BACKGROUND:The oncological equivalence of parenchyma-sparing pancreatectomy versus conventional resection for solid pseudopapillary neoplasm of the pancreas remains debated. This study compares perioperative and long-term outcomes between these approaches. MATERIALS AND METHODS:A retrospective study was conducted on patients undergoing solid pseudopapillary neoplasm resection at a high-volume center between June 2002 and August 2024. Propensity score matching (1:1) balanced baseline characteristics between groups. Outcomes included morbidity, recurrence-free survival, and metabolic sequelae. RESULTS:Among 261 patients, 49 (18.8%) had enucleations, 28 (10.7%) had central pancreatectomies, 2 (0.8%) had duodenum-preserving pancreatic head resections, and 182 (69.7%) underwent conventional resection. After propensity score matching, 60 pairs were analyzed. Parenchyma-sparing pancreatectomy demonstrated reduced blood loss (100 vs 200 mL, P < .001), shorter operative time (3.0 vs 5.0 hours, P < .001), and shorter hospital stay (9 vs 10.5 days, P = .008). However, parenchyma-sparing pancreatectomy had a higher overall complication rate (60.0% vs 36.7%, P = .011), driven primarily by postoperative pancreatic fistula. Long-term recurrence-free survival was equivalent between groups (P = .971), with resection type not predicting recurrence. Although not statistically significant, parenchyma-sparing pancreatectomy showed numerically lower rates of new-onset diabetes mellitus (5.2% vs 12.7%, P = .279) and pancreatic exocrine insufficiency (10.3% vs 16.4%, P = .346). CONCLUSION:Parenchyma-sparing pancreatectomy for solid pseudopapillary neoplasm offers equivalent oncological control and superior perioperative efficiency compared with conventional resection, albeit with a higher incidence of manageable postoperative pancreatic fistula. Given the potential for preserved endocrine/exocrine function, parenchyma-sparing pancreatectomy is a viable strategy for carefully selected patients when performed by experienced surgeons.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease, with over one-third of patients developing liver metastasis following neoadjuvant chemotherapy (NAC). This study aimed to investigate how the effect of chemotherapy on the primary tumor shapes the hepatic pre-metastatic niches (PMNs), which remains poorly understood. Methods RNA sequencing was performed in a PDAC cohort to identify transcriptomic features associated with metastasis. We employed orthotopic and liver metastatic tumor models in mice to investigate the effects of extracellular vesicles derived from chemotherapy-treated PDAC cells, referred to as senescence-associated extracellular vesicles (S-EVs), on the hepatic PMNs. Mechanistically, we integrated proteomics and metabolomics to elucidate the molecular mechanisms by which S-EVs mediate hepatic metabolic reprogramming. Further, we utilized hepatocyte-specific Ache-knockout mice to validate the molecular mechanisms through which S-EVs promote liver metastasis in vivo. Results Chemotherapy-induced senescence in primary tumors correlated with PDAC liver metastasis and poor prognosis. S-EVs facilitated PMNs formation by promoting hepatic phosphatidylcholine (PC) accumulation. Mechanistically, S-EV-delivered hnRNPA1 stabilized AChE mRNA, thereby driving PC accumulation in the liver. In vitro co-culture system, PC depletion in hepatocytes successfully restored the impaired cytotoxicity of CD8⁺ T cells caused by S-EVs. Consistently, hepatocyte-specific Ache ablation in vivo restored S-EV-impaired CD8⁺ T cells cytotoxicity. Inhibition of AChE with pyridostigmine remodeled the hepatic PMNs and suppressed liver metastasis. Conclusions S-EVs from chemotherapy-induced senescent PDAC cells reshaped hepatic PMNs through AChE-dependent PC accumulation, thereby impairing CD8⁺ T cell cytotoxicity and promoting PDAC liver metastasis. Targeting AChE with pyridostigmine represented a promising strategy to prevent metastasis and augment the therapeutic efficacy of NAC.

IntroductionA subgroup of pancreatic cancer with unstable genome, such as BRCA mutation, may be more sensitive to platinum-based chemotherapy. How to define the patients with homologous recombination deficiency (HRD) status other than BRCA mutation has been a clinical challenge and interest.MethodsIn this retrospective cohort study, we collected NGS data of 163 pancreatic cancer patients from July 2020 to April 2024. HRD score was calculated by 3DMed-HRD algorithm. The median of HRD score of our study population was used as potential cut-off value to determine HRD status. Cox regression was used to evaluate association of HRD status, platinum-based chemotherapy and overall survival (OS). Kaplan-Meier method with log-rank test was performed to analyze OS among different subgroups.ResultsAmong the 163 patients, the HRD score ranged from 0 to 76. The mean value was 10.48. The median was 6. With a criterion of HRD ≥6 and/or germline Homologous Recombination Repair (HRR) mutation, a total of 89 patients were considered to be HRD+. HRD+ status was associated with a poor prognosis (HR: 1.46, 95%CI:1.01-2.11, p=0.04). Platinum-based all-time usage would reduce the hazard of death by 34% (HR: 0.66, 95%CI: 0.45-0.97, p=0.03). Among the HRD+ subjects, the initiation of platinum-based chemotherapy might be associated with a longer overall survival (OS: 19.92 vs 15.38, Log-Rank test, p=0.09).ConclusionHRD score could be a potential indicator for genome unstable pancreatic cancer patients who would benefit from platinum derivatives. Future study with better design and larger population size would help to determine a proper threshold for clinical application.

Aim: To test the hypothesis that intraoperative warming (IOW) can improve surgical outcomes after pancreaticoduodenectomy with portal vein reconstruction (PD-PVR). Methods: Patients diagnosed with pancreatic head ductal adenocarcinoma who underwent PD-PVR at Huashan Hospital between January 1, 2017, and January 1, 2022, were retrospectively divided into two groups according to whether IOW was implemented. The primary outcome was the incidence of textbook outcome (TO) after pancreatectomy. The secondary outcomes were intraoperative hypothermia and adjuvant chemotherapy (AC) completion rate. Results: Among the 196 included patients, 122 underwent IOW while 74 did not. Both average (35.2℃ vs. 36.2℃, p < 0.001) and minimum (34.0℃ vs. 35.6℃, p < 0.001) intraoperative body temperature were significantly higher in the IOW group compared with the non-IOW one. Satisfactory surgical outcomes were observed in the IOW group, due to a higher incidence of TOs (51.4% vs. 68.9%, p = 0.021), lower incidence of post-pancreatectomy hemorrhage (13.5% vs. 3.3%, p = 0.010), earlier AC initiation (48 day vs. 40 day, p < 0.001), and AC completion rate (59.5% vs. 76.2%, p = 0.020). IOW was the independent influential factor for TOs, intraoperative hypothermia, and AC completion. In survival analysis, the median overall survival was longer with AC completion (month, 8.6 vs. 27.5, p < 0.001) or TO (month, 16.2 vs. 20.0, p = 0.002). Intraoperative hypothermia (hazard ratio, 1.53; 95% confidence interval: 1.03–2.25, p = 0.033) was the independent risk factor of overall survival. Conclusions: Intraoperative hypothermia occurred frequently in patients with PD-PVR. IOW had a positive impact on surgical outcomes of PD-PVR, resulting in higher rates of TOs and postoperative AC completion.

Background:Neoadjuvant therapy (NAT) is a key component of the treatment strategy for borderline resectable pancreatic cancer (BRPC). However, early recurrence (ER) frequently occurs, leading to a poor prognosis. Effective approaches for ER risk stratification in patients with BRPC undergoing NAT have not been well established currently. This study aimed to develop biomarker-based perioperative scoring systems to predict ER in patients with BRPC who underwent resection after NAT. Methods:Patients with BRPC who underwent radical resection following NAT at our institute between 2018 and 2023 were retrospectively enrolled. Serum biochemical marker tests and imaging examinations were performed to evaluate recurrence. Perioperative biochemical and clinicopathological parameters were analyzed. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors for recurrence and to construct nomograms for ER prediction. Internal validation was conducted using the bootstrapping method. The accuracy in predicting ER was evaluated using receiver operating characteristic curve analysis. Survival analysis was performed using the Kaplan-Meier survival plots and log-rank test. Results:A total of 194 patients were enrolled. Recurrence occurred in 69.0% of all patients, and 61.1% of all recurrences were found within 6 months postoperatively. A preoperative scoring system was developed based on preoperative carbohydrate antigen 19-9 (CA19-9) and CA125 levels to predict ER [area under the curve (AUC), 0.700; 95% confidence interval (95% CI): 0.614-0.786] with 86.4% specificity and 48.7% sensitivity (cut-off value was 0.35886). Patients with a post-NAT prognostic score (PNPS) ≥0.35886 exhibited significantly poorer recurrence-free survival (RFS) (P<0.001) and overall survival (OS) (P<0.001) than those with a PNPS <0.35886. A postoperative scoring system based on the postoperative CA19-9 response was established to predict ER (AUC, 0.785; 95% CI: 0.705-0.866) with 65.4% specificity and 80.8% sensitivity (cut-off value was 0.43949). Patients with a postoperative prognostic score (PPS) ≥0.43949 exhibited poorer RFS (P<0.001) and OS (P<0.001) than those with a PPS <0.43949. For patients with normal CA19-9 levels after NAT, PNPS ≥0.35886 or PPS ≥0.43949 indicated a poor prognosis after surgery. For patients without normal CA19-9 levels after NAT, PNPS <0.35886 or PPS <0.43949 was associated with a favorable prognosis after surgery. Conclusions:The preoperative and postoperative scoring systems provide risk stratification for ER in patients with BRPC undergoing NAT. This may provide references to clinicians in identifying suitable candidates and optimal timing for surgery during NAT, and administering tailored adjuvant therapy (AT) after surgery.

This study assessed the safety, preliminary antitumor activity, and pharmacokinetics of HR070803 (a novel liposomal irinotecan) in combination with 5-FU/LV and oxaliplatin for treatment-naive patients with unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). This multicenter, open-label, single-arm, dose-escalation phase 1 study recruited treatment-naive patients aged 18–70 years with unresectable locally advanced or metastatic PDAC. Treatment doses were escalated from 40/60 (HR070803 40 mg/m2 plus 5-FU/LV and oxaliplatin 60 mg/m2) to 60/60 and 60/85. The primary endpoints were maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary endpoints included safety, preliminary antitumor activity, and pharmacokinetics. A total of 41 patients were enrolled, including 6, 17, and 18 patients in the 40/60, 60/60, and 60/85 group, respectively. Only one patient in the 60/60 group experienced dose-limiting toxicities of grade 3 increased alanine aminotransferase and grade 3 increased aspartate aminotransferase, and the MTD was not reached. Adverse events of grade ≥ 3 were reported in 31 (75.6

BACKGROUND:Literature on factors influencing prognosis after periarterial divestment for borderline resectable or locally advanced pancreatic ductal adenocarcinoma and preventative measures for postpancreatectomy hemorrhage is scarce. This study aimed to evaluate the efficacy of Neuro-Patch for arterial reinforcement in preventing postpancreatectomy hemorrhage and explore the oncologic outcomes of patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma following periarterial divestment. METHODS:We conducted a retrospective analysis of 125 patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma involving arteries who underwent periarterial divestment between January 2018 and May 2022. RESULTS:Among the study cohort, 54 patients underwent pancreaticoduodenectomy, 43 had distal pancreatectomy, and 28 received total pancreatectomy, with 74 patients also undergoing combined venous resection. Periarterial divestment was performed on the hepatic artery in 47 patients, the celiac artery in 3, the superior mesenteric artery in 22, and multiple arteries in 53. Neoadjuvant chemotherapy was administered to 24% of patients, with an R0 resection rate of 33.6%. The median postoperative hospital stay was 10 days, with a 90-day mortality rate of 3.2%. Neuro-Patch was used in 51 patients, leading to a significant reduction in postpancreatectomy hemorrhage (odds ratio 0.073, 95% confidence interval 0.007-0.783, P = .031). The median overall survival was 20.6 months, with 1- and 3-year survival rates estimated at 73.2% and 22.9%, respectively. Neoadjuvant chemotherapy (hazard ratio 0.494, 95% confidence interval 0.291-0.839, P = .009) and venous invasion (hazard ratio 2.041, 95% confidence interval 1.308-3.186, P = .002) emerged as independent predictors of overall survival. CONCLUSION:Neoadjuvant chemotherapy significantly enhances survival outcomes of patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma undergoing periarterial divestment, and it should be regarded as a standard preoperative approach. The Neuro-Patch provides structural reinforcement to the arterial wall, potentially reducing the risk of postpancreatectomy hemorrhage. However, randomized controlled trials are necessary to substantiate its efficacy and safety.

BACKGROUND:Tecotabart vedotin (LM-302) is a novel antibody-drug conjugate (ADC) targeting CLDN18.2, a promising therapeutic target in gastrointestinal cancers. This phase 1/2 study evaluated the safety, pharmacokinetics, immunogenicity, and preliminary anti-tumor activity of tecotabart vedotin in patients with advanced solid tumors, with a focus on CLDN18.2-positive gastric/gastroesophageal junction (G/GEJ) cancer. METHODS:This open-label, multicenter study utilized a Bayesian adaptive design. Phase 1 enrolled patients with advanced solid tumors; phase 2 focused on CLDN18.2-positive G/GEJ, pancreatic, biliary tract cancer, or gastrointestinal tumors with low to moderate CLDN18.2 expression. Tecotabart vedotin was administered at 0.2-2.8 mg/kg every 3 weeks (Q3W) or 1.8-2.0 mg/kg every 2 weeks (Q2W). Primary endpoints included dose-limiting toxicities (DLTs) and safety in phase 1, and objective response rate (ORR) in phase 2. Secondary endpoints included safety, pharmacokinetics, immunogenicity, and other anti-tumor activity outcomes. RESULTS:Overall, 153 patients received tecotabart vedotin (phase 1: 38; phase 2: 115). DLTs occurred in 5 patients at higher dose levels. The maximum tolerated dose was 2.4 mg/kg Q3W; recommended phase 2 doses were 1.8 mg/kg Q2W and 2.4 mg/kg Q3W. Among 52 evaluable patients with CLDN18.2-positive G/GEJ cancer receiving 1.8 mg/kg Q2W, ORR was 32.7 % (95 % confidence interval [CI] 20.3-47.1), with median progression-free survival of 4.9 months (95 % CI 2.7-6.9), and overall survival of 10.9 months (95 % CI 9.1-17.1). Adverse events were manageable and consistent with monomethyl auristatin E-based ADCs. CONCLUSIONS:Tecotabart vedotin demonstrated encouraging anti-tumor activity and manageable safety in CLDN18.2-positive G/GEJ cancer, supporting further clinical development in gastrointestinal malignancies.

BackgroundThe typical pathological feature of pancreatic ductal adenocarcinoma (PDAC) is a significant increase in stromal reaction, leading to a hypoxic and poorly vascularized tumor microenvironment. Tumor cells undergo metabolic reprogramming, such as the Warburg effect, yet the underlying mechanisms are not fully understood.MethodsInterference and overexpression experiments were conducted to analyze the in vivo and in vitro effects of USP7 on the growth and glycolysis of tumor cells. Small-molecule inhibitors of USP7 and transgenic mouse models of PDAC were employed to assess the consequences of targeting USP7 in PDAC. The molecular mechanism underlying USP7-induced c-Myc stabilization was determined by RNA sequencing, co-IP and western blot analyses.ResultsUSP7 is abnormally overexpressed in PDAC and predicts a poor prognosis. Hypoxia and extracellular matrix stiffness can induce USP7 expression in PDAC cells. Genetic silencing of USP7 inhibits the glycolytic phenotypes in PDAC cells, while its overexpression has the opposite effect, as demonstrated by glucose uptake, lactate production, and extracellular acidification rate. Importantly, USP7 promotes PDAC tumor growth in a glycolysis-dependent manner. The small-molecule inhibitor P5091 targeting USP7 effectively suppresses the Warburg effect and cell growth in PDAC. In a transgenic mouse model of PDAC, named KPC, P5091 effectively blocks tumor progression. Mechanistically, USP7 interacts with c-Myc, enhancing its stability and expression, which in turn upregulates expression of glycolysis-related genes.ConclusionsThis study sheds light on the molecular mechanisms underlying the Warburg effect in PDAC and unveils USP7 as a potential therapeutic target for improving PDAC treatment.

