New pediatric COVID-19 cases increased for the third straight week as a substantial number of children under age 5 years started to receive their second doses of the vaccine.

Despite the 3-week trend, however, there are some positive signs. The new-case count for the latest reporting week (July 22-28) was over 95,000, but the 3.9% increase over the previous week’s 92,000 cases is much smaller than that week’s (July 15-21) corresponding jump of almost 22% over the July 8-14 total (75,000), according to the American Academy of Pediatrics and the Children’s Hospital Association.

On the not-so-positive side is the trend in admissions among children aged 0-17 years, which continue to climb steadily and have nearly equaled the highest rate seen during the Delta surge in 2021. The rate on July 29 was 0.46 admissions per 100,000 population, and the highest rate over the course of the Delta surge was 0.47 per 100,000, but the all-time high from the Omicron surge – 1.25 per 100,000 in mid-January – is still a long way off, based on data from the Centers for Disease Control and Prevention.

A similar situation is occurring with emergency department visits, but there is differentiation by age group. Among those aged 0-11 years, visits with diagnosed COVID made up 6.5% of all their ED visits on July 25, which was well above the high (4.0%) during the Delta surge, the CDC said.

That is not the case, however, for the older children, for whom rates are rising more slowly. Those aged 12-15 have reached 3.4% so far this summer, as have the 16- to 17-years-olds, versus Delta highs last year of around 7%, the CDC said on its COVID Data Tracker. As with admissions, though, current rates are well below the all-time Omicron high points, the CDC data show.
 

Joining the ranks of the fully vaccinated

Over the last 2 weeks, the first children to receive the COVID vaccine after its approval for those under age 5 years have been coming back for their second doses. Almost 50,000, about 0.3% of all those in that age group, had done so by July 27. Just over 662,000, about 3.4% of the total under-5 population, have received at least one dose, the CDC said.

Meanwhile, analysis of “data from the first several weeks following availability of the vaccine in this age group indicate high variability across states,” the AAP said in its weekly vaccination report. In the District of Columbia, 20.7% of all children under age 5 have received an initial dose as of July 27, as have 15.5% of those in Vermont and 12.5% in Massachusetts. No other state was above 10%, but Mississippi, at 0.7%, was the only one below 1%.

The older children, obviously, have a head start, so their numbers are much higher. At the state level, Vermont has the highest initial dose rate, 69%, for those aged 5-11 years, while Alabama, Mississippi, and Wyoming, at 17%, are looking up at everyone else in the country. Among children aged 12-17 years, D.C. is the highest with 100% vaccination – Massachusetts and Rhode Island are at 98% – and Wyoming is the lowest with 40%, the AAP said.

[email protected]

New pediatric COVID-19 cases increased for the third straight week as a substantial number of children under age 5 years started to receive their second doses of the vaccine.

Despite the 3-week trend, however, there are some positive signs. The new-case count for the latest reporting week (July 22-28) was over 95,000, but the 3.9% increase over the previous week’s 92,000 cases is much smaller than that week’s (July 15-21) corresponding jump of almost 22% over the July 8-14 total (75,000), according to the American Academy of Pediatrics and the Children’s Hospital Association.

On the not-so-positive side is the trend in admissions among children aged 0-17 years, which continue to climb steadily and have nearly equaled the highest rate seen during the Delta surge in 2021. The rate on July 29 was 0.46 admissions per 100,000 population, and the highest rate over the course of the Delta surge was 0.47 per 100,000, but the all-time high from the Omicron surge – 1.25 per 100,000 in mid-January – is still a long way off, based on data from the Centers for Disease Control and Prevention.

A similar situation is occurring with emergency department visits, but there is differentiation by age group. Among those aged 0-11 years, visits with diagnosed COVID made up 6.5% of all their ED visits on July 25, which was well above the high (4.0%) during the Delta surge, the CDC said.

That is not the case, however, for the older children, for whom rates are rising more slowly. Those aged 12-15 have reached 3.4% so far this summer, as have the 16- to 17-years-olds, versus Delta highs last year of around 7%, the CDC said on its COVID Data Tracker. As with admissions, though, current rates are well below the all-time Omicron high points, the CDC data show.
 

Joining the ranks of the fully vaccinated

Over the last 2 weeks, the first children to receive the COVID vaccine after its approval for those under age 5 years have been coming back for their second doses. Almost 50,000, about 0.3% of all those in that age group, had done so by July 27. Just over 662,000, about 3.4% of the total under-5 population, have received at least one dose, the CDC said.

Meanwhile, analysis of “data from the first several weeks following availability of the vaccine in this age group indicate high variability across states,” the AAP said in its weekly vaccination report. In the District of Columbia, 20.7% of all children under age 5 have received an initial dose as of July 27, as have 15.5% of those in Vermont and 12.5% in Massachusetts. No other state was above 10%, but Mississippi, at 0.7%, was the only one below 1%.

The older children, obviously, have a head start, so their numbers are much higher. At the state level, Vermont has the highest initial dose rate, 69%, for those aged 5-11 years, while Alabama, Mississippi, and Wyoming, at 17%, are looking up at everyone else in the country. Among children aged 12-17 years, D.C. is the highest with 100% vaccination – Massachusetts and Rhode Island are at 98% – and Wyoming is the lowest with 40%, the AAP said.

[email protected]

New pediatric COVID-19 cases increased for the third straight week as a substantial number of children under age 5 years started to receive their second doses of the vaccine.

Despite the 3-week trend, however, there are some positive signs. The new-case count for the latest reporting week (July 22-28) was over 95,000, but the 3.9% increase over the previous week’s 92,000 cases is much smaller than that week’s (July 15-21) corresponding jump of almost 22% over the July 8-14 total (75,000), according to the American Academy of Pediatrics and the Children’s Hospital Association.

On the not-so-positive side is the trend in admissions among children aged 0-17 years, which continue to climb steadily and have nearly equaled the highest rate seen during the Delta surge in 2021. The rate on July 29 was 0.46 admissions per 100,000 population, and the highest rate over the course of the Delta surge was 0.47 per 100,000, but the all-time high from the Omicron surge – 1.25 per 100,000 in mid-January – is still a long way off, based on data from the Centers for Disease Control and Prevention.

A similar situation is occurring with emergency department visits, but there is differentiation by age group. Among those aged 0-11 years, visits with diagnosed COVID made up 6.5% of all their ED visits on July 25, which was well above the high (4.0%) during the Delta surge, the CDC said.

That is not the case, however, for the older children, for whom rates are rising more slowly. Those aged 12-15 have reached 3.4% so far this summer, as have the 16- to 17-years-olds, versus Delta highs last year of around 7%, the CDC said on its COVID Data Tracker. As with admissions, though, current rates are well below the all-time Omicron high points, the CDC data show.
 

Joining the ranks of the fully vaccinated

Over the last 2 weeks, the first children to receive the COVID vaccine after its approval for those under age 5 years have been coming back for their second doses. Almost 50,000, about 0.3% of all those in that age group, had done so by July 27. Just over 662,000, about 3.4% of the total under-5 population, have received at least one dose, the CDC said.

Meanwhile, analysis of “data from the first several weeks following availability of the vaccine in this age group indicate high variability across states,” the AAP said in its weekly vaccination report. In the District of Columbia, 20.7% of all children under age 5 have received an initial dose as of July 27, as have 15.5% of those in Vermont and 12.5% in Massachusetts. No other state was above 10%, but Mississippi, at 0.7%, was the only one below 1%.

The older children, obviously, have a head start, so their numbers are much higher. At the state level, Vermont has the highest initial dose rate, 69%, for those aged 5-11 years, while Alabama, Mississippi, and Wyoming, at 17%, are looking up at everyone else in the country. Among children aged 12-17 years, D.C. is the highest with 100% vaccination – Massachusetts and Rhode Island are at 98% – and Wyoming is the lowest with 40%, the AAP said.

[email protected]

While tracking the extent of physician practice acquisition by private equity firms may be difficult, new research highlights what specialties and U.S. regions are most affected by such purchases.

The study, supported by the National Institute for Health Care Management (NIHCM), examined 97,094 physicians practicing in six specialties, 4,738 of whom worked in private equity–acquired practices. Of these specialties, the number of physicians working in private equity–acquired practices was highest in dermatology, gastroenterology, urology, ophthalmology, obstetrics and gynecology, and orthopedics.

Reducing competition, increasing focus on patient care

Researchers found significant geographical trends for private equity penetration, as it varies across the country. It is highest in the Northeast, Florida, and Arizona in hospital referral regions. Researchers are still analyzing the cause of this occurrence.

Geographic concentration of private equity penetration likely reflects strategic selection of investment opportunities by private equity funds as the decision to invest in a practice does not happen at random, Ms. Singh noted.

Ms. Singh said she hopes that by documenting a variation and geographic concentration that the NIHCM is providing the first foundational step to tackle questions related to incentives and regulations that facilitate investment.

“Understanding the regulatory and economic environments that facilitate private equity activity is an interesting and important question to explore further,” she said in an interview. “This can include supply-side factors that can shape the business environment, e.g., taxation environment, regulatory burden to complete acquisitions, as well as demand-side factors that facilitate growth.”

Researchers found that continued growth of private equity penetration may lead to consolidation among independent practices facing financial pressures, as well as reduced competition and increased prices within each local health care market.

“Localized consolidation in certain markets has the potential for competition to reduce, [and] reduced competition has been shown in a variety of settings to be associated with increases in prices and reduced access for patients,” said Ms. Singh.

Conversely, Ms. Singh addressed several benefits of growing private equity presence. Companies can exploit their full potential through the addition of private equity expertise and contacts. Specifically, health care development of technological infrastructure is likely, along with reduced patient wait times and the expansion of business hours. It could also be a way for practices to offload administrative responsibilities and for physicians to focus more on the care delivery process.

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

While tracking the extent of physician practice acquisition by private equity firms may be difficult, new research highlights what specialties and U.S. regions are most affected by such purchases.

The study, supported by the National Institute for Health Care Management (NIHCM), examined 97,094 physicians practicing in six specialties, 4,738 of whom worked in private equity–acquired practices. Of these specialties, the number of physicians working in private equity–acquired practices was highest in dermatology, gastroenterology, urology, ophthalmology, obstetrics and gynecology, and orthopedics.

Reducing competition, increasing focus on patient care

Researchers found significant geographical trends for private equity penetration, as it varies across the country. It is highest in the Northeast, Florida, and Arizona in hospital referral regions. Researchers are still analyzing the cause of this occurrence.

Geographic concentration of private equity penetration likely reflects strategic selection of investment opportunities by private equity funds as the decision to invest in a practice does not happen at random, Ms. Singh noted.

Ms. Singh said she hopes that by documenting a variation and geographic concentration that the NIHCM is providing the first foundational step to tackle questions related to incentives and regulations that facilitate investment.

“Understanding the regulatory and economic environments that facilitate private equity activity is an interesting and important question to explore further,” she said in an interview. “This can include supply-side factors that can shape the business environment, e.g., taxation environment, regulatory burden to complete acquisitions, as well as demand-side factors that facilitate growth.”

Researchers found that continued growth of private equity penetration may lead to consolidation among independent practices facing financial pressures, as well as reduced competition and increased prices within each local health care market.

“Localized consolidation in certain markets has the potential for competition to reduce, [and] reduced competition has been shown in a variety of settings to be associated with increases in prices and reduced access for patients,” said Ms. Singh.

Conversely, Ms. Singh addressed several benefits of growing private equity presence. Companies can exploit their full potential through the addition of private equity expertise and contacts. Specifically, health care development of technological infrastructure is likely, along with reduced patient wait times and the expansion of business hours. It could also be a way for practices to offload administrative responsibilities and for physicians to focus more on the care delivery process.

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

While tracking the extent of physician practice acquisition by private equity firms may be difficult, new research highlights what specialties and U.S. regions are most affected by such purchases.

The study, supported by the National Institute for Health Care Management (NIHCM), examined 97,094 physicians practicing in six specialties, 4,738 of whom worked in private equity–acquired practices. Of these specialties, the number of physicians working in private equity–acquired practices was highest in dermatology, gastroenterology, urology, ophthalmology, obstetrics and gynecology, and orthopedics.

Reducing competition, increasing focus on patient care

Researchers found significant geographical trends for private equity penetration, as it varies across the country. It is highest in the Northeast, Florida, and Arizona in hospital referral regions. Researchers are still analyzing the cause of this occurrence.

Geographic concentration of private equity penetration likely reflects strategic selection of investment opportunities by private equity funds as the decision to invest in a practice does not happen at random, Ms. Singh noted.

Ms. Singh said she hopes that by documenting a variation and geographic concentration that the NIHCM is providing the first foundational step to tackle questions related to incentives and regulations that facilitate investment.

“Understanding the regulatory and economic environments that facilitate private equity activity is an interesting and important question to explore further,” she said in an interview. “This can include supply-side factors that can shape the business environment, e.g., taxation environment, regulatory burden to complete acquisitions, as well as demand-side factors that facilitate growth.”

Researchers found that continued growth of private equity penetration may lead to consolidation among independent practices facing financial pressures, as well as reduced competition and increased prices within each local health care market.

“Localized consolidation in certain markets has the potential for competition to reduce, [and] reduced competition has been shown in a variety of settings to be associated with increases in prices and reduced access for patients,” said Ms. Singh.

