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An investigational oral drug that targets RAS, the dominant oncogenic driver in pancreatic cancer, nearly doubled overall survival compared with common second-line chemotherapy regimens in patients with previously treated metastatic disease.

In the 500-patient phase 3 RASolute 302 trial, patients who received daraxonrasib, a RAS(ON) multi-selective inhibitor, lived a median of 13.2 months compared with 6.7 months for those who received chemotherapy. The drug also doubled progression-free survival, tripled the response rate, and delayed deterioration in both pain and quality of life.

“Results from RASolute 302 support daraxonrasib as a new standard of care for patients with previously treated metastatic pancreatic cancer,” said lead investigator Brian Wolpin, MD, MPH, director of the Hale Family Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute in Boston, who presented the findings at the American Society of Clinical Oncology (ASCO) 2026. The study was also published simultaneously on May 31 in The New England Journal of Medicine.

Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with most patients presenting with advanced disease at diagnosis. For those whose cancer progresses after first-line chemotherapy, no single standard second-line treatment has been established. Available regimens typically produce median progression-free survival of 3-4 months and a median overall survival of 6-7 months.

More than 90% of pancreatic cancers harbor activating RAS mutations — most commonly KRAS G12D and G12V — that drive tumor growth. The first approved KRAS inhibitors — sotorasib and adagrasib for certain lung and colorectal cancers — target KRAS G12C, which is rare in pancreatic cancer. So far, no RAS-targeted therapy has been approved for pancreatic cancer.

Daraxonrasib takes a broader approach. The oral agent can target a range of RAS variants, including mutant and wild-type RAS, by binding the active form of RAS and blocking downstream signaling.

In the phase 3 open-label RASolute 302 trial, researchers randomized 500 patients with previously treated metastatic pancreatic cancer 1:1 to receive daraxonrasib 300 mg orally once daily or investigator’s choice of chemotherapy. The most used regimens in the control arm were gemcitabine plus nab-paclitaxel (56.5%) and liposomal irinotecan plus fluorouracil and leucovorin (32.7%).

Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Documented RAS mutational status was required, and nearly 92% of patients had RAS G12 mutations.

The dual primary endpoints were overall survival and progression-free survival in the RAS G12 population. Key secondary endpoints included the same measures in the overall population as well as objective response rate and patient-reported quality of life. The median follow-up was 8.5 months.

In the RAS G12 population, daraxonrasib reduced the risk for death by 60% (hazard ratio [HR], 0.40; P < .001). The median overall survival was 13.2 months with daraxonrasib vs 6.6 months with chemotherapy. Results were nearly identical in the overall population: 13.2 vs 6.7 months (HR, 0.40; P < .001).

Progression-free survival in the RAS G12 population was 7.3 vs 3.5 months (HR, 0.45; P < .001). The objective response rate was 33.2% vs 11.8%.

Daraxonrasib significantly delayed deterioration in pain (median, 9.0 vs 3.7 months; HR, 0.51; P < .001) and global quality of life (5.6 vs 2.4 months; HR, 0.60; P < .001).

Treatment-related adverse events of grade ≥ 3 occurred in 43.6% of patients on daraxonrasib vs 57.5% of patients on chemotherapy. The most common high-grade events with daraxonrasib were rash (13.7%) and stomatitis (12.0%), whereas neutropenia (27.6%) and anemia (16.4%) were most common with chemotherapy.

One patient in the daraxonrasib arm died from treatment-related pneumonitis. Discontinuation due to adverse events occurred in 1.2% of patients on daraxonrasib vs 11.2% of patients on chemotherapy.

The median duration of treatment was 6.2 months with daraxonrasib vs 1.5-3.2 months across chemotherapy regimens, and 42% of patients on daraxonrasib remained on treatment at data cutoff, Wolpin said.

The open-label design is a limitation. About 15% of patients randomized to chemotherapy never received treatment, largely after learning their treatment assignment, although all were included in the intention-to-treat analysis.

Invited discussant Jennifer Knox, MD, a medical oncologist at Princess Margaret Cancer Center and professor of medicine at the University of Toronto in Toronto, Ontario, Canada, called daraxonrasib a game changer, describing the drug as “probably the most exciting strategy in five decades” for pancreatic cancer.

“It is an absolutely beautiful curve,” Knox said of the overall survival data, noting that the Kaplan-Meier curves separated early and continued to widen over time — a pattern rarely seen in pancreatic cancer trials where initial separation between treatment arms typically narrows as patients in both groups deteriorate.

Knox highlighted the pain and quality-of-life data as “the most important endpoints for our patients,” given the severity of the disease.

She pointed out, however, that the combination of rash and stomatitis will be “challenging” in practice, and called for improved supportive care and closer collaboration with dermatology as oncologists gain experience with this first-in-class drug.

Knox said RAS-targeted therapy “should dominate trials across the full spectrum of pancreatic cancer clinical presentations,” pointing to first-line combination trials already underway and noting that treating a larger, earlier population would have the greatest impact.

“This is the first glimpse at the real power of targeting RAS in pancreas cancer,” Knox said.

The study was funded by Revolution Medicines. Wolpin reported consulting or advisory roles with Revolution Medicines, Mirati Therapeutics, Ipsen, and others, and institutional research funding from Revolution Medicines, Agios, Amgen, AstraZeneca, Lilly, and Novartis. Knox reported receiving honoraria from Astellas Pharma, AstraZeneca, Incyte, and Ipsen, and consulting or advisory roles with AstraZeneca/MedImmune, Incyte, and Ipsen.

A version of this article was previously published on Medscape.com.

An investigational oral drug that targets RAS, the dominant oncogenic driver in pancreatic cancer, nearly doubled overall survival compared with common second-line chemotherapy regimens in patients with previously treated metastatic disease.

In the 500-patient phase 3 RASolute 302 trial, patients who received daraxonrasib, a RAS(ON) multi-selective inhibitor, lived a median of 13.2 months compared with 6.7 months for those who received chemotherapy. The drug also doubled progression-free survival, tripled the response rate, and delayed deterioration in both pain and quality of life.

“Results from RASolute 302 support daraxonrasib as a new standard of care for patients with previously treated metastatic pancreatic cancer,” said lead investigator Brian Wolpin, MD, MPH, director of the Hale Family Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute in Boston, who presented the findings at the American Society of Clinical Oncology (ASCO) 2026. The study was also published simultaneously on May 31 in The New England Journal of Medicine.

Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with most patients presenting with advanced disease at diagnosis. For those whose cancer progresses after first-line chemotherapy, no single standard second-line treatment has been established. Available regimens typically produce median progression-free survival of 3-4 months and a median overall survival of 6-7 months.

More than 90% of pancreatic cancers harbor activating RAS mutations — most commonly KRAS G12D and G12V — that drive tumor growth. The first approved KRAS inhibitors — sotorasib and adagrasib for certain lung and colorectal cancers — target KRAS G12C, which is rare in pancreatic cancer. So far, no RAS-targeted therapy has been approved for pancreatic cancer.

Daraxonrasib takes a broader approach. The oral agent can target a range of RAS variants, including mutant and wild-type RAS, by binding the active form of RAS and blocking downstream signaling.

In the phase 3 open-label RASolute 302 trial, researchers randomized 500 patients with previously treated metastatic pancreatic cancer 1:1 to receive daraxonrasib 300 mg orally once daily or investigator’s choice of chemotherapy. The most used regimens in the control arm were gemcitabine plus nab-paclitaxel (56.5%) and liposomal irinotecan plus fluorouracil and leucovorin (32.7%).

Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Documented RAS mutational status was required, and nearly 92% of patients had RAS G12 mutations.

The dual primary endpoints were overall survival and progression-free survival in the RAS G12 population. Key secondary endpoints included the same measures in the overall population as well as objective response rate and patient-reported quality of life. The median follow-up was 8.5 months.

In the RAS G12 population, daraxonrasib reduced the risk for death by 60% (hazard ratio [HR], 0.40; P < .001). The median overall survival was 13.2 months with daraxonrasib vs 6.6 months with chemotherapy. Results were nearly identical in the overall population: 13.2 vs 6.7 months (HR, 0.40; P < .001).

Progression-free survival in the RAS G12 population was 7.3 vs 3.5 months (HR, 0.45; P < .001). The objective response rate was 33.2% vs 11.8%.

Daraxonrasib significantly delayed deterioration in pain (median, 9.0 vs 3.7 months; HR, 0.51; P < .001) and global quality of life (5.6 vs 2.4 months; HR, 0.60; P < .001).

Treatment-related adverse events of grade ≥ 3 occurred in 43.6% of patients on daraxonrasib vs 57.5% of patients on chemotherapy. The most common high-grade events with daraxonrasib were rash (13.7%) and stomatitis (12.0%), whereas neutropenia (27.6%) and anemia (16.4%) were most common with chemotherapy.

One patient in the daraxonrasib arm died from treatment-related pneumonitis. Discontinuation due to adverse events occurred in 1.2% of patients on daraxonrasib vs 11.2% of patients on chemotherapy.

The median duration of treatment was 6.2 months with daraxonrasib vs 1.5-3.2 months across chemotherapy regimens, and 42% of patients on daraxonrasib remained on treatment at data cutoff, Wolpin said.

The open-label design is a limitation. About 15% of patients randomized to chemotherapy never received treatment, largely after learning their treatment assignment, although all were included in the intention-to-treat analysis.

Invited discussant Jennifer Knox, MD, a medical oncologist at Princess Margaret Cancer Center and professor of medicine at the University of Toronto in Toronto, Ontario, Canada, called daraxonrasib a game changer, describing the drug as “probably the most exciting strategy in five decades” for pancreatic cancer.

“It is an absolutely beautiful curve,” Knox said of the overall survival data, noting that the Kaplan-Meier curves separated early and continued to widen over time — a pattern rarely seen in pancreatic cancer trials where initial separation between treatment arms typically narrows as patients in both groups deteriorate.

Knox highlighted the pain and quality-of-life data as “the most important endpoints for our patients,” given the severity of the disease.

She pointed out, however, that the combination of rash and stomatitis will be “challenging” in practice, and called for improved supportive care and closer collaboration with dermatology as oncologists gain experience with this first-in-class drug.

Knox said RAS-targeted therapy “should dominate trials across the full spectrum of pancreatic cancer clinical presentations,” pointing to first-line combination trials already underway and noting that treating a larger, earlier population would have the greatest impact.

“This is the first glimpse at the real power of targeting RAS in pancreas cancer,” Knox said.

The study was funded by Revolution Medicines. Wolpin reported consulting or advisory roles with Revolution Medicines, Mirati Therapeutics, Ipsen, and others, and institutional research funding from Revolution Medicines, Agios, Amgen, AstraZeneca, Lilly, and Novartis. Knox reported receiving honoraria from Astellas Pharma, AstraZeneca, Incyte, and Ipsen, and consulting or advisory roles with AstraZeneca/MedImmune, Incyte, and Ipsen.

A version of this article was previously published on Medscape.com.

An investigational oral drug that targets RAS, the dominant oncogenic driver in pancreatic cancer, nearly doubled overall survival compared with common second-line chemotherapy regimens in patients with previously treated metastatic disease.

In the 500-patient phase 3 RASolute 302 trial, patients who received daraxonrasib, a RAS(ON) multi-selective inhibitor, lived a median of 13.2 months compared with 6.7 months for those who received chemotherapy. The drug also doubled progression-free survival, tripled the response rate, and delayed deterioration in both pain and quality of life.

“Results from RASolute 302 support daraxonrasib as a new standard of care for patients with previously treated metastatic pancreatic cancer,” said lead investigator Brian Wolpin, MD, MPH, director of the Hale Family Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute in Boston, who presented the findings at the American Society of Clinical Oncology (ASCO) 2026. The study was also published simultaneously on May 31 in The New England Journal of Medicine.

Pancreatic ductal adenocarcinoma is one of the most lethal cancers, with most patients presenting with advanced disease at diagnosis. For those whose cancer progresses after first-line chemotherapy, no single standard second-line treatment has been established. Available regimens typically produce median progression-free survival of 3-4 months and a median overall survival of 6-7 months.

More than 90% of pancreatic cancers harbor activating RAS mutations — most commonly KRAS G12D and G12V — that drive tumor growth. The first approved KRAS inhibitors — sotorasib and adagrasib for certain lung and colorectal cancers — target KRAS G12C, which is rare in pancreatic cancer. So far, no RAS-targeted therapy has been approved for pancreatic cancer.

Daraxonrasib takes a broader approach. The oral agent can target a range of RAS variants, including mutant and wild-type RAS, by binding the active form of RAS and blocking downstream signaling.

In the phase 3 open-label RASolute 302 trial, researchers randomized 500 patients with previously treated metastatic pancreatic cancer 1:1 to receive daraxonrasib 300 mg orally once daily or investigator’s choice of chemotherapy. The most used regimens in the control arm were gemcitabine plus nab-paclitaxel (56.5%) and liposomal irinotecan plus fluorouracil and leucovorin (32.7%).

Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1. Documented RAS mutational status was required, and nearly 92% of patients had RAS G12 mutations.

The dual primary endpoints were overall survival and progression-free survival in the RAS G12 population. Key secondary endpoints included the same measures in the overall population as well as objective response rate and patient-reported quality of life. The median follow-up was 8.5 months.

In the RAS G12 population, daraxonrasib reduced the risk for death by 60% (hazard ratio [HR], 0.40; P < .001). The median overall survival was 13.2 months with daraxonrasib vs 6.6 months with chemotherapy. Results were nearly identical in the overall population: 13.2 vs 6.7 months (HR, 0.40; P < .001).

Progression-free survival in the RAS G12 population was 7.3 vs 3.5 months (HR, 0.45; P < .001). The objective response rate was 33.2% vs 11.8%.

Daraxonrasib significantly delayed deterioration in pain (median, 9.0 vs 3.7 months; HR, 0.51; P < .001) and global quality of life (5.6 vs 2.4 months; HR, 0.60; P < .001).

Treatment-related adverse events of grade ≥ 3 occurred in 43.6% of patients on daraxonrasib vs 57.5% of patients on chemotherapy. The most common high-grade events with daraxonrasib were rash (13.7%) and stomatitis (12.0%), whereas neutropenia (27.6%) and anemia (16.4%) were most common with chemotherapy.

One patient in the daraxonrasib arm died from treatment-related pneumonitis. Discontinuation due to adverse events occurred in 1.2% of patients on daraxonrasib vs 11.2% of patients on chemotherapy.

The median duration of treatment was 6.2 months with daraxonrasib vs 1.5-3.2 months across chemotherapy regimens, and 42% of patients on daraxonrasib remained on treatment at data cutoff, Wolpin said.

The open-label design is a limitation. About 15% of patients randomized to chemotherapy never received treatment, largely after learning their treatment assignment, although all were included in the intention-to-treat analysis.

Invited discussant Jennifer Knox, MD, a medical oncologist at Princess Margaret Cancer Center and professor of medicine at the University of Toronto in Toronto, Ontario, Canada, called daraxonrasib a game changer, describing the drug as “probably the most exciting strategy in five decades” for pancreatic cancer.

“It is an absolutely beautiful curve,” Knox said of the overall survival data, noting that the Kaplan-Meier curves separated early and continued to widen over time — a pattern rarely seen in pancreatic cancer trials where initial separation between treatment arms typically narrows as patients in both groups deteriorate.

Knox highlighted the pain and quality-of-life data as “the most important endpoints for our patients,” given the severity of the disease.

She pointed out, however, that the combination of rash and stomatitis will be “challenging” in practice, and called for improved supportive care and closer collaboration with dermatology as oncologists gain experience with this first-in-class drug.

Knox said RAS-targeted therapy “should dominate trials across the full spectrum of pancreatic cancer clinical presentations,” pointing to first-line combination trials already underway and noting that treating a larger, earlier population would have the greatest impact.

“This is the first glimpse at the real power of targeting RAS in pancreas cancer,” Knox said.

The study was funded by Revolution Medicines. Wolpin reported consulting or advisory roles with Revolution Medicines, Mirati Therapeutics, Ipsen, and others, and institutional research funding from Revolution Medicines, Agios, Amgen, AstraZeneca, Lilly, and Novartis. Knox reported receiving honoraria from Astellas Pharma, AstraZeneca, Incyte, and Ipsen, and consulting or advisory roles with AstraZeneca/MedImmune, Incyte, and Ipsen.

A version of this article was previously published on Medscape.com.

A US Department of Veterans Affairs (VA) Office of Inspector General (OIG) report has found that many patients who scored high on a screening for alcohol use are not receiving recommended counseling interventions.

The OIG report evaluated Veterans Health Administration (VHA) primary care staff adherence to the screening requirements and intervention interventions during fiscal year 2024 (October 1, 2023, to September 30, 2024). VHA primary care clinicians used the Alcohol Use Disorders Identification Test – Consumption (AUDIT-C), which produces a score of 0 to 12, to screen almost 4 million patients.

Based on sex-specific thresholds, the report found 8% of men and 11% of women screened positive for unhealthy alcohol use (AUDIT-C score ≥ 4 for men and ≥ 3 for women). However, because VHA electronic health record prompts clinicians to provide intervention for patients with scores ≥ 5, 54% of men and 75% of women who may have benefited from brief intervention did not.

A brief intervention with a clinician consists of a 5-minute counseling session, with individualized feedback and a discussion on strategies for the patient to reduce or abstain from alcohol.

Aligning with VHA guidance, clinicians provided brief intervention to 77% of men and 75% of women who recorded an AUDIT-C score ≥ 5. However, < 2% of patients with a score at the sex-specific threshold received brief intervention.  

Veterans have high rates of unhealthy alcohol use, which is associated with increased risk of interpersonal violence and poor health outcomes. In a May 2026 study, 44% of 3117 veterans met criteria for alcohol use disorder; 44% reported past 30-day alcohol use.