Background Deciphering the role of plasma proteins in pancreatic cancer (PC) susceptibility can aid in identifying novel targets for diagnosis and treatment.Methods We examined the relationship between genetically determined levels of plasma proteins and PC through a systemic proteome-wide Mendelian randomization (MR) analysis utilizing cis-pQTLs from multiple centers. Rigorous sensitivity analyses, colocalization, reverse MR, replications with varying instrumental variable selections and additional datasets, as well as subsequent meta-analysis, were utilized to confirm the robustness of significant findings. The causative effect of corresponding protein-coding genes' expression and their expression pattern in single-cell types were then investigated. Enrichment analysis, between-protein interaction and causation, knock-out mice models, and mediation analysis with established PC risk factors were applied to indicate the pathogenetic pathways. These candidate targets were ultimately prioritized upon druggability and potential side effects predicted by a phenome-wide MR.Results Twenty-one PC-related circulating proteins were identified in the exploratory phase with no evidence for horizontal pleiotropy or reverse causation. Of these, 11 were confirmed in a meta-analysis integrating external validations. The causality at a transcription level was repeated for neutrophil elastase, hydroxyacylglutathione hydrolase, lipase member N, protein disulfide-isomerase A5, xyloside xylosyltransferase 1. The carbohydrate sulfotransferase 11 and histo-blood group ABO system transferase exhibited high-support genetic colocalization evidence and were found to affect PC carcinogenesis partially through modulating body mass index and type 2 diabetes, respectively. Approved drugs have been established for eight candidate targets, which could potentially be repurposed for PC therapies. The phenome-wide investigation revealed 12 proteins associated with 51 non-PC traits, and interference on protein disulfide-isomerase A5 and cystatin-D would increase the risk of other malignancies.Conclusions By employing comprehensive methodologies, this study demonstrated a genetic predisposition linking 21 circulating proteins to PC risk. Our findings shed new light on the PC etiology and highlighted potential targets as priorities for future efforts in early diagnosis and therapeutic strategies of PC.

Patients with advanced pancreatic cancer (PC) need a cost-effective treatment regimen. The present study was designed to compare the efficacy and safety of nab-paclitaxel plus S-1 (AS) and gemcitabine plus S-1 (GS) regimens in patients with chemotherapy-na & iuml;ve advanced PC. In this open-label, multicenter, randomized study named AvGmPC, eligible patients with chemotherapy-na & iuml;ve advanced PC were randomly assigned (1:1) to receive AS (125 mg/m2 nab-paclitaxel, days 1 and 8; 80-120 mg S-1, days 1-14) or GS (1,000 mg/m2 gemcitabine, days 1 and 8; 80-120 mg S-1, days 1-14). The treatment was administered every 3 weeks until intolerable toxicity or disease progression occurred. The primary endpoint was progression-free survival (PFS). Between December 2018 and March 2022, 101 of 106 randomized patients were treated and evaluated for analysis (AS, n=49; GS, n=52). As of the data cutoff, the median follow-up time was 11.37 months [95% confidence interval (CI), 9.31-13.24]. The median PFS was 7.16 months (95% CI, 5.19-12.32) for patients treated with AS and 6.41 months (95% CI, 3.72-8.84) for patients treated with GS (HR=0.78; 95% CI, 0.51-1.21; P=0.264). The AS regimen showed a slightly improved overall survival (OS; 13.27 vs. 10.64 months) and a significantly improved ORR (44.90 vs. 15.38%; P=0.001) compared with the GS regimen. In the subgroup analyses, PFS and OS benefits were observed in patients treated with the AS regimen who had KRAS gene mutations and high C-reactive protein (CRP) levels (>= 5 mg/l). The most common grade >= 3 adverse events were neutropenia, anemia and alopecia in the two groups. Thrombocytopenia occurred more frequently in the GS group than in the AS group. While the study did not meet the primary endpoint, the response benefit observed for AS may be suggestive of meaningful clinical activity in this population. In particular, promising survival benefits were observed in the subsets of patients with KRAS gene mutations and high CRP levels, which is encouraging and warrants further investigation. This trial was retrospectively registered as ChiCTR1900024588 on July 18, 2019.

