Social inequalities in mortality and health have been recognised as serious public health issues since the 1980s, yet researchers continue to find social gradients in health nearly everywhere they look.1,2 Despite decades of research, our understanding of how and when socioeconomic factors and health interact to produce health inequalities remains work in progress. Some research on health inequalities has extended focus from adulthood social position to parental social background and early life conditions, and the accumulation of advantage and disadvantage across the life course.
[Articles] The effects of the Rx Kids unconditional cash prescription programme during pregnancy and infancy on birth outcomes in the USA: a population-based, quasi-experimental study
With significant reductions in adverse birth outcomes, the treatment of perinatal poverty with a place-based intervention as replicable and scalable as Rx Kids has important implications for infants and society. These findings suggest that the economic hardship of the perinatal period, starting in utero, contributes to adverse outcomes and is addressable.
Self-Monitoring Risk Factors for Diabetic Foot Ulceration With the Feetchecker App: Mixed Methods Study
Background: A prevalent and serious complication of diabetes mellitus is the development of diabetic foot ulcer (DFU). There is a need for effective solutions that help prevent DFU to support our increasingly stressed health care systems. The use of mobile health (mHealth) tools has been shown to improve awareness and effective self-care management skills in people at risk of developing diabetic foot ulceration. Objective: In this study, we aimed to investigate the perceived usefulness, engagement, and overall user experience of the Feetchecker app, a self-monitoring mHealth app for people at risk of DFU. Methods: A total of 24 patients (mean age 71, SD 8.6 years) with type 2 diabetes mellitus at risk of developing diabetic foot ulceration completed a 3-month evaluation period (70 recruited, 36 included, 12 dropped out) of a self-monitoring mobile app called Feetchecker app. A mixed methods approach was used to combine insights from app data with qualitative data from a pre- and postsurvey as well as interviews with patients and involved podiatrists. Data were analyzed using descriptive statistics and thematic analysis. We evaluated overall use of the app, patient engagement, and user experiences. Results: Patients who fully completed the study conducted 393 feetchecks. In total, 7 patients sent in 9 pictures; all 7 were called for follow-up by a podiatrist. Overall, patients had a positive experience with the app and perceived the Feetchecker app as a valuable tool to monitor their feet for potential risk factors of DFU. Ease of use in performing a feetcheck and sending the podiatrist a picture was described as an important feature. Three main types of engagement with the Feetchecker app emerged: continuous, frequent, and no to little engagement. These patterns highlight enablers for self-monitoring such as ease-of-use, easy access to a podiatrist, and social support, as well as barriers such as digital skills and sustained engagement. Podiatrists highlighted the benefits of having patients report potential issues quicker and the ability to monitor their patients remotely. Challenges remain in integrating the promotion of the Feetchecker app into their consultations. Conclusions: The Feetchecker app supported patients in self-monitoring risk factors associated with DFU through routine checks and quick contact with a health care professional in case of a potential issue. Overall, patients described a positive user experience and considered the app helpful. While mHealth tools are not for everyone, user engagement for many patients was high and shows that such apps can offer support for people able to use them. Future research should focus on improving usability and engagement with the app as well as extend the way patients can communicate with health care professionals beyond a picture.
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Sea Cucumber Tissues Demonstrate Natural Immortality in Seawater
From the revived corpse of Frankenstein’s monster to the disembodied hand, “Thing,” in the Addams Family, reanimated tissue is one of the most enduring images in science fiction. The discovery of a sea floor-dwelling sea cucumber that scientists are calling a “real-life zombie” suggests that there may be some basis for that image in nature.
Scientists headed by a team at Memorial University of Newfoundland showed the continued viability of amputated tissue from the sea cucumber Psolus fabricii for more than three years in natural seawater. It’s the first known report of the long-term survival—and continued growth—of discarded tissue outside of a highly controlled, sterilized environment.
