Tag: Medication

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Bladder Cancer: Urine Test Improves Relapse Predictions

Stanford researchers have developed a urine test that can accurately predict which patients with bladder cancer will respond to standard surgery and immunotherapy treatments. In a study published in Cell, they report that this DNA test takes into account background mutations caused by aging that existing tests may otherwise mistake for cancer. 

“Our test can detect minimal residual disease non-invasively after bladder cancer treatment, while accounting for mutations present in normal urothelium that have complicated prior studies,” said Joseph C. Liao, MD, professor of urology and senior author of the study. “For the first time, we were able to distinguish patients likely cured by [immunotherapy] from those cured by surgery.”

Even when detected in early stages, bladder cancer has a high relapse rate. Patients with non-muscle invasive bladder cancer (NMIBC), whose tumors are still confined to the inner layers of the bladder, are typically treated with surgery. Those with higher risk profiles are then given a bacillus Calmette Guerin (BCG) immunotherapy, which can significantly reduce recurrence risk after surgery. 

However, while some patients respond well to surgery without immunotherapy, others may end up relapsing even after receiving BCG immunotherapy. Until now, there was no reliable way to predict which patients will respond to each of these treatments, making it difficult for physicians and patients alike to make informed clinical decisions. 

The molecular test developed by Liao and colleagues analyzes urine tumor DNA in urine samples to detect the presence of tumor DNA and predict whether a patient will respond to standard surgery or BCG treatment. Importantly, the test was designed to account for the “field effect,” a phenomenon where even healthy people can carry cancer-associated mutations in the bladder’s lining, with these mutations becoming increasingly common as the person ages. 

“By correcting for the field effect, a known confounder of mutation-based bladder cancer detection, we improved the specificity of urine tumor DNA liquid biopsies,” said William Y. Shi, MD/PhD student at Stanford School of Medicine and lead author of the study. “This allowed us to molecularly distinguish the relative contributions of surgery and BCG to disease control.”

The researchers evaluated the urine test in a cohort of 261 NMIBC patients who underwent surgery and BCG treatment. Results revealed three distinct molecular patterns of treatment response. These included surgery responders, for whom tumor DNA disappeared after surgery; BCG responders, who showed tumor DNA after surgery that was eliminated with the immunotherapy; and non-responders who saw tumor DNA levels remain stable or even increase after both treatments. 

“The ability to distinguish responders from non-responders to the two treatments also allowed us to study which molecular properties make tumors more likely to benefit from each therapy,” said Max Diehn, MD, PhD, professor of radiation oncology and senior author of the study. 

The study also revealed distinct molecular patterns driving response to surgery and response to BCG immunotherapy. On the one hand, patients who relapsed after surgery had tumors with genetic activity linked to cell growth and invasion. On the other hand, tumors who responded to BCG had a higher mutation burden and tended to have features that made them more visible to the immune system. 

Following validation in a larger patient cohort, this urine test could help spare patients who respond well to surgery from receiving an unnecessary course of immunotherapy. In particular, BCG supply has suffered from shortages for the past decade, leaving many patients waiting for longer than necessary. In the face of shortages, a predictive test could help prioritize those who are most likely to benefit from it. 

For patients who are unlikely to respond to both surgery and BCG, the urine test could also prove valuable in escalating treatment early on. In the study, the test was able to identify recurrence risk in patients for whom routine cystoscopy exams appeared normal, meaning it could be able to detect relapse earlier than the current standard. 

“These kinds of predictive biomarkers are critical,” said Eila C. Skinner, MD, professor of urology and chair of Stanford’s Department of Urology. “We have new treatments that are costly and carry risk of side effects. We would love to personalize therapy to ensure each patient receives the best treatment for their individual cancer.”

The post Bladder Cancer: Urine Test Improves Relapse Predictions appeared first on Inside Precision Medicine.

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Gene Therapy Improves Outcomes of Nerve Graft Surgery in Mice

Researchers from Ohio State University have developed a gene therapy that promotes blood vessel growth following nerve graft surgery. A study published today in Science Advances reports a significant improvement in both nerve growth and muscle strength in treated mice. 

Peripheral nerve injury can cause long-term disability, weakness, numbness, or loss of function. While nerve grafts can help repair some of these injuries by regrowing damaged nerves and reconnecting any gaps left by the original injury, many patients still can’t fully recover mobility or feeling. 

The new approach developed at Ohio State combines traditional nerve graft surgery with a gene therapy delivered using quick electrical pulses to the nerve drafts. This technique, known as tissue nanotransfection (TNT) is used to introduce three genes (Etv2, Fli1 and Foxc2) into graft cells that promote the formation of new blood vessels. 

