the subgroup of patients with AT/AU, who had a median SALT score of 80.3 (signifying 80.3% hair loss) at baseline, were only modestly lower than those in the overall trial.

At 24 months, about 50% of patients achieved a SALT score of 20, according to Melissa Piliang, MD, chair of Dermatology at the Cleveland Clinic, Cleveland, Ohio, who presented the data. In this group, as in the non-AT/AU population, responses climbed over time, and these responses have been maintained for as long as patients have remained on therapy.

At the more rigorous threshold of SALT < 10, the proportion of responders was only slightly lower, meaning a substantial proportion of patients with AT/AU “are achieving 90% or more of hair regrowth, so really an excellent response,” Dr. Piliang said.

For the subgroup with AU, specifically, regrowth of eyebrows and eyelashes was also observed in a substantial proportion, according to Dr. Piliang. Attributed to the often-devastating psychological burden of hair loss, patient-reported assessments of these responses global were generally “even better” than those reported by the investigators.

However, Dr. Piliang advised clinicians to treat AA as early as possible. Despite the benefits seen in the AT/AU subgroup, she pointed out that starting treatment before total hair loss is associated with a higher likelihood of complete or nearly complete hair regrowth.

There are no data from the ALLEGRO trial to determine how long hair regrowth persists after discontinuation of ritlecitinib, which has been approved for the treatment of AA, but Dr. Piliang said that patients should be told that lifelong therapy should be expected in the vast majority of individuals, whether or not AA has advanced to AT/AU.

“In my experience with JAK inhibitors, you lose response when you come off these drugs,” she said.

Dr. Meariman reported a financial relationship with AbbVie. Dr. Piliang reported financial relationships with Eli Lilly, Pfizer, and Proctor & Gamble. Dr. Armstrong reported financial relationships with more than 30 pharmaceutical companies, including those that manufacture JAK inhibitors. Dr. Guttman-Yassky reported financial relationships with more than 30 companies, including those that manufacture JAK inhibitors.

A version of this article appeared on Medscape.com.

FROM AAD 2024

SAN DIEGO — In separate studies evaluating treatments for severe forms of alopecia, inhibitors of Janus kinases (JAKs) produced clinically meaningful hair regrowth, according to late-breaking data presented at the annual meeting of  the American Academy of Dermatology.

In one study of brepocitinib, the target was cicatricial alopecia (CA), a form of hair loss for which there are no approved therapies. In the other, a subanalysis from phase 3 trials of ritlecitinib for alopecia areata (AA), hair regrowth was shown in the subset of patients who entered the study with alopecia totalis or alopecia universalis (AT/AU).

Reflecting comments from several experts, including one of the late-breaking session moderators, April W. Armstrong, MD, MPH, professor and chief of dermatology, University of California, Los Angeles, said that the CA study, which matched clinical response to changes in CA biomarkers, suggested that the results are a potential breakthrough.

“This is the first placebo-controlled study with an oral JAK inhibitor that not only shows that scarring alopecia can be reversible but also gives insights to the mechanism of action and which patients might respond best,” Emma Guttman-Yassky, MD, PhD, said in an interview. Dr. Guttman-Yassky, professor of Dermatology and Immunology, and director of the Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York City, was the study’s senior investigator.

Scarring Alopecia and Brepocitinib

For the study of scarring alopecia, 49 patients with CA were randomized in a 3:1 ratio to brepocitinib, a first-in-class inhibitor that targets both JAK1 and TYK2, or placebo. Because of the small size of the study, the primary endpoint was the change in CA biomarkers. The secondary outcome was clinical response, but because of a correlation between the two, these were mutually reinforcing.

Of the subtypes, nine patients enrolled in the study had frontal fibrosing alopecia (FFA), 16 had lichen planopilaris (LPP) alopecia, and 24 had central centrifugal cicatricial alopecia (CCCA). All of the forms of CA are more common in women overall and women of color specifically, particularly CCCA. For this analysis, the FFA and LPP subtypes were considered similar for assessing response and were combined.

The data included a comparison of response and safety during the 24-week randomization phase, as well as an additional follow-up conducted after another 24 weeks of open-label treatment. During the second phase, all patients on placebo were switched to active treatment.

Overall, there was a reduction in all four of the key scalp inflammatory biomarkers measured among those in the combined FFA/LLP group. In the placebo group, each of these markers — interferon gamma (IFN-gamma), CCLS, CXCL10, and STAT1 — increased over the same time period. In almost all cases, the differences were statistically significant.

In the CCCA subgroup, the same pattern (an increase among those on placebo but a decrease among those on brepocitinib) was observed for CCLS and CXCL10. For IFN-gamma and STAT1, a rise was observed among those on placebo and those on active treatment, although the rise was greater for placebo.

For clinical response, improvement on brepocitinib was observed on disease activity indexes, particularly among those in the FFA/LLP group, according to Marguerite Meariman, MD, a dermatology resident at Mount Sinai, who presented the results. She called the improvement in clinical activity scores at 48 weeks “dramatic.” Moreover, improvement was apparent within 4 weeks of starting therapy.

For CCCA, a more challenging condition to treat, Dr. Meariman said that no further progression might represent an acceptable response for many patients, but there were also cases of hair regrowth in this subset. Although improvement was not generally on the order seen among those with FFA/LLP, she suggested that there is promise even in these more difficult patients.

Further studies are planned, but Dr. Meariman said that it might be important to focus on early treatment regardless of CA subtype. She noted that patients with less than 5 years disease duration typically did better than those with longer durations.

Ritlecitinib for AT/AU

The analysis of patients with AT/AU was based on a subset analysis from the ALLEGRO phase 2b/3 study of ritlecitinib, which targets JAK3 and TEC kinases. The full results of the ALLEGRO trial were published last year in The Lancet. In the new late-breaker analysis, Severity of Alopecia Tool (SALT) scores were evaluated on an observed or last-observation-carried-forward basis. Generally, responses in the subgroup of patients with AT/AU, who had a median SALT score of 80.3 (signifying 80.3% hair loss) at baseline, were only modestly lower than those in the overall trial.

At 24 months, about 50% of patients achieved a SALT score of 20, according to Melissa Piliang, MD, chair of Dermatology at the Cleveland Clinic, Cleveland, Ohio, who presented the data. In this group, as in the non-AT/AU population, responses climbed over time, and these responses have been maintained for as long as patients have remained on therapy.

At the more rigorous threshold of SALT < 10, the proportion of responders was only slightly lower, meaning a substantial proportion of patients with AT/AU “are achieving 90% or more of hair regrowth, so really an excellent response,” Dr. Piliang said.

For the subgroup with AU, specifically, regrowth of eyebrows and eyelashes was also observed in a substantial proportion, according to Dr. Piliang. Attributed to the often-devastating psychological burden of hair loss, patient-reported assessments of these responses global were generally “even better” than those reported by the investigators.

However, Dr. Piliang advised clinicians to treat AA as early as possible. Despite the benefits seen in the AT/AU subgroup, she pointed out that starting treatment before total hair loss is associated with a higher likelihood of complete or nearly complete hair regrowth.

There are no data from the ALLEGRO trial to determine how long hair regrowth persists after discontinuation of ritlecitinib, which has been approved for the treatment of AA, but Dr. Piliang said that patients should be told that lifelong therapy should be expected in the vast majority of individuals, whether or not AA has advanced to AT/AU.

“In my experience with JAK inhibitors, you lose response when you come off these drugs,” she said.

Dr. Meariman reported a financial relationship with AbbVie. Dr. Piliang reported financial relationships with Eli Lilly, Pfizer, and Proctor & Gamble. Dr. Armstrong reported financial relationships with more than 30 pharmaceutical companies, including those that manufacture JAK inhibitors. Dr. Guttman-Yassky reported financial relationships with more than 30 companies, including those that manufacture JAK inhibitors.

A version of this article appeared on Medscape.com.

FROM AAD 2024

SAN DIEGO — In separate studies evaluating treatments for severe forms of alopecia, inhibitors of Janus kinases (JAKs) produced clinically meaningful hair regrowth, according to late-breaking data presented at the annual meeting of  the American Academy of Dermatology.

In one study of brepocitinib, the target was cicatricial alopecia (CA), a form of hair loss for which there are no approved therapies. In the other, a subanalysis from phase 3 trials of ritlecitinib for alopecia areata (AA), hair regrowth was shown in the subset of patients who entered the study with alopecia totalis or alopecia universalis (AT/AU).

Reflecting comments from several experts, including one of the late-breaking session moderators, April W. Armstrong, MD, MPH, professor and chief of dermatology, University of California, Los Angeles, said that the CA study, which matched clinical response to changes in CA biomarkers, suggested that the results are a potential breakthrough.

“This is the first placebo-controlled study with an oral JAK inhibitor that not only shows that scarring alopecia can be reversible but also gives insights to the mechanism of action and which patients might respond best,” Emma Guttman-Yassky, MD, PhD, said in an interview. Dr. Guttman-Yassky, professor of Dermatology and Immunology, and director of the Laboratory of Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York City, was the study’s senior investigator.

Scarring Alopecia and Brepocitinib

For the study of scarring alopecia, 49 patients with CA were randomized in a 3:1 ratio to brepocitinib, a first-in-class inhibitor that targets both JAK1 and TYK2, or placebo. Because of the small size of the study, the primary endpoint was the change in CA biomarkers. The secondary outcome was clinical response, but because of a correlation between the two, these were mutually reinforcing.

Of the subtypes, nine patients enrolled in the study had frontal fibrosing alopecia (FFA), 16 had lichen planopilaris (LPP) alopecia, and 24 had central centrifugal cicatricial alopecia (CCCA). All of the forms of CA are more common in women overall and women of color specifically, particularly CCCA. For this analysis, the FFA and LPP subtypes were considered similar for assessing response and were combined.

The data included a comparison of response and safety during the 24-week randomization phase, as well as an additional follow-up conducted after another 24 weeks of open-label treatment. During the second phase, all patients on placebo were switched to active treatment.

Overall, there was a reduction in all four of the key scalp inflammatory biomarkers measured among those in the combined FFA/LLP group. In the placebo group, each of these markers — interferon gamma (IFN-gamma), CCLS, CXCL10, and STAT1 — increased over the same time period. In almost all cases, the differences were statistically significant.

In the CCCA subgroup, the same pattern (an increase among those on placebo but a decrease among those on brepocitinib) was observed for CCLS and CXCL10. For IFN-gamma and STAT1, a rise was observed among those on placebo and those on active treatment, although the rise was greater for placebo.

For clinical response, improvement on brepocitinib was observed on disease activity indexes, particularly among those in the FFA/LLP group, according to Marguerite Meariman, MD, a dermatology resident at Mount Sinai, who presented the results. She called the improvement in clinical activity scores at 48 weeks “dramatic.” Moreover, improvement was apparent within 4 weeks of starting therapy.

For CCCA, a more challenging condition to treat, Dr. Meariman said that no further progression might represent an acceptable response for many patients, but there were also cases of hair regrowth in this subset. Although improvement was not generally on the order seen among those with FFA/LLP, she suggested that there is promise even in these more difficult patients.

Further studies are planned, but Dr. Meariman said that it might be important to focus on early treatment regardless of CA subtype. She noted that patients with less than 5 years disease duration typically did better than those with longer durations.

Ritlecitinib for AT/AU

The analysis of patients with AT/AU was based on a subset analysis from the ALLEGRO phase 2b/3 study of ritlecitinib, which targets JAK3 and TEC kinases. The full results of the ALLEGRO trial were published last year in The Lancet. In the new late-breaker analysis, Severity of Alopecia Tool (SALT) scores were evaluated on an observed or last-observation-carried-forward basis. Generally, responses in the subgroup of patients with AT/AU, who had a median SALT score of 80.3 (signifying 80.3% hair loss) at baseline, were only modestly lower than those in the overall trial.

At 24 months, about 50% of patients achieved a SALT score of 20, according to Melissa Piliang, MD, chair of Dermatology at the Cleveland Clinic, Cleveland, Ohio, who presented the data. In this group, as in the non-AT/AU population, responses climbed over time, and these responses have been maintained for as long as patients have remained on therapy.

At the more rigorous threshold of SALT < 10, the proportion of responders was only slightly lower, meaning a substantial proportion of patients with AT/AU “are achieving 90% or more of hair regrowth, so really an excellent response,” Dr. Piliang said.

For the subgroup with AU, specifically, regrowth of eyebrows and eyelashes was also observed in a substantial proportion, according to Dr. Piliang. Attributed to the often-devastating psychological burden of hair loss, patient-reported assessments of these responses global were generally “even better” than those reported by the investigators.

However, Dr. Piliang advised clinicians to treat AA as early as possible. Despite the benefits seen in the AT/AU subgroup, she pointed out that starting treatment before total hair loss is associated with a higher likelihood of complete or nearly complete hair regrowth.