The discovery that these living P. fabricii explants (LiPfe) can survive for years in natural seawater without any supplementation challenges assumptions of what’s possible for tissue immortality and could have implications in areas including regenerative biology and tissue engineering. The findings could also lead to the development of experimental models for biological research that are more widely accessible, without the ethical and logistical challenges associated with many existing cell lines.
“We haven’t grown a new, complete sea cucumber yet, but we are seeing pretty stunning growth and diversification of cells literally years after this tissue was removed,” said research lead Rachel Sipler, PhD, a Bigelow Laboratory for Ocean Sciences senior research scientist. “It’s like a lizard that loses its tail. We know some lizards can grow new tails; we’re talking about whether the tail can grow a new lizard.”
Reporting on their findings in Science Advances (“Natural tissue immortality: Indefinite survival of sea cucumber explants,”) Sipler and colleagues stated, “Our findings challenge conventional perceptions of tissue immortality and present a new class of experimental model, free from ethical concerns, with substantial implications for regenerative biology, biomedical research, and tissue engineering.”
Over the last 200 years, scientists have tried to achieve cellular and tissular survival outside living hosts, “… but efforts have been met with limited success due to the highly degradable nature of tissue itself,” the authors wrote. Since the mid-20th century, scientists have made significant breakthroughs with immortal cell lines, such as HeLa cells, that can be grown in a lab and proliferate indefinitely for long-term research. In earlier studies, tissue cultures have only been maintained under axenic conditions that are tightly controlled, rigorously maintained, and lack any bacteria or other organisms. Even then, they have not demonstrated signs of actual healing and growth, nor retained the ability to move independently. “While immortal cell lines demonstrate indefinite proliferation in vitro, they lack structural integrity and complex tissue interactions,” the team continued. “Achieving this with complex, structured tissue represents the next step.”
Many echinoderms, including sea cucumbers, are known to display impressive regeneration capacity and negligible cell aging. “In the ongoing effort to understand tissue culture, regeneration, and immortality, researchers have naturally been drawn to echinoderms, a phylum with genetic and evolutionary links to vertebrates and examples of both extreme regenerative capacity and negligible cellular senescence,” the investigators noted. Lost tissue, though, was always assumed to eventually decay or die.
Yet, in what Sipler calls a product of “keen observation,” the researchers noticed that some discarded tissue from a tube foot of a sea cucumber hadn’t decayed after a number of weeks. In fact, it seemed to be growing. The researchers then ran a number of experiments in flowing seawater with tissue removed from the feet, main body, and tentacles of three individuals of P. fabricii, a cold-water species of sea cucumber.
They found evidence of diversifying cells, immune activity, and tissue reorganization in the explanted tissue. “In experimental trials, these explants, termed LiPfe (living immortal P. fabricii explants), displayed immune activity, cell cycling, tissue reorganization, and absorption of dissolved amino acids, underscoring their active living state,” they noted. And in the absence of a mouth, the cells appeared to be getting nutrients by absorbing amino acids dissolved in the seawater.
Even after three years, when the researchers stopped the experiments in order to publish, the tissue was still active. This ability to survive in a complex, stressful environment, Sipler said, makes this cell line unique compared to other tissue cultures. “Compared to other cells or tissues grown under laboratory setups that required strict parameters, including axenic conditions, LiPfe required nothing apart from natural running seawater,” they wrote. “Comparative experiments conducted on explanted tissues from related species demonstrated no equivalent tissue survival, highlighting the unique properties of P. fabricii, which do not have parallels in the current literature.”
“Natural seawater is just about the most microbially diverse, least clean approach we could take experimentally,” Sipler added. “Yet, that rich environment full of bacteria and all this organic matter was actually feeding them and allowing this tissue to heal and grow.”
The implications for biomedical sciences and engineering, the authors said, are profound, with potential applications in everything from tissue regrowth to anti-microbial healing. In their paper, the authors stated, “The discovery of LiPfe challenges the boundary between organismal life and cellular autonomy, compelling a redefinition of what it means for tissue to be alive.”
