Jim Kling

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

In a phase 2 cohort study, the KRAS (G12C) inhibitor adagrasib induced an objective response in about one out of three patients with KRAS (G12C)–mutated non–small cell lung cancer (NSCLC) who had previously been treated with platinum-based chemotherapy and immune therapy.

Adagrasib targets KRAS (G12C), which had long been thought undruggable until research published in 2013 revealed a new binding pocket that did not compete directly against the protein’s natural binding partner. The new trial further validates the approach. “It supports that clinically effective targeted therapies can be developed for patients with KRAS (G12C)–mutant NSCLC,” said Pasi Jänne, MD, PhD, who is the lead author of the study describing the new results published online in the New England Journal of Medicine.

KRAS is the most frequently mutated oncogene in human cancers. A mutated form is found in about 25% of NSCLCs. KRAS plays a key role in cell signaling governing growth, maturation, and cell death. The mutated form is linked to cancer growth and spread. Patients with mutated KRAS have few effective treatment options.

Adagrasib is currently under study and not yet approved by the Food and Drug Administration. However, sotorasib (Lumakras, Amgen), which also inhibits KRAS (G12C), was approved in May 2021 by the FDA for KRAS (G12C)–mutated NSCLC. There are some key differences between the drugs. Adagrasib has a half-life of 23 hours versus 5 hours for sotorasib, and the newer drug has the potential to penetrate the central nervous system. That could be an important consideration in NSCLC since it often metastasizes to the brain. “Having pharmacological approaches to treat brain metastases is a wonderful new therapeutic option for lung cancer patients,” said Dr. Jänne, who is director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, Boston.

Adagrasib is being investigated as part of the KRYSTAL-1 study, alone and as part of combinations in various solid tumors. Previously treated NSCLC KRAS (G12C) patients are also being enrolled in a phase 3 study of adagrasib combined with docetaxel, as well as another phase 2 study of adagrasib combined with pembrolizumab as first-line therapy for NSCLC KRAS (G12C).

Adagrasib is likely to remain a second-line therapy following chemotherapy and immunotherapy. “The activity by itself at the moment is not sufficient to be a first-line treatment. That may change in the future in combination with a standard of care agent or in a subset of patients with KRAS (G12C)–mutant NSCLC, although no subset with higher efficacy has been identified to date. Identification of predictive biomarkers for patients likely to benefit from single agent or an adagrasib combination treatment remains a high priority,” Dr. Jänne said.

The study included 116 patients who had previously been treated with platinum-based chemotherapy and anti–programmed death 1 or programmed death–ligand 1 therapy. They received 600 mg oral adagrasib twice per day over a median follow-up period of 12.9 months. About 42.9% (95% confidence interval, 33.5%-52.6%) experienced a confirmed objective response with a median duration of 8.5 months (95% CI, 6.2-13.8 months). The median progression-free survival was 6.5 months (95% CI, 4.7-8.4 months). After a median follow-up of 15.6 months, the median overall survival was 12.6 months (95% CI, 9.2-19.2 months). The estimated overall survival at 1 year was 50.8% (95% CI, 40.9%-60.0%).

33 patients had stable central nervous system metastases that had been previously treated. About 33.3% had an intracranial confirmed objective response (95% CI, 18.0-51.8%) with a median duration of response of 11.2 months (95% CI, 2.99 months to not available).

Adverse events are similar to what is seen with other targeted therapies, according to Dr. Jänne. 97.4% of patient reported a treatment-related adverse event; 52.6% had grade 1-2 adverse events, and 44.8% had grade 3 adverse events. 6.9% discontinued the drug as a result.

Dr. Jänne has consulted for Mirati Therapeutics and is a member of its scientific advisory board. The study was funded by Mirati Therapeutics.

Incidence and mortality for biliary tract cancer (BTC) are both on the rise worldwide, according to a new analysis of data from the International Agency for Research on Cancer and the World Health Organization.

This diverse group of hepatic and perihepatic cancers include gallbladder cancer (GBC), intrahepatic and extrahepatic cholangiocarcinoma (ICC and ECC), and ampulla of Vater cancer. Although BTC is considered rare, incidence of its subtypes can vary significantly by geographic region. Because BTC is typically asymptomatic in its early stage, diagnosis is often made after tumors have spread, when there are few therapeutic options available. In the United States and Europe, 5-year survival is less than 20%.

Although previous studies have examined worldwide BTC incidence, few looked at multiple global regions or at all subtypes. Instead, subtypes may be grouped together and reported as composites, or BTC is lumped together with primary liver cancer. “To our knowledge, this is the first report combining data on worldwide incidence and mortality of all BTC subtypes per the International Classification of Diseases, Tenth Revision,” the authors wrote in the study, published online in Gastro Hep Advances.

The researchers pointed out that classification coding systems have improved at defining BTC subtypes, so that studies using older coding subtypes could cause misinterpretation of incidence rates.

BTC subtypes also have unique sets of risk factors and different prognoses and treatment outcomes. “Thus, there is a need to define accurate epidemiologic trends that will allow specific risk factors to be identified, guiding experts in implementing policies to improve diagnosis and survival,” the authors wrote.

The study included data from 22 countries. BTC incidence ranged from 1.12 cases per 100,000 person-years in Vietnam to 12.42 in Chile. As expected, incidence rates were higher in the Asia-Pacific region (1.12-9.00) and South America (2.73-12.42), compared with Europe (2.00-3.59) and North America (2.33-2.35). Within the United States, Asian Americans had a higher BTC incidence than the general population (2.99 vs. 2.33).

In most countries, new cases were dominated by GBC, while ICC was the most common cause of death.

In each country, older patients were 5-10 times more likely to die than BTC patients generally. The sixth and seventh decades of life are the most common time of diagnosis, and treatment options may be limited in older patients.

Risk factors for BTC may include common comorbidities like obesity, nonalcoholic fatty liver disease, and diabetes. Each is increasing individually, which may in turn contribute to rising BTC incidence. Observational analyses suggest that obesity may contribute to risk of ECC and gallbladder cancer, while diabetes and obesity may raise the risk of ICC. Smoking is associated with increased risk of all BTC subtypes except GBC, and alcohol consumption is associated with ICC.

“This study highlights how each subtype may be vulnerable to specific risk factors and emphasizes the value of separating epidemiologic data by subtype in order to better understand disease etiology,” the researchers wrote.

Risk factors associated with incidence and mortality from BTC aren’t limited to clinical characteristics. Genetic susceptibility may also play a role in incidence and mortality of different subtypes. There is also a relationship between gallstones and BTC risk. In Chile, about 50% of women have gallstones versus 17% of women in the United States. The cancer incidence is 27 per 100,000 person-years in Chile and 2 per 100,000 person-years in the United States. BTC is also the leading cause of cancer death among women in Chile.

The authors also highlighted the high rates of gallbladder cancer in India, despite a low prevalence of gallstones. Incidences can vary with geography along the flow of the Ganges River, which might reflect varying risks from contamination caused by agricultural runoff or industrial or human waste.

Worldwide BTC incidence and mortality was generally higher among women than men, with the exception of ampulla of Vater cancer, which was more common in men.

The study is limited by quality of data, which varied significantly between countries. Mortality data was missing from some countries know to have high BTC incidence. The databases had little survival data, which could have provided insights into treatment efficacy.

The study was funded by AstraZeneca. The authors have extensive financial relationships with pharmaceutical companies.

Incidence and mortality for biliary tract cancer (BTC) are both on the rise worldwide, according to a new analysis of data from the International Agency for Research on Cancer and the World Health Organization.

This diverse group of hepatic and perihepatic cancers include gallbladder cancer (GBC), intrahepatic and extrahepatic cholangiocarcinoma (ICC and ECC), and ampulla of Vater cancer. Although BTC is considered rare, incidence of its subtypes can vary significantly by geographic region. Because BTC is typically asymptomatic in its early stage, diagnosis is often made after tumors have spread, when there are few therapeutic options available. In the United States and Europe, 5-year survival is less than 20%.

Although previous studies have examined worldwide BTC incidence, few looked at multiple global regions or at all subtypes. Instead, subtypes may be grouped together and reported as composites, or BTC is lumped together with primary liver cancer. “To our knowledge, this is the first report combining data on worldwide incidence and mortality of all BTC subtypes per the International Classification of Diseases, Tenth Revision,” the authors wrote in the study, published online in Gastro Hep Advances.

The researchers pointed out that classification coding systems have improved at defining BTC subtypes, so that studies using older coding subtypes could cause misinterpretation of incidence rates.

BTC subtypes also have unique sets of risk factors and different prognoses and treatment outcomes. “Thus, there is a need to define accurate epidemiologic trends that will allow specific risk factors to be identified, guiding experts in implementing policies to improve diagnosis and survival,” the authors wrote.

The study included data from 22 countries. BTC incidence ranged from 1.12 cases per 100,000 person-years in Vietnam to 12.42 in Chile. As expected, incidence rates were higher in the Asia-Pacific region (1.12-9.00) and South America (2.73-12.42), compared with Europe (2.00-3.59) and North America (2.33-2.35). Within the United States, Asian Americans had a higher BTC incidence than the general population (2.99 vs. 2.33).

In most countries, new cases were dominated by GBC, while ICC was the most common cause of death.

In each country, older patients were 5-10 times more likely to die than BTC patients generally. The sixth and seventh decades of life are the most common time of diagnosis, and treatment options may be limited in older patients.

Risk factors for BTC may include common comorbidities like obesity, nonalcoholic fatty liver disease, and diabetes. Each is increasing individually, which may in turn contribute to rising BTC incidence. Observational analyses suggest that obesity may contribute to risk of ECC and gallbladder cancer, while diabetes and obesity may raise the risk of ICC. Smoking is associated with increased risk of all BTC subtypes except GBC, and alcohol consumption is associated with ICC.

“This study highlights how each subtype may be vulnerable to specific risk factors and emphasizes the value of separating epidemiologic data by subtype in order to better understand disease etiology,” the researchers wrote.

Risk factors associated with incidence and mortality from BTC aren’t limited to clinical characteristics. Genetic susceptibility may also play a role in incidence and mortality of different subtypes. There is also a relationship between gallstones and BTC risk. In Chile, about 50% of women have gallstones versus 17% of women in the United States. The cancer incidence is 27 per 100,000 person-years in Chile and 2 per 100,000 person-years in the United States. BTC is also the leading cause of cancer death among women in Chile.

The authors also highlighted the high rates of gallbladder cancer in India, despite a low prevalence of gallstones. Incidences can vary with geography along the flow of the Ganges River, which might reflect varying risks from contamination caused by agricultural runoff or industrial or human waste.

Worldwide BTC incidence and mortality was generally higher among women than men, with the exception of ampulla of Vater cancer, which was more common in men.

The study is limited by quality of data, which varied significantly between countries. Mortality data was missing from some countries know to have high BTC incidence. The databases had little survival data, which could have provided insights into treatment efficacy.

The study was funded by AstraZeneca. The authors have extensive financial relationships with pharmaceutical companies.

Incidence and mortality for biliary tract cancer (BTC) are both on the rise worldwide, according to a new analysis of data from the International Agency for Research on Cancer and the World Health Organization.

This diverse group of hepatic and perihepatic cancers include gallbladder cancer (GBC), intrahepatic and extrahepatic cholangiocarcinoma (ICC and ECC), and ampulla of Vater cancer. Although BTC is considered rare, incidence of its subtypes can vary significantly by geographic region. Because BTC is typically asymptomatic in its early stage, diagnosis is often made after tumors have spread, when there are few therapeutic options available. In the United States and Europe, 5-year survival is less than 20%.

Although previous studies have examined worldwide BTC incidence, few looked at multiple global regions or at all subtypes. Instead, subtypes may be grouped together and reported as composites, or BTC is lumped together with primary liver cancer. “To our knowledge, this is the first report combining data on worldwide incidence and mortality of all BTC subtypes per the International Classification of Diseases, Tenth Revision,” the authors wrote in the study, published online in Gastro Hep Advances.

The researchers pointed out that classification coding systems have improved at defining BTC subtypes, so that studies using older coding subtypes could cause misinterpretation of incidence rates.

BTC subtypes also have unique sets of risk factors and different prognoses and treatment outcomes. “Thus, there is a need to define accurate epidemiologic trends that will allow specific risk factors to be identified, guiding experts in implementing policies to improve diagnosis and survival,” the authors wrote.

