N6-methyladenosine modified TGFB2 triggers lipid metabolism reprogramming to confer pancreatic ductal adenocarcinoma gemcitabine resistance.

Gemcitabine resistance is a major obstacle to the effectiveness of chemotherapy in pancreatic ductal adenocarcinoma (PDAC). Therefore, new strategies are needed to sensitize cancer cells to gemcitabine. Here, we constructed gemcitabine-resistant PDAC cells and analyzed them with RNA-sequence. Employing an integrated approach involving bioinformatic analyses from multiple databases, TGFB2 is identified as a crucial gene in gemcitabine-resistant PDAC and is significantly associated with poor gemcitabine therapeutic response. The patient-derived xenograft (PDX) model further substantiates the gradual upregulation of TGFB2 expression during gemcitabine-induced resistance. Silencing TGFB2 expression can enhance the chemosensitivity of gemcitabine against PDAC. Mechanistically, TGFB2, post-transcriptionally stabilized by METTL14-mediated m6A modification, can promote lipid accumulation and the enhanced triglyceride accumulation drives gemcitabine resistance by lipidomic profiling. TGFB2 upregulates the lipogenesis regulator sterol regulatory element binding factor 1 (SREBF1) and its downstream lipogenic enzymes via PI3K-AKT signaling. Moreover, SREBF1 is responsible for TGFB2-mediated lipogenesis to promote gemcitabine resistance in PDAC. Importantly, TGFB2 inhibitor imperatorin combined with gemcitabine shows synergistic effects in gemcitabine-resistant PDAC PDX model. This study sheds new light on an avenue to mitigate PDAC gemcitabine resistance by targeting TGFB2 and lipid metabolism and develops the potential of imperatorin as a promising chemosensitizer in clinical translation.

ADAR1 promotes cisplatin resistance in intrahepatic cholangiocarcinoma by regulating BRCA2 expression through A-to-I editing manner.

Aberrant A-to-I RNA editing, mediated by ADAR1 has been found to be associated with increased tumourigenesis and the development of chemotherapy resistance in various types of cancer. Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with a poor prognosis, and overcoming chemotherapy resistance poses a significant clinical challenge. This study aimed to clarify the roles of ADAR1 in tumour resistance to cisplatin in iCCA. We discovered that ADAR1 expression is elevated in iCCA patients, particularly in those resistant to cisplatin, and associated with poor clinical outcomes. Downregulation of ADAR1 can increase the sensitivity of iCCA cells to cisplatin treatment, whereas its overexpression has the inverse effect. By integrating RNA sequencing and Sanger sequencing, we identified BRCA2, a critical DNA damage repair gene, as a downstream target of ADAR1 in iCCA. ADAR1 mediates the A-to-I editing in BRCA2 3'UTR, inhibiting miR-3157-5p binding, consequently increasing BRCA2 mRNA and protein levels. Furthermore, ADAR1 enhances cellular DNA damage repair ability and facilitates cisplatin resistance in iCCA cells. Combining ADAR1 targeting with cisplatin treatment markedly enhances the anticancer efficacy of cisplatin. In conclusion, ADAR1 promotes tumour progression and cisplatin resistance of iCCA. ADAR1 targeting could inform the development of innovative combination therapies for iCCA.

Robotic-assisted organ-preserving or parenchymal-sparing pancreatectomy in pancreatic benign or low-grade malignant tumors: a single institute's experience.

AIM: Robotic-assisted pancreatectomy has been widely used. Organ-preserving pancreatectomy (OPP) and parenchymal-sparing pancreatectomy (PSP) has been gradually adopted for pancreatic benign or low-grade malignant tumors. This study aimed to evaluate the safety and efficacy of robotic-assisted OPP/PSP in our institute. METHODS: Patients undergoing robotic-assisted OPS/PSP at First Affiliated Hospital of Sun Yat-sen University between July 2015 and October 2021 were included in this study. The short-term and long-term outcomes of patients were retrospectively analyzed. RESULTS: Seventy-two patients were enrolled, including spleen-preserving distal pancreatectomy, central pancreatectomy, duodenum-preserving pancreatic head resection, and enucleation. Patients included were more likely to be young female (female: 46/72, median age: 47 years old). The median intraoperative blood loss and operation time was 50 ml and 255 min, respectively. Clinically relevant postoperative pancreatic fistula was 20.8% (grade B: 15/72, 20.8%; no grade C). The overall complication rate was 22.2% with the median postoperative length-of-stay of 8 days. At a median follow-up time of 28.5 months, the 5-year overall survival and recurrence-free survival rate were 100.0% and 100.0%, respectively. CONCLUSION: The short-term and long-term outcomes of patients receiving robotic-assisted OPP/PSP were acceptable. Robotic-assisted OPP/PSP was a feasible and safe technique for pancreatic benign or low-grade malignant lesions.

