Major Liver Research Articles

Higher Postoperative Mortality and Inferior Survival After Right-Sided Liver Resection for Perihilar Cholangiocarcinoma: Left-Sided Resection is Preferred When Possible.

A right- or left-sided liver resection can be considered in about half of patients with perihilar cholangiocarcinoma (pCCA), depending on tumor location and vascular involvement. This study compared postoperative mortality and long-term survival of right- versus left-sided liver resections for pCCA. Patients who underwent major liver resection for pCCA at 25 Western centers were stratified according to the type of hepatectomy-left, extended left, right, and extended right. The primary outcomes were 90-day mortality and overall survival (OS). Between 2000 and 2022, 1701 patients underwent major liver resection for pCCA. The 90-day mortality was 9% after left-sided and 18% after right-sided liver resection (p<0.001). The 90-day mortality rates were 8% (44/540) after left, 11% (29/276) after extended left, 17% (51/309) after right, and 19% (108/576) after extended right hepatectomy (p<0.001). Median OS was 30 months (95% confidence interval [CI] 27-34) after left and 23 months (95% CI 20-25) after right liver resection (p<0.001), and 33 months (95% CI 28-38), 27 months (95% CI 23-32), 25 months (95% CI 21-30), and 21 months (95% CI 18-24) after left, extended left, right, and extended right hepatectomy, respectively (p<0.001). A left-sided resection was an independent favorable prognostic factor for both 90-day mortality and OS compared with right-sided resection, with similar results after excluding 90-day fatalities. A left or extended left hepatectomy is associated with a lower 90-day mortality and superior OS compared with an (extended) right hepatectomy for pCCA. When both a left and right liver resection are feasible, a left-sided liver resection is preferred.

Weighing the outcomes: the role of BMI in complex robotic esophageal and hepatobiliary operations.

The correlation between body mass index (BMI) and surgical outcomes has emerged as a critical consideration in complex abdominal operations. While elevated BMI is often associated with increased perioperative risk, its specific effects on the outcomes of robotic surgeries remain inadequately explored. This study assesses the impact of BMI on perioperative variables of complex esophageal and hepatopancreaticobiliary (HPB) robotic operations. Following IRB approval, we prospectively followed 607 patients undergoing pancreaticoduodenectomy, trans-hiatal esophagectomy (THE), major liver resection or distal pancreatectomy with splenectomy, all performed robotically. Perioperative data retrieved included operative duration, estimated blood loss (EBL), intraoperative and postoperative complications, conversions to an 'open' operation and length of stay (LOS). Z scores were assigned to each variable to standardize operations, and the variables were then regressed against BMI. For illustrative purposes, data are presented as median(mean ± standard deviation). Between 2012 and 2020, surgeries included 71 THE, 122 distal pancreatectomies with splenectomies, 129 major hepatectomies and 285 pancreaticoduodenectomies. Median age was 67(65 ± 12.5) years old, and BMI was 27(28 ± 5.5) kg/m2. Operative duration for all operations was 349(355 ± 124.5) min and had a positive correlation with increasing BMI (p = 0.004), specifically for robotic THE and robotic pancreaticoduodenectomy, with both operative durations having positive correlation with increasing BMI (p = 0.02 and p = 0.05). No significant correlation with BMI was found for EBL, intraoperative or postoperative complications, conversion to 'open' surgery, or LOS. Elevated BMI is associated with longer operative durations in select robotic surgeries, such as trans-hiatal esophagectomy and pancreaticoduodenectomy, and highlights the need for strategic planning in these patients.

Incidence of incisional hernia following liver surgery for colorectal liver metastases. Does the laparoscopic approach reduce the risk? A comparative study.

