Characterization of Pancreatic Fistula after Post-pancreatectomy Acute Pancreatitis.

OBJECTIVE: This study aimed to investigate the clinical significance and risk factors of postoperative pancreatic fistula (POPF) after post-pancreatectomy acute pancreatitis (PPAP) in patients who underwent pancreaticoduodenectomy (PD). SUMMARY BACKGROUND DATA: PPAP has been recognized as a critical factor in the pathophysiology of POPF after PD. METHODS: A total of 817 consecutive patients who underwent elective PD between January 2020 and June 2022 were included. PPAP and POPF were defined in accordance with the International Study Group for Pancreatic Surgery (ISGPS) definitions. Multivariate logistic analyses were performed to investigate the risk factors for POPF. Comparisons between PPAP-associated POPF and non-PPAP-associated POPF were made to further characterize this intriguing complication. RESULTS: Overall, 159 (19.5%) patients developed POPF after PD, of which 73 (45.9%) occurred following PPAP, and the remaining 86 (54.1%) had non-PPAP-associated POPF. Patients with PPAP-associated POPF experienced significantly higher morbidity than patients without POPF. Multivariate analyses revealed distinct risk factors for each POPF type. For PPAP-associated POPF, independent risk factors included estimated blood loss >200 mL (OR 1.93), MPD ≤3 cm (OR 2.88), and soft pancreatic texture (OR 2.01), largely overlapping with FRS (Fistula Risk Score) elements. On the other hand, non-PPAP-associated POPF was associated with age >65 years (OR 1.95), male (OR 2.10), and MPD ≤3 cm (OR 2.57). Notably, among patients with PPAP, the incidence of POPF consistently hovered around 50% regardless of the FRS stratification. CONCLUSIONS: PPAP-associated POPF presents as a distinct pathophysiology in the development of POPF after PD, potentially opening doors for future prevention strategies targeting the early postoperative period.

TP53 missense mutation reveals gain-of-function properties in small-sized KRAS transformed pancreatic ductal adenocarcinoma.

BACKGROUND: Although the molecular features of pancreatic ductal adenocarcinoma (PDAC) have been well described, the impact of detailed gene mutation subtypes on disease progression remained unclear. This study aimed to evaluate the impact of different TP53 mutation subtypes on clinical characteristics and outcomes of patients with PDAC. METHODS: We included 639 patients treated with PDAC in Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine between Jan 2019 and Jun 2021. The genomic alterations of PDAC were analyzed, and the association of TP53 mutation subtypes and other core gene pathway alterations with patients' clinical characteristics were evaluated by Chi-squared test, Kaplan-Meier method and Cox regression model. RESULTS: TP53 missense mutation was significantly associated with poor differentiation in KRASmut PDAC (50.7% vs. 36.1%, P = 0.001). In small-sized (≤ 2 cm) KRASmut tumors, significantly higher LNs involvement (54.8% vs. 23.5%, P = 0.010) and distal metastic rate (20.5% vs. 2.9%, P = 0.030) were observed in those with TP53 missense mutation instead of truncating mutation. Compared with TP53 truncating mutation, missense mutation was significantly associated with reduced DFS (6.6 [5.6-7.6] vs. 9.2 [5.2-13.3] months, HR 0.368 [0.200-0.677], P = 0.005) and OS (9.6 [8.0-11.1] vs. 18.3 [6.7-30.0] months, HR 0.457 [0.248-0.842], P = 0.012) in patients who failed to receive chemotherapy, while higher OS (24.2 [20.8-27.7] vs. 23.8 [19.0-28.5] months, HR 1.461 [1.005-2.124], P = 0.047) was observed in TP53missense cases after chemotherapy. CONCLUSIONS: TP53 missense mutation was associated with poor tumor differentiation, and revealed gain-of-function properties in small-sized KRAS transformed PDAC. Nonetheless, it was not associated with insensitivity to chemotherapy, highlighting the neoadjuvant therapy before surgery as the potential optimized strategy for the treatment of a subset of patients.

A deep-learning radiomics-based lymph node metastasis predictive model for pancreatic cancer: a diagnostic study.