“This study is the first to combine TNT with nerve graft surgery,” said Daniel Gallego-Perez, PhD, professor of biomedical engineering at Ohio State and senior author of the study. “While healing nerves do need oxygen and nutrients, blood vessels do much more than just deliver supplies—they help guide and support the repair process. By helping the body quickly grow new blood vessels, our approach creates a healthier environment that allows nerves to heal more effectively.”

In a mouse model of peripheral nerve injury, mice treated with the gene therapy grew more blood vessels than those only receiving a conventional nerve graft surgery. The treatment did not just help nerves regrow and reconnect, but also improved function and general health outcomes in mice. 

“We saw improvements not just under the microscope, but in real function like stronger muscle contractions and better grip strength,” said Amy Moore, MD, chair of Ohio State’s Department of Plastic and Reconstructive Surgery and interim dean of the university’s College of Medicine. “The findings from this study advance our ability to reconstruct long nerve gaps and restore function to limbs with devastating nerve injuries.” 

Moore noted that this approach could make a significant difference when treating severe, complex nerve injuries common among military services injured in training or combat. The treatment is being developed as part of the Military Medicine Program at Ohio State, which focuses on offering surgical reconstruction and pain management care for wounded service members.  

Development of the gene therapy will continue with studies in larger animals before human trials can begin. Next, the research team plans to investigate how long the benefits of the treatment last.

This novel approach could one day become part of routine nerve graft surgery, adding a simple short step to significantly improve the outcomes of a well-established procedure. Salazar-Puerta added: “This is designed to fit into the operating room and is a single treatment that could have lasting benefits.” 

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23andMe Reports Genetic Predictors of Response to GLP-1 Drugs for Obesity

On any given morning, skyrocketing numbers of people reach for a small injection pen (and soon a pill) that, just a few years ago, was barely available outside of diabetes clinics. Drugs like semaglutide and tirzepatide have become cultural phenomena, reshaping not only medicine but also public discourse and the advertising industry around weight, metabolism, and obesity. Today, it is impossible to open a magazine, turn on the TV or radio, or walk down the grocery aisle without encountering some form of advertisement for these GLP-1 receptor agonists (GLP-1RAs). 

Almost any individual in the United States can obtain a subscription to a GLP-1RA without having to visit a doctor’s office. Just visit Hims/Hers, Ro, or Noom and answer a few questions about weight, height, goals, and concerns to get a prescription. (One such site claims it is taking weight and height data and “combining with clinical data,” whatever that means, before presenting a plan and steps for ordering a prescription.) 

But there are some major problems, one being that these drugs don’t work uniformly. Some patients respond to GLP-1RAs almost immediately, reporting diminished cravings within days. Others see little change. Side effects, too, can vary dramatically, from mild discomfort to debilitating nausea and vomiting. The spread of outcomes is wide and not fully understood. 

Before blindly beginning to take a drug that, on the one hand, has seemingly miraculous effects and, on the other hand, might cause serious side effects like pancreatitis, gallbladder disease, and kidney failure, wouldn’t prescribers and prescription seekers want to know this information? 

A study published in Nature Medicine by the 23andMe Research Institute—the new nonprofit entity founded by the company’s co-founder, Anne Wojcicki, for $305 million to replace the bankrupt biotechnology company—suggests the answer may be found, at least in part, in something far more fundamental than diet or willpower: our genes. 

In speaking with Inside Precision Medicine for the first time since the company filed for bankruptcy and was resold to the nonprofit public benefit corporation, Adam Auton, PhD, vice president of Human Genetics at the 23andMe Research Institute, said, “The ‘GLP-1s’ have completely transformed weight loss management. A huge fraction of the population is benefiting. It’s a very natural question: Are people’s experiences on GLP-1s modulated by genetics?”  

The short answer is, yes. Auton and 23andMe Research Institute scientists have provided genetic evidence that variation in drug target genes contributes to variability in response among individuals, laying the groundwork for consumer-based precision medicine approaches to obesity treatment and beyond. 

Crowd-sourcing GLP-1 genetics 

To better understand why responses to GLP-1 receptor agonists vary so widely, the 23andMe Research Institute team leveraged its uniquely large and engaged research cohort. Over the past decade, the company has assembled genetic data from more than 15 million participants who consented to research, enabling analyses that would be difficult in traditional clinical trials. Immediately following the company’s filing for bankruptcy in March 2025, 23andMe reported that over 1.9 million users requested for their data to be deleted. Auton told Inside Precision Medicine that the current number of consented customers is around 11 million. 