The study included data from 22 countries. BTC incidence ranged from 1.12 cases per 100,000 person-years in Vietnam to 12.42 in Chile. As expected, incidence rates were higher in the Asia-Pacific region (1.12-9.00) and South America (2.73-12.42), compared with Europe (2.00-3.59) and North America (2.33-2.35). Within the United States, Asian Americans had a higher BTC incidence than the general population (2.99 vs. 2.33).

In most countries, new cases were dominated by GBC, while ICC was the most common cause of death.

In each country, older patients were 5-10 times more likely to die than BTC patients generally. The sixth and seventh decades of life are the most common time of diagnosis, and treatment options may be limited in older patients.

Risk factors for BTC may include common comorbidities like obesity, nonalcoholic fatty liver disease, and diabetes. Each is increasing individually, which may in turn contribute to rising BTC incidence. Observational analyses suggest that obesity may contribute to risk of ECC and gallbladder cancer, while diabetes and obesity may raise the risk of ICC. Smoking is associated with increased risk of all BTC subtypes except GBC, and alcohol consumption is associated with ICC.

“This study highlights how each subtype may be vulnerable to specific risk factors and emphasizes the value of separating epidemiologic data by subtype in order to better understand disease etiology,” the researchers wrote.

Risk factors associated with incidence and mortality from BTC aren’t limited to clinical characteristics. Genetic susceptibility may also play a role in incidence and mortality of different subtypes. There is also a relationship between gallstones and BTC risk. In Chile, about 50% of women have gallstones versus 17% of women in the United States. The cancer incidence is 27 per 100,000 person-years in Chile and 2 per 100,000 person-years in the United States. BTC is also the leading cause of cancer death among women in Chile.

The authors also highlighted the high rates of gallbladder cancer in India, despite a low prevalence of gallstones. Incidences can vary with geography along the flow of the Ganges River, which might reflect varying risks from contamination caused by agricultural runoff or industrial or human waste.

Worldwide BTC incidence and mortality was generally higher among women than men, with the exception of ampulla of Vater cancer, which was more common in men.

The study is limited by quality of data, which varied significantly between countries. Mortality data was missing from some countries know to have high BTC incidence. The databases had little survival data, which could have provided insights into treatment efficacy.

The study was funded by AstraZeneca. The authors have extensive financial relationships with pharmaceutical companies.

A new study among patients with inflammatory bowel disease (IBD) suggests that viral antigen persistence in the gut may contribute to post-acute COVID-19 syndrome.

Postacute COVID-19 syndrome is now understood to be a multiorgan condition with symptoms that may include fatigue, cognitive dysfunction, and pain. Poor baseline health and severe acute infection are risk factors for the condition, but nonhospitalized illness can also lead to persistent symptoms.

Researchers found that nearly two-thirds of IBD patients had persistence of the antigen in infected tissues up to 8 months after a mild (nonhospitalized) acute COVID-19 infection. The study is the first to tie gut antigen persistence to post-acute COVID symptoms, and the results imply that the antigen may lead to immune perturbation and ongoing symptoms.

The study was published online in Gastroenterology.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the membrane-bound angiotensin-converting enzyme 2 to gain entry into cells, which is expressed in the brush border enterocytes, as well as elsewhere in the body.

Previous research using intestinal epithelial organoids confirmed that SARS-CoV-2 is capable of infecting the human epithelium and that the virus can be detected in anal swabs long after it is cleared from nasal passages.

One potential explanation is viral immune perturbation or inflammatory tissue injury. Supporting evidence includes neural accumulation of memory T cells in patients with neuropsychiatric symptoms such as malaise and depression, and similar changes are seen with age-related immune senescence and tissue injury. Hyperactivated B and T cells, as well as other innate immune cells, have also been linked to postacute COVID-19, as has heightened expression of proinflammatory cytokines.

To explore the potential role of persistent viral antigens, the researchers gathered biopsies during upper- and lower-gastrointestinal endoscopy in 46 patients with IBD whose prior COVID-19 infection (mean, 7.3 months previous) had been confirmed by polymerase chain reaction and who were seen at the IBD outpatient unit of the investigators’ institution. In all, 43.5% of patients were female, and the average age was 44.67 years. Overall, 67.4% had been diagnosed with Crohn’s disease, 28.3% with ulcerative colitis, and 4.3% had unclassified IBD; 23.9% had a history of exposure to anti–tumor necrosis factor therapy. Among patients in the study, 32 of the patients tested positive for mucosal SARS-CoV-2 RNA, and there was no association between the presence of viral RNA and IBD type.

The researchers found that 52%-70% of patients had antigen persistence in any gut segment, as measured by nucleocapsid immunofluorescence or expression of one of four viral transcripts. They detected persistence of the nucleocapsid in epithelial cells and CD8+ T cells. Viral antigens persisted in patients with and without exposure to immunosuppressive therapy, and there was no association with antigen persistence and severity of acute COVID-19 infection or the presence of inflammation at the time of the endoscopy.

The researchers believed that the persistent viral antigen reflects incomplete clearance from the original infection rather than a latent or persistent infection because they could not replicate the virus in biopsy samples. Most biopsies within a patient produced some, but not all, of the viral transcripts tested. The authors suggest that immunosuppressive therapy may lead to incomplete viral clearance. Some patients lacked humoral nucleocapsid IgG antibodies, especially among those with gut antigen persistence.

In fact, only patients with gut viral RNA persistence had symptoms of postacute COVID. “This observation strongly argues for a role of viral antigen persistence in postacute COVID-19 and it appears plausible that SARS-CoV-2 antigen persistence, possibly in infected tissues beyond the gut, could impact host immune responses underlying the postacute COVID-19 syndrome,” the researchers wrote.

There is precedent for such a phenomenon in influenza. Mouse models have shown that ineffective clearance can influence adaptive immune responses and memory T-cell formation in lymph nodes of the lung. Another report found that COVID-19 pneumonia survivors have persistent changes to pulmonary CD8+ T cells.

The study is limited by its small sample size and a lack of a replication cohort. The study was also conducted in IBD patients because the researchers believed they were at higher risk of COVID-19 infection, although the researchers note that viral antigen persistence has been observed 2 months after recovery from COVID-19 in patients without IBD or exposure to immunosuppressants.

The researchers call for studies in patients without IBD to determine whether viral antigen persistence is a key mechanism in postacute COVID-19.

The researchers have no relevant financial disclosures.

A new study among patients with inflammatory bowel disease (IBD) suggests that viral antigen persistence in the gut may contribute to post-acute COVID-19 syndrome.

Postacute COVID-19 syndrome is now understood to be a multiorgan condition with symptoms that may include fatigue, cognitive dysfunction, and pain. Poor baseline health and severe acute infection are risk factors for the condition, but nonhospitalized illness can also lead to persistent symptoms.

Researchers found that nearly two-thirds of IBD patients had persistence of the antigen in infected tissues up to 8 months after a mild (nonhospitalized) acute COVID-19 infection. The study is the first to tie gut antigen persistence to post-acute COVID symptoms, and the results imply that the antigen may lead to immune perturbation and ongoing symptoms.

The study was published online in Gastroenterology.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the membrane-bound angiotensin-converting enzyme 2 to gain entry into cells, which is expressed in the brush border enterocytes, as well as elsewhere in the body.

Previous research using intestinal epithelial organoids confirmed that SARS-CoV-2 is capable of infecting the human epithelium and that the virus can be detected in anal swabs long after it is cleared from nasal passages.

One potential explanation is viral immune perturbation or inflammatory tissue injury. Supporting evidence includes neural accumulation of memory T cells in patients with neuropsychiatric symptoms such as malaise and depression, and similar changes are seen with age-related immune senescence and tissue injury. Hyperactivated B and T cells, as well as other innate immune cells, have also been linked to postacute COVID-19, as has heightened expression of proinflammatory cytokines.

To explore the potential role of persistent viral antigens, the researchers gathered biopsies during upper- and lower-gastrointestinal endoscopy in 46 patients with IBD whose prior COVID-19 infection (mean, 7.3 months previous) had been confirmed by polymerase chain reaction and who were seen at the IBD outpatient unit of the investigators’ institution. In all, 43.5% of patients were female, and the average age was 44.67 years. Overall, 67.4% had been diagnosed with Crohn’s disease, 28.3% with ulcerative colitis, and 4.3% had unclassified IBD; 23.9% had a history of exposure to anti–tumor necrosis factor therapy. Among patients in the study, 32 of the patients tested positive for mucosal SARS-CoV-2 RNA, and there was no association between the presence of viral RNA and IBD type.

The researchers found that 52%-70% of patients had antigen persistence in any gut segment, as measured by nucleocapsid immunofluorescence or expression of one of four viral transcripts. They detected persistence of the nucleocapsid in epithelial cells and CD8+ T cells. Viral antigens persisted in patients with and without exposure to immunosuppressive therapy, and there was no association with antigen persistence and severity of acute COVID-19 infection or the presence of inflammation at the time of the endoscopy.

The researchers believed that the persistent viral antigen reflects incomplete clearance from the original infection rather than a latent or persistent infection because they could not replicate the virus in biopsy samples. Most biopsies within a patient produced some, but not all, of the viral transcripts tested. The authors suggest that immunosuppressive therapy may lead to incomplete viral clearance. Some patients lacked humoral nucleocapsid IgG antibodies, especially among those with gut antigen persistence.

In fact, only patients with gut viral RNA persistence had symptoms of postacute COVID. “This observation strongly argues for a role of viral antigen persistence in postacute COVID-19 and it appears plausible that SARS-CoV-2 antigen persistence, possibly in infected tissues beyond the gut, could impact host immune responses underlying the postacute COVID-19 syndrome,” the researchers wrote.

There is precedent for such a phenomenon in influenza. Mouse models have shown that ineffective clearance can influence adaptive immune responses and memory T-cell formation in lymph nodes of the lung. Another report found that COVID-19 pneumonia survivors have persistent changes to pulmonary CD8+ T cells.

The study is limited by its small sample size and a lack of a replication cohort. The study was also conducted in IBD patients because the researchers believed they were at higher risk of COVID-19 infection, although the researchers note that viral antigen persistence has been observed 2 months after recovery from COVID-19 in patients without IBD or exposure to immunosuppressants.

The researchers call for studies in patients without IBD to determine whether viral antigen persistence is a key mechanism in postacute COVID-19.

The researchers have no relevant financial disclosures.

A new study among patients with inflammatory bowel disease (IBD) suggests that viral antigen persistence in the gut may contribute to post-acute COVID-19 syndrome.

Postacute COVID-19 syndrome is now understood to be a multiorgan condition with symptoms that may include fatigue, cognitive dysfunction, and pain. Poor baseline health and severe acute infection are risk factors for the condition, but nonhospitalized illness can also lead to persistent symptoms.

Researchers found that nearly two-thirds of IBD patients had persistence of the antigen in infected tissues up to 8 months after a mild (nonhospitalized) acute COVID-19 infection. The study is the first to tie gut antigen persistence to post-acute COVID symptoms, and the results imply that the antigen may lead to immune perturbation and ongoing symptoms.

The study was published online in Gastroenterology.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the membrane-bound angiotensin-converting enzyme 2 to gain entry into cells, which is expressed in the brush border enterocytes, as well as elsewhere in the body.

Previous research using intestinal epithelial organoids confirmed that SARS-CoV-2 is capable of infecting the human epithelium and that the virus can be detected in anal swabs long after it is cleared from nasal passages.

One potential explanation is viral immune perturbation or inflammatory tissue injury. Supporting evidence includes neural accumulation of memory T cells in patients with neuropsychiatric symptoms such as malaise and depression, and similar changes are seen with age-related immune senescence and tissue injury. Hyperactivated B and T cells, as well as other innate immune cells, have also been linked to postacute COVID-19, as has heightened expression of proinflammatory cytokines.

To explore the potential role of persistent viral antigens, the researchers gathered biopsies during upper- and lower-gastrointestinal endoscopy in 46 patients with IBD whose prior COVID-19 infection (mean, 7.3 months previous) had been confirmed by polymerase chain reaction and who were seen at the IBD outpatient unit of the investigators’ institution. In all, 43.5% of patients were female, and the average age was 44.67 years. Overall, 67.4% had been diagnosed with Crohn’s disease, 28.3% with ulcerative colitis, and 4.3% had unclassified IBD; 23.9% had a history of exposure to anti–tumor necrosis factor therapy. Among patients in the study, 32 of the patients tested positive for mucosal SARS-CoV-2 RNA, and there was no association between the presence of viral RNA and IBD type.

