Plectin-1-targeted recognition for enhancing comprehensive therapy in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) poses a formidable challenge due to its aggressive nature and poor prognosis. Gemcitabine (Gem), a primary therapeutic option, functions by inhibiting DNA synthesis and promoting apoptosis, thereby impeding the progression of PDAC. However, Gem is hindered by suboptimal pharmacokinetics and efficacy. In response to these challenges, we have developed a nanoparticle (NP) designed for specific recognition of plectin-1 in PDAC cell membranes. The NPs encapsulate Gem while demonstrating pH-responsive drug release characteristics in the acidic tumor microenvironment. This targeted approach enhances local drug delivery while alleviating concerns about systemic toxicity. Furthermore, the NPs are enriched with indocyanine green (ICG), renowned for its strong photothermal effects, thereby further enhancing therapeutic outcomes. This study presents an innovative therapeutic strategy for PDAC based on a plectin-1-targeted recognition delivery approach. The approach is applied to enhance chemotherapy, combined with photothermal therapy (PTT), inducing apoptosis in PDAC cell lines and improving the pharmacokinetics of Gem. In conclusion, the delivery strategy based on plectin-1-targeted recognition shows promising preclinical prospects for enhancing therapeutic efficacy in PDAC, offering valuable insights for future clinical applications.

Injectable Hydrogel-Encapsulating Pickering Emulsion for Overcoming Lenvatinib-Resistant Hepatocellular Carcinoma via Cuproptosis Induction and Stemness Inhibition.

Lenvatinib resistance (LenR) presents a significant challenge in hepatocellular carcinoma (HCC) treatment, leading to high cancer-related mortality rates globally. Unlike traditional chemotherapy resistance mechanisms, LenR in HCC is primarily driven by increased cancer cell stemness. Disulfiram, (DSF), functioning as a Cu ionophore, can coordinate with Cu2+ to overcome LenR in HCC by inhibiting cancer cell stemness and cuproptosis. However, DSF faces challenges due to its poor water solubility, while copper ions present issues related to systemic toxicity during widespread use. To address this, DSF and CuO nanoparticles (NPs) were co-encapsulated to form an oil-in-water Pickering emulsion (DSF@CuO), effectively elevating DSF and copper ion concentrations within the tumor microenvironment (TME). DSF@CuO was then combined with sodium alginate (SA) to form a DSF@CuO-SA solution, which gelatinizes in situ with Ca2+ in the TME to form a DSF@CuO Gel, enhancing Pickering emulsion stability and sustaining DSF and copper ion release. A DSF@CuO Gel exhibits enhanced stability and therapeutic efficacy compared to conventional administration methods. It effectively induces mitochondrial dysfunction and cuproptosis in LenR HCC cells by downregulating DLAT, LIAS, and CDKN2A, while upregulating FDX1. Furthermore, it suppresses cancer stemness pathways through activation of the JNK/p38 MAPK pathway and inhibition of the NF-κB and NOTCH signaling pathways. These findings suggest that DSF@CuO Gels are a promising therapeutic strategy for treating LenR HCC. In vivo and in vitro LenR HCC models demonstrated significant therapeutic efficacy. In conclusion, this novel approach underscores DSF@CuO Gel's potential to overcome LenR in HCC, offering a novel approach to address this clinical challenge.

Impact of an AI-Based laparoscopic cholecystectomy coaching program on the surgical performance: a randomized controlled trial.