CSNK2A1 confers gemcitabine resistance to pancreatic ductal adenocarcinoma via inducing autophagy.

Gemcitabine, a pivotal chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC), frequently encounters drug resistance, posing a significant clinical challenge with implications for PDAC patient prognosis. In this study, employing an integrated approach involving bioinformatic analyses from multiple databases, we unveil CSNK2A1 as a key regulatory factor. The patient-derived xenograft (PDX) model further substantiates the critical role of CSNK2A1 in gemcitabine resistance within the context of PDAC. Additionally, targeted silencing of CSNK2A1 expression significantly enhances sensitivity of PDAC cells to gemcitabine treatment. Mechanistically, CSNK2A1's transcriptional regulation is mediated by H3K27 acetylation in PDAC. Moreover, we identify CSNK2A1 as a pivotal activator of autophagy, and enhanced autophagy drives gemcitabine resistance. Silmitasertib, an established CSNK2A1 inhibitor, can effectively inhibit autophagy. Notably, the combinatorial treatment of Silmitasertib with gemcitabine demonstrates remarkable efficacy in treating PDAC. In summary, our study reveals CSNK2A1 as a potent predictive factor for gemcitabine resistance in PDAC. Moreover, targeted CSNK2A1 inhibition by Silmitasertib represents a promising therapeutic strategy to restore gemcitabine sensitivity in PDAC, offering hope for improved clinical outcomes.

A radiomics-based interpretable model to predict the pathological grade of pancreatic neuroendocrine tumors.

OBJECTIVES: To develop a computed tomography (CT) radiomics-based interpretable machine learning (ML) model to predict the pathological grade of pancreatic neuroendocrine tumors (pNETs) in a non-invasive manner. METHODS: Patients with pNETs who underwent contrast-enhanced abdominal CT between 2010 and 2022 were included in this retrospective study. Radiomics features were extracted, and five radiomics-based ML models, namely logistic regression (LR), random forest (RF), support vector machine (SVM), XGBoost, and GaussianNB, were developed. The performance of these models was evaluated using a time-independent testing set, and metrics such as sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC) were calculated. The accuracy of the radiomics model was compared to that of needle biopsy. The Shapley Additive Explanation (SHAP) tool and the correlation between radiomics and biological features were employed to explore the interpretability of the model. RESULTS: A total of 122 patients (mean age: 50 ± 14 years; 53 male) were included in the training set, whereas 100 patients (mean age: 48 ± 13 years; 50 male) were included in the testing set. The AUCs for LR, SVM, RF, XGBoost, and GaussianNB were 0.758, 0.742, 0.779, 0.744, and 0.745, respectively, with corresponding accuracies of 73.0%, 70.0%, 77.0%, 71.9%, and 72.9%. The SHAP tool identified two features of the venous phase as the most significant, which showed significant differences among the Ki-67 index or mitotic count subgroups (p < 0.001). CONCLUSIONS: An interpretable radiomics-based RF model can effectively differentiate between G1 and G2/3 of pNETs, demonstrating favorable interpretability. CLINICAL RELEVANCE STATEMENT: The radiomics-based interpretable model developed in this study has significant clinical relevance as it offers a non-invasive method for assessing the pathological grade of pancreatic neuroendocrine tumors and holds promise as an important complementary tool to traditional tissue biopsy. KEY POINTS: • A radiomics-based interpretable model was developed to predict the pathological grade of pNETs and compared with preoperative needle biopsy in terms of accuracy. • The model, based on CT radiomics, demonstrated favorable interpretability. • The radiomics model holds potential as a valuable complementary technique to preoperative needle biopsy; however, it should not be considered a replacement for biopsy.

Learning curve of robotic-assisted splenic vessel-preserving spleen-preserving distal pancreatectomy by one single surgeon: a retrospective cohort study.