Conversely, Ms. Singh addressed several benefits of growing private equity presence. Companies can exploit their full potential through the addition of private equity expertise and contacts. Specifically, health care development of technological infrastructure is likely, along with reduced patient wait times and the expansion of business hours. It could also be a way for practices to offload administrative responsibilities and for physicians to focus more on the care delivery process.

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

Low dietary calcium and potassium intake are important risk factors for the development of incident kidney stones as well as their symptomatic recurrence, a population-based study of dietary factors shows.

“Our research is of particular importance as recommendations for preventing symptomatic recurrence of kidney stones has largely been based on dietary factors associated with the incidence rather than the recurrence of stone formation,” Api Chewcharat, MD, Mayo Clinic, Rochester, Minn., said in a video discussing the study.

“We recommend a daily intake of calcium of approximately 1,200 mg and a diet that is high in potassium, especially high in fruits and vegetables, in order to prevent both incident and recurrent symptomatic kidney stone formation,” he stressed.

The study was published online in Mayo Clinic Proceedings.
 

Lower dietary calcium, potassium, and fluid associated with increased incidence

Some 411 patients with incident symptomatic kidney stone formation were recruited. Diets were compared between them and 384 controls. Patients were seen at the Mayo Clinic in either Minnesota or Florida between Jan. 1, 2009, and Aug. 31, 2018. “Dietary factors were based on a Viocare food frequency questionnaire administered during a baseline in-person study visit,” Dr. Chewcharat and colleagues observed.

During a median follow-up of 4.1 years, 73 patients experienced a symptomatic recurrence. In a fully adjusted analysis, a dietary calcium intake less than 1,200 mg/d was associated with incident stone formation. Similarly, among participants with a fluid intake less than 3,400 mL/d – about nine 12-oz glasses of fluid – was also associated with incident stone formation, as was a lower intake of dietary potassium, caffeine, and phytate. Phytate is an antioxidant found in whole grains, nuts, and other foods that can increase calcium absorption and urinary calcium excretion.

After excluding patients who were taking either a thiazide diuretic or a calcium supplement, lower dietary calcium and potassium, fluid, and phytate intake remained significantly associated with incident stone formation.

However, only lower dietary calcium intake was associated with a higher risk for symptomatic recurrence, although a lower dietary potassium intake was also associated with a higher risk for symptomatic recurrence in an analysis that adjusted for body mass index, fluid, and energy intake.

As the authors suggested, patients may be less keen to adjust their diet to prevent the development of incident kidney stones. On the other hand, they may be much more willing to adjust their diet to prevent their symptomatic recurrence. The Department of Agriculture currently recommends that individuals get approximately 1,200 mg/d of dietary calcium which, given the study results, appears to be justified for the prevention of symptomatic stone recurrence.

A higher-calcium diet is associated with a higher urinary pH, and citrate confers an alkali load which helps protect against the formation of calcium oxalate stones. Foods that are high in potassium also contain more fluid, citrate, and phytate, which, again, have been reported to be protective against kidney stones. “Changing your diet to prevent kidney stones can be very difficult,” Andrew Rule, MD, a nephrologist at the Mayo Clinic said in a statement.

“Thus, knowing the dietary factors that are most important for preventing kidney stone recurrence can help patients and providers know what to prioritize,” he added.

The authors have no conflicts of interest to declare.

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

Low dietary calcium and potassium intake are important risk factors for the development of incident kidney stones as well as their symptomatic recurrence, a population-based study of dietary factors shows.

“Our research is of particular importance as recommendations for preventing symptomatic recurrence of kidney stones has largely been based on dietary factors associated with the incidence rather than the recurrence of stone formation,” Api Chewcharat, MD, Mayo Clinic, Rochester, Minn., said in a video discussing the study.

“We recommend a daily intake of calcium of approximately 1,200 mg and a diet that is high in potassium, especially high in fruits and vegetables, in order to prevent both incident and recurrent symptomatic kidney stone formation,” he stressed.

The study was published online in Mayo Clinic Proceedings.
 

Lower dietary calcium, potassium, and fluid associated with increased incidence

Some 411 patients with incident symptomatic kidney stone formation were recruited. Diets were compared between them and 384 controls. Patients were seen at the Mayo Clinic in either Minnesota or Florida between Jan. 1, 2009, and Aug. 31, 2018. “Dietary factors were based on a Viocare food frequency questionnaire administered during a baseline in-person study visit,” Dr. Chewcharat and colleagues observed.

During a median follow-up of 4.1 years, 73 patients experienced a symptomatic recurrence. In a fully adjusted analysis, a dietary calcium intake less than 1,200 mg/d was associated with incident stone formation. Similarly, among participants with a fluid intake less than 3,400 mL/d – about nine 12-oz glasses of fluid – was also associated with incident stone formation, as was a lower intake of dietary potassium, caffeine, and phytate. Phytate is an antioxidant found in whole grains, nuts, and other foods that can increase calcium absorption and urinary calcium excretion.

After excluding patients who were taking either a thiazide diuretic or a calcium supplement, lower dietary calcium and potassium, fluid, and phytate intake remained significantly associated with incident stone formation.

However, only lower dietary calcium intake was associated with a higher risk for symptomatic recurrence, although a lower dietary potassium intake was also associated with a higher risk for symptomatic recurrence in an analysis that adjusted for body mass index, fluid, and energy intake.

As the authors suggested, patients may be less keen to adjust their diet to prevent the development of incident kidney stones. On the other hand, they may be much more willing to adjust their diet to prevent their symptomatic recurrence. The Department of Agriculture currently recommends that individuals get approximately 1,200 mg/d of dietary calcium which, given the study results, appears to be justified for the prevention of symptomatic stone recurrence.

A higher-calcium diet is associated with a higher urinary pH, and citrate confers an alkali load which helps protect against the formation of calcium oxalate stones. Foods that are high in potassium also contain more fluid, citrate, and phytate, which, again, have been reported to be protective against kidney stones. “Changing your diet to prevent kidney stones can be very difficult,” Andrew Rule, MD, a nephrologist at the Mayo Clinic said in a statement.

“Thus, knowing the dietary factors that are most important for preventing kidney stone recurrence can help patients and providers know what to prioritize,” he added.

The authors have no conflicts of interest to declare.

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

Low dietary calcium and potassium intake are important risk factors for the development of incident kidney stones as well as their symptomatic recurrence, a population-based study of dietary factors shows.

“Our research is of particular importance as recommendations for preventing symptomatic recurrence of kidney stones has largely been based on dietary factors associated with the incidence rather than the recurrence of stone formation,” Api Chewcharat, MD, Mayo Clinic, Rochester, Minn., said in a video discussing the study.

“We recommend a daily intake of calcium of approximately 1,200 mg and a diet that is high in potassium, especially high in fruits and vegetables, in order to prevent both incident and recurrent symptomatic kidney stone formation,” he stressed.

The study was published online in Mayo Clinic Proceedings.
 

Lower dietary calcium, potassium, and fluid associated with increased incidence

Some 411 patients with incident symptomatic kidney stone formation were recruited. Diets were compared between them and 384 controls. Patients were seen at the Mayo Clinic in either Minnesota or Florida between Jan. 1, 2009, and Aug. 31, 2018. “Dietary factors were based on a Viocare food frequency questionnaire administered during a baseline in-person study visit,” Dr. Chewcharat and colleagues observed.

During a median follow-up of 4.1 years, 73 patients experienced a symptomatic recurrence. In a fully adjusted analysis, a dietary calcium intake less than 1,200 mg/d was associated with incident stone formation. Similarly, among participants with a fluid intake less than 3,400 mL/d – about nine 12-oz glasses of fluid – was also associated with incident stone formation, as was a lower intake of dietary potassium, caffeine, and phytate. Phytate is an antioxidant found in whole grains, nuts, and other foods that can increase calcium absorption and urinary calcium excretion.

After excluding patients who were taking either a thiazide diuretic or a calcium supplement, lower dietary calcium and potassium, fluid, and phytate intake remained significantly associated with incident stone formation.

However, only lower dietary calcium intake was associated with a higher risk for symptomatic recurrence, although a lower dietary potassium intake was also associated with a higher risk for symptomatic recurrence in an analysis that adjusted for body mass index, fluid, and energy intake.

As the authors suggested, patients may be less keen to adjust their diet to prevent the development of incident kidney stones. On the other hand, they may be much more willing to adjust their diet to prevent their symptomatic recurrence. The Department of Agriculture currently recommends that individuals get approximately 1,200 mg/d of dietary calcium which, given the study results, appears to be justified for the prevention of symptomatic stone recurrence.

A higher-calcium diet is associated with a higher urinary pH, and citrate confers an alkali load which helps protect against the formation of calcium oxalate stones. Foods that are high in potassium also contain more fluid, citrate, and phytate, which, again, have been reported to be protective against kidney stones. “Changing your diet to prevent kidney stones can be very difficult,” Andrew Rule, MD, a nephrologist at the Mayo Clinic said in a statement.

“Thus, knowing the dietary factors that are most important for preventing kidney stone recurrence can help patients and providers know what to prioritize,” he added.

The authors have no conflicts of interest to declare.

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

Skin symptoms, like systemic symptoms, differ by COVID-19 variant, according to a large retrospective study that compared clinical data from more than 300,000 participants in the United Kingdom during the Omicron and Delta waves.

Among the key findings, the study shows that skin involvement during the Omicron wave was less frequent than during the Delta wave (11.4% vs. 17.6%), skin symptoms generally resolved more quickly, and that the risk for skin symptoms was similar whether patients had or had not been vaccinated, according to a team led by Alessia Visconti, PhD, a research fellow in the department of twin research and genetic epidemiology, King’s College, London.

These data are consistent with the experience of those dermatologists who have been following this area closely, according to Esther Freeman, MD, PhD, associate professor of dermatology at Harvard Medical School and director of MGH Global Health Dermatology at Massachusetts General Hospital, both in Boston.

“Anecdotally, we thought we were seeing fewer skin symptoms with Omicron versus Delta and the ancestral strains, and now this study shows it is true,” said Dr. Freeman, who is also principal investigator of the American Academy of Dermatology’s International Dermatology COVID-19 Registry.

The data also confirm that the skin is less likely to be involved than in past waves of COVID-19 infections.

“Up to this point, it was hard to know if we were seeing fewer referrals for COVID-related skin rashes or if clinicians had just become more comfortable with these rashes and were not referring them as often,” added Dr. Freeman, who was among the study coauthors.

Data captured from 348,691 patients

The data from the study was generated by 348,691 users in the United Kingdom of the ZOE COVID study app, a smartphone-based tool introduced relatively early in the pandemic. It asked users to provide demographic data, information on COVID-19 symptoms, including those involving the skin, and treatments. Of 33 COVID-related symptoms included in the app, five related to the skin (acral rash, burning rash, erythematopapular rash, urticarial rash, and unusual hair loss).

While the focus of this study was to compare skin manifestations during the Omicron wave with the Delta wave of COVID-19, the investigators also had data on the experience in 2020 with wild-type COVID-19 that preceded both variants. Overall, this showed a stepwise decline in skin symptoms overall, as well in as skin symptoms that occurred in the absence of systemic symptoms.

“The shift in the skin manifestations makes sense when you think about the change that is also being seen in the systemic symptoms,” said Dr. Freeman, referring to lower rates of cough and loss of smell but higher rates of sore throat and fatigue. “Omicron is achieving immune escape, which is why there is a shift in involved tissues,” she said in an interview.

Previous data collected during the wild-type COVID-19 stage of the pandemic by the same group of investigators showed that 17% of patients reported skin rash as the first symptom of COVID-19 infection, and 21% reported skin rash as the only clinical sign of infection.

In the Delta and Omicron waves, skin rash was an isolated initial symptom in only 0.8% and 0.5% of patients, respectively. (The authors noted that, in the United Kingdom, the first documented samples of the Delta variant were detected in October 2020, and the first documented samples of the Omicron variant were detected in November 2021.)

During the early stages of wild-type COVID, an acral rash was characteristic, occurring in 3.1% of patients, according to the U.K. data. In the Delta wave, acral rashes, at an incidence of 1.1% remained positively correlated with a diagnosis of COVID-19 infection. In the Omicron wave, acral rashes were observed in only 0.7% of patients and were no longer statistically correlated with a positive COVID diagnosis.


 

Characteristic cutaneous symptoms are evolving

Early in the course of the COVID-19 epidemic, more than 30 types of rashes were observed in patients with COVID-19 infection. Cutaneous symptoms continue to be diverse, but some, such as acral rash, are being seen less frequently. For example, the odds ratio of a positive COVID-19 diagnosis among those with an erythematopapular rash fell from 1.76 to 1.08 between the Delta and Omicron waves.

While specific cutaneous symptoms are less predictive of a diagnosis of COVID-19, clinicians should not discount cutaneous symptoms as a sign of disease, according to Veronique Bataille, MD, PhD, a consultant dermatologist at King’s College.

“You need to keep an open mind” regarding cutaneous signs and a diagnosis of COVID-19, Dr. Bataille, one of the coauthors of the U.K. report, said in an interview. In general, she considers a low threshold of suspicion appropriate. “If the patient has no past history of skin disease and no other triggers for a rash, then, in a high prevalence area, COVID must be suspected.”

