A single-molecule biosensor in development could enable earlier, less invasive identification of high-risk pancreatic cysts through analysis of cyst fluid samples.
“Early detection of pancreatic cancer represents the only chance for cure of this extraordinarily aggressive disease,” Irene Esposito, MD, of the Institute of Pathology at Heinrich-Heine University and University Hospital of
Dusseldorf, Germany, and colleagues wrote in
Gastro Hep Advances. “This implies the detection and surgical resection of high-risk cystic lesions, that is,
intraductal papillary
mucinous neoplasms and
mucinous cystic neoplasms bearing high-grade dysplasia. Application of multidisciplinary guidelines has improved the detection of high-risk precursors, but the proportion of false negative and false positive cases remains high.”
To address these gaps, the authors evaluated the Single Molecule Bio-Electronic Smart System Array for Clinical Testing (SiMBiT), a novel portable diagnostic platform based on single-molecule-with-a-large-transistor (SiMoT) technology. The device is designed to detect molecular biomarkers at extremely low concentrations, delivering rapid results without the need for extensive sample processing or sequencing.
The researchers analyzed 92 liquid samples (73 pancreatic cyst fluids and 19 plasma samples) collected consecutively from 82 patients undergoing routine evaluation for newly diagnosed pancreatic cystic lesions. After applying predefined quality criteria, 79 samples from 71 patients were included in the final analysis. The researchers used a multidisciplinary approach for diagnoses, integrating clinical features, imaging, cytology or histology when available, and next generation sequencing-based cyst fluid analysis.
Among 61 cyst fluid samples, SiMBiT demonstrated strong performance for identifying mucin-producing cystic neoplasms, misclassifying only three cases. Sensitivity was 91%, specificity 99%, and both positive and negative predictive values were 95%.
Performance was higher for detecting high-grade dysplasia. All high-grade lesions in cyst fluid were correctly identified. Even when two indeterminate cases were conservatively considered false positives, sensitivity remained 100% and specificity 96%, with a negative predictive value of 100%.
In blood alone, SiMBiT achieved 100% sensitivity and 100% specificity for detection of high-grade mucin-producing neoplasms in this small cohort. If validated in larger studies, these results suggest that a simple blood test could identify patients harboring clinically significant pancreatic cysts—potentially reducing the need for invasive EUS-guided sampling in a substantial subset of patients.
“We envision the use of SiMoT technology at the point of care for cyst fluid and especially blood-based testing in patients with clinically suspicious pancreatic cysts,” the authors concluded. “The clinical decision should always occur in the context of multidisciplinary expertise, considering the still high rates of morbidity and mortality of pancreatic surgery, which would follow a positive result.”
This project has received funding from the European Union’s Horizon 2020 research and innovation program. The authors reported having no disclosures.
Author Insights
GI & Hepatology News invited study authors Irene Esposito, MD, of the Institute of Pathology, Heinrich-Heine University and University Hospital of Dusseldorf, Germany and Luisa Torsi, PhD, of the Department of Chemistry and Centre for Colloid and Surface Science, University of Bari Aldo Moro, Bari, Italy, to comment on the work.
What makes this study important, and what unmet gaps in knowledge or therapeutics does it address?
This work is important because it tackles a central bottleneck in pancreatic cancer prevention: identifying which pancreatic cystic lesions are truly high-risk (high-grade dysplasia and/or incipient cancer) early enough to enable curative intervention — while avoiding unnecessary invasive procedures and surgery for low-risk lesions. Current guideline-based management and conventional workups still leave substantial false positives and negatives, and advanced molecular approaches (e.g., broad NGS [Next Generation Sequencing] panels) can be accurate but are costly and typically restricted to specialized centers, limiting accessibility. By leveraging the Single Molecule Bio-Electronic Smart System Array for Clinical Testing (SiMBiT) prototype platform, the study addresses an unmet diagnostic gap: a rapid, portable, multiplex, minimally invasive test that can read out both genetic and protein biomarkers at the single-molecule limit-of-identification, with the design goal of keeping false positives and negatives very low, in principle below 1%.
What are the possible clinical implications of this research?
In clinical terms, the results suggest that this technology could meaningfully improve the way pancreatic cystic lesions are evaluated, particularly by enabling blood-based-test risk stratification. From a practical standpoint, the work also points toward realistic point-of-care implementation. The SiMBiT approach is based on a disposable, ELISA-like cartridge integrating 96 independent sensors, coupled to a reusable electronic reader, with a workflow designed for near-patient testing and rapid turnaround. In a related clinical study, multiplexed detection of KRASmut, MUC1, and CD55 at the single-molecule limit of identification was achieved in approximately 1.5 hours, with downstream classification supported by machine-learning analysis. This combination of sensitivity, speed, and operational simplicity distinguishes the platform from more complex molecular workflows currently confined to specialized laboratories.
What further research is needed, and what gaps in knowledge remain?
Key next steps are primarily translational and clinical in nature. Larger prospective, multi-center studies will be needed to validate these findings in well-defined patient populations, using standardized reference standards, in order to narrow confidence intervals and confirm that the performance observed to date is robust and generalizable. Equally important are longitudinal follow-up studies to determine whether patients classified as high risk truly progress to advanced disease over time, and whether those classified as low risk can be safely managed with less intensive surveillance.
Is there anything else you'd like to say about this work?