BACKGROUND: Laparoscopic cholecystectomy (LC) is the gold standard for treating symptomatic gallstones but carries inherent risks like bile duct injury (BDI). While critical view of safety (CVS) is advocated to mitigate BDI, its real-world adoption is limited. Additionally, significant variations in surgeon performance impede procedural standardization, highlighting the need for a feasible, innovative, and effective training approach. The aim of this study is to develop an Artificial Intelligence (AI)-assisted coaching program for LC to enhance surgical education and improve surgeon's performance. MATERIALS AND METHODS: We conducted a multi-center, randomized controlled trial from May 2022 to August 2023 to assess the impact of an AI-based coaching program, SmartCoach, on novice performing LC. Surgeons and patients meeting specific inclusion criteria were randomly assigned to either a coaching group with AI-enhanced feedback or a self-learning group. The primary outcome was assessed using the Laparoscopic Cholecystectomy Rating Form (LCRF), with secondary outcomes including surgical safety, efficiency, and adverse events. Statistical analyses were performed using SPSS, with significance set at P-value less than 0.05. RESULTS: Between May 2022 and August 2023, 22 surgeons were initially enrolled from 10 hospitals, with 18 completing the study. No demographic differences were noted between coaching and self-learning groups. In terms of surgical performance (LCRF scores), the coaching group showed significant improvement over time (31 to 40, P=0.008), outperforming the self-learning group by study end (40 vs 38, P=0.032). Significant improvements in CVS achievement were also noted in the coaching group (11% to 78%, P=0.021). Overall, the coaching program was well-received, outpacing traditional educational methods in both understanding and execution of CVS and participants in the intervention group expressed strongly satisfaction with the program. CONCLUSIONS: The AI-assisted surgical coaching program effectively improved surgical performance and safety for novice surgeons in LC procedures. The model holds significant promise for advancing surgical education.

A pilot study of virtual liver segment projection technology in subsegment-oriented laparoscopic anatomical liver resection when indocyanine green staining fails (with video).

BACKGROUND: Precision surgery for liver tumors favors laparoscopic anatomical liver resection (LALR), involving the removal of specific liver segments or subsegments. Indocyanine green (ICG)-negative staining is a commonly used method for defining resection boundaries but may be prone to failure. The challenge arises when ICG staining fails, as it cannot be repeated during surgery. In this study, we employed the virtual liver segment projection (VLSP) technology as a salvage approach for precise boundary determination. Our aim was to assess the feasibility of the VLSP to be used for the determination of the boundaries of the liver resection in this situation. METHODS: Between January 2021 and June 2023, 12 consecutive patients undergoing subsegment-oriented LALR were included in this pilot series. The VLSP technology was utilized to define the resection boundaries at the time of ICG-negative staining failure. Routine surgical parameters and short-term outcomes were evaluated to assess the safety of VLSP in this procedure. In addition, its feasibility was assessed by analyzing the accuracy between the predicted resected liver volume (PRLV) and actual resected liver volume (ARLV). RESULTS: Of the 12 enrolled patients, the mean operation time was 444.58 ± 101.70 min (range 290-570 min), with a mean blood loss of 125.00 ± 96.53 ml (range 50-400 mL). One patient (8.3%) was converted to laparotomy for subsequent parenchymal transection, four (33.3%) received blood transfusions and four (33.3%) had postoperative complications. All patients received an R0 resection. The Pearson correlation coefficient (r) between PRLV and ARLV was 0.98 (R2 = 0.96, p < 0.05), and the relative error (RE) was 8.62 ± 6.66% in the 12 patients, indicating agreement. CONCLUSION: Failure of intraoperative ICG-negative staining during subsegment-oriented LALR is possible, and VLSP may be an alternative to define the resection boundaries in such cases.

Laparoscopic left hemihepatectomy using augmented reality navigation plus ICG fluorescence imaging for hepatolithiasis: a retrospective single-arm cohort study (with video).

BACKGROUND: Laparoscopic left hemihepatectomy (LLH) has been shown to be an effective and safe method for treating hepatolithiasis primarily affecting the left hemiliver. However, this procedure still presents challenges. Due to pathological changes in intrahepatic duct stones, safely dissecting the hilar vessels and determining precise resection boundaries remains difficult, even with fluorescent imaging. Our team proposed a new method of augmented reality navigation (ARN) combined with Indocyanine green (ICG) fluorescence imaging for LLH in hepatolithiasis cases. This study aimed to investigate the feasibility of this combined approach in the procedure. METHODS: Between May 2021 and September 2023, 16 patients with hepatolithiasis who underwent LLH were included. All patients underwent preoperative 3D evaluation and were then guided using ARN and ICG fluorescence imaging during the procedure. Perioperative and short-term postoperative outcomes were assessed to evaluate the safety and efficacy of the method. RESULTS: All 16 patients successfully underwent LLH. The mean operation time was 380.31 ± 92.17 min, with a mean estimated blood loss of 116.25 ± 64.49 ml. ARN successfully aided in guiding hilar vessel dissection in all patients. ICG fluorescence imaging successfully identified liver resection boundaries in 11 patients (68.8%). In the remaining 5 patients (31.3%) where fluorescence imaging failed, virtual liver segment projection (VLSP) successfully identified their resection boundaries. No major complications occurred in any patients. Immediate stone residual rate, stone recurrence rate, and stone extraction rate through the T-tube sinus tract were 12.5%, 6.3%, and 6.3%, respectively. CONCLUSION: The combination of ARN and ICG fluorescence imaging enhances the safety and precision of LLH for hepatolithiasis. Moreover, ARN may serve as a safe and effective tool for identifying precise resection boundaries in cases where ICG fluorescence imaging fails.