No reports to compare incisional hernia (IH) incidence between laparoscopic and open colorectal liver metastases (CRLM) resections have previously been made. This is the first comparative study. Single-center retrospective review of patients who underwent CRLM surgery between January 2011 and December 2018. IH relating to liver surgery was confirmed by computed tomography. Patients were divided into laparoscopic liver resection (LLR) and open liver resection (OLR) groups. Data collection included age, sex, presence of diabetes mellitus, steroid intake, history of previous hernia or liver resection, subcutaneous and peri-renal fat thickness, preoperative creatinine and albumin, American Society of Anesthesiologists (ASA) score, major liver resection, surgical site infection, synchronous presentation, and preoperative chemotherapy. Two hundred and forty-seven patients were included with a mean follow-up period of 41 ± 29 months (mean ± standard deviation). Eighty seven (35%) patients had LLR and 160 patients had OLR. No significant difference in the incidence of IH between LLR and OLR was found at 1 and 3 years, respectively ([10%, 19%] vs. [10%, 19%], p = 0.95). On multivariate analysis, previous hernia history (hazard ratio [HR], 2.22; 95% confidence interval [CI], 1.56-4.86) and subcutaneous fat thickness (HR, 2.22; 95% CI, 1.19-4.13) were independent risk factors. Length of hospital stay was shorter in LLR (6 ± 4 days vs. 10 ± 8 days, p < 0.001), in comparison to OLR. In CRLM, no difference in the incidence of IH between LLR and OLR was found. Previous hernia and subcutaneous fat thickness were risk factors. Further studies are needed to assess modifiable risk factors to develop IH in LLR.

Hospital variation and outcomes after repeat hepatic resection for colorectal liver metastases: a nationwide cohort study

BackgroundApproximately 70% of patients with colorectal liver metastases (CRLM) experiences intrahepatic recurrence after initial liver resection. This study assessed outcomes and hospital variation in repeat liver resections (R-LR). MethodsThis population-based study included all patients who underwent liver resection for CRLM between 2014 and 2022 in the Netherlands. Overall survival (OS) was collected for patients operated on between 2014 and 2018 by linkage to the insurance database. ResultsData of 7479 liver resections (1391 (18.6%) repeat and 6088 (81.4%) primary) were analysed. Major morbidity and mortality were not different. Factors associated with major morbidity included ASA 3+, major liver resection, extrahepatic disease, and open surgery. Five-year OS after repeat versus primary liver resection was 42.3% versus 44.8%, P = 0.37. Factors associated with worse OS included largest CRLM >5 cm (aHR 1.58, 95% CI: 1.07–2.34, P = 0.023), >3 CRLM (aHR 1.33, 95% CI: 1.00–1.75, P = 0.046), extrahepatic disease (aHR 1.60, 95% CI: 1.25–2.04, P = 0.001), positive tumour margins (aHR 1.42, 95% CI: 1.09–1.85, P = 0.009). Significant hospital variation in performance of R-LR was observed, median 18.9% (8.2% to 33.3%). ConclusionSignificant hospital variation was observed in performance of R-LR in the Netherlands reflecting different treatment decisions upon recurrence. On a population-based level R-LR leads to satisfactory survival.

Short-term outcomes of laparoscopic extended hepatectomy versus major hepatectomy: a single-center experience

IntroductionLaparoscopic major hepatectomy (LMH) remains restricted to a few specialized centers and poses a challenge to surgeons performing laparoscopic resections. Laparoscopic extended resections are even more complex and rarely conducted. MethodsFrom a single-institution database, we compared the short-term outcomes of patients who underwent major and extended laparoscopic resections, stratifying the entire retrospective cohort into four groups: right hepatectomy, left hepatectomy, right extended hepatectomy, and left extended hepatectomy. Patient demographics, tumor characteristics, operative variables, and especially postoperative outcomes were evaluated. Results250 patients underwent major and extended laparoscopic liver resections, including 160 right, 31 right extended, 36 left, and 23 left extended laparoscopic hepatectomies. The most common indication for resection was colorectal liver metastases (64%). Laparoscopic extended hepatectomy (LEH) showed significantly longer operative time, more blood loss, need for Pringle maneuver, conversion to open surgery, higher rates of liver failure, postoperative ascites, and intra-abdominal hemorrhage, R1 margins and length of stay when compared with the LMH group. Mortality rates were similar between groups. Multivariate analysis revealed intraoperative blood transfusion (OR = 5.1[CI-95%: 1.15–6.79]; p = 0.02) as an independent predictor for major complications. ConclusionsLEH showed to be feasible, however with higher blood loss and significantly associated to major complications.

