Neoadjuvant Therapy is Essential for Resectable Pancreatic Cancer.

BACKGROUND: Awareness of the benefits of neoadjuvant therapy is increasing, but its use as an initial therapeutic option for patients with resectable pancreatic cancer remains controversial, especially for those patients without high-risk prognostic features. Even for patients with high-risk features who are candidates to receive neoadjuvant therapy, no standard regimen exists. METHODS: In this review, we examined available data on the neoadjuvant therapy in patients with resectable pancreatic cancer, including prospective studies, retrospective studies, and ongoing clinical trials, by searching PubMed/MEDLINE, ClinicalTrials.gov, Web of Science, and Cochrane Library. The characteristics and results of screened studies were described. RESULTS: Retrospective and prospective studies with reported results and ongoing randomized studies were included. For patients with resectable pancreatic cancer, neoadjuvant therapy provides benefits such as increased survival, decreased risk of comorbidities and mortality, and improved cost-effectiveness due to an increased completion rate of multimodal treatment. Highly active regimens such as FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin) or gemcitabine plus nab-paclitaxel are considered acceptable therapeutic regimens. Additionally, platinum-containing regimens other than FOLFIRINOX are acceptable for selected patients. Other therapies, such as chemoradiation treatment, immuno-oncology agents, and targeted therapies are being explored and the results are highly anticipated. CONCLUSION: This review highlights the benefits of neoadjuvant therapy for resectable pancreatic cancer. Some regimens are currently acceptable, but need more evidence from well-designed clinical trials or should be used after being carefully examined by a multidisciplinary team.

Tumor-Infiltrating NETs Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Tumor-infiltrating neutrophils (TINs) indicate poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). Activated neutrophils can generate neutrophil extracellular traps (NETs). Little is known about the presence and prognostic significance of tumor-infiltrating NETs in PDAC. METHODS: This study enrolled 317 patients, in two independent sets (training and validation), who underwent curative pancreatectomy for PDAC in Shanghai Cancer Center. TINs and NETs were identified by immunohistochemical staining for CD15 and citrullinated histone H3, respectively. The relationship between clinicopathological features and outcomes was analyzed. Accuracy of prognostic prediction models was evaluated using concordance index (C-index) and Akaike information criterion (AIC). RESULTS: NETs were associated with OS (both, P < 0.001) and RFS (both, P < 0.001) in the training and validation sets. Tumor-infiltrating NETs predicted poor postsurgical survival of patients with PDAC. Moreover, multivariate analysis identified NETs and AJCC TNM stage as two independent prognostic factors for OS and RFS. Combination of NETs with the 8th edition TNM staging system (C-index, 0.6994 and 0.6669, respectively; AIC, 1067 and 1126, respectively) generated a novel model that improved the predictive accuracy for survival in both sets (C-index, 0.7254 and 0.7117, respectively; AIC, 1047 and 1102, respectively). The model combining presence of NETs with the 7th edition AJCC TNM staging system also had improved predictive accuracy. CONCLUSIONS: NETs were an independent prognostic factor in PDAC and incorporation of NETs along with the standard TNM stating system refined risk-stratification and predicted survival in PDAC with improved accuracy.

Angiogenesis in pancreatic cancer: current research status and clinical implications.

Pancreatic cancer is one of the most lethal malignancies worldwide. Although the standard of care in pancreatic cancer has improved, prognoses for patients remain poor with a 5-year survival rate of < 5%. Angiogenesis, namely, the formation of new blood vessels from pre-existing vessels, is an important event in tumor growth and hematogenous metastasis. It is a dynamic and complex process involving multiple mechanisms and is regulated by various molecules. Inhibition of angiogenesis has been an established therapeutic strategy for many solid tumors. However, clinical outcomes are far from satisfying for pancreatic cancer patients receiving anti-angiogenic therapies. In this review, we summarize the current status of angiogenesis in pancreatic cancer research and explore the reasons for the poor efficacy of anti-angiogenic therapies, aiming to identify some potential therapeutic targets that may enhance the effectiveness of anti-angiogenic treatments.

The Significance of Liquid Biopsy in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer. The 5-year survival rate for PDAC remains low because it is always diagnosed at an advanced stage and it is resistant to therapy. A biomarker, which could detect asymptomatic premalignant or early malignant tumors and predict the response to treatment, will benefit patients with PDAC. However, traditional biopsy has its limitations. There is an urgent need for a tumor biomarker that could easily and repeatedly sample and monitor, in real time, the progress of tumor development. Liquid biopsy could be a tool to assess potential biomarkers. In this review, we focused on the latest discoveries and advancements of liquid biopsy technology in pancreatic cancer research and demonstrated how this technology is being used in clinical applications.