In most cases, the rash resolves on its own, but Dr. Bataille emphasized the need for individualized care. Even as the risk of life-threatening COVID-19 infections appears to be diminishing with current variants, cutaneous manifestations can be severe.

“There are cases of long COVID affecting the skin, such as urticaria or a lichenoid erythematopapular rash, both of which can be very pruritic and difficult to control,” she said.

Dr. Freeman echoed the importance of an individualized approach. She agreed that most cutaneous symptoms are self-limited, but there are exceptions and treatments vary for the different types of skin involvement. “I think another point to consider when examining skin lesions is monkey pox. The fact that these are overlapping outbreaks should not be ignored. You need to be alert for both.”

Dr. Visconti, Dr. Freeman, and Dr. Bataille reported no potential conflicts of interest.

Skin symptoms, like systemic symptoms, differ by COVID-19 variant, according to a large retrospective study that compared clinical data from more than 300,000 participants in the United Kingdom during the Omicron and Delta waves.

Among the key findings, the study shows that skin involvement during the Omicron wave was less frequent than during the Delta wave (11.4% vs. 17.6%), skin symptoms generally resolved more quickly, and that the risk for skin symptoms was similar whether patients had or had not been vaccinated, according to a team led by Alessia Visconti, PhD, a research fellow in the department of twin research and genetic epidemiology, King’s College, London.

These data are consistent with the experience of those dermatologists who have been following this area closely, according to Esther Freeman, MD, PhD, associate professor of dermatology at Harvard Medical School and director of MGH Global Health Dermatology at Massachusetts General Hospital, both in Boston.

“Anecdotally, we thought we were seeing fewer skin symptoms with Omicron versus Delta and the ancestral strains, and now this study shows it is true,” said Dr. Freeman, who is also principal investigator of the American Academy of Dermatology’s International Dermatology COVID-19 Registry.

The data also confirm that the skin is less likely to be involved than in past waves of COVID-19 infections.

“Up to this point, it was hard to know if we were seeing fewer referrals for COVID-related skin rashes or if clinicians had just become more comfortable with these rashes and were not referring them as often,” added Dr. Freeman, who was among the study coauthors.

Data captured from 348,691 patients

The data from the study was generated by 348,691 users in the United Kingdom of the ZOE COVID study app, a smartphone-based tool introduced relatively early in the pandemic. It asked users to provide demographic data, information on COVID-19 symptoms, including those involving the skin, and treatments. Of 33 COVID-related symptoms included in the app, five related to the skin (acral rash, burning rash, erythematopapular rash, urticarial rash, and unusual hair loss).

While the focus of this study was to compare skin manifestations during the Omicron wave with the Delta wave of COVID-19, the investigators also had data on the experience in 2020 with wild-type COVID-19 that preceded both variants. Overall, this showed a stepwise decline in skin symptoms overall, as well in as skin symptoms that occurred in the absence of systemic symptoms.

“The shift in the skin manifestations makes sense when you think about the change that is also being seen in the systemic symptoms,” said Dr. Freeman, referring to lower rates of cough and loss of smell but higher rates of sore throat and fatigue. “Omicron is achieving immune escape, which is why there is a shift in involved tissues,” she said in an interview.

Previous data collected during the wild-type COVID-19 stage of the pandemic by the same group of investigators showed that 17% of patients reported skin rash as the first symptom of COVID-19 infection, and 21% reported skin rash as the only clinical sign of infection.

In the Delta and Omicron waves, skin rash was an isolated initial symptom in only 0.8% and 0.5% of patients, respectively. (The authors noted that, in the United Kingdom, the first documented samples of the Delta variant were detected in October 2020, and the first documented samples of the Omicron variant were detected in November 2021.)

During the early stages of wild-type COVID, an acral rash was characteristic, occurring in 3.1% of patients, according to the U.K. data. In the Delta wave, acral rashes, at an incidence of 1.1% remained positively correlated with a diagnosis of COVID-19 infection. In the Omicron wave, acral rashes were observed in only 0.7% of patients and were no longer statistically correlated with a positive COVID diagnosis.


 

Characteristic cutaneous symptoms are evolving

Early in the course of the COVID-19 epidemic, more than 30 types of rashes were observed in patients with COVID-19 infection. Cutaneous symptoms continue to be diverse, but some, such as acral rash, are being seen less frequently. For example, the odds ratio of a positive COVID-19 diagnosis among those with an erythematopapular rash fell from 1.76 to 1.08 between the Delta and Omicron waves.

While specific cutaneous symptoms are less predictive of a diagnosis of COVID-19, clinicians should not discount cutaneous symptoms as a sign of disease, according to Veronique Bataille, MD, PhD, a consultant dermatologist at King’s College.

“You need to keep an open mind” regarding cutaneous signs and a diagnosis of COVID-19, Dr. Bataille, one of the coauthors of the U.K. report, said in an interview. In general, she considers a low threshold of suspicion appropriate. “If the patient has no past history of skin disease and no other triggers for a rash, then, in a high prevalence area, COVID must be suspected.”

In most cases, the rash resolves on its own, but Dr. Bataille emphasized the need for individualized care. Even as the risk of life-threatening COVID-19 infections appears to be diminishing with current variants, cutaneous manifestations can be severe.

“There are cases of long COVID affecting the skin, such as urticaria or a lichenoid erythematopapular rash, both of which can be very pruritic and difficult to control,” she said.

Dr. Freeman echoed the importance of an individualized approach. She agreed that most cutaneous symptoms are self-limited, but there are exceptions and treatments vary for the different types of skin involvement. “I think another point to consider when examining skin lesions is monkey pox. The fact that these are overlapping outbreaks should not be ignored. You need to be alert for both.”

Dr. Visconti, Dr. Freeman, and Dr. Bataille reported no potential conflicts of interest.

Skin symptoms, like systemic symptoms, differ by COVID-19 variant, according to a large retrospective study that compared clinical data from more than 300,000 participants in the United Kingdom during the Omicron and Delta waves.

Among the key findings, the study shows that skin involvement during the Omicron wave was less frequent than during the Delta wave (11.4% vs. 17.6%), skin symptoms generally resolved more quickly, and that the risk for skin symptoms was similar whether patients had or had not been vaccinated, according to a team led by Alessia Visconti, PhD, a research fellow in the department of twin research and genetic epidemiology, King’s College, London.

These data are consistent with the experience of those dermatologists who have been following this area closely, according to Esther Freeman, MD, PhD, associate professor of dermatology at Harvard Medical School and director of MGH Global Health Dermatology at Massachusetts General Hospital, both in Boston.

“Anecdotally, we thought we were seeing fewer skin symptoms with Omicron versus Delta and the ancestral strains, and now this study shows it is true,” said Dr. Freeman, who is also principal investigator of the American Academy of Dermatology’s International Dermatology COVID-19 Registry.

The data also confirm that the skin is less likely to be involved than in past waves of COVID-19 infections.

“Up to this point, it was hard to know if we were seeing fewer referrals for COVID-related skin rashes or if clinicians had just become more comfortable with these rashes and were not referring them as often,” added Dr. Freeman, who was among the study coauthors.

Data captured from 348,691 patients

The data from the study was generated by 348,691 users in the United Kingdom of the ZOE COVID study app, a smartphone-based tool introduced relatively early in the pandemic. It asked users to provide demographic data, information on COVID-19 symptoms, including those involving the skin, and treatments. Of 33 COVID-related symptoms included in the app, five related to the skin (acral rash, burning rash, erythematopapular rash, urticarial rash, and unusual hair loss).

While the focus of this study was to compare skin manifestations during the Omicron wave with the Delta wave of COVID-19, the investigators also had data on the experience in 2020 with wild-type COVID-19 that preceded both variants. Overall, this showed a stepwise decline in skin symptoms overall, as well in as skin symptoms that occurred in the absence of systemic symptoms.

“The shift in the skin manifestations makes sense when you think about the change that is also being seen in the systemic symptoms,” said Dr. Freeman, referring to lower rates of cough and loss of smell but higher rates of sore throat and fatigue. “Omicron is achieving immune escape, which is why there is a shift in involved tissues,” she said in an interview.

Previous data collected during the wild-type COVID-19 stage of the pandemic by the same group of investigators showed that 17% of patients reported skin rash as the first symptom of COVID-19 infection, and 21% reported skin rash as the only clinical sign of infection.

In the Delta and Omicron waves, skin rash was an isolated initial symptom in only 0.8% and 0.5% of patients, respectively. (The authors noted that, in the United Kingdom, the first documented samples of the Delta variant were detected in October 2020, and the first documented samples of the Omicron variant were detected in November 2021.)

During the early stages of wild-type COVID, an acral rash was characteristic, occurring in 3.1% of patients, according to the U.K. data. In the Delta wave, acral rashes, at an incidence of 1.1% remained positively correlated with a diagnosis of COVID-19 infection. In the Omicron wave, acral rashes were observed in only 0.7% of patients and were no longer statistically correlated with a positive COVID diagnosis.


 

Characteristic cutaneous symptoms are evolving

Early in the course of the COVID-19 epidemic, more than 30 types of rashes were observed in patients with COVID-19 infection. Cutaneous symptoms continue to be diverse, but some, such as acral rash, are being seen less frequently. For example, the odds ratio of a positive COVID-19 diagnosis among those with an erythematopapular rash fell from 1.76 to 1.08 between the Delta and Omicron waves.

While specific cutaneous symptoms are less predictive of a diagnosis of COVID-19, clinicians should not discount cutaneous symptoms as a sign of disease, according to Veronique Bataille, MD, PhD, a consultant dermatologist at King’s College.

“You need to keep an open mind” regarding cutaneous signs and a diagnosis of COVID-19, Dr. Bataille, one of the coauthors of the U.K. report, said in an interview. In general, she considers a low threshold of suspicion appropriate. “If the patient has no past history of skin disease and no other triggers for a rash, then, in a high prevalence area, COVID must be suspected.”

In most cases, the rash resolves on its own, but Dr. Bataille emphasized the need for individualized care. Even as the risk of life-threatening COVID-19 infections appears to be diminishing with current variants, cutaneous manifestations can be severe.

“There are cases of long COVID affecting the skin, such as urticaria or a lichenoid erythematopapular rash, both of which can be very pruritic and difficult to control,” she said.

Dr. Freeman echoed the importance of an individualized approach. She agreed that most cutaneous symptoms are self-limited, but there are exceptions and treatments vary for the different types of skin involvement. “I think another point to consider when examining skin lesions is monkey pox. The fact that these are overlapping outbreaks should not be ignored. You need to be alert for both.”

Dr. Visconti, Dr. Freeman, and Dr. Bataille reported no potential conflicts of interest.

New devices that use artificial intelligence (AI) to diagnose skin cancer – such as smartphone apps – have been popping up over the past few years, but there is some concern over the accuracy of these tools.

So far, the U.S. Food and Drug Administration has cleared two devices. Both are computer-aided skin lesion classification devices meant to help clinicians assess cases of suspected melanoma.

Both were given a class III designation. That classification is intended for products that are considered to have a high risk of harm because of flawed design or implementation. Many such devices are under development, and there has been a proposal to include these devices in class II, which is less restrictive.

The FDA turned to one of its expert panels for advice. At a meeting held on Aug. 29, experts on the panel offered differing views and expressed concerns about the accuracy of these devices.

This was the second day of meetings of the general and plastic surgery devices panel of the FDA’s Medical Devices Advisory Committee. On the previous day, the panel held a wide-ranging discussion about expanding use of skin lesion analyzer devices.

The FDA sought the expert panel’s advice concerning a field that appears to be heating up quickly after relatively quiet times.

Two devices have been approved by the FDA so far, but only one is still being promoted – SciBase AB’s Nevisense. The Swedish company announced in May 2020 that it had received FDA approval for Nevisense 3.0, the third generation of their Nevisense system for early melanoma detection, an AI-based point-of-care system for the noninvasive evaluation of irregular moles.

The other device, known as MelaFind, was acquired by Strata Skin Sciences, but the company said in 2017 that it discontinued research and development, sales, and support activity related to the device, according to a filing with the Securities and Exchange Commission.

But there’s been a swell in recent years in the number of publications related to the use of AI and machine learning, which could give rise to new tools for aiding in the diagnosis of skin conditions, including cancer. Google is among the companies that are involved in these efforts.

So, the FDA asked the expert panel to discuss a series of questions related to how the agency should weigh the risks of computer-aided devices for melanoma diagnosis. The agency also asked the panel to provide feedback about how well risks associated with such devices and tools might be managed and to offer suggestions.

The discussion at the July 29 meeting spun beyond narrow questions about reclassification of the current class III devices to topics involving emerging technology, such as efforts to apply AI to dermatology.

“Innovation continues. Medical device developers are anxious to plan how they might be able to develop the level of evidence that would meet your expectations” for future products, Binita Ashar, MD, a senior official in FDA’s Center for Devices and Radiological Health, told the panel.


 

Company CEO backs tougher regulation

Simon Grant, the chief executive of SciBase, which markets Nevisense, the first and only skin cancer–detecting device currently on the U.S. market, sought to make a case for sticking with the tougher class III regulations.

Speaking during the public comment session, Mr. Grant said switching to class II designations would weaken the standards used in clearing products that analyze skin lesions so as to put patients at risk.