Discovery of 2,9-diaryl-6-carbamoylpurines as a novel class of antitubercular agents

A series of novel 9-alkyl/aryl-2-aryl-6-carbamoylpurines were synthesized, and their activity against Mycobacterium tuberculosis strain H37Rv was assessed. The SAR analysis on the first set of derivatives, with an alkyl or aryl unit at N-9 and a phenolic unit at C-2, showed that the activity depends on the purine ring substituents at N-9 and C-2. A phenyl group at N-9 combined with a 3-hydroxyphenyl or 4-hydroxyphenyl at C-2 improve the activity. The most active compound of this set has a phenyl group at N-9 and a 4-hydroxyphenyl group at C-2, displaying an IC90 = 1.2 μg/mL and a selectivity index higher than 25.5. This compound served as a Hit to design the second set of derivatives. A phenyl group at N-9 was maintained, and the group at C-2 was diversified. The SAR analysis showed that the aryl unit at C-2 must have an oxygen or nitrogen atom bonded in the para position. A proton, a small alkyl or a substituted aryl group may also be bonded to the oxygen. The compound with the 4-methoxyphenyl group at C-2, 1Bd, exhibits the highest activity with an IC90 < 0.19 μg/mL. This compound is highly potent against M. tuberculosis strain H37Rv and non-toxic for VERO mammalian cells with an SI > 153.8. Compound 1Bd was also non-cytotoxic against primary macrophage cultures at IC90, 2xIC90, and 10xIC90 and significantly reduced the bacterial load in M. tuberculosis-infected macrophages at the same concentrations. Compound 1Bd showed a favorable pharmacokinetic profile when administered orally, with major lung and liver accumulation. In vivo antimycobacterial efficacy of 1Bd was tested at 25 mg/kg. At the tested regimen, a decrease in bacterial burden was observed in the liver. Optimization of the treatment regimen should be performed to fully potentiate the in vivo efficacy of our lead molecule, particularly in the lung, the main target organ of M. tuberculosis.

Attitudes towards transjugular intrahepatic portosystemic shunt (TIPS) in Australia: a national survey of TIPS centres

BackgroundTransjugular intrahepatic portosystemic shunt (TIPS) is a minimally invasive therapeutic option to treat the sequelae of portal hypertension. It is unclear whether current international recommendations are reflected in current clinical...

Risk of major adverse liver outcomes among first-degree relatives of individuals with MASLD.

Previous studies have suggested an increased risk of major adverse liver outcomes (MALO) in relatives of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, granular and longitudinal evidence is lacking on the future risk of MALO among family members of individuals with MASLD. We identified 3526 first-degree relatives (FDRs) and 11 079 general population comparators to 1328 patients with MASLD diagnosed between 1974 and 2021, with detailed clinical data, including liver histology in 71% of patients. MALO was defined through diagnostic coding for cirrhosis or its complications. Cox regression models were used to estimate adjusted hazard ratios (aHRs) for MALO among FDRs compared to general population comparators. Cumulative incidence accounting for competing risks was calculated. During a median follow-up of 13.4 years, there were 65 (2%, 1.12/1000 person-years) and 225 (2%, 1.26/1000 person-years) MALO events in FDRs and general population comparators respectively. After adjusting for demographic factors and comorbidities, FDRs were at no increased risk of MALO (aHR = 0.99, 95% CI: 0.74-1.33). Increased relative rates of MALOs were, however, observed in some subgroups, including parents, although absolute risk estimates were low and comparable to the general population. FDRs of patients with MASLD did not have a higher rate of incident MALO than the general population. Since the absolute risk of MALO in relatives of patients with MASLD was low, these results do not support systematic screening of MASLD-related fibrosis in relatives of patients with MASLD.