The researchers found that 52%-70% of patients had antigen persistence in any gut segment, as measured by nucleocapsid immunofluorescence or expression of one of four viral transcripts. They detected persistence of the nucleocapsid in epithelial cells and CD8+ T cells. Viral antigens persisted in patients with and without exposure to immunosuppressive therapy, and there was no association with antigen persistence and severity of acute COVID-19 infection or the presence of inflammation at the time of the endoscopy.

The researchers believed that the persistent viral antigen reflects incomplete clearance from the original infection rather than a latent or persistent infection because they could not replicate the virus in biopsy samples. Most biopsies within a patient produced some, but not all, of the viral transcripts tested. The authors suggest that immunosuppressive therapy may lead to incomplete viral clearance. Some patients lacked humoral nucleocapsid IgG antibodies, especially among those with gut antigen persistence.

In fact, only patients with gut viral RNA persistence had symptoms of postacute COVID. “This observation strongly argues for a role of viral antigen persistence in postacute COVID-19 and it appears plausible that SARS-CoV-2 antigen persistence, possibly in infected tissues beyond the gut, could impact host immune responses underlying the postacute COVID-19 syndrome,” the researchers wrote.

There is precedent for such a phenomenon in influenza. Mouse models have shown that ineffective clearance can influence adaptive immune responses and memory T-cell formation in lymph nodes of the lung. Another report found that COVID-19 pneumonia survivors have persistent changes to pulmonary CD8+ T cells.

The study is limited by its small sample size and a lack of a replication cohort. The study was also conducted in IBD patients because the researchers believed they were at higher risk of COVID-19 infection, although the researchers note that viral antigen persistence has been observed 2 months after recovery from COVID-19 in patients without IBD or exposure to immunosuppressants.

The researchers call for studies in patients without IBD to determine whether viral antigen persistence is a key mechanism in postacute COVID-19.

The researchers have no relevant financial disclosures.

Two genes that have been linked separately to rare intestinal diseases appear to share a functional relationship. The genes have independently been linked to osteo-oto-hepato-enteric (O2HE) syndrome and microvillus inclusion disease (MVID), which are characterized by congenital diarrhea and, in some patients, intrahepatic cholestasis.

It appears that one gene, UNC45A, is directly responsible for the proper function of the protein encoded by the other gene, called MYO5B, according to investigators, who published their findings in Cellular and Molecular Gastroenterology and Hepatology. UNC45A is a chaperone protein that helps proteins fold properly. It has been linked to O2HE patients experiencing congenital diarrhea and intrahepatic cholestasis. The mutation has been identified in four patients from three different families with O2HE, which can also present with sensorineural hearing loss and bone fragility. Cellular analyses have shown that the mutation leads to reduction in protein expression by 70%-90%.

Intestinal symptoms similar to those in O2HE have also been described in diseases caused by mutations in genes that encode the myosin motor proteins that are involved in cellular protein trafficking. This group of disorders includes MVID. The researchers hypothesized that the UNC45A mutation in O2HE might lead to similar symptoms as MVID and others through the altered protein’s failure to assist in the folding of myosin proteins, although to date only the myosin IIa protein has been shown to be a target of UNC45A.

To investigate the possibility, they examined in more detail the relationship between UNC45A and intestinal symptoms. There are various known mutations in myosin proteins. Some have been linked to deafness, but these do not appear to contribute to intestinal symptoms since patients with myelin-related inherited deafness don’t typically have diarrhea. Bone fragility, also sometimes caused by myosin mutations, also appears to be unrelated to intestinal symptoms.

Previous experiments in yeast suggest that the related gene UNC45 may serve as a chaperone for type V myosin: Loss of a yeast version of UNC45 caused a type V myosin called MYO4P to be mislocalized in yeast. In zebrafish, reduction in intestinal levels of the UNC45A gene or the fish’s version of MYO5B interfered with development of intestinal folds.

The researchers used CRISPR-Cas9 gene editing and site-directed mutagenesis in intestinal epithelial and liver cell lines to investigate the relationships between UNC45A and MYO5B mutants. UNC45A depletion or introduction of the UNC45A mutation found in patients led to lower MYO5B expression. Within epithelial cells, loss of UNC45A led to changes in MYO5B–linked processes that are known to play a role in MVID pathogenesis. These included alteration of microvilli development and interference with the location of rat sarcoma–associated binding protein (RAB) 11A–positive recycling endosomes. When normal UNC45A was reintroduced to these cells, MYO5B expression returned. Reintroduction of either UNC45A or MYO5B repaired the alterations to recycling endosome position and microvilli development.

Loss of UNC45A did not appear to affect transcription of the MYO5B gen, which suggests a suggesting a functional interaction between the two at a protein level.

UNC45A has been shown to destabilize microtubules. Exposure of a kidney epithelial cell line to the microtubule-stabilizing drug taxol also led to displacement of RAB11A-positve recycling endosomes, though the specific changes were different than what is seen in MYO5B mutants. The researchers were unable to validate the findings in tissue derived from O2HE patients because of insufficient material, but they maintain that the cell lines used have proven to be highly predictive for the cellular characteristics of MVID.

Overall, the study suggests that reductions in MYO5B and subsequent changes to the cellular processes that depend on it may underlie the intestinal symptoms in O2HE.

The researchers noted that O2HE patients have different phenotypes. Of the four patients they studied, three had severe chronic diarrhea and required parenteral nutrition. One patient later had the diarrhea resolve and her sister did not have diarrhea at all. This heterogeneity in severity and duration of clinical symptoms may be driven by differences in the molecular effects of patient-specific mutations. The two siblings had mutations in a different region of the UNC45A gene than the other two participants.

“Taken together, this study revealed a functional relationship between UNC45A and MYO5B protein expression, thereby connecting two rare congenital diseases with overlapping intestinal symptoms at the molecular level,” the authors wrote.

The authors reported that they had no conflicts of interest.

This article was updated 7/13/22.

Two genes that have been linked separately to rare intestinal diseases appear to share a functional relationship. The genes have independently been linked to osteo-oto-hepato-enteric (O2HE) syndrome and microvillus inclusion disease (MVID), which are characterized by congenital diarrhea and, in some patients, intrahepatic cholestasis.

It appears that one gene, UNC45A, is directly responsible for the proper function of the protein encoded by the other gene, called MYO5B, according to investigators, who published their findings in Cellular and Molecular Gastroenterology and Hepatology. UNC45A is a chaperone protein that helps proteins fold properly. It has been linked to O2HE patients experiencing congenital diarrhea and intrahepatic cholestasis. The mutation has been identified in four patients from three different families with O2HE, which can also present with sensorineural hearing loss and bone fragility. Cellular analyses have shown that the mutation leads to reduction in protein expression by 70%-90%.

Intestinal symptoms similar to those in O2HE have also been described in diseases caused by mutations in genes that encode the myosin motor proteins that are involved in cellular protein trafficking. This group of disorders includes MVID. The researchers hypothesized that the UNC45A mutation in O2HE might lead to similar symptoms as MVID and others through the altered protein’s failure to assist in the folding of myosin proteins, although to date only the myosin IIa protein has been shown to be a target of UNC45A.

To investigate the possibility, they examined in more detail the relationship between UNC45A and intestinal symptoms. There are various known mutations in myosin proteins. Some have been linked to deafness, but these do not appear to contribute to intestinal symptoms since patients with myelin-related inherited deafness don’t typically have diarrhea. Bone fragility, also sometimes caused by myosin mutations, also appears to be unrelated to intestinal symptoms.

Previous experiments in yeast suggest that the related gene UNC45 may serve as a chaperone for type V myosin: Loss of a yeast version of UNC45 caused a type V myosin called MYO4P to be mislocalized in yeast. In zebrafish, reduction in intestinal levels of the UNC45A gene or the fish’s version of MYO5B interfered with development of intestinal folds.

The researchers used CRISPR-Cas9 gene editing and site-directed mutagenesis in intestinal epithelial and liver cell lines to investigate the relationships between UNC45A and MYO5B mutants. UNC45A depletion or introduction of the UNC45A mutation found in patients led to lower MYO5B expression. Within epithelial cells, loss of UNC45A led to changes in MYO5B–linked processes that are known to play a role in MVID pathogenesis. These included alteration of microvilli development and interference with the location of rat sarcoma–associated binding protein (RAB) 11A–positive recycling endosomes. When normal UNC45A was reintroduced to these cells, MYO5B expression returned. Reintroduction of either UNC45A or MYO5B repaired the alterations to recycling endosome position and microvilli development.

Loss of UNC45A did not appear to affect transcription of the MYO5B gen, which suggests a suggesting a functional interaction between the two at a protein level.

UNC45A has been shown to destabilize microtubules. Exposure of a kidney epithelial cell line to the microtubule-stabilizing drug taxol also led to displacement of RAB11A-positve recycling endosomes, though the specific changes were different than what is seen in MYO5B mutants. The researchers were unable to validate the findings in tissue derived from O2HE patients because of insufficient material, but they maintain that the cell lines used have proven to be highly predictive for the cellular characteristics of MVID.

Overall, the study suggests that reductions in MYO5B and subsequent changes to the cellular processes that depend on it may underlie the intestinal symptoms in O2HE.

The researchers noted that O2HE patients have different phenotypes. Of the four patients they studied, three had severe chronic diarrhea and required parenteral nutrition. One patient later had the diarrhea resolve and her sister did not have diarrhea at all. This heterogeneity in severity and duration of clinical symptoms may be driven by differences in the molecular effects of patient-specific mutations. The two siblings had mutations in a different region of the UNC45A gene than the other two participants.

“Taken together, this study revealed a functional relationship between UNC45A and MYO5B protein expression, thereby connecting two rare congenital diseases with overlapping intestinal symptoms at the molecular level,” the authors wrote.

The authors reported that they had no conflicts of interest.

This article was updated 7/13/22.

Two genes that have been linked separately to rare intestinal diseases appear to share a functional relationship. The genes have independently been linked to osteo-oto-hepato-enteric (O2HE) syndrome and microvillus inclusion disease (MVID), which are characterized by congenital diarrhea and, in some patients, intrahepatic cholestasis.

It appears that one gene, UNC45A, is directly responsible for the proper function of the protein encoded by the other gene, called MYO5B, according to investigators, who published their findings in Cellular and Molecular Gastroenterology and Hepatology. UNC45A is a chaperone protein that helps proteins fold properly. It has been linked to O2HE patients experiencing congenital diarrhea and intrahepatic cholestasis. The mutation has been identified in four patients from three different families with O2HE, which can also present with sensorineural hearing loss and bone fragility. Cellular analyses have shown that the mutation leads to reduction in protein expression by 70%-90%.

Intestinal symptoms similar to those in O2HE have also been described in diseases caused by mutations in genes that encode the myosin motor proteins that are involved in cellular protein trafficking. This group of disorders includes MVID. The researchers hypothesized that the UNC45A mutation in O2HE might lead to similar symptoms as MVID and others through the altered protein’s failure to assist in the folding of myosin proteins, although to date only the myosin IIa protein has been shown to be a target of UNC45A.

To investigate the possibility, they examined in more detail the relationship between UNC45A and intestinal symptoms. There are various known mutations in myosin proteins. Some have been linked to deafness, but these do not appear to contribute to intestinal symptoms since patients with myelin-related inherited deafness don’t typically have diarrhea. Bone fragility, also sometimes caused by myosin mutations, also appears to be unrelated to intestinal symptoms.

Previous experiments in yeast suggest that the related gene UNC45 may serve as a chaperone for type V myosin: Loss of a yeast version of UNC45 caused a type V myosin called MYO4P to be mislocalized in yeast. In zebrafish, reduction in intestinal levels of the UNC45A gene or the fish’s version of MYO5B interfered with development of intestinal folds.

The researchers used CRISPR-Cas9 gene editing and site-directed mutagenesis in intestinal epithelial and liver cell lines to investigate the relationships between UNC45A and MYO5B mutants. UNC45A depletion or introduction of the UNC45A mutation found in patients led to lower MYO5B expression. Within epithelial cells, loss of UNC45A led to changes in MYO5B–linked processes that are known to play a role in MVID pathogenesis. These included alteration of microvilli development and interference with the location of rat sarcoma–associated binding protein (RAB) 11A–positive recycling endosomes. When normal UNC45A was reintroduced to these cells, MYO5B expression returned. Reintroduction of either UNC45A or MYO5B repaired the alterations to recycling endosome position and microvilli development.

Loss of UNC45A did not appear to affect transcription of the MYO5B gen, which suggests a suggesting a functional interaction between the two at a protein level.