Efficacy of hepatectomy for hepatolithiasis using 3D visualization combined with ICG fluorescence imaging: A retrospective cohort study.

BACKGROUND: Hepatolithiasis is a complex condition that poses challenges and difficulties in surgical treatment. Three-dimensional visualization technology combined with fluorescence imaging (3DVT-FI) enables accurate preoperative assessment and real-time intraoperative navigation. However, the perioperative outcomes of 3DVT-FI in hepatolithiasis have not been reported. We aim to evaluate the efficacy of 3DVT-FI in the treatment of hepatolithiasis. METHODS: A retrospective analysis was performed on 128 patients who underwent hepatectomy for hepatolithiasis at the Department of Hepatobiliary Surgery, Zhujiang Hospital, between January 2017 and December 2022. Among them, 50 patients underwent hepatectomy using 3DVT-FI (3DVT-FI group), while 78 patients underwent conventional hepatectomy without 3DVT-FI (CH group). The operative data, postoperative liver function indices, complication rates and stone residue were compared between the two groups. RESULTS: There were no significant differences in preoperative baseline data between the two groups (p > 0.05). Compared with the CH group, the 3DVT-FI group exhibited lower intraoperative blood loss (140.00 ± 112.12 vs. 225.99 ± 186.50 mL, p = 0.001), and a lower intraoperative transfusion rate (8.0% vs. 23.1%, p = 0.027). The overall incidence of postoperative complications did not differ significantly (22.0% vs. 35.9%, p = 0.096). The 3DVT-FI group was associated with a lower immediate residual stone rate (16.0% vs. 34.6%, p = 0.021). There were no perioperative deaths in the 3DVT-FI group, while one perioperative death occurred in the CH group. CONCLUSIONS: The 3DVT-FI may offer significant benefits in terms of surgical safety, reduced intraoperative bleeding and decreased stone residue during hepatectomy for hepatolithiasis.

Second Near-Infrared Macrophage-Biomimetic Nanoprobes for Photoacoustic Imaging of Neuroinflammation.

Neuroinflammation is a significant pathological event involving the neurodegenerative process associated with many neurological disorders. Diagnosis and treatment of neuroinflammation in its early stage are essential for the prevention and management of neurological diseases. Herein, we designed macrophage membrane-coated photoacoustic (PA) probes (MSINPs), with targeting specificities based on naturally existing target-ligand interactions for the early diagnosis of neuroinflammation. The second near-infrared dye, IR1061, was doped into silica as the core and was encapsulated with a macrophage membrane. In vitro as well as in vivo, the MSINPs could target inflammatory cells via the inflammation chemotactic effect. PA imaging was used to trace the MSINPs in a neuroinflammation mouse model and showed a great targeted effect of MSINPs in the prefrontal cortex. Therefore, the biomimetic nanoprobe prepared in this study offers a new strategy for PA molecular imaging of neuroinflammation, which can enhance our understanding of the evolution of neuroinflammation in specific brain regions.

Relief of tumor hypoxia using a nanoenzyme amplifies NIR-II photoacoustic-guided photothermal therapy.