Building on this resource, Auton and colleagues launched a targeted survey asking participants detailed questions about their GLP-1 drug use, including medication type, duration, dosage, weight loss, and side effects. More than 27,885 customers responded, providing a rich, real-world dataset. “That’s the power of having a large, engaged cohort,” said Auton. “You can ask a question and very rapidly get meaningful data back.”

Using these data, Auton and colleagues conducted a genome-wide association study (GWAS), scanning millions of genetic variants to identify those associated with treatment outcomes. “You’re starting with the entire genome,” Auton explained. “You’re testing every variant for correlation with the trait of interest. And when you see a signal, it tends to be overwhelming.”  

The team focused on two primary traits: weight loss and the presence of side effects. The strongest association emerged in GLP1R, the gene encoding the GLP-1 receptor—the direct target of these drugs. A missense variant, rs10305420, was linked to significantly greater weight loss, with each copy associated with an additional 0.76 kilograms lost.  

“It made very clear biological sense,” Auton said. “This is the receptor that the drug is acting on.” The missense variant may affect how much receptor is expressed on the cell surface, meaning individuals with more receptors could experience a stronger response to the same dose. 

A second key finding involved a substitution in GIPR (rs1800437; p.Glu354Gln), which encodes the receptor for glucose-dependent insulinotropic polypeptide and is targeted by dual agonists such as tirzepatide. Unlike the GLP1R result, this association was not related to weight loss but to drug tolerability. Carriers of the variant were more likely to report nausea and vomiting—but only when taking medications that act on the GIP receptor. No such effect was observed among users of semaglutide, which does not target GIPR.  

“It was very, very clean,” Auton said. “We saw this effect specifically in people taking the medications that actually target that receptor.”  

Together, these findings underscore a central principle of pharmacogenetics: genetic variation can shape not only whether a drug works, but also how it is experienced, often in highly drug-specific ways. 

Who is represented 

One of the study’s more unconventional aspects is its reliance on self-reported data, a method sometimes viewed with skepticism in clinical research given the limits of memory and potential inaccuracies in reporting weight loss or medication use. Anticipating this concern, scientists at the 23andMe Research Institute validated their findings using a subset of participants who also shared electronic health records (EHRs), enabling direct comparison between self-reported and clinically recorded data.

The results were reassuring: survey-reported weight loss closely tracked with medical records, and medication histories aligned well across both sources. Although participants tended to slightly overestimate weight loss, they also reported longer treatment durations, effects that largely offset each other. Importantly, the genetic associations remained robust under independent scrutiny, with replication in the All of Us Research Program, a large, federally funded dataset based on clinical records rather than self-report. 

While weight loss is the headline feature of GLP-1RAs, side effects often determine whether patients persist with treatment. Nausea, vomiting, and gastrointestinal discomfort are among the most common reasons for discontinuation, yet they are frequently underreported in traditional clinical datasets. EHRs may document when a medication is stopped but rarely capture why. Self-reported data addresses this gap by directly capturing patient experience. 

“We were able to ask people directly about their experiences,” Auton said. “That’s something that’s often missing from clinical datasets.” By linking these experiences to genetic variation, the study enables a more refined understanding of drug tolerability, moving beyond population averages to individualized risk profiles. 

As with many large-scale genetic studies, statistical power was greatest among individuals of European ancestry, reflecting broader imbalances in genomic datasets. However, the key findings were consistent across multiple ancestral groups, supporting their generalizability.

“We’re not seeing fundamentally different genetic effects across populations,” Auton said. Still, increasing diversity in genetic research remains essential to ensure equitable advances in precision medicine. As digital tools continue to integrate genetic, clinical, and self-reported data, this participant-driven model may play an increasingly central role in biomedical discovery. 

Putting pharmacogenomics in patients’ hands 

Identifying genetic variants is only the first step, of course. The larger goal is to translate those discoveries into tools that can guide real-world decisions. To that end, the 23andMe Research Institute scientists developed predictive models that combine genetic information with clinical factors to estimate treatment outcomes. 

The vision is straightforward: before starting a GLP-1 drug, a patient could receive a personalized profile indicating likely weight loss and risk of side effects. “People are making decisions about whether these medications are right for them,” Auton said. “Can we give them information to help with that decision?” 

Such tools could have immediate clinical applications. A patient with a high predicted risk of nausea, for example, might start at a lower dose or follow a slower titration schedule. Another with a favorable genetic profile might be reassured about expected benefits. 