Under the FDA’s rules, the agency designates as class III devices that present potential unreasonable risk of illness or injury. Only about 10% of devices fall into this category. Such devices include implantable pacemakers and breast implants, as well as SciBase’s Nevisense.

About 43% of medical devices fall into the class II category, which includes powered wheelchairs and some pregnancy test kits, the FDA website says.

Class I medical devices pose minimal potential for harm and tend to be simpler in design. These include enema kits and elastic bandages, the FDA says.

Mr. Grant told the meeting that in his career he has worked on two class III products and about 20 class II products. (He had previously worked at medical startups Synectics Medical and Neoventa, as well as established multinationals such as Medtronic.)

“I can tell you that – practically – the FDA has many fewer sticks and much less control when it comes to class II devices,” he said. He offered an example of a manufacturer of a class II device having more latitude in making small changes to products without notifying the FDA.

In his hypothetical example, such a change could have unintended consequences, and “with AI systems, small changes can result in large and nonlinear or even random effects,” Mr. Grant said. “But it’s too late if the product is on the market and the harm has already occurred,” he said.

The American Society for Dermatologic Surgery Association also protested the reclassifying of approved computer-aided melanoma detection class III devices.

In a statement posted on the FDA website as part of the materials for the meeting, the ASDSA raised a series of concerns about the prospects of expanded U.S. use of tools for assisting in diagnosing melanoma, including ones that would be marketed to consumers.

“To the extent that algorithms and devices for patient self-diagnosis of skin lesions are already widely available, they should be required to include detailed disclaimers that include that they are for entertainment and educational purposes and not a diagnostic device, that they are not approved by dermatologists or a recognized medical regulatory authority for self-diagnosis,” the ASDSA said.

Devices and algorithms in screening tools “are not highly regulated and remain unproven. They may result in wrong diagnoses, missed diagnoses, or over- or underdiagnosis,” the ASDSA added. “Both patients at low risk and those at high risk are better served by scheduling an in-person examination with a board-certified dermatologist, who can also help them determine the appropriate future skin screening schedule that is most appropriate for them.”

 

‘Stepping stone’

However, there is strong consumer demand for better information about skin conditions, and many patients face hurdles in going to dermatologists.

Google research has shown that consumers are seeking “a stepping stone” between the information they can easily find online and what they could get from a medical professional, said Lily Peng, MD, PhD, a director of product management for the health AI team at Google. Dr. Peng was a scheduled presenter at the July 29 meeting.

Consumers often are looking for more information on common conditions such as acne and poison ivy, and they sometimes face challenges in getting access to clinicians, she said.

“There are many unmet needs for consumers experiencing skin issues, many of which are lower-acuity conditions. There’s a big opportunity to increase accessibility and relevance of health journeys for consumers,” Dr. Peng said. “We have heard from consumers that they would like to have a self-help tool for nonserious conditions so they can decide when to seek medical attention.”

Dr. Peng’s presentation was not directly related to the question of class II or class III designation for existing products. Instead, her talk served as a glimpse into the work already underway in creating apps and tools for consumers.

Google researchers have published a number of studies in recent years about the use of AI to improve dermatology diagnosis.

A 2020 article reported on Google’s test of a form of AI known as deep learning system (DLS) to provide a differential diagnosis of skin conditions. On 963 validation cases, where a rotating panel of three board-certified dermatologists defined the reference standard, the DLS was noninferior to six other dermatologists and was superior to six primary care physicians (PCPs) and six nurse practitioners (NPs), according to a summary of the article.

A 2021 report published in JAMA Network Open said that use of an AI tool was associated with a higher agreement rate with dermatologists’ reference diagnoses for both PCPs and NPs.

In a 2021 blog post, Google scientists wrote that their AI model that powers a tool for checking skin conditions had earned European clearance, known as a CE mark, as a class I medical device.

SkinVision has an app that the company says “is available worldwide (with the exception of the USA and Canada).” The firm’s website includes a link where people in the United States and Canada can sign up for notifications about when SkinVision will be available in these nations. 


 

‘Not ready for prime time’

The FDA panel did not cast formal votes at the July 29 meeting. Rather, the members engaged in broad discussions about risks and potential benefits of new tools for aiding in the detection of skin cancer.

Among the key issues discussed was a question of whether the FDA could impose requirements and restrictions, known as special controls, to provide “reasonable assurance of safety and effectiveness” for computer-aided devices that provide adjunctive diagnostic information to dermatologists about lesions suspicious for melanoma.

Among the potential special controls would be clinical performance testing in regards to rates of the sensitivity (true-positive rate) and specificity (true-negative rate).

The FDA could also look at requirements on software validation and verification and cybersecurity testing, as well as directions on labeling so as to mitigate risk.

Dermatologists serving on the panel called for caution in proceeding with steps that would make it easier for companies to market tools for aiding in melanoma diagnosis than it would be within the class III framework used for MelaFind and Nevisense.

Many expressed concerns about the need to design studies that would answer questions about how well new tools could accurately identify concerning lesions.

The phrase “not ready for prime time” was used at least three times during the discussion.

FDA panelist Maral Skelsey, MD, a skin cancer specialist from Chevy Chase, Maryland, said that over the years, she had used both Nevisense and MelaFind.

She said she had found MelaFind “unusable,” owing in large part to the high number of false positives it generated. The device also was limited as to where on patients’ bodies it could be used.

However, she spoke with enthusiasm about the prospects for better devices to aid in diagnosis of skin lesions. “It’s an area where we’re on the verge, and we really need these devices. There’s a need for patients to be able to examine themselves, for nondermatologists to be able to assess lesions,” Dr. Skelsey said.

But this field is “just not ready for prime time” yet, even with special controls, Dr. Skelsey said. To loosen approval standards too quickly could be a “detriment to what’s coming down the pipeline,” she said.

“It’s harmful to things that are likely to be around the corner,” she said.

FDA panelist Renata Block, PA-C, who works in a Chicago dermatology practice, pressed for maintaining a class III designation. “We are not ready for prime time yet, though the data that is coming down the pipeline on what we have is quite exciting,” Ms. Block said.

FDA panelist Karla V. Ballman, PhD, a statistician from Weill Cornell Medicine, New York, said there would need to be a clear standard for clinical performance before proceeding toward reclassification of devices for aid in detecting melanoma. “I just don’t think it’s ready for prime time at this point and should remain in class III,” she said.

But there was support from some panelists for the idea of a lower bar for clearance, combined with special controls to ensure patient safety.

In expressing her view, FDA panelist Katalin Roth, MD, JD, professor of medicine, George Washington University, Washington, said she was an outlier in her support for the agency’s view that these risks could be managed and that future tools could allow more patients to take a step on the pathway toward critical diagnoses.

“I deal with a lot of people with cancer as a palliative care physician,” Dr. Roth said. “I think what we’re missing here is the issue of time. Melanoma is a terrible disease, and missing the diagnosis is a terrible thing, but I think special controls would be sufficient to counter the concerns of my colleagues on the committee.”

The FDA’s Dr. Ashar ended the meeting with questions posed to one panelist, Veronica Rotemberg, MD, PhD, a dermatologist at Memorial Sloan Kettering Cancer Center in New York.

Dr. Rotemberg has for years been working in the field of research on developing AI and other computer-based tools for detecting and diagnosing melanoma, the deadliest form of skin cancer.

She has been publicly skeptical of the performance of commercial apps that scan moles and other lesions and that claim to identify which are cancerous. A May blog post on the Memorial Sloan Kettering website highlighted a recent British Journal of Dermatology article in which Dr. Rotemberg and coauthors reported on their evaluations of commercial apps. They judged them to be on average only 59% accurate, the blog post said.

However, during an earlier discussion at the meeting, she had spoken more positively about the prospects for using special controls in the near term to mitigate risk, although she said she would have a “very long list” of these requirements.

In the closing exchange with Dr. Ashar, Dr. Rotemberg outlined steps that could potentially ensure the safe use of tools to aid in melanoma screening. These included a need for postmarketing surveillance, which would require evaluation over time of algorithms used in tools meant to detect skin cancer.

“We need to have a mechanism for sampling,” Dr. Rotemberg said. “Most of our data is electronic now anyway, so comparing an algorithm and performance with biopsy results should not be that challenging.”

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

New devices that use artificial intelligence (AI) to diagnose skin cancer – such as smartphone apps – have been popping up over the past few years, but there is some concern over the accuracy of these tools.

So far, the U.S. Food and Drug Administration has cleared two devices. Both are computer-aided skin lesion classification devices meant to help clinicians assess cases of suspected melanoma.

Both were given a class III designation. That classification is intended for products that are considered to have a high risk of harm because of flawed design or implementation. Many such devices are under development, and there has been a proposal to include these devices in class II, which is less restrictive.

The FDA turned to one of its expert panels for advice. At a meeting held on Aug. 29, experts on the panel offered differing views and expressed concerns about the accuracy of these devices.

This was the second day of meetings of the general and plastic surgery devices panel of the FDA’s Medical Devices Advisory Committee. On the previous day, the panel held a wide-ranging discussion about expanding use of skin lesion analyzer devices.

The FDA sought the expert panel’s advice concerning a field that appears to be heating up quickly after relatively quiet times.

Two devices have been approved by the FDA so far, but only one is still being promoted – SciBase AB’s Nevisense. The Swedish company announced in May 2020 that it had received FDA approval for Nevisense 3.0, the third generation of their Nevisense system for early melanoma detection, an AI-based point-of-care system for the noninvasive evaluation of irregular moles.

The other device, known as MelaFind, was acquired by Strata Skin Sciences, but the company said in 2017 that it discontinued research and development, sales, and support activity related to the device, according to a filing with the Securities and Exchange Commission.

But there’s been a swell in recent years in the number of publications related to the use of AI and machine learning, which could give rise to new tools for aiding in the diagnosis of skin conditions, including cancer. Google is among the companies that are involved in these efforts.

So, the FDA asked the expert panel to discuss a series of questions related to how the agency should weigh the risks of computer-aided devices for melanoma diagnosis. The agency also asked the panel to provide feedback about how well risks associated with such devices and tools might be managed and to offer suggestions.

The discussion at the July 29 meeting spun beyond narrow questions about reclassification of the current class III devices to topics involving emerging technology, such as efforts to apply AI to dermatology.

“Innovation continues. Medical device developers are anxious to plan how they might be able to develop the level of evidence that would meet your expectations” for future products, Binita Ashar, MD, a senior official in FDA’s Center for Devices and Radiological Health, told the panel.


 

Company CEO backs tougher regulation

Simon Grant, the chief executive of SciBase, which markets Nevisense, the first and only skin cancer–detecting device currently on the U.S. market, sought to make a case for sticking with the tougher class III regulations.

Speaking during the public comment session, Mr. Grant said switching to class II designations would weaken the standards used in clearing products that analyze skin lesions so as to put patients at risk.

Under the FDA’s rules, the agency designates as class III devices that present potential unreasonable risk of illness or injury. Only about 10% of devices fall into this category. Such devices include implantable pacemakers and breast implants, as well as SciBase’s Nevisense.

About 43% of medical devices fall into the class II category, which includes powered wheelchairs and some pregnancy test kits, the FDA website says.

Class I medical devices pose minimal potential for harm and tend to be simpler in design. These include enema kits and elastic bandages, the FDA says.

Mr. Grant told the meeting that in his career he has worked on two class III products and about 20 class II products. (He had previously worked at medical startups Synectics Medical and Neoventa, as well as established multinationals such as Medtronic.)

“I can tell you that – practically – the FDA has many fewer sticks and much less control when it comes to class II devices,” he said. He offered an example of a manufacturer of a class II device having more latitude in making small changes to products without notifying the FDA.

In his hypothetical example, such a change could have unintended consequences, and “with AI systems, small changes can result in large and nonlinear or even random effects,” Mr. Grant said. “But it’s too late if the product is on the market and the harm has already occurred,” he said.

The American Society for Dermatologic Surgery Association also protested the reclassifying of approved computer-aided melanoma detection class III devices.

In a statement posted on the FDA website as part of the materials for the meeting, the ASDSA raised a series of concerns about the prospects of expanded U.S. use of tools for assisting in diagnosing melanoma, including ones that would be marketed to consumers.

“To the extent that algorithms and devices for patient self-diagnosis of skin lesions are already widely available, they should be required to include detailed disclaimers that include that they are for entertainment and educational purposes and not a diagnostic device, that they are not approved by dermatologists or a recognized medical regulatory authority for self-diagnosis,” the ASDSA said.

Devices and algorithms in screening tools “are not highly regulated and remain unproven. They may result in wrong diagnoses, missed diagnoses, or over- or underdiagnosis,” the ASDSA added. “Both patients at low risk and those at high risk are better served by scheduling an in-person examination with a board-certified dermatologist, who can also help them determine the appropriate future skin screening schedule that is most appropriate for them.”

 

‘Stepping stone’

However, there is strong consumer demand for better information about skin conditions, and many patients face hurdles in going to dermatologists.

Google research has shown that consumers are seeking “a stepping stone” between the information they can easily find online and what they could get from a medical professional, said Lily Peng, MD, PhD, a director of product management for the health AI team at Google. Dr. Peng was a scheduled presenter at the July 29 meeting.

Consumers often are looking for more information on common conditions such as acne and poison ivy, and they sometimes face challenges in getting access to clinicians, she said.