The VHA requires annual screening using the AUDIT-C. In a study of 63,397 VHA patients, 25% of women and 28% of men screened positive for unhealthy alcohol use. The prevalence of alcohol and other substance abuse disorders increased with increasing AUDIT-C scores, ranging as high as 82% for women and 69% for men. 

A 2018 analysis found that tailoring the AUDIT-C binge-drinking item, AUDIT-C scoring, or both increased detection of unhealthy alcohol use in women. In 2020, VHA adjusted the binge drinking item for women, reducing it to 4 drinks on an occasion from 6 to characterize binge drinking. Despite this adjustment, the VHA maintained an AUDIT-C score ≥ 5 to prompt brief intervention for both women and men.

A 2022 study of 4148 veterans found that 15% were not properly screened for alcohol despite 1 in 11 met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for alcohol abuse/dependence. A lack of screening may not be the issue, however. In the OIG report, VHA found 95% adherence to alcohol use screening in 2024 using a sample-based performance measure and 79% adherence after transitioning that year to a population-based measure. OIG determined that the population-based measure provides a more accurate representation of screening documentation.

Following the OIG recommendations, VA Under Secretary for Health John J. Bartrum, JD, MBA, provided an action plan to evaluate factors that affect screening, identify facilities for performance improvement, and evaluate the use of sex-specific alcohol use screening thresholds. 

A US Department of Veterans Affairs (VA) Office of Inspector General (OIG) report has found that many patients who scored high on a screening for alcohol use are not receiving recommended counseling interventions.

The OIG report evaluated Veterans Health Administration (VHA) primary care staff adherence to the screening requirements and intervention interventions during fiscal year 2024 (October 1, 2023, to September 30, 2024). VHA primary care clinicians used the Alcohol Use Disorders Identification Test – Consumption (AUDIT-C), which produces a score of 0 to 12, to screen almost 4 million patients.

Based on sex-specific thresholds, the report found 8% of men and 11% of women screened positive for unhealthy alcohol use (AUDIT-C score ≥ 4 for men and ≥ 3 for women). However, because VHA electronic health record prompts clinicians to provide intervention for patients with scores ≥ 5, 54% of men and 75% of women who may have benefited from brief intervention did not.

A brief intervention with a clinician consists of a 5-minute counseling session, with individualized feedback and a discussion on strategies for the patient to reduce or abstain from alcohol.

Aligning with VHA guidance, clinicians provided brief intervention to 77% of men and 75% of women who recorded an AUDIT-C score ≥ 5. However, < 2% of patients with a score at the sex-specific threshold received brief intervention.  

Veterans have high rates of unhealthy alcohol use, which is associated with increased risk of interpersonal violence and poor health outcomes. In a May 2026 study, 44% of 3117 veterans met criteria for alcohol use disorder; 44% reported past 30-day alcohol use.

The VHA requires annual screening using the AUDIT-C. In a study of 63,397 VHA patients, 25% of women and 28% of men screened positive for unhealthy alcohol use. The prevalence of alcohol and other substance abuse disorders increased with increasing AUDIT-C scores, ranging as high as 82% for women and 69% for men. 

A 2018 analysis found that tailoring the AUDIT-C binge-drinking item, AUDIT-C scoring, or both increased detection of unhealthy alcohol use in women. In 2020, VHA adjusted the binge drinking item for women, reducing it to 4 drinks on an occasion from 6 to characterize binge drinking. Despite this adjustment, the VHA maintained an AUDIT-C score ≥ 5 to prompt brief intervention for both women and men.

A 2022 study of 4148 veterans found that 15% were not properly screened for alcohol despite 1 in 11 met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for alcohol abuse/dependence. A lack of screening may not be the issue, however. In the OIG report, VHA found 95% adherence to alcohol use screening in 2024 using a sample-based performance measure and 79% adherence after transitioning that year to a population-based measure. OIG determined that the population-based measure provides a more accurate representation of screening documentation.

Following the OIG recommendations, VA Under Secretary for Health John J. Bartrum, JD, MBA, provided an action plan to evaluate factors that affect screening, identify facilities for performance improvement, and evaluate the use of sex-specific alcohol use screening thresholds. 

A US Department of Veterans Affairs (VA) Office of Inspector General (OIG) report has found that many patients who scored high on a screening for alcohol use are not receiving recommended counseling interventions.

The OIG report evaluated Veterans Health Administration (VHA) primary care staff adherence to the screening requirements and intervention interventions during fiscal year 2024 (October 1, 2023, to September 30, 2024). VHA primary care clinicians used the Alcohol Use Disorders Identification Test – Consumption (AUDIT-C), which produces a score of 0 to 12, to screen almost 4 million patients.

Based on sex-specific thresholds, the report found 8% of men and 11% of women screened positive for unhealthy alcohol use (AUDIT-C score ≥ 4 for men and ≥ 3 for women). However, because VHA electronic health record prompts clinicians to provide intervention for patients with scores ≥ 5, 54% of men and 75% of women who may have benefited from brief intervention did not.

A brief intervention with a clinician consists of a 5-minute counseling session, with individualized feedback and a discussion on strategies for the patient to reduce or abstain from alcohol.

Aligning with VHA guidance, clinicians provided brief intervention to 77% of men and 75% of women who recorded an AUDIT-C score ≥ 5. However, < 2% of patients with a score at the sex-specific threshold received brief intervention.  

Veterans have high rates of unhealthy alcohol use, which is associated with increased risk of interpersonal violence and poor health outcomes. In a May 2026 study, 44% of 3117 veterans met criteria for alcohol use disorder; 44% reported past 30-day alcohol use.

The VHA requires annual screening using the AUDIT-C. In a study of 63,397 VHA patients, 25% of women and 28% of men screened positive for unhealthy alcohol use. The prevalence of alcohol and other substance abuse disorders increased with increasing AUDIT-C scores, ranging as high as 82% for women and 69% for men. 

A 2018 analysis found that tailoring the AUDIT-C binge-drinking item, AUDIT-C scoring, or both increased detection of unhealthy alcohol use in women. In 2020, VHA adjusted the binge drinking item for women, reducing it to 4 drinks on an occasion from 6 to characterize binge drinking. Despite this adjustment, the VHA maintained an AUDIT-C score ≥ 5 to prompt brief intervention for both women and men.

A 2022 study of 4148 veterans found that 15% were not properly screened for alcohol despite 1 in 11 met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for alcohol abuse/dependence. A lack of screening may not be the issue, however. In the OIG report, VHA found 95% adherence to alcohol use screening in 2024 using a sample-based performance measure and 79% adherence after transitioning that year to a population-based measure. OIG determined that the population-based measure provides a more accurate representation of screening documentation.

Following the OIG recommendations, VA Under Secretary for Health John J. Bartrum, JD, MBA, provided an action plan to evaluate factors that affect screening, identify facilities for performance improvement, and evaluate the use of sex-specific alcohol use screening thresholds. 

The Association of Veterans Affairs Hematology/Oncology (AVAHO) will provide more than education during a special virtual session on July 18 devoted to 4 rare and ultra-rare disorders in classical hematology. The program includes 2.25 free continuing education credits and the organization hopes it will spur hematology pathways within the US Department of Veterans Affairs (VA) National Oncology Program, according to AVAHO President Nicholas Burwick, MD.

“Guidance on hematology disorders lag far behind oncologic disorders at the national level,” said Burwick, who specializes in hematology and bone marrow transplant at the Veterans Affairs Puget Sound Health Care System in Seattle. 

“Providers are facing real diagnostic and treatment decisions, and there are more and more treatment options available, some with significant cost implications,” Burwick said.

Burwick He is optimistic the session will have a lasting impact. He expanded on the 4 disorders slated for discussion at the meeting: aplastic anemia, thrombotic thrombocytopenic purpura (TTP), hereditary hemorrhagic telangiectasia (HHT), and acquired hemophilia A in a discussion with Federal Practitioner. The interview transcript has been edited for length and clarity.

What is aplastic anemia?

Aplastic anemia is a true bone marrow failure. The marrow stops producing cells. At a referral center like Seattle, we might see a few [cases] a year because we also do bone marrow transplant. Most facilities are probably seeing 1 or 2 a year at most.

Different mechanisms are behind it: immune-mediated causes, genetic predispositions, and acquired toxic injury. In the military population, aplastic anemia due to toxic exposure is a significant concern.

Who tends to develop aplastic anemia?

The age spectrum is broader than people think. We do see it in patients in their 40s and 50s, not just seniors. The general rule has been, if a patient is under 40, pursue transplant; over 40, pursue immunosuppressive therapy. However, that cutoff is somewhat arbitrary. 

What are some things clinicians should understand about this disease? 

Clinicians need to know the diagnostic criteria, what tests to run, how to put in transplant referral requests, and how to get a case on the radar at a transplant center like Nashville or Seattle. 

Patients need referral quickly. They often don’t respond to standard treatments like growth factors, so they end up requiring a lot of transfusions. You don’t want to sit around. 

Even if the transplant happens outside the VA, it usually runs through a transplant center for review first. There’s also the question of whether a condition qualifies as a service-connected disability or if the diagnosis is a presumptive condition for certain exposures.

How often do you see TTP, which produces small blood clots in blood vessels?

Some clinicians may see 1 case every 3 to 4 years, or possibly 1 case in an entire career. There is an inherited form and an acquired form. We’re primarily focused on the acquired autoimmune form, which can present in young adulthood or later.

What should clinicians know?

These patients come in needing urgent treatment. Recognizing the diagnosis quickly, ordering the right tests, and acting fast are all critical. This can be life-threatening within days without treatment.

Treatment involves plasma exchange, which not every facility is equipped to perform. There are also medications: steroids are standard, but there’s also caplacizumab, which is highly specific to TTP and unlikely to be stocked in a VA pharmacy because of how rarely it’s needed. Pharmacies often have to procure it on demand once the diagnosis is made, which can delay care. A key part of managing these cases is knowing who to reach out to and when to transfer a patient to an academic or community partner that has plasma exchange capability.

Are VA clinicians likely to see HHT, an inherited disorder that causes bleeding due to malformed blood vessels?

There’s a misconception that veterans don’t have inherited bleeding disorders, the assumption being that they wouldn’t have gotten into the military (had they had them). But many of these conditions don’t get diagnosed until later in life: symptoms can be mild initially or not present until young adulthood or later. 

Patients might come in with recurrent nosebleeds or unexplained [gastrointestinal] bleeding. We probably all have patients with HHT in our practices without knowing it because we’re not always doing appropriate diagnostic testing.

How are treatments evolving? 

Recent developments include both local options like laser treatment and systemic medications such as pomalidomide, which was approved recently, and bevacizumab. [The virtual session] speaker has been involved in clinical trials for pomalidomide and will speak to when to use these medications and how to choose between them now that there are options, both of which are expensive.

What is acquired hemophilia A?

It occurs when someone without a genetic predisposition loses their factor VIII activity due to an autoimmune process. It presents quickly, often with bleeding or bruising, and patients frequently show up in the [emergency department]. 

The treatment challenge is distinct from inherited hemophilia. Standard factor VIII replacement doesn’t work here because the autoantibody breaks it down. Treatment requires bypassing factor VIII—options include factor VIIa and emicizumab. 

Emicizumab is FDA-approved for inherited hemophilia A and used off-label for the acquired form. Procuring it in a VA facility can be difficult, and that is exactly where a VA clinical pathway would help. 

The VA doesn’t currently have strong hemophilia expertise internally. So, engaging with hemophilia treatment centers is important, as is developing subject matter experts within VA hematology who can serve as go-to resources for less-resourced facilities.

What unites these 4 rare hematology conditions? 

There are common threads: rare presentations requiring urgent decision-making, diagnostic criteria that aren’t always familiar, and treatments that may be hard to procure quickly. VA-specific resources—pathways, referral contacts, teleoncology consults—can make the difference in patient outcomes. 

A centralized virtual hematology hub, where providers could reach a knowledgeable hematologist for consultation, would go a long way. That’s what we’re ultimately trying to build toward.

The AVAHO Virtual Session on Rare and Ultra-Rare Hematologic Disorders will be held on July 18, 2026, from 12-2:30 p.m. EST.

The program is available to any health care professional who wants to learn more about the diagnosis and management of these hematologic disorders; 2.25 free continuing education credits are available.

The speakers are:

• Aplastic anemia: Emma Groarke, MB, BCh, BAO, MD, National Institutes of Health

• Thrombotic thrombocytopenic purpura: Yazan Abou-Ismail, MD, University of Utah

• Hereditary hemorrhagic telangiectasia: Hanny Al-Samkari, MD, Massachusetts General Hospital/Harvard Medical School; and

• Acquired hemophilia A, Aaron Boothby, MD, University of Washington/Fred Hutchinson Cancer Center.

The Association of Veterans Affairs Hematology/Oncology (AVAHO) will provide more than education during a special virtual session on July 18 devoted to 4 rare and ultra-rare disorders in classical hematology. The program includes 2.25 free continuing education credits and the organization hopes it will spur hematology pathways within the US Department of Veterans Affairs (VA) National Oncology Program, according to AVAHO President Nicholas Burwick, MD.

“Guidance on hematology disorders lag far behind oncologic disorders at the national level,” said Burwick, who specializes in hematology and bone marrow transplant at the Veterans Affairs Puget Sound Health Care System in Seattle. 

“Providers are facing real diagnostic and treatment decisions, and there are more and more treatment options available, some with significant cost implications,” Burwick said.

Burwick He is optimistic the session will have a lasting impact. He expanded on the 4 disorders slated for discussion at the meeting: aplastic anemia, thrombotic thrombocytopenic purpura (TTP), hereditary hemorrhagic telangiectasia (HHT), and acquired hemophilia A in a discussion with Federal Practitioner. The interview transcript has been edited for length and clarity.

What is aplastic anemia?

Aplastic anemia is a true bone marrow failure. The marrow stops producing cells. At a referral center like Seattle, we might see a few [cases] a year because we also do bone marrow transplant. Most facilities are probably seeing 1 or 2 a year at most.

Different mechanisms are behind it: immune-mediated causes, genetic predispositions, and acquired toxic injury. In the military population, aplastic anemia due to toxic exposure is a significant concern.

Who tends to develop aplastic anemia?

The age spectrum is broader than people think. We do see it in patients in their 40s and 50s, not just seniors. The general rule has been, if a patient is under 40, pursue transplant; over 40, pursue immunosuppressive therapy. However, that cutoff is somewhat arbitrary. 

What are some things clinicians should understand about this disease? 

Clinicians need to know the diagnostic criteria, what tests to run, how to put in transplant referral requests, and how to get a case on the radar at a transplant center like Nashville or Seattle. 

Patients need referral quickly. They often don’t respond to standard treatments like growth factors, so they end up requiring a lot of transfusions. You don’t want to sit around. 

Even if the transplant happens outside the VA, it usually runs through a transplant center for review first. There’s also the question of whether a condition qualifies as a service-connected disability or if the diagnosis is a presumptive condition for certain exposures.

How often do you see TTP, which produces small blood clots in blood vessels?

Some clinicians may see 1 case every 3 to 4 years, or possibly 1 case in an entire career. There is an inherited form and an acquired form. We’re primarily focused on the acquired autoimmune form, which can present in young adulthood or later.

What should clinicians know?

These patients come in needing urgent treatment. Recognizing the diagnosis quickly, ordering the right tests, and acting fast are all critical. This can be life-threatening within days without treatment.

Treatment involves plasma exchange, which not every facility is equipped to perform. There are also medications: steroids are standard, but there’s also caplacizumab, which is highly specific to TTP and unlikely to be stocked in a VA pharmacy because of how rarely it’s needed. Pharmacies often have to procure it on demand once the diagnosis is made, which can delay care. A key part of managing these cases is knowing who to reach out to and when to transfer a patient to an academic or community partner that has plasma exchange capability.

Are VA clinicians likely to see HHT, an inherited disorder that causes bleeding due to malformed blood vessels?

There’s a misconception that veterans don’t have inherited bleeding disorders, the assumption being that they wouldn’t have gotten into the military (had they had them). But many of these conditions don’t get diagnosed until later in life: symptoms can be mild initially or not present until young adulthood or later. 

Patients might come in with recurrent nosebleeds or unexplained [gastrointestinal] bleeding. We probably all have patients with HHT in our practices without knowing it because we’re not always doing appropriate diagnostic testing.

How are treatments evolving? 

Recent developments include both local options like laser treatment and systemic medications such as pomalidomide, which was approved recently, and bevacizumab. [The virtual session] speaker has been involved in clinical trials for pomalidomide and will speak to when to use these medications and how to choose between them now that there are options, both of which are expensive.

What is acquired hemophilia A?

It occurs when someone without a genetic predisposition loses their factor VIII activity due to an autoimmune process. It presents quickly, often with bleeding or bruising, and patients frequently show up in the [emergency department]. 

The treatment challenge is distinct from inherited hemophilia. Standard factor VIII replacement doesn’t work here because the autoantibody breaks it down. Treatment requires bypassing factor VIII—options include factor VIIa and emicizumab. 

Emicizumab is FDA-approved for inherited hemophilia A and used off-label for the acquired form. Procuring it in a VA facility can be difficult, and that is exactly where a VA clinical pathway would help. 

The VA doesn’t currently have strong hemophilia expertise internally. So, engaging with hemophilia treatment centers is important, as is developing subject matter experts within VA hematology who can serve as go-to resources for less-resourced facilities.

What unites these 4 rare hematology conditions? 

There are common threads: rare presentations requiring urgent decision-making, diagnostic criteria that aren’t always familiar, and treatments that may be hard to procure quickly. VA-specific resources—pathways, referral contacts, teleoncology consults—can make the difference in patient outcomes. 

A centralized virtual hematology hub, where providers could reach a knowledgeable hematologist for consultation, would go a long way. That’s what we’re ultimately trying to build toward.

The AVAHO Virtual Session on Rare and Ultra-Rare Hematologic Disorders will be held on July 18, 2026, from 12-2:30 p.m. EST.

The program is available to any health care professional who wants to learn more about the diagnosis and management of these hematologic disorders; 2.25 free continuing education credits are available.