There are no data from the ALLEGRO trial to determine how long hair regrowth persists after discontinuation of ritlecitinib, which has been approved for the treatment of AA, but Dr. Piliang said that patients should be told that lifelong therapy should be expected in the vast majority of individuals, whether or not AA has advanced to AT/AU.

“In my experience with JAK inhibitors, you lose response when you come off these drugs,” she said.

Dr. Meariman reported a financial relationship with AbbVie. Dr. Piliang reported financial relationships with Eli Lilly, Pfizer, and Proctor & Gamble. Dr. Armstrong reported financial relationships with more than 30 pharmaceutical companies, including those that manufacture JAK inhibitors. Dr. Guttman-Yassky reported financial relationships with more than 30 companies, including those that manufacture JAK inhibitors.

A version of this article appeared on Medscape.com.

More Black men with elevated prostate-specific antigen (PSA) counts are diagnosed with prostate cancer than their White counterparts, but incidence of advanced prostate cancer is similar for Black and White men within 1 year of the PSA test, a new study finds.

There was a substantial difference in prostate cancer diagnosis across ethnic groups: 25% of Black men with a raised PSA were diagnosed with prostate cancer within 1 year of being tested, compared with 20% of White men and 13% of Asian men, in the analysis of a large primary care cohort in the United Kingdom.

Incidence of advanced prostate cancer for Asian men with a raised PSA result was 4.5%, compared with 7.5% for White men and 7.0% for Black men.

Men included in the study were aged 40 and older and had no prior cancer diagnosis. Their ethnicity and PSA test result were logged in a national dataset between 2010 and 2017.

The study of more than 730,000 men, published in BMC Medicine, didn’t explore reasons for the differences, but experts offer their thoughts on what led to the findings and what these results imply.

Why the Higher Diagnosis Rates but Not More Advanced Disease in Black Men?

Lead author Liz Down, a graduate research assistant at the University of Exeter, Exeter, England, suggests the higher diagnosis rates but not more advanced disease in Black men may be linked to genetic variations.

Her team’s studies have shown that Black men in the United Kingdom and United States have higher levels of PSA. The PSA value is used to identify patients who might benefit from specialist investigation, and current guidelines in the UK and US don’t distinguish between ethnic groups.

As most men have slow-growing prostate cancer, this may lead to a disproportionately higher number of Black men being diagnosed with prostate cancer, she said.

“One possible interpretation,” Ms. Down notes, “is that prostate cancer follows a similar trajectory in Black and White men. What is different, however, is that Black men have higher PSA levels.”

As to why the advanced-cancer incidence is similar in Black and White patients in the study, Daniel George, MD, director of genitourinary oncology at Duke Cancer Institute in Durham, North Carolina, says it’s important to understand that the Black men in this study “are not necessarily representative of the Black population at large.”

In this study, “they’re a little bit more healthcare inclined,” Dr. George notes. The study population is actively seeking the PSA test. Their socioeconomic profile might be closer to their White counterparts’, and that may make results more similar, he said.

“It’s possible that because this is a screening and not just men coming in for symptoms or cause, that we’re not seeing as much advanced disease,” he continued.

Amar Kishan, MD, chief of the genitourinary oncology service at University of California Los Angeles (UCLA) Health, says the genomic factors and environmental stressors that lead to elevated PSA counts don’t necessarily translate into aggressiveness of disease.

Why do Different Races have Different Prostate Cancer Risk?

Dr. George points out that the study also highlights that Asian men were significantly less likely to be diagnosed with prostate cancer within 1 year of the test.

The reasons for differences in prostate risk by race are complex, he notes. There are some clues that biologic factors may be at work. For instance, early puberty has a link to prostate cancer as it does to breast cancer, and height is also associated with a greater risk of prostate cancer, Dr. George said.

It’s not necessarily a racial association but there are some biological factors associated with prostate cancer later in life, he explained. “These may be enriched in certain populations, including northern Europeans and patients with African ancestries.”

The study also notes that Black men are more likely to die from prostate cancer than are White men, and Asian men are less likely than White or Black men to die from it.

Ms. Down said the difference in prostate cancer mortality between Black vs White men, in particular, may be related to a number of factors, and age, and lifetime risk of prostate cancer may play a major role, at least in the UK.

Should There Be Different ‘Normal’ PSA Levels for Different Races?

Dr. George says there is likely a need to change the system because a PSA level in one race may not signal the same risk it does in another. So medicine probably needs to standardize what a “normal” PSA is by race, he says, adding that he is a coauthor of an upcoming paper regarding that issue.

The lowest instances of prostate cancer were in Asian patients so this isn’t just a Black and White issue, Dr. George notes. “Being able to establish benchmarks by race and ethnicity is something that is probably needed in the field,” he says.

Dr. Kishan, on the other hand, says data from this study are not enough to support differentiating PSA levels based on race. He noted a limitation of the study is that it was not able to calculate the false-negative rate of PSA tests.

What are the Implications for Treating and Screening for Prostate Cancer

Dr. Kishan says there may be a role for increased intensity of screening, whether at an earlier age or with different intervals, but prostate cancer treatment should not differ by race.

“Our prior study, as well as others,” he says, “have shown that when you balance Black and White patients for every factor that might impact prognosis other than race — such as age, disease aggressiveness, etc. — Black men actually tend to have better  outcomes than White men. Thus, it would mean potentially overtreating (i.e., causing unnecessary side effects) to increase treatment intensity purely based on race with the available data.”

According to the paper, prostate cancer incidence in men with higher PSA levels increases with increasing age, even when using age-adjusted thresholds.

Dr. George says we know from this study and other studies as well that Black men are more likely to be diagnosed with prostate at a younger age. “Therefore, we probably need to be thinking about screening Black men starting at a younger age. These are the men who are most likely to benefit from an intervention — patients who have life expectancies of 20 years or more.”

What are the Downsides to Overdiagnosing Prostate Cancer in Men?

“It’s one of the biggest concerns that men have in proactively seeking healthcare,” Dr. George says. “They’re more likely to undergo treatment for this disease if they’re getting screened because (clinicians are) more likely to find it.”

Some of those men, he says, are going to undergo treatment for disease that won’t ultimately kill them, but may cause complications the men shouldn’t have had at all or otherwise may have had later.

“Overtreatment is a real concern. That’s why active surveillance is so important to minimize overtreatment of patients by finding out which cancers are low risk for progression and which are becoming more aggressive,” Dr. George says.

Authors of the study write that “the potential for overdiagnosis and the subsequent psychological and physical impact of diagnosis and treatment is an important consideration.”

All authors of the new paper received financial support from Cancer Research UK, the National Institute for Health and Care Research (NIHR), and the Higgins family for the submitted work.

Dr. George reports no relevant financial relationships.

Dr. Kishan reports consulting fees and speaking honoraria from Varian Medical Systems, Janssen, and Boston Scientific; research funding from PointBioPharma, Lantheus, and Janssen; and serving on advisory boards for Lantheus, Janssen and Boston Scientific.

More Black men with elevated prostate-specific antigen (PSA) counts are diagnosed with prostate cancer than their White counterparts, but incidence of advanced prostate cancer is similar for Black and White men within 1 year of the PSA test, a new study finds.

There was a substantial difference in prostate cancer diagnosis across ethnic groups: 25% of Black men with a raised PSA were diagnosed with prostate cancer within 1 year of being tested, compared with 20% of White men and 13% of Asian men, in the analysis of a large primary care cohort in the United Kingdom.

Incidence of advanced prostate cancer for Asian men with a raised PSA result was 4.5%, compared with 7.5% for White men and 7.0% for Black men.

Men included in the study were aged 40 and older and had no prior cancer diagnosis. Their ethnicity and PSA test result were logged in a national dataset between 2010 and 2017.

The study of more than 730,000 men, published in BMC Medicine, didn’t explore reasons for the differences, but experts offer their thoughts on what led to the findings and what these results imply.

Why the Higher Diagnosis Rates but Not More Advanced Disease in Black Men?

Lead author Liz Down, a graduate research assistant at the University of Exeter, Exeter, England, suggests the higher diagnosis rates but not more advanced disease in Black men may be linked to genetic variations.

Her team’s studies have shown that Black men in the United Kingdom and United States have higher levels of PSA. The PSA value is used to identify patients who might benefit from specialist investigation, and current guidelines in the UK and US don’t distinguish between ethnic groups.

As most men have slow-growing prostate cancer, this may lead to a disproportionately higher number of Black men being diagnosed with prostate cancer, she said.

“One possible interpretation,” Ms. Down notes, “is that prostate cancer follows a similar trajectory in Black and White men. What is different, however, is that Black men have higher PSA levels.”

As to why the advanced-cancer incidence is similar in Black and White patients in the study, Daniel George, MD, director of genitourinary oncology at Duke Cancer Institute in Durham, North Carolina, says it’s important to understand that the Black men in this study “are not necessarily representative of the Black population at large.”

In this study, “they’re a little bit more healthcare inclined,” Dr. George notes. The study population is actively seeking the PSA test. Their socioeconomic profile might be closer to their White counterparts’, and that may make results more similar, he said.

“It’s possible that because this is a screening and not just men coming in for symptoms or cause, that we’re not seeing as much advanced disease,” he continued.

Amar Kishan, MD, chief of the genitourinary oncology service at University of California Los Angeles (UCLA) Health, says the genomic factors and environmental stressors that lead to elevated PSA counts don’t necessarily translate into aggressiveness of disease.

Why do Different Races have Different Prostate Cancer Risk?

Dr. George points out that the study also highlights that Asian men were significantly less likely to be diagnosed with prostate cancer within 1 year of the test.

The reasons for differences in prostate risk by race are complex, he notes. There are some clues that biologic factors may be at work. For instance, early puberty has a link to prostate cancer as it does to breast cancer, and height is also associated with a greater risk of prostate cancer, Dr. George said.

It’s not necessarily a racial association but there are some biological factors associated with prostate cancer later in life, he explained. “These may be enriched in certain populations, including northern Europeans and patients with African ancestries.”

The study also notes that Black men are more likely to die from prostate cancer than are White men, and Asian men are less likely than White or Black men to die from it.

Ms. Down said the difference in prostate cancer mortality between Black vs White men, in particular, may be related to a number of factors, and age, and lifetime risk of prostate cancer may play a major role, at least in the UK.

Should There Be Different ‘Normal’ PSA Levels for Different Races?

Dr. George says there is likely a need to change the system because a PSA level in one race may not signal the same risk it does in another. So medicine probably needs to standardize what a “normal” PSA is by race, he says, adding that he is a coauthor of an upcoming paper regarding that issue.

The lowest instances of prostate cancer were in Asian patients so this isn’t just a Black and White issue, Dr. George notes. “Being able to establish benchmarks by race and ethnicity is something that is probably needed in the field,” he says.

Dr. Kishan, on the other hand, says data from this study are not enough to support differentiating PSA levels based on race. He noted a limitation of the study is that it was not able to calculate the false-negative rate of PSA tests.

What are the Implications for Treating and Screening for Prostate Cancer

Dr. Kishan says there may be a role for increased intensity of screening, whether at an earlier age or with different intervals, but prostate cancer treatment should not differ by race.

“Our prior study, as well as others,” he says, “have shown that when you balance Black and White patients for every factor that might impact prognosis other than race — such as age, disease aggressiveness, etc. — Black men actually tend to have better  outcomes than White men. Thus, it would mean potentially overtreating (i.e., causing unnecessary side effects) to increase treatment intensity purely based on race with the available data.”

According to the paper, prostate cancer incidence in men with higher PSA levels increases with increasing age, even when using age-adjusted thresholds.

Dr. George says we know from this study and other studies as well that Black men are more likely to be diagnosed with prostate at a younger age. “Therefore, we probably need to be thinking about screening Black men starting at a younger age. These are the men who are most likely to benefit from an intervention — patients who have life expectancies of 20 years or more.”

What are the Downsides to Overdiagnosing Prostate Cancer in Men?

“It’s one of the biggest concerns that men have in proactively seeking healthcare,” Dr. George says. “They’re more likely to undergo treatment for this disease if they’re getting screened because (clinicians are) more likely to find it.”

Some of those men, he says, are going to undergo treatment for disease that won’t ultimately kill them, but may cause complications the men shouldn’t have had at all or otherwise may have had later.

“Overtreatment is a real concern. That’s why active surveillance is so important to minimize overtreatment of patients by finding out which cancers are low risk for progression and which are becoming more aggressive,” Dr. George says.

Authors of the study write that “the potential for overdiagnosis and the subsequent psychological and physical impact of diagnosis and treatment is an important consideration.”

All authors of the new paper received financial support from Cancer Research UK, the National Institute for Health and Care Research (NIHR), and the Higgins family for the submitted work.

Dr. George reports no relevant financial relationships.

Dr. Kishan reports consulting fees and speaking honoraria from Varian Medical Systems, Janssen, and Boston Scientific; research funding from PointBioPharma, Lantheus, and Janssen; and serving on advisory boards for Lantheus, Janssen and Boston Scientific.