Primary neuroendocrine tumor of the liver

Neuroendocrine tumors generally originate in the digestive tract or pancreas, developing liver metastases throughout their evolution. The presence of a primary neuroendocrine tumor of the liver is still controversial and there are very few cases. We present a case of a primary neuroendocrine tumor of the liver confirmed by anatomo-pathological study and images. The patient underwent two major liver resections, lastly preserving only segment IV.

The risk factors for perioperative blood transfusion in open liver resection, a retrospective cohort study

Purpose: Liver resection is the current treatment for hepatic neoplasms but may be associated with intraoperative hemorrhage and the need for blood transfusions. The aim of this study is to identify the risk factors for predicting the requirement of a perioperative blood transfusion in open liver resection. Methods: A total of 808 consecutive patients who had undergone elective open liver resection from 2006 to 2017 were retrospectively reviewed using the database. Baseline characteristics and intra-operative data were collected. Perioperative blood transfusion was defined as the transfusion of allogenic packed red cells during surgery and the 48 hours following surgery. An analysis of logistic regression was used to determine the independent risk factors for blood transfusion in open liver resection. Results: Three hundred and seventy-seven patients (46.7%) received perioperative packed red cell transfusions. The independent risk factors associated with perioperative blood transfusion included ASA classification&gt;2, preoperative anemia (Hb&lt;12 g/dL for women, Hb&lt;13 g/dL for men), thrombocytopenia (platelet count&lt;100×103/mm3), albumin&lt;3.5 g/dL, largest tumor size&gt;4 cm., major liver resection, and surgeon experience performing&lt;50 cases of major open liver resection. Conclusion: Preoperative risk factors may be utilized to assess and predict patients who require perioperative blood transfusions following liver resection. Modifiable risk factors may also be treated prior to surgery. Furthermore, patient blood management and methods to minimize blood loss and blood transfusions during surgery should be implemented in patients who require high-risk transfusions.

GLP1 agonists and risk of major adverse liver outcomes.

GLP1 agonists and risk of major adverse liver outcomes.

Experts vs. machine – comparison of machine learning to expert-informed prediction of outcome after major liver surgery

BackgroundMachine learning (ML) has been successfully implemented for classification tasks (e.g., cancer diagnosis). ML performance for more challenging predictions is largely unexplored. This study's objective was to compare machine learning vs. expert-informed predictions for surgical outcome in patients undergoing major liver surgery. MethodsSingle tertiary center data on preoperative parameters and postoperative complications for elective hepatic surgery patients were included (2008–2021). Expert-informed prediction models were established on 14 parameters identified by two expert liver surgeons to impact on postoperative outcome. ML models used all available preoperative patient variables (n = 62). Model performance was compared for predicting 3-month postoperative overall morbidity. Temporal validation and additional analysis in major liver resection patients were conducted. Results889 patients included. Expert-informed models showed low average bias (2–5 CCI points) with high over/underprediction. ML models performed similarly: average prediction 5–10 points higher than observed CCI values with high variability (95% CI −30 to 50). No performance improvement for major liver surgery patients. ConclusionNo clinical relevance in the application of ML for predicting postoperative overall morbidity was found. Despite being a novel hype, ML has the potential for application in clinical practice. However, at this stage it does not replace established approaches of prediction modelling.

Novel multiparametric MRI detects improved future liver remnant quality post-dual vein embolization

BackgroundOptimisation of the future liver remnant (FLR) is crucial to outcomes of extended liver resections. This study aimed to assess the quality of the FLR before and after dual vein embolization (DVE) by quantitative multiparametric MRI. MethodsOf 100 patients with liver metastases recruited in a clinical trial (Precision1:NCT04597710), ten consecutive patients with insufficient FLR underwent quantitative multiparametric MRI pre- and post-DVE (right portal and hepatic vein). FLR volume, liver fibro-inflammation (corrected T1) scores and fat percentage (proton density fat fraction, PDFF) were determined. Patient metrics were compared by Wilcoxon signed-rank test and statistical analysis done using R software. ResultsAll patients underwent uncomplicated DVE with improvement in liver remnant health, median 37 days after DVE: cT1 scores reduced from median (interquartile range) 790 ms (753–833 ms) to 741 ms (708–760 ms) p = 0.014 [healthy range <795 ms], as did PDFF from 11% (4–21%), to 3% (2–12%) p = 0.017 [healthy range <5.6%]. There was a significant increase in median (interquartile range) FLR volume from 33% (30–37%)% to 49% (44–52%), p = 0.002. ConclusionThis non-invasive and reproducible MRI technique showed improvement in volume and quality of the FLR after DVE. This is a significant advance in our understanding of how to prevent liver failure in patients undergoing major liver surgery.