“There are many unmet needs for consumers experiencing skin issues, many of which are lower-acuity conditions. There’s a big opportunity to increase accessibility and relevance of health journeys for consumers,” Dr. Peng said. “We have heard from consumers that they would like to have a self-help tool for nonserious conditions so they can decide when to seek medical attention.”

Dr. Peng’s presentation was not directly related to the question of class II or class III designation for existing products. Instead, her talk served as a glimpse into the work already underway in creating apps and tools for consumers.

Google researchers have published a number of studies in recent years about the use of AI to improve dermatology diagnosis.

A 2020 article reported on Google’s test of a form of AI known as deep learning system (DLS) to provide a differential diagnosis of skin conditions. On 963 validation cases, where a rotating panel of three board-certified dermatologists defined the reference standard, the DLS was noninferior to six other dermatologists and was superior to six primary care physicians (PCPs) and six nurse practitioners (NPs), according to a summary of the article.

A 2021 report published in JAMA Network Open said that use of an AI tool was associated with a higher agreement rate with dermatologists’ reference diagnoses for both PCPs and NPs.

In a 2021 blog post, Google scientists wrote that their AI model that powers a tool for checking skin conditions had earned European clearance, known as a CE mark, as a class I medical device.

SkinVision has an app that the company says “is available worldwide (with the exception of the USA and Canada).” The firm’s website includes a link where people in the United States and Canada can sign up for notifications about when SkinVision will be available in these nations. 


 

‘Not ready for prime time’

The FDA panel did not cast formal votes at the July 29 meeting. Rather, the members engaged in broad discussions about risks and potential benefits of new tools for aiding in the detection of skin cancer.

Among the key issues discussed was a question of whether the FDA could impose requirements and restrictions, known as special controls, to provide “reasonable assurance of safety and effectiveness” for computer-aided devices that provide adjunctive diagnostic information to dermatologists about lesions suspicious for melanoma.

Among the potential special controls would be clinical performance testing in regards to rates of the sensitivity (true-positive rate) and specificity (true-negative rate).

The FDA could also look at requirements on software validation and verification and cybersecurity testing, as well as directions on labeling so as to mitigate risk.

Dermatologists serving on the panel called for caution in proceeding with steps that would make it easier for companies to market tools for aiding in melanoma diagnosis than it would be within the class III framework used for MelaFind and Nevisense.

Many expressed concerns about the need to design studies that would answer questions about how well new tools could accurately identify concerning lesions.

The phrase “not ready for prime time” was used at least three times during the discussion.

FDA panelist Maral Skelsey, MD, a skin cancer specialist from Chevy Chase, Maryland, said that over the years, she had used both Nevisense and MelaFind.

She said she had found MelaFind “unusable,” owing in large part to the high number of false positives it generated. The device also was limited as to where on patients’ bodies it could be used.

However, she spoke with enthusiasm about the prospects for better devices to aid in diagnosis of skin lesions. “It’s an area where we’re on the verge, and we really need these devices. There’s a need for patients to be able to examine themselves, for nondermatologists to be able to assess lesions,” Dr. Skelsey said.

But this field is “just not ready for prime time” yet, even with special controls, Dr. Skelsey said. To loosen approval standards too quickly could be a “detriment to what’s coming down the pipeline,” she said.

“It’s harmful to things that are likely to be around the corner,” she said.

FDA panelist Renata Block, PA-C, who works in a Chicago dermatology practice, pressed for maintaining a class III designation. “We are not ready for prime time yet, though the data that is coming down the pipeline on what we have is quite exciting,” Ms. Block said.

FDA panelist Karla V. Ballman, PhD, a statistician from Weill Cornell Medicine, New York, said there would need to be a clear standard for clinical performance before proceeding toward reclassification of devices for aid in detecting melanoma. “I just don’t think it’s ready for prime time at this point and should remain in class III,” she said.

But there was support from some panelists for the idea of a lower bar for clearance, combined with special controls to ensure patient safety.

In expressing her view, FDA panelist Katalin Roth, MD, JD, professor of medicine, George Washington University, Washington, said she was an outlier in her support for the agency’s view that these risks could be managed and that future tools could allow more patients to take a step on the pathway toward critical diagnoses.

“I deal with a lot of people with cancer as a palliative care physician,” Dr. Roth said. “I think what we’re missing here is the issue of time. Melanoma is a terrible disease, and missing the diagnosis is a terrible thing, but I think special controls would be sufficient to counter the concerns of my colleagues on the committee.”

The FDA’s Dr. Ashar ended the meeting with questions posed to one panelist, Veronica Rotemberg, MD, PhD, a dermatologist at Memorial Sloan Kettering Cancer Center in New York.

Dr. Rotemberg has for years been working in the field of research on developing AI and other computer-based tools for detecting and diagnosing melanoma, the deadliest form of skin cancer.

She has been publicly skeptical of the performance of commercial apps that scan moles and other lesions and that claim to identify which are cancerous. A May blog post on the Memorial Sloan Kettering website highlighted a recent British Journal of Dermatology article in which Dr. Rotemberg and coauthors reported on their evaluations of commercial apps. They judged them to be on average only 59% accurate, the blog post said.

However, during an earlier discussion at the meeting, she had spoken more positively about the prospects for using special controls in the near term to mitigate risk, although she said she would have a “very long list” of these requirements.

In the closing exchange with Dr. Ashar, Dr. Rotemberg outlined steps that could potentially ensure the safe use of tools to aid in melanoma screening. These included a need for postmarketing surveillance, which would require evaluation over time of algorithms used in tools meant to detect skin cancer.

“We need to have a mechanism for sampling,” Dr. Rotemberg said. “Most of our data is electronic now anyway, so comparing an algorithm and performance with biopsy results should not be that challenging.”

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

New devices that use artificial intelligence (AI) to diagnose skin cancer – such as smartphone apps – have been popping up over the past few years, but there is some concern over the accuracy of these tools.

So far, the U.S. Food and Drug Administration has cleared two devices. Both are computer-aided skin lesion classification devices meant to help clinicians assess cases of suspected melanoma.

Both were given a class III designation. That classification is intended for products that are considered to have a high risk of harm because of flawed design or implementation. Many such devices are under development, and there has been a proposal to include these devices in class II, which is less restrictive.

The FDA turned to one of its expert panels for advice. At a meeting held on Aug. 29, experts on the panel offered differing views and expressed concerns about the accuracy of these devices.

This was the second day of meetings of the general and plastic surgery devices panel of the FDA’s Medical Devices Advisory Committee. On the previous day, the panel held a wide-ranging discussion about expanding use of skin lesion analyzer devices.

The FDA sought the expert panel’s advice concerning a field that appears to be heating up quickly after relatively quiet times.

Two devices have been approved by the FDA so far, but only one is still being promoted – SciBase AB’s Nevisense. The Swedish company announced in May 2020 that it had received FDA approval for Nevisense 3.0, the third generation of their Nevisense system for early melanoma detection, an AI-based point-of-care system for the noninvasive evaluation of irregular moles.

The other device, known as MelaFind, was acquired by Strata Skin Sciences, but the company said in 2017 that it discontinued research and development, sales, and support activity related to the device, according to a filing with the Securities and Exchange Commission.

But there’s been a swell in recent years in the number of publications related to the use of AI and machine learning, which could give rise to new tools for aiding in the diagnosis of skin conditions, including cancer. Google is among the companies that are involved in these efforts.

So, the FDA asked the expert panel to discuss a series of questions related to how the agency should weigh the risks of computer-aided devices for melanoma diagnosis. The agency also asked the panel to provide feedback about how well risks associated with such devices and tools might be managed and to offer suggestions.

The discussion at the July 29 meeting spun beyond narrow questions about reclassification of the current class III devices to topics involving emerging technology, such as efforts to apply AI to dermatology.

“Innovation continues. Medical device developers are anxious to plan how they might be able to develop the level of evidence that would meet your expectations” for future products, Binita Ashar, MD, a senior official in FDA’s Center for Devices and Radiological Health, told the panel.


 

Company CEO backs tougher regulation

Simon Grant, the chief executive of SciBase, which markets Nevisense, the first and only skin cancer–detecting device currently on the U.S. market, sought to make a case for sticking with the tougher class III regulations.

Speaking during the public comment session, Mr. Grant said switching to class II designations would weaken the standards used in clearing products that analyze skin lesions so as to put patients at risk.

Under the FDA’s rules, the agency designates as class III devices that present potential unreasonable risk of illness or injury. Only about 10% of devices fall into this category. Such devices include implantable pacemakers and breast implants, as well as SciBase’s Nevisense.

About 43% of medical devices fall into the class II category, which includes powered wheelchairs and some pregnancy test kits, the FDA website says.

Class I medical devices pose minimal potential for harm and tend to be simpler in design. These include enema kits and elastic bandages, the FDA says.

Mr. Grant told the meeting that in his career he has worked on two class III products and about 20 class II products. (He had previously worked at medical startups Synectics Medical and Neoventa, as well as established multinationals such as Medtronic.)

“I can tell you that – practically – the FDA has many fewer sticks and much less control when it comes to class II devices,” he said. He offered an example of a manufacturer of a class II device having more latitude in making small changes to products without notifying the FDA.

In his hypothetical example, such a change could have unintended consequences, and “with AI systems, small changes can result in large and nonlinear or even random effects,” Mr. Grant said. “But it’s too late if the product is on the market and the harm has already occurred,” he said.

The American Society for Dermatologic Surgery Association also protested the reclassifying of approved computer-aided melanoma detection class III devices.

In a statement posted on the FDA website as part of the materials for the meeting, the ASDSA raised a series of concerns about the prospects of expanded U.S. use of tools for assisting in diagnosing melanoma, including ones that would be marketed to consumers.

“To the extent that algorithms and devices for patient self-diagnosis of skin lesions are already widely available, they should be required to include detailed disclaimers that include that they are for entertainment and educational purposes and not a diagnostic device, that they are not approved by dermatologists or a recognized medical regulatory authority for self-diagnosis,” the ASDSA said.

Devices and algorithms in screening tools “are not highly regulated and remain unproven. They may result in wrong diagnoses, missed diagnoses, or over- or underdiagnosis,” the ASDSA added. “Both patients at low risk and those at high risk are better served by scheduling an in-person examination with a board-certified dermatologist, who can also help them determine the appropriate future skin screening schedule that is most appropriate for them.”

 

‘Stepping stone’

However, there is strong consumer demand for better information about skin conditions, and many patients face hurdles in going to dermatologists.

Google research has shown that consumers are seeking “a stepping stone” between the information they can easily find online and what they could get from a medical professional, said Lily Peng, MD, PhD, a director of product management for the health AI team at Google. Dr. Peng was a scheduled presenter at the July 29 meeting.

Consumers often are looking for more information on common conditions such as acne and poison ivy, and they sometimes face challenges in getting access to clinicians, she said.

“There are many unmet needs for consumers experiencing skin issues, many of which are lower-acuity conditions. There’s a big opportunity to increase accessibility and relevance of health journeys for consumers,” Dr. Peng said. “We have heard from consumers that they would like to have a self-help tool for nonserious conditions so they can decide when to seek medical attention.”

Dr. Peng’s presentation was not directly related to the question of class II or class III designation for existing products. Instead, her talk served as a glimpse into the work already underway in creating apps and tools for consumers.

Google researchers have published a number of studies in recent years about the use of AI to improve dermatology diagnosis.

A 2020 article reported on Google’s test of a form of AI known as deep learning system (DLS) to provide a differential diagnosis of skin conditions. On 963 validation cases, where a rotating panel of three board-certified dermatologists defined the reference standard, the DLS was noninferior to six other dermatologists and was superior to six primary care physicians (PCPs) and six nurse practitioners (NPs), according to a summary of the article.

A 2021 report published in JAMA Network Open said that use of an AI tool was associated with a higher agreement rate with dermatologists’ reference diagnoses for both PCPs and NPs.

In a 2021 blog post, Google scientists wrote that their AI model that powers a tool for checking skin conditions had earned European clearance, known as a CE mark, as a class I medical device.

SkinVision has an app that the company says “is available worldwide (with the exception of the USA and Canada).” The firm’s website includes a link where people in the United States and Canada can sign up for notifications about when SkinVision will be available in these nations. 


 

‘Not ready for prime time’

The FDA panel did not cast formal votes at the July 29 meeting. Rather, the members engaged in broad discussions about risks and potential benefits of new tools for aiding in the detection of skin cancer.

Among the key issues discussed was a question of whether the FDA could impose requirements and restrictions, known as special controls, to provide “reasonable assurance of safety and effectiveness” for computer-aided devices that provide adjunctive diagnostic information to dermatologists about lesions suspicious for melanoma.

Among the potential special controls would be clinical performance testing in regards to rates of the sensitivity (true-positive rate) and specificity (true-negative rate).

The FDA could also look at requirements on software validation and verification and cybersecurity testing, as well as directions on labeling so as to mitigate risk.

Dermatologists serving on the panel called for caution in proceeding with steps that would make it easier for companies to market tools for aiding in melanoma diagnosis than it would be within the class III framework used for MelaFind and Nevisense.

Many expressed concerns about the need to design studies that would answer questions about how well new tools could accurately identify concerning lesions.

The phrase “not ready for prime time” was used at least three times during the discussion.