The speakers are:

• Aplastic anemia: Emma Groarke, MB, BCh, BAO, MD, National Institutes of Health

• Thrombotic thrombocytopenic purpura: Yazan Abou-Ismail, MD, University of Utah

• Hereditary hemorrhagic telangiectasia: Hanny Al-Samkari, MD, Massachusetts General Hospital/Harvard Medical School; and

• Acquired hemophilia A, Aaron Boothby, MD, University of Washington/Fred Hutchinson Cancer Center.

The Association of Veterans Affairs Hematology/Oncology (AVAHO) will provide more than education during a special virtual session on July 18 devoted to 4 rare and ultra-rare disorders in classical hematology. The program includes 2.25 free continuing education credits and the organization hopes it will spur hematology pathways within the US Department of Veterans Affairs (VA) National Oncology Program, according to AVAHO President Nicholas Burwick, MD.

“Guidance on hematology disorders lag far behind oncologic disorders at the national level,” said Burwick, who specializes in hematology and bone marrow transplant at the Veterans Affairs Puget Sound Health Care System in Seattle. 

“Providers are facing real diagnostic and treatment decisions, and there are more and more treatment options available, some with significant cost implications,” Burwick said.

Burwick He is optimistic the session will have a lasting impact. He expanded on the 4 disorders slated for discussion at the meeting: aplastic anemia, thrombotic thrombocytopenic purpura (TTP), hereditary hemorrhagic telangiectasia (HHT), and acquired hemophilia A in a discussion with Federal Practitioner. The interview transcript has been edited for length and clarity.

What is aplastic anemia?

Aplastic anemia is a true bone marrow failure. The marrow stops producing cells. At a referral center like Seattle, we might see a few [cases] a year because we also do bone marrow transplant. Most facilities are probably seeing 1 or 2 a year at most.

Different mechanisms are behind it: immune-mediated causes, genetic predispositions, and acquired toxic injury. In the military population, aplastic anemia due to toxic exposure is a significant concern.

Who tends to develop aplastic anemia?

The age spectrum is broader than people think. We do see it in patients in their 40s and 50s, not just seniors. The general rule has been, if a patient is under 40, pursue transplant; over 40, pursue immunosuppressive therapy. However, that cutoff is somewhat arbitrary. 

What are some things clinicians should understand about this disease? 

Clinicians need to know the diagnostic criteria, what tests to run, how to put in transplant referral requests, and how to get a case on the radar at a transplant center like Nashville or Seattle. 

Patients need referral quickly. They often don’t respond to standard treatments like growth factors, so they end up requiring a lot of transfusions. You don’t want to sit around. 

Even if the transplant happens outside the VA, it usually runs through a transplant center for review first. There’s also the question of whether a condition qualifies as a service-connected disability or if the diagnosis is a presumptive condition for certain exposures.

How often do you see TTP, which produces small blood clots in blood vessels?

Some clinicians may see 1 case every 3 to 4 years, or possibly 1 case in an entire career. There is an inherited form and an acquired form. We’re primarily focused on the acquired autoimmune form, which can present in young adulthood or later.

What should clinicians know?

These patients come in needing urgent treatment. Recognizing the diagnosis quickly, ordering the right tests, and acting fast are all critical. This can be life-threatening within days without treatment.

Treatment involves plasma exchange, which not every facility is equipped to perform. There are also medications: steroids are standard, but there’s also caplacizumab, which is highly specific to TTP and unlikely to be stocked in a VA pharmacy because of how rarely it’s needed. Pharmacies often have to procure it on demand once the diagnosis is made, which can delay care. A key part of managing these cases is knowing who to reach out to and when to transfer a patient to an academic or community partner that has plasma exchange capability.

Are VA clinicians likely to see HHT, an inherited disorder that causes bleeding due to malformed blood vessels?

There’s a misconception that veterans don’t have inherited bleeding disorders, the assumption being that they wouldn’t have gotten into the military (had they had them). But many of these conditions don’t get diagnosed until later in life: symptoms can be mild initially or not present until young adulthood or later. 

Patients might come in with recurrent nosebleeds or unexplained [gastrointestinal] bleeding. We probably all have patients with HHT in our practices without knowing it because we’re not always doing appropriate diagnostic testing.

How are treatments evolving? 

Recent developments include both local options like laser treatment and systemic medications such as pomalidomide, which was approved recently, and bevacizumab. [The virtual session] speaker has been involved in clinical trials for pomalidomide and will speak to when to use these medications and how to choose between them now that there are options, both of which are expensive.

What is acquired hemophilia A?

It occurs when someone without a genetic predisposition loses their factor VIII activity due to an autoimmune process. It presents quickly, often with bleeding or bruising, and patients frequently show up in the [emergency department]. 

The treatment challenge is distinct from inherited hemophilia. Standard factor VIII replacement doesn’t work here because the autoantibody breaks it down. Treatment requires bypassing factor VIII—options include factor VIIa and emicizumab. 

Emicizumab is FDA-approved for inherited hemophilia A and used off-label for the acquired form. Procuring it in a VA facility can be difficult, and that is exactly where a VA clinical pathway would help. 

The VA doesn’t currently have strong hemophilia expertise internally. So, engaging with hemophilia treatment centers is important, as is developing subject matter experts within VA hematology who can serve as go-to resources for less-resourced facilities.

What unites these 4 rare hematology conditions? 

There are common threads: rare presentations requiring urgent decision-making, diagnostic criteria that aren’t always familiar, and treatments that may be hard to procure quickly. VA-specific resources—pathways, referral contacts, teleoncology consults—can make the difference in patient outcomes. 

A centralized virtual hematology hub, where providers could reach a knowledgeable hematologist for consultation, would go a long way. That’s what we’re ultimately trying to build toward.

The AVAHO Virtual Session on Rare and Ultra-Rare Hematologic Disorders will be held on July 18, 2026, from 12-2:30 p.m. EST.

The program is available to any health care professional who wants to learn more about the diagnosis and management of these hematologic disorders; 2.25 free continuing education credits are available.

The speakers are:

• Aplastic anemia: Emma Groarke, MB, BCh, BAO, MD, National Institutes of Health

• Thrombotic thrombocytopenic purpura: Yazan Abou-Ismail, MD, University of Utah

• Hereditary hemorrhagic telangiectasia: Hanny Al-Samkari, MD, Massachusetts General Hospital/Harvard Medical School; and

• Acquired hemophilia A, Aaron Boothby, MD, University of Washington/Fred Hutchinson Cancer Center.

TOPLINE: Serum P21 Activated Kinase 6 (PAK6) demonstrated diagnostic accuracy comparable to pro-gastrin-releasing peptide (ProGRP) for small cell lung cancer (SCLC), with area under the curve (AUC) values of 0.892 and 0.935, respectively, in a study of 109 patients with SCLC. Combining PAK6, ProGRP, and neuron-specific enolase (NSE) achieved diagnostic efficiency of 0.98. Elevated baseline PAK6 levels correlated with shorter progression-free survival and increased risk for disease progression.

METHODOLOGY:

• Participants included 380 people in China: 109 with SCLC, 92 with non–small cell lung cancer (NSCLC), 85 with benign pulmonary nodules, and 94 healthy controls who received routine physical examinations. 

• Laboratory testing measured serum PAK6 by ELISA, while NSE, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and ProGRP were quantified by chemiluminescence. 

• Pretreatment and posttreatment serum samples from 56 patients with SCLC were analyzed to evaluate changes in biomarker levels following 3 months of treatment. 

• Progression-free survival data were collected through case review and follow-up, defined as time from treatment initiation to radiographic disease progression per RECIST 1.1 criteria or death from any cause.

TAKEAWAY:

• Median serum PAK6 is reported as 56.44 ng/L in SCLC vs 41.06 ng/L in NSCLC, 37.82 ng/L in pulmonary nodules, and 34.75 ng/L in healthy controls (P < .01). 

• PAK6 demonstrated diagnostic efficacy with and AUC of 0.892 (95% CI, 0.857-0.927), sensitivity of 0.82, and specificity of 0.86 at optimal cut-off value of 47.30 ng/L, comparable to ProGRP (AUC, 0.935) and superior to CEA (AUC, 0.676) and CA19-9 (AUC, 0.611). 

• In 56 paired SCLC samples, PAK6, NSE, and ProGRP decrease after 3 months of treatment (P < .001), while CEA and CA19-9 display no meaningful change. 

• Elevated baseline PAK6 expression correlated with shorter progression-free survival, with high-expression patients demonstrating median survival of 92 days vs 194 days in low-expression patients (HR, 2.02; 95% CI, 1.33-3.07; P = .001).

IN PRACTICE: “We identify PAK6 as a multi-faceted biomarker for SCLC with diagnostic, prognostic, and therapeutic monitoring value. Its cost-effective ELISA quantification facilitates clinical translation,” wrote the authors of the study. “Integrating PAK6 with emerging technologies could further refine SCLC management paradigms.”

SOURCE:The study was led by Simei Chen, Department of Blood Transfusion, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University in Nanchang, China. It was published online in PeerJ.

LIMITATIONS: A single-center design and modest sample size may limit generalizability of the diagnostic and prognostic estimates. The authors also note the absence of immunohistochemical validation, leaving tissue-level correlation of PAK6 unaddressed. Finally, insufficient overall survival data were reported, which constrains interpretation beyond PFS and supports the need for prospective follow-up and larger multi-center validation.

DISCLOSURES: Grant support came from the Science and Technology Program Project of Jiangxi Provincial Administration of Traditional Chinese Medicine (Grant 2024B1433). The authors stated the funders had no role in study design, data collection and analysis, the decision to publish, or manuscript preparation. No competing interests were disclosed.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: Serum P21 Activated Kinase 6 (PAK6) demonstrated diagnostic accuracy comparable to pro-gastrin-releasing peptide (ProGRP) for small cell lung cancer (SCLC), with area under the curve (AUC) values of 0.892 and 0.935, respectively, in a study of 109 patients with SCLC. Combining PAK6, ProGRP, and neuron-specific enolase (NSE) achieved diagnostic efficiency of 0.98. Elevated baseline PAK6 levels correlated with shorter progression-free survival and increased risk for disease progression.

METHODOLOGY:

• Participants included 380 people in China: 109 with SCLC, 92 with non–small cell lung cancer (NSCLC), 85 with benign pulmonary nodules, and 94 healthy controls who received routine physical examinations. 

• Laboratory testing measured serum PAK6 by ELISA, while NSE, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and ProGRP were quantified by chemiluminescence. 

• Pretreatment and posttreatment serum samples from 56 patients with SCLC were analyzed to evaluate changes in biomarker levels following 3 months of treatment. 

• Progression-free survival data were collected through case review and follow-up, defined as time from treatment initiation to radiographic disease progression per RECIST 1.1 criteria or death from any cause.

TAKEAWAY:

• Median serum PAK6 is reported as 56.44 ng/L in SCLC vs 41.06 ng/L in NSCLC, 37.82 ng/L in pulmonary nodules, and 34.75 ng/L in healthy controls (P < .01). 

• PAK6 demonstrated diagnostic efficacy with and AUC of 0.892 (95% CI, 0.857-0.927), sensitivity of 0.82, and specificity of 0.86 at optimal cut-off value of 47.30 ng/L, comparable to ProGRP (AUC, 0.935) and superior to CEA (AUC, 0.676) and CA19-9 (AUC, 0.611). 

• In 56 paired SCLC samples, PAK6, NSE, and ProGRP decrease after 3 months of treatment (P < .001), while CEA and CA19-9 display no meaningful change. 

• Elevated baseline PAK6 expression correlated with shorter progression-free survival, with high-expression patients demonstrating median survival of 92 days vs 194 days in low-expression patients (HR, 2.02; 95% CI, 1.33-3.07; P = .001).

IN PRACTICE: “We identify PAK6 as a multi-faceted biomarker for SCLC with diagnostic, prognostic, and therapeutic monitoring value. Its cost-effective ELISA quantification facilitates clinical translation,” wrote the authors of the study. “Integrating PAK6 with emerging technologies could further refine SCLC management paradigms.”

SOURCE:The study was led by Simei Chen, Department of Blood Transfusion, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University in Nanchang, China. It was published online in PeerJ.

LIMITATIONS: A single-center design and modest sample size may limit generalizability of the diagnostic and prognostic estimates. The authors also note the absence of immunohistochemical validation, leaving tissue-level correlation of PAK6 unaddressed. Finally, insufficient overall survival data were reported, which constrains interpretation beyond PFS and supports the need for prospective follow-up and larger multi-center validation.

DISCLOSURES: Grant support came from the Science and Technology Program Project of Jiangxi Provincial Administration of Traditional Chinese Medicine (Grant 2024B1433). The authors stated the funders had no role in study design, data collection and analysis, the decision to publish, or manuscript preparation. No competing interests were disclosed.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

TOPLINE: Serum P21 Activated Kinase 6 (PAK6) demonstrated diagnostic accuracy comparable to pro-gastrin-releasing peptide (ProGRP) for small cell lung cancer (SCLC), with area under the curve (AUC) values of 0.892 and 0.935, respectively, in a study of 109 patients with SCLC. Combining PAK6, ProGRP, and neuron-specific enolase (NSE) achieved diagnostic efficiency of 0.98. Elevated baseline PAK6 levels correlated with shorter progression-free survival and increased risk for disease progression.

METHODOLOGY:

• Participants included 380 people in China: 109 with SCLC, 92 with non–small cell lung cancer (NSCLC), 85 with benign pulmonary nodules, and 94 healthy controls who received routine physical examinations. 

• Laboratory testing measured serum PAK6 by ELISA, while NSE, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and ProGRP were quantified by chemiluminescence. 

• Pretreatment and posttreatment serum samples from 56 patients with SCLC were analyzed to evaluate changes in biomarker levels following 3 months of treatment. 

• Progression-free survival data were collected through case review and follow-up, defined as time from treatment initiation to radiographic disease progression per RECIST 1.1 criteria or death from any cause.

TAKEAWAY:

• Median serum PAK6 is reported as 56.44 ng/L in SCLC vs 41.06 ng/L in NSCLC, 37.82 ng/L in pulmonary nodules, and 34.75 ng/L in healthy controls (P < .01). 

• PAK6 demonstrated diagnostic efficacy with and AUC of 0.892 (95% CI, 0.857-0.927), sensitivity of 0.82, and specificity of 0.86 at optimal cut-off value of 47.30 ng/L, comparable to ProGRP (AUC, 0.935) and superior to CEA (AUC, 0.676) and CA19-9 (AUC, 0.611). 

• In 56 paired SCLC samples, PAK6, NSE, and ProGRP decrease after 3 months of treatment (P < .001), while CEA and CA19-9 display no meaningful change. 

• Elevated baseline PAK6 expression correlated with shorter progression-free survival, with high-expression patients demonstrating median survival of 92 days vs 194 days in low-expression patients (HR, 2.02; 95% CI, 1.33-3.07; P = .001).

IN PRACTICE: “We identify PAK6 as a multi-faceted biomarker for SCLC with diagnostic, prognostic, and therapeutic monitoring value. Its cost-effective ELISA quantification facilitates clinical translation,” wrote the authors of the study. “Integrating PAK6 with emerging technologies could further refine SCLC management paradigms.”

SOURCE:The study was led by Simei Chen, Department of Blood Transfusion, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University in Nanchang, China. It was published online in PeerJ.

LIMITATIONS: A single-center design and modest sample size may limit generalizability of the diagnostic and prognostic estimates. The authors also note the absence of immunohistochemical validation, leaving tissue-level correlation of PAK6 unaddressed. Finally, insufficient overall survival data were reported, which constrains interpretation beyond PFS and supports the need for prospective follow-up and larger multi-center validation.

DISCLOSURES: Grant support came from the Science and Technology Program Project of Jiangxi Provincial Administration of Traditional Chinese Medicine (Grant 2024B1433). The authors stated the funders had no role in study design, data collection and analysis, the decision to publish, or manuscript preparation. No competing interests were disclosed.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Asthma biologics significantly improved lung function in children with asthma using race-based reference points, based on new data from 115 individuals.

Data on the effect of biologics on lung function in pediatric asthma are limited, and the main previous study of this relationship, the VOYAGE trial, was limited by its reliance on older, race-specific spirometry equations, according to Ken Wu, medical student at Indiana University School of Medicine in Indianapolis.

Newer, race-neutral reference equations prevent the systematic underestimation of asthma severity in Black patients and consequently provide a more accurate assessment of therapeutic benefits, said Wu. “Our study offers a novel contribution to the literature as the first known to utilize race-neutral equations to evaluate lung function following biologic therapy in a pediatric asthma population,” he said.

In a new study, presented at the American Thoracic Society (ATS) 2026 International Conference, the researchers conducted a real-world analysis with race-neutral reference equations developed by the Global Lung Function Initiative to assess the effect of biologics on lung function. They reviewed data from 115 pediatric patients with asthma who started biologics for the first time between 2015 and 2025. Their analysis included height, weight, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratios. The mean age of the patients was 11.4 years, 52% were male, and 62% were Black. A majority (97 patients) received dupilumab; 13 received omalizumab, and 5 received mepolizumab.

The analysis included an average of three spirometry measures 1 year before starting biologics and an average of four measures during the year after starting biologics.

Treatment with dupilumab was associated with a significant improvement in lung function, with an increase in the average FEV₁ from 86.4 percent-predicted prior to biologics to 91.7 after biologics (mean difference, 5.31; P = .044). No significant differences appeared among omalizumab or mepolizumab patients, likely because of the small numbers, the researchers noted.

Overall, in a linear mixed model adjusting for biologic type, FEV₁ remained significantly higher after use of biologics than in the period prior to use (97.9 vs. 92.5), with a mean difference of 5.37 (P = .039).

The primary finding that dupilumab improved the percent-predicted FEV₁ by 5.31 is considered a modest effect size and mainly aligns with previous research, said Wu. “We are currently in the process of conducting additional analysis of whether there is a difference in lung function when we use the older race-specific equations versus our current findings with the newer race-neutral equations,” he said.