Hypoxia is a critical tumor microenvironment (TME) component. It significantly impacts tumor growth and metastasis and is known to be a major obstacle for cancer therapy. Integrating hypoxia modulation with imaging-based monitoring represents a promising strategy that holds the potential for enhancing tumor theranostics. Herein, a kind of nanoenzyme Prussian blue (PB) is synthesized as a metal-organic framework (MOF) to load the second near-infrared (NIR-II) small molecule dye IR1061, which could catalyze hydrogen peroxide to produce oxygen and provide a photothermal conversion element for photoacoustic imaging (PAI) and photothermal therapy (PTT). To enhance stability and biocompatibility, silica was used as a coating for an integrated nanoplatform (SPI). SPI was found to relieve the hypoxic nature of the TME effectively, thus suppressing tumor cell migration and downregulating the expression of heat shock protein 70 (HSP70), both of which led to an amplified NIR-II PTT effect in vitro and in vivo, guided by the NIR-II PAI. Furthermore, label-free multi-spectral PAI permitted the real-time evaluation of SPI as a putative tumor treatment. A clinical histological analysis confirmed the amplified treatment effect. Hence, SPI combined with PAI could offer a new approach for tumor diagnosing, treating, and monitoring.

Impact of three-dimensional reconstruction visualization technology on short-term and long-term outcomes after hepatectomy in patients with hepatocellular carcinoma: a propensity-score-matched and inverse probability of treatment-weighted multicenter study.

BACKGROUND: Three-dimensional reconstruction visualization technology (3D-RVT) is an important tool in the preoperative assessment of patients undergoing liver resection. However, it is not clear whether this technique can improve short-term and long-term outcomes in patients with hepatocellular carcinoma (HCC) compared with two-dimensional (2D) imaging. METHOD: A total of 3402 patients from five centers were consecutively enrolled from January 2016 to December 2020, and grouped based on the use of 3D-RVT or 2D imaging for preoperative assessment. Baseline characteristics were balanced using propensity score matching (PSM, 1:1) and stabilized inverse probability of treatment-weighting (IPTW) to reduce potential selection bias. The perioperative outcomes, long-term overall survival (OS), and recurrence-free survival (RFS) were compared between the two groups. Cox-regression analysis was used to identify the risk factors associated with RFS. RESULTS: A total of 1681 patients underwent 3D-RVT assessment before hepatectomy (3D group), while 1721 patients used 2D assessment (2D group). The PSM cohort included 892 patient pairs. In the IPTW cohort, there were 1608.3 patients in the 3D group and 1777.9 patients in the 2D group. In both cohorts, the 3D group had shorter operation times, lower morbidity and liver failure rates, as well as shorter postoperative hospital stays. The 3D group had more margins ≥10 mm and better RFS than the 2D group. The presence of tumors with a diameter ≥5 cm, intraoperative blood transfusion and multiple tumors were identified as independent risk factors for RFS, while 3D assessment and anatomical resection were independent protective factors. CONCLUSION: In this multicenter study, perioperative outcomes and RFS of HCC patients following 3D-RVT assessment were significantly different from those following 2D imaging assessment. Thus, 3D-RVT may be a feasible alternative assessment method before hepatectomy for these patients.

Quantitative anatomy of the large variant right hepatic vein: A systematic three-dimensional analysis.

Anatomical variations of the right hepatic vein, especially large variant right hepatic veins (≥5 mm), have important clinical implications in liver transplantation and resection. This study aimed to evaluate anatomical variations of the right hepatic vein using quantitative three-dimensional visualization analysis. Computed tomography images of 650 patients were retrospectively analyzed, and three-dimensional visualization was applied using the derived data to analyze large variant right hepatic veins. The proportion of the large variant right hepatic vein was 16.92% (110/650). According to the location and number of the variant right hepatic veins, the configuration of the right hepatic venous system was divided into seven subtypes. The length of the retrohepatic inferior vena cava had a positive correlation with the diameter of the right hepatic vein (rs = 0.266, p = 0.001) and the variant right hepatic veins (rs = 0.211, p = 0.027). The diameter of the right hepatic vein was positively correlated with that of the middle hepatic vein (rs = 0.361, p < 0.001), while it was inversely correlated with that of the variant right hepatic veins (rs = -0.267, p = 0.005). The right hepatic vein diameter was positively correlated with the drainage volume (rs = 0.489, p < 0.001), while the correlation with the variant right hepatic veins drainage volume was negative (rs = -0.460, p < 0.001). The number of the variant right hepatic veins and their relative diameters were positively correlated (p < 0.001). The volume and percentage of the drainage area of the right hepatic vein decreased significantly as the number of the variant right hepatic vein increased (p < 0.001). The findings of this study concerning the variations of the hepatic venous system may be useful for the surgical planning of liver resection or transplantation.