More Black men with elevated prostate-specific antigen (PSA) counts are diagnosed with prostate cancer than their White counterparts, but incidence of advanced prostate cancer is similar for Black and White men within 1 year of the PSA test, a new study finds.

There was a substantial difference in prostate cancer diagnosis across ethnic groups: 25% of Black men with a raised PSA were diagnosed with prostate cancer within 1 year of being tested, compared with 20% of White men and 13% of Asian men, in the analysis of a large primary care cohort in the United Kingdom.

Incidence of advanced prostate cancer for Asian men with a raised PSA result was 4.5%, compared with 7.5% for White men and 7.0% for Black men.

Men included in the study were aged 40 and older and had no prior cancer diagnosis. Their ethnicity and PSA test result were logged in a national dataset between 2010 and 2017.

The study of more than 730,000 men, published in BMC Medicine, didn’t explore reasons for the differences, but experts offer their thoughts on what led to the findings and what these results imply.

Why the Higher Diagnosis Rates but Not More Advanced Disease in Black Men?

Lead author Liz Down, a graduate research assistant at the University of Exeter, Exeter, England, suggests the higher diagnosis rates but not more advanced disease in Black men may be linked to genetic variations.

Her team’s studies have shown that Black men in the United Kingdom and United States have higher levels of PSA. The PSA value is used to identify patients who might benefit from specialist investigation, and current guidelines in the UK and US don’t distinguish between ethnic groups.

As most men have slow-growing prostate cancer, this may lead to a disproportionately higher number of Black men being diagnosed with prostate cancer, she said.

“One possible interpretation,” Ms. Down notes, “is that prostate cancer follows a similar trajectory in Black and White men. What is different, however, is that Black men have higher PSA levels.”

As to why the advanced-cancer incidence is similar in Black and White patients in the study, Daniel George, MD, director of genitourinary oncology at Duke Cancer Institute in Durham, North Carolina, says it’s important to understand that the Black men in this study “are not necessarily representative of the Black population at large.”

In this study, “they’re a little bit more healthcare inclined,” Dr. George notes. The study population is actively seeking the PSA test. Their socioeconomic profile might be closer to their White counterparts’, and that may make results more similar, he said.

“It’s possible that because this is a screening and not just men coming in for symptoms or cause, that we’re not seeing as much advanced disease,” he continued.

Amar Kishan, MD, chief of the genitourinary oncology service at University of California Los Angeles (UCLA) Health, says the genomic factors and environmental stressors that lead to elevated PSA counts don’t necessarily translate into aggressiveness of disease.

Why do Different Races have Different Prostate Cancer Risk?

Dr. George points out that the study also highlights that Asian men were significantly less likely to be diagnosed with prostate cancer within 1 year of the test.

The reasons for differences in prostate risk by race are complex, he notes. There are some clues that biologic factors may be at work. For instance, early puberty has a link to prostate cancer as it does to breast cancer, and height is also associated with a greater risk of prostate cancer, Dr. George said.

It’s not necessarily a racial association but there are some biological factors associated with prostate cancer later in life, he explained. “These may be enriched in certain populations, including northern Europeans and patients with African ancestries.”

The study also notes that Black men are more likely to die from prostate cancer than are White men, and Asian men are less likely than White or Black men to die from it.

Ms. Down said the difference in prostate cancer mortality between Black vs White men, in particular, may be related to a number of factors, and age, and lifetime risk of prostate cancer may play a major role, at least in the UK.

Should There Be Different ‘Normal’ PSA Levels for Different Races?

Dr. George says there is likely a need to change the system because a PSA level in one race may not signal the same risk it does in another. So medicine probably needs to standardize what a “normal” PSA is by race, he says, adding that he is a coauthor of an upcoming paper regarding that issue.

The lowest instances of prostate cancer were in Asian patients so this isn’t just a Black and White issue, Dr. George notes. “Being able to establish benchmarks by race and ethnicity is something that is probably needed in the field,” he says.

Dr. Kishan, on the other hand, says data from this study are not enough to support differentiating PSA levels based on race. He noted a limitation of the study is that it was not able to calculate the false-negative rate of PSA tests.

What are the Implications for Treating and Screening for Prostate Cancer

Dr. Kishan says there may be a role for increased intensity of screening, whether at an earlier age or with different intervals, but prostate cancer treatment should not differ by race.

“Our prior study, as well as others,” he says, “have shown that when you balance Black and White patients for every factor that might impact prognosis other than race — such as age, disease aggressiveness, etc. — Black men actually tend to have better  outcomes than White men. Thus, it would mean potentially overtreating (i.e., causing unnecessary side effects) to increase treatment intensity purely based on race with the available data.”

According to the paper, prostate cancer incidence in men with higher PSA levels increases with increasing age, even when using age-adjusted thresholds.

Dr. George says we know from this study and other studies as well that Black men are more likely to be diagnosed with prostate at a younger age. “Therefore, we probably need to be thinking about screening Black men starting at a younger age. These are the men who are most likely to benefit from an intervention — patients who have life expectancies of 20 years or more.”

What are the Downsides to Overdiagnosing Prostate Cancer in Men?

“It’s one of the biggest concerns that men have in proactively seeking healthcare,” Dr. George says. “They’re more likely to undergo treatment for this disease if they’re getting screened because (clinicians are) more likely to find it.”

Some of those men, he says, are going to undergo treatment for disease that won’t ultimately kill them, but may cause complications the men shouldn’t have had at all or otherwise may have had later.

“Overtreatment is a real concern. That’s why active surveillance is so important to minimize overtreatment of patients by finding out which cancers are low risk for progression and which are becoming more aggressive,” Dr. George says.

Authors of the study write that “the potential for overdiagnosis and the subsequent psychological and physical impact of diagnosis and treatment is an important consideration.”

All authors of the new paper received financial support from Cancer Research UK, the National Institute for Health and Care Research (NIHR), and the Higgins family for the submitted work.

Dr. George reports no relevant financial relationships.

Dr. Kishan reports consulting fees and speaking honoraria from Varian Medical Systems, Janssen, and Boston Scientific; research funding from PointBioPharma, Lantheus, and Janssen; and serving on advisory boards for Lantheus, Janssen and Boston Scientific.

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Melanoma in situ manifesting as longitudinal melanonychia (LM) in a single digit in a Black man. Dermoscopy showed irregular dark bands of brown pigmentation and micro-Hutchinson sign on the cuticle (inset).

B Melanoma manifesting as LM with a prominent Hutchinson sign in a Hispanic man, with variable shades of brown covering more than 50% of the nail width.

C Longitudinal melanonychia of at least 2 nails with a pseudo-Hutchinson sign (pigment on the nail folds in a benign case of LM) in a young Black man demonstrating ethnic/racial melanosis. The longitudinal bands, which were caused by benign melanocytic activation, are more gray than brown and are less than 3 mm wide.

Longitudinal melanonychia (LM) is a pigmented linear band—brown, black, or gray—spanning the length of the nail plate due to the presence of excess melanin, which may be attributed to a benign or malignant process and may warrant further investigation.^1,2 The majority of patients who present with LM are diagnosed with melanocytic activation of the nail matrix due to their inherent darker skin tone or various triggers including trauma, infection, and medications. Longitudinal melanonychia secondary to melanocytic activation often occurs spontaneously in patients with skin of color.³ Less commonly, LM is caused by a nail matrix nevus or lentigo; however, LM may arise secondary to subungual melanoma, a more dangerous cause.

A thorough clinical history including duration, recent changes in LM manifestation, nail trauma, or infection is helpful in evaluating patients with LM; however, a history of nail trauma can be misleading, as nail changes attributed to the trauma may in fact be melanoma. Irregularly spaced vertical lines of pigmentation ranging from brown to black with variations in spacing and width are characteristic of subungual melanoma.⁴ Nail dystrophy, granular hyperpigmentation, and Hutchinson sign (extension of pigmentation to the nail folds) also are worrisome features.⁵ In recent years, dermoscopy has become an important tool in the clinical examination of LM, with the development of criteria based on color and pattern recognition.^5,6 Dermoscopy can be useful in screening potential candidates for biopsy. Although clinical examination and dermoscopy are essential to evaluating LM, the gold-standard diagnostic test when malignancy is suspected is a nail matrix biopsy.^1,2,6,7

Epidemiology

It is not unusual for patients with darker skin tones to develop LM due to melanocytic activation of multiple nails with age. This finding can be seen in approximately 80% of African American individuals, 30% of Japanese individuals, and 50% of Hispanic individuals.² It has even been reported that approximately 100% of Black patients older than 50 years will have evidence of LM.³

In a retrospective analysis, children presenting with LM tend to have a higher prevalence of nail matrix nevi compared to adults (56.1% [60/106] vs 34.3% [23/66]; P=.005).⁸ Involvement of a single digit in children is most likely indicative of a nevus; however, when an adult presents with LM in a single digit, suspicion for subungual melanoma should be raised.^2,3,9

Two separate single-center retrospective studies showed the prevalence of subungual melanoma in patients presenting with melanonychia in Asia. Jin et al10 reported subungual melanoma in 6.2% (17/275) of Korean patients presenting with melanonychia at a general dermatology clinic from 2002 to 2014. Lyu et al⁸ studied LM in 172 Chinese patients in a dermatology clinic from 2018 to 2021 and reported 9% (6/66) of adults (aged ≥18 years) with subungual melanoma, with no reported cases in childhood (aged <18 years).

Although the prevalence of subungual melanoma in patients with LM is low, it is an important diagnosis that should not be missed. In confirmed cases of subungual melanoma, two-thirds of lesions manifested as LM.^3,10,11 Thus, LM arising in an adult in a single digit is more concerning for malignancy.^2,3,7,9

Individuals of African and Asian descent as well as American Indian individuals are at highest risk for subungual melanoma with a poor prognosis compared to other types of melanoma, largely due to diagnosis at an advanced stage of disease.^3,9 In a retrospective study of 25 patients with surgically treated subungual melanoma, the mean recurrence-free survival was 33.6 months. The recurrence-free survival was 66% at 1 year and 40% at 3 years, and the overall survival rate was 37% at 3 years.¹²

Key clinical features in individuals with darker skin tones

• In patients with darker skin tones, LM tends to occur on multiple nails as a result of melanocytic activation.^2,13
• Several longitudinal bands may be noted on the same nail and the pigmentation of the bands may vary. With age, these longitudinal bands typically increase in number and width.¹³
• Pseudo-Hutchinson sign may be present due to ethnic melanosis of the proximal nail fold.^13,14
• Dermoscopic findings of LM in patients with skin of color include wider bands (P=.0125), lower band brightness (P<.032), and higher frequency of changing appearance of bands (P=.0071).¹⁵

Worth noting

When patients present with LM, thorough examination of the nail plate, periungual skin, and distal pulp of all digits on all extremities with adequate lighting is important.² Dermoscopy is useful, and a gel interface helps for examining the nail plates.⁷

Clinicians should be encouraged to biopsy or immediately refer patients with concerning nail unit lesions. Cases of LM most likely are benign, but if some doubt exists, the lesions should be biopsied or tracked closely with clinical and dermoscopic images, with a biopsy if changes occur.¹⁶ In conjunction with evaluation by a qualified clinician, patients also should be encouraged to take photographs, as the evolution of nail changes is a critical part of clinical decision-making on the need for a biopsy or referral.

Health disparity highlight

Despite the disproportionately high mortality rates from subungual melanoma in Black and Hispanic populations,^3,9 studies often do not adequately represent these populations. Although subungual melanoma is rare, a delay in the diagnosis contributes to high morbidity and mortality rates.

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Melanoma in situ manifesting as longitudinal melanonychia (LM) in a single digit in a Black man. Dermoscopy showed irregular dark bands of brown pigmentation and micro-Hutchinson sign on the cuticle (inset).

B Melanoma manifesting as LM with a prominent Hutchinson sign in a Hispanic man, with variable shades of brown covering more than 50% of the nail width.

C Longitudinal melanonychia of at least 2 nails with a pseudo-Hutchinson sign (pigment on the nail folds in a benign case of LM) in a young Black man demonstrating ethnic/racial melanosis. The longitudinal bands, which were caused by benign melanocytic activation, are more gray than brown and are less than 3 mm wide.

Longitudinal melanonychia (LM) is a pigmented linear band—brown, black, or gray—spanning the length of the nail plate due to the presence of excess melanin, which may be attributed to a benign or malignant process and may warrant further investigation.^1,2 The majority of patients who present with LM are diagnosed with melanocytic activation of the nail matrix due to their inherent darker skin tone or various triggers including trauma, infection, and medications. Longitudinal melanonychia secondary to melanocytic activation often occurs spontaneously in patients with skin of color.³ Less commonly, LM is caused by a nail matrix nevus or lentigo; however, LM may arise secondary to subungual melanoma, a more dangerous cause.