The findings were limited by several factors, including the relatively small study population and inclusion of only 3 types of biologics, with samples of omalizumab and mepolizumab that were underpowered to detect differences in lung function, said Wu. Additional studies with larger sample sizes, more biologics (including benralizumab and tezepelumab), and longer follow-up periods are needed to compare benefits across agents, he said.

Promising Implications for Practice

The ATS has recommended abandoning the previous race-adjusted pulmonary function test norms, said Timothy Joos, MD, who practices internal medicine and pediatrics at a community health center in Seattle.

These norms assigned smaller lung volumes to Black and Asian individuals and tended to underestimate lung disease in these populations, said Joos, who was not involved in the new study.

The current study, though small, showed with race-neutral reference equations that biologic agents significantly improved FEV1 values in children with severe asthma, said Joos. The association was especially strong with dupilumab, used by 85% of the patients, he noted. However, additional studies are needed with larger patient populations and other biologic agents to confirm the results, he said.

The study was supported by the Indiana Clinical and Translational Sciences Institute. The previous VOYAGE trial received funding from Sanofi and Regeneron Pharmaceuticals. The researchers reported having no financial conflicts to disclose. Joos reported having no financial conflicts to disclose.

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

Asthma biologics significantly improved lung function in children with asthma using race-based reference points, based on new data from 115 individuals.

Data on the effect of biologics on lung function in pediatric asthma are limited, and the main previous study of this relationship, the VOYAGE trial, was limited by its reliance on older, race-specific spirometry equations, according to Ken Wu, medical student at Indiana University School of Medicine in Indianapolis.

Newer, race-neutral reference equations prevent the systematic underestimation of asthma severity in Black patients and consequently provide a more accurate assessment of therapeutic benefits, said Wu. “Our study offers a novel contribution to the literature as the first known to utilize race-neutral equations to evaluate lung function following biologic therapy in a pediatric asthma population,” he said.

In a new study, presented at the American Thoracic Society (ATS) 2026 International Conference, the researchers conducted a real-world analysis with race-neutral reference equations developed by the Global Lung Function Initiative to assess the effect of biologics on lung function. They reviewed data from 115 pediatric patients with asthma who started biologics for the first time between 2015 and 2025. Their analysis included height, weight, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratios. The mean age of the patients was 11.4 years, 52% were male, and 62% were Black. A majority (97 patients) received dupilumab; 13 received omalizumab, and 5 received mepolizumab.

The analysis included an average of three spirometry measures 1 year before starting biologics and an average of four measures during the year after starting biologics.

Treatment with dupilumab was associated with a significant improvement in lung function, with an increase in the average FEV₁ from 86.4 percent-predicted prior to biologics to 91.7 after biologics (mean difference, 5.31; P = .044). No significant differences appeared among omalizumab or mepolizumab patients, likely because of the small numbers, the researchers noted.

Overall, in a linear mixed model adjusting for biologic type, FEV₁ remained significantly higher after use of biologics than in the period prior to use (97.9 vs. 92.5), with a mean difference of 5.37 (P = .039).

The primary finding that dupilumab improved the percent-predicted FEV₁ by 5.31 is considered a modest effect size and mainly aligns with previous research, said Wu. “We are currently in the process of conducting additional analysis of whether there is a difference in lung function when we use the older race-specific equations versus our current findings with the newer race-neutral equations,” he said.

The findings were limited by several factors, including the relatively small study population and inclusion of only 3 types of biologics, with samples of omalizumab and mepolizumab that were underpowered to detect differences in lung function, said Wu. Additional studies with larger sample sizes, more biologics (including benralizumab and tezepelumab), and longer follow-up periods are needed to compare benefits across agents, he said.

Promising Implications for Practice

The ATS has recommended abandoning the previous race-adjusted pulmonary function test norms, said Timothy Joos, MD, who practices internal medicine and pediatrics at a community health center in Seattle.

These norms assigned smaller lung volumes to Black and Asian individuals and tended to underestimate lung disease in these populations, said Joos, who was not involved in the new study.

The current study, though small, showed with race-neutral reference equations that biologic agents significantly improved FEV1 values in children with severe asthma, said Joos. The association was especially strong with dupilumab, used by 85% of the patients, he noted. However, additional studies are needed with larger patient populations and other biologic agents to confirm the results, he said.

The study was supported by the Indiana Clinical and Translational Sciences Institute. The previous VOYAGE trial received funding from Sanofi and Regeneron Pharmaceuticals. The researchers reported having no financial conflicts to disclose. Joos reported having no financial conflicts to disclose.

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

Asthma biologics significantly improved lung function in children with asthma using race-based reference points, based on new data from 115 individuals.

Data on the effect of biologics on lung function in pediatric asthma are limited, and the main previous study of this relationship, the VOYAGE trial, was limited by its reliance on older, race-specific spirometry equations, according to Ken Wu, medical student at Indiana University School of Medicine in Indianapolis.

Newer, race-neutral reference equations prevent the systematic underestimation of asthma severity in Black patients and consequently provide a more accurate assessment of therapeutic benefits, said Wu. “Our study offers a novel contribution to the literature as the first known to utilize race-neutral equations to evaluate lung function following biologic therapy in a pediatric asthma population,” he said.

In a new study, presented at the American Thoracic Society (ATS) 2026 International Conference, the researchers conducted a real-world analysis with race-neutral reference equations developed by the Global Lung Function Initiative to assess the effect of biologics on lung function. They reviewed data from 115 pediatric patients with asthma who started biologics for the first time between 2015 and 2025. Their analysis included height, weight, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratios. The mean age of the patients was 11.4 years, 52% were male, and 62% were Black. A majority (97 patients) received dupilumab; 13 received omalizumab, and 5 received mepolizumab.

The analysis included an average of three spirometry measures 1 year before starting biologics and an average of four measures during the year after starting biologics.

Treatment with dupilumab was associated with a significant improvement in lung function, with an increase in the average FEV₁ from 86.4 percent-predicted prior to biologics to 91.7 after biologics (mean difference, 5.31; P = .044). No significant differences appeared among omalizumab or mepolizumab patients, likely because of the small numbers, the researchers noted.

Overall, in a linear mixed model adjusting for biologic type, FEV₁ remained significantly higher after use of biologics than in the period prior to use (97.9 vs. 92.5), with a mean difference of 5.37 (P = .039).

The primary finding that dupilumab improved the percent-predicted FEV₁ by 5.31 is considered a modest effect size and mainly aligns with previous research, said Wu. “We are currently in the process of conducting additional analysis of whether there is a difference in lung function when we use the older race-specific equations versus our current findings with the newer race-neutral equations,” he said.

The findings were limited by several factors, including the relatively small study population and inclusion of only 3 types of biologics, with samples of omalizumab and mepolizumab that were underpowered to detect differences in lung function, said Wu. Additional studies with larger sample sizes, more biologics (including benralizumab and tezepelumab), and longer follow-up periods are needed to compare benefits across agents, he said.

Promising Implications for Practice

The ATS has recommended abandoning the previous race-adjusted pulmonary function test norms, said Timothy Joos, MD, who practices internal medicine and pediatrics at a community health center in Seattle.

These norms assigned smaller lung volumes to Black and Asian individuals and tended to underestimate lung disease in these populations, said Joos, who was not involved in the new study.

The current study, though small, showed with race-neutral reference equations that biologic agents significantly improved FEV1 values in children with severe asthma, said Joos. The association was especially strong with dupilumab, used by 85% of the patients, he noted. However, additional studies are needed with larger patient populations and other biologic agents to confirm the results, he said.

The study was supported by the Indiana Clinical and Translational Sciences Institute. The previous VOYAGE trial received funding from Sanofi and Regeneron Pharmaceuticals. The researchers reported having no financial conflicts to disclose. Joos reported having no financial conflicts to disclose.

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

This transcript has been edited for clarity.

Hello, everyone. This is Dr Bishal Gyawali, from Queens University, Kingston, Canada. Today, I’m back with you to talk about some of the fallacies that I have seen in medicine, oncology, and the drug regulatory space. I wanted to clarify some of these fallacies.

In my last video, I talked about the FDA denying the approval of a new cancer drug. Let me start with one of the fallacies that is pertinent to that, which is that some people make an argument that patients are dying from a certain condition, such as cancer, or even any other disease besides cancer. That is an absolutely true statement, but that does not necessarily mean there should be a lower bar for drug approvals or we should be approving any drug that has a hint of benefit.

In fact, if we have increased mortality rates and our patients are dying from a certain condition, that means we actually need to have good drugs. We need to have drugs that prevent mortality. We need to have drugs that improve outcomes. Just having any drug out there, if we lower our threshold and are letting any drug be used in these patients because the argument is that people are dying, then in fact, it can have negative consequences.

First, there will be opportunity costs. If you can get any lousy drug into the market and make billions of dollars out of it, then there is no strong motivation to produce drugs that actually remarkably improve outcomes.

Second, patients will also be misled. It’s the patient’s opportunity cost in that they will use whatever time they have remaining to pursue these treatments that were not going to improve their outcomes anyway. This is time they could have better spent either in pursuing better treatments, if those treatments are out there, or to prioritize their time accordingly. This rather gives them a false hope, which can be harmful in the long term.

The first fallacy is that just because people are dying does not necessarily mean we should have more new drugs with a lower bar for approval.

The second fallacy I want to talk about, which is also related to this, is that if a certain cancer is rare, the bar for new drug approval should be quite low.

Of course, rare cancers are a special category, and rare cancers should be treated differently from a regulatory perspective. Absolutely. If the cancer is rare, we cannot have trials with large sample sizes to generate evidence. That problem is there, but that does not necessarily translate to the decision that we should approve anything, even something with a small hint of benefit.

There are other methods to make sure that, even in rare cancers, we can generate good-quality evidence. In fact, from an equity perspective, why should patients with rare cancer not deserve drugs that have good-quality evidence?

We can’t tell someone that, “Your cancer is rare, so you should get drugs that only have a benefit in terms of response rate whereas other cancers that are not rare will have drugs based on survival.”

Going back to the point about the difficulty in doing big trials in patients with rare cancers, that is absolutely true and there should be regulatory flexibility in this. I think accelerated approval is a pathway that allows for this regulatory flexibility, which allows access to these drugs early on based on earlier signals of benefit. You can continue to generate evidence in the future and confirm the clinical benefit.

There are also other nuances to this. One is that we should also make sure that this regulatory flexibility with rare cancers should not be misused. What do I mean by that? First, all rare cancers are not the same. There are some cancers that are ultra rare, and then there are some cancers that technically might fit the definition of rare, but trials are possible. Case in point: adrenocortical cancer. It is considered to be a very rare cancer, but there have been randomized trials in adrenocortical cancer.

Our efforts should be to maximize our collaboration globally so that a cancer that is rare locally will still not be so rare globally when we collect all these patients.

In certain situations, like let’s say, based on the molecular subtypes, any common cancer can be sliced and diced into a rare subtype: MSI-high, BRAF-negative, HER2-positive, right-sided colon cancer. If you start to slice cancers into these smaller and smaller molecular subtypes, you can consider anything as a rare cancer. That should not be misused as an excuse to get away from doing proper trials and generating adequate evidence for our patients.

The third fallacy I want to talk about is that increasing cancer incidence in a certain subgroup of population does not automatically translate into, “We should start screening this subgroup of population.”

A certain cancer — let’s say cancer X or cancer Y — is increasing in a young population, so therefore, we should lower the age of the screening of young populations. This cancer is increasing in this ethnic population, so therefore we should start screening this ethnic population more frequently. This cancer is increasing in this type of minority, so therefore, we should start screening this minority more.

No, it does not work like that. Increasing incidence will make us concerned, of course, but that does not necessarily translate into, “We should start screening them.” In order for a screening test to be useful, it has to fulfill a number of criteria.

The goal is not to detect cancers. The goal is to detect cancers that are not indolent enough that they would have never caused problems, nor speed up the diagnosis of aggressive cancers that are going to be lethal pretty soon anyway. The goal is to detect those cancers in the middle, so that by detecting early, we can intervene and improve the outcomes and improve the mortality from that cancer.

This type of intervention requires a thoughtful consideration of the increasing incidence of the cancer, of course, but also the utility of the screening test in that subgroup of population; the life expectancy of this subgroup of patients with and without cancer; the interventions available to address that increasing burden of cancer; and whether by intervening we are going to reduce the mortality rates.

Just because we can detect cancers does not mean we should detect cancers. That’s the third fallacy I wanted to talk about.

The fourth fallacy is related to when someone is asking for more evidence for anything. There is a new drug for this cancer,so what is the evidence? Or there is this new intervention that will detect ctDNA or whatever before the cancer relapses, or before the cancer even shows up as a screening test.

Whenever there is any treatment that is being promoted and someone asks for evidence, people sometimes try to make personal attacks by saying, “Oh, so, you’re okay with patients dying. You don’t want to save lives.”

Absolutely we want to save lives. That’s why we’re in this field, and that’s why we’re asking for more evidence. You should not consider someone who is asking for evidence as evil or that this person does not want this new drug, or this person does not want this innovation. No, that person actually wants to make sure that that innovation actually helps people. That’s why that person is asking for more evidence.

If we stop asking for evidence, then our whole practice becomes based on emotions, faith, and trust rather than science. You could extrapolate it to the other extreme, like if you are not asking for evidence. If it is interpreted as someone who is asking for evidence is evil, or someone who does not want patients to get new drugs, then you could extrapolate these to people also making claims about alternative medicines or ivermectin nowadays, and claiming that this cures cancer.

Science is science. You need to be the same no matter the circumstances. If you are asking for data for ivermectin, you should also be asking data for your cancer drug that you think is going to work. We should always ask for evidence.

Asking for evidence is not a sign that whoever is asking for evidence does not want the patient to have access to the drug. It is showing that the person who is asking for evidence actually wants to make sure that the patients who get this drug are actually being helped by the drug rather than being harmed.

I’m talking about 5 fallacies today. The final, fifth fallacy is that clinical expertise does not equal expertise in making public health decisions or even expertise in critical appraisal. Someone can be a fantastic breast cancer doctor, the best oncologist for breast cancer. That does not automatically make that person the best person to evaluate clinical trials of breast cancer drugs.

Someone can be a fantastic colon cancer doctor. That does not make that person automatically the best person to evaluate whether or not colonoscopy or colon cancer screening is indicated in a certain patient population.

These population-level decisions — including should this drug be approved, should this drug be funded, and should this screening test be made a public health measure, all of these public health decisions that are done at a population level — require different expertise in critical appraisal, clinical epidemiology, and public health.

Just because someone is a fantastic clinician does not make that person a fantastic public health expert. I see on social media often that a famous doctor with expertise in their domain, let’s say a famous neurosurgeon, might say, “I think brain tumors are increasing in incidence in young persons, so we should be targeting an MRI screening for everyone over the age of 30.”

I’m just making this up, but we see examples of things not dissimilar to this. Just because someone is a neurosurgeon does not make them an expert on brain tumor epidemiology, surveillance, or screening. We should separate clinical expertise from public health expertise.

Thank you.

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

This transcript has been edited for clarity.

Hello, everyone. This is Dr Bishal Gyawali, from Queens University, Kingston, Canada. Today, I’m back with you to talk about some of the fallacies that I have seen in medicine, oncology, and the drug regulatory space. I wanted to clarify some of these fallacies.

In my last video, I talked about the FDA denying the approval of a new cancer drug. Let me start with one of the fallacies that is pertinent to that, which is that some people make an argument that patients are dying from a certain condition, such as cancer, or even any other disease besides cancer. That is an absolutely true statement, but that does not necessarily mean there should be a lower bar for drug approvals or we should be approving any drug that has a hint of benefit.

In fact, if we have increased mortality rates and our patients are dying from a certain condition, that means we actually need to have good drugs. We need to have drugs that prevent mortality. We need to have drugs that improve outcomes. Just having any drug out there, if we lower our threshold and are letting any drug be used in these patients because the argument is that people are dying, then in fact, it can have negative consequences.

First, there will be opportunity costs. If you can get any lousy drug into the market and make billions of dollars out of it, then there is no strong motivation to produce drugs that actually remarkably improve outcomes.

Second, patients will also be misled. It’s the patient’s opportunity cost in that they will use whatever time they have remaining to pursue these treatments that were not going to improve their outcomes anyway. This is time they could have better spent either in pursuing better treatments, if those treatments are out there, or to prioritize their time accordingly. This rather gives them a false hope, which can be harmful in the long term.

The first fallacy is that just because people are dying does not necessarily mean we should have more new drugs with a lower bar for approval.

The second fallacy I want to talk about, which is also related to this, is that if a certain cancer is rare, the bar for new drug approval should be quite low.

Of course, rare cancers are a special category, and rare cancers should be treated differently from a regulatory perspective. Absolutely. If the cancer is rare, we cannot have trials with large sample sizes to generate evidence. That problem is there, but that does not necessarily translate to the decision that we should approve anything, even something with a small hint of benefit.

There are other methods to make sure that, even in rare cancers, we can generate good-quality evidence. In fact, from an equity perspective, why should patients with rare cancer not deserve drugs that have good-quality evidence?

We can’t tell someone that, “Your cancer is rare, so you should get drugs that only have a benefit in terms of response rate whereas other cancers that are not rare will have drugs based on survival.”

Going back to the point about the difficulty in doing big trials in patients with rare cancers, that is absolutely true and there should be regulatory flexibility in this. I think accelerated approval is a pathway that allows for this regulatory flexibility, which allows access to these drugs early on based on earlier signals of benefit. You can continue to generate evidence in the future and confirm the clinical benefit.

There are also other nuances to this. One is that we should also make sure that this regulatory flexibility with rare cancers should not be misused. What do I mean by that? First, all rare cancers are not the same. There are some cancers that are ultra rare, and then there are some cancers that technically might fit the definition of rare, but trials are possible. Case in point: adrenocortical cancer. It is considered to be a very rare cancer, but there have been randomized trials in adrenocortical cancer.

Our efforts should be to maximize our collaboration globally so that a cancer that is rare locally will still not be so rare globally when we collect all these patients.

In certain situations, like let’s say, based on the molecular subtypes, any common cancer can be sliced and diced into a rare subtype: MSI-high, BRAF-negative, HER2-positive, right-sided colon cancer. If you start to slice cancers into these smaller and smaller molecular subtypes, you can consider anything as a rare cancer. That should not be misused as an excuse to get away from doing proper trials and generating adequate evidence for our patients.

The third fallacy I want to talk about is that increasing cancer incidence in a certain subgroup of population does not automatically translate into, “We should start screening this subgroup of population.”

A certain cancer — let’s say cancer X or cancer Y — is increasing in a young population, so therefore, we should lower the age of the screening of young populations. This cancer is increasing in this ethnic population, so therefore we should start screening this ethnic population more frequently. This cancer is increasing in this type of minority, so therefore, we should start screening this minority more.

No, it does not work like that. Increasing incidence will make us concerned, of course, but that does not necessarily translate into, “We should start screening them.” In order for a screening test to be useful, it has to fulfill a number of criteria.

The goal is not to detect cancers. The goal is to detect cancers that are not indolent enough that they would have never caused problems, nor speed up the diagnosis of aggressive cancers that are going to be lethal pretty soon anyway. The goal is to detect those cancers in the middle, so that by detecting early, we can intervene and improve the outcomes and improve the mortality from that cancer.

This type of intervention requires a thoughtful consideration of the increasing incidence of the cancer, of course, but also the utility of the screening test in that subgroup of population; the life expectancy of this subgroup of patients with and without cancer; the interventions available to address that increasing burden of cancer; and whether by intervening we are going to reduce the mortality rates.

Just because we can detect cancers does not mean we should detect cancers. That’s the third fallacy I wanted to talk about.

The fourth fallacy is related to when someone is asking for more evidence for anything. There is a new drug for this cancer,so what is the evidence? Or there is this new intervention that will detect ctDNA or whatever before the cancer relapses, or before the cancer even shows up as a screening test.

Whenever there is any treatment that is being promoted and someone asks for evidence, people sometimes try to make personal attacks by saying, “Oh, so, you’re okay with patients dying. You don’t want to save lives.”

Absolutely we want to save lives. That’s why we’re in this field, and that’s why we’re asking for more evidence. You should not consider someone who is asking for evidence as evil or that this person does not want this new drug, or this person does not want this innovation. No, that person actually wants to make sure that that innovation actually helps people. That’s why that person is asking for more evidence.

If we stop asking for evidence, then our whole practice becomes based on emotions, faith, and trust rather than science. You could extrapolate it to the other extreme, like if you are not asking for evidence. If it is interpreted as someone who is asking for evidence is evil, or someone who does not want patients to get new drugs, then you could extrapolate these to people also making claims about alternative medicines or ivermectin nowadays, and claiming that this cures cancer.

Science is science. You need to be the same no matter the circumstances. If you are asking for data for ivermectin, you should also be asking data for your cancer drug that you think is going to work. We should always ask for evidence.

Asking for evidence is not a sign that whoever is asking for evidence does not want the patient to have access to the drug. It is showing that the person who is asking for evidence actually wants to make sure that the patients who get this drug are actually being helped by the drug rather than being harmed.

I’m talking about 5 fallacies today. The final, fifth fallacy is that clinical expertise does not equal expertise in making public health decisions or even expertise in critical appraisal. Someone can be a fantastic breast cancer doctor, the best oncologist for breast cancer. That does not automatically make that person the best person to evaluate clinical trials of breast cancer drugs.

Someone can be a fantastic colon cancer doctor. That does not make that person automatically the best person to evaluate whether or not colonoscopy or colon cancer screening is indicated in a certain patient population.

These population-level decisions — including should this drug be approved, should this drug be funded, and should this screening test be made a public health measure, all of these public health decisions that are done at a population level — require different expertise in critical appraisal, clinical epidemiology, and public health.

Just because someone is a fantastic clinician does not make that person a fantastic public health expert. I see on social media often that a famous doctor with expertise in their domain, let’s say a famous neurosurgeon, might say, “I think brain tumors are increasing in incidence in young persons, so we should be targeting an MRI screening for everyone over the age of 30.”

I’m just making this up, but we see examples of things not dissimilar to this. Just because someone is a neurosurgeon does not make them an expert on brain tumor epidemiology, surveillance, or screening. We should separate clinical expertise from public health expertise.

Thank you.

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

This transcript has been edited for clarity.

Hello, everyone. This is Dr Bishal Gyawali, from Queens University, Kingston, Canada. Today, I’m back with you to talk about some of the fallacies that I have seen in medicine, oncology, and the drug regulatory space. I wanted to clarify some of these fallacies.

In my last video, I talked about the FDA denying the approval of a new cancer drug. Let me start with one of the fallacies that is pertinent to that, which is that some people make an argument that patients are dying from a certain condition, such as cancer, or even any other disease besides cancer. That is an absolutely true statement, but that does not necessarily mean there should be a lower bar for drug approvals or we should be approving any drug that has a hint of benefit.

In fact, if we have increased mortality rates and our patients are dying from a certain condition, that means we actually need to have good drugs. We need to have drugs that prevent mortality. We need to have drugs that improve outcomes. Just having any drug out there, if we lower our threshold and are letting any drug be used in these patients because the argument is that people are dying, then in fact, it can have negative consequences.

First, there will be opportunity costs. If you can get any lousy drug into the market and make billions of dollars out of it, then there is no strong motivation to produce drugs that actually remarkably improve outcomes.

Second, patients will also be misled. It’s the patient’s opportunity cost in that they will use whatever time they have remaining to pursue these treatments that were not going to improve their outcomes anyway. This is time they could have better spent either in pursuing better treatments, if those treatments are out there, or to prioritize their time accordingly. This rather gives them a false hope, which can be harmful in the long term.

The first fallacy is that just because people are dying does not necessarily mean we should have more new drugs with a lower bar for approval.

The second fallacy I want to talk about, which is also related to this, is that if a certain cancer is rare, the bar for new drug approval should be quite low.

Of course, rare cancers are a special category, and rare cancers should be treated differently from a regulatory perspective. Absolutely. If the cancer is rare, we cannot have trials with large sample sizes to generate evidence. That problem is there, but that does not necessarily translate to the decision that we should approve anything, even something with a small hint of benefit.

There are other methods to make sure that, even in rare cancers, we can generate good-quality evidence. In fact, from an equity perspective, why should patients with rare cancer not deserve drugs that have good-quality evidence?

We can’t tell someone that, “Your cancer is rare, so you should get drugs that only have a benefit in terms of response rate whereas other cancers that are not rare will have drugs based on survival.”

Going back to the point about the difficulty in doing big trials in patients with rare cancers, that is absolutely true and there should be regulatory flexibility in this. I think accelerated approval is a pathway that allows for this regulatory flexibility, which allows access to these drugs early on based on earlier signals of benefit. You can continue to generate evidence in the future and confirm the clinical benefit.

There are also other nuances to this. One is that we should also make sure that this regulatory flexibility with rare cancers should not be misused. What do I mean by that? First, all rare cancers are not the same. There are some cancers that are ultra rare, and then there are some cancers that technically might fit the definition of rare, but trials are possible. Case in point: adrenocortical cancer. It is considered to be a very rare cancer, but there have been randomized trials in adrenocortical cancer.

Our efforts should be to maximize our collaboration globally so that a cancer that is rare locally will still not be so rare globally when we collect all these patients.

In certain situations, like let’s say, based on the molecular subtypes, any common cancer can be sliced and diced into a rare subtype: MSI-high, BRAF-negative, HER2-positive, right-sided colon cancer. If you start to slice cancers into these smaller and smaller molecular subtypes, you can consider anything as a rare cancer. That should not be misused as an excuse to get away from doing proper trials and generating adequate evidence for our patients.

The third fallacy I want to talk about is that increasing cancer incidence in a certain subgroup of population does not automatically translate into, “We should start screening this subgroup of population.”

A certain cancer — let’s say cancer X or cancer Y — is increasing in a young population, so therefore, we should lower the age of the screening of young populations. This cancer is increasing in this ethnic population, so therefore we should start screening this ethnic population more frequently. This cancer is increasing in this type of minority, so therefore, we should start screening this minority more.

No, it does not work like that. Increasing incidence will make us concerned, of course, but that does not necessarily translate into, “We should start screening them.” In order for a screening test to be useful, it has to fulfill a number of criteria.

The goal is not to detect cancers. The goal is to detect cancers that are not indolent enough that they would have never caused problems, nor speed up the diagnosis of aggressive cancers that are going to be lethal pretty soon anyway. The goal is to detect those cancers in the middle, so that by detecting early, we can intervene and improve the outcomes and improve the mortality from that cancer.

This type of intervention requires a thoughtful consideration of the increasing incidence of the cancer, of course, but also the utility of the screening test in that subgroup of population; the life expectancy of this subgroup of patients with and without cancer; the interventions available to address that increasing burden of cancer; and whether by intervening we are going to reduce the mortality rates.

Just because we can detect cancers does not mean we should detect cancers. That’s the third fallacy I wanted to talk about.

The fourth fallacy is related to when someone is asking for more evidence for anything. There is a new drug for this cancer,so what is the evidence? Or there is this new intervention that will detect ctDNA or whatever before the cancer relapses, or before the cancer even shows up as a screening test.

Whenever there is any treatment that is being promoted and someone asks for evidence, people sometimes try to make personal attacks by saying, “Oh, so, you’re okay with patients dying. You don’t want to save lives.”

Absolutely we want to save lives. That’s why we’re in this field, and that’s why we’re asking for more evidence. You should not consider someone who is asking for evidence as evil or that this person does not want this new drug, or this person does not want this innovation. No, that person actually wants to make sure that that innovation actually helps people. That’s why that person is asking for more evidence.

If we stop asking for evidence, then our whole practice becomes based on emotions, faith, and trust rather than science. You could extrapolate it to the other extreme, like if you are not asking for evidence. If it is interpreted as someone who is asking for evidence is evil, or someone who does not want patients to get new drugs, then you could extrapolate these to people also making claims about alternative medicines or ivermectin nowadays, and claiming that this cures cancer.

Science is science. You need to be the same no matter the circumstances. If you are asking for data for ivermectin, you should also be asking data for your cancer drug that you think is going to work. We should always ask for evidence.

Asking for evidence is not a sign that whoever is asking for evidence does not want the patient to have access to the drug. It is showing that the person who is asking for evidence actually wants to make sure that the patients who get this drug are actually being helped by the drug rather than being harmed.

I’m talking about 5 fallacies today. The final, fifth fallacy is that clinical expertise does not equal expertise in making public health decisions or even expertise in critical appraisal. Someone can be a fantastic breast cancer doctor, the best oncologist for breast cancer. That does not automatically make that person the best person to evaluate clinical trials of breast cancer drugs.

Someone can be a fantastic colon cancer doctor. That does not make that person automatically the best person to evaluate whether or not colonoscopy or colon cancer screening is indicated in a certain patient population.

These population-level decisions — including should this drug be approved, should this drug be funded, and should this screening test be made a public health measure, all of these public health decisions that are done at a population level — require different expertise in critical appraisal, clinical epidemiology, and public health.

Just because someone is a fantastic clinician does not make that person a fantastic public health expert. I see on social media often that a famous doctor with expertise in their domain, let’s say a famous neurosurgeon, might say, “I think brain tumors are increasing in incidence in young persons, so we should be targeting an MRI screening for everyone over the age of 30.”

I’m just making this up, but we see examples of things not dissimilar to this. Just because someone is a neurosurgeon does not make them an expert on brain tumor epidemiology, surveillance, or screening. We should separate clinical expertise from public health expertise.

Thank you.

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

The fastest way to a new anticoagulation therapy that prevents blood clots without prolonging bleeding or healing time may be a land snail.

A recent preclinical study in ACS Central Science investigating bioactive molecules derived from the land snail Camaena cicatricosa identified a compound that significantly reduced clot formation without prolonging bleeding time and wound healing in rodent models, directly challenging the assumption that effective anticoagulant therapy must inherently disrupt physiologic repair processes.

“I was quite excited,” said Lisha Lin, PhD, lead author on the study and research assistant at the State Key Laboratory of Phytochemistry and Natural Medicines at the Kunming Institute of Botany, Chinese Academy of Sciences, in Kunming, China. “A novel polysaccharide was identified, and more importantly, it showed anticoagulant activity by inhibiting a novel target, with different action mechanism from heparins.”

What Led to the Land Snail?

The choice of C cicatricosa reflects a shift in thinking. The team screened a range of mollusk-derived biomolecules in search of safer anticoagulation strategies, ultimately isolating a novel galactosylated glycosaminoglycan (CCG) from this terrestrial species.

“We compared the anticoagulant activity of glycosaminoglycans from three snail species,” said Lin. They initially studied polysaccharides from C cicatricosa, Achatina fulica, and Helix lucorum — all sulfated glycosaminoglycans with similar structures. “However, we only found CCG from [C cicatricosa] showed anticoagulant activity but not other snail polysaccharides.”

This unexpected selectivity proved crucial. “The result indicated that the galactose branches and special sulfate substitution were important,” she explained, helping to explain why this particular species stood out among structurally similar compounds.

While CCG shares some similarities with heparin-like molecules, it notably lacks the specific pentasaccharide sequence required for antithrombin binding. Researchers hypothesized that this absence could reduce bleeding risk while maintaining antithrombotic activity.

Rather than broadly inhibiting coagulation, the compound selectively disrupts the intrinsic tenase complex, a pathway more closely associated with pathologic thrombosis than with physiologic hemostasis. This mechanism’s selectivity is central to the study’s findings and helps explain why normal wound healing remained intact in preclinical models.

The isolated compound demonstrated a rare combination in anticoagulant research: potent inhibition of pathologic thrombosis with no significant increase in bleeding time and intact wound healing across multiple experimental models. The compound did not act as a broad-spectrum anticoagulant, instead selectively targeting pathways more relevant to disease-associated clot formation.

The Hope of Lowering Bleeding Risk

For decades, anticoagulation therapy has been built on the assumption that inhibiting clot formation inevitably increases bleeding risk. For physicians treating patients with deep vein thrombosis or atrial fibrillation or those requiring postsurgical attention, the balancing act is constant. Prevent clot formation aggressively enough and the bleeding risk rises. Reduce intensity and thrombosis risk returns.

Current therapies, including heparin and direct oral anticoagulants (DOACs), function by broadly targeting the coagulation cascade. This lack of specialty is precisely what limits them. Even when carefully dosed, the treatments interfere with both pathologic clot formation and physiologic hemostasis.

Physicians managing patients on heparin and DOACs frequently encounter recurrent epistaxis, gastrointestinal bleeding ranging from occult to clinically significant, and urogenital bleeding. A degree of mild bleeding after surgery is often expected and usually resolves on its own. However, it’s crucial to evaluate in the context of ongoing anticoagulation to rule out early signs of clinically significant complications.

“There is definitely a lot of interest in the concept of ‘uncoupling’ thrombosis from hemostasis,” said Yazan Abou-Ismail, MD, hematologist and associate professor of medicine at the University of Utah Health in Salt Lake City, who was not involved in the research. “This concept highlights the differences in pathways essential for normal hemostasis at sites of vessel injury, in contrast with those needed for clot propagation and blood vessel lumen occlusion.”

Abou-Ismail noted that this approach has been explored with Factor XI (FXI) inhibitors currently in clinical trials. However, he raised an important mechanistic concern.

“This mechanism may not necessarily accomplish that goal of uncoupling thrombosis from hemostasis, although it might at narrow therapeutic windows,” Abou-Ismail said. “The tenase complex is a central component of coagulation whose deficiency underlies hemophilia A and B, diseases that cause significant bleeding in humans, and it is more essential to hemostasis than [FXI inhibitors]. Tenase inhibition seems like it may pose a higher bleeding risk in humans.”

He explained that FXI inhibitors have a strong mechanistic rationale because they target the feedback loop that amplifies clot propagation, which is less essential for hemostasis. “FXI inhibitors have clinical trial data demonstrating that FXI inhibition is in fact associated with less bleeding compared to current established anticoagulants,” he said. “However, CCG disrupts the FIXa/FVIIIa intrinsic tenase complex itself, which is considered essential for hemostasis.”

Surprises and Confirmations

The researchers were not anticipating such a clear separation between antithrombotic activity and bleeding risk. The preservation of normal wound healing was equally surprising, directly challenging the belief that interfering with clot formation inevitably disrupts tissue repair.

However, the path to these conclusions was not straightforward. “The structural definition of complex macromolecules like sulfated polysaccharides is a common challenge in the research field,” Lin said. “We spent a lot of time to analyze the structure of CCG.”

Even after identifying the candidate compound, the team had to rigorously confirm that its effects were truly anticoagulant in nature, rather than secondary to anti-inflammatory or vascular remodeling properties. Mechanistic studies were essential in demonstrating its targeted disruption of the intrinsic tenase complex, helping to explain how thrombosis could be reduced without broadly impairing coagulation.

Lin is excited but knows patience and skepticism are needed. “Our research is still at the basic stage, but based on the available data, we may provide a potential anticoagulant option with low bleeding risk,” she said. “In the discussion section of our paper, we also stated that ‘the data suggest a wide therapeutic window of CCG, which may offer therapeutic advantages for patients with bleeding contraindication, such as elderly patients and those with renal failure, as well as for safer long-term anticoagulation.’”

A New Direction for Heparin Alternatives?

Despite these concerns, Abou-Ismail acknowledged that the research has genuinely noteworthy aspects. “A future anticoagulant with a novel mechanism of action may be useful in patients who have experienced anticoagulant failure or breakthrough thrombosis from currently established anticoagulants,” he said. “Having another option might be useful when all other options have failed or are not feasible.”