For now, these findings are unlikely to immediately change prescribing practices, as clinical guidelines will require further validation through prospective studies. However, the trajectory is clear. In the near future, patients considering GLP-1 therapies may undergo genetic testing as part of routine care, with treatment decisions—such as drug choice, dosing, and expectations—guided in part by their DNA. For a class of drugs already transforming millions of lives, this approach could further enhance both efficacy and tolerability, underscoring that responses to GLP-1 therapies are shaped not only by pharmacology but also by the subtle variations of the human genome. 

The broader significance of the study lies in its contribution to precision medicine: the idea that treatments should be tailored to individual biology rather than applied uniformly. In fields like oncology, this approach is already standard. But precision obesity treatment is in far earlier stages.  

Auton is quick to re-emphasize that genetics is only one piece of the puzzle. Lifestyle, environment, treatment adherence, and underlying health conditions all shape outcomes. Still, even a partial predictive signal could be transformative in a field where trial-and-error prescribing is common. 

As researchers continue to study GLP-1RAs, their potential appears to extend far beyond weight and blood sugar. Early evidence suggests benefits in cardiovascular health, inflammation, and even neurological conditions. Some studies are exploring their role in addiction and compulsive behaviors. “There’s an increasing literature that they’re beneficial in multiple areas,” Auton said. 

This expanding scope makes understanding variability even more important. If GLP-1 drugs are to be used to treat a wide range of conditions, predicting who will benefit and who may be at risk becomes one of the most important, if not the most important, challenges.

What about sequencing? 

Throughout our conversation, there was at least one elephant in the room. One is that this is not the first study to identify genetic variants influencing responses to GLP-1 drugs, as prior research has also implicated rs10305420. Slovenian researchers showed that genetic variability in GLP1R is associated with inter-individual differences in the weight-lowering-lowering potential of GLP-1 drugs in obese women with polycystic ovary syndrome (PCOS) in 2015, at a time when the main GLP-1 drug was liraglutide, which required daily injection.

More provocative is that the directionality of the variants’ effect reported in the Nature Medicine paper is the opposite of these previous studies. Auton’s team writes that such discrepancies may stem from differences in disease context, smaller sample sizes, limited statistical power, and variations in drug type, cohorts, and analytical methods.

Additionally, the GIPR variant rs1800437 (p.Glu354Gln) is already a known partial loss-of-function mutation, previously identified in a study of Chinese type 2 diabetes patients in 2019. 

Perhaps the more significant issue is the question of sequencing. It’s not a space that 23andMe has completely avoided, as their premier consumer kit employs exome sequencing. But the cost of whole genome sequencing (WGS) direct-to-consumer products is now often priced lower than 23andMe’s premier kit, which goes for $499. 

When asked about employing WGS, Auton revealed little of the calculus behind why 23andMe hasn’t added WGS to its arsenal of tools for interrogating genomes. “We’re very excited about that space,” Auton said. “Our focus has always been on what we can do in a direct consumer framework. There’s always been a price question there for WGS. It’s great. But when it was $1,000, it wasn’t obvious that that was going to be a compelling consumer offering. The pricing has reached its current level. It’s an area we’re very excited about and we’ll continue to look at.”

With studies like this, 23andMe 2.0 is making a case, perhaps its strongest yet, that its true value lies in something far more consequential: the ability to predict how individuals will respond to medicine before they ever take it. If that vision holds, the implications extend well beyond GLP-1 drugs. It suggests a future where prescribing a medication without first consulting a patient’s genetic profile feels incomplete, even irresponsible. 

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Smart Contact Lens Offers Glaucoma Treatment Potential

A “smart contact lens” can monitor eye pressure and manage and release glaucoma drugs to counteract any rises in this, preclinical research suggests.

The all-polymer, microfluidic lens, described in Science Translational Medicine, represents further progress towards personalized eye technologies in a “theranostic” approach that combines diagnostics and therapy.

The battery-free device was able to monitor intraocular pressure—the most prominent, modifiable risk factor for glaucoma—and could release glaucoma drugs timolol and brimonidine at pressure thresholds in animal studies.

The device could one day provide frequent, real-time pressure monitoring with responsive drug release for patients at home, offering an alternative to the infrequent gold-standard measurements in the office, which only occur every six to 12 months.

“This electronic- and power-free device combines softness, optical transparency, biocompatibility, and cost-effectiveness, offering a noninvasive approach to continuously monitor IOP and deliver individualized therapy,” reported Yuting Cai, PhD, from Hong Kong University of Science and Technology, and co-workers.

They added: “Beyond glaucoma, the platform is compatible with commercial soft contact lenses and can be reconfigured to monitor additional tear biomarkers, enabling a wider range of ocular care applications.”