OBJECTIVES: Preoperative lymph node (LN) status is essential in formulating the treatment strategy among pancreatic cancer patients. However, it is still challenging to evaluate the preoperative LN status precisely now. METHODS: A multivariate model was established based on the multiview-guided two-stream convolution network (MTCN) radiomics algorithms, which focused on primary tumor and peri-tumor features. Regarding discriminative ability, survival fitting, and model accuracy, different models were compared. RESULTS: Three hundred and sixty-three pancreatic cancer patients were divided in to train and test cohorts by 7:3. The modified MTCN (MTCN+) model was established based on age, CA125, MTCN scores, and radiologist judgement. The MTCN+ model outperformed the MTCN model and the artificial model in discriminative ability and model accuracy. [Train cohort area under curve (AUC): 0.823 vs. 0.793 vs. 0.592; train cohort accuracy (ACC): 76.1 vs. 74.4 vs. 56.7%; test cohort AUC: 0.815 vs. 0.749 vs. 0.640; test cohort ACC: 76.1 vs. 70.6 vs. 63.3%; external validation AUC: 0.854 vs. 0.792 vs. 0.542; external validation ACC: 71.4 vs. 67.9 vs. 53.5%]. The survivorship curves fitted well between actual LN status and predicted LN status regarding disease free survival and overall survival. Nevertheless, the MTCN+ model performed poorly in assessing the LN metastatic burden among the LN positive population. Notably, among the patients with small primary tumors, the MTCN+ model performed steadily as well (AUC: 0.823, ACC: 79.5%). CONCLUSIONS: A novel MTCN+ preoperative LN status predictive model was established and outperformed the artificial judgement and deep-learning radiomics judgement. Around 40% misdiagnosed patients judged by radiologists could be corrected. And the model could help precisely predict the survival prognosis.

Who could complete and benefit from the adjuvant chemotherapy regarding pancreatic ductal adenocarcinoma? A multivariate-adjusted analysis at the pre-adjuvant chemotherapy timing.

BACKGROUND: The pre-adjuvant chemotherapy (PAC) status of postoperative pancreatic ductal adenocarcinoma (PDAC) patients has not been studied and elaborated well previously. METHOD: The association of PAC variables and prognoses was explored using a multivariable Cox model, restricted cubic spline analysis, and correlation analysis. The main outcomes were overall survival (OS) and progression-free survival (PFS). The secondary outcome was chemotherapy completeness (CHC). RESULTS: A total of 401 eligible patients were enrolled in sequential surgery and chemotherapy. The chemotherapy regimen, PAC fasting blood glucose (FBG), and elevated fasting blood glucose (eFBG) status were associated with CHC (regimen types: p = 0.005, continuous FBG: p = 0.014, eFBG status: p = 0.012). Early administration of adjuvant chemotherapy (<34 days) was a risk factor for the limited OS and PFS (OS: aHR: 1.61 [1.09-2.38], p = 0.016; PFS: aHR: 1.91 [1.29-2.82], p = 0.001). Patients with higher PAC body mass index (BMI), receiving Gemcap regimen, and with lower PAC tumor marker value were observed with better survival prognoses (PAC BMI: OS: 0.927 [0.875-0.983], p = 0.011; Gemcap: OS: 0.533 [0.312-0.913], p = 0.022; Gemcap: PFS: 0.560 [0.341-0.922], p = 0.023; PAC CA125: OS: 1.004 [1.002-1.006], p < 0.001; PAC CA125: PFS: 1.003 [1.000-1.005], p = 0.031; PAC CEA: OS: 1.050 [1.026-1.074], p < 0.001). The BMI decrease was mainly concentrated in the first 3 months of chemotherapy courses (first 3 months: p < 0.001; latter 3 months: p = 0.097). And CEA, compared to CA125 and CA199, was a better prognostic indicator (CEA: first 3 months: PFS p = 0.011, OS p < 0.001; latter 3 months: PFS p = 0.024, OS p = 0.041). CONCLUSION: PDAC patients should be treated with adjuvant chemotherapy over 34 postoperative days. PAC sarcopenia was a risk factor for OS, but not PFS and limited CHC. Those with higher PAC FBG levels were more likely to finish chemotherapy. CEA, compared to CA125 and CA199, was a better prognostic indicator.

The impact of Omicron pandemic and COVID-19 vaccination on the pancreatic adenocarcinoma patients.