However, he added a note of caution: “If a therapeutic window exists where partial tenase disruption has antithrombotic effect that does not impair hemostasis, then that would definitely be a promising future finding, but it is too early to arrive at that conclusion with this study.”

The search for safer heparin alternatives has been ongoing for decades, but most candidates still operate within the same fundamental paradigm of broad coagulation inhibition. This snail can’t move fast enough.

Abou-Ismail reported having no relevant conflicts. Disclosure information for study authors is available in the original study publication.

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

The fastest way to a new anticoagulation therapy that prevents blood clots without prolonging bleeding or healing time may be a land snail.

A recent preclinical study in ACS Central Science investigating bioactive molecules derived from the land snail Camaena cicatricosa identified a compound that significantly reduced clot formation without prolonging bleeding time and wound healing in rodent models, directly challenging the assumption that effective anticoagulant therapy must inherently disrupt physiologic repair processes.

“I was quite excited,” said Lisha Lin, PhD, lead author on the study and research assistant at the State Key Laboratory of Phytochemistry and Natural Medicines at the Kunming Institute of Botany, Chinese Academy of Sciences, in Kunming, China. “A novel polysaccharide was identified, and more importantly, it showed anticoagulant activity by inhibiting a novel target, with different action mechanism from heparins.”

What Led to the Land Snail?

The choice of C cicatricosa reflects a shift in thinking. The team screened a range of mollusk-derived biomolecules in search of safer anticoagulation strategies, ultimately isolating a novel galactosylated glycosaminoglycan (CCG) from this terrestrial species.

“We compared the anticoagulant activity of glycosaminoglycans from three snail species,” said Lin. They initially studied polysaccharides from C cicatricosa, Achatina fulica, and Helix lucorum — all sulfated glycosaminoglycans with similar structures. “However, we only found CCG from [C cicatricosa] showed anticoagulant activity but not other snail polysaccharides.”

This unexpected selectivity proved crucial. “The result indicated that the galactose branches and special sulfate substitution were important,” she explained, helping to explain why this particular species stood out among structurally similar compounds.

While CCG shares some similarities with heparin-like molecules, it notably lacks the specific pentasaccharide sequence required for antithrombin binding. Researchers hypothesized that this absence could reduce bleeding risk while maintaining antithrombotic activity.

Rather than broadly inhibiting coagulation, the compound selectively disrupts the intrinsic tenase complex, a pathway more closely associated with pathologic thrombosis than with physiologic hemostasis. This mechanism’s selectivity is central to the study’s findings and helps explain why normal wound healing remained intact in preclinical models.

The isolated compound demonstrated a rare combination in anticoagulant research: potent inhibition of pathologic thrombosis with no significant increase in bleeding time and intact wound healing across multiple experimental models. The compound did not act as a broad-spectrum anticoagulant, instead selectively targeting pathways more relevant to disease-associated clot formation.

The Hope of Lowering Bleeding Risk

For decades, anticoagulation therapy has been built on the assumption that inhibiting clot formation inevitably increases bleeding risk. For physicians treating patients with deep vein thrombosis or atrial fibrillation or those requiring postsurgical attention, the balancing act is constant. Prevent clot formation aggressively enough and the bleeding risk rises. Reduce intensity and thrombosis risk returns.

Current therapies, including heparin and direct oral anticoagulants (DOACs), function by broadly targeting the coagulation cascade. This lack of specialty is precisely what limits them. Even when carefully dosed, the treatments interfere with both pathologic clot formation and physiologic hemostasis.

Physicians managing patients on heparin and DOACs frequently encounter recurrent epistaxis, gastrointestinal bleeding ranging from occult to clinically significant, and urogenital bleeding. A degree of mild bleeding after surgery is often expected and usually resolves on its own. However, it’s crucial to evaluate in the context of ongoing anticoagulation to rule out early signs of clinically significant complications.

“There is definitely a lot of interest in the concept of ‘uncoupling’ thrombosis from hemostasis,” said Yazan Abou-Ismail, MD, hematologist and associate professor of medicine at the University of Utah Health in Salt Lake City, who was not involved in the research. “This concept highlights the differences in pathways essential for normal hemostasis at sites of vessel injury, in contrast with those needed for clot propagation and blood vessel lumen occlusion.”

Abou-Ismail noted that this approach has been explored with Factor XI (FXI) inhibitors currently in clinical trials. However, he raised an important mechanistic concern.

“This mechanism may not necessarily accomplish that goal of uncoupling thrombosis from hemostasis, although it might at narrow therapeutic windows,” Abou-Ismail said. “The tenase complex is a central component of coagulation whose deficiency underlies hemophilia A and B, diseases that cause significant bleeding in humans, and it is more essential to hemostasis than [FXI inhibitors]. Tenase inhibition seems like it may pose a higher bleeding risk in humans.”

He explained that FXI inhibitors have a strong mechanistic rationale because they target the feedback loop that amplifies clot propagation, which is less essential for hemostasis. “FXI inhibitors have clinical trial data demonstrating that FXI inhibition is in fact associated with less bleeding compared to current established anticoagulants,” he said. “However, CCG disrupts the FIXa/FVIIIa intrinsic tenase complex itself, which is considered essential for hemostasis.”

Surprises and Confirmations

The researchers were not anticipating such a clear separation between antithrombotic activity and bleeding risk. The preservation of normal wound healing was equally surprising, directly challenging the belief that interfering with clot formation inevitably disrupts tissue repair.

However, the path to these conclusions was not straightforward. “The structural definition of complex macromolecules like sulfated polysaccharides is a common challenge in the research field,” Lin said. “We spent a lot of time to analyze the structure of CCG.”

Even after identifying the candidate compound, the team had to rigorously confirm that its effects were truly anticoagulant in nature, rather than secondary to anti-inflammatory or vascular remodeling properties. Mechanistic studies were essential in demonstrating its targeted disruption of the intrinsic tenase complex, helping to explain how thrombosis could be reduced without broadly impairing coagulation.

Lin is excited but knows patience and skepticism are needed. “Our research is still at the basic stage, but based on the available data, we may provide a potential anticoagulant option with low bleeding risk,” she said. “In the discussion section of our paper, we also stated that ‘the data suggest a wide therapeutic window of CCG, which may offer therapeutic advantages for patients with bleeding contraindication, such as elderly patients and those with renal failure, as well as for safer long-term anticoagulation.’”

A New Direction for Heparin Alternatives?

Despite these concerns, Abou-Ismail acknowledged that the research has genuinely noteworthy aspects. “A future anticoagulant with a novel mechanism of action may be useful in patients who have experienced anticoagulant failure or breakthrough thrombosis from currently established anticoagulants,” he said. “Having another option might be useful when all other options have failed or are not feasible.”

However, he added a note of caution: “If a therapeutic window exists where partial tenase disruption has antithrombotic effect that does not impair hemostasis, then that would definitely be a promising future finding, but it is too early to arrive at that conclusion with this study.”

The search for safer heparin alternatives has been ongoing for decades, but most candidates still operate within the same fundamental paradigm of broad coagulation inhibition. This snail can’t move fast enough.

Abou-Ismail reported having no relevant conflicts. Disclosure information for study authors is available in the original study publication.

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

The fastest way to a new anticoagulation therapy that prevents blood clots without prolonging bleeding or healing time may be a land snail.

A recent preclinical study in ACS Central Science investigating bioactive molecules derived from the land snail Camaena cicatricosa identified a compound that significantly reduced clot formation without prolonging bleeding time and wound healing in rodent models, directly challenging the assumption that effective anticoagulant therapy must inherently disrupt physiologic repair processes.

“I was quite excited,” said Lisha Lin, PhD, lead author on the study and research assistant at the State Key Laboratory of Phytochemistry and Natural Medicines at the Kunming Institute of Botany, Chinese Academy of Sciences, in Kunming, China. “A novel polysaccharide was identified, and more importantly, it showed anticoagulant activity by inhibiting a novel target, with different action mechanism from heparins.”

What Led to the Land Snail?

The choice of C cicatricosa reflects a shift in thinking. The team screened a range of mollusk-derived biomolecules in search of safer anticoagulation strategies, ultimately isolating a novel galactosylated glycosaminoglycan (CCG) from this terrestrial species.

“We compared the anticoagulant activity of glycosaminoglycans from three snail species,” said Lin. They initially studied polysaccharides from C cicatricosa, Achatina fulica, and Helix lucorum — all sulfated glycosaminoglycans with similar structures. “However, we only found CCG from [C cicatricosa] showed anticoagulant activity but not other snail polysaccharides.”

This unexpected selectivity proved crucial. “The result indicated that the galactose branches and special sulfate substitution were important,” she explained, helping to explain why this particular species stood out among structurally similar compounds.

While CCG shares some similarities with heparin-like molecules, it notably lacks the specific pentasaccharide sequence required for antithrombin binding. Researchers hypothesized that this absence could reduce bleeding risk while maintaining antithrombotic activity.

Rather than broadly inhibiting coagulation, the compound selectively disrupts the intrinsic tenase complex, a pathway more closely associated with pathologic thrombosis than with physiologic hemostasis. This mechanism’s selectivity is central to the study’s findings and helps explain why normal wound healing remained intact in preclinical models.

The isolated compound demonstrated a rare combination in anticoagulant research: potent inhibition of pathologic thrombosis with no significant increase in bleeding time and intact wound healing across multiple experimental models. The compound did not act as a broad-spectrum anticoagulant, instead selectively targeting pathways more relevant to disease-associated clot formation.

The Hope of Lowering Bleeding Risk

For decades, anticoagulation therapy has been built on the assumption that inhibiting clot formation inevitably increases bleeding risk. For physicians treating patients with deep vein thrombosis or atrial fibrillation or those requiring postsurgical attention, the balancing act is constant. Prevent clot formation aggressively enough and the bleeding risk rises. Reduce intensity and thrombosis risk returns.

Current therapies, including heparin and direct oral anticoagulants (DOACs), function by broadly targeting the coagulation cascade. This lack of specialty is precisely what limits them. Even when carefully dosed, the treatments interfere with both pathologic clot formation and physiologic hemostasis.

Physicians managing patients on heparin and DOACs frequently encounter recurrent epistaxis, gastrointestinal bleeding ranging from occult to clinically significant, and urogenital bleeding. A degree of mild bleeding after surgery is often expected and usually resolves on its own. However, it’s crucial to evaluate in the context of ongoing anticoagulation to rule out early signs of clinically significant complications.

“There is definitely a lot of interest in the concept of ‘uncoupling’ thrombosis from hemostasis,” said Yazan Abou-Ismail, MD, hematologist and associate professor of medicine at the University of Utah Health in Salt Lake City, who was not involved in the research. “This concept highlights the differences in pathways essential for normal hemostasis at sites of vessel injury, in contrast with those needed for clot propagation and blood vessel lumen occlusion.”

Abou-Ismail noted that this approach has been explored with Factor XI (FXI) inhibitors currently in clinical trials. However, he raised an important mechanistic concern.

“This mechanism may not necessarily accomplish that goal of uncoupling thrombosis from hemostasis, although it might at narrow therapeutic windows,” Abou-Ismail said. “The tenase complex is a central component of coagulation whose deficiency underlies hemophilia A and B, diseases that cause significant bleeding in humans, and it is more essential to hemostasis than [FXI inhibitors]. Tenase inhibition seems like it may pose a higher bleeding risk in humans.”

He explained that FXI inhibitors have a strong mechanistic rationale because they target the feedback loop that amplifies clot propagation, which is less essential for hemostasis. “FXI inhibitors have clinical trial data demonstrating that FXI inhibition is in fact associated with less bleeding compared to current established anticoagulants,” he said. “However, CCG disrupts the FIXa/FVIIIa intrinsic tenase complex itself, which is considered essential for hemostasis.”

Surprises and Confirmations

The researchers were not anticipating such a clear separation between antithrombotic activity and bleeding risk. The preservation of normal wound healing was equally surprising, directly challenging the belief that interfering with clot formation inevitably disrupts tissue repair.

However, the path to these conclusions was not straightforward. “The structural definition of complex macromolecules like sulfated polysaccharides is a common challenge in the research field,” Lin said. “We spent a lot of time to analyze the structure of CCG.”

Even after identifying the candidate compound, the team had to rigorously confirm that its effects were truly anticoagulant in nature, rather than secondary to anti-inflammatory or vascular remodeling properties. Mechanistic studies were essential in demonstrating its targeted disruption of the intrinsic tenase complex, helping to explain how thrombosis could be reduced without broadly impairing coagulation.

Lin is excited but knows patience and skepticism are needed. “Our research is still at the basic stage, but based on the available data, we may provide a potential anticoagulant option with low bleeding risk,” she said. “In the discussion section of our paper, we also stated that ‘the data suggest a wide therapeutic window of CCG, which may offer therapeutic advantages for patients with bleeding contraindication, such as elderly patients and those with renal failure, as well as for safer long-term anticoagulation.’”

A New Direction for Heparin Alternatives?

Despite these concerns, Abou-Ismail acknowledged that the research has genuinely noteworthy aspects. “A future anticoagulant with a novel mechanism of action may be useful in patients who have experienced anticoagulant failure or breakthrough thrombosis from currently established anticoagulants,” he said. “Having another option might be useful when all other options have failed or are not feasible.”

However, he added a note of caution: “If a therapeutic window exists where partial tenase disruption has antithrombotic effect that does not impair hemostasis, then that would definitely be a promising future finding, but it is too early to arrive at that conclusion with this study.”

The search for safer heparin alternatives has been ongoing for decades, but most candidates still operate within the same fundamental paradigm of broad coagulation inhibition. This snail can’t move fast enough.

Abou-Ismail reported having no relevant conflicts. Disclosure information for study authors is available in the original study publication.

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

Military sexual trauma (MST) remained “persistently prevalent” between 2013 and 2026, experiencing a slight overall increase from 7.6% to 8.2% in the time period, according to a research letter written by researchers from Yale University and the Veterans Affairs (VA) Connecticut Healthcare System and published in JAMA Psychiatry. Prevalence among female veterans jumped from 32.4% to 43.3%, with many citing MST as a factor in their decision to leave military service earlier than planned.

The researchers analyzed data from 3 independent nationally representative cohorts of veterans surveyed as part of the National Health and Resilience in Veterans Study. In 2025 and 2026, 189 veterans reported sexual harassment and 80 veterans reported sexual assault. Among female veterans, 128 (42.7%) reported harassment and 55 (21.2%) reported assault; 61 male veterans (3.6%) reported harassment and 25 (1.4%) reported assault. 

Many veterans experienced multiple MSTs. In 2025 and 2026, 61 women and 23 men reported 2 or 3 occurrences of MST, and 57 (42 women, 15 men) reported ≥ 4 occurrences. Most indicated ≥ 1 MST occurrence was perpetrated by a higher-ranking military member. Women were more likely to report ≥ 2 MST occurrences and MST perpetrated by a higher-ranking military member, according to the letter.

MST can have potentially disproportionate consequences for women in terms of military workforce composition, leadership representation, and long-term force readiness, the researchers say. Findings based on 2024 national veteran population data suggest that roughly 1 in 6 women and 1 in 100 men will leave military service after MST. 

History of MST has been independently associated with elevated risk for suicidal thoughts and behaviors, including future suicidal intent. In this study, compared with veterans without MST, those with MST had nearly triple the rates of past-year suicidal ideation and > 4 times the rates of lifetime suicide attempt. They were also significantly more likely to indicate future suicidal intent (6.9% vs 1.2%). Predicted probabilities of suicidal ideation (34.2% vs 28.3%) and suicide attempt (18.5% vs 13.4%) were significantly higher among females than males.

Female service members who experienced MST are also nearly 3 times more likely to have moderate to severe posttraumatic stress disorder (PTSD) symptoms, compared with female service members who did not experience MST. Women veterans who report MST and have PTSD are also more likely to have comorbid mental health diagnoses, including major depression, anxiety, eating disorders, and substance use disorders. 

The researchers claim the research is the first nationally representative characterization of MST contextual features and updated estimates of treatment utilization. They found that fewer than half of survivors received MST-related treatment.

In 2021, President Biden directed the US Department of Defense to establish the Independent Review Commission on Sexual Assault in the Military (IRC). An overview of the IRC commission findings underscored the need for screening. The increased risk of suicidal thoughts and behaviors, it says, makes “integration of crosscutting prevention initiatives within MST care and suicide prevention at VA” critical. 

The Veterans Health Administration universal MST screening program is part of a web of MST-related services. Analysis of medical record data demonstrates that the program yields clinically meaningful information, and increases the likelihood of mental health treatment. Despite the barriers to care for all MST survivors noted in qualitative studies, the commission report says, quantitative research agrees that veterans with a positive MST screen are more likely to engage in health care in VA.

Military sexual trauma (MST) remained “persistently prevalent” between 2013 and 2026, experiencing a slight overall increase from 7.6% to 8.2% in the time period, according to a research letter written by researchers from Yale University and the Veterans Affairs (VA) Connecticut Healthcare System and published in JAMA Psychiatry. Prevalence among female veterans jumped from 32.4% to 43.3%, with many citing MST as a factor in their decision to leave military service earlier than planned.

The researchers analyzed data from 3 independent nationally representative cohorts of veterans surveyed as part of the National Health and Resilience in Veterans Study. In 2025 and 2026, 189 veterans reported sexual harassment and 80 veterans reported sexual assault. Among female veterans, 128 (42.7%) reported harassment and 55 (21.2%) reported assault; 61 male veterans (3.6%) reported harassment and 25 (1.4%) reported assault. 

Many veterans experienced multiple MSTs. In 2025 and 2026, 61 women and 23 men reported 2 or 3 occurrences of MST, and 57 (42 women, 15 men) reported ≥ 4 occurrences. Most indicated ≥ 1 MST occurrence was perpetrated by a higher-ranking military member. Women were more likely to report ≥ 2 MST occurrences and MST perpetrated by a higher-ranking military member, according to the letter.