Biosafety assessment of AP-TSCL-Timo and AP-TSCL-Pro after two weeks of wear [Yangzhi Zhu, Terasaki Institute for Biomedical Innovation]

Glaucoma is often referred to as the “silent thief of sight” and is the leading cause of irreversible blindness worldwide.

Its prevalence is predicted to increase sharply due to aging populations, rising from 80 million people in 2020 to around 134 million in 2040.

Although it is progressive and incurable, early diagnosis and treatment can preserve vision and maintain quality of life, although this requires reliable tools to identify those at risk and deliver therapies.

While smart contact lenses represent a promising platform to deliver this, the need to embed electronics, power sources, and manufacturing costs represent potential barriers in terms of patient comfort and accessibility.

To address this, the team developed an all-polymer theranostic smart contact lens (AP-TSCL) capable of continuously measuring intraocular pressure with autonomous programmable drug delivery without the need for bulky electronic components or manual operation.

The lens integrates a noninvasive, real-time microfluidic sensor that measures intraocular pressure together with a multidose, feedback-responsive drug release unit.

A biomimetic silk sponge enhances both its sensing sensitivity and the consistency of drug delivery, providing high mechanical robustness and operates well over a physiological pressure range of 16 to 32 mmHg.

By coupling the intraocular pressure readout with pressure-gated drug release, the platform is designed to enhance therapeutic efficacy while reducing unnecessary exposure under normotensive conditions. This may help mitigate ocular irritation and systemic side effects associated with conventional topical β-blockers in susceptible patients, the authors explain.

Comprehensive in vitro, ex vivo studies in cow eyes, and in vivo studies in rabbits validated its biocompatibility, accuracy, and therapeutic efficacy, demonstrating its potential as a low-cost, patient-compliant platform for personalized glaucoma therapy in real-world settings.

“This power- and electronic-free SCL represents a remarkable advancement toward multifunctional ocular medical devices that integrate diagnostics and therapeutics for intelligent ocular health care delivery,” the research team maintained.

“It lays the groundwork for developing a family of pharmacy-on-a-contact-lens tools capable of delivering clinically relevant information about human health and establishes the foundation for next-generation, self-powered, electronic-free SCLs capable of accessible diagnosis and therapeutics.”

 

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Smart contact lens monitors eye pressure and delivers glaucoma drugs in early tests

Glaucoma is the second-leading cause of blindness, and a silent one at that. It’s estimated that half of the patients who develop it are unaware of their condition, as they lose peripheral vision only when the disease is more advanced, and the damage is irreversible. 

There isn’t a cure, and while medication can control hypertension in the eye to slow or stop further damage to the optical nerve, it has shortcomings. 

Read the rest…

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Smart MRI Agents Combine Cancer Imaging and Therapy in Single Platform

Researchers at NYU Abu Dhabi have developed manganese-based molecules that combine cancer detection and treatment within a single system, allowing for simultaneous imaging and therapy using magnetic resonance imaging (MRI). The research, published in the Journal of the American Chemical Society, details the development of metal–organic structures that remain stable in healthy tissue but become active within the tumor microenvironment, where they both enhance MRI contrast and induce cancer cell death.

“Our goal was to create materials that allow doctors to see cancer clearly and treat it at the same time,” said lead author Farah Benyettou, PhD, a research scientist at NYU Abu Dhabi. “The ability to image and target brain tumors with high precision is particularly exciting.”

The molecules the researchers developed are composed of manganese ions coordinated with organic frameworks arranged into interlocked topologies. Unlike conventional drugs, which are small and relatively simple, these molecules have interlocked structures that resemble knots and rings. This design allows them to behave differently inside the body, improving both imaging and therapeutic performance.

“Manganese (Mn)-based metal–organic architectures offer a unique avenue for integrating magnetic resonance imaging (MRI) and cancer therapy within a single molecular platform,” the researchers wrote. The geometrical complexity and electropositive, pH-labile coordination framework allow the molecules to remain intact in normal tissue but disassemble when exposed to the acidic tumor microenvironment.

This pH-responsive behavior is the key to their dual function. In healthy tissue, the molecules maintain stability and limit off-target effects. Once inside tumors, where acidity is elevated, they release Mn2+ ions. These ions enhance T1-weighted MRI signals, making tumors more visible, while also triggering biological pathways that lead to cancer cell death. The researchers wrote that this process culminates in “lysosomal acidification, pH-triggered disassembly, Mn2+ release, ROS accumulation, and caspase-dependent apoptosis,” marrying their imaging capability directly to therapeutic action.