UNC45A has been shown to destabilize microtubules. Exposure of a kidney epithelial cell line to the microtubule-stabilizing drug taxol also led to displacement of RAB11A-positve recycling endosomes, though the specific changes were different than what is seen in MYO5B mutants. The researchers were unable to validate the findings in tissue derived from O2HE patients because of insufficient material, but they maintain that the cell lines used have proven to be highly predictive for the cellular characteristics of MVID.

Overall, the study suggests that reductions in MYO5B and subsequent changes to the cellular processes that depend on it may underlie the intestinal symptoms in O2HE.

The researchers noted that O2HE patients have different phenotypes. Of the four patients they studied, three had severe chronic diarrhea and required parenteral nutrition. One patient later had the diarrhea resolve and her sister did not have diarrhea at all. This heterogeneity in severity and duration of clinical symptoms may be driven by differences in the molecular effects of patient-specific mutations. The two siblings had mutations in a different region of the UNC45A gene than the other two participants.

“Taken together, this study revealed a functional relationship between UNC45A and MYO5B protein expression, thereby connecting two rare congenital diseases with overlapping intestinal symptoms at the molecular level,” the authors wrote.

The authors reported that they had no conflicts of interest.

This article was updated 7/13/22.

For the first time, the American Society for Clinical Oncology (ASCO) has released guidelines for the treatment of metastatic clear cell renal cell carcinoma.

This year in the U.S., it is estimated that 79,000 men and women will be diagnosed with kidney cancer. Clear cell renal cell carcinoma (ccRCC) is the most common subtype and is a leading source of morbidity and mortality. It is also commonly used to study new targeted molecular therapies. The resulting influx of phase III trial results has transformed ccRCC care. “We have an array of different treatment options, and the structure in which these treatments would be applied needed to have expert input. It is an exciting time for kidney cancer, and optimizing therapy now has immediate and meaningful impact into patients longevity,” guideline lead author W. Kimryn Rathmell, MD, PhD, said in an interview.

“The key developments are the emergence of targeted therapies in addition to immune therapies as well as combinations. The order of treatments matters and different patients will have different needs,” said Dr. Rathmell, professor of medicine at Vanderbilt University, Nashville, Tenn.

Dr. Rathmell highlighted the section of the guideline that discusses the need for robust tissue-based diagnosis, as well as active surveillance or cytoreductive nephrectomy. She also emphasized sections on differentiating courses of treatment and plans the use of International Metastatic RCC Database Consortium (IMDC) risk model.

Cytoreductive nephrectomy is an option for patients with one risk factor in which a significant majority of the tumor is within the kidney. The patients should also have good Eastern Cooperative Oncology Group (ECOG) performance status, and no brain, bone, or liver metastases.

Some with metastatic ccRCC can be offered active surveillance. Defining characteristics include favorable or immediate risk, few or no symptoms, a favorable histologic profile, a long interval between nephrectomy and onset of metastasis, or low burden of metastatic disease.

The guidelines also discuss the need to stratify patients within risk groups. Patients rated as intermediate or poor risk in the first line setting should be treated with two immune checkpoint inhibitors (ICI) or an ICI combined with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI). ICI combined with a VEGFR TKI can be appropriate for patients with favorable risk but requiring systemic therapy. Those with favorable risk or another medical condition can be offered monotherapy with a VEGFR TKI or an ICI. Another first-line option is high-dose interleukin 2, but there are no established criteria for determining which patients are most likely to benefit.

The guideline discusses second- or later-line therapy options, metastasis-directed therapies, and metastatic subsets including bone, brain, and sarcomatoid carcinomas.

The authors pointed out that significant disparity exists among patients with ccRCC, with some patients having much less access to health care because of racial, geographic, or socioeconomic inequities. There are also known biases within ccRCC care: Females and African Americans are less likely than are males to receive systemic therapy and more likely to receive no treatment; African Americans are less likely to receive systemic therapy; and non-Hispanic African Americans and Hispanics less often undergo cytoreductive nephropathy. African Americans with ccRCC have a pattern of worse survival outcomes than do Whites.

The recommendations cannot be applied to renal cell carcinoma with non-clear cell histology.

“It is important to be comfortable with all of the treatment options for ccRCC, because applying them in the best order, and with the most informed ability to determine efficacy, will have a real impact on patient survival. We are near a goal to offer cure to an increasing number of patients, so choosing therapies that offer that option when it may be possible is important, and when cure is not on the table, we can rationally select therapies that allow patients to have more time with their families, with side effects that are manageable,” Dr. Rathmell said.

The IMDC risk stratification methodology needs to be more widely used in routine practice, Dr. Rathmell said.

“The impact was not significant in patient care until we reached a point of having multiple competing options for treatment. The stakes are higher now, so using this resource is important until we get to the next level with biological classifications,” he said.

Similarly, since the stakes are so high, having an accurate diagnosis is important. Even experts in the field are fooled by imaging findings, and over- or undertreatment of patients has a major impact on outcomes. “This is a message that we need to share for establishing best practices,” he said.

“Just because we have agents, the time to use them is as important as the selection of agent. Similarly, for the cytoreductive nephrectomy issue, new data both clarified and caused some confusion. Not every patient has the luxury of a comprehensive and multidisciplinary tumor board, so we felt it was important to provide some guidance that help making those complex decisions,” Dr. Rathmell said.

Dr. Rathmell has no relevant financial disclosures.

For the first time, the American Society for Clinical Oncology (ASCO) has released guidelines for the treatment of metastatic clear cell renal cell carcinoma.

This year in the U.S., it is estimated that 79,000 men and women will be diagnosed with kidney cancer. Clear cell renal cell carcinoma (ccRCC) is the most common subtype and is a leading source of morbidity and mortality. It is also commonly used to study new targeted molecular therapies. The resulting influx of phase III trial results has transformed ccRCC care. “We have an array of different treatment options, and the structure in which these treatments would be applied needed to have expert input. It is an exciting time for kidney cancer, and optimizing therapy now has immediate and meaningful impact into patients longevity,” guideline lead author W. Kimryn Rathmell, MD, PhD, said in an interview.

“The key developments are the emergence of targeted therapies in addition to immune therapies as well as combinations. The order of treatments matters and different patients will have different needs,” said Dr. Rathmell, professor of medicine at Vanderbilt University, Nashville, Tenn.

Dr. Rathmell highlighted the section of the guideline that discusses the need for robust tissue-based diagnosis, as well as active surveillance or cytoreductive nephrectomy. She also emphasized sections on differentiating courses of treatment and plans the use of International Metastatic RCC Database Consortium (IMDC) risk model.

Cytoreductive nephrectomy is an option for patients with one risk factor in which a significant majority of the tumor is within the kidney. The patients should also have good Eastern Cooperative Oncology Group (ECOG) performance status, and no brain, bone, or liver metastases.

Some with metastatic ccRCC can be offered active surveillance. Defining characteristics include favorable or immediate risk, few or no symptoms, a favorable histologic profile, a long interval between nephrectomy and onset of metastasis, or low burden of metastatic disease.

The guidelines also discuss the need to stratify patients within risk groups. Patients rated as intermediate or poor risk in the first line setting should be treated with two immune checkpoint inhibitors (ICI) or an ICI combined with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI). ICI combined with a VEGFR TKI can be appropriate for patients with favorable risk but requiring systemic therapy. Those with favorable risk or another medical condition can be offered monotherapy with a VEGFR TKI or an ICI. Another first-line option is high-dose interleukin 2, but there are no established criteria for determining which patients are most likely to benefit.

The guideline discusses second- or later-line therapy options, metastasis-directed therapies, and metastatic subsets including bone, brain, and sarcomatoid carcinomas.

The authors pointed out that significant disparity exists among patients with ccRCC, with some patients having much less access to health care because of racial, geographic, or socioeconomic inequities. There are also known biases within ccRCC care: Females and African Americans are less likely than are males to receive systemic therapy and more likely to receive no treatment; African Americans are less likely to receive systemic therapy; and non-Hispanic African Americans and Hispanics less often undergo cytoreductive nephropathy. African Americans with ccRCC have a pattern of worse survival outcomes than do Whites.

The recommendations cannot be applied to renal cell carcinoma with non-clear cell histology.

“It is important to be comfortable with all of the treatment options for ccRCC, because applying them in the best order, and with the most informed ability to determine efficacy, will have a real impact on patient survival. We are near a goal to offer cure to an increasing number of patients, so choosing therapies that offer that option when it may be possible is important, and when cure is not on the table, we can rationally select therapies that allow patients to have more time with their families, with side effects that are manageable,” Dr. Rathmell said.

The IMDC risk stratification methodology needs to be more widely used in routine practice, Dr. Rathmell said.

“The impact was not significant in patient care until we reached a point of having multiple competing options for treatment. The stakes are higher now, so using this resource is important until we get to the next level with biological classifications,” he said.

Similarly, since the stakes are so high, having an accurate diagnosis is important. Even experts in the field are fooled by imaging findings, and over- or undertreatment of patients has a major impact on outcomes. “This is a message that we need to share for establishing best practices,” he said.

“Just because we have agents, the time to use them is as important as the selection of agent. Similarly, for the cytoreductive nephrectomy issue, new data both clarified and caused some confusion. Not every patient has the luxury of a comprehensive and multidisciplinary tumor board, so we felt it was important to provide some guidance that help making those complex decisions,” Dr. Rathmell said.

Dr. Rathmell has no relevant financial disclosures.

For the first time, the American Society for Clinical Oncology (ASCO) has released guidelines for the treatment of metastatic clear cell renal cell carcinoma.

This year in the U.S., it is estimated that 79,000 men and women will be diagnosed with kidney cancer. Clear cell renal cell carcinoma (ccRCC) is the most common subtype and is a leading source of morbidity and mortality. It is also commonly used to study new targeted molecular therapies. The resulting influx of phase III trial results has transformed ccRCC care. “We have an array of different treatment options, and the structure in which these treatments would be applied needed to have expert input. It is an exciting time for kidney cancer, and optimizing therapy now has immediate and meaningful impact into patients longevity,” guideline lead author W. Kimryn Rathmell, MD, PhD, said in an interview.

“The key developments are the emergence of targeted therapies in addition to immune therapies as well as combinations. The order of treatments matters and different patients will have different needs,” said Dr. Rathmell, professor of medicine at Vanderbilt University, Nashville, Tenn.

Dr. Rathmell highlighted the section of the guideline that discusses the need for robust tissue-based diagnosis, as well as active surveillance or cytoreductive nephrectomy. She also emphasized sections on differentiating courses of treatment and plans the use of International Metastatic RCC Database Consortium (IMDC) risk model.

Cytoreductive nephrectomy is an option for patients with one risk factor in which a significant majority of the tumor is within the kidney. The patients should also have good Eastern Cooperative Oncology Group (ECOG) performance status, and no brain, bone, or liver metastases.

Some with metastatic ccRCC can be offered active surveillance. Defining characteristics include favorable or immediate risk, few or no symptoms, a favorable histologic profile, a long interval between nephrectomy and onset of metastasis, or low burden of metastatic disease.

The guidelines also discuss the need to stratify patients within risk groups. Patients rated as intermediate or poor risk in the first line setting should be treated with two immune checkpoint inhibitors (ICI) or an ICI combined with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI). ICI combined with a VEGFR TKI can be appropriate for patients with favorable risk but requiring systemic therapy. Those with favorable risk or another medical condition can be offered monotherapy with a VEGFR TKI or an ICI. Another first-line option is high-dose interleukin 2, but there are no established criteria for determining which patients are most likely to benefit.

The guideline discusses second- or later-line therapy options, metastasis-directed therapies, and metastatic subsets including bone, brain, and sarcomatoid carcinomas.

The authors pointed out that significant disparity exists among patients with ccRCC, with some patients having much less access to health care because of racial, geographic, or socioeconomic inequities. There are also known biases within ccRCC care: Females and African Americans are less likely than are males to receive systemic therapy and more likely to receive no treatment; African Americans are less likely to receive systemic therapy; and non-Hispanic African Americans and Hispanics less often undergo cytoreductive nephropathy. African Americans with ccRCC have a pattern of worse survival outcomes than do Whites.

The recommendations cannot be applied to renal cell carcinoma with non-clear cell histology.

“It is important to be comfortable with all of the treatment options for ccRCC, because applying them in the best order, and with the most informed ability to determine efficacy, will have a real impact on patient survival. We are near a goal to offer cure to an increasing number of patients, so choosing therapies that offer that option when it may be possible is important, and when cure is not on the table, we can rationally select therapies that allow patients to have more time with their families, with side effects that are manageable,” Dr. Rathmell said.