FDA panelist Maral Skelsey, MD, a skin cancer specialist from Chevy Chase, Maryland, said that over the years, she had used both Nevisense and MelaFind.

She said she had found MelaFind “unusable,” owing in large part to the high number of false positives it generated. The device also was limited as to where on patients’ bodies it could be used.

However, she spoke with enthusiasm about the prospects for better devices to aid in diagnosis of skin lesions. “It’s an area where we’re on the verge, and we really need these devices. There’s a need for patients to be able to examine themselves, for nondermatologists to be able to assess lesions,” Dr. Skelsey said.

But this field is “just not ready for prime time” yet, even with special controls, Dr. Skelsey said. To loosen approval standards too quickly could be a “detriment to what’s coming down the pipeline,” she said.

“It’s harmful to things that are likely to be around the corner,” she said.

FDA panelist Renata Block, PA-C, who works in a Chicago dermatology practice, pressed for maintaining a class III designation. “We are not ready for prime time yet, though the data that is coming down the pipeline on what we have is quite exciting,” Ms. Block said.

FDA panelist Karla V. Ballman, PhD, a statistician from Weill Cornell Medicine, New York, said there would need to be a clear standard for clinical performance before proceeding toward reclassification of devices for aid in detecting melanoma. “I just don’t think it’s ready for prime time at this point and should remain in class III,” she said.

But there was support from some panelists for the idea of a lower bar for clearance, combined with special controls to ensure patient safety.

In expressing her view, FDA panelist Katalin Roth, MD, JD, professor of medicine, George Washington University, Washington, said she was an outlier in her support for the agency’s view that these risks could be managed and that future tools could allow more patients to take a step on the pathway toward critical diagnoses.

“I deal with a lot of people with cancer as a palliative care physician,” Dr. Roth said. “I think what we’re missing here is the issue of time. Melanoma is a terrible disease, and missing the diagnosis is a terrible thing, but I think special controls would be sufficient to counter the concerns of my colleagues on the committee.”

The FDA’s Dr. Ashar ended the meeting with questions posed to one panelist, Veronica Rotemberg, MD, PhD, a dermatologist at Memorial Sloan Kettering Cancer Center in New York.

Dr. Rotemberg has for years been working in the field of research on developing AI and other computer-based tools for detecting and diagnosing melanoma, the deadliest form of skin cancer.

She has been publicly skeptical of the performance of commercial apps that scan moles and other lesions and that claim to identify which are cancerous. A May blog post on the Memorial Sloan Kettering website highlighted a recent British Journal of Dermatology article in which Dr. Rotemberg and coauthors reported on their evaluations of commercial apps. They judged them to be on average only 59% accurate, the blog post said.

However, during an earlier discussion at the meeting, she had spoken more positively about the prospects for using special controls in the near term to mitigate risk, although she said she would have a “very long list” of these requirements.

In the closing exchange with Dr. Ashar, Dr. Rotemberg outlined steps that could potentially ensure the safe use of tools to aid in melanoma screening. These included a need for postmarketing surveillance, which would require evaluation over time of algorithms used in tools meant to detect skin cancer.

“We need to have a mechanism for sampling,” Dr. Rotemberg said. “Most of our data is electronic now anyway, so comparing an algorithm and performance with biopsy results should not be that challenging.”

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

MONTREAL – Interim results of ALLIANCE, the first head-to-head trial comparing two different tenofovir-containing antiretroviral regimens for the treatment of HIV and hepatitis B (HBV) coinfection, demonstrate the superiority of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) over dolutegravir plus tenofovir disoproxil fumarate (DTG + F/TDF), researchers reported at a meeting of the International AIDS Society.

While both regimens showed similar efficacy for HIV control, the B/F/TAF regimen produced better HBV results, with more HBV DNA suppression and significantly more seroconversion, reported lead investigator Anchalee Avihingsanon, MD, PhD, at a press conference during the meeting. Dr. Avihingsanon heads the medical department of the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) at the Thai Red Cross AIDS Research Centre, Bangkok.

The ongoing phase 3, multicountry study has 48-week results for 243 participants, who were HIV/HBV coinfected and treatment naive. All subjects received three pills of ART per day, with blinded randomization to (active B/F/TAF + placebo DTG + placebo TDF/FTC or placebo B/F/TAF + active DTG + active TDF/FTC). The primary endpoints at 48 weeks were proportion of participants with HIV-1 RNA less than 50 copies/mL and plasma HBV DNA less than 29 IU/mL.

For the HIV endpoint, results showed both the B/F/TAF and DTG + F/TDF arms had high rates of suppression (95% and 91%, respectively, P = .21), but the B/F/TAF group had significantly higher rates of HBV DNA suppression (63% vs 43.4%, P = .0023) and HBeAg seroconversion (23.3% vs. 11.3%), with numerically higher, but not statistically significant differences in HBsAg loss/seroconversion (12.6% vs. 5.8% and 8.4% vs. 3.3%), HBeAg loss (25.6% vs 14.4%), and ALT normalization (73.3% vs 55.3%).

No participant developed treatment-emergent HIV-1 drug resistance while on B/F/TAF, and there were few study-drug–related AEs or discontinuations, she reported.

“There is hardly any good reason to give the two-pill DTG regimen over single-tablet BTG/TAF/FTC in HBV-coinfected people living with HIV [PLWH],” commented Babafemi Taiwo, MD, chief of infectious diseases and professor of medicine at Northwestern University in Evanston, Ill., who was not involved in the research. “This gives me confidence to prescribe bictegravir/TAF/FTC, which has the added advantage of being a single-tablet formulation, to HBV coinfected PLWH,” he said in an interview. However, he added, the results “call for some head-scratching since TAF is not known to be better than TDF for HBV treatment in persons without HIV.”

“The lower response rate of the TDF group is still poorly understood,” agreed Dr. Avihingsanon, emphasizing that “HBV and HIV/HBV are not the same, and TDF and TAF are also different. TAF has slightly more drug-drug interactions than TDF. I guess its end product in the liver might be higher. What is exciting to me is that there was such a high rate of HBsAg loss and HBs seroconversion in HIV/HBV coinfection, which is totally different from HBV monoinfection [< 1% at 48 weeks]. For me as an investigator, this important finding has additional benefit to further explore the immunologic outcome for possible HBV cure strategy.” She said the study remains blinded until week 96, at which time further data may shed light on this question. 

“Perhaps a larger study would help clarify impact of TAF versus TDF on measures that did not achieve statistical significance in this study. Long-term follow up to better understand the clinical implications of these results could be helpful as well,” Dr. Taiwo added.

The study was funded by Gilead. Dr. Avihingsanon reported no relevant disclosures. Dr. Taiwo disclosed that he has served as consultant to ViiV/GlaxoSmithKline, Johnson & Johnson, and Merck, and consulted for Gilead on COVID.

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

MONTREAL – Interim results of ALLIANCE, the first head-to-head trial comparing two different tenofovir-containing antiretroviral regimens for the treatment of HIV and hepatitis B (HBV) coinfection, demonstrate the superiority of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) over dolutegravir plus tenofovir disoproxil fumarate (DTG + F/TDF), researchers reported at a meeting of the International AIDS Society.

While both regimens showed similar efficacy for HIV control, the B/F/TAF regimen produced better HBV results, with more HBV DNA suppression and significantly more seroconversion, reported lead investigator Anchalee Avihingsanon, MD, PhD, at a press conference during the meeting. Dr. Avihingsanon heads the medical department of the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) at the Thai Red Cross AIDS Research Centre, Bangkok.

The ongoing phase 3, multicountry study has 48-week results for 243 participants, who were HIV/HBV coinfected and treatment naive. All subjects received three pills of ART per day, with blinded randomization to (active B/F/TAF + placebo DTG + placebo TDF/FTC or placebo B/F/TAF + active DTG + active TDF/FTC). The primary endpoints at 48 weeks were proportion of participants with HIV-1 RNA less than 50 copies/mL and plasma HBV DNA less than 29 IU/mL.

For the HIV endpoint, results showed both the B/F/TAF and DTG + F/TDF arms had high rates of suppression (95% and 91%, respectively, P = .21), but the B/F/TAF group had significantly higher rates of HBV DNA suppression (63% vs 43.4%, P = .0023) and HBeAg seroconversion (23.3% vs. 11.3%), with numerically higher, but not statistically significant differences in HBsAg loss/seroconversion (12.6% vs. 5.8% and 8.4% vs. 3.3%), HBeAg loss (25.6% vs 14.4%), and ALT normalization (73.3% vs 55.3%).

No participant developed treatment-emergent HIV-1 drug resistance while on B/F/TAF, and there were few study-drug–related AEs or discontinuations, she reported.

“There is hardly any good reason to give the two-pill DTG regimen over single-tablet BTG/TAF/FTC in HBV-coinfected people living with HIV [PLWH],” commented Babafemi Taiwo, MD, chief of infectious diseases and professor of medicine at Northwestern University in Evanston, Ill., who was not involved in the research. “This gives me confidence to prescribe bictegravir/TAF/FTC, which has the added advantage of being a single-tablet formulation, to HBV coinfected PLWH,” he said in an interview. However, he added, the results “call for some head-scratching since TAF is not known to be better than TDF for HBV treatment in persons without HIV.”

“The lower response rate of the TDF group is still poorly understood,” agreed Dr. Avihingsanon, emphasizing that “HBV and HIV/HBV are not the same, and TDF and TAF are also different. TAF has slightly more drug-drug interactions than TDF. I guess its end product in the liver might be higher. What is exciting to me is that there was such a high rate of HBsAg loss and HBs seroconversion in HIV/HBV coinfection, which is totally different from HBV monoinfection [< 1% at 48 weeks]. For me as an investigator, this important finding has additional benefit to further explore the immunologic outcome for possible HBV cure strategy.” She said the study remains blinded until week 96, at which time further data may shed light on this question. 

“Perhaps a larger study would help clarify impact of TAF versus TDF on measures that did not achieve statistical significance in this study. Long-term follow up to better understand the clinical implications of these results could be helpful as well,” Dr. Taiwo added.

The study was funded by Gilead. Dr. Avihingsanon reported no relevant disclosures. Dr. Taiwo disclosed that he has served as consultant to ViiV/GlaxoSmithKline, Johnson & Johnson, and Merck, and consulted for Gilead on COVID.

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

MONTREAL – Interim results of ALLIANCE, the first head-to-head trial comparing two different tenofovir-containing antiretroviral regimens for the treatment of HIV and hepatitis B (HBV) coinfection, demonstrate the superiority of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) over dolutegravir plus tenofovir disoproxil fumarate (DTG + F/TDF), researchers reported at a meeting of the International AIDS Society.

While both regimens showed similar efficacy for HIV control, the B/F/TAF regimen produced better HBV results, with more HBV DNA suppression and significantly more seroconversion, reported lead investigator Anchalee Avihingsanon, MD, PhD, at a press conference during the meeting. Dr. Avihingsanon heads the medical department of the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) at the Thai Red Cross AIDS Research Centre, Bangkok.

The ongoing phase 3, multicountry study has 48-week results for 243 participants, who were HIV/HBV coinfected and treatment naive. All subjects received three pills of ART per day, with blinded randomization to (active B/F/TAF + placebo DTG + placebo TDF/FTC or placebo B/F/TAF + active DTG + active TDF/FTC). The primary endpoints at 48 weeks were proportion of participants with HIV-1 RNA less than 50 copies/mL and plasma HBV DNA less than 29 IU/mL.

For the HIV endpoint, results showed both the B/F/TAF and DTG + F/TDF arms had high rates of suppression (95% and 91%, respectively, P = .21), but the B/F/TAF group had significantly higher rates of HBV DNA suppression (63% vs 43.4%, P = .0023) and HBeAg seroconversion (23.3% vs. 11.3%), with numerically higher, but not statistically significant differences in HBsAg loss/seroconversion (12.6% vs. 5.8% and 8.4% vs. 3.3%), HBeAg loss (25.6% vs 14.4%), and ALT normalization (73.3% vs 55.3%).

No participant developed treatment-emergent HIV-1 drug resistance while on B/F/TAF, and there were few study-drug–related AEs or discontinuations, she reported.

“There is hardly any good reason to give the two-pill DTG regimen over single-tablet BTG/TAF/FTC in HBV-coinfected people living with HIV [PLWH],” commented Babafemi Taiwo, MD, chief of infectious diseases and professor of medicine at Northwestern University in Evanston, Ill., who was not involved in the research. “This gives me confidence to prescribe bictegravir/TAF/FTC, which has the added advantage of being a single-tablet formulation, to HBV coinfected PLWH,” he said in an interview. However, he added, the results “call for some head-scratching since TAF is not known to be better than TDF for HBV treatment in persons without HIV.”

“The lower response rate of the TDF group is still poorly understood,” agreed Dr. Avihingsanon, emphasizing that “HBV and HIV/HBV are not the same, and TDF and TAF are also different. TAF has slightly more drug-drug interactions than TDF. I guess its end product in the liver might be higher. What is exciting to me is that there was such a high rate of HBsAg loss and HBs seroconversion in HIV/HBV coinfection, which is totally different from HBV monoinfection [< 1% at 48 weeks]. For me as an investigator, this important finding has additional benefit to further explore the immunologic outcome for possible HBV cure strategy.” She said the study remains blinded until week 96, at which time further data may shed light on this question. 