European fellowship training opportunities for hepato-pancreato-biliary surgery: an international survey of fellows and program directors

BackgroundThere are no established training pathways for hepato-pancreato-biliary (HPB) surgery in Europe. This study aims to overview the current status of fellowship training from both fellows' and institutions' perspectives. MethodsA web-based snapshot survey was distributed to all members of the European-African Hepato-Pancreato-Biliary Association (E-AHPBA) to reach for former fellows and program directors of European HPB surgery fellowships held between 2013 and 2023. ResultsA total of 37 fellows and 13 program directors replied describing 32 different programs in 13 European countries. The median (range) age at fellowship start was 34 (30–45 years). Fellowship duration was most commonly one (36 %) or two (40 %) years. Fellowships were funded in 70 % and fellows were required to learn a new language in 27 %. Most fellows performed between none and 10 pancreatic (68 %), major (67 %) and minor (60 %) liver resections as 1st surgeon, while the number of operations performed as 1st assistant were more heterogeneous. Program directors estimated a higher number of operations performed by fellows as first surgeons. The percentage of procedures performed minimally invasively did not exceed 10 %. ConclusionThere is substantial heterogeneity between HPB fellowship programs in Europe. A wider standardization of clinical curriculum, including minimally invasive surgery, is desirable.

A Biomimetic Multifunctional Nanoframework for Symptom Relief and Restorative Treatment of Acute Liver Failure.

Acute liver failure (ALF) is a rare and serious condition characterized by major hepatocyte death and liver dysfunction. Owing to the limited therapeutic options, this disease generally has a poor prognosis and a high mortality rate. When ALF cannot be reversed by medications, liver transplantation is often needed. However, transplant rejection and the shortage of donor organs still remain major challenges. Most recently, stem cell therapy has emerged as a promising alternative for the treatment of liver diseases. However, the limited cell delivery routes and poor stability of live cell products have greatly hindered the feasibility and therapeutic efficacy of stem cell therapy. Inspired by the functions of mesenchymal stem cells (MSCs) primarily through the secretion of several factors, we developed an MSC-inspired biomimetic multifunctional nanoframework (MBN) that encapsulates the growth-promoting factors secreted by MSCs via combination with hydrophilic or hydrophobic drugs. The red blood cell (RBC) membrane was coated with the MBN to enhance its immunological tolerance and prolong its circulation time in blood. Importantly, the MBN can respond to the oxidative microenvironment, where it accumulates and degrades to release the payload. In this work, two biomimetic nanoparticles, namely, rhein-encapsulated MBN (RMBN) and N-acetylcysteine (NAC)-encapsulated MBN (NMBN), were designed and synthesized. In lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced and acetaminophen (APAP)-induced ALF mouse models, RMBN and NMBN could effectively target liver lesions, relieve the acute symptoms of ALF, and promote liver cell regeneration by virtue of their strong antioxidative, anti-inflammatory, and regenerative activities. This study demonstrated the feasibility of the use of an MSC-inspired biomimetic nanoframework for treating ALF.

Perioperative LiMAx Test Analysis: Impact of Portal Vein Embolisation, Chemotherapy and Major Liver Resection.