The IMDC risk stratification methodology needs to be more widely used in routine practice, Dr. Rathmell said.

“The impact was not significant in patient care until we reached a point of having multiple competing options for treatment. The stakes are higher now, so using this resource is important until we get to the next level with biological classifications,” he said.

Similarly, since the stakes are so high, having an accurate diagnosis is important. Even experts in the field are fooled by imaging findings, and over- or undertreatment of patients has a major impact on outcomes. “This is a message that we need to share for establishing best practices,” he said.

“Just because we have agents, the time to use them is as important as the selection of agent. Similarly, for the cytoreductive nephrectomy issue, new data both clarified and caused some confusion. Not every patient has the luxury of a comprehensive and multidisciplinary tumor board, so we felt it was important to provide some guidance that help making those complex decisions,” Dr. Rathmell said.

Dr. Rathmell has no relevant financial disclosures.

The anti–PD-1 agent nivolumab may have some utility as monotherapy in the treatment of naive advanced clear cell renal cell carcinoma (ccRCC), according results from a new phase 2 clinical trial (HCRN GU16-260).

Patients received nivolumab (Opdivo, Bristol-Myers Squibb) monotherapy in the first phase of the study, with qualifying patients moving on to dual therapy with nivolumab and the anti–CTLA-4 agent ipilimumab (Yervoy, Bristol-Myers Squibb).

“At the moment, monotherapy with anti–PD-1 is not FDA approved in patients with treatment-naive ccRCC. Based on the results of this study, it might be applicable in patients with favorable risk disease where only tyrosine kinase inhibitors or TKI-containing combinations are approved,” lead investigator Michael Atkins, MD, said in an interview. The study was published online in the Journal of Clinical Oncology.

“It shows the contribution of [nivolumab] to the combination in treatment-naive patients. This data was not previously available as nivolumab monotherapy had only been formally tested in patients with prior history of TKI therapy. It also gives valuable information on the role of PD-L1 as a biomarker in response and landmark progression-free survival in patients treated with anti–PD-1 monotherapy,” said Dr. Atkins, who serves as deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

Patients with higher expression rates of PD-L1 had a higher overall response rate and higher probability of progression-free survival at 1 year.

“Nivolumab monotherapy might be an option to consider for patients who want a pure immunotherapy-based regimen but there is concern about risk of toxicity if ipilimumab is added. These might include elderly patients and those with a history or autoimmune conditions,” Dr. Atkins said.

Next on the agenda for the researchers are more extensive biomarker studies of the tissues obtained in the phase 2 study. They hope to identify factors that predict response and resistance in the absence of confounders like combination therapy, primary versus metastatic tumors, and use of nonimmunotherapy endpoints. They will also track treatment-free survival following cessation of therapy at 2 years.

The study “provides much needed first-line data for check point inhibitor monotherapy in an era that is heavily invested in combination strategies,” Martin Voss, MD, wrote in an accompanying editorial. Further studies currently in progress should shed even more light on monotherapy in this patient population. These include the phase 3 CheckMate 8Y8 trial comparing nivolumab with ipilimumab/nivolumab in untreated patients, and the phase 3 PDIGREE23 trial, which is comparing upfront, response-adaptive ipilimumab/nivolumab with escalation through addition of TKIs in patients with progressive disease and de-escalation to nivolumab monotherapy in patients who achieve a complete response, and randomization between the two strategies for nonprogressive disease and non–complete response patients.

However, these phase 3 studies are limited to intermediate- to poor-risk patients. For favorable-risk patients, small cohort studies like HCRN GU16-260 represent the best currently available guide to treatment, Dr. Voss wrote.

In part A of the study, 123 patients received nivolumab for 96 weeks. 35 patients who experienced progressive disease or had a best response of stable disease at 48 weeks became eligible for part B, in which they received the combination of nivolumab and ipilimumab for 12 weeks, and then nivolumab monotherapy for 48 weeks. All patients underwent PD-L1 testing, and tumors were categorized by percentage of tumor cells expressing PD-L1 as 0%, 1%-5%, greater than 5%-20%, and greater than 20%.

The overall objective response rate was 34.1%. 6.5% had a complete response. Patients categorized by International Metastatic RCC Database Consortium category as intermediate or poor risk had an ORR of 25.0%. Those categorized as favorable risk had an ORR of 57.1%, with a complete response rate of 11.4%. Just one patient with favorable risk had progressive disease at their 12-week CT scan. The ORR was higher with increasing percentages of PD-L1 expression, from 26.9% in PD-L1 0 to 50% in PD-L1 1-20 and 75.0% in PD-L1 greater than 20% (P = .002). Five of 7 (71.4%) patients with PD-L1 values of 1 or more had a tumor response to nivolumab monotherapy, but 14 of 23 (60.9%) of those with favorable risk disease and PD-L1 of zero also responded.

The median duration of response was 27.6 months, and progression-free survival was 34.6% at 1 year in the PD-L1 0 and 75.0% in the PD-L1 greater than 20 categories (P = .050). Among patients eligible for part B, the ORR was 11.4%.

Dr. Atkins has consulted or been on the advisory board for Bristol-Myers Squibb.

The anti–PD-1 agent nivolumab may have some utility as monotherapy in the treatment of naive advanced clear cell renal cell carcinoma (ccRCC), according results from a new phase 2 clinical trial (HCRN GU16-260).

Patients received nivolumab (Opdivo, Bristol-Myers Squibb) monotherapy in the first phase of the study, with qualifying patients moving on to dual therapy with nivolumab and the anti–CTLA-4 agent ipilimumab (Yervoy, Bristol-Myers Squibb).

“At the moment, monotherapy with anti–PD-1 is not FDA approved in patients with treatment-naive ccRCC. Based on the results of this study, it might be applicable in patients with favorable risk disease where only tyrosine kinase inhibitors or TKI-containing combinations are approved,” lead investigator Michael Atkins, MD, said in an interview. The study was published online in the Journal of Clinical Oncology.

“It shows the contribution of [nivolumab] to the combination in treatment-naive patients. This data was not previously available as nivolumab monotherapy had only been formally tested in patients with prior history of TKI therapy. It also gives valuable information on the role of PD-L1 as a biomarker in response and landmark progression-free survival in patients treated with anti–PD-1 monotherapy,” said Dr. Atkins, who serves as deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

Patients with higher expression rates of PD-L1 had a higher overall response rate and higher probability of progression-free survival at 1 year.

“Nivolumab monotherapy might be an option to consider for patients who want a pure immunotherapy-based regimen but there is concern about risk of toxicity if ipilimumab is added. These might include elderly patients and those with a history or autoimmune conditions,” Dr. Atkins said.

Next on the agenda for the researchers are more extensive biomarker studies of the tissues obtained in the phase 2 study. They hope to identify factors that predict response and resistance in the absence of confounders like combination therapy, primary versus metastatic tumors, and use of nonimmunotherapy endpoints. They will also track treatment-free survival following cessation of therapy at 2 years.

The study “provides much needed first-line data for check point inhibitor monotherapy in an era that is heavily invested in combination strategies,” Martin Voss, MD, wrote in an accompanying editorial. Further studies currently in progress should shed even more light on monotherapy in this patient population. These include the phase 3 CheckMate 8Y8 trial comparing nivolumab with ipilimumab/nivolumab in untreated patients, and the phase 3 PDIGREE23 trial, which is comparing upfront, response-adaptive ipilimumab/nivolumab with escalation through addition of TKIs in patients with progressive disease and de-escalation to nivolumab monotherapy in patients who achieve a complete response, and randomization between the two strategies for nonprogressive disease and non–complete response patients.

However, these phase 3 studies are limited to intermediate- to poor-risk patients. For favorable-risk patients, small cohort studies like HCRN GU16-260 represent the best currently available guide to treatment, Dr. Voss wrote.

In part A of the study, 123 patients received nivolumab for 96 weeks. 35 patients who experienced progressive disease or had a best response of stable disease at 48 weeks became eligible for part B, in which they received the combination of nivolumab and ipilimumab for 12 weeks, and then nivolumab monotherapy for 48 weeks. All patients underwent PD-L1 testing, and tumors were categorized by percentage of tumor cells expressing PD-L1 as 0%, 1%-5%, greater than 5%-20%, and greater than 20%.

The overall objective response rate was 34.1%. 6.5% had a complete response. Patients categorized by International Metastatic RCC Database Consortium category as intermediate or poor risk had an ORR of 25.0%. Those categorized as favorable risk had an ORR of 57.1%, with a complete response rate of 11.4%. Just one patient with favorable risk had progressive disease at their 12-week CT scan. The ORR was higher with increasing percentages of PD-L1 expression, from 26.9% in PD-L1 0 to 50% in PD-L1 1-20 and 75.0% in PD-L1 greater than 20% (P = .002). Five of 7 (71.4%) patients with PD-L1 values of 1 or more had a tumor response to nivolumab monotherapy, but 14 of 23 (60.9%) of those with favorable risk disease and PD-L1 of zero also responded.

The median duration of response was 27.6 months, and progression-free survival was 34.6% at 1 year in the PD-L1 0 and 75.0% in the PD-L1 greater than 20 categories (P = .050). Among patients eligible for part B, the ORR was 11.4%.

Dr. Atkins has consulted or been on the advisory board for Bristol-Myers Squibb.

The anti–PD-1 agent nivolumab may have some utility as monotherapy in the treatment of naive advanced clear cell renal cell carcinoma (ccRCC), according results from a new phase 2 clinical trial (HCRN GU16-260).

Patients received nivolumab (Opdivo, Bristol-Myers Squibb) monotherapy in the first phase of the study, with qualifying patients moving on to dual therapy with nivolumab and the anti–CTLA-4 agent ipilimumab (Yervoy, Bristol-Myers Squibb).

“At the moment, monotherapy with anti–PD-1 is not FDA approved in patients with treatment-naive ccRCC. Based on the results of this study, it might be applicable in patients with favorable risk disease where only tyrosine kinase inhibitors or TKI-containing combinations are approved,” lead investigator Michael Atkins, MD, said in an interview. The study was published online in the Journal of Clinical Oncology.

“It shows the contribution of [nivolumab] to the combination in treatment-naive patients. This data was not previously available as nivolumab monotherapy had only been formally tested in patients with prior history of TKI therapy. It also gives valuable information on the role of PD-L1 as a biomarker in response and landmark progression-free survival in patients treated with anti–PD-1 monotherapy,” said Dr. Atkins, who serves as deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.

Patients with higher expression rates of PD-L1 had a higher overall response rate and higher probability of progression-free survival at 1 year.

“Nivolumab monotherapy might be an option to consider for patients who want a pure immunotherapy-based regimen but there is concern about risk of toxicity if ipilimumab is added. These might include elderly patients and those with a history or autoimmune conditions,” Dr. Atkins said.

Next on the agenda for the researchers are more extensive biomarker studies of the tissues obtained in the phase 2 study. They hope to identify factors that predict response and resistance in the absence of confounders like combination therapy, primary versus metastatic tumors, and use of nonimmunotherapy endpoints. They will also track treatment-free survival following cessation of therapy at 2 years.

The study “provides much needed first-line data for check point inhibitor monotherapy in an era that is heavily invested in combination strategies,” Martin Voss, MD, wrote in an accompanying editorial. Further studies currently in progress should shed even more light on monotherapy in this patient population. These include the phase 3 CheckMate 8Y8 trial comparing nivolumab with ipilimumab/nivolumab in untreated patients, and the phase 3 PDIGREE23 trial, which is comparing upfront, response-adaptive ipilimumab/nivolumab with escalation through addition of TKIs in patients with progressive disease and de-escalation to nivolumab monotherapy in patients who achieve a complete response, and randomization between the two strategies for nonprogressive disease and non–complete response patients.

However, these phase 3 studies are limited to intermediate- to poor-risk patients. For favorable-risk patients, small cohort studies like HCRN GU16-260 represent the best currently available guide to treatment, Dr. Voss wrote.

In part A of the study, 123 patients received nivolumab for 96 weeks. 35 patients who experienced progressive disease or had a best response of stable disease at 48 weeks became eligible for part B, in which they received the combination of nivolumab and ipilimumab for 12 weeks, and then nivolumab monotherapy for 48 weeks. All patients underwent PD-L1 testing, and tumors were categorized by percentage of tumor cells expressing PD-L1 as 0%, 1%-5%, greater than 5%-20%, and greater than 20%.