“Perhaps a larger study would help clarify impact of TAF versus TDF on measures that did not achieve statistical significance in this study. Long-term follow up to better understand the clinical implications of these results could be helpful as well,” Dr. Taiwo added.

The study was funded by Gilead. Dr. Avihingsanon reported no relevant disclosures. Dr. Taiwo disclosed that he has served as consultant to ViiV/GlaxoSmithKline, Johnson & Johnson, and Merck, and consulted for Gilead on COVID.

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

A new study sheds light on some of the risk factors for the development of psychosis, including the potentially causative role of sexual assault.

Investigators conducted an exposome-wide association analysis on more than 155,000 individuals. Of more than 140 correlates of psychotic experiences that they identified, they narrowed it down to 36 variables, which they further explored using Mendelian randomization analysis.

The analysis found that having been the victim of a sexual assault might be a potential causal risk factor for psychotic experiences. On the other hand, having experienced a physical violent crime, cannabis use, and prolonged worry after embarrassment showed a pleiotropic association and appeared to be an aftereffect of psychotic experience.

“From a public health perspective, we need more investment in comprehensive strategies to prevent traumatic experiences at the population level to decrease the burden of psychosis,” senior author Sinan Gülöksüz, MD, PhD, associate professor in the department of psychiatry and neuropsychiatry, Maastricht University Medical Center, the Netherlands, said in an interview.

“From a clinical perspective, clinicians should be aware of the harmful influence of traumatic experiences on mental health and address this through interventions such as trauma-informed care,” he said.

The study was published online in JAMA Psychiatry.

‘Disentangling’ cause and effect

“Previous research has shown associations between psychosis and a few environmental factors, such as substance use, urbanicity, pregnancy complications, and traumatic experiences, but research has so far investigated only a few specific environmental factors by singling them out in individual studies,” Dr. Gülöksüz said.

“Yet, environment is a much more complex and interactive network that includes many factors shaping our health – where we live, what we eat, our lifestyle preferences and habits such as exercise and smoking, and our social surrounding,” he continued. “Rarely has it been possible to understand whether these environmental factors have causal roles in developing psychosis.”

To investigate the question, the researchers turned to the UK Biobank, one of the largest population-based datasets in the world. The current study focused on individuals with completed data on mental questionnaires that assessed psychotic experiences (n = 155,247; mean [SD] age, 55.94 [7.74] years; 57% female).

They began by conducting an exposome-wide association study, using logistic regression analyses with psychotic experiences as the outcome and adjusting all analyses for age and sex.

“Initially, we identified many associations between environmental factors and psychotic experiences in this large cohort,” Dr. Gülöksüz reported.

In the final multivariable model, variables associated with psychotic experiences were further analyzed using “genetically informed approaches to probe potential associations.”

The researchers utilized Mendelian randomization (MR) methodology “to disentangle cause and effect in this observational study,” Dr. Gülöksüz said. “This method reduces confounding and reverse causation in observational studies by using genetic variants that have been passed on from generation to generation randomly as instruments.”

MR analysis “has allowed us to assess whether these associations reflect potentially causal influences of environmental factors on psychotic experiences,” he added.
 

Well-studied and unexplored risk factors

The researchers identified 162 variables associated with psychotic experiences in the discovery dataset and were able to replicate 148. When these 148 variables were subjected to multivariable analyses, 36 were found to be statistically significantly associated with psychotic experiences. Of these variables, 28 had “significant genetic overlap” with psychotic experiences.

When the researchers conducted one-sample MR analyses, they found forward associations with three variables and reverse associations with three variables.

Forward associations were found with ever having experienced sexual assault (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.14-1.52; P = 2.67), and forward associations (with pleiotropy) were found with ever having experienced a physically violent crime and risk-taking behavior (OR, 1.25, 95% CI, 1.11-1.41; P = 3.28 and OR, 1.21, 95% CI, 1.08-1.35; P = 1.34, respectively).

“The allele scores for these 3 variables explained 0.03% to 0.23% variance of the corresponding variable” and the F statistics “ranged from 21.53 to 181.84, indicating that the results did not suffer from a weak-instrument bias,” the authors reported.

The researchers calculated an instrument based on increasing psychotic experiences risk allele scores and found that these scores explained 0.14% variance of psychotic experiences (F statistic, 19.26).

Using that calculation, they found a reverse association with having experienced a physically violent crime (OR, 1.08; 95% CI, 1.04-1.13; P = 3.92 × 10-4), cannabis use (OR, 1.11; 95% CI, 1.06-1.15; P = 2.64 × 10-6), and worrying too long after embarrassment (OR, 1.06; 95% CI, 1.03-1.10; P = 3.96 × 10-4). They then validated these associations.

The presence of all five correlates was associated with tenfold increased odds of psychotic experiences (OR, 10.63; 95% CI, 8.27-13.65, P = 1.2 × 10-114).

“Associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables,” the authors stated.
 

Era of ‘big data’

In a comment, Chirag Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, who was not involved with the study, said he thought the study was “a nice example of a data-driven and comprehensive study of the environment coupled with attempts to triangulate evidence from genetics, made possible by biobank data.

“To guide public health policies and implementation of prevention strategies for psychosis, we need more systematic analyses and triangulate evidence with genetically informed methods to identify potentially modifiable risk factors in the era of ‘big data,’ ” he said.

“For instance, traumatic experiences contribute to poor mental and physical health, including psychosis,” Dr. Gülöksüz added.

The Kootstra Talent Fellowship, the Ophelia Research Project, and the Vidi Award from the Netherlands Scientific Organization provided funding to individual investigators. Dr. Gülöksüz and coauthors declared no relevant financial conflicts. Dr. Patel served as a reviewer on the study.

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

A new study sheds light on some of the risk factors for the development of psychosis, including the potentially causative role of sexual assault.

Investigators conducted an exposome-wide association analysis on more than 155,000 individuals. Of more than 140 correlates of psychotic experiences that they identified, they narrowed it down to 36 variables, which they further explored using Mendelian randomization analysis.

The analysis found that having been the victim of a sexual assault might be a potential causal risk factor for psychotic experiences. On the other hand, having experienced a physical violent crime, cannabis use, and prolonged worry after embarrassment showed a pleiotropic association and appeared to be an aftereffect of psychotic experience.

“From a public health perspective, we need more investment in comprehensive strategies to prevent traumatic experiences at the population level to decrease the burden of psychosis,” senior author Sinan Gülöksüz, MD, PhD, associate professor in the department of psychiatry and neuropsychiatry, Maastricht University Medical Center, the Netherlands, said in an interview.

“From a clinical perspective, clinicians should be aware of the harmful influence of traumatic experiences on mental health and address this through interventions such as trauma-informed care,” he said.

The study was published online in JAMA Psychiatry.

‘Disentangling’ cause and effect

“Previous research has shown associations between psychosis and a few environmental factors, such as substance use, urbanicity, pregnancy complications, and traumatic experiences, but research has so far investigated only a few specific environmental factors by singling them out in individual studies,” Dr. Gülöksüz said.

“Yet, environment is a much more complex and interactive network that includes many factors shaping our health – where we live, what we eat, our lifestyle preferences and habits such as exercise and smoking, and our social surrounding,” he continued. “Rarely has it been possible to understand whether these environmental factors have causal roles in developing psychosis.”

To investigate the question, the researchers turned to the UK Biobank, one of the largest population-based datasets in the world. The current study focused on individuals with completed data on mental questionnaires that assessed psychotic experiences (n = 155,247; mean [SD] age, 55.94 [7.74] years; 57% female).

They began by conducting an exposome-wide association study, using logistic regression analyses with psychotic experiences as the outcome and adjusting all analyses for age and sex.

“Initially, we identified many associations between environmental factors and psychotic experiences in this large cohort,” Dr. Gülöksüz reported.

In the final multivariable model, variables associated with psychotic experiences were further analyzed using “genetically informed approaches to probe potential associations.”

The researchers utilized Mendelian randomization (MR) methodology “to disentangle cause and effect in this observational study,” Dr. Gülöksüz said. “This method reduces confounding and reverse causation in observational studies by using genetic variants that have been passed on from generation to generation randomly as instruments.”

MR analysis “has allowed us to assess whether these associations reflect potentially causal influences of environmental factors on psychotic experiences,” he added.
 

Well-studied and unexplored risk factors

The researchers identified 162 variables associated with psychotic experiences in the discovery dataset and were able to replicate 148. When these 148 variables were subjected to multivariable analyses, 36 were found to be statistically significantly associated with psychotic experiences. Of these variables, 28 had “significant genetic overlap” with psychotic experiences.

When the researchers conducted one-sample MR analyses, they found forward associations with three variables and reverse associations with three variables.

Forward associations were found with ever having experienced sexual assault (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.14-1.52; P = 2.67), and forward associations (with pleiotropy) were found with ever having experienced a physically violent crime and risk-taking behavior (OR, 1.25, 95% CI, 1.11-1.41; P = 3.28 and OR, 1.21, 95% CI, 1.08-1.35; P = 1.34, respectively).

“The allele scores for these 3 variables explained 0.03% to 0.23% variance of the corresponding variable” and the F statistics “ranged from 21.53 to 181.84, indicating that the results did not suffer from a weak-instrument bias,” the authors reported.

The researchers calculated an instrument based on increasing psychotic experiences risk allele scores and found that these scores explained 0.14% variance of psychotic experiences (F statistic, 19.26).

Using that calculation, they found a reverse association with having experienced a physically violent crime (OR, 1.08; 95% CI, 1.04-1.13; P = 3.92 × 10-4), cannabis use (OR, 1.11; 95% CI, 1.06-1.15; P = 2.64 × 10-6), and worrying too long after embarrassment (OR, 1.06; 95% CI, 1.03-1.10; P = 3.96 × 10-4). They then validated these associations.

The presence of all five correlates was associated with tenfold increased odds of psychotic experiences (OR, 10.63; 95% CI, 8.27-13.65, P = 1.2 × 10-114).

“Associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables,” the authors stated.
 

Era of ‘big data’

In a comment, Chirag Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, who was not involved with the study, said he thought the study was “a nice example of a data-driven and comprehensive study of the environment coupled with attempts to triangulate evidence from genetics, made possible by biobank data.

“To guide public health policies and implementation of prevention strategies for psychosis, we need more systematic analyses and triangulate evidence with genetically informed methods to identify potentially modifiable risk factors in the era of ‘big data,’ ” he said.

“For instance, traumatic experiences contribute to poor mental and physical health, including psychosis,” Dr. Gülöksüz added.

The Kootstra Talent Fellowship, the Ophelia Research Project, and the Vidi Award from the Netherlands Scientific Organization provided funding to individual investigators. Dr. Gülöksüz and coauthors declared no relevant financial conflicts. Dr. Patel served as a reviewer on the study.

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

A new study sheds light on some of the risk factors for the development of psychosis, including the potentially causative role of sexual assault.

Investigators conducted an exposome-wide association analysis on more than 155,000 individuals. Of more than 140 correlates of psychotic experiences that they identified, they narrowed it down to 36 variables, which they further explored using Mendelian randomization analysis.

The analysis found that having been the victim of a sexual assault might be a potential causal risk factor for psychotic experiences. On the other hand, having experienced a physical violent crime, cannabis use, and prolonged worry after embarrassment showed a pleiotropic association and appeared to be an aftereffect of psychotic experience.

“From a public health perspective, we need more investment in comprehensive strategies to prevent traumatic experiences at the population level to decrease the burden of psychosis,” senior author Sinan Gülöksüz, MD, PhD, associate professor in the department of psychiatry and neuropsychiatry, Maastricht University Medical Center, the Netherlands, said in an interview.

“From a clinical perspective, clinicians should be aware of the harmful influence of traumatic experiences on mental health and address this through interventions such as trauma-informed care,” he said.

The study was published online in JAMA Psychiatry.

‘Disentangling’ cause and effect

“Previous research has shown associations between psychosis and a few environmental factors, such as substance use, urbanicity, pregnancy complications, and traumatic experiences, but research has so far investigated only a few specific environmental factors by singling them out in individual studies,” Dr. Gülöksüz said.

“Yet, environment is a much more complex and interactive network that includes many factors shaping our health – where we live, what we eat, our lifestyle preferences and habits such as exercise and smoking, and our social surrounding,” he continued. “Rarely has it been possible to understand whether these environmental factors have causal roles in developing psychosis.”

To investigate the question, the researchers turned to the UK Biobank, one of the largest population-based datasets in the world. The current study focused on individuals with completed data on mental questionnaires that assessed psychotic experiences (n = 155,247; mean [SD] age, 55.94 [7.74] years; 57% female).

They began by conducting an exposome-wide association study, using logistic regression analyses with psychotic experiences as the outcome and adjusting all analyses for age and sex.

“Initially, we identified many associations between environmental factors and psychotic experiences in this large cohort,” Dr. Gülöksüz reported.

In the final multivariable model, variables associated with psychotic experiences were further analyzed using “genetically informed approaches to probe potential associations.”

The researchers utilized Mendelian randomization (MR) methodology “to disentangle cause and effect in this observational study,” Dr. Gülöksüz said. “This method reduces confounding and reverse causation in observational studies by using genetic variants that have been passed on from generation to generation randomly as instruments.”