The discovery opens up new opportunities for biological research and education more broadly. The tissue they’ve preserved not only shows an unprecedented ability to maintain its structural integrity and complexity in culture. It can also be grown more easily in the lab and, as an invertebrate, isn’t subject to as many research restrictions, making it useful in contexts where there are legal obstacles or limited biosafety infrastructure for using human-based or other vertebrate cell lines.
As an oceanographer, Sipler noted that the exciting discovery drives home the incredible untapped potential of ocean life. “The best advances in science are made when you find a natural analog for what you’re studying,” she said. “Here is this species that has this groundbreaking ability, and we had no idea. It’s a reminder of how much is yet to be discovered in the marine environment, and how important it is to protect these resources that may hold really valuable knowledge for us.”
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Accuracy in the Estimation of Self-Reported Knee Brace Wear Time in Young Adults With a Symptomatic Knee Following ACL Reconstruction: Secondary Analysis of a Pilot Randomized Controlled Trial
Background: Knee braces may improve symptoms and physical function following anterior cruciate ligament reconstruction (ACLR). However, their effectiveness depends on adherence, which typically relies on self-reported wear time, prone to recall and response bias. Objective measures (eg, temperature sensors), validated in footwear and orthotics research, offer a potentially more accurate alternative to self-reporting. Despite this, there is no research comparing self-reported and sensor-measured wear times in a knee brace. Objective: This study aimed to determine how well self-reported wear times reflect sensor-measured data in a slim-fit knee brace. Methods: Young adults (aged 18-45 years), 1-8 years post-ACLR, with a symptomatic knee (the 4 Knee injury and Osteoarthritis Outcome Score subscales [KOOS] score <80/100) wore a slim-fit brace during a 6-week feasibility trial. This study reports a secondary analysis of participants allocated to the brace group. Self-reported wear times were recorded in daily logs. An undisclosed, embedded temperature sensor recorded temperature every 10 minutes. A wear detection algorithm identified brace donning and doffing. These data were used to calculate aggregated measures (ie, summary measures across the entire 6-week intervention period, including cumulative wear time, average daily wear time, and total number of days worn) and repeated measures (daily wear duration, 3- and 7-day rolling averages, where wear time is averaged over consecutive days). Agreement between self-reported and sensor-based measures was assessed using concordance correlation coefficients (CCCs) and limits of agreement (LoA). Results: Of the 14 randomized participants, 10 (30% male [n=3]; mean age: 33, SD 6 years; time post-ACLR: 4, SD 1 years) had both temperature sensor and self-reported wear data. Six participants (60%) underreported average daily wear time (mean 29, SD 24 minutes across all 10 participants), while nine (90%) overreported the number of days worn (mean 9, SD 6 days across all 10 participants). Daily wear time showed moderate agreement between the sensor and self-reporting (CCC 0.70, 95% CI 0.58-0.79), but wide LoA (−223 to 217 minutes). Using 3- or 7-day rolling averages narrowed LoA (−47 to 36 minutes per day and −14 to 10 minutes per day, respectively) and slightly improved CCCs (0.74, 95% CI 0.58-0.85, and 0.73, 95% CI 0.51-0.86, respectively). Greater agreement was observed with more aggregated outcomes; for total 6-week wear time, the CCC was 0.84 (95%CI 0.50-0.95). When expressed as daily average wear time, the CCC was excellent (0.92, 95% CI 0.73-0.98), although daily LoA remained wide (−68 to 32 minutes), indicating substantial individual variability between self-reported and sensor-based measures. For the total number of days worn, the CCC was moderate (0.64, 95% CI 0.15-0.88) and LoA was wide (−10 to 22 days). Conclusions: Self-reported daily brace wear time is inaccurate compared to wear time measured by the temperature sensor. Aggregated data and rolling averages showed better agreement. Future intervention studies should consider objective adherence measures. Failing this, averaging self-reported wear time across the intervention period could improve accuracy. Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12623001027606; https://tinyurl.com/2spr7bnu
Largest Rare Variant–Lipid Association Study Finds Heart Disease Targets
A landmark week for cardiovascular genetics opened with huge news from the gene-editing field: Eli Lilly’s experimental therapy VERVE-102, a single-dose PCSK9 base editor designed for patients with heterozygous familial hypercholesterolemia (FH) and premature coronary artery disease (CAD), demonstrated durable cholesterol-lowering effects in early studies. While the result marks one of the strongest signs yet that in vivo gene editing could become a practical treatment for inherited cardiovascular disease, it’s just scratching the surface of the enormous number of uncharacterized genetic variants that influence cholesterol levels and heart disease risk across global populations.