Background: The coronavirus disease 2019 (COVID-19) pandemic resulted in enormous medical and economic burden worldwide during the past 3 years. The vaccination was deemed the effective option to prevent the severe symptoms, and especially recommended among cancer patients. Shanghai experienced the first lockdown during the recent Omicron pandemic since 2019. How patients with pancreatic adenocarcinoma (PAC) suffered from the pandemic and how vaccination influenced their oncological outcomes were unexplored yet. Method: The retrospective study was carried out in a high-volume referral center including 1157 consecutively enrolled patients with PAC experiencing the COVID-19 pandemic. The primary outcome was the overall survival (OS). Results: Limited postoperative patients (9.21%) received the vaccination. The lockdown in Shanghai (April to May, 2022) was not observed impacting the survival prognoses of patients with PAC. Though vaccination was not significantly associated with OS itself (adjusted hazard ratio (aHR): 2.032 [0.940-4.391], p = 0.071), it was discovered to synergistically improve the chemotherapy effect in the multivariate analyses (interaction p = 0.023). Conclusion: The vaccination itself did not influence the survival prognoses of patients with PAC. A potential positive interaction was observed between chemotherapy and vaccination despite the limited follow-up time. The postoperative patients should consider the vaccination more. The patients with PAC did not suffer worse prognostic outcomes from the strict sanitary policy during the wave of COVID-19 pandemic in Shanghai.

Higher body mass index indicated better overall survival in pancreatic ductal adenocarcinoma patients: a real-world study of 2010 patients.

BACKGROUND: The association between body mass index (BMI) and the overall survival (OS) of pancreatic ductal adenocarcinoma (PDAC) patients remains controversial and unclear, METHOD: A total of 2010 patients from a high-volume center were enrolled in the study. The OS of PDAC patients was evaluated based on restricted cubic spline (RCS), propensity score (PS) and multivariable risk adjustment analyses. RESULT: BMI was linearly related to the OS (total P = 0.004, nonlinear P = 0.124). BMI was analyzed as categorical data based on X-tile software-defined cutoffs and World Health Organization (WHO)-recommended cutoffs. Adjusted with confounding covariates, higher BMI manifested as a positive prognostic predictor. Furthermore, BMI was proven to be associated with the OS in the PS analysis. (UnderweightXtile vs. NormalXtileP = 0.003, OverweightXtile vs. NormalXtileP = 0.019; UnderweightWHO vs. NormalWHOP < 0.001, OverweightWHO vs. NormalWHOP = 0.024). It was also revealed that patients with higher BMI benefitted more from chemotherapy. (Adjusted hazard ratio (aHR): UnderweightXtile vs. NormalXtile vs. OverweightXtile: 0.565 vs. 0.474 vs. 0.409; UnderweightWHO vs. NormalWHO vs. OverweightWHO: 0.613 vs. 0.464 vs. 0.425). CONCLUSION: Among PDAC patients, there was a positive association between BMI and the OS, especially in patients treated with chemotherapy.

Worth it or not? Primary tumor resection for stage IV pancreatic cancer patients: A SEER-based analysis of 15,836 cases.

BACKGROUND: Primary tumor resection (PTR) as a treatment option for patients with stage IV pancreatic cancer (PC) is controversial. PATIENTS AND METHODS: Stage IV PC patients, with treatment data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER), were screened. The main outcomes were overall survival (OS) and cancer-specific survival (CSS). RESULTS: We enrolled 15,836 stage IV PC patients in this study. Propensity score-matched analyses revealed improved OS and CSS of patients receiving chemotherapy plus PTR versus chemotherapy (median survival time [MSTOS ]: 13 vs. 9 months, p = 0.024; MSTCSS : 14 vs. 10 months, p = 0.035), and chemoradiotherapy plus PTR versus chemoradiotherapy (MSTOS : 14 vs. 7 months, p = 0.044; MSTCSS : 14 vs. 7 months, p = 0.066). Multivariate adjusted analyses further confirmed these results. Stratified with different metastatic modalities, multivariate analyses suggested that PTR significantly improved the OS and CSS among patients with ≤1 metastatic organ, and that patients with brain metastasis might not benefit from chemotherapy treatment. CONCLUSION: PTR improves the OS and CSS of stage IV PC patients on the basis of chemotherapy or chemoradiotherapy, provided that the metastases involve ≤1 organ. Chemotherapy, however, should be carefully considered in patients with metastases involving the brain.

Original study: The rescue staging for pancreatic ductal adenocarcinoma with inadequate examined lymph nodes.