A thorough clinical history including duration, recent changes in LM manifestation, nail trauma, or infection is helpful in evaluating patients with LM; however, a history of nail trauma can be misleading, as nail changes attributed to the trauma may in fact be melanoma. Irregularly spaced vertical lines of pigmentation ranging from brown to black with variations in spacing and width are characteristic of subungual melanoma.⁴ Nail dystrophy, granular hyperpigmentation, and Hutchinson sign (extension of pigmentation to the nail folds) also are worrisome features.⁵ In recent years, dermoscopy has become an important tool in the clinical examination of LM, with the development of criteria based on color and pattern recognition.^5,6 Dermoscopy can be useful in screening potential candidates for biopsy. Although clinical examination and dermoscopy are essential to evaluating LM, the gold-standard diagnostic test when malignancy is suspected is a nail matrix biopsy.^1,2,6,7

Epidemiology

It is not unusual for patients with darker skin tones to develop LM due to melanocytic activation of multiple nails with age. This finding can be seen in approximately 80% of African American individuals, 30% of Japanese individuals, and 50% of Hispanic individuals.² It has even been reported that approximately 100% of Black patients older than 50 years will have evidence of LM.³

In a retrospective analysis, children presenting with LM tend to have a higher prevalence of nail matrix nevi compared to adults (56.1% [60/106] vs 34.3% [23/66]; P=.005).⁸ Involvement of a single digit in children is most likely indicative of a nevus; however, when an adult presents with LM in a single digit, suspicion for subungual melanoma should be raised.^2,3,9

Two separate single-center retrospective studies showed the prevalence of subungual melanoma in patients presenting with melanonychia in Asia. Jin et al10 reported subungual melanoma in 6.2% (17/275) of Korean patients presenting with melanonychia at a general dermatology clinic from 2002 to 2014. Lyu et al⁸ studied LM in 172 Chinese patients in a dermatology clinic from 2018 to 2021 and reported 9% (6/66) of adults (aged ≥18 years) with subungual melanoma, with no reported cases in childhood (aged <18 years).

Although the prevalence of subungual melanoma in patients with LM is low, it is an important diagnosis that should not be missed. In confirmed cases of subungual melanoma, two-thirds of lesions manifested as LM.^3,10,11 Thus, LM arising in an adult in a single digit is more concerning for malignancy.^2,3,7,9

Individuals of African and Asian descent as well as American Indian individuals are at highest risk for subungual melanoma with a poor prognosis compared to other types of melanoma, largely due to diagnosis at an advanced stage of disease.^3,9 In a retrospective study of 25 patients with surgically treated subungual melanoma, the mean recurrence-free survival was 33.6 months. The recurrence-free survival was 66% at 1 year and 40% at 3 years, and the overall survival rate was 37% at 3 years.¹²

Key clinical features in individuals with darker skin tones

• In patients with darker skin tones, LM tends to occur on multiple nails as a result of melanocytic activation.^2,13
• Several longitudinal bands may be noted on the same nail and the pigmentation of the bands may vary. With age, these longitudinal bands typically increase in number and width.¹³
• Pseudo-Hutchinson sign may be present due to ethnic melanosis of the proximal nail fold.^13,14
• Dermoscopic findings of LM in patients with skin of color include wider bands (P=.0125), lower band brightness (P<.032), and higher frequency of changing appearance of bands (P=.0071).¹⁵

Worth noting

When patients present with LM, thorough examination of the nail plate, periungual skin, and distal pulp of all digits on all extremities with adequate lighting is important.² Dermoscopy is useful, and a gel interface helps for examining the nail plates.⁷

Clinicians should be encouraged to biopsy or immediately refer patients with concerning nail unit lesions. Cases of LM most likely are benign, but if some doubt exists, the lesions should be biopsied or tracked closely with clinical and dermoscopic images, with a biopsy if changes occur.¹⁶ In conjunction with evaluation by a qualified clinician, patients also should be encouraged to take photographs, as the evolution of nail changes is a critical part of clinical decision-making on the need for a biopsy or referral.

Health disparity highlight

Despite the disproportionately high mortality rates from subungual melanoma in Black and Hispanic populations,^3,9 studies often do not adequately represent these populations. Although subungual melanoma is rare, a delay in the diagnosis contributes to high morbidity and mortality rates.

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Melanoma in situ manifesting as longitudinal melanonychia (LM) in a single digit in a Black man. Dermoscopy showed irregular dark bands of brown pigmentation and micro-Hutchinson sign on the cuticle (inset).

B Melanoma manifesting as LM with a prominent Hutchinson sign in a Hispanic man, with variable shades of brown covering more than 50% of the nail width.

C Longitudinal melanonychia of at least 2 nails with a pseudo-Hutchinson sign (pigment on the nail folds in a benign case of LM) in a young Black man demonstrating ethnic/racial melanosis. The longitudinal bands, which were caused by benign melanocytic activation, are more gray than brown and are less than 3 mm wide.

Longitudinal melanonychia (LM) is a pigmented linear band—brown, black, or gray—spanning the length of the nail plate due to the presence of excess melanin, which may be attributed to a benign or malignant process and may warrant further investigation.^1,2 The majority of patients who present with LM are diagnosed with melanocytic activation of the nail matrix due to their inherent darker skin tone or various triggers including trauma, infection, and medications. Longitudinal melanonychia secondary to melanocytic activation often occurs spontaneously in patients with skin of color.³ Less commonly, LM is caused by a nail matrix nevus or lentigo; however, LM may arise secondary to subungual melanoma, a more dangerous cause.

A thorough clinical history including duration, recent changes in LM manifestation, nail trauma, or infection is helpful in evaluating patients with LM; however, a history of nail trauma can be misleading, as nail changes attributed to the trauma may in fact be melanoma. Irregularly spaced vertical lines of pigmentation ranging from brown to black with variations in spacing and width are characteristic of subungual melanoma.⁴ Nail dystrophy, granular hyperpigmentation, and Hutchinson sign (extension of pigmentation to the nail folds) also are worrisome features.⁵ In recent years, dermoscopy has become an important tool in the clinical examination of LM, with the development of criteria based on color and pattern recognition.^5,6 Dermoscopy can be useful in screening potential candidates for biopsy. Although clinical examination and dermoscopy are essential to evaluating LM, the gold-standard diagnostic test when malignancy is suspected is a nail matrix biopsy.^1,2,6,7

Epidemiology

It is not unusual for patients with darker skin tones to develop LM due to melanocytic activation of multiple nails with age. This finding can be seen in approximately 80% of African American individuals, 30% of Japanese individuals, and 50% of Hispanic individuals.² It has even been reported that approximately 100% of Black patients older than 50 years will have evidence of LM.³

In a retrospective analysis, children presenting with LM tend to have a higher prevalence of nail matrix nevi compared to adults (56.1% [60/106] vs 34.3% [23/66]; P=.005).⁸ Involvement of a single digit in children is most likely indicative of a nevus; however, when an adult presents with LM in a single digit, suspicion for subungual melanoma should be raised.^2,3,9

Two separate single-center retrospective studies showed the prevalence of subungual melanoma in patients presenting with melanonychia in Asia. Jin et al10 reported subungual melanoma in 6.2% (17/275) of Korean patients presenting with melanonychia at a general dermatology clinic from 2002 to 2014. Lyu et al⁸ studied LM in 172 Chinese patients in a dermatology clinic from 2018 to 2021 and reported 9% (6/66) of adults (aged ≥18 years) with subungual melanoma, with no reported cases in childhood (aged <18 years).

Although the prevalence of subungual melanoma in patients with LM is low, it is an important diagnosis that should not be missed. In confirmed cases of subungual melanoma, two-thirds of lesions manifested as LM.^3,10,11 Thus, LM arising in an adult in a single digit is more concerning for malignancy.^2,3,7,9

Individuals of African and Asian descent as well as American Indian individuals are at highest risk for subungual melanoma with a poor prognosis compared to other types of melanoma, largely due to diagnosis at an advanced stage of disease.^3,9 In a retrospective study of 25 patients with surgically treated subungual melanoma, the mean recurrence-free survival was 33.6 months. The recurrence-free survival was 66% at 1 year and 40% at 3 years, and the overall survival rate was 37% at 3 years.¹²

Key clinical features in individuals with darker skin tones

• In patients with darker skin tones, LM tends to occur on multiple nails as a result of melanocytic activation.^2,13
• Several longitudinal bands may be noted on the same nail and the pigmentation of the bands may vary. With age, these longitudinal bands typically increase in number and width.¹³
• Pseudo-Hutchinson sign may be present due to ethnic melanosis of the proximal nail fold.^13,14
• Dermoscopic findings of LM in patients with skin of color include wider bands (P=.0125), lower band brightness (P<.032), and higher frequency of changing appearance of bands (P=.0071).¹⁵

Worth noting

When patients present with LM, thorough examination of the nail plate, periungual skin, and distal pulp of all digits on all extremities with adequate lighting is important.² Dermoscopy is useful, and a gel interface helps for examining the nail plates.⁷

Clinicians should be encouraged to biopsy or immediately refer patients with concerning nail unit lesions. Cases of LM most likely are benign, but if some doubt exists, the lesions should be biopsied or tracked closely with clinical and dermoscopic images, with a biopsy if changes occur.¹⁶ In conjunction with evaluation by a qualified clinician, patients also should be encouraged to take photographs, as the evolution of nail changes is a critical part of clinical decision-making on the need for a biopsy or referral.

Health disparity highlight

Despite the disproportionately high mortality rates from subungual melanoma in Black and Hispanic populations,^3,9 studies often do not adequately represent these populations. Although subungual melanoma is rare, a delay in the diagnosis contributes to high morbidity and mortality rates.

Some things are universal, or at least worldwide.

She didn’t speak a word of English, but I don’t speak any Mandarin. Fortunately, her concerned son was fluent in both.

A nice lady in her 60s, here from China to visit her son and his family for a month. The visit was going fine until she abruptly developed double vision. Through the modern miracle of email she contacted her doctor in Beijing, who told her to find a neurologist here or go to an ER.

I’d had a last minute cancellation a few minutes before her son called and so was able to see her that afternoon. Both were scared that I was going to admit her to a hospital.

Fortunately, people are wired the same no matter where they’re from. The electrical fibers of the nervous system are predictable across international borders, as are the maladies.

A history and exam made the diagnosis of a diabetic cranial nerve palsy most likely, and I was able to reassure them. I ordered the usual imaging studies (fortunately she’d bought travelers’ insurance in advance). As anticipated, they were normal.

Her son and I spoke by phone to close things out, with her in the background and him translating between us. By the time she left 2 weeks later the symptoms were resolving. I made sure she went home with copies of my notes and the MRI reports, figuring someone there would be able to translate them for her physician.

These sorts of encounters are uncommon in my little solo practice, but still drive home the point that people around the world have more in common than not. Disease prevalence varies by regions, and there are certain genetic issues one has to take into account, but the basic principles of medicine are the same.

Not to mention families. The mother traveling around the world to see her son and grandchildren. The child concerned for the welfare of his parent and helping her get care. These, too, are human universals, regardless of the language spoken. There isn’t a culture on Earth that doesn’t value family connections, nor is there one that didn’t develop (albeit in different forms) doctors.

The human population is 8 billion. Everyone is different, and yet everyone, overall, is the same. Fellow travelers on a small planet.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Some things are universal, or at least worldwide.

She didn’t speak a word of English, but I don’t speak any Mandarin. Fortunately, her concerned son was fluent in both.

A nice lady in her 60s, here from China to visit her son and his family for a month. The visit was going fine until she abruptly developed double vision. Through the modern miracle of email she contacted her doctor in Beijing, who told her to find a neurologist here or go to an ER.

I’d had a last minute cancellation a few minutes before her son called and so was able to see her that afternoon. Both were scared that I was going to admit her to a hospital.

Fortunately, people are wired the same no matter where they’re from. The electrical fibers of the nervous system are predictable across international borders, as are the maladies.

A history and exam made the diagnosis of a diabetic cranial nerve palsy most likely, and I was able to reassure them. I ordered the usual imaging studies (fortunately she’d bought travelers’ insurance in advance). As anticipated, they were normal.

Her son and I spoke by phone to close things out, with her in the background and him translating between us. By the time she left 2 weeks later the symptoms were resolving. I made sure she went home with copies of my notes and the MRI reports, figuring someone there would be able to translate them for her physician.

These sorts of encounters are uncommon in my little solo practice, but still drive home the point that people around the world have more in common than not. Disease prevalence varies by regions, and there are certain genetic issues one has to take into account, but the basic principles of medicine are the same.

Not to mention families. The mother traveling around the world to see her son and grandchildren. The child concerned for the welfare of his parent and helping her get care. These, too, are human universals, regardless of the language spoken. There isn’t a culture on Earth that doesn’t value family connections, nor is there one that didn’t develop (albeit in different forms) doctors.