AIM: Splenic vessel-preserving spleen-preserving distal pancreatectomy (SVP-SPDP) has a lower risk of splenic infarction than the splenicvessel-sacrificing SPDP, but it is more technically demanding. Learning curve of robotic-assisted SVP-SPDP (RSVP-SPDP) remains unreported. This study sought to analyze the perioperative outcomes and learning curve of RSVP-SPDP by one single surgeon. METHODS: Seventy-four patients who were intended to receive RSVP-SPDP at the First Affiliated Hospital of Sun Yat-sen University between May 2015 and January 2023 were included. The learning curve were retrospectively analyzed by using cumulative sum (CUSUM) analyses. RESULTS: Sixty-two patients underwent RSVP-SPDP (spleen preservation rate: 83.8%). According to CUSUM curve, the operation time (median, 318 vs. 220 min; P < 0.001) and intraoperative blood loss (median, 50 vs. 50 mL; P = 0.012) was improved significantly after 16 cases. Blood transfusion rate (12.5% vs. 3.4%; P = 0.202), postoperative major morbidity rate (6.3% vs. 3.4%; P = 0.524), and postoperative length-of-stay (median, 10 vs. 8 days; P = 0.120) improved after 16 cases but did not reach statistical difference. None of the patients had splenic infarction or abscess postoperatively. CONCLUSION: RSVP-SPDP was a safe and feasible approach for selected patients after learning curve. The improvement of operation time and intraoperative blood loss was achieved after 16 cases.

Learning curves of resection and reconstruction procedures in robotic-assisted pancreatoduodenectomy by a single surgeon: a retrospective cohort study of 160 consecutive cases.

Background: Robotic-assisted pancreatoduodenectomy (RPD) has been routinely performed in a few of centers worldwide. This study aimed to evaluate the perioperative outcomes and the learning curves of resection and reconstruction procedures in RPD by one single surgeon. Methods: Consecutive patients undergoing RPD by a single surgeon at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between July 2016 and October 2022 were included. The perioperative outcomes and learning curves were retrospectively analysed by using cumulative sum (CUSUM) analyses. Results: One-hundred and sixty patients were included. According to the CUSUM curve, the times of resection and reconstruction procedures were shortened significantly after 30 cases (median, 284 vs 195 min; P < 0.001) and 45 cases (median, 138 vs 120 min; P < 0.001), respectively. The estimated intraoperative blood loss (median, 100 vs 50 mL; P < 0.001) and the incidence of clinically relevant post-operative pancreatic fistula (29.2% vs 12.5%; P = 0.035) decreased significantly after 20 and 120 cases, respectively. There were no significant differences in the total number of lymph nodes examined, post-operative major complications, or post-operative length-of-stay between the two groups. Conclusions: Optimization of the resection procedure and the acquisition of visual feedback facilitated the performance of RPD. RPD was a safe and feasible procedure in the selected patients.

Evaluation of the short-term outcomes of robotic-assisted radical resection for perihilar cholangiocarcinoma: a propensity-scored matching analysis.

Background: The application of robotic-assisted radical resection in perihilar cholangiocarcinoma (pCCA) remains poorly defined. This study aimed to evaluate the safety and efficacy of robotic-assisted radical resection for pCCA in our institute. Methods: Between July 2017 and July 2022, pCCA patients undergoing robotic-assisted and open radical resection at First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) were included. The short-term outcomes were compared by using propensity-scored matching (PSM) analysis. Results: Eighty-six pCCA patients were enrolled. After PSM at a ratio of 1:2, 10 and 20 patients were assigned to the robotic-assisted and open groups, respectively. There were no significant disparities in the clinicopathological features between the two groups. The robotic-assisted group had significantly longer operation time (median: 548 vs 353 min, P = 0.004) and larger total number of lymph nodes examined (median: 11 vs 5, P = 0.010) than the open group. The robotic-assisted group tended to have a lower intraoperative blood loss (median: 125 vs 350 mL, P = 0.067), blood transfusion rates (30.0% vs 70.0%, P = 0.056), and post-operative overall morbidities (30.0% vs 70.0%, P = 0.056) than the open group, even though the differences were not statistically significant. There were no significant differences in the negative resection margin, post-operative major morbidities, or post-operative length-of-stay between the robotic-assisted and open groups (all P > 0.05). Conclusions: Robotic-assisted radical resection of pCCA may get a larger total number of lymph nodes examined than open surgery. Provided robotic-assisted surgery may be a feasible and safe technique for selected pCCA patients.