BACKGROUND: In previous studies, it's recommended that the lymph node involvement should be evaluated with enough examined lymph nodes (eLNs) in the 8th American Joint Committee on Cancer (AJCC) staging system for pancreatic cancer. This study aims to put forward a rescue staging system for pancreatic ductal adenocarcinoma (PDAC) patients with inadequate eLNs after pancreatoduodenectomy (PD). METHOD: 11,224 PDAC patients undergoing PD in The Surveillance, Epidemiology, and End Results (SEER) database were included. Another Ruijin Pancreatic Disease Center (RJPDC) database consisted of 821 patients was utilized for external validation. RESULTS: The proportions of patients with eLNs≥15 were 44.7% and 32.8% in SEER and RJPDC database separately. The rescue staging system was put forward relying on LNR (HR = 1.83, 95% CI 1.74-1.92, P < 0.001) for N staging of eLNs<15 population and pLNs for the rest. The TNM modalities were also rearranged in the rescue system for better survival coordination. The C-index of rescue staging system was 0.638 while that of AJCC 8th staging system was 0.613 in SEER database. Similar phenomena were observed in RJPDC database. Kaplan-Meier analyses revealed reliable internal coherences (SEER: Ib: P = 0.26; IIa: P = 0.063; IIb: P = 0.53; IIIa: P = 0.11. RJPDC: Ib: P = 0.32; IIa: P = 0.66; IIb: P = 0.76; IIIa: P = 0.66) and significant staging efficiency (SEER: P < 0.001; RJPDC: P = 0.002). CONCLUSION: A rescue staging system was put forward regardless of the eLNs number. And the novel system manifested better predictive capacity than 8th AJCC staging system.

Oncological outcomes of robotic-assisted versus open pancreatoduodenectomy for pancreatic ductal adenocarcinoma: a propensity score-matched analysis.

BACKGROUND: Robotic-assisted minimally invasive surgery is associated with worse oncologic outcomes for some but not other types of cancers. We conducted a propensity score-matched analysis to compare oncologic outcomes of robotic-assisted laparoscopic (RPD) vs. open pancreatoduodenectomy (OPD) for pancreatic ductal adenocarcinoma (PDAC). METHODS: Treatment-naïve PDAC patients undergoing either RPD or OPD at our hospital between January 2013 and December 2017 were included. Propensity score matching was conducted at a ratio of 1:2. The primary outcome was disease-free survival (DFS) and overall survival (OS). RESULTS: A total of 672 cases were identified. The propensity score-matched cohort included 105 patients receiving RPD and 210 patients receiving OPD. The 2 groups did not differ in the number of retrieved lymph nodes [11 (7-16) vs. 11 (6-17), P = 0.622] and R0 resection rate (88.6% vs. 89.0%, P = 0.899). There was no statistically significant difference in median DFS (14 [95% CI 11-22] vs. 12 [95% CI 10-14] months (HR 0.94; 95% CI 0.87-1.50; log-rank P = 0.345) and median OS (27 [95% CI 22-35] vs. 20 [95% CI 18-24] months (HR 0.77; 95% CI 0.57-1.04; log-rank P = 0.087) between the two groups. Multivariate COX analysis showed that RPD was not an independent predictor of DFS (HR 0.90; 95% CI 0.68-1.19, P = 0.456) or OS (HR 0.77; 95% CI 0.57-1.05, P = 0.094). CONCLUSION: Comparable DFS and OS were observed between patients receiving RPD and OPD. This preliminary finding requires further confirmation with prospective randomized controlled trials.

Accuracy of Nodal Positivity in Inadequate Lymphadenectomy in Pancreaticoduodenectomy for Pancreatic Ductal Adenocarcinoma: A Population Study Using the US SEER Database.

Objectives: The optimal number of the examined lymph nodes (ELNs) in pancreaticoduodenectomy for pancreatic ductal adenocarcinoma has been widely studied. However, the accuracy of nodal positivity for the patients with inadequate lymphadenectomy is still unclear. The purpose of our study was to determine the accuracy of the number of positive nodes reported for patients with 1-3 positive nodes and the probability that 4 or more nodes could be positive along with tumor size and number of nodes examined. Methods: We obtained data on patients who underwent pancreaticoduodenectomy for resectable pancreatic ductal adenocarcinoma diagnosed during 2004-2013 from the US Surveillance, Epidemiology, and End Results registry. An mathematical model based on Hypergeometric Distribution and Bayes' Theorem was used to estimate the accuracy. Results: Among the 9,945 patients, 55.6% underwent inadequate lymphadenectomy. Of them, 1,842, 6,049, and 2,054 had T1, T2, and T3 stage disease, respectively. The accuracy of the number of observed positive nodes increased as the number of ELNs increased and the tumor size decreased. To rule out the possibility of N2 stage (4 and more positive nodes), there should be at least 13 ELNs for the patients with 1 observed positive lymph node and 14 for the patients with 2. Conclusion: Inadequate lymphadenectomy could result in underestimation of the N stage, and this would have adverse impact on recurrence, efficacy of postoperative treatment, and even overall survival. This model combined with the observed positive lymph nodes, the number of ELNs, and tumor size could provide a more accurate determination of nodal positivity of these patients.

Adjudin delays cellular senescence through Sirt3­mediated attenuation of ROS production.