The human population is 8 billion. Everyone is different, and yet everyone, overall, is the same. Fellow travelers on a small planet.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Some things are universal, or at least worldwide.

She didn’t speak a word of English, but I don’t speak any Mandarin. Fortunately, her concerned son was fluent in both.

A nice lady in her 60s, here from China to visit her son and his family for a month. The visit was going fine until she abruptly developed double vision. Through the modern miracle of email she contacted her doctor in Beijing, who told her to find a neurologist here or go to an ER.

I’d had a last minute cancellation a few minutes before her son called and so was able to see her that afternoon. Both were scared that I was going to admit her to a hospital.

Fortunately, people are wired the same no matter where they’re from. The electrical fibers of the nervous system are predictable across international borders, as are the maladies.

A history and exam made the diagnosis of a diabetic cranial nerve palsy most likely, and I was able to reassure them. I ordered the usual imaging studies (fortunately she’d bought travelers’ insurance in advance). As anticipated, they were normal.

Her son and I spoke by phone to close things out, with her in the background and him translating between us. By the time she left 2 weeks later the symptoms were resolving. I made sure she went home with copies of my notes and the MRI reports, figuring someone there would be able to translate them for her physician.

These sorts of encounters are uncommon in my little solo practice, but still drive home the point that people around the world have more in common than not. Disease prevalence varies by regions, and there are certain genetic issues one has to take into account, but the basic principles of medicine are the same.

Not to mention families. The mother traveling around the world to see her son and grandchildren. The child concerned for the welfare of his parent and helping her get care. These, too, are human universals, regardless of the language spoken. There isn’t a culture on Earth that doesn’t value family connections, nor is there one that didn’t develop (albeit in different forms) doctors.

The human population is 8 billion. Everyone is different, and yet everyone, overall, is the same. Fellow travelers on a small planet.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

This transcript has been edited for clarity.

I’m delighted to talk about a very interesting topic in this commentary. This is an area that we generally don’t discuss, but it’s one that’s obviously very topical, which includes the question of social media.

The paper I’m referring to is entitled, “More Than a Song and Dance”: Exploration of Patient Perspectives and Educational Quality of Gynecologic Cancer Content on TikTok. The paper was published in Gynecologic Oncology in 2023.

The investigators, very interestingly, looked at the most common hashtags for the five most common gynecologic cancers on TikTok. They had a total of 466.7 million views. They looked at 430 of the 500 top posts that were eligible, looked at 11 central themes, did an objective analysis of educational content based on published strategy for looking at this.

What they found, unfortunately but not surprisingly, overall was that the educational quality and reliability were quite poor. They also noticed considerable differences in disparities based on racial background and really emphasized in their analysis not only how common it is for individuals to look at this content on TikTok but also concerns about what it is that the public, patients, and their families are actually seeing.

This, of course, specifically relates to gynecologic cancers, but almost certainly relates to other cancers as well. Clearly, this is a topic that needs to be discussed widely. It’s very complex and very controversial, but when you think about the information that might be provided to our patients and their families going to social media, it’s important that we understand what they’re seeing, what they’re hearing, what they’re viewing, and the impact this might have on their care and outcomes.

I encourage you to read this very interesting paper if you have an interest in this topic. Again, it was recently published in Gynecologic Oncology. I thank you for your attention.

Dr. Markman is professor, Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California; president of Medicine & Science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed ties with GlaxoSmithKline and AstraZeneca.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I’m delighted to talk about a very interesting topic in this commentary. This is an area that we generally don’t discuss, but it’s one that’s obviously very topical, which includes the question of social media.

The paper I’m referring to is entitled, “More Than a Song and Dance”: Exploration of Patient Perspectives and Educational Quality of Gynecologic Cancer Content on TikTok. The paper was published in Gynecologic Oncology in 2023.

The investigators, very interestingly, looked at the most common hashtags for the five most common gynecologic cancers on TikTok. They had a total of 466.7 million views. They looked at 430 of the 500 top posts that were eligible, looked at 11 central themes, did an objective analysis of educational content based on published strategy for looking at this.

What they found, unfortunately but not surprisingly, overall was that the educational quality and reliability were quite poor. They also noticed considerable differences in disparities based on racial background and really emphasized in their analysis not only how common it is for individuals to look at this content on TikTok but also concerns about what it is that the public, patients, and their families are actually seeing.

This, of course, specifically relates to gynecologic cancers, but almost certainly relates to other cancers as well. Clearly, this is a topic that needs to be discussed widely. It’s very complex and very controversial, but when you think about the information that might be provided to our patients and their families going to social media, it’s important that we understand what they’re seeing, what they’re hearing, what they’re viewing, and the impact this might have on their care and outcomes.

I encourage you to read this very interesting paper if you have an interest in this topic. Again, it was recently published in Gynecologic Oncology. I thank you for your attention.

Dr. Markman is professor, Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California; president of Medicine & Science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed ties with GlaxoSmithKline and AstraZeneca.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I’m delighted to talk about a very interesting topic in this commentary. This is an area that we generally don’t discuss, but it’s one that’s obviously very topical, which includes the question of social media.

The paper I’m referring to is entitled, “More Than a Song and Dance”: Exploration of Patient Perspectives and Educational Quality of Gynecologic Cancer Content on TikTok. The paper was published in Gynecologic Oncology in 2023.

The investigators, very interestingly, looked at the most common hashtags for the five most common gynecologic cancers on TikTok. They had a total of 466.7 million views. They looked at 430 of the 500 top posts that were eligible, looked at 11 central themes, did an objective analysis of educational content based on published strategy for looking at this.

What they found, unfortunately but not surprisingly, overall was that the educational quality and reliability were quite poor. They also noticed considerable differences in disparities based on racial background and really emphasized in their analysis not only how common it is for individuals to look at this content on TikTok but also concerns about what it is that the public, patients, and their families are actually seeing.

This, of course, specifically relates to gynecologic cancers, but almost certainly relates to other cancers as well. Clearly, this is a topic that needs to be discussed widely. It’s very complex and very controversial, but when you think about the information that might be provided to our patients and their families going to social media, it’s important that we understand what they’re seeing, what they’re hearing, what they’re viewing, and the impact this might have on their care and outcomes.

I encourage you to read this very interesting paper if you have an interest in this topic. Again, it was recently published in Gynecologic Oncology. I thank you for your attention.

Dr. Markman is professor, Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California; president of Medicine & Science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed ties with GlaxoSmithKline and AstraZeneca.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

The American Cancer Society has just published its cancer statistics for 2024. This is an annual report, the latest version of which has some alarming news for gastroenterologists. Usually, we think of being “number one” as a positive thing, but that’s not the case this year when it comes to the projections for colorectal cancer.

But first, let’s discuss the report’s overall findings. Broadly speaking, the news is quite good in that there’s been an aversion of over 4 million deaths since 1991. That decline over the past four decades is due to reductions in smoking, earlier detection, and improved screening and treatments for localized or metastatic disease. But these gains are now threatened by some offsets that we’re seeing, with increasing rates of six of the top 10 cancers in the past several years.
 

Increasing Rates of Gastrointestinal Cancers

The incidence rate of pancreas cancer has increased from 0.6% to 1% annually.

Pancreas cancer has a 5-year relative survival rate of 13%, which ranks as one of the three worst rates for cancers. This cancer represents a real screening challenge for us, as it typically presents asymptomatically.

Women have experienced a 2%-3% annual increase in incidence rates for liver cancer.

I suspect that this is due to cases of fibrotic liver disease resulting from viral hepatitis and metabolic liver diseases with nonalcoholic fatty liver and advanced fibrosis (F3 and F4). These cases may be carried over from before, thereby contributing to the increasing incremental cancer risk.

We can’t overlook the need for risk reduction here and should focus on applying regular screening efforts in our female patients. However, it’s also true that we require better liver cancer screening tests to accomplish that goal.
 

In Those Under 50, CRC the Leading Cause of Cancer Death in Men, Second in Women

I really want to focus on the news around colorectal cancer.

To put this in perspective, in the late 1990s, colorectal cancer was the fourth leading cause of death in men and women. The current report extrapolated 2024 projections using the Surveillance, Epidemiology, and End Results (SEER) database ending in 2020, which was necessary given the incremental time it takes to develop cancers. The SEER database suggests that in 2024, colorectal cancer in those younger than 50 years of age will become the number-one leading cause of cancer death in men and number-two in women. The increasing incidence of colorectal cancer in younger people is probably the result of a number of epidemiologic and other reasons.

The current report offers evidence of racial disparities in cancer mortality rates in general, which are twofold higher in Black people compared with White people, particularly for gastric cancer. There is also an evident disparity in Native Americans, who have higher rates of gastric and liver cancer. This is a reminder of the increasing need for equity to address racial disparities across these populations.

But returning to colon cancer, it’s a marked change to go from being the fourth-leading cause of cancer death in those younger than 50 years of age to being number one for men and number two for women.

Being “number one” is supposed to make you famous. This “number one,” however, should in fact be infamous. It’s a travesty, because colorectal cancer is a potentially preventable disease.

As we move into March, which happens to be Colorectal Cancer Awareness Month, hopefully this fires up some of the conversations you have with your younger at-risk population, who may be reticent or resistant to colorectal cancer screening.

We have to do better at getting this message out to that population at large. “Number one” is not where we want to be for this potentially preventable problem.
 

Dr. Johnson is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease. He has disclosed ties with ISOTHRIVE and Johnson & Johnson.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

The American Cancer Society has just published its cancer statistics for 2024. This is an annual report, the latest version of which has some alarming news for gastroenterologists. Usually, we think of being “number one” as a positive thing, but that’s not the case this year when it comes to the projections for colorectal cancer.

But first, let’s discuss the report’s overall findings. Broadly speaking, the news is quite good in that there’s been an aversion of over 4 million deaths since 1991. That decline over the past four decades is due to reductions in smoking, earlier detection, and improved screening and treatments for localized or metastatic disease. But these gains are now threatened by some offsets that we’re seeing, with increasing rates of six of the top 10 cancers in the past several years.
 

Increasing Rates of Gastrointestinal Cancers

The incidence rate of pancreas cancer has increased from 0.6% to 1% annually.

Pancreas cancer has a 5-year relative survival rate of 13%, which ranks as one of the three worst rates for cancers. This cancer represents a real screening challenge for us, as it typically presents asymptomatically.

Women have experienced a 2%-3% annual increase in incidence rates for liver cancer.

I suspect that this is due to cases of fibrotic liver disease resulting from viral hepatitis and metabolic liver diseases with nonalcoholic fatty liver and advanced fibrosis (F3 and F4). These cases may be carried over from before, thereby contributing to the increasing incremental cancer risk.

We can’t overlook the need for risk reduction here and should focus on applying regular screening efforts in our female patients. However, it’s also true that we require better liver cancer screening tests to accomplish that goal.
 

In Those Under 50, CRC the Leading Cause of Cancer Death in Men, Second in Women

I really want to focus on the news around colorectal cancer.

To put this in perspective, in the late 1990s, colorectal cancer was the fourth leading cause of death in men and women. The current report extrapolated 2024 projections using the Surveillance, Epidemiology, and End Results (SEER) database ending in 2020, which was necessary given the incremental time it takes to develop cancers. The SEER database suggests that in 2024, colorectal cancer in those younger than 50 years of age will become the number-one leading cause of cancer death in men and number-two in women. The increasing incidence of colorectal cancer in younger people is probably the result of a number of epidemiologic and other reasons.

The current report offers evidence of racial disparities in cancer mortality rates in general, which are twofold higher in Black people compared with White people, particularly for gastric cancer. There is also an evident disparity in Native Americans, who have higher rates of gastric and liver cancer. This is a reminder of the increasing need for equity to address racial disparities across these populations.

But returning to colon cancer, it’s a marked change to go from being the fourth-leading cause of cancer death in those younger than 50 years of age to being number one for men and number two for women.

Being “number one” is supposed to make you famous. This “number one,” however, should in fact be infamous. It’s a travesty, because colorectal cancer is a potentially preventable disease.

As we move into March, which happens to be Colorectal Cancer Awareness Month, hopefully this fires up some of the conversations you have with your younger at-risk population, who may be reticent or resistant to colorectal cancer screening.

We have to do better at getting this message out to that population at large. “Number one” is not where we want to be for this potentially preventable problem.
 

Dr. Johnson is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease. He has disclosed ties with ISOTHRIVE and Johnson & Johnson.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

The American Cancer Society has just published its cancer statistics for 2024. This is an annual report, the latest version of which has some alarming news for gastroenterologists. Usually, we think of being “number one” as a positive thing, but that’s not the case this year when it comes to the projections for colorectal cancer.

But first, let’s discuss the report’s overall findings. Broadly speaking, the news is quite good in that there’s been an aversion of over 4 million deaths since 1991. That decline over the past four decades is due to reductions in smoking, earlier detection, and improved screening and treatments for localized or metastatic disease. But these gains are now threatened by some offsets that we’re seeing, with increasing rates of six of the top 10 cancers in the past several years.
 