Values of debulking surgery for unresectable well-differentiated metastatic pancreatic neuroendocrine tumors: a comparative study.

Background and objective: The value of debulking surgery for unresectable well-differentiated metastatic pancreatic neuroendocrine tumor (m-PNET) remains poorly defined. This study aimed to evaluate the outcomes of m-PNET following debulking surgery in our institute. Methods: Patients with well-differentiated m-PNET in our hospital between February 2014 and March 2022 were collected. Clinicopathological and long-term outcomes of patients treated with radical resection, debulking surgery, and conservative therapy were compared retrospectively. Results: Fifty-three patients with well-differentiated m-PNET were reviewed, including 47 patients with unresectable m-PNET (debulking surgery, 25; conservative therapy, 22) and 6 patients with resectable m-PNET (radical resection). Patients undergoing debulking surgery had a post-operative Clavien-Dindo ≥ III complication rate of 16.0% without mortality. The 5-year overall survival (OS) rate of patients treated with debulking surgery was significantly higher than that of those treated with conservative therapy alone (87.5% vs 37.8%, log-rank P = 0.022). Besides, the 5-year OS rate of patients treated with debulking surgery was comparable to that of patients with resectable m-PNET undergoing radical resection (87.5% vs 100%, log-rank P = 0.724). Conclusions: Patients with unresectable well-differentiated m-PNET who underwent resection had better long-term outcomes than those who received conservative therapy alone. The 5-year OS of patients undergoing debulking surgery and radical resection were comparable. Debulking surgery could be considered for patients with unresectable well-differentiated m-PNET if no contraindication exists.

Values of spleen-preserving distal pancreatectomy in well-differentiated non-functioning pancreatic neuroendocrine tumors: a comparative study.

Background: The feasibility of spleen-preserving distal pancreatectomy (SPDP) to treat well-differentiated non-functioning pancreatic neuroendocrine tumors (NF-pNETs) located at the body and/or tail of the pancreas remains controversial. Distal pancreatectomy with splenectomy (DPS) has been widely applied in the treatment of NF-pNETs; however, it may increase the post-operative morbidities. This study aimed to evaluate whether SPDP is inferior to DPS in post-operative outcomes and survivals when being used to treat patients with NF-pNETs in our institute. Methods: Clinicopathological features of patients with NF-pNETs who underwent curative SPDP or DPS at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between January 2010 and January 2022 were collected. Short-term outcomes and 5-year survivals were compared between patients undergoing SPDP and those undergoing DPS. Results: Sixty-three patients (SPDP, 27; DPS, 36) with well-differentiated NF-pNETs were enrolled. All patients had grade 1/2 tumors. After identifying patients with T1-T2 NF-pNETs (SPDP, 27; DPS, 15), there was no disparity between the SPDP and DPS groups except for tumor size (median, 1.4 vs 2.6 cm, P = 0.001). There were no differences in operation time (median, 250 vs 295 min, P = 0.478), intraoperative blood loss (median, 50 vs 100 mL, P = 0.145), post-operative major complications (3.7% vs 13.3%, P = 0.287), clinically relevant post-operative pancreatic fistula (22.2% vs 6.7%, P = 0.390), or post-operative hospital stays (median, 9 vs 9 days, P = 0.750) between the SPDP and DPS groups. Kaplan-Meier curve showed no significant differences in the 5-year overall survival rate (100% vs 100%, log-rank P > 0.999) or recurrence-free survival (100% vs 100%, log-rank P > 0.999) between patients with T1-T2 NF-pNETs undergoing SPDP and those undergoing DPS. Conclusions: In patients with T1-T2 well-differentiated NF-pNETs, SPDP could achieve comparable post-operative outcomes and prognosis compared with DPS.

Development and validation of nomogram to predict lymph node metastasis preoperatively in patients with pancreatic neuroendocrine tumor.