The largest rare variant association with blood lipids study ever reported may provide the roadmap to heart disease mechanistic and clinical insights. In a Nature Genetics study analyzing data from more than one million individuals, researchers identified thousands of rare coding variants linked to cholesterol and triglyceride (TG) levels, including several genes strongly associated with coronary artery disease. The findings could accelerate the development of precision medicines for dyslipidemia and improve the diagnosis of inherited lipid disorders such as familial hypercholesterolemia.
Diversity and scale
FH is caused by rare mutations that raise LDL-C, increasing the risk of early-onset CAD, a leading cause of premature death worldwide. Although statins and other lipid-lowering therapies can significantly lower cardiovascular risk, FH is underdiagnosed and undertreated. Many FH-associated variants have variable penetrance, so some carriers have severe disease and others have milder symptoms, adding to the complexity.
Accurate variant-specific risk assessment is becoming increasingly important as genetic screening expands. Most genetic databases are biased toward Europeans, making it difficult to classify disease-causing variants in non-Europeans.
To fill this gap, Satoshi Koyama, MD, PhD, led a research team across academic and medical institutions in the Boston area that analyzed exome sequencing and blood lipid data (total cholesterol, LDL-C, HDL-C, and TG) from Million Veteran Program, UK Biobank, and All of Us participants. More than 230,000 participants came from historically underrepresented populations, making this one of the most diverse large-scale lipid genetics studies conducted to date.
Mechanistic and clinical implications
Their analysis uncovered nearly three million rare coding variants, including more than 214,000 predicted loss-of-function mutations, 2.7 million missense variants, and over 23,000 cryptic splice variants that may disrupt gene processing. In total, the team evaluated over 10 million variant-phenotype associations. The results revealed 800 exome-wide significant additive associations across 184 genetic loci, along with 109 recessive associations involving 53 genes. Many of the strongest signals appeared in genes already known to regulate lipid metabolism and cardiovascular disease, including PCSK9, LDLR, APOB, NPC1L1, and APOC3.
The study also identified five lipid-associated genes significantly linked to CAD risk, highlighting potential therapeutic targets. One particularly intriguing gene was RORC, which encodes the transcription factor RORγ. Previous laboratory and animal studies suggested that suppressing RORγ improves metabolic health and reduces atherosclerosis. Consistent with those findings, the study showed that loss-of-function variants in RORC appeared protective against CAD in humans.
Another key finding involved cryptic splice variants, a class of mutations often overlooked in clinical genetics. The researchers used machine-learning-based splice prediction tools to show that these variants had biological effects similar to canonical loss-of-function mutations, suggesting that many clinically important variants may be underestimated.
The study also found that 13% of missense mutations produced hypermorphic alleles that increased gene activity, unlike most loss-of-function variants. Existing computational prediction tools frequently fail to identify these variants, potentially limiting the sensitivity of current genetic testing approaches.
Koyama and colleagues also detected strong recessive genetic effects that standard additive models may miss entirely. Because homozygous rare variants are uncommon, their contribution to disease has historically been difficult to measure. The findings suggest that recessive inheritance may explain part of the “missing heritability” in complex cardiovascular disease.
The researchers found that most rare variants exerted similar effects across populations, even when variant frequencies differed substantially between ancestries. The study identified 130 alleles observed primarily or exclusively in non-European populations, emphasizing the importance of expanding genetic research beyond European cohorts to improve equitable diagnosis and drug discovery.