Increasing Rates of Gastrointestinal Cancers

The incidence rate of pancreas cancer has increased from 0.6% to 1% annually.

Pancreas cancer has a 5-year relative survival rate of 13%, which ranks as one of the three worst rates for cancers. This cancer represents a real screening challenge for us, as it typically presents asymptomatically.

Women have experienced a 2%-3% annual increase in incidence rates for liver cancer.

I suspect that this is due to cases of fibrotic liver disease resulting from viral hepatitis and metabolic liver diseases with nonalcoholic fatty liver and advanced fibrosis (F3 and F4). These cases may be carried over from before, thereby contributing to the increasing incremental cancer risk.

We can’t overlook the need for risk reduction here and should focus on applying regular screening efforts in our female patients. However, it’s also true that we require better liver cancer screening tests to accomplish that goal.
 

In Those Under 50, CRC the Leading Cause of Cancer Death in Men, Second in Women

I really want to focus on the news around colorectal cancer.

To put this in perspective, in the late 1990s, colorectal cancer was the fourth leading cause of death in men and women. The current report extrapolated 2024 projections using the Surveillance, Epidemiology, and End Results (SEER) database ending in 2020, which was necessary given the incremental time it takes to develop cancers. The SEER database suggests that in 2024, colorectal cancer in those younger than 50 years of age will become the number-one leading cause of cancer death in men and number-two in women. The increasing incidence of colorectal cancer in younger people is probably the result of a number of epidemiologic and other reasons.

The current report offers evidence of racial disparities in cancer mortality rates in general, which are twofold higher in Black people compared with White people, particularly for gastric cancer. There is also an evident disparity in Native Americans, who have higher rates of gastric and liver cancer. This is a reminder of the increasing need for equity to address racial disparities across these populations.

But returning to colon cancer, it’s a marked change to go from being the fourth-leading cause of cancer death in those younger than 50 years of age to being number one for men and number two for women.

Being “number one” is supposed to make you famous. This “number one,” however, should in fact be infamous. It’s a travesty, because colorectal cancer is a potentially preventable disease.

As we move into March, which happens to be Colorectal Cancer Awareness Month, hopefully this fires up some of the conversations you have with your younger at-risk population, who may be reticent or resistant to colorectal cancer screening.

We have to do better at getting this message out to that population at large. “Number one” is not where we want to be for this potentially preventable problem.
 

Dr. Johnson is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease. He has disclosed ties with ISOTHRIVE and Johnson & Johnson.

A version of this article appeared on Medscape.com.

In my previous article, “Mental Health Characteristics of Refugee Children,” we learned that in recent decades, refugeeism has become a growing problem that disproportionately affects children. Refugee children and their families experience a variety of traumas, often sustained across years and even decades, because of armed conflict, persecution, social upheavals, or environmental disasters. Refugees are at greater risks for PTSD and affective and psychotic disorders presumably due to increased traumatic life events before, during, and after migration. I used my own experience as a child refugee from Vietnam to elucidate the stressors evident in various phases of forced displacement.¹

Risk Factors and Protective Factors

To a certain extent, the experiences of refugees are universal. All refugees experience some sort of humanitarian crisis that forces an emergent escape from their home across international borders to a new resettlement area. It is important to note that internally displaced people do not meet the United Nations’ (UN) official designation of refugee status; however, some agencies use a broader definition where they are designated as such.^2,3 We will refer to those not meeting the UN criteria as displaced people, while refugees are those that do meet the UN criteria. Dr. Mina Fazel’s 2012 systematic review in The Lancet of mental health risk factors and protective factors for displaced and refugee children is the most comprehensive of its kind.⁴ It will be summarized in this section with some relevant personal reflection.

In terms of risk factors, external displacement likely results in additional stress and trauma, presumably from the lack of assess to one’s culture and the host country’s language. Understandably, this makes rebuilding of one’s life more difficult. Several studies show that displaced/refugee children experience more difficulty with psychosocial adaptation than non-displaced children. Violence, directly experienced or indirectly feared, both to the child and their parents, was the strongest predictor of mental health problems and withdrawn behavior. Children who were separated from their parents clearly fared worst in their mental health than those who did not, which is not surprising given the nature of their dependence on caregivers for protection and guidance. During resettlement, experienced or perceived discrimination from the host country was also a risk factor, as well as instability in housing and a drawn-out resettlement process. Female sex was a risk factor mainly for emotional problems. Poor financial support post-migration is associated with depression, but it is unclear whether pre-migration financial status was protective. From my own experience, it is likely not, given that once one becomes a refugee one does not have access to one’s wealth, except that which could be hidden on one’s body. Another risk factor was also if one’s parent had psychiatric problems or was single. Due to the migration, my mother was separated permanently from her husband, which caused her extraordinary isolation and loneliness, something that was palpably felt by myself as I grew up.

In terms of protective factors, family cohesion and cultural continuity appear critical. For myself, not only would I not have survived without my mother and aunt, but they constantly protected me from the harsh realities. My mother would distract me with seemingly trivial goals once we got to America, like finally tasting a hamburger, or talking about school and being reunited with my uncle. This is in line with another finding — that children have better mental health outcomes when their parents do not talk about their hardships. Once my family was resettled with my uncle and his family, they played a critical role in smoothing our transition, not only by providing us with housing, but also cultural knowledge. Cultural havens can restore some of the social position and way of life that refugees lose when they are able to reconnect with a society that recognizes their previous achievements and status. Finally, religion also seemed to be a protective factor.
 

Mental Health Interventions

In 2018, Dr. Fazel identified mental health interventions for refugee children in a narrative review.⁵ She acknowledged that these conclusions are limited by the paucity of preventive mental health research in children in general, as well as the mobile nature and complex cultural differences of refugee children. This is exacerbated by the small evidence base. Given that, she makes these recommendations for varying levels of interventions: individual, group, family, living circumstances, social interactions, and school.

On an individual level, effective interventions developed to address PTSD include narrative exposure therapy, trauma-focused cognitive behavior therapy, and eye-movement and desensitization therapy. Group-based interventions for trauma, for example school-based PTSD intervention programs in conflicted areas, have either been shown to not be effective, or only effective for reducing depression. The mental health of unaccompanied children separated from family fare better when placed in foster care, rather than other types of social support. This is further enhanced if the foster family is the same ethnicity.

On a family level, improvements in parenting style and parental mental health, family engagement with local culture and structures, and family-based mental health interventions all positively impact refugee children. Not surprisingly, refugee parents have a greater prevalence of mental health conditions. Several studies on refugeeism point out a greater occurrence of intimate partner violence (that negatively affects children) as well has harsher discipline and maltreatment of refugee children. Thus, mental health treatment for parents also directly improves the well-being of their children. Teaching parenting skills to mitigate the violent effect of their PTSD symptoms, as well as parenting classes that teach gentler styles, have been shown to reduce harsh parenting and mitigate aggressive behaviors in these children. These improvements are enhanced when these classes are taught by other refugees themselves.

School is key for helping refugee children since it is a site where they can access language proficiency, successful acculturation, and medical and mental health services. Several studies have identified the positive effects of better parental engagement with school, resulting in improved academic performance and reduced levels of depressive and PTSD symptoms. A review of learning problems in refugee children identified several factors for success. These include high academic and life ambition, parental involvement in education, accurate educational assessment and grade placement, teacher understanding of linguistic and cultural heritage, culturally appropriate school transition, supportive peer relationships, and successful acculturation. School certainly was key for my acculturation and language proficiency. When I arrived at 6 years old I was selectively mute for my year in first grade, namely because I did not know how to speak English and because I did not share the culture. However, my teacher correctly identified my deficiency and chose to place me in kindergarten, which allowed me the time to gain English proficiency. Though I was always the oldest one in class, that remediation was key in allowing eventual success in school leading up to my admission to UC Berkeley.
 

Summary

In recent decades, refugeeism has become a growing problem that disproportionately affects children leading to traumas sustained across years and even decades, and greater risks for PTSD, as well as affective and psychotic disorders. Risk factors include the experience of violence, the separation from family, female gender, discrimination in the host country, unstable housing, and a drawn-out resettlement process. Protective factors consist of family cohesion, cultural continuity, support at schools, being protected from the truth of their harsh reality, stable housing, language acquisition, and quick resettlement. From these factors, effective mental interventions have been found to be the promotion of these protective factors as well as support for parental mental health and parenting skills, better parental engagement at school, and schools that correctly identify and address these children’s educational needs.

Dr. Nguyen is a second-year resident at UCSF Fresno Psychiatry Residency. He was a public high school English teacher for 15 years previously.*

References

1. Nguyen D. Mental Health Characteristics of Refugee Children. Pediatric News. 2023 Nov. 14. https://www.mdedge.com/pediatrics/article/266518/mental-health/mental-health-characteristics-refugee-children.

2. Office of the United Nations High Commissioner for Refugees. The Refugee Concept Under International Law. Global Compact for Safe, Orderly and Regular Migration. 2018 March 8. https://www.unhcr.org/sites/default/files/legacy-pdf/5aa290937.pdf.

3. Winer JP. Mental Health Practice with Immigrant and Refugee Youth [Power Point Slides]. Michigan Medicine. 2021 June 24. https://www.youtube.com/watch?v=ICkg4132SQY

4. Fazel M et al. Mental Health of Displaced and Refugee Children Resettled in High-Income Countries: Risk and Protective Factors. Lancet. 2012 Jan 21;379(9812):266-282. doi: 10.1016/S0140-6736(11)60051-2.

5. Fazel M, Betancourt TS. Preventive Mental Health Interventions for Refugee Children and Adolescents in High-Income Settings. Lancet Child Adolesc Health. 2018 Feb;2(2):121-132. doi: 10.1016/S2352-4642(17)30147-5.

*Correction, 2/27: An earlier version of this article misstated Dr. Nguyen's affiliation.

In my previous article, “Mental Health Characteristics of Refugee Children,” we learned that in recent decades, refugeeism has become a growing problem that disproportionately affects children. Refugee children and their families experience a variety of traumas, often sustained across years and even decades, because of armed conflict, persecution, social upheavals, or environmental disasters. Refugees are at greater risks for PTSD and affective and psychotic disorders presumably due to increased traumatic life events before, during, and after migration. I used my own experience as a child refugee from Vietnam to elucidate the stressors evident in various phases of forced displacement.¹

Risk Factors and Protective Factors

To a certain extent, the experiences of refugees are universal. All refugees experience some sort of humanitarian crisis that forces an emergent escape from their home across international borders to a new resettlement area. It is important to note that internally displaced people do not meet the United Nations’ (UN) official designation of refugee status; however, some agencies use a broader definition where they are designated as such.^2,3 We will refer to those not meeting the UN criteria as displaced people, while refugees are those that do meet the UN criteria. Dr. Mina Fazel’s 2012 systematic review in The Lancet of mental health risk factors and protective factors for displaced and refugee children is the most comprehensive of its kind.⁴ It will be summarized in this section with some relevant personal reflection.

In terms of risk factors, external displacement likely results in additional stress and trauma, presumably from the lack of assess to one’s culture and the host country’s language. Understandably, this makes rebuilding of one’s life more difficult. Several studies show that displaced/refugee children experience more difficulty with psychosocial adaptation than non-displaced children. Violence, directly experienced or indirectly feared, both to the child and their parents, was the strongest predictor of mental health problems and withdrawn behavior. Children who were separated from their parents clearly fared worst in their mental health than those who did not, which is not surprising given the nature of their dependence on caregivers for protection and guidance. During resettlement, experienced or perceived discrimination from the host country was also a risk factor, as well as instability in housing and a drawn-out resettlement process. Female sex was a risk factor mainly for emotional problems. Poor financial support post-migration is associated with depression, but it is unclear whether pre-migration financial status was protective. From my own experience, it is likely not, given that once one becomes a refugee one does not have access to one’s wealth, except that which could be hidden on one’s body. Another risk factor was also if one’s parent had psychiatric problems or was single. Due to the migration, my mother was separated permanently from her husband, which caused her extraordinary isolation and loneliness, something that was palpably felt by myself as I grew up.

In terms of protective factors, family cohesion and cultural continuity appear critical. For myself, not only would I not have survived without my mother and aunt, but they constantly protected me from the harsh realities. My mother would distract me with seemingly trivial goals once we got to America, like finally tasting a hamburger, or talking about school and being reunited with my uncle. This is in line with another finding — that children have better mental health outcomes when their parents do not talk about their hardships. Once my family was resettled with my uncle and his family, they played a critical role in smoothing our transition, not only by providing us with housing, but also cultural knowledge. Cultural havens can restore some of the social position and way of life that refugees lose when they are able to reconnect with a society that recognizes their previous achievements and status. Finally, religion also seemed to be a protective factor.
 

