The role of adjuvant transcatheter arterial chemoembolization following repeated curative resection/ablation for hepatocellular carcinoma with early recurrence: a propensity score matching analysis.

BACKGROUND: The role of adjuvant transcatheter arterial chemoembolization (TACE) following repeated resection/ablation for recurrent hepatocellular carcinoma (HCC) remains uncertain. The aim of this study was to assess the effectiveness of adjuvant TACE following repeated resection or ablation in patients with early recurrent HCC. METHODS: Information for patients who underwent repeated surgery or radiofrequency ablation (RFA) for early recurrent HCCs (< 2 years) at our institution from January 2017 to December 2020 were collected. Patients were divided into adjuvant TACE and observation groups according to whether they received adjuvant TACE or not. The recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups before and after propensity score matching (PSM). RESULTS: Of the 225 patients enrolled, the median time of HCC recurrence was 11 months (IQR, 6-16 months). After repeated surgery or radiofrequency ablation (RFA) for recurrent tumors, 45 patients (20%) received adjuvant TACE while the remaining 180 (80%) didn't. There were no significant differences in RFS (P = 0.325) and OS (P = 0.072) between adjuvant TACE and observation groups before PSM. There were also no significant differences in RFS (P = 0.897) and OS (P = 0.090) between the two groups after PSM. Multivariable analysis suggested that multiple tumors, liver cirrhosis, and RFA were independent risk factors for the re-recurrence of HCC. CONCLUSION: Adjuvant TACE after repeated resection or ablation for early recurrent HCCs was not associated with a long-term survival benefit in this single-center cohort.

Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance.

Accumulating evidence suggests that cancer-associated fibroblast (CAF) macroautophagy/autophagy is crucial in tumor development and may be a therapeutic target for pancreatic ductal adenocarcinoma (PDAC). However, the role of CAF autophagy during immune surveillance and cancer immunotherapy is unclear. The present study revealed that the inhibition of CAF autophagy suppresses in vivo tumor development in immune-deficient xenografts. This deletion compromises anti-tumor immunity and anti-tumor efficacy both in vitro and in vivo by upregulating CD274/PDL1 levels in an immune-competent mouse model. A block in CAF autophagy reduced the production of IL6 (interleukin 6), disrupting high desmoplastic TME and decreasing USP14 expression at the transcription level in pancreatic cancer cells. We further identify USP14 as the post-translational factor responsible for downregulating CD274 expression by removing K63 linked-ubiquitination at the K280 residue. Finally, chloroquine diphosphate-loaded mesenchymal stem cell (MSC)-liposomes, by accurately targeting CAFs, inhibited CAF autophagy, improving the efficacy of immunochemotherapy to combat pancreatic cancer.Abbreviation: AIR: adaptive immune resistance; ATRA: all-trans-retinoicacid; CAF: cancer-associated fibroblast; CD274/PDL1: CD274 molecule; CM: conditioned medium; CQ: chloroquine diphosphate; CyTOF: Mass cytometry; FGF2/bFGF: fibroblast growth factor 2; ICB: immune checkpoint blockade; IF: immunofluorescence; IHC: immunohistochemistry; IP: immunoprecipitation; MS: mass spectrometer; MSC: mesenchymal stem cell; PDAC: pancreatic ductal adenocarcinoma; TEM: transmission electron microscopy; TILs: tumor infiltrating lymphocytes; TME: tumor microenvironment; USP14: ubiquitin specific peptidase 14.