From screening to saving hearts
Beyond biological discovery, the study carries important clinical implications. By comparing their findings with curated pathogenic variant databases, the investigators confirmed many established classifications while identifying variants that may warrant reclassification. Two newly highlighted variants enriched in non-European populations may represent previously underrecognized causes of familial hypercholesterolemia.
Although the research focused mainly on rare coding variants rather than noncoding DNA, the authors argue that population-scale sequencing studies can now provide clinically actionable insights into disease mechanisms, pathogenicity, penetrance, and prognosis. Together, the findings offer a powerful new resource for cardiovascular genetics at a time when therapies such as PCSK9 gene editing are beginning to move from concept to clinic.
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STAT+: Heart patch engineered from stem cells revved up weakened hearts
Hearts can’t heal themselves.
After a heart attack or other cardiovascular insult, hearts can’t regenerate weakened muscles, leaving them less able to pump blood throughout the body. While medications to manage symptoms of heart failure — including newer obesity drugs — have been improving outcomes, many people ultimately face only two solutions: a heart transplant or heart device implant.
Now a small new study reports progress with a novel method. After people received patches of heart muscle engineered from induced pluripotent stem cells, their re-muscularized heart walls thickened, revving up pumping ability and modestly improving quality of life. The biological ventricular assist tissue in a patch, called BioVAT for short, was conceived as a bridge to either transplant, where wait times are long, or to implantation of a left ventricular assist device, or LVAD, in end-stage heart failure. A larger trial will help determine who might be the best candidate for this approach and how durable it might be.
Women’s Memory Decline Linked to ECM Changes from Brain Estrogen Loss
New research from investigators at Northwestern Medicine, published in Aging Cell, shows that loss of estrogen production in the brain after menopause is associated with changes in the brain’s extracellular matrix (ECM), a structure between brain cells that supports communication and memory. The findings suggest that estrogen decline may alter hippocampal brain environment in ways that contribute to memory impairment and may help explain why nearly two-thirds of all people with Alzheimer’s disease (AD) are women.
“This study tells us that females—but not males—may be uniquely sensitive to loss of brain estrogen at old age, potentially contributing to an increased risk of Alzheimer’s disease,” said senior author Hong Zhao, MD, PhD, a research professor of obstetrics and gynecology in the division of reproductive science in medicine at Northwestern University Feinberg School of Medicine.
The researchers found that estrogen loss, aging, and female sex are closely linked to changes in the ECM in the hippocampus, a brain region central to learning and memory. The ECM is a network of molecules that fills the spaces between neurons and glial cells to support cell communication and function. It makes up nearly 20% of brain volume and is important for memory and brain development.
To date, most research into AD has focused on neurons and glial cells, with less attention paid to the ECM. In the Northwestern study, ECM changes were examined as a central feature of brain biology affected by estrogen loss, the first study of its kind, the researchers noted.
For their research, the investigators use genetically engineered mouse models in which estrogen production was disrupted by removing aromatase, an enzyme required for estrogen synthesis. The enzyme was eliminated either throughout the body or restricted to the brain. The investigators examined young and old male and female mice, allowing comparison of sex-specific and age-related effects. The team assessed, behavior and social function, and also collected data on genome-wide gene expression changes in the hippocampus.
The research also built upon the current understanding of estrogen’s role in brain function. In the brain, estrogen has been associated with memory and mood-related functions.
“We have provided some of the most compelling evidence that estrogen is so important for memory function and other mood functions in the female brain,” said author Serdar Bulun, MD, chair of the department of obstetrics and gynecology at Feinberg and a Northwestern Medicine physician. “This should motivate clinicians to be more aware of the essential role of estrogen for women’s brains, because once memory is gone, it’s gone.”
The findings indicate that loss of brain estrogen may disrupt ECM organization in the hippocampus, which may impair communication between brain cells. Because the ECM provides a structural and signaling environment for neurons, any alterations of the ECM potentially affect processes required for memory formation and maintenance.
Prior research has shown that women with AD may have lower brain estrogen levels than women without AD. Hormone replacement therapy (HRT), created restore estrogen levels, has produced mixed results in clinical studies however.