Mental Health Interventions

In 2018, Dr. Fazel identified mental health interventions for refugee children in a narrative review.⁵ She acknowledged that these conclusions are limited by the paucity of preventive mental health research in children in general, as well as the mobile nature and complex cultural differences of refugee children. This is exacerbated by the small evidence base. Given that, she makes these recommendations for varying levels of interventions: individual, group, family, living circumstances, social interactions, and school.

On an individual level, effective interventions developed to address PTSD include narrative exposure therapy, trauma-focused cognitive behavior therapy, and eye-movement and desensitization therapy. Group-based interventions for trauma, for example school-based PTSD intervention programs in conflicted areas, have either been shown to not be effective, or only effective for reducing depression. The mental health of unaccompanied children separated from family fare better when placed in foster care, rather than other types of social support. This is further enhanced if the foster family is the same ethnicity.

On a family level, improvements in parenting style and parental mental health, family engagement with local culture and structures, and family-based mental health interventions all positively impact refugee children. Not surprisingly, refugee parents have a greater prevalence of mental health conditions. Several studies on refugeeism point out a greater occurrence of intimate partner violence (that negatively affects children) as well has harsher discipline and maltreatment of refugee children. Thus, mental health treatment for parents also directly improves the well-being of their children. Teaching parenting skills to mitigate the violent effect of their PTSD symptoms, as well as parenting classes that teach gentler styles, have been shown to reduce harsh parenting and mitigate aggressive behaviors in these children. These improvements are enhanced when these classes are taught by other refugees themselves.

School is key for helping refugee children since it is a site where they can access language proficiency, successful acculturation, and medical and mental health services. Several studies have identified the positive effects of better parental engagement with school, resulting in improved academic performance and reduced levels of depressive and PTSD symptoms. A review of learning problems in refugee children identified several factors for success. These include high academic and life ambition, parental involvement in education, accurate educational assessment and grade placement, teacher understanding of linguistic and cultural heritage, culturally appropriate school transition, supportive peer relationships, and successful acculturation. School certainly was key for my acculturation and language proficiency. When I arrived at 6 years old I was selectively mute for my year in first grade, namely because I did not know how to speak English and because I did not share the culture. However, my teacher correctly identified my deficiency and chose to place me in kindergarten, which allowed me the time to gain English proficiency. Though I was always the oldest one in class, that remediation was key in allowing eventual success in school leading up to my admission to UC Berkeley.
 

Summary

In recent decades, refugeeism has become a growing problem that disproportionately affects children leading to traumas sustained across years and even decades, and greater risks for PTSD, as well as affective and psychotic disorders. Risk factors include the experience of violence, the separation from family, female gender, discrimination in the host country, unstable housing, and a drawn-out resettlement process. Protective factors consist of family cohesion, cultural continuity, support at schools, being protected from the truth of their harsh reality, stable housing, language acquisition, and quick resettlement. From these factors, effective mental interventions have been found to be the promotion of these protective factors as well as support for parental mental health and parenting skills, better parental engagement at school, and schools that correctly identify and address these children’s educational needs.

Dr. Nguyen is a second-year resident at UCSF Fresno Psychiatry Residency. He was a public high school English teacher for 15 years previously.*

References

1. Nguyen D. Mental Health Characteristics of Refugee Children. Pediatric News. 2023 Nov. 14. https://www.mdedge.com/pediatrics/article/266518/mental-health/mental-health-characteristics-refugee-children.

2. Office of the United Nations High Commissioner for Refugees. The Refugee Concept Under International Law. Global Compact for Safe, Orderly and Regular Migration. 2018 March 8. https://www.unhcr.org/sites/default/files/legacy-pdf/5aa290937.pdf.

3. Winer JP. Mental Health Practice with Immigrant and Refugee Youth [Power Point Slides]. Michigan Medicine. 2021 June 24. https://www.youtube.com/watch?v=ICkg4132SQY

4. Fazel M et al. Mental Health of Displaced and Refugee Children Resettled in High-Income Countries: Risk and Protective Factors. Lancet. 2012 Jan 21;379(9812):266-282. doi: 10.1016/S0140-6736(11)60051-2.

5. Fazel M, Betancourt TS. Preventive Mental Health Interventions for Refugee Children and Adolescents in High-Income Settings. Lancet Child Adolesc Health. 2018 Feb;2(2):121-132. doi: 10.1016/S2352-4642(17)30147-5.

*Correction, 2/27: An earlier version of this article misstated Dr. Nguyen's affiliation.

In my previous article, “Mental Health Characteristics of Refugee Children,” we learned that in recent decades, refugeeism has become a growing problem that disproportionately affects children. Refugee children and their families experience a variety of traumas, often sustained across years and even decades, because of armed conflict, persecution, social upheavals, or environmental disasters. Refugees are at greater risks for PTSD and affective and psychotic disorders presumably due to increased traumatic life events before, during, and after migration. I used my own experience as a child refugee from Vietnam to elucidate the stressors evident in various phases of forced displacement.¹

Risk Factors and Protective Factors

To a certain extent, the experiences of refugees are universal. All refugees experience some sort of humanitarian crisis that forces an emergent escape from their home across international borders to a new resettlement area. It is important to note that internally displaced people do not meet the United Nations’ (UN) official designation of refugee status; however, some agencies use a broader definition where they are designated as such.^2,3 We will refer to those not meeting the UN criteria as displaced people, while refugees are those that do meet the UN criteria. Dr. Mina Fazel’s 2012 systematic review in The Lancet of mental health risk factors and protective factors for displaced and refugee children is the most comprehensive of its kind.⁴ It will be summarized in this section with some relevant personal reflection.

In terms of risk factors, external displacement likely results in additional stress and trauma, presumably from the lack of assess to one’s culture and the host country’s language. Understandably, this makes rebuilding of one’s life more difficult. Several studies show that displaced/refugee children experience more difficulty with psychosocial adaptation than non-displaced children. Violence, directly experienced or indirectly feared, both to the child and their parents, was the strongest predictor of mental health problems and withdrawn behavior. Children who were separated from their parents clearly fared worst in their mental health than those who did not, which is not surprising given the nature of their dependence on caregivers for protection and guidance. During resettlement, experienced or perceived discrimination from the host country was also a risk factor, as well as instability in housing and a drawn-out resettlement process. Female sex was a risk factor mainly for emotional problems. Poor financial support post-migration is associated with depression, but it is unclear whether pre-migration financial status was protective. From my own experience, it is likely not, given that once one becomes a refugee one does not have access to one’s wealth, except that which could be hidden on one’s body. Another risk factor was also if one’s parent had psychiatric problems or was single. Due to the migration, my mother was separated permanently from her husband, which caused her extraordinary isolation and loneliness, something that was palpably felt by myself as I grew up.

In terms of protective factors, family cohesion and cultural continuity appear critical. For myself, not only would I not have survived without my mother and aunt, but they constantly protected me from the harsh realities. My mother would distract me with seemingly trivial goals once we got to America, like finally tasting a hamburger, or talking about school and being reunited with my uncle. This is in line with another finding — that children have better mental health outcomes when their parents do not talk about their hardships. Once my family was resettled with my uncle and his family, they played a critical role in smoothing our transition, not only by providing us with housing, but also cultural knowledge. Cultural havens can restore some of the social position and way of life that refugees lose when they are able to reconnect with a society that recognizes their previous achievements and status. Finally, religion also seemed to be a protective factor.
 

Mental Health Interventions

In 2018, Dr. Fazel identified mental health interventions for refugee children in a narrative review.⁵ She acknowledged that these conclusions are limited by the paucity of preventive mental health research in children in general, as well as the mobile nature and complex cultural differences of refugee children. This is exacerbated by the small evidence base. Given that, she makes these recommendations for varying levels of interventions: individual, group, family, living circumstances, social interactions, and school.

On an individual level, effective interventions developed to address PTSD include narrative exposure therapy, trauma-focused cognitive behavior therapy, and eye-movement and desensitization therapy. Group-based interventions for trauma, for example school-based PTSD intervention programs in conflicted areas, have either been shown to not be effective, or only effective for reducing depression. The mental health of unaccompanied children separated from family fare better when placed in foster care, rather than other types of social support. This is further enhanced if the foster family is the same ethnicity.

On a family level, improvements in parenting style and parental mental health, family engagement with local culture and structures, and family-based mental health interventions all positively impact refugee children. Not surprisingly, refugee parents have a greater prevalence of mental health conditions. Several studies on refugeeism point out a greater occurrence of intimate partner violence (that negatively affects children) as well has harsher discipline and maltreatment of refugee children. Thus, mental health treatment for parents also directly improves the well-being of their children. Teaching parenting skills to mitigate the violent effect of their PTSD symptoms, as well as parenting classes that teach gentler styles, have been shown to reduce harsh parenting and mitigate aggressive behaviors in these children. These improvements are enhanced when these classes are taught by other refugees themselves.

School is key for helping refugee children since it is a site where they can access language proficiency, successful acculturation, and medical and mental health services. Several studies have identified the positive effects of better parental engagement with school, resulting in improved academic performance and reduced levels of depressive and PTSD symptoms. A review of learning problems in refugee children identified several factors for success. These include high academic and life ambition, parental involvement in education, accurate educational assessment and grade placement, teacher understanding of linguistic and cultural heritage, culturally appropriate school transition, supportive peer relationships, and successful acculturation. School certainly was key for my acculturation and language proficiency. When I arrived at 6 years old I was selectively mute for my year in first grade, namely because I did not know how to speak English and because I did not share the culture. However, my teacher correctly identified my deficiency and chose to place me in kindergarten, which allowed me the time to gain English proficiency. Though I was always the oldest one in class, that remediation was key in allowing eventual success in school leading up to my admission to UC Berkeley.
 

Summary

In recent decades, refugeeism has become a growing problem that disproportionately affects children leading to traumas sustained across years and even decades, and greater risks for PTSD, as well as affective and psychotic disorders. Risk factors include the experience of violence, the separation from family, female gender, discrimination in the host country, unstable housing, and a drawn-out resettlement process. Protective factors consist of family cohesion, cultural continuity, support at schools, being protected from the truth of their harsh reality, stable housing, language acquisition, and quick resettlement. From these factors, effective mental interventions have been found to be the promotion of these protective factors as well as support for parental mental health and parenting skills, better parental engagement at school, and schools that correctly identify and address these children’s educational needs.

Dr. Nguyen is a second-year resident at UCSF Fresno Psychiatry Residency. He was a public high school English teacher for 15 years previously.*

References

1. Nguyen D. Mental Health Characteristics of Refugee Children. Pediatric News. 2023 Nov. 14. https://www.mdedge.com/pediatrics/article/266518/mental-health/mental-health-characteristics-refugee-children.

2. Office of the United Nations High Commissioner for Refugees. The Refugee Concept Under International Law. Global Compact for Safe, Orderly and Regular Migration. 2018 March 8. https://www.unhcr.org/sites/default/files/legacy-pdf/5aa290937.pdf.

3. Winer JP. Mental Health Practice with Immigrant and Refugee Youth [Power Point Slides]. Michigan Medicine. 2021 June 24. https://www.youtube.com/watch?v=ICkg4132SQY

4. Fazel M et al. Mental Health of Displaced and Refugee Children Resettled in High-Income Countries: Risk and Protective Factors. Lancet. 2012 Jan 21;379(9812):266-282. doi: 10.1016/S0140-6736(11)60051-2.

5. Fazel M, Betancourt TS. Preventive Mental Health Interventions for Refugee Children and Adolescents in High-Income Settings. Lancet Child Adolesc Health. 2018 Feb;2(2):121-132. doi: 10.1016/S2352-4642(17)30147-5.

*Correction, 2/27: An earlier version of this article misstated Dr. Nguyen's affiliation.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

This article was originally published on February 10 in Eric Topol’s substack “Ground Truths.”

It’s astounding how devious cancer cells and tumor tissue can be. This week in Science we learned how certain lung cancer cells can function like “Catch Me If You Can” — changing their driver mutation and cell identity to escape targeted therapy. This histologic transformation, as seen in an experimental model, is just one of so many cancer tricks that we are learning about.

Recently, as shown by single-cell sequencing, cancer cells can steal the mitochondria from T cells, a double whammy that turbocharges cancer cells with the hijacked fuel supply and, at the same time, dismantles the immune response.

Last week, we saw how tumor cells can release a virus-like protein that unleashes a vicious autoimmune response.

And then there’s the finding that cancer cell spread predominantly is occurring while we sleep.

As I previously reviewed, the ability for cancer cells to hijack neurons and neural circuits is now well established, no less their ability to reprogram neurons to become adrenergic and stimulate tumor progression, and interfere with the immune response. Stay tuned on that for a new Ground Truths podcast with Prof Michelle Monje, a leader in cancer neuroscience, which will post soon.

Add advancing age’s immunosenescence as yet another challenge to the long and growing list of formidable ways that cancer cells, and the tumor microenvironment, evade our immune response.