Targeting leucine-rich repeat serine/threonine-protein kinase 2 sensitizes pancreatic ductal adenocarcinoma to anti-PD-L1 immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to immune checkpoint blockade therapy, and negative feedback of tumor immune evasion might be partly responsible. We isolated CD8+ T cells and cultured them in vitro. Proteomics analysis was performed to compare changes in Panc02 cell lines cultured with conditioned medium, and leucine-rich repeat kinase 2 (LRRK2) was identified as a differential gene. LRRK2 expression was related to CD8+ T cell spatial distribution in PDAC clinical samples and upregulated by CD8+ T cells via interferon gamma (IFN-γ) simulation in vitro. Knockdown or pharmacological inhibition of LRRK2 activated an anti-pancreatic cancer immune response in mice, which meant that LRRK2 acted as an immunosuppressive gene. Mechanistically, LRRK2 phosphorylated PD-L1 at T210 to inhibit its ubiquitination-mediated proteasomal degradation. LRRK2 inhibition attenuated PD-1/PD-L1 blockade-mediated, T cell-induced upregulation of LRRK2/PD-L1, thus sensitizing the mice to anti-PD-L1 therapy. In addition, adenosylcobalamin, the activated form of vitamin B12, which was found to be a broad-spectrum inhibitor of LRRK2, could inhibit LRRK2 in vivo and sensitize PDAC to immunotherapy as well, which potentially endows LRRK2 inhibition with clinical translational value. Therefore, PD-L1 blockade combined with LRRK2 inhibition could be a novel therapy strategy for PDAC.

Immune Checkpoint Neuropilins as Novel Biomarkers and Therapeutic Targets for Pancreatic Cancer.

The traditional immune checkpoint blockade therapy benefits some patients with cancer, but elicits no response in certain cancers, such as pancreatic adenocarcinoma (PAAD); thus, novel checkpoints and effective targets are required. Here, we found that there was a higher Neuropilin (NRP) expression in tumor tissues as novel immune checkpoints, which was associated with poor prognosis and pessimistic responses to immune checkpoint blockade therapy. In the tumor microenvironment of PAAD samples, NRPs were widely expressed in tumor, immune and stromal cells. The relationship of NRPs with tumor immunological features in PAAD and pan-cancer was evaluated using bioinformatics methods; it was positively correlated with the infiltration of myeloid immune cells and the expression of most immune checkpoint genes. Bioinformatics analysis, in vitro and in vivo experiments suggested that NRPs exhibit potential immune-related and immune-independent pro-tumor effects. NRPs, especially NRP1, are attractive biomarkers and therapeutic targets for cancers, particularly PAAD.

Targeting ubiquitin-specific protease 8 sensitizes anti-programmed death-ligand 1 immunotherapy of pancreatic cancer.

Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) help tumor cells evade immune surveillance, and are regarded as important targets of anti-tumor immunotherapy. Post-translational modification of PD-L1 has potential value in immunosuppression. Here, we identified that ubiquitin-specific protease 8 (USP8) deubiquitinates PD-L1. Pancreatic cancer tissues exhibited significantly increased USP8 levels compared with those in normal tissues. Clinically, the expression of USP8 showed a significant association with the tumor-node-metastasis stage in multiple patient-derived cohorts of pancreatic cancer. Meanwhile, USP8 deficiency could reduce tumor invasion and migration and tumor size in an immunity-dependent manner, and improve anti-tumor immunogenicity. USP8 inhibitor pretreatment led to reduced tumorigenesis and immunocompetent mice with Usp8 knockdown tumors exhibited extended survival. Moreover, USP8 interacted positively with PD-L1 and upregulated its expression by inhibiting the ubiquitination-regulated proteasome degradation pathway in pancreatic cancer. Combination therapy with a USP8 inhibitor and anti-PD-L1 effectively suppressed pancreatic tumor growth by activation of cytotoxic T-cells and the anti-tumor immunity was mainly dependent on the PD-L1 pathway and CD8 + T cells. Our findings highlight the importance of targeting USP8, which can sensitize PD-L1-targeted pancreatic cancer to immunotherapy and might represent a novel therapeutic strategy to treat patients with pancreatic tumors in the future.

Adjuvant therapy with gemcitabine and stereotactic body radiation therapy versus gemcitabine alone for resected stage II pancreatic cancer: a prospective, randomized, open-label, single center trial.