The overall objective response rate was 34.1%. 6.5% had a complete response. Patients categorized by International Metastatic RCC Database Consortium category as intermediate or poor risk had an ORR of 25.0%. Those categorized as favorable risk had an ORR of 57.1%, with a complete response rate of 11.4%. Just one patient with favorable risk had progressive disease at their 12-week CT scan. The ORR was higher with increasing percentages of PD-L1 expression, from 26.9% in PD-L1 0 to 50% in PD-L1 1-20 and 75.0% in PD-L1 greater than 20% (P = .002). Five of 7 (71.4%) patients with PD-L1 values of 1 or more had a tumor response to nivolumab monotherapy, but 14 of 23 (60.9%) of those with favorable risk disease and PD-L1 of zero also responded.

The median duration of response was 27.6 months, and progression-free survival was 34.6% at 1 year in the PD-L1 0 and 75.0% in the PD-L1 greater than 20 categories (P = .050). Among patients eligible for part B, the ORR was 11.4%.

Dr. Atkins has consulted or been on the advisory board for Bristol-Myers Squibb.

CHICAGO – Mortality rates from melanoma have fallen in recent years, likely due to the introduction of checkpoint inhibitors, according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.

“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.

According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.

Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).

“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.

The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.

Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.

The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).

The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.

On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.

The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.

CHICAGO – Mortality rates from melanoma have fallen in recent years, likely due to the introduction of checkpoint inhibitors, according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.

“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.

According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.

Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).

“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.

The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.

Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.

The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).

The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.

On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.

The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.

CHICAGO – Mortality rates from melanoma have fallen in recent years, likely due to the introduction of checkpoint inhibitors, according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.

“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.

According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.

Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).

“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.

The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.

Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.

The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).

The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.

On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.

The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.

Pain is common in patients with cirrhosis, and its management presents significant challenges to health care providers, such as worries about GI bleeding, renal injury, falls, and hepatic encephalopathy.

To address those issues, researchers at the University of Michigan, Ann Arbor, authored a review, published in Hepatology, that describes the pain syndromes experienced by patients, as well as pharmaceutical and nonpharmaceutical treatment options.

“I think it’s a very pragmatic approach to a very common problem. Health care providers are concerned about prescribing analgesia for people with cirrhosis for a number of different reasons. One of them is acetaminophen can be toxic to the liver, but generally only in pretty large doses. It’s actually a pretty good option in a dose of less than about 2 g/day because it doesn’t have some of the side effects that other painkillers such as the NSAIDs have. It doesn’t irritate the stomach, and it doesn’t affect kidney function,” said Paul Martin, MD, who was asked to comment on the review. He is chief of digestive health and liver diseases at the University of Miami.

He appreciated the discussion of both pharmacologic and nonpharmacologic interventions, including diet and psychological interventions. “And I think it provides a useful overview of the pharmacological agents we can use in patients with cirrhosis, so I think it’s a very useful contribution to the literature,” said Dr. Martin.

An estimated 40%-79% of cirrhosis patients experience chronic pain, and it can be a key factor in worsening functional status and quality of life. The authors noted that, although recent practice guidance had recommended involving palliative care providers, psychiatry, and physical therapy in for patients with decompensated cirrhosis, this is not always feasible. The authors also pointed out that there are different pain phenotypes in cirrhosis, and these require different management strategies.

They described three mechanistic categories of chronic pain: Nociceptive pain involves tissue damage and inflammation; neuropathic pain results from nerve damage; and nociplastic pain describes situations in which there is no evidence of tissue or nerve damage, but clinical or psychophysical signs suggest changes to nociception.

The different pain types are best assessed using different tools: The 2016 Fibromyalgia Survey Criteria is useful for nociplastic pain, the Neuropathic Pain Questionnaire and painDETECT can be useful for neuropathic pain, and a physical examination can pinpoint nociceptive pain.

When managing chronic pain, the initial patient workup should include a complete evaluation of the location, quality, and severity of pain, along with any functional interference or associated symptoms like fatigue, mood disturbance, or sensory sensitivity. One option is to use a body map to assess how widespread the pain is. Multisite pain is often a signal that it could be nociplastic. Any comorbid psychiatric disorders should be identified and treated.

The first treatment option for any pain should be self-directed, nonpharmacologic interventions. This is because most analgesics are only modestly effective in the treatment of chronic pain, leading to improvement in only about one in three cases, the authors noted. Opioids have poor efficacy against chronic pain, particularly nociplastic pain, which may even be worsened by opioid use.

Mladen Zivkovic/iStock/Getty Images

Although there is evidence that patients are motivated to seek out nonpharmacologic pain treatment, they have reported frustration by a dearth of simple, evidence-based therapies. The authors noted that digital self-management tools for pain have been developed, including their own PainGuide, which focuses on exercise and behavioral interventions for chronic pain. Other nonpharmacologic approaches include diet modification and sleep hygiene. Patients should be allowed to choose the approach that interests them most, with the physician emphasizing the importance of self-directed management.

Pharmacologic therapy may be added to these approaches, but they have limited utility and are associated with adverse effects. For nociceptive pain, topical NSAIDs like diclofenac gel can be used, as can acetaminophen (500 mg every 6 hours, maximum dose of 2 g/day). Opioids can be employed for short-term treatment of acute pain (for example: hydromorphone 1 mg every 6 hours as needed, oxycodone 2.5 mg by mouth every 6-8 hours as needed, or fentanyl patch in select patients). Tricyclic antidepressants may be used for multiple symptoms or neuropathic pain, but with caution. Neuropathic pain, as well as associated depression or fatigue, can be treated with low-dose serotonin and norepinephrine reuptake inhibitors, though there is a small risk of hepatotoxicity. Neuropathic pain, sleep difficulties, or anxiety can be treated with gabapentin at low starting doses (for example, 300 mg/day) or pregabalin (for example, 50 mg twice a day). Lidocaine patches are an option for peripheral neuropathic pain or postherpetic neuralgia, and topical capsaicin may be used for peripheral neuropathic pain.

“Since all pain types can co-occur, interventions to address nociplastic pain may be broadly therapeutic,” the authors concluded. “The treatment of nociplastic pain emphasizes nonpharmacologic management, including self-management techniques addressing mood, cognitions, behaviors, sleep, and environment. Future research should continue to explore methods of pain phenotyping, as well as self-management therapies, including implementation tools.”

The authors and Dr. Martin reported no relevant conflicts of interest.

Pain is common in patients with cirrhosis, and its management presents significant challenges to health care providers, such as worries about GI bleeding, renal injury, falls, and hepatic encephalopathy.

To address those issues, researchers at the University of Michigan, Ann Arbor, authored a review, published in Hepatology, that describes the pain syndromes experienced by patients, as well as pharmaceutical and nonpharmaceutical treatment options.

“I think it’s a very pragmatic approach to a very common problem. Health care providers are concerned about prescribing analgesia for people with cirrhosis for a number of different reasons. One of them is acetaminophen can be toxic to the liver, but generally only in pretty large doses. It’s actually a pretty good option in a dose of less than about 2 g/day because it doesn’t have some of the side effects that other painkillers such as the NSAIDs have. It doesn’t irritate the stomach, and it doesn’t affect kidney function,” said Paul Martin, MD, who was asked to comment on the review. He is chief of digestive health and liver diseases at the University of Miami.

He appreciated the discussion of both pharmacologic and nonpharmacologic interventions, including diet and psychological interventions. “And I think it provides a useful overview of the pharmacological agents we can use in patients with cirrhosis, so I think it’s a very useful contribution to the literature,” said Dr. Martin.

An estimated 40%-79% of cirrhosis patients experience chronic pain, and it can be a key factor in worsening functional status and quality of life. The authors noted that, although recent practice guidance had recommended involving palliative care providers, psychiatry, and physical therapy in for patients with decompensated cirrhosis, this is not always feasible. The authors also pointed out that there are different pain phenotypes in cirrhosis, and these require different management strategies.

They described three mechanistic categories of chronic pain: Nociceptive pain involves tissue damage and inflammation; neuropathic pain results from nerve damage; and nociplastic pain describes situations in which there is no evidence of tissue or nerve damage, but clinical or psychophysical signs suggest changes to nociception.

The different pain types are best assessed using different tools: The 2016 Fibromyalgia Survey Criteria is useful for nociplastic pain, the Neuropathic Pain Questionnaire and painDETECT can be useful for neuropathic pain, and a physical examination can pinpoint nociceptive pain.

When managing chronic pain, the initial patient workup should include a complete evaluation of the location, quality, and severity of pain, along with any functional interference or associated symptoms like fatigue, mood disturbance, or sensory sensitivity. One option is to use a body map to assess how widespread the pain is. Multisite pain is often a signal that it could be nociplastic. Any comorbid psychiatric disorders should be identified and treated.

The first treatment option for any pain should be self-directed, nonpharmacologic interventions. This is because most analgesics are only modestly effective in the treatment of chronic pain, leading to improvement in only about one in three cases, the authors noted. Opioids have poor efficacy against chronic pain, particularly nociplastic pain, which may even be worsened by opioid use.

Mladen Zivkovic/iStock/Getty Images

Although there is evidence that patients are motivated to seek out nonpharmacologic pain treatment, they have reported frustration by a dearth of simple, evidence-based therapies. The authors noted that digital self-management tools for pain have been developed, including their own PainGuide, which focuses on exercise and behavioral interventions for chronic pain. Other nonpharmacologic approaches include diet modification and sleep hygiene. Patients should be allowed to choose the approach that interests them most, with the physician emphasizing the importance of self-directed management.

Pharmacologic therapy may be added to these approaches, but they have limited utility and are associated with adverse effects. For nociceptive pain, topical NSAIDs like diclofenac gel can be used, as can acetaminophen (500 mg every 6 hours, maximum dose of 2 g/day). Opioids can be employed for short-term treatment of acute pain (for example: hydromorphone 1 mg every 6 hours as needed, oxycodone 2.5 mg by mouth every 6-8 hours as needed, or fentanyl patch in select patients). Tricyclic antidepressants may be used for multiple symptoms or neuropathic pain, but with caution. Neuropathic pain, as well as associated depression or fatigue, can be treated with low-dose serotonin and norepinephrine reuptake inhibitors, though there is a small risk of hepatotoxicity. Neuropathic pain, sleep difficulties, or anxiety can be treated with gabapentin at low starting doses (for example, 300 mg/day) or pregabalin (for example, 50 mg twice a day). Lidocaine patches are an option for peripheral neuropathic pain or postherpetic neuralgia, and topical capsaicin may be used for peripheral neuropathic pain.

“Since all pain types can co-occur, interventions to address nociplastic pain may be broadly therapeutic,” the authors concluded. “The treatment of nociplastic pain emphasizes nonpharmacologic management, including self-management techniques addressing mood, cognitions, behaviors, sleep, and environment. Future research should continue to explore methods of pain phenotyping, as well as self-management therapies, including implementation tools.”

The authors and Dr. Martin reported no relevant conflicts of interest.

Pain is common in patients with cirrhosis, and its management presents significant challenges to health care providers, such as worries about GI bleeding, renal injury, falls, and hepatic encephalopathy.

To address those issues, researchers at the University of Michigan, Ann Arbor, authored a review, published in Hepatology, that describes the pain syndromes experienced by patients, as well as pharmaceutical and nonpharmaceutical treatment options.

“I think it’s a very pragmatic approach to a very common problem. Health care providers are concerned about prescribing analgesia for people with cirrhosis for a number of different reasons. One of them is acetaminophen can be toxic to the liver, but generally only in pretty large doses. It’s actually a pretty good option in a dose of less than about 2 g/day because it doesn’t have some of the side effects that other painkillers such as the NSAIDs have. It doesn’t irritate the stomach, and it doesn’t affect kidney function,” said Paul Martin, MD, who was asked to comment on the review. He is chief of digestive health and liver diseases at the University of Miami.

He appreciated the discussion of both pharmacologic and nonpharmacologic interventions, including diet and psychological interventions. “And I think it provides a useful overview of the pharmacological agents we can use in patients with cirrhosis, so I think it’s a very useful contribution to the literature,” said Dr. Martin.

An estimated 40%-79% of cirrhosis patients experience chronic pain, and it can be a key factor in worsening functional status and quality of life. The authors noted that, although recent practice guidance had recommended involving palliative care providers, psychiatry, and physical therapy in for patients with decompensated cirrhosis, this is not always feasible. The authors also pointed out that there are different pain phenotypes in cirrhosis, and these require different management strategies.