Postoperative liver failure (PLF) is a severe complication after major liver resection (MLR). To increase the safety of patients, clinical bedside tests are of great importance. However, limitations of their applicability and validity impair their value. Preoperative measurements of the liver maximum capacity (LiMAx) were performed in n = 40 patients, who underwent MLR (≥3 segments). Matched postoperative LiMAx was measured in n = 21 patients. Liver function was compared between pretreated patients (n = 11 with portal vein embolisation (PVE) and n = 19 patients with preoperative chemotherapy) and therapy naïve patients. The LiMAx values were compared with liver-specific blood parameters and volumetric analysis. In total, n = 40 patients were enrolled in this study. The majority of patients (n = 33; 82.5%) had high preoperative LiMAx values (>315 µg/kg/h), while only seven patients (17.5%) had medium values (140-315 µg/kg/h), and none of the patients had low values (<140 µg/kg/h). A comparison of pretreated patients (with PVE and/or chemotherapy) and therapy naïve patients showed no significant difference in the preoperative LiMAx values (p > 0.05). The preoperative LiMAx values were significantly higher than the matched postoperative values on postoperative day 1 (p < 0.0001). A comparison between the expected and measured postoperative LiMAx showed a difference (≥10%) in 7 out of 13 patients (53.8%). After an initial postoperative decrease in the LiMAx, the patients without complications (n = 12) showed a continuous increase until 14 days after surgery. In the patients with postoperative complications, a decrease in the LiMAx was associated with a prolonged recovery. For patients undergoing MLR within the 0.5% rule, which is the clinical gold standard, the LiMAx values do not offer any additional information. Additionally, the LiMAx may have reflected liver function, but it did not deliver additional information regarding postoperative liver recovery. The clinical use of LiMAx might be relevant in selected patients beyond the 0.5% rule.

Predictive Value of Preoperative ICG-R15 Testing in Post-hepatectomy Liver Failure Following Major Liver Resection: Indian Experience.

Surgical resection stands as the preeminent therapeutic approach for both primary hepatocellular carcinoma and metastatic liver malignancies. Its efficacy is contingent upon the attainment of a comprehensive excision while ensuring a sufficient future liver remnant (FLR). However, post-hepatectomy liver failure (PHLF) remains a significant challenge, particularly in patients with preexisting liver disease. The present study aims to investigate the predictive value of the preoperative indocyanine green retention test at 15min (ICG-R15) in identifying patients at risk of PHLF following major liver resection. This retrospective review focused on patients who underwent the ICG-R15 test before major liver resection between August 2021 and January 2023. All patients underwent standard preoperative evaluation and staging. Patients with primary or metastatic liver cancer planned for major resection and undergoing ICG-R15 were included in the study. Patients with elevated serum bilirubin (> 3mg/dl) and those not undergoing liver resection or minor liver resection (< 3 segments) were excluded from the study. PHLF was defined by the International Study Group of Liver Surgery (ISGLS) criteria. Follow-up was performed to identify 90-day morbidity. Using univariate and multivariate logistic regression analyses, we confirmed independent risk parameters that predicted postoperative major complications and severe PHLF. The study included 72 patients who underwent preoperative ICG-R15 testing prior to major liver resection. PHLF occurred in 28 patients (38.9%), with 24 patients (33.3%) classified as severity score B and 3 patients (4.16%) had severity score C. Univariate analysis revealed future liver remnant (FLR), ICG-R15, and blood transfusion as predictors of PHLF. Multivariate analysis confirmed FLR (p = 0.019) and ICG-R15 (p = 0.032) as significant predictors. Receiver operating characteristic curve analysis yielded an area under the curve of 0.642 for ICG-R15 in predicting PHLF. An optimal cut-point of 7.5 was determined. Our study highlights the importance of preoperative risk assessment of liver function evaluation using the ICG-R15 test, to predict the risk of PHLF following liver resection. Implementing appropriate interventions, especially in patients with borderline FLR, can improve surgical outcomes and enhance patient safety. Further research and prospective studies are essential to refine risk prediction models and improve rates of PHLF after liver resections.

Glucagon-like peptide-1 receptor agonists and risk of major adverse liver outcomes in patients with chronic liver disease and type 2 diabetes

ObjectivePhase II trials suggest glucagon-like peptide-1 receptor (GLP1) agonists resolve metabolic dysfunction-associated steatohepatitis but do not affect fibrosis regression. We aimed to determine the long-term causal effect of GLP1 agonists...