An Ever-Expanding Armamentarium

All of this is telling us how we need to ramp up our game if we are going to be able to use our immune system to quash a cancer. Fortunately, we have abundant and ever-growing capabilities for doing just that.

Immune Checkpoint Inhibitors

The field of immunotherapies took off with the immune checkpoint inhibitors, first approved by the FDA in 2011, that take the brakes off of T cells, with the programmed death-1 (PD-1), PD-ligand1, and anti-CTLA-4 monoclonal antibodies.

But we’re clearly learning they are not enough to prevail over cancer with common recurrences, only short term success in most patients, with some notable exceptions. Adding other immune response strategies, such as a vaccine, or antibody-drug conjugates, or engineered T cells, are showing improved chances for success.

Therapeutic Cancer Vaccines

There are many therapeutic cancer vaccines in the works, as reviewed in depth here.

Here’s a list of ongoing clinical trials of cancer vaccines. You’ll note most of these are on top of a checkpoint inhibitor and use personalized neoantigens (cancer cell surface proteins) derived from sequencing (whole-exome or whole genome, RNA-sequencing and HLA-profiling) the patient’s tumor.

An example of positive findings is with the combination of an mRNA-nanoparticle vaccine with up to 34 personalized neoantigens and pembrolizumab (Keytruda) vs pembrolizumab alone in advanced melanoma after resection, with improved outcomes at 3-year follow-up, cutting death or relapse rate in half.

Antibody-Drug Conjugates (ADC)

There is considerable excitement about antibody-drug conjugates (ADC) whereby a linker is used to attach a chemotherapy agent to the checkpoint inhibitor antibody, specifically targeting the cancer cell and facilitating entry of the chemotherapy into the cell. Akin to these are bispecific antibodies (BiTEs, binding to a tumor antigen and T cell receptor simultaneously), both of these conjugates acting as “biologic” or “guided” missiles.

A very good example of the potency of an ADC was seen in a “HER2-low” breast cancer randomized trial. The absence or very low expression or amplification of the HER2 receptor is common in breast cancer and successful treatment has been elusive. A randomized trial of an ADC (trastuzumab deruxtecan) compared to physician’s choice therapy demonstrated a marked success for progression-free survival in HER2-low patients, which was characterized as “unheard-of success” by media coverage.

This strategy is being used to target some of the most difficult cancer driver mutations such as TP53 and KRAS.

Oncolytic Viruses

Modifying viruses to infect the tumor and make it more visible to the immune system, potentiating anti-tumor responses, known as oncolytic viruses, have been proposed as a way to rev up the immune response for a long time but without positive Phase 3 clinical trials.

After decades of failure, a recent trial in refractory bladder cancer showed marked success, along with others, summarized here, now providing very encouraging results. It looks like oncolytic viruses are on a comeback path.

Engineering T Cells (Chimeric Antigen Receptor [CAR-T])

As I recently reviewed, there are over 500 ongoing clinical trials to build on the success of the first CAR-T approval for leukemia 7 years ago. I won’t go through that all again here, but to reiterate most of the success to date has been in “liquid” blood (leukemia and lymphoma) cancer tumors. This week in Nature is the discovery of a T cell cancer mutation, a gene fusion CARD11-PIK3R3, from a T cell lymphoma that can potentially be used to augment CAR-T efficacy. It has pronounced and prolonged effects in the experimental model. Instead of 1 million cells needed for treatment, even 20,000 were enough to melt the tumor. This is a noteworthy discovery since CAR-T work to date has largely not exploited such naturally occurring mutations, while instead concentrating on those seen in the patient’s set of key tumor mutations.

As currently conceived, CAR-T, and what is being referred to more broadly as adoptive cell therapies, involves removing T cells from the patient’s body and engineering their activation, then reintroducing them back to the patient. This is laborious, technically difficult, and very expensive. Recently, the idea of achieving all of this via an injection of virus that specifically infects T cells and inserts the genes needed, was advanced by two biotech companies with preclinical results, one in non-human primates.

Gearing up to meet the challenge of solid tumor CAR-T intervention, there’s more work using CRISPR genome editing of T cell receptors. A.I. is increasingly being exploited to process the data from sequencing and identify optimal neoantigens.

Instead of just CAR-T, we’re seeing the emergence of CAR-macrophage and CAR-natural killer (NK) cells strategies, and rapidly expanding potential combinations of all the strategies I’ve mentioned. No less, there’s been maturation of on-off suicide switches programmed in, to limit cytokine release and promote safety of these interventions. Overall, major side effects of immunotherapies are not only cytokine release syndromes, but also include interstitial pneumonitis and neurotoxicity.

Summary

Given the multitude of ways cancer cells and tumor tissue can evade our immune response, durably successful treatment remains a daunting challenge. But the ingenuity of so many different approaches to unleash our immune response, and their combinations, provides considerable hope that we’ll increasingly meet the challenge in the years ahead. We have clearly learned that combining different immunotherapy strategies will be essential for many patients with the most resilient solid tumors.

Of concern, as noted by a recent editorial in The Lancet, entitled “Cancer Research Equity: Innovations For The Many, Not The Few,” is that these individualized, sophisticated strategies are not scalable; they will have limited reach and benefit. The movement towards “off the shelf” CAR-T and inexpensive, orally active checkpoint inhibitors may help mitigate this issue.

Notwithstanding this important concern, we’re seeing an array of diverse and potent immunotherapy strategies that are providing highly encouraging results, engendering more excitement than we’ve seen in this space for some time. These should propel substantial improvements in outcomes for patients in the years ahead. It can’t happen soon enough.

Thanks for reading this edition of Ground Truths. If you found it informative, please share it with your colleagues.

Dr. Topol has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for Dexcom; Illumina; Molecular Stethoscope; Quest Diagnostics; Blue Cross Blue Shield Association. Received research grant from National Institutes of Health.

A version of this article appeared on Medscape.com.

“He was one of those fresh Jewish types you want to kill at sight ... she on the other hand looked Italian, a goaty slant to her eyes ... She looked dirty. So did he ... And she smelled, the usual smell of sweat and dirt you find among people who habitually do not wash or bathe ... People like that belong in clinics ... Just dumb oxen. Why the hell do they let them into the country? Half idiots at best.”

Who wrote that? Some hate-mongering pundit on a cable channel? A Twitter troll?

Nope. It was William Carlos Williams, MD, the patron saint of physician-writers.

You’re thinking “No! Not him!” We all read “The Use of Force” and “Red Wheelbarrow” in high school or college. But this blatant anti-Semitism and xenophobia?

The short story is “A Face of Stone” from his collection “The Doctor Stories” (highly recommended). When Williams was asked to remove those parts before publication, he refused because they’re a key part of the story. And I agree with him.

The point, as in so much of life, is the big picture. Despite his vivid disgust, he examines their infant, reassuring the mother that everything is okay, and later helping her with her leg pain and walking difficulties. At the end of the short story he realizes that his impressions were wrong and that people he started out hating are, well, just people who need help. And, as doctors, isn’t helping what we’re here to do?

It’s not just Williams, it’s all of us. First impressions aren’t always correct, but we rely on them — a lot. We’re programmed to. Our ancestors in the caves didn’t have much time to decided friend or foe when they encountered others.

So we initially judge people on their faces, expressions, hair, clothes, religious symbols (if present), jewelry ... The things that are registered by the brain in a split-second before the first words are exchanged.

All of us are constantly “scanning” others we encounter. In the office, store, restaurant, whatever. Usually those impressions are fleeting as we forget that person within a minute or two since we don’t see them again. But as doctors we do get to know them as patients, and so are constantly “updating” our mental files as new information comes in.

As Williams tells the story, he realizes that the “face of stone” isn’t that of the young mother he mentally derided — it’s his own face, turned that way by his first dismissive impression of the family, and then melted as he realizes he was wrong and learns from the experience to be a better doctor.

In vivid terms he reminds us that, although doctors, we are still susceptible to the same foibles, errors, and incorrect snap-judgments that all people are, but what matters is that we can, and have to, overcome them.

As a wall plaque in St. Mary’s General Hospital in Passaic, New Jersey, reminds us: “We walk the wards that Williams walked.”

We all do. Everyday. Everywhere.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

“He was one of those fresh Jewish types you want to kill at sight ... she on the other hand looked Italian, a goaty slant to her eyes ... She looked dirty. So did he ... And she smelled, the usual smell of sweat and dirt you find among people who habitually do not wash or bathe ... People like that belong in clinics ... Just dumb oxen. Why the hell do they let them into the country? Half idiots at best.”

Who wrote that? Some hate-mongering pundit on a cable channel? A Twitter troll?

Nope. It was William Carlos Williams, MD, the patron saint of physician-writers.

You’re thinking “No! Not him!” We all read “The Use of Force” and “Red Wheelbarrow” in high school or college. But this blatant anti-Semitism and xenophobia?

The short story is “A Face of Stone” from his collection “The Doctor Stories” (highly recommended). When Williams was asked to remove those parts before publication, he refused because they’re a key part of the story. And I agree with him.

The point, as in so much of life, is the big picture. Despite his vivid disgust, he examines their infant, reassuring the mother that everything is okay, and later helping her with her leg pain and walking difficulties. At the end of the short story he realizes that his impressions were wrong and that people he started out hating are, well, just people who need help. And, as doctors, isn’t helping what we’re here to do?

It’s not just Williams, it’s all of us. First impressions aren’t always correct, but we rely on them — a lot. We’re programmed to. Our ancestors in the caves didn’t have much time to decided friend or foe when they encountered others.

So we initially judge people on their faces, expressions, hair, clothes, religious symbols (if present), jewelry ... The things that are registered by the brain in a split-second before the first words are exchanged.

All of us are constantly “scanning” others we encounter. In the office, store, restaurant, whatever. Usually those impressions are fleeting as we forget that person within a minute or two since we don’t see them again. But as doctors we do get to know them as patients, and so are constantly “updating” our mental files as new information comes in.

As Williams tells the story, he realizes that the “face of stone” isn’t that of the young mother he mentally derided — it’s his own face, turned that way by his first dismissive impression of the family, and then melted as he realizes he was wrong and learns from the experience to be a better doctor.

In vivid terms he reminds us that, although doctors, we are still susceptible to the same foibles, errors, and incorrect snap-judgments that all people are, but what matters is that we can, and have to, overcome them.

As a wall plaque in St. Mary’s General Hospital in Passaic, New Jersey, reminds us: “We walk the wards that Williams walked.”

We all do. Everyday. Everywhere.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

“He was one of those fresh Jewish types you want to kill at sight ... she on the other hand looked Italian, a goaty slant to her eyes ... She looked dirty. So did he ... And she smelled, the usual smell of sweat and dirt you find among people who habitually do not wash or bathe ... People like that belong in clinics ... Just dumb oxen. Why the hell do they let them into the country? Half idiots at best.”

Who wrote that? Some hate-mongering pundit on a cable channel? A Twitter troll?

Nope. It was William Carlos Williams, MD, the patron saint of physician-writers.

You’re thinking “No! Not him!” We all read “The Use of Force” and “Red Wheelbarrow” in high school or college. But this blatant anti-Semitism and xenophobia?

The short story is “A Face of Stone” from his collection “The Doctor Stories” (highly recommended). When Williams was asked to remove those parts before publication, he refused because they’re a key part of the story. And I agree with him.

The point, as in so much of life, is the big picture. Despite his vivid disgust, he examines their infant, reassuring the mother that everything is okay, and later helping her with her leg pain and walking difficulties. At the end of the short story he realizes that his impressions were wrong and that people he started out hating are, well, just people who need help. And, as doctors, isn’t helping what we’re here to do?

It’s not just Williams, it’s all of us. First impressions aren’t always correct, but we rely on them — a lot. We’re programmed to. Our ancestors in the caves didn’t have much time to decided friend or foe when they encountered others.

So we initially judge people on their faces, expressions, hair, clothes, religious symbols (if present), jewelry ... The things that are registered by the brain in a split-second before the first words are exchanged.

All of us are constantly “scanning” others we encounter. In the office, store, restaurant, whatever. Usually those impressions are fleeting as we forget that person within a minute or two since we don’t see them again. But as doctors we do get to know them as patients, and so are constantly “updating” our mental files as new information comes in.

As Williams tells the story, he realizes that the “face of stone” isn’t that of the young mother he mentally derided — it’s his own face, turned that way by his first dismissive impression of the family, and then melted as he realizes he was wrong and learns from the experience to be a better doctor.

In vivid terms he reminds us that, although doctors, we are still susceptible to the same foibles, errors, and incorrect snap-judgments that all people are, but what matters is that we can, and have to, overcome them.

As a wall plaque in St. Mary’s General Hospital in Passaic, New Jersey, reminds us: “We walk the wards that Williams walked.”

We all do. Everyday. Everywhere.
 

Dr. Block has a solo neurology practice in Scottsdale, Ariz.