MST can have potentially disproportionate consequences for women in terms of military workforce composition, leadership representation, and long-term force readiness, the researchers say. Findings based on 2024 national veteran population data suggest that roughly 1 in 6 women and 1 in 100 men will leave military service after MST. 

History of MST has been independently associated with elevated risk for suicidal thoughts and behaviors, including future suicidal intent. In this study, compared with veterans without MST, those with MST had nearly triple the rates of past-year suicidal ideation and > 4 times the rates of lifetime suicide attempt. They were also significantly more likely to indicate future suicidal intent (6.9% vs 1.2%). Predicted probabilities of suicidal ideation (34.2% vs 28.3%) and suicide attempt (18.5% vs 13.4%) were significantly higher among females than males.

Female service members who experienced MST are also nearly 3 times more likely to have moderate to severe posttraumatic stress disorder (PTSD) symptoms, compared with female service members who did not experience MST. Women veterans who report MST and have PTSD are also more likely to have comorbid mental health diagnoses, including major depression, anxiety, eating disorders, and substance use disorders. 

The researchers claim the research is the first nationally representative characterization of MST contextual features and updated estimates of treatment utilization. They found that fewer than half of survivors received MST-related treatment.

In 2021, President Biden directed the US Department of Defense to establish the Independent Review Commission on Sexual Assault in the Military (IRC). An overview of the IRC commission findings underscored the need for screening. The increased risk of suicidal thoughts and behaviors, it says, makes “integration of crosscutting prevention initiatives within MST care and suicide prevention at VA” critical. 

The Veterans Health Administration universal MST screening program is part of a web of MST-related services. Analysis of medical record data demonstrates that the program yields clinically meaningful information, and increases the likelihood of mental health treatment. Despite the barriers to care for all MST survivors noted in qualitative studies, the commission report says, quantitative research agrees that veterans with a positive MST screen are more likely to engage in health care in VA.

Military sexual trauma (MST) remained “persistently prevalent” between 2013 and 2026, experiencing a slight overall increase from 7.6% to 8.2% in the time period, according to a research letter written by researchers from Yale University and the Veterans Affairs (VA) Connecticut Healthcare System and published in JAMA Psychiatry. Prevalence among female veterans jumped from 32.4% to 43.3%, with many citing MST as a factor in their decision to leave military service earlier than planned.

The researchers analyzed data from 3 independent nationally representative cohorts of veterans surveyed as part of the National Health and Resilience in Veterans Study. In 2025 and 2026, 189 veterans reported sexual harassment and 80 veterans reported sexual assault. Among female veterans, 128 (42.7%) reported harassment and 55 (21.2%) reported assault; 61 male veterans (3.6%) reported harassment and 25 (1.4%) reported assault. 

Many veterans experienced multiple MSTs. In 2025 and 2026, 61 women and 23 men reported 2 or 3 occurrences of MST, and 57 (42 women, 15 men) reported ≥ 4 occurrences. Most indicated ≥ 1 MST occurrence was perpetrated by a higher-ranking military member. Women were more likely to report ≥ 2 MST occurrences and MST perpetrated by a higher-ranking military member, according to the letter.

MST can have potentially disproportionate consequences for women in terms of military workforce composition, leadership representation, and long-term force readiness, the researchers say. Findings based on 2024 national veteran population data suggest that roughly 1 in 6 women and 1 in 100 men will leave military service after MST. 

History of MST has been independently associated with elevated risk for suicidal thoughts and behaviors, including future suicidal intent. In this study, compared with veterans without MST, those with MST had nearly triple the rates of past-year suicidal ideation and > 4 times the rates of lifetime suicide attempt. They were also significantly more likely to indicate future suicidal intent (6.9% vs 1.2%). Predicted probabilities of suicidal ideation (34.2% vs 28.3%) and suicide attempt (18.5% vs 13.4%) were significantly higher among females than males.

Female service members who experienced MST are also nearly 3 times more likely to have moderate to severe posttraumatic stress disorder (PTSD) symptoms, compared with female service members who did not experience MST. Women veterans who report MST and have PTSD are also more likely to have comorbid mental health diagnoses, including major depression, anxiety, eating disorders, and substance use disorders. 

The researchers claim the research is the first nationally representative characterization of MST contextual features and updated estimates of treatment utilization. They found that fewer than half of survivors received MST-related treatment.

In 2021, President Biden directed the US Department of Defense to establish the Independent Review Commission on Sexual Assault in the Military (IRC). An overview of the IRC commission findings underscored the need for screening. The increased risk of suicidal thoughts and behaviors, it says, makes “integration of crosscutting prevention initiatives within MST care and suicide prevention at VA” critical. 

The Veterans Health Administration universal MST screening program is part of a web of MST-related services. Analysis of medical record data demonstrates that the program yields clinically meaningful information, and increases the likelihood of mental health treatment. Despite the barriers to care for all MST survivors noted in qualitative studies, the commission report says, quantitative research agrees that veterans with a positive MST screen are more likely to engage in health care in VA.

Treatment with ralinepag, an investigational prostacyclin receptor agonist, reduced the risk for clinical disease worsening by 55% compared to placebo in patients with pulmonary arterial hypertension (PAH), based on new data from the ADVANCE Outcomes study presented at the American Thoracic Society (ATS) 2026 International Conference.

Ralinepag works by restoring prostacyclin signaling and activating prostacyclin receptors to affect pathways that play a role in the progression of PAH. The drug was originally formulated as an immediate-release capsule but modified to the extended-release tablet used in the current study as a way to optimize once daily dosing.

“The prostacyclin pathway is foundational in the management of PAH, and advancing prostacyclin science has benefited patients over the years,” said lead author Vallerie V. McLaughlin, MD, professor of cardiovascular medicine and director of the Pulmonary Hypertension Program at the University of Michigan, Ann Arbor, Michigan, who presented the findings at the meeting. Although other oral prostacyclin pathway agents available, ralinepag has the advantages of high potency and longer half-life that could be effective and well-tolerated in a more patient-friendly once daily formulation, McLaughlin said.

The international study population included 687 adults with PAH from 30 countries across five continents. Participants were randomized to ralinepag or placebo in addition to their standard PAH background therapies. Ralinepag was orally dosed once daily and titrated for tolerability and response. The mean age of the participants was 52 years, 80% were White, and the median time since PAH diagnosis was 2.3 years. A majority of 62% had idiopathic or heritable PAH, 28.2% had PAH as a result of connective tissue disease, 4.1% had a congenital heart defect, 3.1% had drug- or toxin-induced PAH, and 2.6% had PAH as a result of HIV infection. More than two thirds were considered low risk (characterized as Functional Class II).

The primary endpoint was the time to first indication of clinical worsening, which was defined as death, hospital admission for worsening PAH, initiation of a parenteral or inhaled prostacyclin pathway agent for worsening PAH, or unsatisfactory long-term clinical response.

Overall, patients treated with ralinepag were significantly less likely to experience a clinical worsening event than placebo patients (hazard ratio [HR], 0.45; 95% CI, 0.33-0.62; P < .0001), and 47% more likely to achieve the secondary endpoint of clinical improvement (P = .015).

Patients treated with ralinepag also showed significant improvements over placebo patients in the secondary endpoints of pro-B-type natriuretic peptide levels (24.3% reduction from baseline to week 28 over placebo; P = .0013), and in the 6-minute walk test (a placebo-corrected difference of 20.4 m from baseline to week 28; P = .0033).

Although more than 90% of participants treated with ralinepag reported an adverse event related to the drug, approximately 5% experienced drug-related serious adverse events, and the overall safety profile reflected previous ralinepag studies, with a positive risk-benefit ratio, the investigators noted.

Support for Early Introduction

The researchers expected the efficacy associated with prostacyclin therapy, said McLaughlin. “We were very pleased to see such a strong treatment effect in a relatively low-risk population, primarily Functional Class II with a mean 6-minute walk of nearly 440 meters, with the majority of patients on dual oral therapy,” she said.

If approved, ralinepag could help optimized risk status in PAH, said McLaughlin. “Many patients do not get to low risk with first-line therapy, and oral and inhaled prostacyclin pathway agents are often used in addition to dual therapy with phosphodiesterase type-5 inhibitors and endothelin receptor antagonists,” she said. “The impressive treatment effect of ralinepag in patients primarily treated with dual oral therapy reflects this real-world scenario,” she added. The significant event reduction makes a case for earlier introduction of ralinepag in relatively low-risk patients; a highly effective therapy that targets the prostacyclin pathway may reduce the need for more cumbersome and invasive prostacyclin therapies, McLaughlin added.

Ralinepag remains an investigational drug, but the company plans to seek a New Drug Application from the FDA for the treatment of PAH by the second half of 2026, according to a press release.

The research team would like to continue evaluating the ADVANCE Outcomes database to learn more about dose response, tolerability, and subgroup response, said McLaughlin. At that point, real-world data would be useful, and additional research areas in that setting would include combination therapy with other agents such as sotatercept, as well as the use of ralinepag to transition patients on more complicated and invasive therapy, she said.

Attention to Adverse Effects

Prostacyclin therapies are often offered in oral, inhaled, and the most invasive intravenous/subcutaneous routes, but a gap remains between the strong efficacy seen with parenteral therapy and what many patients are willing or able to use in real-world practice, said Parth M. Rali, MD, director of the Temple University Health System Pulmonary Embolism Response Team Program, Section Temple Lung Pulmonary Vascular Disease Program, Philadelphia, who was not involved in the study.

“Ralinepag provides sustained activation of IP receptors and has very long effective half-life, giving drug exposure comparable to parenteral therapy, and offers the first daily treatment option, which is important for the patients with PAH who are often on multiple drugs therapies,” Rali said.

Given the encouraging phase 2 findings demonstrating meaningful reductions in pulmonary vascular resistance and signals toward clinical benefit, we would like to see a favorable outcome in the phase 3 program. Primary outcome studied was time to clinical worsening in the large, randomized trial that involved global populations from the US, Europe, Latin-America, and Asia Pacific Region. Ralinepag arm had 55% reduction in risk for clinical worsening (HR, ~ 0.45) compared to placebo arm. “The positive results of the trial were primarily driven by disease progression, initiation of prostacyclin therapy, and unsatisfactory long-term clinical response at 28 weeks in ralinepag group compared to placebo group,” Rali said.

Although ralinepag offers a good option for once-a-day oral prostacyclin options for the patients, the significant number of patients in the new study who discontinued because of adverse effects is notable, said Rali. “Treating clinicians will have to watch very closely, as the real-world patient population seems to be more complex than clinical trial populations,” he said. “At the same time, clinicians will have an option to weigh against growing list of inhaled prostacyclin pathway therapies that may not have systemic side effects of the oral agents,” he added.

“Given the strong scientific data in the ADVANCE trials, ralinepag may become drug of choice for oral prostacyclin pathway agents,” Rali added. However, its place in the treatment sequence, whether it is best used early in the disease course, as an add-on for patients already receiving dual oral therapy, or potentially part of upfront combination strategies, will call for some clinician judgement, Rali said. “Patient education and gradual dose titration will likely play a major role in improving adherence and limiting prostacyclin-related adverse effects,” he added.

Questions for future research include what percentage of the patients were able to tolerate the maximum dose of the drug, and whether any changes in primary or secondary outcomes occurred depending on the dose, said Rali. Other areas of interest include whether certain patient populations derive greater benefit than others, including connective tissue disease-associated PAH, idiopathic PAH, and higher-risk patient populations. “Comparative effectiveness data against currently available oral prostacyclin pathway agents and studies evaluating transition strategies from parenteral or inhaled therapies would help clinicians better understand where ralinepag ultimately fits in the PAH treatment algorithm,” Rali said. “I also would be curious to see what the authors thought of the failure to achieve the primary endpoint in cohorts of patients from Latin America and Asia Pacific regions,” he added.

The study was funded by United Therapeutics, and McLaughlin disclosed serving as a consultant for the company. Rali had no financial conflicts to disclose.

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

Treatment with ralinepag, an investigational prostacyclin receptor agonist, reduced the risk for clinical disease worsening by 55% compared to placebo in patients with pulmonary arterial hypertension (PAH), based on new data from the ADVANCE Outcomes study presented at the American Thoracic Society (ATS) 2026 International Conference.

Ralinepag works by restoring prostacyclin signaling and activating prostacyclin receptors to affect pathways that play a role in the progression of PAH. The drug was originally formulated as an immediate-release capsule but modified to the extended-release tablet used in the current study as a way to optimize once daily dosing.

“The prostacyclin pathway is foundational in the management of PAH, and advancing prostacyclin science has benefited patients over the years,” said lead author Vallerie V. McLaughlin, MD, professor of cardiovascular medicine and director of the Pulmonary Hypertension Program at the University of Michigan, Ann Arbor, Michigan, who presented the findings at the meeting. Although other oral prostacyclin pathway agents available, ralinepag has the advantages of high potency and longer half-life that could be effective and well-tolerated in a more patient-friendly once daily formulation, McLaughlin said.

The international study population included 687 adults with PAH from 30 countries across five continents. Participants were randomized to ralinepag or placebo in addition to their standard PAH background therapies. Ralinepag was orally dosed once daily and titrated for tolerability and response. The mean age of the participants was 52 years, 80% were White, and the median time since PAH diagnosis was 2.3 years. A majority of 62% had idiopathic or heritable PAH, 28.2% had PAH as a result of connective tissue disease, 4.1% had a congenital heart defect, 3.1% had drug- or toxin-induced PAH, and 2.6% had PAH as a result of HIV infection. More than two thirds were considered low risk (characterized as Functional Class II).

The primary endpoint was the time to first indication of clinical worsening, which was defined as death, hospital admission for worsening PAH, initiation of a parenteral or inhaled prostacyclin pathway agent for worsening PAH, or unsatisfactory long-term clinical response.

Overall, patients treated with ralinepag were significantly less likely to experience a clinical worsening event than placebo patients (hazard ratio [HR], 0.45; 95% CI, 0.33-0.62; P < .0001), and 47% more likely to achieve the secondary endpoint of clinical improvement (P = .015).

Patients treated with ralinepag also showed significant improvements over placebo patients in the secondary endpoints of pro-B-type natriuretic peptide levels (24.3% reduction from baseline to week 28 over placebo; P = .0013), and in the 6-minute walk test (a placebo-corrected difference of 20.4 m from baseline to week 28; P = .0033).

Although more than 90% of participants treated with ralinepag reported an adverse event related to the drug, approximately 5% experienced drug-related serious adverse events, and the overall safety profile reflected previous ralinepag studies, with a positive risk-benefit ratio, the investigators noted.

Support for Early Introduction

The researchers expected the efficacy associated with prostacyclin therapy, said McLaughlin. “We were very pleased to see such a strong treatment effect in a relatively low-risk population, primarily Functional Class II with a mean 6-minute walk of nearly 440 meters, with the majority of patients on dual oral therapy,” she said.

If approved, ralinepag could help optimized risk status in PAH, said McLaughlin. “Many patients do not get to low risk with first-line therapy, and oral and inhaled prostacyclin pathway agents are often used in addition to dual therapy with phosphodiesterase type-5 inhibitors and endothelin receptor antagonists,” she said. “The impressive treatment effect of ralinepag in patients primarily treated with dual oral therapy reflects this real-world scenario,” she added. The significant event reduction makes a case for earlier introduction of ralinepag in relatively low-risk patients; a highly effective therapy that targets the prostacyclin pathway may reduce the need for more cumbersome and invasive prostacyclin therapies, McLaughlin added.

Ralinepag remains an investigational drug, but the company plans to seek a New Drug Application from the FDA for the treatment of PAH by the second half of 2026, according to a press release.

The research team would like to continue evaluating the ADVANCE Outcomes database to learn more about dose response, tolerability, and subgroup response, said McLaughlin. At that point, real-world data would be useful, and additional research areas in that setting would include combination therapy with other agents such as sotatercept, as well as the use of ralinepag to transition patients on more complicated and invasive therapy, she said.

Attention to Adverse Effects

Prostacyclin therapies are often offered in oral, inhaled, and the most invasive intravenous/subcutaneous routes, but a gap remains between the strong efficacy seen with parenteral therapy and what many patients are willing or able to use in real-world practice, said Parth M. Rali, MD, director of the Temple University Health System Pulmonary Embolism Response Team Program, Section Temple Lung Pulmonary Vascular Disease Program, Philadelphia, who was not involved in the study.

“Ralinepag provides sustained activation of IP receptors and has very long effective half-life, giving drug exposure comparable to parenteral therapy, and offers the first daily treatment option, which is important for the patients with PAH who are often on multiple drugs therapies,” Rali said.

Given the encouraging phase 2 findings demonstrating meaningful reductions in pulmonary vascular resistance and signals toward clinical benefit, we would like to see a favorable outcome in the phase 3 program. Primary outcome studied was time to clinical worsening in the large, randomized trial that involved global populations from the US, Europe, Latin-America, and Asia Pacific Region. Ralinepag arm had 55% reduction in risk for clinical worsening (HR, ~ 0.45) compared to placebo arm. “The positive results of the trial were primarily driven by disease progression, initiation of prostacyclin therapy, and unsatisfactory long-term clinical response at 28 weeks in ralinepag group compared to placebo group,” Rali said.

Although ralinepag offers a good option for once-a-day oral prostacyclin options for the patients, the significant number of patients in the new study who discontinued because of adverse effects is notable, said Rali. “Treating clinicians will have to watch very closely, as the real-world patient population seems to be more complex than clinical trial populations,” he said. “At the same time, clinicians will have an option to weigh against growing list of inhaled prostacyclin pathway therapies that may not have systemic side effects of the oral agents,” he added.