BACKGROUND: The role of adjuvant radiation in pancreatic adenocarcinoma (PDAC) remains unclear. We aimed to investigate the efficacy of gemcitabine combined with stereotactic body radiation therapy (SBRT) as adjuvant therapy for resected stage II PDAC. METHODS: In this single-center randomized controlled trial, patients with stage II PDAC that underwent margin-negative resection were randomly assigned to gemcitabine-alone adjuvant chemotherapy or adjuvant SBRT followed by gemcitabine chemotherapy. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included locoregional recurrence-free survival (LRFS), overall survival (OS), and incidence of adverse events. RESULTS: Forty patients were randomly assigned to treatment between Sep 1, 2015 and Mar 31, 2018. Of these, 38 were included in the intention-to-treat analysis (20 in gemcitabine arm and 18 in gemcitabine plus SBRT arm). The median RFS and OS were 9.70, 28.0 months in the gemcitabine arm and 5.30, 15.0 months in the gemcitabine plus SBRT arm (RFS, P = 0.53; OS, P = 0.20), respectively. The median LRFS in both arms was unreached (P = 0.81). Grade 3 or 4 adverse events were all comparable between the two arms. Evaluation of data from the enrolled patients indicated that the addition of adjuvant SBRT was not associated with either better local disease control or recurrence-free survival. CONCLUSIONS: Adjuvant SBRT neither provided a survival benefit nor improved local disease control in resected stage II PDAC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02461836 . Registered 03/06/2015.

RCAN1-mediated calcineurin inhibition as a target for cancer therapy.

Cancer is the leading cause of mortality worldwide. Regulator of calcineurin 1 (RCAN1), as a patent endogenous inhibitor of calcineurin, plays crucial roles in the pathogenesis of cancers. Except for hypopharyngeal and laryngopharynx cancer, high expression of RCAN1 inhibits tumor progression. Molecular antitumor functions of RCAN1 are largely dependent on calcineurin. In this review, we highlight current research on RCAN1 characteristics, and the interaction between RCAN1 and calcineurin. Moreover, the dysregulation of RCAN1 in various cancers is reviewed, and the potential of targeting RCAN1 as a new therapeutic approach is discussed.

Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors.

BACKGROUNDS: In advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy. METHODS: Tumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry, immunofluorescence, western blotting, and ELISAs. The in vitro mechanism that TNFR2 regulates programmed cell death 1 ligand 1 (PD-L1) was investigated using immunofluorescence, immunohistochemistry, flow cytometry, western blotting, and chromatin immunoprecipitation (ChIP). In vivo efficacy and mechanistic studies, using C57BL/6 mice and nude mice with KPC cell-derived subcutaneous and orthotopic tumors, employed antibodies against TNFR2 and PD-L1. Survival curves were constructed for the orthotopic model and a genetically engineered PDAC model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre). Mass cytometry, immunohistochemistry, and flow cytometry analyzed local and systemic alterations in the immunophenotype. RESULTS: TNFR2 showed high expression and is a prognostic factor in CD8+ T cell-enriched pancreatic cancer. TNFR2 promotes tumorigenesis and progression of pancreatic cancer via dual effect: suppressing cancer immunogenicity and partially accelerating tumor growth. TNFR2 positivity correlated with PD-L1, and in vitro and in vivo, it could regulate the expression of PDL1 at the transcription level via the p65 NF-κB pathway. Combining anti-TNFR2 and PD-L1 antibodies eradicated tumors, prolonged overall survival in pancreatic cancer, and induced strong antitumor immune memory and secondary prevention by reducing the infiltration of Tregs and tumor-associated macrophages and inducing CD8+ T cell activation in the PDAC microenvironment. Finally, the antitumor immune response derived from combination therapy is mainly dependent on CD8+ T cells, partially dependent on CD4+ T cells, and independent of natural killer cells. CONCLUSIONS: Anti-TNFR2 and anti-PD-L1 combination therapy eradicated tumors by inhibiting their growth, relieving tumor immunosuppression, and generating robust memory recall.

NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1.

Despite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically "hot" pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy.

Non-cytomembrane PD-L1: An atypical target for cancer.