BACKGROUND: Routine lymphadenectomy in pancreatic neuroendocrine tumors (pNETs) is debated. There lacks accurate model to predict lymph node metastasis (LNM) preoperatively in pNETs. Therefore, this study aimed at developing a nomogram in predicting LNM in pNETs preoperatively. METHODS: Patients undergoing surgery from Surveillance, Epidemiology, and End Results (SEER) database (design cohort, n = 2742) and First Affiliated Hospital of Sun Yat-sen University (validation cohort, n = 136) were enrolled. Nomogram was developed based on risk factors determined by logistic regression analyses. The performance of nomogram was evaluated by area under receiver operating characteristics curve (AUC), calibration curve, and decision curve analysis. RESULTS: In design cohort, 915 of 2742 patients had LNM. Tumor in the pancreatic head, T stage, and tumor size were significantly associated with LNM (all p < 0.05). Prediction of nomogram was accurate with AUC of 0.776 in design cohort and 0.622 in validation cohort. The nomogram showed good agreement between prediction and observation in the design and validation cohort. Based on nomogram-predicted risk, patients with higher risk of LNM had worse overall survival over patients with lower risk of LNM (log-rank p < 0.001). CONCLUSIONS: The novel nomogram could accurately predict LNM in pNET preoperatively. For patients with high risk of LNM, lymphadenectomy was recommended.

METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner.

N6-methyladenosine (m6A) RNA methylation has recently been found involving in regulatory mechanism of the tumor progression. Our aim was to explore the biological function and clinical significance of the m6A methyltransferase METTL3 in intrahepatic cholangiocarcinoma (ICC). In this study, we revealed that METTL3 was upregulated and predicted poor prognosis of patients with ICC. Multivariate regression analysis demonstrated that METTL3 expression was an independent predictor for overall survival in patients with ICC. Moreover, METTL3 knockdown inhibited ICC progression, while METTL3 overexpression showed the opposite effect. METTL3 inhibitor STM2457 also showed anti-tumor effect in ICC. Mechanistically, METTL3 transcription was driven by H3K4me3 activation. Upregulation of METTL3 mediated m6A modification of IFIT2 mRNA and accelerated IFIT2 mRNA decay in a YTHDF2-dependent manner, which promoted the development of ICC and lead to poorer prognosis. In summary, our findings revealed that H3K4me3 activation-driven METTL3 transcription promotes ICC progression by YTHDF2-mediated IFIT2 mRNA degradation, suggesting that METTL3 may serve as a potential target for human ICC therapy.

Establishment and validation of a nomogram for predicting overall survival of node-negative perihilar cholangiocarcinoma.

AIM: There lacks a predictive model for overall survival (OS) of node-negative perihilar cholangiocarcinoma (PHC). This study aimed at developing and validating a prognostic nomogram to predict OS of node-negative PHC after resection. METHODS: We established a nomogram via multivariate regression analysis by using the design cohort (n = 410, obtained from Surveillance, Epidemiology, and End Results database), and its external verification was done in the validation cohort (n = 100, the First Affiliated Hospital of Sun Yat-sen University). Predictive accuracy of the nomogram was assessed by concordance-index (C-index), calibration curves, and decision curve analysis (DCA). Performance of the nomogram was compared with the American Joint Committee on Cancer (AJCC) staging system. RESULTS: Multivariate regression analysis revealed that age, tumor grade, and the count of examined lymph nodes were independent prognostic factors for OS of node-negative PHC. The nomogram had a C-index of 0.603 and 0.626 in design cohort and validation cohort, respectively, which was better than that of AJCC staging system (both p < 0.05). The calibration curves showed good consistency between actual and nomogram-predicted OS probabilities. DCA showed that nomogram had better clinical usefulness. Furthermore, the nomogram-predicted scores could stratify the patients into three risk groups, and patients in higher risk group had worse prognosis than those in lower risk group (all p < 0.05). CONCLUSION: The proposed nomogram had a better prognostic accuracy than the AJCC staging system in predicting postoperative OS of node-negative PHC. It was helpful to guide the adjuvant therapeutic strategies for node-negative PHC.

Nanomaterial-Facilitated Cyclin-Dependent Kinase 7 Inhibition Suppresses Gallbladder Cancer Progression via Targeting Transcriptional Addiction.