They described three mechanistic categories of chronic pain: Nociceptive pain involves tissue damage and inflammation; neuropathic pain results from nerve damage; and nociplastic pain describes situations in which there is no evidence of tissue or nerve damage, but clinical or psychophysical signs suggest changes to nociception.

The different pain types are best assessed using different tools: The 2016 Fibromyalgia Survey Criteria is useful for nociplastic pain, the Neuropathic Pain Questionnaire and painDETECT can be useful for neuropathic pain, and a physical examination can pinpoint nociceptive pain.

When managing chronic pain, the initial patient workup should include a complete evaluation of the location, quality, and severity of pain, along with any functional interference or associated symptoms like fatigue, mood disturbance, or sensory sensitivity. One option is to use a body map to assess how widespread the pain is. Multisite pain is often a signal that it could be nociplastic. Any comorbid psychiatric disorders should be identified and treated.

The first treatment option for any pain should be self-directed, nonpharmacologic interventions. This is because most analgesics are only modestly effective in the treatment of chronic pain, leading to improvement in only about one in three cases, the authors noted. Opioids have poor efficacy against chronic pain, particularly nociplastic pain, which may even be worsened by opioid use.

Mladen Zivkovic/iStock/Getty Images

Although there is evidence that patients are motivated to seek out nonpharmacologic pain treatment, they have reported frustration by a dearth of simple, evidence-based therapies. The authors noted that digital self-management tools for pain have been developed, including their own PainGuide, which focuses on exercise and behavioral interventions for chronic pain. Other nonpharmacologic approaches include diet modification and sleep hygiene. Patients should be allowed to choose the approach that interests them most, with the physician emphasizing the importance of self-directed management.

Pharmacologic therapy may be added to these approaches, but they have limited utility and are associated with adverse effects. For nociceptive pain, topical NSAIDs like diclofenac gel can be used, as can acetaminophen (500 mg every 6 hours, maximum dose of 2 g/day). Opioids can be employed for short-term treatment of acute pain (for example: hydromorphone 1 mg every 6 hours as needed, oxycodone 2.5 mg by mouth every 6-8 hours as needed, or fentanyl patch in select patients). Tricyclic antidepressants may be used for multiple symptoms or neuropathic pain, but with caution. Neuropathic pain, as well as associated depression or fatigue, can be treated with low-dose serotonin and norepinephrine reuptake inhibitors, though there is a small risk of hepatotoxicity. Neuropathic pain, sleep difficulties, or anxiety can be treated with gabapentin at low starting doses (for example, 300 mg/day) or pregabalin (for example, 50 mg twice a day). Lidocaine patches are an option for peripheral neuropathic pain or postherpetic neuralgia, and topical capsaicin may be used for peripheral neuropathic pain.

“Since all pain types can co-occur, interventions to address nociplastic pain may be broadly therapeutic,” the authors concluded. “The treatment of nociplastic pain emphasizes nonpharmacologic management, including self-management techniques addressing mood, cognitions, behaviors, sleep, and environment. Future research should continue to explore methods of pain phenotyping, as well as self-management therapies, including implementation tools.”

The authors and Dr. Martin reported no relevant conflicts of interest.

A randomized clinical trial indicated that add-on baclofen may be of benefit to patients on adequate doses of proton pump inhibitors (PPI) with refractory gastroesophageal reflux disease (GERD). However, the benefit was limited to a subset of patients with positive symptom association probability (SAP), which was calculated using 24-hour combined multichannel intraluminal impedance and pH monitoring (24h pH-MII).

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“Empirical add-on therapy with baclofen in GERD patients with persisting typical symptoms in spite of double-dose PPI therapy does not seem justified. The use of baclofen should be limited to patients who display a positive SAP for typical reflux symptoms (heartburn and/or regurgitation) during PPI therapy,” researchers led by Ans Pauwels, PhD, MPharmSc, of the Catholic University of Leuven (Belgium) concluded in Alimentary Pharmacology & Therapeutics.

Asked to comment, Philip Katz, MD, professor of medicine and director of GI Function Laboratories at Weill Cornell Medicine and a co-author of some recent GERD guidelines said, “What it tells me is that baclofen may be useful to a patient population that has an accurate diagnosis of reflux hypersensitivity. The difficulty with this study is that the patients you would expect to be helped by baclofen, which were patients who satisfied the criteria for true GERD, didn’t have any improvement.”

PPIs are effective at reducing acid reflux and promoting esophageal healing in GERD patients, but they have little effect on non-acid reflux. Heartburn is most often tied to acid reflux, but regurgitation occurs with similar frequency during both acid and non-acid episodes.

Up to 50% of patients still have reflux despite PPI treatment, and many of these patients will respond to higher PPI doses. However, those who don’t respond are left with few treatment choices.

Reflux events generally occur during transient lower esophageal sphincter relaxations (TLOSRs), and this mechanism is predominant in mild and moderate GERD. A gamma-aminobutyric acid type B receptor agonist, baclofen reduces TLOSRs and associated reflux episodes following meals. Few studies have examined the clinical potential of baclofen in refractory GERD, and it generally is only used after determining that ongoing weakly acidic reflux is responsible for symptoms, using 24h pH-MII.

The study included about 60 patients who underwent 24-hour monitoring while taking a PPI twice daily. Over a 2-week run-in period, participants filled out daily diaries and were randomized to placebo or baclofen 3 times daily over 4 weeks. The baclofen dose was 5 mg for the first week, then 10 mg for the next 3 weeks.

At the end of treatment, 24h pH-MII was repeated. The researchers found no significant decreases in non-acid reflux events after placebo treatment (corrected P = .74) and a trend towards a reduction following baclofen treatment (corrected P = .12).

Although the results won’t change his practice significantly, Dr. Katz congratulated the authors on the thoroughness of the study. However, he noted that wellbeing is a difficult endpoint to study: “The importance of this study to me is that it confirms that baclofen shouldn’t be used empirically, since there was no improvement in patients who were functional, and it was hard to find improvement in any group. This reinforces the need for a thorough work-up of the patient with GERD.”

The drug also had some tolerability issues: 16% of patients on baclofen discontinued its use because of adverse events such as drowsiness, dizziness, headache, and nausea.

An important limitation of the study is that the researchers recruited patients with persistent GERD symptoms despite use of PPIs. “Calling it refractory GERD is tricky because they didn’t prove they had GERD before they were enrolled in the study. That being said, the researchers did a very rigorous, very careful study to try and find potentially some place that baclofen might benefit patients,” said Dr. Katz.

The authors of the study and Dr. Katz have no relevant financial disclosures.

A randomized clinical trial indicated that add-on baclofen may be of benefit to patients on adequate doses of proton pump inhibitors (PPI) with refractory gastroesophageal reflux disease (GERD). However, the benefit was limited to a subset of patients with positive symptom association probability (SAP), which was calculated using 24-hour combined multichannel intraluminal impedance and pH monitoring (24h pH-MII).

copyright nebari/Thinkstock

“Empirical add-on therapy with baclofen in GERD patients with persisting typical symptoms in spite of double-dose PPI therapy does not seem justified. The use of baclofen should be limited to patients who display a positive SAP for typical reflux symptoms (heartburn and/or regurgitation) during PPI therapy,” researchers led by Ans Pauwels, PhD, MPharmSc, of the Catholic University of Leuven (Belgium) concluded in Alimentary Pharmacology & Therapeutics.

Asked to comment, Philip Katz, MD, professor of medicine and director of GI Function Laboratories at Weill Cornell Medicine and a co-author of some recent GERD guidelines said, “What it tells me is that baclofen may be useful to a patient population that has an accurate diagnosis of reflux hypersensitivity. The difficulty with this study is that the patients you would expect to be helped by baclofen, which were patients who satisfied the criteria for true GERD, didn’t have any improvement.”

PPIs are effective at reducing acid reflux and promoting esophageal healing in GERD patients, but they have little effect on non-acid reflux. Heartburn is most often tied to acid reflux, but regurgitation occurs with similar frequency during both acid and non-acid episodes.

Up to 50% of patients still have reflux despite PPI treatment, and many of these patients will respond to higher PPI doses. However, those who don’t respond are left with few treatment choices.

Reflux events generally occur during transient lower esophageal sphincter relaxations (TLOSRs), and this mechanism is predominant in mild and moderate GERD. A gamma-aminobutyric acid type B receptor agonist, baclofen reduces TLOSRs and associated reflux episodes following meals. Few studies have examined the clinical potential of baclofen in refractory GERD, and it generally is only used after determining that ongoing weakly acidic reflux is responsible for symptoms, using 24h pH-MII.

The study included about 60 patients who underwent 24-hour monitoring while taking a PPI twice daily. Over a 2-week run-in period, participants filled out daily diaries and were randomized to placebo or baclofen 3 times daily over 4 weeks. The baclofen dose was 5 mg for the first week, then 10 mg for the next 3 weeks.

At the end of treatment, 24h pH-MII was repeated. The researchers found no significant decreases in non-acid reflux events after placebo treatment (corrected P = .74) and a trend towards a reduction following baclofen treatment (corrected P = .12).

Although the results won’t change his practice significantly, Dr. Katz congratulated the authors on the thoroughness of the study. However, he noted that wellbeing is a difficult endpoint to study: “The importance of this study to me is that it confirms that baclofen shouldn’t be used empirically, since there was no improvement in patients who were functional, and it was hard to find improvement in any group. This reinforces the need for a thorough work-up of the patient with GERD.”

The drug also had some tolerability issues: 16% of patients on baclofen discontinued its use because of adverse events such as drowsiness, dizziness, headache, and nausea.

An important limitation of the study is that the researchers recruited patients with persistent GERD symptoms despite use of PPIs. “Calling it refractory GERD is tricky because they didn’t prove they had GERD before they were enrolled in the study. That being said, the researchers did a very rigorous, very careful study to try and find potentially some place that baclofen might benefit patients,” said Dr. Katz.

The authors of the study and Dr. Katz have no relevant financial disclosures.

A randomized clinical trial indicated that add-on baclofen may be of benefit to patients on adequate doses of proton pump inhibitors (PPI) with refractory gastroesophageal reflux disease (GERD). However, the benefit was limited to a subset of patients with positive symptom association probability (SAP), which was calculated using 24-hour combined multichannel intraluminal impedance and pH monitoring (24h pH-MII).

copyright nebari/Thinkstock

“Empirical add-on therapy with baclofen in GERD patients with persisting typical symptoms in spite of double-dose PPI therapy does not seem justified. The use of baclofen should be limited to patients who display a positive SAP for typical reflux symptoms (heartburn and/or regurgitation) during PPI therapy,” researchers led by Ans Pauwels, PhD, MPharmSc, of the Catholic University of Leuven (Belgium) concluded in Alimentary Pharmacology & Therapeutics.

Asked to comment, Philip Katz, MD, professor of medicine and director of GI Function Laboratories at Weill Cornell Medicine and a co-author of some recent GERD guidelines said, “What it tells me is that baclofen may be useful to a patient population that has an accurate diagnosis of reflux hypersensitivity. The difficulty with this study is that the patients you would expect to be helped by baclofen, which were patients who satisfied the criteria for true GERD, didn’t have any improvement.”

PPIs are effective at reducing acid reflux and promoting esophageal healing in GERD patients, but they have little effect on non-acid reflux. Heartburn is most often tied to acid reflux, but regurgitation occurs with similar frequency during both acid and non-acid episodes.

Up to 50% of patients still have reflux despite PPI treatment, and many of these patients will respond to higher PPI doses. However, those who don’t respond are left with few treatment choices.

Reflux events generally occur during transient lower esophageal sphincter relaxations (TLOSRs), and this mechanism is predominant in mild and moderate GERD. A gamma-aminobutyric acid type B receptor agonist, baclofen reduces TLOSRs and associated reflux episodes following meals. Few studies have examined the clinical potential of baclofen in refractory GERD, and it generally is only used after determining that ongoing weakly acidic reflux is responsible for symptoms, using 24h pH-MII.

The study included about 60 patients who underwent 24-hour monitoring while taking a PPI twice daily. Over a 2-week run-in period, participants filled out daily diaries and were randomized to placebo or baclofen 3 times daily over 4 weeks. The baclofen dose was 5 mg for the first week, then 10 mg for the next 3 weeks.

At the end of treatment, 24h pH-MII was repeated. The researchers found no significant decreases in non-acid reflux events after placebo treatment (corrected P = .74) and a trend towards a reduction following baclofen treatment (corrected P = .12).