Programmed death ligand 1 (PD-L1) has conventionally been considered as a type I transmembrane protein that can interact with its receptor, programmed cell death 1 (PD-1), thus inducing T cell deactivation and immune escape. However, targeting the PD-1/PD-L1 axis has achieved adequate clinical responses in very few specific malignancies. Recent studies have explored the extracellularly and subcellularly located PD-L1, namely, nuclear PD-L1 (nPD-L1), cytoplasmic PD-L1 (cPD-L1), soluble PD-L1 (sPD-L1), and extracellular vesicle PD-L1 (EV PD-L1), which might shed light on the resistance to anti-PD1/PDL1 therapy. In this review, we summarize the four atypical localizations of PD-L1 with a focus on their novel functions, such as gene transcription regulation, therapeutic efficacy prediction, and resistance to various cancer therapies. Additionally, we highlight that non-cytomembrane PD-L1s are of significant cancer diagnostic value and are promising therapeutic targets to treat cancer.

Regulator of calcineurin 1 gene isoform 4 in pancreatic ductal adenocarcinoma regulates the progression of tumor cells.

Therapeutic strategies to treat pancreatic ductal adenocarcinoma (PDAC) remain unsatisfying and limited. Therefore, it is imperative to fully determine the mechanisms underlying PDAC progression. In the present study, we report a novel role of regulator of calcineurin 1, isoform 4 (RCAN1.4) in regulating PDAC progression. We demonstrated that RCAN1.4 expression was decreased significantly in PDAC tissues compared with that in para-cancerous tissues, and correlated with poor prognosis of patients with pancreatic cancer. In vitro, stable high expression of RCAN1.4 could suppress the metastasis and proliferation and angiogenesis of pancreatic tumor cells. In addition, interferon alpha inducible protein 27 (IFI27) was identified as having a functional role in RCAN1.4-mediated PDAC migration and invasion, while VEGFA play a vital role in RCAN1.4-mediated PDAC angiogenesis. Analysis of mice with subcutaneously/orthotopic implanted xenograft tumors and liver metastasis model confirmed that RCAN1.4 could modulate the growth, metastasis, and angiogenesis of tumors via IFI27/VEGFA in vivo. In conclusion, our results suggested that RCAN1.4 suppresses the growth, metastasis, and angiogenesis of PDAC, functioning partly via IFI27 and VEGFA. Importantly, our results provided possible diagnostic criteria and therapeutic targets for PDAC.

External validation of alternative fistula risk score (a-FRS) for predicting pancreatic fistula after pancreatoduodenectomy.

BACKGROUND: The utility of the proposed alternative fistula risk score (a-FRS) for predicting risk of clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD) has not been validated widely. METHODS: This retrospective analysis included data of patients undergoing open and laparoscopic PD during March 2012-May 2018 in our institution. The predictive abilities of a-FRS and original-FRS were compared. Risk factors for CR-POPF were also evaluated by multivariate regression analysis. RESULTS: Of the 370 patients, 80 (21.62%) developed CR-POPF. The incidences of CR-POPF in patients classified as low risk, intermediate risk, and high risk by a-FRS were 5.88%, 24.38%, and 57.69%, respectively (R2 = 0.97). The incidences of CR-POPF in patients classified as negligible risk, low risk, intermediate risk, and high-risk by original-FRS were 0%, 8.62%, 21.51%, and 52.50%, respectively (R2 = 0.92). The area under the ROC curve (AUC) was 0.74 for a-FRS vs. 0.70 for original-FRS. The a-FRS performed better than original-FRS for prediction of CR-POPF in open PD patients (AUC: 0.74 vs. 0.69) and was comparable with original- FRS in laparoscopic PD patients (AUC: 0.70 vs. 0.72). CONCLUSIONS: The a-FRS appears to be an accurate and convenient tool for predicting occurrence of CR-POPF after PD.

Endogenous Interleukin 18 Suppresses Liver Regeneration After Hepatectomy in Mice.