Aging, marked by the physical and functional decline in numerous biological processes, is associated with multiple pathologies including cancer, neurodegenerative diseases and cardiocerebral vascular diseases. The accumulation of reactive oxygen species (ROS) production is considered one of the major causes of aging­associated diseases and a major therapeutic target. Hydroxyurea has been widely used for cellular senescence model. The expression level of cell cycle-related protein, ROS production and senescence-associated ß-galactosidase are considered to be markers of cellular senescence. Strategies to slow senescence may be beneficial for various aging­associated diseases. The results of the current study indicated that adjudin, a multi­functional small molecule compound, delayed hydroxyurea­induced senescence in mouse embryo fibroblasts (MEFs). Adjudin reduced the proportion of senescence­associated ß­galactosidase­positive cells and decreased the expression levels of senescence­associated markers, p16 and p21. Mechanistically, adjudin exerted its anti­senescence effect by elevating the expression level of sirtuin 3 (Sirt3), which attenuated ROS production through the regulation of forkhead box O3a and manganese superoxide dismutase expression. Furthermore, by comparing wild­type and Sirt3­knockout MEFs, it was demonstrated that Sirt3 mediated the anti­senescence effect of adjudin. Taken together, the findings indicated that adjudin has anti­aging properties that may be exploited to treat aging­associated diseases.

Thromboxane A2 receptor antagonist SQ29548 attenuates SH­SY5Y neuroblastoma cell impairments induced by oxidative stress.

Thromboxane A2 receptor (TXA2R) serves a vital role in numerous neurological disorders. Our previous study indicated that SQ29548, an antagonist of TXA2R, attenuated the induced neuron damage in cerebral infarction animals; however, the underlying mechanism remains unknown. Certain studies revealed a new role of TXA2R in the regulation of oxidative stress, which is one of the basic pathological processes in neurological disorders. Thus, the present study attempted to examine whether the inhibition of TXA2R with SQ29548 helped to protect the nerve cells against oxidative stress. SQ29548 was utilized as a TXA2R antagonist, and relevant assays were performed to detect the cell viability, cellular reactive oxygen species (ROS) level, cell apoptosis, expression levels of superoxide dismutase­2 (SOD2), catalase and caspases, and activation of mitogen­activated protein kinase (MAPK) pathways. It was observed that hydrogen peroxide (H2O2) dose­dependently reduced the viability of SH­SY5Y cells. In addition, H2O2 raised the level of ROS in cells, inhibited the expression levels of SOD2 and catalase, and potentially enhanced cell apoptosis and the expression of caspases via activating the MAPK pathways. Pretreatment with SQ29548 not only rescued the viability of SH­SY5Y cells, but also ameliorated the intracellular ROS level and the expression levels of SOD2 and catalase. Furthermore, it decreased the cell apoptosis and the expression of caspases, possibly via the inhibition of MAPK pathways. In conclusion, SQ29548, an antagonist of TXA2R, improved the antioxidant capacities of SH­SY5Y cells and reduced the cell apoptosis through the inhibition of MAPK pathways.

Adjudin-preconditioned neural stem cells enhance neuroprotection after ischemia reperfusion in mice.

BACKGROUND: Transplantation of neural stem cells (NSCs) has been proposed as a promising therapeutic strategy for the treatment of ischemia/reperfusion (I/R)-induced brain injury. However, existing evidence has also challenged this therapy on its limitations, such as the difficulty for stem cells to survive after transplantation due to the unfavorable microenvironment in the ischemic brain. Herein, we have investigated whether preconditioning of NSCs with adjudin, a small molecule compound, could enhance their survivability and further improve the therapeutic effect for NSC-based stroke therapy. METHOD: We aimed to examine the effect of adjudin pretreatment on NSCs by measuring a panel of parameters after their transplantation into the infarct area of ipsilateral striatum 24 hours after I/R in mice. RESULTS: We found that pretreatment of NSCs with adjudin could enhance the viability of NSCs after their transplantation into the stroke-induced infarct area. Compared with the untreated NSC group, the adjudin-preconditioned group showed decreased infarct volume and neurobehavioral deficiency through ameliorating blood-brain barrier disruption and promoting the expression and secretion of brain-derived neurotrophic factor. We also employed H2O2-induced cell death model in vitro and found that adjudin preconditioning could promote NSC survival through inhibition of oxidative stress and activation of Akt signaling pathway. CONCLUSION: This study showed that adjudin could be used to precondition NSCs to enhance their survivability and improve recovery in the stroke model, unveiling the value of adjudin for stem cell-based stroke therapy.