The novel molecule design builds on prior prior research of manganese-based imaging agents and topological chemistry. The researchers noted that conventional gadolinium-based contrast agents have safety limitations, including toxicity and accumulation in tissues, while earlier manganese agents lacked stability and tumor targeting. “These drawbacks underscore the need for next-generation Mn platforms with enhanced stability and tumor specificity,” the researchers wrote. In previous studies, the NYU Abu Dhabi researchers had demonstrated that metal-templated trefoil knots could induce apoptosis in drug-resistant cancer cells, a finding that spurred their efforts to integrate therapeutic activity with an imaging agent.

To evaluate the new molecules, the team conducted both in vitro and in vivo experiments, focused on glioblastoma. In cell studies, Mn-TK and Mn-BR showed selective toxicity toward cancer cells while sparing normal cells. In animal models, the molecules accumulated in tumors, produced strong MRI contrast, and inhibited tumor growth.

An important finding of the study was data that showed both Mn-TK and Mn-BR were able to cross the blood–brain barrier and accumulate in glioblastoma tumors. This has traditionally been a major limitation of MRI contrast agents, which often fail to image tumors in the brain.

The implications for clinical care include the potential to replace separate diagnostic and therapeutic steps with a single intervention. By combining imaging and treatment, the molecules could provide earlier detection, more accurate tumor delineation, and targeted therapy with reduced side effects. The manganese-based design may also offer a safer alternative to gadolinium, which could produce long-term retention and toxicity.

“This work introduces a generalizable strategy for designing manganese-based theranostic agents by integrating topological coordination chemistry with tunable lipophilicity and electrostatics,” the researchers noted, adding that this method could be used to develop additional agents tailored to different cancers or imaging needs.

Next steps for the team include further evaluation of safety, optimization of molecular design, and studies to support clinical translation. The researchers identify Mn-TK and Mn-BR as leading candidates due to their combination of tumor targeting, imaging performance, and therapeutic activity. Continued work will likely focus on refining these properties and assessing their performance in additional disease models.

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The Parafascicular Role in Updating Action from a Spatial to a Visual Strategy Is Driven by Its Glutamatergic Mesencephalic Locomotor Region Inputs

The ability to update actions depends on the thalamus’s parafascicular nucleus (PF); however, which PF’s inputs control this function is unknown. Here, using fiber photometry, retrograde labeling, ex vivo electrophysiology, and optogenetic manipulations, we identify the contribution of the PF and its glutamatergic inputs to the update from a spatial to a visually guided strategy in a set-shifting task conducted in mice (of either sex). Our results show the following: (1) GCaMP signals from the PF recorded along the update from a spatial to a visual strategy correlate with the probability of selecting the correct action based on a light stimulus. (2) Optogenetic inhibition of the PF during this update decreases the probability of selecting the correct action. (3) The mesencephalic locomotor region (MLR) was found to have the highest probability of synaptic connections with the PF. (4) GCaMP recordings from the MLR->PF input support it as a main driver in allowing the PF update function. (5) Inhibition of the MLR->PF connection decreases the probability of updating the contingency. These findings identify the inputs from the MLR as a crucial driver of the PF’s role in controlling the update of actions.

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Lung Screening Incidental Findings May Guide Follow-Up for Other Cancers

An analysis of the US National Lung Screening Trial (NLST) has found that the presence of certain types of abnormalities in regions outside of the lungs on low-dose computed tomography (LDCT) images may be associated with a significantly increased risk for extrapulmonary cancer.

The abnormalities, termed significant incidental findings (SIFs), could help clinicians decide when follow-up care is likely to catch extrapulmonary cancer early and when it may not be necessary.

“In this paper, we provide an evidence base for making decisions on abnormalities outside of the lungs that might be seen at lung screening,” said study author Ilana Gareen, PhD, a professor of epidemiology at Brown University School of Public Health. “The goal is to give physicians and patients better data so that they can make more informed choices about those abnormalities that should be considered for follow-up and those that most likely can be ignored.”

Writing in JAMA Network Open, Gareen and co-authors explain that LDCT lung cancer screening frequently detects SIFs unrelated to lung cancer; in the NLST, 34% of 26,455 patients screened with LDCT had SIFs reported but the nature of the SIFs varied.

And although there are recommendations for reporting and addressing SIFs, there is limited evidence for an association between SIFs detected at LDCT lung cancer screening and extrapulmonary cancer diagnoses.

To address this, Gareen and team analyzed data from 75,104 LDCT screening rounds performed in 26,445 individuals (mean age, 61 years; 59.0% men) who were randomly assigned to receive LDCT during the NSLT. The participants had a history of heavy smoking (≥30 pack–years), meaning they are also at high risk for several extrapulmonary cancers, including pancreatic, bladder, and kidney cancer.