“Given the strong scientific data in the ADVANCE trials, ralinepag may become drug of choice for oral prostacyclin pathway agents,” Rali added. However, its place in the treatment sequence, whether it is best used early in the disease course, as an add-on for patients already receiving dual oral therapy, or potentially part of upfront combination strategies, will call for some clinician judgement, Rali said. “Patient education and gradual dose titration will likely play a major role in improving adherence and limiting prostacyclin-related adverse effects,” he added.

Questions for future research include what percentage of the patients were able to tolerate the maximum dose of the drug, and whether any changes in primary or secondary outcomes occurred depending on the dose, said Rali. Other areas of interest include whether certain patient populations derive greater benefit than others, including connective tissue disease-associated PAH, idiopathic PAH, and higher-risk patient populations. “Comparative effectiveness data against currently available oral prostacyclin pathway agents and studies evaluating transition strategies from parenteral or inhaled therapies would help clinicians better understand where ralinepag ultimately fits in the PAH treatment algorithm,” Rali said. “I also would be curious to see what the authors thought of the failure to achieve the primary endpoint in cohorts of patients from Latin America and Asia Pacific regions,” he added.

The study was funded by United Therapeutics, and McLaughlin disclosed serving as a consultant for the company. Rali had no financial conflicts to disclose.

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

Treatment with ralinepag, an investigational prostacyclin receptor agonist, reduced the risk for clinical disease worsening by 55% compared to placebo in patients with pulmonary arterial hypertension (PAH), based on new data from the ADVANCE Outcomes study presented at the American Thoracic Society (ATS) 2026 International Conference.

Ralinepag works by restoring prostacyclin signaling and activating prostacyclin receptors to affect pathways that play a role in the progression of PAH. The drug was originally formulated as an immediate-release capsule but modified to the extended-release tablet used in the current study as a way to optimize once daily dosing.

“The prostacyclin pathway is foundational in the management of PAH, and advancing prostacyclin science has benefited patients over the years,” said lead author Vallerie V. McLaughlin, MD, professor of cardiovascular medicine and director of the Pulmonary Hypertension Program at the University of Michigan, Ann Arbor, Michigan, who presented the findings at the meeting. Although other oral prostacyclin pathway agents available, ralinepag has the advantages of high potency and longer half-life that could be effective and well-tolerated in a more patient-friendly once daily formulation, McLaughlin said.

The international study population included 687 adults with PAH from 30 countries across five continents. Participants were randomized to ralinepag or placebo in addition to their standard PAH background therapies. Ralinepag was orally dosed once daily and titrated for tolerability and response. The mean age of the participants was 52 years, 80% were White, and the median time since PAH diagnosis was 2.3 years. A majority of 62% had idiopathic or heritable PAH, 28.2% had PAH as a result of connective tissue disease, 4.1% had a congenital heart defect, 3.1% had drug- or toxin-induced PAH, and 2.6% had PAH as a result of HIV infection. More than two thirds were considered low risk (characterized as Functional Class II).

The primary endpoint was the time to first indication of clinical worsening, which was defined as death, hospital admission for worsening PAH, initiation of a parenteral or inhaled prostacyclin pathway agent for worsening PAH, or unsatisfactory long-term clinical response.

Overall, patients treated with ralinepag were significantly less likely to experience a clinical worsening event than placebo patients (hazard ratio [HR], 0.45; 95% CI, 0.33-0.62; P < .0001), and 47% more likely to achieve the secondary endpoint of clinical improvement (P = .015).

Patients treated with ralinepag also showed significant improvements over placebo patients in the secondary endpoints of pro-B-type natriuretic peptide levels (24.3% reduction from baseline to week 28 over placebo; P = .0013), and in the 6-minute walk test (a placebo-corrected difference of 20.4 m from baseline to week 28; P = .0033).

Although more than 90% of participants treated with ralinepag reported an adverse event related to the drug, approximately 5% experienced drug-related serious adverse events, and the overall safety profile reflected previous ralinepag studies, with a positive risk-benefit ratio, the investigators noted.

Support for Early Introduction

The researchers expected the efficacy associated with prostacyclin therapy, said McLaughlin. “We were very pleased to see such a strong treatment effect in a relatively low-risk population, primarily Functional Class II with a mean 6-minute walk of nearly 440 meters, with the majority of patients on dual oral therapy,” she said.

If approved, ralinepag could help optimized risk status in PAH, said McLaughlin. “Many patients do not get to low risk with first-line therapy, and oral and inhaled prostacyclin pathway agents are often used in addition to dual therapy with phosphodiesterase type-5 inhibitors and endothelin receptor antagonists,” she said. “The impressive treatment effect of ralinepag in patients primarily treated with dual oral therapy reflects this real-world scenario,” she added. The significant event reduction makes a case for earlier introduction of ralinepag in relatively low-risk patients; a highly effective therapy that targets the prostacyclin pathway may reduce the need for more cumbersome and invasive prostacyclin therapies, McLaughlin added.

Ralinepag remains an investigational drug, but the company plans to seek a New Drug Application from the FDA for the treatment of PAH by the second half of 2026, according to a press release.

The research team would like to continue evaluating the ADVANCE Outcomes database to learn more about dose response, tolerability, and subgroup response, said McLaughlin. At that point, real-world data would be useful, and additional research areas in that setting would include combination therapy with other agents such as sotatercept, as well as the use of ralinepag to transition patients on more complicated and invasive therapy, she said.

Attention to Adverse Effects

Prostacyclin therapies are often offered in oral, inhaled, and the most invasive intravenous/subcutaneous routes, but a gap remains between the strong efficacy seen with parenteral therapy and what many patients are willing or able to use in real-world practice, said Parth M. Rali, MD, director of the Temple University Health System Pulmonary Embolism Response Team Program, Section Temple Lung Pulmonary Vascular Disease Program, Philadelphia, who was not involved in the study.

“Ralinepag provides sustained activation of IP receptors and has very long effective half-life, giving drug exposure comparable to parenteral therapy, and offers the first daily treatment option, which is important for the patients with PAH who are often on multiple drugs therapies,” Rali said.

Given the encouraging phase 2 findings demonstrating meaningful reductions in pulmonary vascular resistance and signals toward clinical benefit, we would like to see a favorable outcome in the phase 3 program. Primary outcome studied was time to clinical worsening in the large, randomized trial that involved global populations from the US, Europe, Latin-America, and Asia Pacific Region. Ralinepag arm had 55% reduction in risk for clinical worsening (HR, ~ 0.45) compared to placebo arm. “The positive results of the trial were primarily driven by disease progression, initiation of prostacyclin therapy, and unsatisfactory long-term clinical response at 28 weeks in ralinepag group compared to placebo group,” Rali said.

Although ralinepag offers a good option for once-a-day oral prostacyclin options for the patients, the significant number of patients in the new study who discontinued because of adverse effects is notable, said Rali. “Treating clinicians will have to watch very closely, as the real-world patient population seems to be more complex than clinical trial populations,” he said. “At the same time, clinicians will have an option to weigh against growing list of inhaled prostacyclin pathway therapies that may not have systemic side effects of the oral agents,” he added.

“Given the strong scientific data in the ADVANCE trials, ralinepag may become drug of choice for oral prostacyclin pathway agents,” Rali added. However, its place in the treatment sequence, whether it is best used early in the disease course, as an add-on for patients already receiving dual oral therapy, or potentially part of upfront combination strategies, will call for some clinician judgement, Rali said. “Patient education and gradual dose titration will likely play a major role in improving adherence and limiting prostacyclin-related adverse effects,” he added.

Questions for future research include what percentage of the patients were able to tolerate the maximum dose of the drug, and whether any changes in primary or secondary outcomes occurred depending on the dose, said Rali. Other areas of interest include whether certain patient populations derive greater benefit than others, including connective tissue disease-associated PAH, idiopathic PAH, and higher-risk patient populations. “Comparative effectiveness data against currently available oral prostacyclin pathway agents and studies evaluating transition strategies from parenteral or inhaled therapies would help clinicians better understand where ralinepag ultimately fits in the PAH treatment algorithm,” Rali said. “I also would be curious to see what the authors thought of the failure to achieve the primary endpoint in cohorts of patients from Latin America and Asia Pacific regions,” he added.

The study was funded by United Therapeutics, and McLaughlin disclosed serving as a consultant for the company. Rali had no financial conflicts to disclose.

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

TOPLINE:

Higher baseline counts of blood eosinophils (EOS) were associated with an increased risk for exacerbations in patients with asthma over 1 year, and higher baseline levels of fractional exhaled nitric oxide (FeNO) were linked to increased odds of exacerbations treated with only oral corticosteroids (OCS) in asthma and asthma plus chronic obstructive pulmonary disease (COPD) but linked to a decreased risk for all exacerbations in COPD.

METHODOLOGY:

• Researchers analyzed data from the multinational NOVELTY study to assess whether blood EOS counts and FeNO levels, alone and together, predict the risk for future exacerbations in patients with asthma, COPD, or both.
• Overall, 4319 patients were included in the EOS analysis (2138 with asthma, 1541 with COPD, and 640 with asthma plus COPD), and 7770 patients were included in the FeNO analysis (4166 with asthma, 2588 with COPD, and 1016 with asthma plus COPD).
• Baseline data included demographics, treatments, exacerbations, and lung function (spirometry and FeNO levels).
• Outcomes were assessed over the first year of follow‑up, and patients received usual care from their treating physicians.
• Exacerbation subtypes were categorized as all exacerbations, exacerbations treated with only antibiotics, and exacerbations treated with only OCS.

TAKEAWAY:

• Higher EOS counts at baseline were associated with an increased risk for all exacerbations in asthma (incidence rate ratio [IRR], 1.09; P = .033), meaning each doubling of the count corresponded to a 9% higher exacerbation rate; a similar trend of higher risk was seen in COPD that did not reach statistical significance.
• Higher FeNO levels at baseline were associated with a lower risk for all exacerbations in COPD (IRR, 0.91; P = .025). In asthma, FeNO levels showed no association with an overall risk for exacerbations; in asthma plus COPD, neither biomarker predicted the overall risk.
• In asthma, higher FeNO levels at baseline were linked to increased odds of exacerbations treated with only OCS (odds ratio [OR], 1.16) but decreased odds of exacerbations treated with only antibiotics (OR, 0.75); in asthma plus COPD, higher FeNO levels were also linked to increased odds of exacerbations treated with only OCS (OR, 1.55; P < .05 for all).
• In an analysis including both biomarkers, higher EOS counts at baseline independently predicted all exacerbations in asthma; however, both higher EOS counts and lower FeNO levels were independently associated with a higher risk for all exacerbations in COPD (P < .05 for all).

IN PRACTICE:

“[The study] finding is of importance for future studies and daily clinical practice as it indicates that assessment of exacerbation subtype might improve personalized treatment management,” the authors wrote.

SOURCE:

This study was led by Susan Muiser, University Medical Centre Groningen, Groningen, Netherlands. It was published online on April 21, 2026, in Thorax.

LIMITATIONS:

Diagnoses were assigned by treating physicians without standardized diagnostic criteria. Physicians had access to type 2 inflammation biomarker results, which may have influenced treatment decisions. Exacerbation subtypes were categorized using medical records and patient-reported information, introducing a potential recall bias.

DISCLOSURES:

The NOVELTY study was funded by AstraZeneca. Four authors reported being employees of AstraZeneca, with 2 of them also being shareholders. Several authors disclosed receiving travel grants, research grants, consulting fees, honoraria, and support to attend meetings; serving on advisory boards; and holding stock or stock options with multiple pharmaceutical companies and organizations, including AstraZeneca and WebMD Global.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

Higher baseline counts of blood eosinophils (EOS) were associated with an increased risk for exacerbations in patients with asthma over 1 year, and higher baseline levels of fractional exhaled nitric oxide (FeNO) were linked to increased odds of exacerbations treated with only oral corticosteroids (OCS) in asthma and asthma plus chronic obstructive pulmonary disease (COPD) but linked to a decreased risk for all exacerbations in COPD.

METHODOLOGY:

• Researchers analyzed data from the multinational NOVELTY study to assess whether blood EOS counts and FeNO levels, alone and together, predict the risk for future exacerbations in patients with asthma, COPD, or both.
• Overall, 4319 patients were included in the EOS analysis (2138 with asthma, 1541 with COPD, and 640 with asthma plus COPD), and 7770 patients were included in the FeNO analysis (4166 with asthma, 2588 with COPD, and 1016 with asthma plus COPD).
• Baseline data included demographics, treatments, exacerbations, and lung function (spirometry and FeNO levels).
• Outcomes were assessed over the first year of follow‑up, and patients received usual care from their treating physicians.
• Exacerbation subtypes were categorized as all exacerbations, exacerbations treated with only antibiotics, and exacerbations treated with only OCS.

TAKEAWAY:

• Higher EOS counts at baseline were associated with an increased risk for all exacerbations in asthma (incidence rate ratio [IRR], 1.09; P = .033), meaning each doubling of the count corresponded to a 9% higher exacerbation rate; a similar trend of higher risk was seen in COPD that did not reach statistical significance.
• Higher FeNO levels at baseline were associated with a lower risk for all exacerbations in COPD (IRR, 0.91; P = .025). In asthma, FeNO levels showed no association with an overall risk for exacerbations; in asthma plus COPD, neither biomarker predicted the overall risk.
• In asthma, higher FeNO levels at baseline were linked to increased odds of exacerbations treated with only OCS (odds ratio [OR], 1.16) but decreased odds of exacerbations treated with only antibiotics (OR, 0.75); in asthma plus COPD, higher FeNO levels were also linked to increased odds of exacerbations treated with only OCS (OR, 1.55; P < .05 for all).
• In an analysis including both biomarkers, higher EOS counts at baseline independently predicted all exacerbations in asthma; however, both higher EOS counts and lower FeNO levels were independently associated with a higher risk for all exacerbations in COPD (P < .05 for all).

IN PRACTICE:

“[The study] finding is of importance for future studies and daily clinical practice as it indicates that assessment of exacerbation subtype might improve personalized treatment management,” the authors wrote.

SOURCE:

This study was led by Susan Muiser, University Medical Centre Groningen, Groningen, Netherlands. It was published online on April 21, 2026, in Thorax.

LIMITATIONS:

Diagnoses were assigned by treating physicians without standardized diagnostic criteria. Physicians had access to type 2 inflammation biomarker results, which may have influenced treatment decisions. Exacerbation subtypes were categorized using medical records and patient-reported information, introducing a potential recall bias.

DISCLOSURES:

The NOVELTY study was funded by AstraZeneca. Four authors reported being employees of AstraZeneca, with 2 of them also being shareholders. Several authors disclosed receiving travel grants, research grants, consulting fees, honoraria, and support to attend meetings; serving on advisory boards; and holding stock or stock options with multiple pharmaceutical companies and organizations, including AstraZeneca and WebMD Global.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

TOPLINE:

Higher baseline counts of blood eosinophils (EOS) were associated with an increased risk for exacerbations in patients with asthma over 1 year, and higher baseline levels of fractional exhaled nitric oxide (FeNO) were linked to increased odds of exacerbations treated with only oral corticosteroids (OCS) in asthma and asthma plus chronic obstructive pulmonary disease (COPD) but linked to a decreased risk for all exacerbations in COPD.

METHODOLOGY:

• Researchers analyzed data from the multinational NOVELTY study to assess whether blood EOS counts and FeNO levels, alone and together, predict the risk for future exacerbations in patients with asthma, COPD, or both.
• Overall, 4319 patients were included in the EOS analysis (2138 with asthma, 1541 with COPD, and 640 with asthma plus COPD), and 7770 patients were included in the FeNO analysis (4166 with asthma, 2588 with COPD, and 1016 with asthma plus COPD).
• Baseline data included demographics, treatments, exacerbations, and lung function (spirometry and FeNO levels).
• Outcomes were assessed over the first year of follow‑up, and patients received usual care from their treating physicians.
• Exacerbation subtypes were categorized as all exacerbations, exacerbations treated with only antibiotics, and exacerbations treated with only OCS.

TAKEAWAY:

• Higher EOS counts at baseline were associated with an increased risk for all exacerbations in asthma (incidence rate ratio [IRR], 1.09; P = .033), meaning each doubling of the count corresponded to a 9% higher exacerbation rate; a similar trend of higher risk was seen in COPD that did not reach statistical significance.
• Higher FeNO levels at baseline were associated with a lower risk for all exacerbations in COPD (IRR, 0.91; P = .025). In asthma, FeNO levels showed no association with an overall risk for exacerbations; in asthma plus COPD, neither biomarker predicted the overall risk.
• In asthma, higher FeNO levels at baseline were linked to increased odds of exacerbations treated with only OCS (odds ratio [OR], 1.16) but decreased odds of exacerbations treated with only antibiotics (OR, 0.75); in asthma plus COPD, higher FeNO levels were also linked to increased odds of exacerbations treated with only OCS (OR, 1.55; P < .05 for all).
• In an analysis including both biomarkers, higher EOS counts at baseline independently predicted all exacerbations in asthma; however, both higher EOS counts and lower FeNO levels were independently associated with a higher risk for all exacerbations in COPD (P < .05 for all).

IN PRACTICE:

“[The study] finding is of importance for future studies and daily clinical practice as it indicates that assessment of exacerbation subtype might improve personalized treatment management,” the authors wrote.

SOURCE:

This study was led by Susan Muiser, University Medical Centre Groningen, Groningen, Netherlands. It was published online on April 21, 2026, in Thorax.

LIMITATIONS:

Diagnoses were assigned by treating physicians without standardized diagnostic criteria. Physicians had access to type 2 inflammation biomarker results, which may have influenced treatment decisions. Exacerbation subtypes were categorized using medical records and patient-reported information, introducing a potential recall bias.

DISCLOSURES:

The NOVELTY study was funded by AstraZeneca. Four authors reported being employees of AstraZeneca, with 2 of them also being shareholders. Several authors disclosed receiving travel grants, research grants, consulting fees, honoraria, and support to attend meetings; serving on advisory boards; and holding stock or stock options with multiple pharmaceutical companies and organizations, including AstraZeneca and WebMD Global.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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