Gelatin-based dynamic response antioxidant, anti-inflammatory multifunctional hydrogel for enhanced diabetic wound repair

Diabetic wound therapy presents significant challenges in the clinical environment, where persistent bleeding, disturbed inflammatory regulation, impaired cellular proliferation, and impaired tissue remodeling are major features of diabetic wound healing. However, current treatment strategies need to be considered in the context of the dynamic and complex needs of chronic wound healing. Here, multifunctional dynamic boronic acid cross-linked hydrogels were prepared by the reaction of gelatin (Gel) inoculated with 5-carboxy 3-nitrophenylboronic acid (NPBA) and Epigallocatechin gallate (EGCG) to achieve rapid gelation at pH = 7.4, EGCG could interact electrostatically with cationic antimicrobial peptides (AMP) to achieve the effective loading of AMP in the hydrogels. This hydrogel can be injected and adhered to skin defects in diabetic patients to provide a barrier and rapid hemostasis. In a high glucose microenvironment, the rapid release of AMP effectively kills bacteria, while the responsive release of EGCG eliminates reactive oxygen species (ROS) and promotes macrophage M2 polarization. In addition, the hydrogel had excellent biocompatibility and degradability properties, degraded completely after 3 days of subcutaneous injection, and was non-toxic in H&E staining of major organs and serum liver function indices in mice. This multifunctional injectable hydrogel accelerates diabetic skin wound repair and is a promising dressing for the precise treatment of diabetic wounds.

Multicenter clinical validation of GutSeer: A cost-effective, blood-based assay for early detection and localization of major gastrointestinal cancers.

739 Background: Gastrointestinal (GI) cancers account for over one-third of cancer-related deaths. We have previously developed GutSeer, a non-invasive assay utilizing cell-free DNA (cfDNA) methylation and fragmentation signatures, to cost-effectively detect and localize five major GI cancers, including colorectal (CC), gastric (GC), liver (LC), esophageal (EC), and pancreatic cancer (PC). Methods: GutSeer was initially developed and validated in a large retrospective cohort of 1844 plasma samples, demonstrating excellent performance with specificity, sensitivity, and tissue of origin (TOO) accuracy at 96.7%, 86.2%, and 82%, respectively. In this study, we conducted a blind, multi-center clinical test for further validation. Participants were recruited from two centers, Beijing (BJ) and Shanghai (SH). Cohort BJ included 42 participants (20 healthy, 22 cancer), and Cohort SH comprised 403 participants (105 healthy, 123 benign, 175 cancer). Over half of the cancer samples in Cohort SH were in early-stage disease (TNM stages I and II). Results: In Cohort BJ, GutSeer showed 100% specificity, 68.2% sensitivity, and 86.7% TOO accuracy. Individual cancer type sensitivities within Cohort BJ were 100% for CC, 57.1% for EC, 75% for GC, 40% for PC, and 100% for LC. In Cohort SH, GutSeer exhibited 94.6% specificity for healthy samples and 86.2% for benign conditions. For cancer samples in Cohort SH, the overall sensitivity achieved 78.9%, with specific sensitivities of 92.3% for CC, 81.0% for EC, 78.4% for GC, 52.9% for PC, and 86.4% for LC. Moreover, GutSeer also efficiently detected early-stage cancers, with stage-wise sensitivities ranging from 64.7% (stage I) to 96.3% (stage IV). TOO accuracy in Cohort SH was 79.0%, with individual cancer types achieving accuracies from 71.7% to 94.7% (72.2% for CC, 71.7% for EC/GC, 94.7% for LC, and 77.8% for PC). Conclusions: GutSeer demonstrates promising potential as a cost-effective, non-invasive test for early detection and localization of major GI cancers. Its consistently high performance in both retrospective and multi-center blind clinical tests implies its potential to revolutionize the screening and diagnosis paradigm for GI cancers.