The researchers focused on SIFs that were labelled as potentially indicative of extrapulmonary cancer (cancer SIF), rather than those that possibly indicated emphysema or cardiovascular disease.

They report that cancer SIFs were recorded for 2265 (3.0%) screening rounds in 1807 (6.8%) participants across the three screening rounds they received.

Participants with cancer SIFs were significantly older than those with no cancer SIF (mean 62.1 vs. 61.4 years) and significantly more likely to have a history of a smoking-related disease (68.6 vs. 65.7%).

Within one year of a screening round, 1025 participants were diagnosed with an extrapulmonary cancer. Of these, 67 (6.5%) had a SIF on LDCT. This corresponds to 3.0% of participants with a cancer SIF.

Overall, the risk for extrapulmonary cancer among the people with a cancer SIF was 29.6 per 1000 screening rounds compared with 13.3 per 1000 screening rounds in those without a cancer SIF. After adjustment for potential confounders, the marginal risk difference between the two groups was 13.9 per 1000 participants, suggesting that for every 1000 people screened, the presence of a cancer SIF is associated with 13.9 additional cases of extrapulmonary cancer.

When the researchers looked at specific cancer types, they found that the marginal risk difference was substantially higher for urinary cancers, at 17.0 per 1000 participants. It was 5.0 for digestive cancer, 12.3 for breast cancer, and 13.8 for other cancers including lymphoma and leukemia.

“In general, if an abnormality is found that might indicate cancer, the patient receives additional imaging to evaluate that abnormality,” Gareen told Inside Precision Medicine. “Our paper provides additional information as to those abnormalities that should be considered to increase the risk of a cancer diagnosis.”

Importantly, mortality from extrapulmonary cancer accounted for 22.3% of the certified deaths in the LDCT arm of the NLST. Therefore “early detection of these cancers may facilitate early treatment and potentially reduce associated morbidity and mortality,” the authors write. “Identification of cancer SIFs associated with extrapulmonary cancers in NLST participants could be used to plan appropriate diagnostic evaluations for patients undergoing lung cancer screening.”

Gareen said the next step will be to determine if the findings are replicated in lung screening in the community, or if the rate in community screening is higher or lower.

In accompanying comment, Patrick Senior and Andrew Creamer, both from Gloucestershire Hospitals NHS Foundation Trust, in Gloucester, United Kingdom, point out that the false positive rate for a cancer SIF was 97% but say “it is hard to imagine a scenario in which an incidental finding with even a possibility of representing cancer would be disregarded.”

However, they note that “when considered in the context of the numbers of people eligible for lung cancer screening programs around the world, acting on such findings poses a considerable additional burden on the health systems that must investigate them.”

Senior and Creamer say that the results “underscore the importance of both a robust health economics analysis of how screening programs manage such incidental findings and patient-centered research to understand the impact that such unexpected results may have on the individual. Further research is needed to ensure that screening programs are confident when faced with information they did not ask for.”

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Neurocrine Grows in Endocrinology, Rare Disease with $2.9B Soleno Buyout

Neurocrine Biosciences has agreed to acquire Soleno Therapeutics for $2.9 billion, the companies said, in a deal designed to bolster the buyer’s portfolio of marketed endocrinology and rare disease therapies.

“This transaction will advance Neurocrine’s mission to deliver life-changing treatments while accelerating our revenue growth and portfolio diversification strategy,” Kyle W. Gano, PhD, Neurocrine’s CEO, said in a statement.

The acquisition would bolster Neurocrine’s offerings to include three treatments that have already reached the market:

  • Crenessity® (crinecerfont), a treatment of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency that received FDA approval in December 2024
  • Ingrezza® (valbenazine), a vesicular monoamine transmitter 2 (VMAT2) drug approved in 2017 as a treatment for tardive dyskinesia and the chorea associated with Huntington’s disease
  • Vykat™ XR (diazoxide choline), approved last year as the first and only therapy indicated to treat hyperphagia in patients ages four and older with Prader-Willi syndrome (PWS).

“Neurocrine is the right strategic partner to expand the reach of Vykat XR in the Prader-Willi syndrome community given their experience in endocrinology and rare disease and their proven ability to execute successful commercial launches,” stated Anish Bhatnagar, MD, Soleno’s chairman and CEO. “We are excited to accelerate Vykat XR’s impact for PWS patients following completion of the transaction by leveraging Neurocrine’s strong commercial capabilities.”

Soleno finished 2025 with $190.4 million in net revenue from sales of Vykat XR—including $91.7 million generated during the fourth quarter, pushing the company to profitability with positive net income of $20.9 million.