Efficacy of Augmented Reality Combined with Indocyanine Green Fluorescence Imaging Guided Laparoscopic Segmentectomy for Hepatocellular Carcinoma.

BACKGROUND: The internal anatomy of the liver is extremely complex. Laparoscopic anatomical segmentectomy requires reference to the position and alignment of intrahepatic vascular. However, the surface of the liver lacks anatomical landmarks and the liver segment boundaries cannot be identified with the naked eye. Augmented reality navigation (ARN) and indocyanine green fluorescence imaging (FI) are emerging navigation tools in liver resection. This study aimed to explore the efficacy and application value of laparoscopic anatomical segmentectomy guided by ARN combined with indocyanine green FI. STUDY DESIGN: Ninety-eight patients who were diagnosed with hepatocellular carcinoma and underwent laparoscopic anatomical segmentectomy from January 2018 to January 2022 were retrospectively analyzed. They were divided into the ARN-FI group (45 patients) and the non-ARN-FI group (53 patients) based on whether ARN combined with FI was applied during the operation. The differences in intraoperative and postoperative outcomes were compared. RESULTS: There was no significant difference in preoperative baseline data and postoperative complication rates between the 2 groups. Compared with the non-ARN-FI group, the ARN-FI group had much lower intraoperative blood loss (100 vs 200 mL, p = 0.005) and a lower incidence of remnant liver ischemia (13.3% vs 30.2%, p = 0.046). The 1- and 3-year disease-free survival rates in the ARN-FI and non-ARN-FI groups were 91.01% vs 71.15% and 70.01% vs 52.46%, respectively; the differences between the 2 groups were statistically significant (p = 0.047). CONCLUSIONS: The ARN-FI technology provides a more standardized approach for liver parenchyma section during laparoscopic liver resection, effectively minimizing intraoperative blood loss, reducing postoperative remnant liver ischemia, and improving oncological prognosis. This method is safe and feasible and has good clinical application prospects.

NIR-II Photoacoustic Imaging-Guided Oxygen Delivery and Controlled Release Improves Photodynamic Therapy for Hepatocellular Carcinoma.

Hypoxia, a prominent hallmark of hepatocellular carcinoma (HCC), undermines curative outcomes, elevates recurrence rates, and fosters metastasis, particularly during photodynamic therapy (PDT) in clinical settings. Studies indicate that alleviating tumor hypoxia enhances PDT efficacy. However, persistent challenges, including suboptimal oxygen delivery efficiency and absence of real-time feedback on blood oxygen fluctuations during PDT, considerably impede therapeutic efficacy in tumor treatment. This study addresses these issues using near-infrared-II (NIR-II) photoacoustic (PA) imaging for tumor-targeted oxygen delivery and controlled release. For this purpose, a biomimetic oxygen delivery system designated BLICP@O2 is developed, which utilizes hybrid tumor cell membranes and thermosensitive liposomes as oxygen carriers, incorporating the NIR-II dye IR1048, photosensitizer chlorin e6 (Ce6), and perfluorohexane. Upon sequential irradiation at 1064 and 690 nm, BLICP@O2 exhibits significant photothermal and photodynamic effects. Photothermal heating triggers oxygen release, enhancing the photodynamic effect of Ce6. Blood oxygen changes during PDT are tracked by multispectral PA imaging. Enhanced PDT efficacy, mediated by hypoxia relief, is convincingly demonstrated both in vitro and in vivo. This work presents an imaging-guided, dual-wavelength programmed cascaded treatment strategy for tumor-targeted oxygen delivery and controlled release, with real-time efficacy monitoring using PA imaging, offering valuable insights for overcoming challenges in PDT-based cancer therapy.

Indocyanine green fluorescence image-guided laparoscopic anatomical S2/3 resection using the TICGL technique.