The investigators noted that understanding how estrogen affects brain structures such as the ECM may help explain variability in HRT outcomes and could serve as a new avenue for developing future treatments. Rather than focusing only on restoring hormone levels, future therapies could address downstream changes in brain architecture.
ECM restoration could represent one such therapeutic approach. If estrogen loss leads to ECM disruption in the hippocampus, then interventions aimed at normalizing ECM structure before memory decline may support brain function in postmenopausal women.
The Northwestern team are continuing their investigation of how estrogen regulates ECM composition and signaling in specific brain regions, and whether these changes directly drive memory impairment. The noted that more research is also needed to determine how ECM-related mechanisms interact with other known AD pathways.
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Virtual Reality Could Pinpoint Early Signs of Alzheimer’s
Researchers in Japan have developed a test that can predict future neurodegeneration in cognitively healthy individuals using virtual reality. The test evaluates an individual’s spatial navigation ability—one of the first skills affected by Alzheimer’s and related diseases before memory loss or cognitive decline can start being noticed.
“Our approach may allow earlier identification of risk of neurodegenerative diseases, including Alzheimer’s disease,” said Kazuya Kawabata, MD, PhD, senior assistant professor at the department of neurology in Fujita Health University. “Over the longer term, it may contribute to a shift toward earlier detection, potentially enabling timely therapeutic interventions at preclinical stages and delaying disease progression, thereby preserving cognitive function and quality of life.”
Subtle changes in the brain leading to Alzheimer’s can emerge years before symptoms become evident. Among the brain regions that are first impacted are the hippocampus and the entorhinal cortex, both of which are involved in spatial navigation. In addition, a region within the entorhinal cortex is one of the first sites where tau neurofibrilary tangles start accumulating in Alzheimer’s.
In their study, published in Alzheimer’s Research & Therapy, Kawabata and colleagues investigated whether deteriorating spatial navigation skills could be an early indication of future cognitive decline in healthy individuals.
They designed an immersive virtual reality (VR) test to assess path integration, a key component of navigation that refers to our ability to track our position and direction as we move around based on internal cues. Participants navigated a circular virtual environment where they were asked to visit two checkpoints and then return to their starting point without relying on any landmarks or visual cues. Their performance was measured by calculating the distance to the original starting point and how much their direction deviated from that leading back to the starting point.
The study followed 71 cognitively healthy adults for approximately one year after completing the VR navigation test. High-resolution MRI scans and plasma biomarkers, including p-tau181 and glial fibrillary acidic protein (GFAP), were also analyzed in each participant one year apart in order to compare their navigation skills with established indicators of early Alzheimer’s.
Results revealed that individuals with poorer performance in the VR path integration test showed greater levels of cortical thinning and volume loss in brain regions affected by early Alzheimer’s and increased levels of p-tau181 and GFAP markers. The test was also able to identify those who experienced the fastest brain decline with high accuracy, especially in parahippocampal regions of the brain.
These findings indicate that the VR test is able to capture both molecular and structural signatures of early neurodegenerative processes that emerge before clinical symptoms can lead to an Alzheimer’s diagnosis. Although more research will be needed to validate this approach before it can be used in a clinical setting, this dual link supports its potential as a tool for early detection and monitoring of an individual’s risk of Alzheimer’s and related conditions, even when they are still cognitively healthy.
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Dual CA19-9 Threshold Improves Risk Stratification in Pancreatic Cancer
Researchers from Taiwan have proposed a dual cut-off for the pancreatic tumor marker carbohydrate antigen 19-9 (CA19-9) in which the lower threshold identifies a small subgroup “nonproducers” with poor prognosis and the higher threshold detects the more common high-risk producers.
The approach “prevents the critical underestimation of disease severity and ensures more accurate risk stratification,” write Yung-Yeh Su, MD, from National Institute of Cancer Research in Tainan, and co-authors in Clinical Cancer Research.