MR analysis “has allowed us to assess whether these associations reflect potentially causal influences of environmental factors on psychotic experiences,” he added.
 

Well-studied and unexplored risk factors

The researchers identified 162 variables associated with psychotic experiences in the discovery dataset and were able to replicate 148. When these 148 variables were subjected to multivariable analyses, 36 were found to be statistically significantly associated with psychotic experiences. Of these variables, 28 had “significant genetic overlap” with psychotic experiences.

When the researchers conducted one-sample MR analyses, they found forward associations with three variables and reverse associations with three variables.

Forward associations were found with ever having experienced sexual assault (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.14-1.52; P = 2.67), and forward associations (with pleiotropy) were found with ever having experienced a physically violent crime and risk-taking behavior (OR, 1.25, 95% CI, 1.11-1.41; P = 3.28 and OR, 1.21, 95% CI, 1.08-1.35; P = 1.34, respectively).

“The allele scores for these 3 variables explained 0.03% to 0.23% variance of the corresponding variable” and the F statistics “ranged from 21.53 to 181.84, indicating that the results did not suffer from a weak-instrument bias,” the authors reported.

The researchers calculated an instrument based on increasing psychotic experiences risk allele scores and found that these scores explained 0.14% variance of psychotic experiences (F statistic, 19.26).

Using that calculation, they found a reverse association with having experienced a physically violent crime (OR, 1.08; 95% CI, 1.04-1.13; P = 3.92 × 10-4), cannabis use (OR, 1.11; 95% CI, 1.06-1.15; P = 2.64 × 10-6), and worrying too long after embarrassment (OR, 1.06; 95% CI, 1.03-1.10; P = 3.96 × 10-4). They then validated these associations.

The presence of all five correlates was associated with tenfold increased odds of psychotic experiences (OR, 10.63; 95% CI, 8.27-13.65, P = 1.2 × 10-114).

“Associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables,” the authors stated.
 

Era of ‘big data’

In a comment, Chirag Patel, PhD, associate professor of biomedical informatics at Harvard Medical School, Boston, who was not involved with the study, said he thought the study was “a nice example of a data-driven and comprehensive study of the environment coupled with attempts to triangulate evidence from genetics, made possible by biobank data.

“To guide public health policies and implementation of prevention strategies for psychosis, we need more systematic analyses and triangulate evidence with genetically informed methods to identify potentially modifiable risk factors in the era of ‘big data,’ ” he said.

“For instance, traumatic experiences contribute to poor mental and physical health, including psychosis,” Dr. Gülöksüz added.

The Kootstra Talent Fellowship, the Ophelia Research Project, and the Vidi Award from the Netherlands Scientific Organization provided funding to individual investigators. Dr. Gülöksüz and coauthors declared no relevant financial conflicts. Dr. Patel served as a reviewer on the study.

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

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

There was no significant increase in the post-COVID pandemic monthly rate of incident diabetes in children and youth in Ontario, compared with the pre-pandemic rate, in new research.

This contrasts with findings from a U.S. study and a German study, but this is “not the final word” about this possible association, lead author Rayzel Shulman, MD, admits, since the study may have been underpowered.

The population-based, cross-sectional study was published recently as a research letter in JAMA Open.

The researchers found a nonsignificant increase in the monthly rate of new diabetes during the first 18 months of the COVID-19 pandemic, compared with the 3 prior years (relative risk 1.09, 95% confidence interval).
 

New study contrasts with previous reports

This differs from a Morbidity and Mortality Weekly Report from the U.S. Centers for Disease Control and Prevention, in which COVID-19 infection was associated with a significant increase in new onset of diabetes in children during March 2020 through June 2021, “although some experts have criticized the study methods and conclusion validity,” Dr. Shulman and colleagues write.

Another study, from Germany, reported a significant 1.15-fold increase in type 1 diabetes in children during the pandemic, they note.

The current study may have been underpowered and too small to show a significant association between COVID-19 and new diabetes, the researchers acknowledge. 

And the 1.30 upper limit of the confidence interval shows that it “cannot rule out a possible 1.3-fold increase” in relative risk of a diagnosis of diabetes related to COVID, Dr. Shulman explained to this news organization. 

It will be important to see how the rates have changed since September 2021 (the end of the current study), added Dr. Shulman, an adjunct scientist at the Institute for Clinical Evaluative Sciences (ICES) and a physician and scientist at the Hospital for Sick Children, Toronto.

The current study did find a decreased (delayed) rate of diagnosis of new diabetes during the first months of the pandemic when there were lockdowns, followed by a “catch-up” increase in rates later on, as has been reported earlier.

“Our study is definitely not the final word on this,” Dr. Shulman summarized in a statement from ICES. “However, our findings call into question whether a direct association between COVID-19 and new-onset diabetes in children exists.”
 

COVID-diabetes link?

The researchers analyzed health administrative data from January 2017 to September 2021.

They identified 2,700,178 children and youth in Ontario who were under age 18 in 2021, who had a mean age of 9.2, and about half were girls.

Between November 2020 and April 2021, an estimated 3.3% of children in Ontario had a SARS-COV-2 infection.

New diagnoses of diabetes in this age group are mostly type 1 diabetes, based on previous studies.

The rate of incident diabetes was 15%-32% lower during the first 3 months of the pandemic, March-May 2020 (1.67-2.34 cases per 100,000), compared with the pre-pandemic monthly rate during 2017, 2018, and 2019 (2.54-2.59 cases per 100,000).

The rate of incident diabetes was 33%-50% higher during February to July 2021 (3.48-4.18 cases per 100,000), compared with the pre-pandemic rate.

The pre-pandemic and pandemic monthly rates of incident diabetes were similar during the other months.

The group concludes: “The lack of both an observable increase in overall diabetes incidence among children during the 18-month pandemic restrictions [in this Ontario study] and a plausible biological mechanism call into question an association between COVID-19 and new-onset diabetes.”

More research is needed. “Given the variability in monthly [relative risks], additional population-based, longer-term data are needed to examine the direct and indirect effects of COVID-19 and diabetes risk among children,” the authors write.

This study was supported by ICES (which is funded by the Ontario Ministry of Health) and by a grant from the Canadian Institutes of Health Research. Dr. Shulman reported receiving fees from Dexcom outside the submitted work, and she and three other authors reported receiving grants from the Canadian Institutes of Health Research outside the submitted work.

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

There was no significant increase in the post-COVID pandemic monthly rate of incident diabetes in children and youth in Ontario, compared with the pre-pandemic rate, in new research.

This contrasts with findings from a U.S. study and a German study, but this is “not the final word” about this possible association, lead author Rayzel Shulman, MD, admits, since the study may have been underpowered.

The population-based, cross-sectional study was published recently as a research letter in JAMA Open.

The researchers found a nonsignificant increase in the monthly rate of new diabetes during the first 18 months of the COVID-19 pandemic, compared with the 3 prior years (relative risk 1.09, 95% confidence interval).
 

New study contrasts with previous reports

This differs from a Morbidity and Mortality Weekly Report from the U.S. Centers for Disease Control and Prevention, in which COVID-19 infection was associated with a significant increase in new onset of diabetes in children during March 2020 through June 2021, “although some experts have criticized the study methods and conclusion validity,” Dr. Shulman and colleagues write.

Another study, from Germany, reported a significant 1.15-fold increase in type 1 diabetes in children during the pandemic, they note.

The current study may have been underpowered and too small to show a significant association between COVID-19 and new diabetes, the researchers acknowledge. 

And the 1.30 upper limit of the confidence interval shows that it “cannot rule out a possible 1.3-fold increase” in relative risk of a diagnosis of diabetes related to COVID, Dr. Shulman explained to this news organization. 

It will be important to see how the rates have changed since September 2021 (the end of the current study), added Dr. Shulman, an adjunct scientist at the Institute for Clinical Evaluative Sciences (ICES) and a physician and scientist at the Hospital for Sick Children, Toronto.

The current study did find a decreased (delayed) rate of diagnosis of new diabetes during the first months of the pandemic when there were lockdowns, followed by a “catch-up” increase in rates later on, as has been reported earlier.

“Our study is definitely not the final word on this,” Dr. Shulman summarized in a statement from ICES. “However, our findings call into question whether a direct association between COVID-19 and new-onset diabetes in children exists.”
 

COVID-diabetes link?

The researchers analyzed health administrative data from January 2017 to September 2021.

They identified 2,700,178 children and youth in Ontario who were under age 18 in 2021, who had a mean age of 9.2, and about half were girls.

Between November 2020 and April 2021, an estimated 3.3% of children in Ontario had a SARS-COV-2 infection.

New diagnoses of diabetes in this age group are mostly type 1 diabetes, based on previous studies.

The rate of incident diabetes was 15%-32% lower during the first 3 months of the pandemic, March-May 2020 (1.67-2.34 cases per 100,000), compared with the pre-pandemic monthly rate during 2017, 2018, and 2019 (2.54-2.59 cases per 100,000).

The rate of incident diabetes was 33%-50% higher during February to July 2021 (3.48-4.18 cases per 100,000), compared with the pre-pandemic rate.

The pre-pandemic and pandemic monthly rates of incident diabetes were similar during the other months.

The group concludes: “The lack of both an observable increase in overall diabetes incidence among children during the 18-month pandemic restrictions [in this Ontario study] and a plausible biological mechanism call into question an association between COVID-19 and new-onset diabetes.”

More research is needed. “Given the variability in monthly [relative risks], additional population-based, longer-term data are needed to examine the direct and indirect effects of COVID-19 and diabetes risk among children,” the authors write.

This study was supported by ICES (which is funded by the Ontario Ministry of Health) and by a grant from the Canadian Institutes of Health Research. Dr. Shulman reported receiving fees from Dexcom outside the submitted work, and she and three other authors reported receiving grants from the Canadian Institutes of Health Research outside the submitted work.

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

There was no significant increase in the post-COVID pandemic monthly rate of incident diabetes in children and youth in Ontario, compared with the pre-pandemic rate, in new research.

This contrasts with findings from a U.S. study and a German study, but this is “not the final word” about this possible association, lead author Rayzel Shulman, MD, admits, since the study may have been underpowered.

The population-based, cross-sectional study was published recently as a research letter in JAMA Open.

The researchers found a nonsignificant increase in the monthly rate of new diabetes during the first 18 months of the COVID-19 pandemic, compared with the 3 prior years (relative risk 1.09, 95% confidence interval).
 

New study contrasts with previous reports

This differs from a Morbidity and Mortality Weekly Report from the U.S. Centers for Disease Control and Prevention, in which COVID-19 infection was associated with a significant increase in new onset of diabetes in children during March 2020 through June 2021, “although some experts have criticized the study methods and conclusion validity,” Dr. Shulman and colleagues write.

Another study, from Germany, reported a significant 1.15-fold increase in type 1 diabetes in children during the pandemic, they note.

The current study may have been underpowered and too small to show a significant association between COVID-19 and new diabetes, the researchers acknowledge. 

And the 1.30 upper limit of the confidence interval shows that it “cannot rule out a possible 1.3-fold increase” in relative risk of a diagnosis of diabetes related to COVID, Dr. Shulman explained to this news organization. 

It will be important to see how the rates have changed since September 2021 (the end of the current study), added Dr. Shulman, an adjunct scientist at the Institute for Clinical Evaluative Sciences (ICES) and a physician and scientist at the Hospital for Sick Children, Toronto.

The current study did find a decreased (delayed) rate of diagnosis of new diabetes during the first months of the pandemic when there were lockdowns, followed by a “catch-up” increase in rates later on, as has been reported earlier.

“Our study is definitely not the final word on this,” Dr. Shulman summarized in a statement from ICES. “However, our findings call into question whether a direct association between COVID-19 and new-onset diabetes in children exists.”
 

COVID-diabetes link?

The researchers analyzed health administrative data from January 2017 to September 2021.

They identified 2,700,178 children and youth in Ontario who were under age 18 in 2021, who had a mean age of 9.2, and about half were girls.

Between November 2020 and April 2021, an estimated 3.3% of children in Ontario had a SARS-COV-2 infection.

New diagnoses of diabetes in this age group are mostly type 1 diabetes, based on previous studies.

The rate of incident diabetes was 15%-32% lower during the first 3 months of the pandemic, March-May 2020 (1.67-2.34 cases per 100,000), compared with the pre-pandemic monthly rate during 2017, 2018, and 2019 (2.54-2.59 cases per 100,000).

The rate of incident diabetes was 33%-50% higher during February to July 2021 (3.48-4.18 cases per 100,000), compared with the pre-pandemic rate.

The pre-pandemic and pandemic monthly rates of incident diabetes were similar during the other months.

The group concludes: “The lack of both an observable increase in overall diabetes incidence among children during the 18-month pandemic restrictions [in this Ontario study] and a plausible biological mechanism call into question an association between COVID-19 and new-onset diabetes.”

More research is needed. “Given the variability in monthly [relative risks], additional population-based, longer-term data are needed to examine the direct and indirect effects of COVID-19 and diabetes risk among children,” the authors write.

This study was supported by ICES (which is funded by the Ontario Ministry of Health) and by a grant from the Canadian Institutes of Health Research. Dr. Shulman reported receiving fees from Dexcom outside the submitted work, and she and three other authors reported receiving grants from the Canadian Institutes of Health Research outside the submitted work.

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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