Although the results won’t change his practice significantly, Dr. Katz congratulated the authors on the thoroughness of the study. However, he noted that wellbeing is a difficult endpoint to study: “The importance of this study to me is that it confirms that baclofen shouldn’t be used empirically, since there was no improvement in patients who were functional, and it was hard to find improvement in any group. This reinforces the need for a thorough work-up of the patient with GERD.”

The drug also had some tolerability issues: 16% of patients on baclofen discontinued its use because of adverse events such as drowsiness, dizziness, headache, and nausea.

An important limitation of the study is that the researchers recruited patients with persistent GERD symptoms despite use of PPIs. “Calling it refractory GERD is tricky because they didn’t prove they had GERD before they were enrolled in the study. That being said, the researchers did a very rigorous, very careful study to try and find potentially some place that baclofen might benefit patients,” said Dr. Katz.

The authors of the study and Dr. Katz have no relevant financial disclosures.

Telemedicine for patients with liver disease has made progress in recent years, but some key hurdles remain. Strategies that rely on patient ownership of mobile devices or reliable internet access will likely miss patients who have the greatest need for remote access.

This is one of the conclusions from a county-by-county study of access to liver specialty care and mortality, using data drawn from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiological Research (WONDER). The study was led by Jacqueline B. Henson, MD, of the Division of Gastroenterology, department of medicine, Duke University, Durham, N.C., and published in Hepatology.
 

Low-access areas

“Ultimately, no single telehealth strategy will be successful in all areas, and these will need to be tailored at the local and state level,” the authors wrote. “They will also depend on the persistence of policy changes enacted during the pandemic which made use and reimbursement for telehealth less restrictive.”

The researchers found that 69.5% of American counties had no gastrointestinal physicians. Moreover, 41.1% of counties were more than 100 miles away from a liver transplant (LT) center; 33.7% had no GI physicians and were more than 100 miles from a LT center. These categories represented populations of 48.8 million, 53.7 million, and 17.8 million. These counties had higher poverty rates, more unemployment, and lower educational attainment than did those that had GI physicians or were closer to LT centers. Distance from LT centers was associated with higher liver-related mortality (r = 0.24; P < .001) and density of GI providers (r = –0.12; P < .001).

Reduced access to specialty care for liver disease was also associated with decreased access to technology, including cell phones, smart phones, and internet service. Among counties in the highest death quartile and lowest access to care, 35.5% of households had no computer, 43.1% had no home internet, and only 19.2% of these had internet at broadband speeds.

“Use of platforms with lower internet speed requirements and that are compatible with mobile devices may help extend access, as could partnerships with local primary care and GI clinics,” they concluded. Further work should be done at the local and state levels to better understand the optimal strategies to reach their populations of need.
 

Missing ‘baseline ingredients’

Commenting on the study, Nancy Reau, MD, professor of medicine and chief of hepatology at Rush University Medical Center, Chicago, said that “anyone who takes care of vulnerable populations, whether elderly individuals or those who may be socioeconomically disadvantaged, realizes that we have to improve access to medical resources, and telehealth is certainly an attractive way of doing that.”

She added that a key message from the study is that attempts to improve access to disadvantaged populations, no matter how well-intentioned, are likely to provide the most benefit to those who have more resources than others. For example, not everyone has access to a smart phone or tablet: “Even if you have a tablet [or cell phone], you might have to go to the public library to get high speed internet, or you may not even have a public library. So, when something sounds like a great idea, such as expanding the academic footprint or access to integrative medicine through something like a virtual option, a lot of the individuals that you are targeting may not be able to engage,” said Dr. Reau.

For those working to expand access, it’s critical to get the perspective of underserved communities and remember that every patient is unique. Physicians may treat patients who are poor, or from disadvantaged areas, who nevertheless have successful telehealth visits. But that doesn’t mean everyone’s experience will be similar. “You can’t use those who have been successful in accessing telemedicine as an example for everyone else. Just because one person can do it doesn’t mean that everyone else can. Involving a practitioner or an advocate from the area that you’re trying to reach is imperative,” she explained.

The COVID-19 pandemic led to a big push for telehealth, and it may be tempting to believe that the transition to telehealth has been smooth. This study “demonstrates in a very granular way that a large number of Americans have no access to high-speed internet, or if they do, many don’t have access to the tools that would let them engage this way. You can’t make assumptions and use them to build a product,” continued Dr. Reau.

Innovative options are needed, such as working with primary care providers in rural or disadvantaged areas to setup pop-up hot spots where e-consultations could be performed. Working directly with broadband internet providers to set up access in specific locations for telehealth, or using products like Amazon Echo Show as a portal for telehealth, can also be tried. “Think about being innovative and recognize that these areas probably don’t have the baseline ingredients we thought they had,” suggested Dr. Reau.

The authors reported having no financial support. Dr. Reau has no relevant financial disclosures.

Telemedicine for patients with liver disease has made progress in recent years, but some key hurdles remain. Strategies that rely on patient ownership of mobile devices or reliable internet access will likely miss patients who have the greatest need for remote access.

This is one of the conclusions from a county-by-county study of access to liver specialty care and mortality, using data drawn from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiological Research (WONDER). The study was led by Jacqueline B. Henson, MD, of the Division of Gastroenterology, department of medicine, Duke University, Durham, N.C., and published in Hepatology.
 

Low-access areas

“Ultimately, no single telehealth strategy will be successful in all areas, and these will need to be tailored at the local and state level,” the authors wrote. “They will also depend on the persistence of policy changes enacted during the pandemic which made use and reimbursement for telehealth less restrictive.”

The researchers found that 69.5% of American counties had no gastrointestinal physicians. Moreover, 41.1% of counties were more than 100 miles away from a liver transplant (LT) center; 33.7% had no GI physicians and were more than 100 miles from a LT center. These categories represented populations of 48.8 million, 53.7 million, and 17.8 million. These counties had higher poverty rates, more unemployment, and lower educational attainment than did those that had GI physicians or were closer to LT centers. Distance from LT centers was associated with higher liver-related mortality (r = 0.24; P < .001) and density of GI providers (r = –0.12; P < .001).

Reduced access to specialty care for liver disease was also associated with decreased access to technology, including cell phones, smart phones, and internet service. Among counties in the highest death quartile and lowest access to care, 35.5% of households had no computer, 43.1% had no home internet, and only 19.2% of these had internet at broadband speeds.

“Use of platforms with lower internet speed requirements and that are compatible with mobile devices may help extend access, as could partnerships with local primary care and GI clinics,” they concluded. Further work should be done at the local and state levels to better understand the optimal strategies to reach their populations of need.
 

Missing ‘baseline ingredients’

Commenting on the study, Nancy Reau, MD, professor of medicine and chief of hepatology at Rush University Medical Center, Chicago, said that “anyone who takes care of vulnerable populations, whether elderly individuals or those who may be socioeconomically disadvantaged, realizes that we have to improve access to medical resources, and telehealth is certainly an attractive way of doing that.”

She added that a key message from the study is that attempts to improve access to disadvantaged populations, no matter how well-intentioned, are likely to provide the most benefit to those who have more resources than others. For example, not everyone has access to a smart phone or tablet: “Even if you have a tablet [or cell phone], you might have to go to the public library to get high speed internet, or you may not even have a public library. So, when something sounds like a great idea, such as expanding the academic footprint or access to integrative medicine through something like a virtual option, a lot of the individuals that you are targeting may not be able to engage,” said Dr. Reau.

For those working to expand access, it’s critical to get the perspective of underserved communities and remember that every patient is unique. Physicians may treat patients who are poor, or from disadvantaged areas, who nevertheless have successful telehealth visits. But that doesn’t mean everyone’s experience will be similar. “You can’t use those who have been successful in accessing telemedicine as an example for everyone else. Just because one person can do it doesn’t mean that everyone else can. Involving a practitioner or an advocate from the area that you’re trying to reach is imperative,” she explained.

The COVID-19 pandemic led to a big push for telehealth, and it may be tempting to believe that the transition to telehealth has been smooth. This study “demonstrates in a very granular way that a large number of Americans have no access to high-speed internet, or if they do, many don’t have access to the tools that would let them engage this way. You can’t make assumptions and use them to build a product,” continued Dr. Reau.

Innovative options are needed, such as working with primary care providers in rural or disadvantaged areas to setup pop-up hot spots where e-consultations could be performed. Working directly with broadband internet providers to set up access in specific locations for telehealth, or using products like Amazon Echo Show as a portal for telehealth, can also be tried. “Think about being innovative and recognize that these areas probably don’t have the baseline ingredients we thought they had,” suggested Dr. Reau.

The authors reported having no financial support. Dr. Reau has no relevant financial disclosures.

Telemedicine for patients with liver disease has made progress in recent years, but some key hurdles remain. Strategies that rely on patient ownership of mobile devices or reliable internet access will likely miss patients who have the greatest need for remote access.

This is one of the conclusions from a county-by-county study of access to liver specialty care and mortality, using data drawn from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiological Research (WONDER). The study was led by Jacqueline B. Henson, MD, of the Division of Gastroenterology, department of medicine, Duke University, Durham, N.C., and published in Hepatology.
 

Low-access areas

“Ultimately, no single telehealth strategy will be successful in all areas, and these will need to be tailored at the local and state level,” the authors wrote. “They will also depend on the persistence of policy changes enacted during the pandemic which made use and reimbursement for telehealth less restrictive.”

The researchers found that 69.5% of American counties had no gastrointestinal physicians. Moreover, 41.1% of counties were more than 100 miles away from a liver transplant (LT) center; 33.7% had no GI physicians and were more than 100 miles from a LT center. These categories represented populations of 48.8 million, 53.7 million, and 17.8 million. These counties had higher poverty rates, more unemployment, and lower educational attainment than did those that had GI physicians or were closer to LT centers. Distance from LT centers was associated with higher liver-related mortality (r = 0.24; P < .001) and density of GI providers (r = –0.12; P < .001).

Reduced access to specialty care for liver disease was also associated with decreased access to technology, including cell phones, smart phones, and internet service. Among counties in the highest death quartile and lowest access to care, 35.5% of households had no computer, 43.1% had no home internet, and only 19.2% of these had internet at broadband speeds.

“Use of platforms with lower internet speed requirements and that are compatible with mobile devices may help extend access, as could partnerships with local primary care and GI clinics,” they concluded. Further work should be done at the local and state levels to better understand the optimal strategies to reach their populations of need.
 

Missing ‘baseline ingredients’

Commenting on the study, Nancy Reau, MD, professor of medicine and chief of hepatology at Rush University Medical Center, Chicago, said that “anyone who takes care of vulnerable populations, whether elderly individuals or those who may be socioeconomically disadvantaged, realizes that we have to improve access to medical resources, and telehealth is certainly an attractive way of doing that.”

She added that a key message from the study is that attempts to improve access to disadvantaged populations, no matter how well-intentioned, are likely to provide the most benefit to those who have more resources than others. For example, not everyone has access to a smart phone or tablet: “Even if you have a tablet [or cell phone], you might have to go to the public library to get high speed internet, or you may not even have a public library. So, when something sounds like a great idea, such as expanding the academic footprint or access to integrative medicine through something like a virtual option, a lot of the individuals that you are targeting may not be able to engage,” said Dr. Reau.

For those working to expand access, it’s critical to get the perspective of underserved communities and remember that every patient is unique. Physicians may treat patients who are poor, or from disadvantaged areas, who nevertheless have successful telehealth visits. But that doesn’t mean everyone’s experience will be similar. “You can’t use those who have been successful in accessing telemedicine as an example for everyone else. Just because one person can do it doesn’t mean that everyone else can. Involving a practitioner or an advocate from the area that you’re trying to reach is imperative,” she explained.

The COVID-19 pandemic led to a big push for telehealth, and it may be tempting to believe that the transition to telehealth has been smooth. This study “demonstrates in a very granular way that a large number of Americans have no access to high-speed internet, or if they do, many don’t have access to the tools that would let them engage this way. You can’t make assumptions and use them to build a product,” continued Dr. Reau.

Innovative options are needed, such as working with primary care providers in rural or disadvantaged areas to setup pop-up hot spots where e-consultations could be performed. Working directly with broadband internet providers to set up access in specific locations for telehealth, or using products like Amazon Echo Show as a portal for telehealth, can also be tried. “Think about being innovative and recognize that these areas probably don’t have the baseline ingredients we thought they had,” suggested Dr. Reau.

The authors reported having no financial support. Dr. Reau has no relevant financial disclosures.