‘A little surprising’

Stifel analysts Paul Matteis and James Condulis called the planned acquisition “a little surprising” since Vykat XR is projected to garner approximately $400 million in annual net revenue, he commented in a note reported by Bloomberg News.

Vykat XR won FDA approval in March 2025. From then through December 31, 859 active patients were prescribed the drug by 630 unique prescribers (136 of them in Q4), while the company received 1,250 patient start forms (207 in Q4).

Neurocrine expects Vykat XR’s numbers to improve in coming years, since the drug is positioned as a foundational first-line therapy for PWS and is supported by a patent portfolio that is expected to protect the drug’s exclusivity into the mid-2040s.

Vykat XR would join Neurocrine’s marketed portfolio which includes Ingrezza and Crenessity. Ingrazza racked up blockbuster net revenue numbers of $2.51 billion up 9% year-over-year (including $657.5 million during Q4, up 7% from the year-ago quarter). Neurocrine has credited double-digit prescription volume growth in total prescriptions and new (first-time) prescriptions, partially offset by a lower net price that the company called new “formulary access investments” designed to support long-term growth.

Crenessity generated $301.2 million in net product sales last year for Neurocrine, including $135.3 million in the fourth quarter, reflecting 2,048 total new patient enrollment start forms, 431 of them in Q4 2025.

Neurocrine reasons that the three drugs will deliver sustained revenue growth for the combined company through the end of the decade.

Also for Neurocrine, a buyout of Soleno presents a “more sensible way into metabolic disease” than by developing its own pipeline candidates, which are in preclinical phases, and risking competitive and regulatory challenges, BMO Capital Markets analyst Evan Seigerman observed in a research note reported by Reuters.

Neurocrine has disclosed plans to begin Phase I studies this year for two preclinical obesity candidates: NBIP-‘2118, a CRF2 agonist; and ‘NBIP-‘1968, a combination of ‘2118 and the company’s own GIP (glucose-dependent insulinotropic polypeptide)/ GLP-1 (glucagon-like peptide-1) preferring triple agonist, which Neurocrine calls “light” on glucagon activity.

News of a potential buyout of Soleno by Neurocrine was first reported Sunday by the Financial Times.

Soleno investors signaled approval of the buyout Monday by sending shares to $52.25, up 32% from Thursday’s close of $39.49 (Markets were closed Friday for Good Friday). However, Neurocrine’s investors weren’t as supportive of the deal as that company’s shares barely budged, closing at $132.48, up 0.67% from $131.60 on Thursday.

Second thoughts?

A potential reason: Neurocrine investors may have second thoughts about a deal that would add to its pipeline Vykat XR, whose prescribing label includes warnings and precautions about past reports of hyperglycemia and fluid retention/edema, as Sumant Kulkarni, a senior analyst covering biotechnology with Canaccord Genuity, commented in a research note.

“We believe NBIX would have to articulate its plans very well for investors to display enthusiasm from the get-go,” Kulkarni wrote.

Yet two things could work in Neurocrine’s favor, Kulkarni added: The company’s solid track record of commercialization as seen with Ingrezza and Crenessity, and the prospect of adding to the portfolio Vykat XR given its approval for a rare form of obesity.

San Diego-based Neurocrine reported approximately 2,000 employees as of December 31, 2025, with plans during the first quarter to complete the expansion of sales teams for Ingrezza and Crenessity “to maximize our commercial momentum.” Soleno is based in Redwood City, CA, and reported a workforce of 182 full-time employees as of the end of 2025.

At $53 per share cash, the purchase price represents a premium of about 34% above Soleno’s closing share price Thursday, and a premium of 51% to Soleno’s 30-day volume-weighted average price (VWAP).

The boards of both Neurocrine and Soleno have approved the transaction, which is expected to close within 90 days subject to satisfying customary closing conditions that include receipt of regulatory approvals.

Neurocrine will acquire Soleno by launching a tender offer for that company’s outstanding shares. Following a successful completion of the tender offer, a wholly owned subsidiary of Neurocrine will merge with Soleno, and the outstanding Soleno shares not tendered in the offer will be converted into the right to receive the same $53 per share in cash paid in the tender offer.

Consummation of the tender offer is subject to the tender of at least a majority of the outstanding shares of Soleno, the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, and other customary conditions.

Neurocine said it will fund its acquisition of Soleno using a “modest amount” of pre-payable debt plus cash on hand. Neurocrine reported $1.48 billion in cash, cash equivalents, and marketable securities as of December 31, 2025—up 37.5% from $1.076 billion a year earlier.

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