Gallbladder cancer (GBC) is the most aggressive malignancy of the biliary tract cancer, and there is a lack of effective treatment. Here, we developed a nanoparticle platform (8P4 NP) that can deliver THZ1, a cyclin-dependent kinase 7 (CDK7) inhibitor, to treat GBC. Analysis of datasets demonstrated that CDK7 was positively correlated with poor prognosis. CDK7 inhibition suppressed cell proliferation, induced apoptosis, and caused cell cycle block in GBC cells. THZ1 downregulated CDK7-mediated phosphorylation of RNA polymerase II (RNAPII), resulting in a significant downregulation of transcriptional programs, with a preferential repression of oncogenic transcription factors. To improve the tumor targeting efficiency of THZ1, 8P4 NPs were prepared and assembled with THZ1 to form THZ1@8P4 NPs. Compared with free THZ1, THZ1@8P4 NPs showed more advantages in prolonging blood circulation, escaping from lysosomes and increasing cellular uptake. Importantly, THZ1@8P4 NPs demonstrated a more significant inhibition effect on GBC cells than free THZ1 in vitro. In addition, THZ1@8P4 NPs could efficiently deliver THZ1 to tumor sites in a patient-derived xenograft model of early recurrence, leading to tumor regression and transcriptional inhibition with minimal toxicity. In summary, we conclude that THZ1@8P4 NPs provide a potent therapeutic strategy that targets CDK7-mediated transcriptional addiction in GBC.

HNRNPC impedes m6A-dependent anti-metastatic alternative splicing events in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with poor prognosis due to early metastasis. The aberrant N6-methyladenosine (m6A) RNA modification has emerged as an important mechanism in cancer progression and metastasis, but its role in PDAC remained largely unknown. Here, we demonstrated that an m6A regulator, heterogeneous nuclear ribonucleoprotein C (HNRNPC), modulated alternative splicing events to promote PDAC metastasis. In clinical PDAC tissues, high expression of HNRNPC was correlated with metastasis, resulting in poor prognosis in PDAC patients. Knockdown of HNRNPC significantly reduced PDAC cell invasion in vitro and metastasis in vivo. In contrast, overexpression of HNRNPC provoked malignant phenotypes of PDAC cells. Mechanistically, HNRNPC antagonized the anti-metastatic isoform of TAF8 (TAF8L) but increased the pro-metastatic alternative splicing isoform of TAF8 (TAF8S). Mutation of the m6A-site of TAF8 attenuated the interaction between HNRNPC and TAF8 transcript, leading to the decrease of TAF8S. Furthermore, experimental manipulation of the anti-metastasis splicing isoform TAF8L revealed that splice isoform switching of TAF8 is crucial for PDAC metastasis. In conclusion, our findings demonstrate the essentiality of HNRNPC-mediated alternative splicing events that impinges on metastatic PDAC.

Use of Nodal Staging Score in Evaluating the Accuracy of Pathologic Nodal Status in Node-Negative Ampullary Carcinoma.

BACKGROUND: The minimum number of lymph nodes (LNs) that should be resected for accurate nodal staging in patients with ampullary carcinoma (AC) remains controversial. This study aimed to establish a nodal staging score (NSS) to evaluate whether a pathological node-negative AC patient is indeed free of a nodal disease. METHODS: A total of 2539 AC patients with stages I-III were retrieved from the Surveillance, Epidemiology and End Result database (design cohort [DC], n = 2382) and First Affiliated Hospital of Sun Yat-sen University (validation cohort [VC], n = 157). NSS was developed to represent the probability that a node-negative patient was correctly staged as a function of the number of examined LNs (ELNs) and pathologic T stage with a beta-binomial model. Its prognostic value in node-negative patients was assessed by survival analysis. RESULTS: The probability of missing a metastatic LN decreased as the number of the ELNs increased. NSS was escalated as the number of ELNs increased. For patients with early-stage (T1-T2) and late-stage (T3-T4) tumors, examining 7 and 33 lymph nodes could ensure an NSS of 80.0%, respectively. Multivariate analysis showed that higher NSS was an independent favorable prognostic factor for overall survival in node-negative patients with AC (DC, p < 0.001; VC, p = 0.001). CONCLUSIONS: NSS model could be used to evaluate the accuracy of nodal staging and predict the prognosis of node-negative AC patients. It could assist in making clinical strategies in node-negative AC patients.

Development and Validation of a New Nomogram for Predicting Clinically Relevant Postoperative Pancreatic Fistula After Pancreatoduodenectomy.