The comprehensive role of interleukin (IL) 18 during liver regeneration is barely studied. Our aim is to evaluate the role of IL18 in liver regeneration after partial hepatectomy (PH) in mice. The expression profile of IL18 in the liver and the gut after 70% PH was measured. Liver samples after 70% and 85% PH from IL18 knockout (IL18-/- ) mice and wild type (WT) mice were collected for comparison of liver regeneration. The effect of recombinant IL18 on liver regeneration was tested in IL18-/- mice, and the utility of IL18 binding protein (BP) was also evaluated following 70% PH in WT mice. Expression levels of IL18 in the liver and the gut elevated after 70% PH. The liver weight/body weight ratios (LBWRs) after PH were significantly higher in IL18-/- mice than those in WT mice. Recombinant IL18 injection significantly decreased LBWR at 7 days after 70% PH in IL18-/- mice. The expression of cyclin D1, EdU labeling index, and Ki-67 proliferation index were much higher in IL18-/- mice than those in WT mice after 70% PH. The expression level of glypican 3 (GPC3) in WT mice significantly elevated during liver regeneration. In contrast, the expression level of GPC3 in IL18-/- mice remained roughly unchanged during liver regeneration. IL18BP injection significantly increased the LBWR at 7 days after 70% PH in WT mice. In conclusion, endogenous IL18 inhibited liver regeneration after PH in mice, possibly through up-regulating GPC3. IL18BP may be an effective agent to promote liver regeneration after PH.

Development of a Novel Multiparametric MRI Radiomic Nomogram for Preoperative Evaluation of Early Recurrence in Resectable Pancreatic Cancer.

BACKGROUND: In pancreatic cancer, methods to predict early recurrence (ER) and identify patients at increased risk of relapse are urgently required. PURPOSE: To develop a radiomic nomogram based on MR radiomics to stratify patients preoperatively and potentially improve clinical practice. STUDY TYPE: Retrospective. POPULATION: We enrolled 303 patients from two medical centers. Patients with a disease-free survival ≤12 months were assigned as the ER group (n = 130). Patients from the first medical center were divided into a training cohort (n = 123) and an internal validation cohort (n = 54). Patients from the second medical center were used as the external independent validation cohort (n = 126). FIELD STRENGTH/SEQUENCE: 3.0T axial T1 -weighted (T1 -w), T2 -weighted (T2 -w), contrast-enhanced T1 -weighted (CET1 -w). ASSESSMENT: ER was confirmed via imaging studies as MRI or CT. Risk factors, including clinical stage, CA19-9, and radiomic-related features of ER were assessed. In addition, to determine the intra- and interobserver reproducibility of radiomic features extraction, the intra- and interclass correlation coefficients (ICC) were calculated. STATISTICAL TESTS: The area under the receiver-operator characteristic (ROC) curve (AUC) was used to evaluate the predictive accuracy of the radiomic signature in both the training and test groups. The results of decision curve analysis (DCA) indicated that the radiomic nomogram achieved the most net benefit. RESULTS: The AUC values of ER evaluation for the radiomics signature were 0.80 (training cohort), 0.81 (internal validation cohort), and 0.78 (external validation cohort). Multivariate logistic analysis identified the radiomic signature, CA19-9 level, and clinical stage as independent parameters of ER. A radiomic nomogram was then developed incorporating the CA19-9 level and clinical stage. The AUC values for ER risk evaluation using the radiomic nomogram were 0.87 (training cohort), 0.88 (internal validation cohort), and 0.85 (external validation cohort). DATA CONCLUSION: The radiomic nomogram can effectively evaluate ER risks in patients with resectable pancreatic cancer preoperatively, which could potentially improve treatment strategies and facilitate personalized therapy in pancreatic cancer. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2020;52:231-245.

Surgical management and outcome of grade-C pancreatic fistulas after pancreaticoduodenectomy: A retrospective multicenter cohort study.

BACKGROUND: Management strategies for grade-C postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy (PD) vary. The aim of this study was to evaluate surgical indications, approaches, and outcomes of grade-C POPF following PD. MATERIALS AND METHODS: The clinical data of grade-C POPF patients from 9 high-volume institutions between January 1, 2012 and December 31, 2016 were retrospectively reviewed. The indications and outcomes of different surgical strategies were analyzed. Risk factors for unfavorable outcomes were evaluated by multivariate regression analysis. RESULTS: Out of 5115 patients that underwent PD, 68 were diagnosed as grade-C POPF, and 53 underwent re-laparotomy. Pancreas-preserving surgical strategies were mostly used in this cohort (96.2%). Postoperative hospital stay in the external wirsungostomy group tended to be shorter than the other two major surgical approaches (20 days vs. 38 days and 34.5 days). Mortality and morbidity were comparable among different surgical strategies. Prolonged high drain amylase level prior to the development of grade-C POPF was negatively associated with unfavorable outcomes after re-laparotomy (OR: 0.20, 95% CI: 0.05-0.82). CONCLUSION: Pancreas-preserving approaches were preferred for grade-C POPF in this multicenter database, although the choice of definite procedure differed according to different clinical scenarios. Longstanding high amylase drainage may predict better outcomes after re-laparotomy.