Serum levels of CA19-9 (also known as sialyl Lewis antigen A) correlate with pancreatic cancer stage and prognosis in that higher levels indicate more advanced disease and a worse prognosis. Currently, a CA19-9 level below 37 units/mL is considered normal or, in the case of a known diagnosis of pancreatic cancer, prognostic for standard-risk disease.
However, approximately 10% of patients with pancreatic cancer do not have elevated CA19-9 levels, even in the presence of advanced disease. The Lewis antigen-negative status of these CA19-9 nonproducers comes from genetic polymorphisms in the FUT3 gene that impair the fucosyltransferase (FUT) activity required to produce CA19-9.
This is “clinically important because genotyping is rarely available, and Lewis-negative patients are often grouped with ‘low CA19-9’ cases, leading to an underestimation of risk,” Su et al. remark.
In 2012, a CA19-9 cut-off of five units/mL was proposed as a surrogate marker for CA19-9 nonproducers, but Su explained that this was largely an empirical observation based on clinicians noticing that Lewis-negative patients tended to exhibit extremely low baseline CA19-9 levels. It did not take genetic sequencing or genomic data into account.
Su and colleagues therefore set out to provide genomically validated evidence, by correlating CA19-9 levels directly with Lewis antigen genotypes, of a CA19-9 cutoff that would capture Lewis antigen-negative patients and better predict their prognosis.
The study included 615 patients with pancreatic ductal adenocarcinoma who underwent germline whole-exome sequencing to determine their FUT2/FUT3 genotypes.
Overall, 10.1% of participants were classified as FUT3-null, 33.0% as FUT-low, 35.6% as FUT-intermediate, and 21.3% as FUT-high.
The researchers report that median CA19-9 levels increased progressively across the FUT functional groups, from 2.4 units/mL in the FUT3-null group to 348 units/mL in the FUT-low group, 453 units/mL in the FUT-intermediate group, and 1300 units/mL in the FUT-high group.
By contrast, median overall survival (OS) was similar among the groups, at 13.5, 15.1, 14.5, and 14.3 months, respectively.
Using receiver operating characteristic analysis, Su and team identified seven units/mL as the optimal CA19-9 cutoff capable of characterizing the FUT3-null population within the clinical reference range of 37 units/mL or lower. At this cut-off, the sensitivity was 76.5% and the accuracy was 87.9%, which the researchers say represents 7.9 and 1.7 percentage point improvements, respectively, on the literature-defined threshold of five units/mL.
The investigators then grouped the patients by CA19-9 cutoff, without genotyping, and showed that OS was lower at each end of the spectrum.
Specifically, median OS was 13.5 months in participants with a CA19-9 of seven units/mL or lower, 23.2 months among those with a level of >7 to 37 units/mL, 22.0 months in those with a CA19-9 of >37 to 200 units/mL, and 12.8 months in the group with a level above 200 units/mL.
After adjusting for confounding factors, the risk for death was a significant 1.96 times higher in participants with the lowest CA19-9 levels and 1.69-fold higher in those with the highest levels, relative to individuals that had a CA19-9 of >7 to 37 U/mL.
“These data tell us that the conventional normal CA19-9 range of less than 37 units/mL does not distinguish between true low tumor burden and Lewis-negative status,” Su said.
He told Inside Precision Medicine that, at present, Lewis antigen genotyping is not standard clinical practice for pancreatic cancer patients due to added costs, turn-around times, and limited availability of routine genetic testing in many centers.
“This clinical gap is precisely why our findings are highly relevant,” Su remarked. “Because genetic testing is often unfeasible or unavailable, proposing a readily accessible serum CA19-9 cut-off (such as seven units/mL) provides clinicians with a highly feasible, cost-effective, and immediate surrogate marker to identify Lewis-negative patients using standard laboratory assays.”
He explained that robust external validation is now needed before the proposed lower cut-off can be adopted into routine clinical practice. “Because our current cohort may reflect specific regional or demographic characteristics, validating this seven U/mL cut-off in diverse cohorts—particularly in Western populations—is critical to ensure its global applicability.”
To address this, an international external validation study is currently underway.
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