Solid pseudopapillary tumor of the pancreas (SPTP) is a rare neoplasm predominantly observed in young females. Pathologically, CTNNB1 mutations, β-catenin nuclear accumulation, and subsequent Wnt-signaling pathway activation are the leading molecular features. Accurate preoperative diagnosis often relies on imaging techniques and endoscopic biopsies. Surgical resection remains the mainstay treatment. Risk models, such as the Fudan Prognostic Index, show promise as predictive tools for assessing the prognosis of SPTP. Establishing three types of metachronous liver metastasis can be beneficial in tailoring individualized treatment and follow-up strategies. Despite advancements, challenges persist in understanding its etiology, establishing standardized treatments for unresectable or metastatic diseases, and developing a widely recognized grading system. This comprehensive review aims to elucidate the enigma by consolidating current knowledge on the epidemiology, clinical presentation, pathology, molecular characteristics, diagnostic methods, treatment options, and prognostic factors.

BACKGROUND Pancreatectomy with concomitant portomesenteric vein resection (PVR) enables patients with portomesenteric vein (PV) involvement to achieve radical resection of pancreatic ductal adenocarcinoma, however, early recurrence (ER) is frequently observed. AIM To predict ER and identify patients at high risk of ER for individualized therapy. METHODS Totally 238 patients undergoing pancreatectomy and PVR were retrospectively enrolled and were allocated to the training or validating cohort. Univariate Cox and LASSO regression analyses were performed to construct serum recurrence score (SRS) based on 26 serum-derived parameters. Uni- and multivariate Cox regression analyses of SRS and 18 clinicopathological variables were performed to establish a Nomogram. Receiver operating characteristic curve analysis was used to evaluate the predictive accuracy. Survival analysis was performed using Kaplan-Meier method and log-rank test. RESULTS Independent serum-derived recurrence-relevant factors of LASSO regression model, including postoperative carbohydrate antigen 19-9, postoperative carcinoembryonic antigen, postoperative carbohydrate antigen 125, preoperative albumin (ALB), preoperative platelet to ALB ratio, and postoperative platelets to lymphocytes ratio, were used to construct SRS [area under the curve (AUC): 0.855, 95%CI: 0.786-0.924]. Independent risk factors of recurrence, including SRS [hazard ratio (HR): 1.688, 95%CI: 1.075-2.652], pain (HR: 1.653, 95%CI: 1.052-2.598), perineural invasion (HR: 2.070, 95%CI: 0.827-5.182), and PV invasion (HR: 1.603, 95%CI: 1.063-2.417), were used to establish the recurrence nomogram (AUC: 0.869, 95%CI: 0.803-0.934). Patients with either SRS > 0.53 or recurrence nomogram score > 4.23 were considered at high risk for ER, and had poor long-term outcomes. CONCLUSION The recurrence scoring system unique for pancreatectomy and PVR, will help clinicians in predicting recurrence efficiently and identifying patients at high risk of ER for individualized therapy.

Background: Para-aortic lymph node (PALN) metastasis affects approximately 20% of patients with pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of PALN metastases and dissection remains unclear. Methods: This retrospective cohort study included patients with PDAC of the pancreatic head who had undergone pancreaticoduodenectomy (PD) at our center between January 2017 and December 2020. Results: A total of 234 patients were included in the study. PALN dissection improved the median overall survival (OS) without statistical significance (24.1 vs 18.1 months, P = .156). The median recurrence-free survival was significantly longer in the PALN-dissection group than the group without PALN dissection (18.2 vs 11.6 months, P = .040). Conversely, there were no significant differences in the long-term prognosis between the PALN-positive and PALN-negative subgroups in the PALN-dissection group. Multivariate analysis showed that PALN metastasis was not an independent risk factor for OS (hazard ratio: 0.831, 95% confidence interval: 0.538–1.285, P = .406). Conclusions: For patients with pancreatic head ductal adenocarcinoma, PD with PALN dissection may achieve survival prolongation and bridge the survival gap between patients with and without PALN metastasis without significantly increasing the perioperative risks.

In prior research, both miRNA-125b and BLZ945 have shown potential in effectively inhibiting M2 macrophage polarization and producing antitumor effects. Nevertheless, their physicochemical characteristics present significant challenges for efficient in vivo delivery. Ionizable cationic lipid nanoparticles (LNPs), recognized for their superior biocompatibility and drug-loading capacity, serve as a novel carrier for nucleic acid-based therapeutics. In our study, we successfully encapsulated both agents within LNPs and conducted a thorough characterization. Subsequently, we investigated their potential to repolarize M2 macrophages in vitro and evaluated their in vivo distribution, biosafety, and antitumor efficacy. The findings revealed that the LNPs maintained excellent drug-loading efficiency, consistent particle size, and stable zeta potential. All formulations effectively inhibited M2 macrophage polarization in vitro. Upon administration in vivo, the LNPs not only demonstrated favorable biosafety profiles but also accumulated efficiently in tumor tissues, substantially reducing tumor burden, particularly notable in co-loaded LNPs. Our results affirm that LNPs are an effective carrier for miRNA-125b and BLZ945, highlighting this encapsulation approach as promising for the treatment of solid tumors and meriting further investigation. Practitioner points: (i) Ionizable cationic nanoparticles provide high and stable encapsulation rates to efficiently load nucleic acid polymers into the LNP, avoiding the rapid accumulation of circulating macrophages, which can lead to reduced penetration of the LNP into target tissues. Therefore, it can be used as a novel drug delivery method to benefit clinical patients. (ii) miRNA-125b LNP/BLZ945 LNP attenuated the depleting effect of BLZ945 on macrophages and significantly inhibited macrophage M2 polarization. It could be effectively distributed in tumors and showed good biosafety while exerting antitumor effects, bringing hope to clinical pancreatic tumor patients.

BACKGROUND:Early recurrence (ER) is associated with dismal outcomes in patients undergoing radical resection for pancreatic ductal adenocarcinoma (PDAC). Approaches for predicting ER will help clinicians in implementing individualized adjuvant therapies. Postoperative serum tumor markers (STMs) are indicators of tumor progression and may improve current systems for predicting ER. AIM:To establish an improved nomogram based on postoperative STMs to predict ER in PDAC. METHODS:We retrospectively enrolled 282 patients who underwent radical resection for PDAC at our institute between 2019 and 2021. Univariate and multivariate Cox regression analyses of variables with or without postoperative STMs, were performed to identify independent risk factors for ER. A nomogram was constructed based on the independent postoperative STMs. Receiver operating characteristic curve analysis was used to evaluate the area under the curve (AUC) of the nomogram. Survival analysis was performed using Kaplan-Meier survival plot and log-rank test. RESULTS:Postoperative carbohydrate antigen 19-9 and carcinoembryonic antigen levels, preoperative carbohydrate antigen 125 levels, perineural invasion, and pTNM stage III were independent risk factors for ER in PDAC. The postoperative STMs-based nomogram (AUC: 0.774, 95%CI: 0.713-0.835) had superior accuracy in predicting ER compared with the nomogram without postoperative STMs (AUC: 0.688, 95%CI: 0.625-0.750) (P = 0.016). Patients with a recurrence nomogram score (RNS) > 1.56 were at high risk for ER, and had significantly poorer recurrence-free survival [median: 3.08 months, interquartile range (IQR): 1.80-8.15] than those with RNS ≤ 1.56 (14.00 months, IQR: 6.67-24.80), P < 0.001). CONCLUSION:The postoperative STMs-based nomogram improves the predictive accuracy of ER in PDAC, stratifies the risk of ER, and identifies patients at high risk of ER for tailored adjuvant therapies.

Objectives: Pancreatic cancer is one of the most common malignant tumors of the digestive tract. Due to its strong concealment and rapid disease progress, it is characterized by high mortality and low cure rate. Current research focuses on screening high-risk populations, preventing the occurrence of pancreatic cancer and developing imaging technology and tumor markers for early diagnosis. This study aimed to investigate the absolute quantitative detection of microRNA-25 (miR-25) and reveal its quantitative changes in the treatment of pancreatic cancer. We compared serum miR-25 level between pancreatic cancer patients and other tumor patients, especially those with gastrointestinal cancer, to provide further evidence for early diagnosis, differential diagnosis and prognosis of pancreatic cancer. Methods: We collected serum samples from 51 pancreatic cancer patients (including 21 patients with preoperative and postoperative samples), 52 pancreatitis patients, 141 other tumor patients, and 50 healthy individuals from Huashan Hospital, Fudan University. The serum levels of miR25, Carbohydrate Antigen 19-9 (CA19-9), Carbohydrate Antigen 125 (CA125) and Carcinoembryonic Antigen (CEA) in these populations were measured to analyze the value of miR-25 quantitative detection in the diagnosis, postoperative assessment and Tumor Node Metastasis (TNM) staging of pancreatic cancer. Results: Among the 51 pancreatic cancer patients, 50 cases (98.04 %) showed miR-25 levels above the threshold (3333 copies/mu l), while all samples in normal group showed negative. The mean level of miR-25 in serum was 5707.45 +/- 361.02 copies/ mu l. In other tumor groups, 21/141 (14.89 %) patients showed positive results and the mean miR-25 level was 847.09 +/- 125.97 copies/mu l. Comparing before and after operation in 21 paired samples, the level of miR-25 declined significantly after operation, with an average decline rate of 86.36 %. Conclusions: Serum miR-25 levels were significantly higher in pancreatic cancer patients compared to both normal and other tumor groups and decreased significantly after surgery. In addition, miR-25 showed higher sensitivity than common tumor markers (CA19-9, CA125, CEA) in early diagnosis of pancreatic cancer, and proved to be of significant value in evaluating the effect of surgical treatment.

Abstract Liposomal irinotecan has shown promising antitumor activity in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) who have undergone prior gemcitabine-based therapies. This randomized, double-blind, parallel-controlled, multicenter phase 3 study (NCT05074589) assessed the efficacy and safety of liposomal irinotecan HR070803 combined with 5-fluorouracil (5-FU) and leucovorin (LV) in this patient population. Patients with unresectable, locally advanced, or metastatic PDAC who had previously received gemcitabine-based therapies were randomized 1:1 to receive either HR070803 (60 mg/m2 anhydrous irinotecan hydrochloride, equal to 56.5 mg/m2 free base) or placebo, both in combination with 5-FU (2000 mg/m2) and LV (200 mg/m2), all given intravenously every two weeks. The primary endpoint of the study was overall survival (OS). A total of 298 patients were enrolled and received HR070803 plus 5-FU/LV (HR070803 group, n = 149) or placebo plus 5-FU/LV (placebo group, n = 149). Median OS was significantly improved in the HR070803 group compared to the placebo group (7.4 months [95% CI 6.1–8.4] versus 5.0 months [95% CI 4.3–6.0]; HR 0.63 [95% CI 0.48–0.84]; two-sided p = 0.0019). The most common grade ≥ 3 adverse events in the HR070803 group were increased gamma-glutamyltransferase (19.0% versus 11.6% in placebo group) and decreased neutrophil count (12.9% versus 0 in placebo group). No treatment-related deaths occurred in the HR070803 group, while the placebo group reported one treatment-related death (abdominal infection). HR070803 in combination with 5-FU/LV has shown promising efficacy and manageable safety in advanced or metastatic PDAC in the second-line setting, representing a potential option in this patient population.

Postoperative pancreatic fistula (POPF) is a frequent complication after pancreatectomy, leading to increased morbidity and mortality. Optimizing prediction models for POPF has emerged as a critical focus in surgical research. Although over sixty models following pancreaticoduodenectomy, predominantly reliant on a variety of clinical, surgical, and radiological parameters, have been documented, their predictive accuracy remains suboptimal in external validation and across diverse populations. As models after distal pancreatectomy continue to be progressively reported, their external validation is eagerly anticipated. Conversely, POPF prediction after central pancreatectomy is in its nascent stage, warranting urgent need for further development and validation. The potential of machine learning and big data analytics offers promising prospects for enhancing the accuracy of prediction models by incorporating an extensive array of variables and optimizing algorithm performance. Moreover, there is potential for the development of personalized prediction models based on patient- or pancreas-specific factors and postoperative serum or drain fluid biomarkers to improve accuracy in identifying individuals at risk of POPF. In the future, prospective multicenter studies and the integration of novel imaging technologies, such as artificial intelligence-based radiomics, may further refine predictive models. Addressing these issues is anticipated to revolutionize risk stratification, clinical decision-making, and postoperative management in patients undergoing pancreatectomy.