Pyogenic Liver Abscess After Pancreaticoduodenectomy: A Single-Center Experience.

BACKGROUND: Pancreaticoduodenectomy (PD) is a complex procedure with a morbidity rate of 40%-50%. We evaluated the incidence, associated factors, etiologic characteristics, and outcome of pyogenic liver abscess (PLA), a rare infectious complication of PD. METHODS: We retrospectively assessed the data of patients who underwent PD (n = 326) between January 2012 and February 2017 at a single institution. Patients who developed PLA after PD were matched (1:3) for age, sex, and pathologic diagnosis with patients without PLA after PD. Patients who developed PLA without abdominal operation history (n = 77) were also reviewed in the same period. RESULTS: Eleven patients (3.4%) developed PLA after PD; diabetes (5/11, 45.5% versus 4/33, 12.1%; P = 0.031) increased the risk of PLA after PD. The preoperative and postoperative fasting blood glucose (FBG) was significantly higher in PLA+ group than PLA- group: preoperative FBG (median: 7.39 versus 4.49; P < 0.01), postoperative FBG (median: 8.98 versus 5.68; P < 0.01). The occurrence of multiple liver abscess was significantly higher in patients with PLA after PD than patients who developed PLA without abdominal operation history (7/11 versus 22/77; P = 0.036). Microbial pus culture was positive in eight patients with PLA after PD (n = 8/11) and in forty-one patients who developed PLA without abdominal operation history (n = 41/77). Klebsiella pneumoniae was the most commonly isolated microorganism in PLA patients with or without a history of PD (5/8, 62.5% versus 34/41, 82.9%; P = 0.333). CONCLUSIONS: Patients with diabetes (including impaired fasting plasma glucose) have a higher risk of developing PLA after PD. Multiple liver abscess was the most common type of PLA after PD; K pneumoniae should be covered when empirically treated patients with PLA.

Pancreas-preserving management of grade-C pancreatic fistula and a novel bridging technique for repeat pancreaticojejunostomy: An observational study.

PURPOSE: Optimal surgical strategy for grade-C postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) is not justified. External wirsungostomy is feasible. However, the subsequent repeat pancreaticojejunostomy (PJ) is challenging. This study aims to introduce our experience of external wirsungostomy for grade-C POPF and a novel technique to do the repeat PJ (re-PJ). MATERIALS AND METHODS: From January 1, 2012 to December 31, 2016, all consecutive patients who underwent pancreaticoduodenectomy (PD) with PJ were identified. The clinical data were retrospectively collected and analyzed. RESULTS: Out of 325 patients, 11 patients (3.38%) underwent salvage re-laparotomy for grade-C POPF. External wirsungostomy was performed in 10 patients (3.08%). Four patients died of severe complications within 90 days postoperatively or tumor progression before the scheduled re-PJ was performed. Three patients got their external pancreatic drainage tube pulled out accidentally without causing severe consequences. Three patients underwent planned re-PJ after external wirsungostomy, including one with duct-to-mucosa PJ and two with the novel bridging technique. The operative times of the two patients undergoing the novel bridging technique were 120 min, 135 min, respectively, and the length of post-operative hospital stay (LPHS) were 7 d, 5 d, respectively. The operative time and the LPHS of whom underwent duct-to-mucosa PJ were 315 min, 24 d, respectively. There was no major post-operative complication. CONCLUSION: External wirsungostomy may be a safe way to preserve the pancreas remnant in grade-C POPF patients. The novel bridging technique may be a simpler alternative to traditional PJ.