BACKGROUND: Segment 2/3 (S2/3) resection, which can preserve more residual liver parenchyma, is a feasible alternative to left lateral sectionectomy. However, it is still challenging to perform anatomical S2/3 resection safely and precisely, especially laparoscopically. This study was designed to evaluate the safety and accuracy of the temporary inflow control of the Glissonean pedicle (TICGL) technique combined with indocyanine green (ICG) fluorescence imaging in laparoscopic anatomical S2/3 resection. PATIENTS AND METHODS: A total of 12 patients recruited at Zhujiang Hospital of Southern Medical University from June 2021 to August 2022 were included in the study. All patients underwent ICG fluorescence imaging guided laparoscopic anatomical S2/3 resection. The TICGL technique was used to control the blood inflow of the target segment. The total time used to control the hepatic inflow of the target segment, the time of hemostasis, the amount of intraoperative blood loss, predicted resected liver volume (PRLV) and actual resected liver volume (ARLV) were used to evaluate the simplicity, safety, and accuracy of the TICGL technique combined ICG fluorescent imaging in guiding laparoscopic anatomical S2/3 resection. RESULTS: Of the 12 included patients, 7 underwent S2 resection and 5 underwent S3 resection. The operation time was 76.92 ± 11.95 min, the intraoperative blood loss was 15.42 ± 5.82 ml, and the time of hepatic blood inflow control was 7.42 ± 2.43 min. There was a strong correlation between PRLV and ARLV (r = 0.903, P < 0.05). CONCLUSION: The combination of the TICGL technique with ICG negative staining fluorescence imaging is a feasible approach for laparoscopic anatomical S2/3 resection.

Dual-crosslinking immunostimulatory hydrogel synchronously suppresses pancreatic fistula and pancreatic cancer relapse post-resection.

In pancreatic cancer (PC), surgical resection remains the sole curative option, albeit patients undergoing resection are susceptible to postoperative pancreatic fistula (PF) formation and tumor recurrence. An unmet need exists for a unified strategy capable of concomitantly averting PF and tumor relapse to mitigate morbidity in PC patients after surgery. Herein, an original dual crosslinked biological sealant hydrogel (methacrylate-hyaluronic acid-dopamine (MA-HA-DA) and sulfhydryl-hyaluronic acid-dopamine (SH-HA-DA)) was engineered as a drug depot and loaded with polydopamine-cloaked cytokine interleukin-15 and platelets conjugated with anti-TIGIT. In vitro analyses validated favorable tissue adhesion, cytocompatibility, and stability of the hydrogels. In a PF rodent model, the hydrogel effectively adhered to the pancreatic stump, sealing the severed pancreatic end and impeding post-operative elevations in amylase and lipase. In PC murine models, hydrogels potently stimulated CD8+ T and NK cells to deter residual tumor re-growth and distant metastasis. This innovative hydrogel strategy establishes a new framework for concomitant prevention of PF and PC recurrence.

Laparoscopic right hemi-hepatectomy plus total caudate lobectomy for perihilar cholangiocarcinoma via anterior approach with augmented reality navigation: a feasibility study.

BACKGROUND: Right hemi-hepatectomy plus total caudate lobectomy is the appropriate procedure for type IIIa or partial type II pCCA. However, the laparoscopic implementation of this procedure remains technically challenging, especially hilar vascular dissection and en bloc resection of the total caudate lobe. Augmented reality navigation can provide intraoperative navigation to enhance visualization of invisible hilar blood vessels and guide the parenchymal transection plane. METHODS: Eleven patients who underwent laparoscopic right hemi-hepatectomy plus total caudate lobectomy from January 2021 to January 2023 were enrolled in this study. Augmented reality navigation technology and the anterior approach were utilized in this operation. Routine operative and short-term postoperative outcomes were assessed to evaluate the feasibility of the novel navigation method in this operation. RESULTS: Right hemi-hepatectomy plus total caudate lobectomy was successfully performed in all 11 enrolled patients. Among the 11 patients, the mean operation time was 454.5 ± 25.0 min and the mean estimated blood loss was 209.1 ± 56.1 ml. Negative surgical margins were achieved in all patients. The postoperative course of all the patients was uneventful, and the mean length of postoperative hospital stay was 10.5 ± 1.2 days. CONCLUSION: Laparoscopic right hemi-hepatectomy plus total caudate lobectomy via the anterior approach may be feasible and safe for pCCA with the assistance of augmented reality navigation.