Stem cell-like circulating tumor cells identified by Pep@MNP and their clinical significance in pancreatic cancer metastasis.

Objective: The circulating tumor cells (CTCs) could be captured by the peptide functionalized magnetic nanoparticles (Pep@MNP) detection system in pancreatic ductal adenocarcinoma (PDAC). CTCs and the CXCR4 expression were detected to explore their clinical significance. The CXCR4+ CTCs, this is highly metastatic-prone stem cell-like subsets of CTCs (HM-CTCs), were found to be associated with the early recurrence and metastasis of PDAC. Methods: CTCs were captured by Pep@MNP. CTCs were identified via immunofluorescence with CD45, cytokeratin antibodies, and the CXCR4 positive CTCs were assigned to be HM-CTCs. Results: The over-expression of CXCR4 could promote the migration of pancreatic cancer cell in vitro and in vivo. In peripheral blood (PB), CTCs were detected positive in 79.0% of all patients (49/62, 9 (0-71)/2mL), among which 63.3% patients (31/49, 3 (0-23)/2mL) were HM-CTCs positive. In portal vein blood (PVB), CTCs were positive in 77.5% of patients (31/40, 10 (0-40)/2mL), and 67.7% of which (21/31, 4 (0-15)/2mL) were HM-CTCs positive CTCs enumeration could be used as diagnostic biomarker of pancreatic cancer (AUC = 0.862), and the combination of CTCs positive and CA19-9 increase shows improved diagnostic accuracy (AUC = 0.963). in addition, PVB HM-CTCs were more accurate to predict the early recurrence and liver metastasis than PB HM-CTCs (AUC 0.825 vs. 0.787 and 0.827 vs. 0.809, respectively). Conclusions: The CTCs identified by Pep@MNP detection system could be used as diagnostic and prognostic biomarkers of PDAC patients. We identified and defined the CXCR4 over-expressed CTC subpopulation as highly metastatic-prone CTCs, which was proved to identify patients who were prone to suffering from early recurrence and metastasis.

Hypoxia-induced epigenetic regulation of miR-485-3p promotes stemness and chemoresistance in pancreatic ductal adenocarcinoma via SLC7A11-mediated ferroptosis.

The mechanism of hypoxia in chemoresistance of pancreatic ductal adenocarcinoma (PDAC) remains elusive. In this study, we revealed the essential role of miR-485-3p in PDAC, particularly its impact on cancer stemness and gemcitabine resistance under hypoxic conditions. We found substantial downregulation of miR-485-3p in PDAC tissues, with lower expression correlating to poor patient outcomes. Mechanistically, miR-485-3p influenced stemness characteristics, as evidenced by reduced tumor-sphere formation and increased sensitivity to gemcitabine upon overexpression. Moreover, we identified SOX9 and SLC7A11 as two targets of miR-485-3p, which play a vital role in stemness and ferroptosis. Under the hypoxic condition, DNMT3B expression was upregulated, leading to hypermethylation of the miR-485-3p promoter region. The reduced miR-485-3p expression promoted stemness and chemoresistance of PDAC. In conclusion, our findings elucidate the intricate interplay of hypoxia, epigenetic modifications, and ferroptosis in PDAC and shed light on potential avenues for targeted interventions that modulate cancer stemness and chemosensitivity, offering prospects for improved therapeutic strategies for PDAC.

Translational PET Imaging of Nectin-4 Expression in Multiple Different Cancers with 68Ga-N188.

Nectin cell adhesion molecule 4 (nectin-4) is a transmembrane protein overexpressed on a variety of cancers and plays an important role in oncogenic and metastatic processes. The nectin-4-targeted antibody-drug conjugate enfortumab vedotin has been approved for treating locally advanced or metastatic urothelial cancer, but the efficacy in other types of cancer remains to be explored. The aim of this study was to evaluate the feasibility of nectin-4-targeted PET imaging with 68Ga-N188 as a noninvasive method to quantify membranous nectin-4 expression in multiple tumor types-an approach that may provide insight for patient stratification and treatment selection. Methods: Sixty-two patients with 16 types of cancer underwent head-to-head 68Ga-N188 and 18F-FDG PET/CT imaging for initial staging or detection of recurrence and metastases. Correlation between lesion SUVmax and nectin-4 expression determined by immunohistochemistry staining was analyzed in 36 of 62 patients. Results: The SUVmax of 68Ga-N188 had a positive correlation with membranous nectin-4 expression in the various tumor types tested (r = 0.458; P = 0.005), whereas no association was observed between the SUVmax and cytoplasmic nectin-4 expression. The detection rates for patient-based analysis of 68Ga-N188 and 18F-FDG PET/CT examinations were comparable (95.00% [57/60] vs. 93.33% [56/60]). In patients with pancreatic cancer, 68Ga-N188 exhibited a potential advantage for detecting residual or locally recurrent tumors; this advantage may assist in clinical decision-making. Conclusion: The correlation between nectin-4-targeted 68Ga-N188 PET imaging and membranous nectin-4 expression indicates the potential of 68Ga-N188 as an effective tool for selecting patients who may benefit from enfortumab vedotin treatment. The PET imaging results provided evidence to explore nectin-4-targeted therapy in a variety of tumors. 68Ga-N188 may improve the restaging of pancreatic cancer but requires further evaluation in a powered, prospective setting.

Single-cell transcriptome profiling of primary tumors and paired organoids of pancreatobiliary cancer.

Single-cell RNA-seq (scRNA-seq) and cancer organoid model have shown promise in investigating tumor microenvironment heterogeneity and facilitating chemotherapeutic drug testing to inform treatment selection. It is still unknown whether the scRNA-seq results based on organoid can faithfully reflect the heterogeneity of primary pancreatobiliary cancer. To reveal the similarities and differences between primary tumors and their matched organoids at transcriptome level, we conducted scRNA-seq for paired primary tumors and organoids from one cholangiocarcinoma (CCA) and two pancreatic ductal adenocarcinoma (PDAC) patients. We identified inter-patient and intra-tumor heterogeneity and found that the organoids retained copy number variation (CNV) patterns of primary tumors. There was no significant difference in cancer stem cell (CSC) properties between the primary tumors and the organoids, whereas organoid from one PDAC case had increased mesenchymal-score and decreased epithelial-score compared with the primary tumors. All organoids showed a transition tendency from the classical subtype to the basal-like subtype in the transcriptional level. Organoids and primary tumors differed in metabolic and unfolded protein response (UPR) signatures. In addition, we revealed the heterogeneity of cancer associated fibroblasts (CAFs) and T cells, and explored the developmental trajectory of T cells. Our findings facilitate further understanding of organoid model and confirm its application prospects in pancreatobiliary cancer.

Single-cell RNA-seq reveals characteristics in tumor microenvironment of PDAC with MSI-H following neoadjuvant chemotherapy with anti-PD-1 therapy.

Accumulating evidence suggests the minority of patients with advanced pancreatic ductal adenocarcinoma (PDAC) that have microsatellite instability high (MSI-H) can benefit from immune checkpoint inhibitors (ICIs). However, the effects of ICIs on the tumor microenvironment (TME) of PDAC remain elusive. We conducted single-cell RNA-seq (scRNA-seq) analysis on a residual lesion from a MSI-H PDAC patient who received a radical operation after eight cycles of neoadjuvant treatment (nab-paclitaxel/gemcitabine plus pembrolizumab). Multiple tumor subclusters were identified in residual lesion after neoadjuvant treatment, one of which was mainly composed of cells in the S and G2M phases. This subcluster also had enriched expression of MKI67 and PCNA and cell cycle-related signatures and was thus defined as a proliferating tumor subcluster. This subcluster had higher S_score, Fatty acid_score, UPR_score, and Glycolysis_score than others. We also identified characteristics of the TME after neoadjuvant treatment by comparing the excised primary tumors form nontreated PDAC and the residual lesion. The residual lesion was characterized with activated pancreatic stellate cells (PSCs) and exhausted T cells (Tex). We compared the receptor-ligand interactions between the two groups, and found that no checkpoint receptor-ligand pairs between T cells and tumor cells were identified in the residual lesion, while there were many checkpoint receptor-ligand pairs in the nontreated primary PDAC. In conclusion, our findings revealed the characteristics of residual lesion of advanced PDAC with MSI-H upon combination treatment of chemotherapy and immunotherapy, which might provide some valuable clues for solving the puzzle of ICI in PDAC.

The benefits of neoadjuvant therapy for patients with resectable pancreatic cancer: an updated systematic review and meta-analysis.

Neoadjuvant therapy (NAT) was effective in improving overall survival (OS) of borderline resectable pancreatic cancer. However, its application in resectable pancreatic cancer remains controversial. This study aimed to determine whether NAT has a greater advantage over conventional upfront surgery (US) in terms of resection rate, R0 resection rate, positive lymph node rate, and OS. We identified articles before October 7, 2022, by searching four electronic databases. The studies included in the meta-analysis all met the inclusion and exclusion criteria. The Newcastle-Ottawa scale was used to evaluate the quality of the articles. OS, DFS, resection rate, R0 resection rate and positive lymph nodes rate were extracted. Odds ratio (OR), hazard ratio (HR) and 95% confidence intervals (CI) were calculated, and sensitivity analysis and publication bias were used to assess the sources of heterogeneity. In total, 24 studies, involving 1384 (35.66%) patients assigned to NAT and 2497 (64.43%) patients assigned to US, were included in the analysis. NAT could effectively prolong OS (HR 0.73, 95% CI 0.65-0.82, P < 0.001) and DFS (HR 0.72, 95% CI 0.62-0.84, P < 0.001). Subgroup analysis results of 6 randomized controlled trials (RCTs) also showed that RPC patients could benefit from NAT in the long term (HR 0.72, 95% CI 0.58-0.90, P = 0.003). NAT decreased resection rate (OR 0.43, 95% CI 0.33-0.55, P < 0.001), but was associated with increased R0 resection rate (OR 2.05, 95% CI 1.47-2.88, P < 0.001) and decreased positive lymph node rate (OR 0.38, 95% CI 0.27-0.52, P < 0.001). Although the application of NAT increases the risk of patients not being able to undergo surgical resection, it can prolong the OS and delay tumor progression in RPC. Therefore, we still expect larger and higher-quality RCTs to confirm the effectiveness of NAT.

Efficacy and safety of early drain removal following pancreatic resections: a meta-analysis.

BACKGROUND: No consensus was reached with regard to the effect of EDR on postoperative outcomes after pancreatic surgery. The meta-analysis was designed to explore the efficacy and safety of early drain removal (EDR). METHODS: Systematic literature search was performed. Data extraction and correction were performed by three researchers. For dichotomous and continuous outcomes, we calculated the pooled risk difference and mean difference with 95% confidence intervals, respectively. The heterogeneity of included studies was evaluated using Cochran's Q and I2 test. The stratified analyses of pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) were performed. RESULTS: A total of 10 studies including 3 RCTs and 7 non RCTs were included for meta-analysis, among which 1780 patients with EDR and 5613 patients with late drain removal (LDR) were enrolled. The meta-analysis of both all the available studies and studies only with selected low risk patients indicated that EDR group had significantly lower incidences of Grade B/C postoperative pancreatic fistula (POPF) and total complications for both PD and DP. However, no advantages of EDR were observed in the meta-analysis of the 3 RCTs. In addition, EDR was associated with a lower incidence of intra-abdominal infection after PD. While for DP, EDR group had decreased risk of delayed gastric emptying and re-operation, and shorter postoperative in-hospital stay. CONCLUSIONS: The meta-analysis demonstrates that EDR is effective and safe for both PD and DP considering POPF and total complications, especially for patients with low concentration of postoperative drain fluid amylase.

Safety evaluation of early drain removal following pancreaticoduodenectomy: A single-center retrospective cohort study.

Objectives: The effects of early drain removal (EDR) on postoperative complications after pancreaticoduodenectomy (PD) remains to be investigated. This single-center retrospective cohort study was designed to explore the safety of EDR after PD. Methods: A total of 112 patients undergoing PD with drain fluid amylase (DFA) on postoperative day (POD) 1 and 3 <= 5000 were divided into EDR and late drain removal (LDR). Propensity Score Matching (PSM) was used. We compared postoperative outcomes between two groups and explore the risk factors of total complications using univariate and multiple logistic regression analyses. Results: No statistical differences were found in primary outcomes, including Grade B/C postoperative pancreatic fistula (POPF) (Original cohort: 5.71% vs. 3.90%; P = 1.000; PSM cohort: 3.33% vs. 6.67%; P = 1.000), and total complications (Original cohort: 17.14% vs. 32.47%; P = 0.093; PSM cohort: 13.33% vs. 33.33%; P = 0.067). The EDR was associated with shorter in-hospital stay (Original cohort: 11 days vs. 15 days; P < 0.0001; PSM cohort: 11 days vs. 15 days; P < 0.0001). Conclusions: EDR on POD 3 is safe for patients undergoing PD with low risk of POPF.

Single Cell RNA-Seq Identifies Immune-Related Prognostic Model and Key Signature-SPP1 in Pancreatic Ductal Adenocarcinoma.

There are no reliable biomarkers for early diagnosis or prognosis evaluation in pancreatic ductal adenocarcinoma (PDAC). Multiple scRNA-seq datasets for PDAC were retrieved from online databases and combined with scRNA-seq results from our previous study. The malignant ductal cells were identified through calculating copy number variation (CNV) scores. The robust markers of malignant ductal cells in PDAC were found. Five immune-related signatures, including SPP1, LINC00683, SNHG10, LINC00237, and CASC19, were used to develop a risk score formula to predict the overall survival of PDAC patients. We also constructed an easy-to-use nomogram, combining risk score, N stage, and margin status. The expression level of SPP1 was related to the prognosis and immune regulators. We found that SPP1 was mainly expressed in ductal cells and macrophages in PDAC. In conclusion, we constructed a promising prognostic model based on immune-related signatures for PDAC using scRNA-seq and TCGA_PAAD datasets.

Predictive Model of Early Death of Resectable Pancreatic Ductal Adenocarcinoma After Curative Resection: A SEER-Based Study.

OBJECTIVE: This study aims to determine the factors that predict early death and establish a predictive model for early death by analyzing clinical characteristics of patients with resectable pancreatic ductal adenocarcinoma (R-PDAC) who die early after radical surgery. MATERIALS AND METHODS: This was a retrospective study of patients who underwent radical surgical resection for R-PDAC in the Surveillance, Epidemiology, and End Results (SEER) database. Patients with overall survival ≤ 12 months were assigned as early death group and above 1 year as the late death group. Univariate and multivariate logistic regression was conducted to identify factors significantly associated with early death. An early death predictive model was constructed based on the identified independent risk factors. RESULTS: A total of 9695 patients were analyzed, and the total incidence of early death was 30.72%. Multivariable analysis showed that factors significantly associated with early death included age at diagnosis, race, marital status, tumor location, tumor size, tumor grade, number of positive lymph nodes, number of examined lymph nodes, positive lymph node ratio, chemotherapy, and radiotherapy. The predictive model showed good discrimination with a C-index of 0.722 (95% confidence interval: 0.711-0.733) and convincing calibration. CONCLUSIONS: We developed a predictive model that may be easily applied to patients with R-PDAC after radical resection to predict the chance of death within 1 year. For patients with high risk of early death, neoadjuvant therapy should be considered. Even after radical resection, more aggressive adjuvant chemotherapy (with or without combined radiotherapy) must be used to minimize the chance of early death.

Early Drain Removal is Safe in Patients With Low or Intermediate Risk of Pancreatic Fistula After Pancreaticoduodenectomy: A Multicenter, Randomized Controlled Trial.

OBJECTIVE: This multicenter randomized controlled trial was designed to test the hypothesis that early drain removal (EDR) could decrease the incidence of grade 2 to 4 complications for patients undoing pancreaticoduodenectomy (PD) with low or intermediate risk of postoperative pancreatic fistula (POPF). BACKGROUND: The safety and effects of EDR on postoperative complications after PD are still controversial. METHODS: A multicenter randomized controlled trial at 6 tertiary referral hospitals was carried out (NCT03055676). Patients who met the inclusion criteria, including drain amylase level less than 5000 U/L on postoperative day (POD) 1 and POD 3, and drain output less than 300 mL per day within 3 days after surgery, were enrolled. Patients were then randomized to the EDR group or the routine drain removal (RDR) group. In the EDR group, all drainage tubes were removed on POD3. In the RDR group, drainage tubes were removed on POD 5 or beyond. Primary outcome was the incidence of Clavien-Dindo grade 2 to 4 complications. Secondary outcomes were comprehensive complication index, grade B/C POPF, total medical expenses and postoperative in-hospital stay etc, within 90 days after surgery. RESULTS: A total of 692 patients were screened, and 312 patients were eligible for randomization. Baseline characteristics were well balanced between the 2 groups and 96.8% of these 312 patients had low or intermediate risk of POPF, according to the 10-point fistula risk score. A total of 20.5% of the patients in the EDR group suffered at least 1 grade 2 to 4 complication, versus 26.3% in the RDR group (P = 0.229). Multi-variate analysis showed older age (>65 years old) and blood transfusion were independent risk factors for grade 2 to 4 complications. The rate of grade B/C POPF was low in either group (3.8% vs 6.4%, P = 0.305). The comprehensive complication index of the 2 groups was also comparable (20.9 vs 20.9, P = 0.253). Total medical expenses were not significantly different. Postoperative in-hospital stay was clinically similar (15 days vs 16 days, P = 0.010). CONCLUSIONS: Nearly half of the patients undergoing PD met the inclusion criteria, predicting low incidence of grade B/C POPF and major complications. EDR was safe in these patients but did not significantly decrease major complications.

Modification of a new subclassification of Grade B postoperative pancreatic fistula: A bicenter retrospective cohort study.

AIM: To propose a modified subclassification of grade B postoperative pancreatic fistula (POPF) based on management approaches in Chinese patients. METHODS: Data of consecutive pancreatoduodenectomy at two hospitals in China from 2013 to 2018 were collected, and outcomes were compared across different groups of POPF. Subclassification of B-POPF was made based on intervention to B1: non-interventional subclass and B2: interventional subclass. RESULTS: A total of 142 of 522 patients had biochemical leaks (BLs) (27.2%), and POPFs developed in 106 of 522 patients (20.3%), with 81 B-POPFs (15.5%) and 25 C-POPFs (4.8%). BL did not differ from the non-fistula condition in almost all outcomes. The differences of outcomes among the non-fistula/BL, B-POPF and C-POPF groups were significant. The prevalence of subclass B1 and B2 was 56.8% (46/81) and 43.2% (35/81), respectively. Compared to the B1 group, patients in the B2 group had worse outcomes, such as post-pancreatectomy hemorrhage (15.2% vs 34.3%, P = .045), biliary fistula (13.0% vs 34.3%, P = .023), postoperative hospital stay (32 vs 39 days, P = .011), and cost ($US28 601.0 vs $US39 314.5, P < .001). CONCLUSION: The recently reported B-POPF subclassification method was modified in Chinese patients according to the intervention, and is more practical, simpler and fits Chinese patients.

Metabolic detection and systems analyses of pancreatic ductal adenocarcinoma through machine learning, lipidomics, and multi-omics.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, characterized by rapid progression, metastasis, and difficulty in diagnosis. However, there are no effective liquid-based testing methods available for PDAC detection. Here we introduce a minimally invasive approach that uses machine learning (ML) and lipidomics to detect PDAC. Through greedy algorithm and mass spectrum feature selection, we optimized 17 characteristic metabolites as detection features and developed a liquid chromatography-mass spectrometry-based targeted assay. In this study, 1033 patients with PDAC at various stages were examined. This approach has achieved 86.74% accuracy with an area under curve (AUC) of 0.9351 in the large external validation cohort and 85.00% accuracy with 0.9389 AUC in the prospective clinical cohort. Accordingly, single-cell sequencing, proteomics, and mass spectrometry imaging were applied and revealed notable alterations of selected lipids in PDAC tissues. We propose that the ML-aided lipidomics approach be used for early detection of PDAC.

Validation and modification of the AJCC 8th TNM staging system for pancreatic ductal adenocarcinoma in a Chinese cohort: A nationwide pancreas data center analysis.

OBJECTIVE: To validate the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for pancreatic ductal adenocarcinoma (PDAC) in a Chinese cohort of radically resected patients and to develop a refined staging system for PDAC. METHODS: Data were collected from the China Pancreas Data Center (CPDC) for patients with resected PDAC in 2016 and 2017, and cancer-specific survival (CSS) was evaluated using the Kaplan-Meier method and log-rank test. Univariate and multivariate analyses based on Cox regression were performed to identify prognostic factors. The recursive partitioning analysis (RPA), Kaplan-Meier method, and log-rank test were performed on the training dataset to generate a proposed modification for the 8th TNM staging system utilizing the preoperative carbohydrate antigen (CA)19-9 level. Validation was performed for both staging systems in the validation cohort. RESULTS: A total of 1,676 PDAC patients were retrieved, and the median CSS was significantly different between the 8th TNM groupings, with no significant difference in survival between stage IB and IIA. The analysis of T and N stages demonstrated a better prognostic value in the N category. Multivariate analysis showed that the preoperative serum CA19-9 level was the strongest prognostic indicator among all the independent risk factors. All patients with CA19-9 >500 U/mL had similar survival, and we proposed a new staging system by combining IB and IIA and stratifying all patients with high CA19-9 into stage III. The modified staging system had a better performance for predicting CSS than the 8th AJCC staging scheme. CONCLUSIONS: The 8th AJCC staging system for PDAC is suitable for a Chinese cohort of resected patients, and the N category has a better prognostic value than the T category. Our modified staging system has superior accuracy in predicting survival than the 8th AJCC TNM staging system.

A modified alternative fistula risk score (a-FRS) obtained from the computed tomography enhancement pattern of the pancreatic parenchyma predicts pancreatic fistula after pancreatoduodenectomy.

BACKGROUND: Alternative fistula risk score (a-FRS) is useful to predict clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatoduodenectomy (PD). METHODS: Clinical data from 239 patients undergoing PD were collected. The CT value of the pancreatic parenchyma was measured in the nonenhanced (N), arterial (A), portal venous (P), and late (L) phases. The A/N, A/P, P/L and A/L ratios were calculated and their correlation with CR-POPF were analyzed. By replacing pancreatic texture with the best CT attenuation ratio, a modified a-FRS was developed. RESULTS: Forty-seven patients developed CR-POPF. The A/P ratio (P < 0.001), P/L ratio (P = 0.002) and A/L ratio (P < 0.001) were significantly higher in the CR-POPF group. The A/L ratio performed best in predicting CR-POPF (AUC: 0.803) and the cut-off value is 1.36. A/L ratio >1.36 (P < 0.001), body mass index (P = 0.005) and duct diameter (P = 0.037) were independently associated with CR-POPF. By replacing soft texture with an A/L ratio >1.36, a modified a-FRS was developed and performed better than the a-FRS (AUC: 0.823 vs 0.748, P = 0.006) in predicting CR-POPF. CONCLUSIONS: The modified a-FRS is an objective and preoperative model for predicting the occurrence of CR-POPF after PD.

Effects of parecoxib after pancreaticoduodenectomy: A single center randomized controlled trial.

BACKGROUND: Parecoxib, a selective cyclooxygenase-2 inhibitor, is a potential alternative analgesic to reduce opioid consumption after Pancreaticoduodenectomy (PD). Further, the safety and efficacy of long-term use of parecoxib for patients after PD remain a major concern. MATERIALS AND METHODS: In this single-center, randomized clinical trial, 134 patients undergoing open PD were randomized into the parecoxib group (group P) and control group (group C) at a 1:1 ratio. Besides a routine patient-controlled epidural analgesia (PCEA) until 3 days postoperatively for both groups, patients in group P (n = 68) received parecoxib (40 mg, intravenously, Q 12 h) for the first 5 postoperative days and were encouraged to receive opioid analgesics to control severe pain as needed. Patients in group C (n = 66) received on-demand opioid analgesics (pethidine or morphine) postoperatively. The primary outcomes included the effectiveness of parecoxib in controlling pain (measured using the visual analog scale (VAS)) and reduction of opioid use (measured as accumulated doses). Secondary outcomes included the postoperative recovery process, rate of postoperative complications, and the anti-inflammatory effect of parecoxib. RESULTS: The VAS scores were not significantly different between the two groups. The number of doses of opioids for patients in group P (3.2 ± 0.3 doses) was significantly lower than in group C (8.5 ± 0.4 doses) (p = 0.0007). The incidence of opioid-related side effects was significantly lower in group P than in group C (p = 0.001). There were no significant differences in postoperative complications or readmission rates between the two groups. The postoperative time to first pass flatus, time to first mobilization out of bed, and time of removal of nasogastric tube in group P were significantly shorter than those in group C (P < 0.05). The postoperative serum IL-6 levels of patients in group P were significantly lower than those in group C at each time point (P < 0.05). CONCLUSIONS: Parecoxib effectively controls pain after PD. Prophylactic analgesia using parecoxib for up to 5 days after PD is safe, feasible, and can provide the same optimal pain control as opioids without adverse effects.

Molecular characterization of circulating tumor cells in pancreatic ductal adenocarcinoma: potential diagnostic and prognostic significance in clinical practice.

BACKGROUND: The clinical value of heterogeneous sub-populations of circulating tumor cells (CTCs) in pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: Peripheral blood samples were obtained from 67 PDAC patients. CTCs were isolated by employing CD45 negative enrichment technique and further characterized for epithelial to mesenchymal transition (EMT) or human equilibrative nucleoside transporter-1 (hENT-1). The relationships between CTCs sub-phenotypes with clinicopathological factors or post-operative recurrence in PDAC patients were analyzed. RESULTS: EMT related CTCs could be isolated and identified from the 81% of patients (54/67), and both the total count (median: 5 vs. 17/mL, P<0.0001) and M-CTC percentage (median: 0.2 vs. 0.345, P=0.0244) of CTCs could differentiate local/regional with metastatic disease. Multivariate analysis showed that both AJCC stage (P=0.025) and M-CTC percentage (P=0.001) were independent prognostic indicators of recurrence free survival (RFS) in resected patients. Moreover, Kaplan-Meier survival analysis showed that M-CTC after 2 courses of chemotherapy was significantly associated with inferior RFS (49.5 weeks vs. undefined, P=0.0288). No significant correlation in hENT-1 expression was found between CTCs and matched tumor tissues, and further multivariate analysis suggested hENT-1 expression in CTCs as independent prognostic factor for RFS (P=0.016). Patients with low hENT-1 expression in CTCs had decreased RFS (32 weeks vs. undefined, P=0.0337). CONCLUSIONS: CTCs could be the promising diagnostic biomarkers in PDAC patients, and phenotypic profiling of CTCs based on EMT or hENT-1 could help establish novel prognostic biomarkers in resected patients undergoing adjuvant gemcitabine-based chemotherapy. KEYWORDS: Circulating tumor cells (CTCs); Pancreatic ductal adenocarcinoma (PDAC); Epithelial to mesenchymal transition (EMT); human equilibrative nucleoside transporter-1 (hENT-1).

Multidisciplinary diagnosis and treatment of recurrent follicular dendritic cell sarcoma in abdomen: A case report.

RATIONALE: Follicular dendritic cell sarcoma (FDCS) is a rare malignant tumor derived from follicular dendritic cells, and is often associated with Castleman disease. Here we present a rare case of paraneoplastic pemphigus (PNP) with FDCS which required multidisciplinary approach for the diagnosis and treatment. PATIENT CONCERNS: A 28-year-old Chinese female had FDCS recurrence, and primary clinical manifestation was PNP. DIAGNOSES: PNP with FDCS. INTERVENTIONS: The patient received gamma globulin infusion, took anlotinib, and underwent plasma exchange therapy. OUTCOMES: The skin lesions recovered and there was no evidence of tumor recurrence. LESSONS: The diagnosis and management of PNP with FDCS require close cooperation among surgeons, dermatologists, hematologists, otolaryngologists, oncologists, radiologists, pathologists, and respiratory doctors. The interesting clinical manifestations of this patient provide a multifaceted approach to the investigation of the interactions among FDCS, Castleman disease, and PNP.

LncRNA H19-Derived miR-675-3p Promotes Epithelial-Mesenchymal Transition and Stemness in Human Pancreatic Cancer Cells by targeting the STAT3 Pathway.

Objective: The functional role and mechanism of the long noncoding RNA (lncRNA) H19 in regulating human pancreatic cancer (PC) cell stemness and invasion have not been completely elucidated. This study aimed to evaluate the role of H19 in regulating the stemness, epithelial-mesenchymal transition (EMT), invasion and chemosensitivity of PC cells. Methods: The sphere-forming ability was assessed using serum-free floating-culture systems. Chemosensitivity was evaluated via CCK-8 and flow cytometry assays in vitro. Migration and invasion were evaluated by transwell assays. The expression of stemness and EMT markers was detected by flow cytometry, qRT-PCR and western blot analyses. Xenograft initiation, growth and sensitivity were examined; Ki-67 nuclear staining intensity was evaluated by immunohistochemistry; and in situ apoptosis was evaluated by a TUNEL assay. Results: H19 played an important role in maintaining PC cell stemness. Upregulated H19 expression in CAPAN-1 cells promoted tumor cell migration, invasion, EMT and chemoresistance. In contrast, downregulated H19 expression in PANC-1 cells yielded the opposite results. These effects were mediated by positively modulating the STAT3 pathway. Furthermore, SOCS5, an endogenous inhibitor of the STAT3 pathway, was a direct target of miR-675-3p, which was positively regulated by H19 in PC cells. Conclusions: The H19/miR-675-3p signaling axis plays a critical role in maintaining the EMT process and stemness of PC cells by directly targeting SOCS5 to activate the STAT3 pathway. These data provide new insights into the oncogenic function of H19 in human PC and reveal potential targets for the development of optimal treatment approaches for this disease.

Spatial heterogeneity in epithelial to mesenchymal transition properties of circulating tumor cells associated with distant recurrence in pancreatic cancer patients.

BACKGROUND: The spatial heterogeneity of epithelial to mesenchymal transition (EMT)-related circulating tumor cells (CTCs) within the circulatory system and its potential clinical relevance remain unclear in pancreatic cancer (PC) patients. We aimed to map the distribution of EMT-related CTCs along the spreading pathway and investigate the prognostic significance due to the potential spatial heterogeneity in the count and phenotypic properties of CTCs. METHODS: Both portal vein (PoV) and peripheral vein (PV) blood samples were collected from 39 PC patients. CTCs were isolated by using a CD45 negative enrichment method, and EMT-related phenotypes in CTCs were analyzed by 4-channel immunofluorescence. The correlations of CTCs with patient characteristics and recurrence-free survival (RFS) were analyzed. RESULTS: Both the number {median CTC total count, 10 [6-16] in PoV vs. 5 [1-7] in PV per mL, P<0.0001} and EMT status of CTCs [median mesenchymal CTC (M-CTC) percentage, 0.33 (0.13-0.52) in PoV vs. 0.2 (0-0.4) in PV, P=0.0211] showed significant spatial heterogeneity during dissemination from the PoV to the PV. Univariate analysis adjusting for patient age and sex revealed that CTC total count and M-CTC percentage in PoV samples could be risk factors for RFS in PC patients (P=0.003 and P=0.001, respectively), and ROC curve analysis found that both of these factors had good performance in distinguishing patients with early distant recurrence (within 6 months), with the optimal cut-off values of 14 cells/mL (AUROC =0.893, sensitivity =0.857, specificity =0.813, P=0.001) and 0.545 (AUROC =0.795, sensitivity =0.714, specificity =0.906, P=0.016), respectively. CONCLUSIONS: Multivascular assessment of EMT-related CTCs suggested profound dynamic alterations in total count and phenotypes during dissemination, and the spatial heterogeneity of CTCs in circulation could help establish novel prognosis markers in PC patients.