BACKGROUND: There lacks an ideal model for accurately predicting clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD). This study aimed at developing a nomogram with high accuracy in predicting CR-POPF after PD. METHODS: A total of 1182 patients undergoing PD in the First Affiliated Hospital of Sun Yat-sen University (FAHSYSU, n = 762) and Fudan University Shanghai Cancer Center (FUSCC, n = 420) between January 2010 and May 2018 were enrolled. The patients from FAHSYSU were assigned as testing cohort, and those from FUSCC were used as external validation cohort. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors for CR-POPF. Nomogram was developed on the basis of significant predictors. The performance of nomogram was evaluated by area under receiver operating characteristic (ROC) curve (AUC), calibration curve, and decision curve analysis. RESULTS: In testing cohort, 87 out of 762 patients developed CR-POPF. Three predictors were significantly associated with CR-POPF, including body mass index ≥24.0 kg/m2, pancreatic duct diameter <3 mm, and drainage fluid amylase on postoperative day 1 ≥2484 units/L (all p ≤ 0.001). Prediction of nomogram was accurate with AUC of 0.934 (95% confidence interval [CI]: 0.914-0.950) in testing cohort and 0.744 (95% CI: 0.699-0.785) in external validation cohort. The predictive accuracy of nomogram was better than that of previously proposed fistula risk scores both in testing and external validation cohort (all p < 0.05). CONCLUSIONS: The novel nomogram based on three easily available parameters could accurately predict CR-POPF after PD. It would have high clinical value due to its accuracy and convenience.

Evaluating the adequacy of nodal status in node-negative gallbladder cancer with T1b-T2 stages: use of nodal staging score.

BACKGROUND: The study aimed at establishing a nodal staging score (NSS) to quantify the likelihood that pathologic node-negative gallbladder cancer (GBC) patients are indeed free of lymph node (LN) metastasis. METHODS: Clinicopathological data of 1374 GBC patients with T1b-T2 stages were collected from the Surveillance, Epidemiology and End Result database (design cohort [DC], n = 1289) and the First Affiliated Hospital of Sun Yat-sen University (validation cohort [VC], n = 85). NSS was derived from the count of examined LNs (ELNs) and T stage by using a beta-binomial model, and represented the probability that a node-negative patient is correctly staged. The prognostic value of NSS in node-negative GBC was evaluated by survival analysis. RESULTS: The probability of missing a nodal disease in node-negative GBC patients with T1b-T2 stages (pT1bN0 and pT2N0) decreased as the number of ELNs increased. NSS increased as the number of ELNs increased. For pT1bN0 and pT2N0 patients, examination of 5 and 27 lymph nodes could ensure an NSS of 90.0%, respectively. Multivariate analysis revealed that NSS was an independent predictor for overall survival in pT1bN0 and pT2N0 GBC patients (DC, HR:0.53, 95%CI: 0.42-0.66, p < 0.001; VC, HR: 0.33, 95%CI: 0.14-0.76, p = 0.009). CONCLUSION: NSS could evaluate the adequacy of nodal staging and predict the prognosis in pT1bN0 and pT2N0 GBC patients, and hence was helpful to guide their treatment strategies.

Identification of Genomic Alterations in Sporadic Pancreatic Neurogenic Tumors.

Pancreatic neurogenic tumors, including schwannoma and neurofibroma, are rare, and their genetic aberrances have not been defined. The present study aimed at investigating the genomic alterations of pancreatic schwannoma and neurofibroma. Two patients with pancreatic schwannoma and 1 patient with neurofibroma, who underwent surgical resection at the First Affiliated Hospital, Sun Yat-sen University between June 2016 and April 2019, were recruited into the study. Their tumor tissues were analyzed by exome sequencing and genome sequencing. Exome sequencing revealed a MUTYH likely pathogenic germline variant in 1 schwannoma with somatic NF2del and NOTCH1 amplification. Pathway enrichment analysis on the other schwannoma case showed that the main abnormal function involved DNA damage repair, mitosis, and cell cycle. In addition, genome sequencing showed the inversion (INV) variant of SPIRE gene and multiple mitochondrial INV variants in both schwannoma cases. Furthermore, exome sequencing revealed NF1del, single nucleotide variation, TP53, and ERBB3 amplification in neurofibroma, whereas genomic duplication/deletion variants and mitochondrial abnormalities were much less than that in schwannoma. In conclusion, variants in NF1 and NF2 genes, amplification of key driver genes, and somatic and mitochondrial INV variants may play important roles in the development of pancreatic schwannoma and neurofibroma.