Two broader points are worth emphasizing. First, this work underscores the importance of a truly multiparametric view of disease biology. Rather than relying on a single type of biomarkers, the strategy deliberately integrates a key genomic alteration, such as KRAS with protein markers associated with malignant transformation and disease aggressiveness, including MUC1 and CD55. This combined molecular readout is designed to better reflect the biological complexity of pancreatic cystic lesions and to overcome the well-known limitations of single type-marker approaches in supporting real clinical decision-making. Second, accessibility is a core scientific and translational objective of the SiMBiT effort. From the outset, the project has aimed to translate single-molecule bioelectronic sensing into a cost-effective, portable diagnostic format with rapid time-to-result, rather than confining ultra-high sensitivity to specialized research laboratories. This focus on decentralization and practicality is intended to enable deployment in a wide range of clinical settings, including environments with limited resources, thereby broadening access to high-performance diagnostics.
The guidelines emphasize four-hour gastric emptying studies over two-hour testing. How do you see this affecting diagnostic workflows in practice?
Dr. Staller: Moving to a four-hour solid-meal scintigraphy will actually simplify decision-making. The two-hour reads miss a meaningful proportion of delayed emptying; standardizing on four hours reduces false negatives and the “maybe gastroparesis” purgatory that leads to repeat testing. Practically, it means closer coordination with nuclear medicine (longer slots, consistent standardized meal), updating order sets to default to a four-hour protocol, and educating front-line teams so patients arrive appropriately prepped. The payoff is fewer equivocal studies and more confident treatment plans.
Metoclopramide and erythromycin are the only agents conditionally recommended for initial therapy. How does this align with what is being currently prescribed?
Dr. Staller: This largely mirrors real-world practice. Metoclopramide remains the only FDA-approved prokinetic for gastroparesis, and short “pulsed” erythromycin courses are familiar to many of us—recognizing tachyphylaxis limits durability. Our recommendation is “conditional” because the underlying evidence is modest and patient responses are heterogeneous, but it formalizes what many clinicians already do: start with metoclopramide (lowest effective dose, limited duration, counsel on neurologic adverse effects) and reserve erythromycin for targeted use (exacerbations, bridging).
Several agents, including domperidone and prucalopride, received recommendations against first-line use. How will that influence discussions with patients who ask about these therapies?
Dr. Staller: Two points I share with patients: evidence and access/safety. For domperidone, the data quality is mixed, and US access is through an FDA IND mechanism; you’re committing patients to EKG monitoring and a non-trivial administrative lift. For prucalopride, the gastroparesis-specific evidence isn’t strong enough yet to justify first-line use. So, our stance is not “never,” it’s just “not first.” If someone fails or cannot tolerate initial therapy, we can revisit these options through shared decision-making, setting expectations about benefit, monitoring, and off-label use. The guideline language helps clinicians have a transparent, evidence-based conversation at the first visit.
The guidelines suggest reserving procedures like G-POEM and gastric electrical stimulation for refractory cases. In your practice, how do you decide when a patient is “refractory” to medical therapy?
Dr. Staller: I define “refractory” with three anchors.
1. Adequate trials of foundational care: dietary optimization and glycemic control; an antiemetic; and at least one prokinetic at appropriate dose/duration (with intolerance documented if stopped early).
2. Persistent, function-limiting symptoms: ongoing nausea/vomiting, weight loss, dehydration, ER visits/hospitalizations, or malnutrition despite the above—ideally tracked with a validated instrument (e.g., GCSI) plus nutritional metrics.
3. Objective correlation: delayed emptying on a standardized 4-hour solid-meal study that aligns with the clinical picture (and medications that slow emptying addressed).
At that point, referral to a center with procedural expertise for G-POEM or consideration of gastric electrical stimulation becomes appropriate, with multidisciplinary evaluation (GI, nutrition, psychology, and, when needed, surgery).
What role do you see dietary modification and glycemic control playing alongside pharmacologic therapy in light of these recommendations?
Dr. Staller: They’re the bedrock. A small-particle, lower-fat, calorie-dense diet—often leaning on nutrient-rich liquids—can meaningfully reduce symptom burden. Partnering with dietitians early pays dividends. For diabetes, tighter glycemic control can improve gastric emptying and symptoms; I explicitly review medications that can slow emptying (e.g., opioids; consider timing/necessity of GLP-1 receptor agonists) and encourage continuous glucose monitor-informed adjustments. Pharmacotherapy sits on top of those pillars; without them, medications will likely underperform.
The guideline notes “considerable unmet need” in gastroparesis treatment. Where do you think future therapies or research are most urgently needed?
Dr. Staller: I see three major areas.
1. Truly durable prokinetics: agents that improve emptying and symptoms over months, with better safety than legacy options (e.g., next-gen motilin/ghrelin agonists, better-studied 5-HT4 strategies).
2. Endotyping and biomarkers: we need to stop treating all gastroparesis as one disease. Clinical, physiologic, and microbiome/omic signatures that predict who benefits from which therapy (drug vs G-POEM vs GES) would transform care.
3. Patient-centered trials: larger, longer RCTs that prioritize validated symptom and quality-of-life outcomes, include nutritional endpoints, and reflect real-world medication confounders.
Our guideline intentionally highlights these gaps to hopefully catalyze better trials and smarter referral pathways.
Dr. Staller is with the Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston.