Despite the prevalence of the KRAS G12D mutation in approximately 40% of pancreatic ductal adenocarcinoma (PDAC) cases and its association with the poorest prognosis among KRAS variants, the downstream transcriptional effectors driving its aggressive metastatic phenotype remain poorly defined. Through integrated bioinformatics and experimental validation, we identified ARNTL2 as a factor associated with KRAS G12D-mutant PDAC. ARNTL2 directly bound to the SERPINE1 promoter to activate its expression, establishing an ARNTL2-SERPINE1 axis that orchestrated epithelial-mesenchymal transition and drove metastasis in vitro and in vivo. Rescue experiments confirmed SERPINE1 as the indispensable downstream mediator. Clinical validation demonstrated that ARNTL2 and SERPINE1 protein levels correlated positively and stratified patients into distinct prognostic subgroups. Furthermore, this axis altered sensitivity to selective KRAS G12D inhibition in vitro. These findings identify an experimentally supported ARNTL2-SERPINE1 transcriptional axis in KRAS G12D-mutant PDAC that warrants further validation in genotype-faithful and clinically relevant models.

Adoptive T cell transfer targeting KRAS G12D can induce tumor regression in advanced epithelial cancers. The safety, efficacy of T cell receptor (TCR)-T cells targeting KRAS G12V, and potential benefit of repeat infusions remain unknown. In a single-arm phase 1/2 clinical trial (NCT04146298), we treated five patients with recurrent pancreatic cancer using adoptive transfer of autologous T cells engineered to express an HLA-A∗11:01-restricted KRAS G12V8-16-specific TCR. Three patients received multiple infusions. Primary endpoints were safety and objective response rate. The most frequent adverse event of grade 3 or higher was hematologic toxicities due to lymphodepletion. One patient with liver metastases experienced a complete response lasting 5.5 months, and two patients experienced short-term stable disease. TCR-T cells were detected in peripheral blood of four patients at 1 month after their first infusion. No clinical responses were observed with TCR-T retreatments. In two patients, there was evidence of hyper-acute rejection of TCR-T cells after retreatment, which was likely mediated by persistent antibodies targeting the engineered KRAS G12V-reactive TCR induced from the prior TCR-T cell infusion. This study provides early results demonstrating safety, therapeutic potential, and considerations for repeat infusion of HLA-A∗11:01-restricted TCR-T cells targeting KRAS G12V in patients with recurrent pancreatic cancer.

Background Pancreatic neuroendocrine neoplasm (PanNEN) represents the second most common epithelial neoplasm of the pancreas, characterized by remarkable heterogeneity among its subtypes. This study aimed to comprehensively characterize the molecular landscape of PanNENs and identify key features associated with tumor progression and therapeutic implications.Results We performed an integrated molecular analysis of 106 PanNEN samples using whole-genome sequencing, whole-exome sequencing, and transcriptome sequencing. PanNEC demonstrated significantly higher mutation burden compared to PanNET, with recurrent mutations in KRAS and TP53. In metastatic PanNET, structural variation rearrangement signatures (RS) emerged as crucial molecular events affecting tumor-related gene expression. Copy number variation (CNV) analysis revealed four distinct PanNET subgroups: chromosomal-scale loss of heterozygosity (LOH), limited CNV events, whole-genome duplication (WGD), and WGD with chromosomal-scale LOH. We proposed a novel evolutionary model for PanNET based on CNV patterns, validated through transcriptomic analysis and clinical sampling. WGD was identified as a pivotal event in PanNET progression, significantly enhancing tumor aggressiveness. Transcriptomic profiling revealed distinct immune signatures associated with RS subtypes and WGD status, with the RS2 subtype showing a particularly favorable immune profile suggesting potential immunotherapy responsiveness.Conclusions In summary, our systematic genomic and transcriptomic analyses revealed distinct biological features among PanNEN subtypes and identified a novel CNV-based evolutionary trajectory in PanNET. We demonstrated that structural variation and whole-genome duplication were critical events driving PanNET progression, providing new insights into PanNET biology with potential clinical implications.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to intrinsic and acquired chemotherapy resistance, particularly after neoadjuvant therapy (NAT). To uncover therapy-induced vulnerabilities, we established matched patient-derived organoids from PDAC tissues obtained before and after NAT, creating a unique platform to track treatment-driven evolution. Comparative analysis of these organoids revealed negligible variation in key driver gene mutations but identified a transition from classical to basal-like subtype in one patient after neoadjuvant therapy. Notably, albumin-bound paclitaxel and gemcitabine (AG) treatment induced the resistance to paclitaxel, accompanied by elevated KRAS and MAPK signaling, which was confirmed by transcriptomic comparison of PDAC patient samples with (30 cases) and without (60 cases) AG treatment. Single-cell RNA sequencing of the organoid-derived xenografts revealed AG treatment promoted the emergence of resistant cell clusters characterized by KRAS and MAPK signaling activation. Importantly, EGFR/KRAS/BRAF signaling inhibitors effectively suppressed the growth of AG-resistant PDAC organoids. In a validation cohort of 29 organoids, pan-KRAS inhibitors exhibited superior efficacy against the residual organoids after AG treatment. These results provided insights into molecular changes in PDAC during treatment process and demonstrate that AG chemotherapy can activate the KRAS and MAPK signaling, presenting a potential target for therapeutic intervention.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with a five-year survival rate below 15

Purpose The present study aimed to clarify the distribution pattern of carcinoma associated fibroblasts (CAFs) across pancreatic ductal adenocarcinoma (PDAC) and its prognostic prediction value.Methods Data of two cohorts were retrospectively collected from consecutive patients who underwent primary pancreatic resection from January 2015 to December 2017. We used tumor specimens to screen out the most suitable markers for the spatial distribution analysis for CAFs subpopulations. We utilized a tissue microarray to assess the spatial intensity of α-SMA expression within the tumor microenvironment. Specifically, we classified CAFs into two types based on their α-SMA spatial expression. Type II CAFs were designated as those located in the juxtatumoural stroma with α-SMA expression that was moderate or higher, and those in the peripheral stroma with α-SMA expression that was less than moderate. All other cases, where the α-SMA expression did not meet these criteria, were categorized as Type I CAFs. Multivariable Cox proportional hazards regression was used to assess risk factors associated with patient outcomes. RNA sequencing data were obtained from bulk tumor samples and isolated CAFs from patients to reveal the distinct pattern and elucidated their fundamental characteristics.Results The α-SMA spatial intensity was the most suitable variable for representative of CAFs spatial characteristics. Patients with Type Ⅰ CAFs were more likely to be allocated into N1 or N2 of the N stage and Ⅱ and Ⅲ of the TNM stage. The spatial distribution pattern of CAFs (Type Ⅰ v.s. Type Ⅱ: HR, 1.568; 95 % CI, 1.053–2.334; P = 0.027) was an independent prognostic factor in the discovery cohort, so as in the validation (Type Ⅰ vs. Type Ⅱ: HR, 2.197; 95 % CI, 1.410–3.422; P = 0.001). RNA sequencing analysis revealed that the differentially expressed genes (DEGs) in Type I CAFs are closely associated with those in corresponding tumor tissues, highlighting the enhanced biological significance of immune-related and oncogenic invasive pathways.Conclusions Our findings that two types of α-SMA-positive CAFs with different spatial patterns present heterogeneously across tissues of PDACs and correlated with patients’ outcomes. The spatial location of CAFs may facilitate patients’ selection in precision medicine of PDACs.

Putting pancreatic adenocarcinoma (PAAD) screening into perspective for high-risk individuals could significantly reduce cancer morbidity and mortality. Previous studies have profiled somatic mutations in PAAD. In contrast, the prevalence of mutations in PAAD predisposition genes has not been defined, especially in the Asian population. Using a multi-tier cohort design and whole genome/exome sequencing, we create a comprehensive germline mutation map of PAAD in 1,123 Chinese cancer patients in comparison with 11 pan-ethnic studies. For well-known pathogenic/likely pathogenic germline variants, Chinese patients exhibit overlapping but distinct germline mutation patterns comparing with Western cohorts, highlighted by lower mutation rates in known PAAD genes including BRCA1, BRCA2, ATM, CDKN2A, and CHEK2, and distinct mutations in CFTR, RAD51D, FANCA, ERCC2, and GNAS exclusive to Chinese patients. CFTR emerges as a top candidate gene following loss of heterozygosity analysis. Using an integrative multi-omics and functional validation paradigm, we discover that deleterious variants of uncertain significance may compromise CFTR's tumor suppressor function, and demonstrate the clinical relevance by using patient derived organoids for drug screen. Our multifaceted approach not only deepens the knowledge of population differences in PAAD germline mutations but also unveils potential avenues for targeted therapeutic interventions.

T cells targeting a KRAS mutation can induce durable tumor regression in some patients with metastatic epithelial cancer. It is unknown whether T cells targeting mutant KRAS that are capable of killing tumor cells can be identified from peripheral blood of patients with pancreatic cancer. We developed an in vitro stimulation approach and identified HLA-A*11:01-restricted KRAS G12V-reactive CD8+ T cells and HLA-DRB1*15:01-restricted KRAS G12V-reactive CD4+ T cells from peripheral blood of 2 out of 6 HLA-A*11:01-positive patients with pancreatic cancer whose tumors expressed KRAS G12V. The HLA-A*11:01-restricted KRAS G12V-reactive T cell receptor (TCR) was isolated and validated to specifically recognize the KRAS G12V8-16 neoepitope. While T cells engineered to express this TCR specifically recognized all 5 tested human HLA-A*11:01+ and KRAS G12V+ pancreatic cancer organoids, the recognition was often modest, and tumor cell killing was observed in only 2 out of 5 organoids. IFN-γ priming of the organoids enhanced the recognition and killing by the TCR-engineered T cells. The TCR-engineered T cells could significantly slow the growth of an established organoid-derived xenograft in immunodeficient mice. Our data suggest that this TCR has potential for use in TCR-gene therapy, but additional strategies that enhance tumor recognition by the TCR-engineered T cells likely will be required to increase clinical activity.

Pancreatic cancer is known for its lethal condition, with most cases being diagnosed at advanced stage. Recently, liquid biopsy has emerged as a promising tool in cancer detection. Here we develop both an early detection model and a prognostic model for pancreatic cancer using cell-free DNA (cfDNA) end motif, fragmentation, nucleosome footprint (NF), and copy number alteration (CNA) features from plasma cfDNA. A total of 975 individuals were enrolled in our study. We developed an integrated model that demonstrated superior performance in distinguishing patients with early-stage pancreatic cancer from non-cancer controls. Moreover, we find that cfDNA features are associated with prognostic outcomes among pancreatic cancer patients. In this study, a cfDNA-based liquid biopsy signature is established for the early detection and prognostic prediction of pancreatic cancer. CfDNA may become a valuable tool for enhancing early diagnosis and prognosis assessment in this challenging disease.

免疫治疗使部分肿瘤患者获益，但对胰腺癌患者无效。系统性免疫生物标志物和免疫评分方法作为肿瘤系统性免疫评价的重要组成部分，在肿瘤诊断、治疗和预后中发挥着重要作用。本文就近年来影响胰腺癌的系统性免疫生物标志物及免疫评分的方法进行综述。

Background: The superior mesenteric artery-first approach has been proved superior in pancreatoduodenectomy compared with the standard procedure. It is unclear whether similar benefits could be obtained in distal pancreatectomy with celiac axis resection. Methods: Perioperative and survival outcomes of patients who underwent distal pancreatectomy with celiac axis resection with the modified artery-first approach or traditional approach between January 2012 and September 2021 were compared. Results: The entire cohort comprised 106 patients (modified artery-first approach, n = 35; traditional approach, n = 71). The most common complication was postoperative pancreatic fistula (n = 18, 17.0 per cent), followed by ischaemic complications (n = 17, 16.0 per cent) and surgical site infection (n = 15, 14.0 per cent). Intraoperative blood loss (400 versus 600ml, P = 0.017) and intraoperative transfusion rate (8.6 versus 29.6 per cent, P = 0.015) were lower in the modified artery-first approach group compared with the traditional approach group. A higher number of harvested lymph nodes (18 versus 13, P = 0.030) and R0 resection rate (88.6 versus 70.4 per cent, P = 0.038) and a lower incidence of ischaemic complications (5.7 versus 21.1 per cent, P = 0.042) was observed in the modified artery-first approach group compared with the traditional approach group. In multivariable analysis, the modified artery-first approach (OR 0.006, 95 per cent c.i., 0 to 0.447; P = 0.020) was protective against ischaemic complications. Conclusions: Compared with the traditional approach, the modified artery-first approach was associated with lower blood loss and fewer ischaemic complications, and a higher number of harvested lymph nodes and R0 resection rate. Thus, it might improve the safety, staging and prognosis of distal pancreatectomy with celiac axis resection for pancreatic cancer.

Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Navy Military Medical University (Second Military Medical University), Shanghai, China Department of General Surgery, Naval Medical Centre of People’s Liberation Army, Shanghai, China Department of Hepatobiliary Surgery, First People’s Hospital of Jining, Jining, China Department of Pathology, Changhai Hospital, Naval Military Medical University (Second Military Medical University), Shanghai, China

胰腺癌是一种常见的消化道肿瘤,恶性程度高,预后极差.目前针对胰腺癌有多种治疗方案,但效果均不太理想.阐明胰腺癌发病机制仍是临床亟需解决的重要难题.可变剪接是真核生物基因表达调控的重要手段,同一基因的剪接异构体介导产生不同生物学表型,其异常可导致诸多疾病的产生.Numb,一种重要的细胞命运决定蛋白,其可变剪接近年来被发现与癌症的发生密切相关.在胰腺癌中Numb的选择性剪接可产生多种不同亚型的Numb蛋白,对癌症相关通路的活化以及肿瘤细胞生物学行为具有不同的调节作用,探索Numb的剪接异构体在胰腺癌中不同功能有利于解释胰腺癌发病机理和新疗法的开发.本文就Numb蛋白在胰腺癌中研究进展进行综述,着重探讨其剪接异构体功能特点以及不同亚型对胰腺癌各方面的调节作用.

Cancer immunotherapy has achieved impressive therapeutic effects in many cancers, while only a small subset of patients benefit from it and some patients even have experienced severe toxicity. It is urgent to develop a feasible large-cohort humanized mouse model to evaluate the pre-clinical efficacy and safety of cancer immunotherapy. Furthermore, developing potentially effective combination therapy between cancer immunotherapy and other therapies also needs humanized mouse model to adequately mimic clinical actual setting. Herein, we established a humanized mouse model engrafted with less human CD34(+) HSCs than ever before and then evaluated reconstitution efficiency and the profiles of human immune cells in this humanized mouse model. Also, this humanized mouse model was used to evaluate the preclinical efficacy and safety of cancer immunotherapy. For each batch of CD34(+) HSCs humanized mouse model, a relatively-large cohort with over 25% human CD45(+) cells in peripheral blood was established. This humanized mouse model could efficiently reconstitute human innate and adaptive immune cells. This humanized mouse model supported patient-derived xenograft tumor growth and tumor infiltration of PD-1(+) human T cells. Furthermore, therapeutic efficacy, re-activation of tumor-infiltrated T cells, and side effects of checkpoint blockade therapy could be monitored in this humanized mouse model. Human T cells from this humanized mouse model were successfully engineered with CD19-CAR. CD19 CAR-T cells could effectively deplete B cells and suppress tumor growth of acute lymphoblastic leukemia in vivo in this humanized mouse model. This humanized mouse model also could be used to demonstrate the efficacy of bispecific antibodies, such as anti-CD19/CD3. Overall, our work provides a feasible large-cohort humanized mouse model for evaluating a variety of cancer immunotherapy approaches including checkpoint inhibitors, adoptive cell therapy, and bispecific antibody therapy, and demonstrates that human T cells from this humanized mouse model possess anti-tumor activities in vitro and in vivo.

Chromatin accessibility plays an essential role in controlling cellular identity and the therapeutic response of human cancers. However, the chromatin accessibility landscape and gene regulatory network of pancreatic cancer are largely uncharacterized. Here, we integrate the chromatin accessibility profiles of 84 pancreatic cancer organoid lines with whole-genome sequencing data, transcriptomic sequencing data and the results of drug sensitivity analysis of 283 epigenetic-related chemicals and 5 chemotherapeutic drugs. We identify distinct transcription factors that distinguish molecular subtypes of pancreatic cancer, predict numerous chromatin accessibility peaks associated with gene regulatory networks, discover regulatory noncoding mutations with potential as cancer drivers, and reveal the chromatin accessibility signatures associated with drug sensitivity. These results not only provide the chromatin accessibility atlas of pancreatic cancer but also suggest a systematic approach to comprehensively understand the gene regulatory network of pancreatic cancer in order to advance diagnosis and potential personalized medicine applications.

Background: Pancreatic cancer is a life-threatening malignant disease with significant diversity among geographic regions and races leading to distinct carcinogenesis and prognosis. Previous studies mainly focused on Western patients, while the genomic landscape of Oriental patients, especially Chinese, remained less investigated. Methods A total of 408 pancreatic cancer patients were enrolled. A panel containing 436 cancer-related genes was used to detect genetic alterations in tumor samples. Results We profiled the genomic alteration landscape of pancreatic duct adenocarcinoma (PDAC), intraductal papillary mucinous neoplasm (IPMN), periampullary carcinoma (PVC), and solid-pseudopapillary tumor (SPT). Comparison with a public database revealed specific gene mutations in Oriental PDAC patients including higher mutation rates of DNA damage repair-related genes. Analysis of mutational signatures showed potential heterogenous carcinogenic factors caused by diabetes mellitus. KRAS mutation, especially KRAS G12D mutation, was associated with poor survival, while patients not harboring the 17 significant copy number variations (CNVs) had a better prognosis. We further identified multiple correlations between clinicopathologic variables and genetic mutations, as well as CNVs. Finally, by network-based stratification, three classes of PDAC patients were robustly clustered. Among these, class 1 (characterized by the Fanconi anemia pathway) achieved the best outcome, while class 2 (involved in the platinum drug resistance pathway) suffered from the worst prognosis. Conclusions In this study, we reported for the first time the genetic alteration landscape of Oriental PDAC patients identifying many Oriental-specific alterations. The relationship between genetic alterations and clinicopathological factors as well as prognosis demonstrated important genomic impact on tumor biology. This study will help to optimize clinical treatment of Oriental PDAC patients and improve their survival.

Purpose The study aimed to investigate the potential benefit of more than 4 courses of S1 adjuvant chemotherapy for patients with pancreatic ductal adenocarcinoma (PDAC) after surgery. Method Data were retrospectively collected from consecutive patients who underwent S-1 adjuvant chemotherapy following curative pancreatectomy between January 2016 and December 2018. Four-courses and > 4 courses cohorts were compared for overall survival (OS) as a primary outcome, and relapse-free survival (RFS) and adverse event incidence as secondary outcomes. Results Four-courses and > 4 courses cohorts comprised 99 patients and 64 ones, respectively. TNM stage (stage II vs. I: HR, 2.125; 95% CI, 1.164–4.213; P = 0.015), duration of S-1 administration (4 vs. > 4 courses: HR, 3.113; 95% CI, 1.531–6.327; P = 0.002) and tumor grade (G3 vs. G1/2: HR, 3.887; 95% CI, 1.922–7.861; P < 0.001) were independent prognostic factors. Under the condition of patients’ survival time beyond 8 months, the OS of patients in > 4 courses cohort was significantly prolonged compared with that of 4 courses cohort (4 vs. > 4 courses: HR, 2.284; 95% CI, 1.197–4.358; P = 0.012), especially for patients in TNM stageII (4 vs. > 4 courses: HR, 2.906; 95% CI, 1.275–6.623; P = 0.011).RFS and adverse events incidence did not signifcantly difer between both cohorts. Conclusion Prolonged duration of S-1 intake is beneficial to prognosis of patients with PDAC resection.

Objective: To evaluate the performance of the European Evidence-based Guidelines on Pancreatic Cystic Neoplasms (EEGPCN)(2018) and International Association of Pancreatology(IAP) Guideline(Version 2017) in predicting high grade dysplasia/invasive carcinoma-intraductal papillary mucinous neoplasm(HGD/INV-IPMN). Methods: A retrospective analysis of 363 patients,who underwent surgical resection in Changhai Hospital affiliated to Navy Medical University from January 2012 to December 2018 and were pathologically identified as (intraductal papillary mucinous neoplasm, IPMN),was performed. The patients,including 230 males and 133 females,aging (61.7±10.1) years(range:19 to 83 years). The proportion of HGD/INV-IPMN who met with the absolute indication(AI) of EEGPCN and high risk stigma(HRS) of IAP were compared. The binary Logistic regression analysis was used to find the independent risk factors of HGD/INV-IPMN.Eight combinations of risk factors derived from relative indication/worrisome feature or risk factors in this study,were made to evaluate the diagnostic efficacy. The area under curve(AUC) of receiver operating characteristics was used to evaluate the the cutoff value of risk factors(①CA19-9≥37 U/ml,②diameter of main pancreatic duct 5.0-9.9 mm,③enhancing mural nodule<5 mm,④(acute) pancreatiti,⑤acyst diameter ≥40 mm,⑤bcyst diameter ≥30 mm, ⑥thickened or enhancing cyst walls,⑦neutrophile granulocyte to lymphocyte ratio(NLR)≥2, ⑧cyst located in head, uncinate or neck,⑨carcinoembryonic antigen(CEA) ≥5 μg/L) number for predicting HGD/INV-IPMN.The accuracy,sensitivity,specificity,positive predictive value,negative predictive value,true positive,true negative,false positive,false negative,positive likelihood ratio,negative likelihood ratio,Youden index and F1 score were calculated. Results: Ninety-two patients(49.5%) of 186 ones who met AI and 85 patients(48.3%) of 176 ones who met HRS were respectively confirmed as HGD/INV-IPMN. In those patients who were not met AI,tumor location,thickened/enhancing cyst wall,CA19-9 elevated,NLR≥2 and CEA elevated were significantly (P<0.05) correlated with HGD/INV-IPMN. And tumor location(head/uncinate/neck vs. body/tail,OR=3.284,95%CI:1.268-8.503,P=0.014),thickened/enhancement cyst wall (with vs.without,OR=2.713,95%CI:1.177-6.252,P=0.019),CA19-9(≥37 U/L vs.<37 U/L, OR=5.086,95%CI:2.05-12.62,P<0.01) and NLR(≥2 vs.<2,OR=2.380,95%CI:1.043-5.434,P=0.039) were the independent risk factors of HGD/INV-IPMN. Patients with ≥4 risk factors of 9 in combination Ⅷ(①②③④⑤b⑥⑦⑧⑨) were diagnosed as HGD/INV-IPMN with the moderate accuracy(71.0%),moderate sensitivity (62.0%) and moderate specificity (73.0%). Patients with ≥4 risk factors of 9 in Combination Ⅶ(①②③④⑤a⑥⑦⑧⑨) were diagnosed as HGD/INV-IPMN with the highest specificity(83.0%) and patients with ≥3 risk factors of 8 in combination Ⅵ(①②③④⑤b⑥⑧⑨) were diagnosed as HGD/INV-IPMN with the highest sensitivity(74.0%). The AUC for diagnosis of HGD/INV-IPMN in combination Ⅵ,Ⅶ and Ⅷ were 0.72,0.75 and 0.75,respectively. Older patients and younger patients could respectively refer to combination Ⅶ and combination Ⅵ to improve the management of IPMN. Conclusions: Patients who meet AI of EEGPCN should undertake resection, otherwise the method we explored is recommended. The method of improvement for diagnosis of HGD/INV-IPMN is relatively applicable and efficient for decision-making of surgery, especially for younger patients with decreasing of missed diagnosis and elder patients with decreasing of misdiagnosis.

BACKGROUND:About 25-37% of resectable pancreatic ductal adenocarcinoma (PDAC) had a great chance of early recurrence after radical resection, which is mainly due to preoperative micrometastasis. We herein demonstrated the profiles of ctDNA in resectable PDAC and use of ctDNA to identify patients with potential micrometastasis.METHODS:A total of 113 and 44 resectable PDACs were enrolled in discovery and validation cohorts, separately. A panel containing 50 genes was used to screen ctDNA by an NGS-based assessment with high specificity.RESULTS:In the discovery cohort, the overall detection rate was 38.05% (43/113). Among positive ctDNA, KRAS mutation had the highest detection rate (23.01%, 26/113), while the others were <5%. Survival analysis showed that plasma KRAS mutations, especially KRAS G12D mutation, had significant association with OS and RFS of resectable PDAC. Plasma KRAS G12D mutation showed a strong correlation with early distant metastasis. In the validation cohort, survival analysis showed similar association between plasma KRAS G12D mutation and poor outcomes.CONCLUSIONS:This study demonstrated that plasma KRAS mutations, especially KRAS G12D mutation, served as a useful predictive biomarker for prognosis of resectable PDAC. More importantly, due to high correlation with micrometastasis, preoperative detection of plasma KRAS G12D mutation helps in optimising surgical selection of resectable PDAC.