Tumor-Infiltrating Platelets Predict Postsurgical Survival in Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Platelets are believed to promote tumor growth and metastasis in several tumor types. The prognostic role of blood platelets in pancreatic ductal adenocarcinoma (PDAC) remains controversial, and the prognostic value of tumor-infiltrating platelets (TIPs) remains unknown. METHODS: A total of 303 patients who underwent curative pancreatectomy for PDAC were enrolled from two independent centers in China and divided into three cohorts. Paired preoperative blood samples and surgical specimens from all patients were analyzed. The correlations between patient outcomes and preoperative blood platelet counts and the presence of TIPs, respectively, were analyzed. TIPs were identified by immunohistochemical staining of CD42b. Prognostic accuracy was estimated by concordance index (C-index) and Akaike information criterion (AIC). RESULTS: TIPs, but not preoperative blood platelet counts, were associated with overall survival (OS; all P < 0.001) and recurrence-free survival (RFS; all P < 0.001) in the training, testing, and validation sets. Positive CD42b expression predicted poor postsurgical survival. Incorporation of TIPs improved the predictive accuracy of the 8th edition American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for OS in each of the three cohorts (C-index: 0.7164, 0.7569, and 0.7050, respectively; AIC: 472, 386, and 1019, respectively). The new predictor system was validated by incorporating TIPs with the 7th edition AJCC TNM staging system (C-index: 0.7052, 0.7623, and 0.7157; AIC: 476, 386, and 1015). CONCLUSION: TIPs were an independent prognostic factor that could be incorporated into the AJCC TNM staging system to refine risk stratification and predict surgical outcomes of patients with PDAC.

Postoperative serum CA19-9, CEA and CA125 predicts the response to adjuvant chemoradiotherapy following radical resection in pancreatic adenocarcinoma.

OBJECTIVE: To evaluate the prediction of benefits from adjuvant chemoradiotherapy by postoperative serum CA19-9, CA125 and CEA. METHODS: The relations between benefits from adjuvant chemoradiotherapy and levels of postoperative serum CA19-9, CA125 and CEA were investigated in 804 pancreatic adenocarcinoma patients who received radical resection. RESULTS: Adjuvant chemoradiotherapy was an independent factor for late recurrence [12.2 vs. 8.5 months, P = 0.001 for recurrence free survival (RFS)] and long survival [23.7 vs. 17.0 months, P < 0.001 for overall survival (OS)] in resected pancreatic adenocarcinoma. Postoperative serum CA19-9, CA125 and CEA were independent risk predictors for poor surgical outcome in pancreatic adenocarcinoma (P < 0.001 for all). Adjuvant chemradiotherapy (hazard ratio: 0.359, 95% confidence interval: 0.253-0.510, P < 0.001 for OS; hazard ratio: 0.522, 95% confidence interval: 0.387-0.705, P < 0.001 for RFS) were confirmed to improve the surgical outcome in patients with abnormal levels of any one of the three postoperative markers, but not in patients with normal levels of the three postoperative markers. In the subgroup of patients with negative lymph node, its improvement of surgical outcome was also significant in patients with abnormal levels of any one of postoperative serum CA19-9, CA125 and CEA (hazard ratio: 0.412, 95% confidence interval: 0.244-0.698, P = 0.001 for OS; hazard ratio: 0.546, 95% confidence interval: 0.352-0.847, P = 0.007 for RFS). CONCLUSION: Postoperative serum CA19-9, CA125 and CEA could serve as predictors of response for adjuvant chemoradiotherapy even if the status of lymph nodes is negative.

The clinicopathological and prognostic significance of PD-L1 expression in pancreatic cancer: A meta-analysis.

BACKGROUND: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC. DATA SOURCES: Electronic search of the PubMed, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis. Meta-analysis was performed to investigate the relationship between PD-1 and overall survival (OS). RESULTS: Nine studies with 989 PDAC patients were included for PD-L1 expression analysis. And 5 studies with 688 PDAC patients were included in the prognostic analysis. The PD-L1 positive rate measured by immunohistochemistry (IHC) was higher than that measured by polymerase chain reaction (PCR) (P < 0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS (HR = 2.34; 95% CI: 1.78-3.08). Subgroup analysis showed that the prognostic effect of PD-L1 levels was similar between the IHC and PCR methods. The PD-L1 positive rate was associated with PDAC T stages; the PD-L1 positive rate in the T3-4 group was higher than that in the T1-2 group (OR = 0.37; P = 0.001). CONCLUSIONS: High PD-L1 expression levels predicted a poor prognosis in PDAC patients. Thus, PD-L1 status helps determine treatment in PDAC patients.

RIPK4/PEBP1 axis promotes pancreatic cancer cell migration and invasion by activating RAF1/MEK/ERK signaling.

Pancreatic cancer is a lethal disease with a high metastatic potential. In our previous study, we identified a specific subgroup of patients with pancreatic cancer with a serum signature of carcinoembryonic antigen (CEA)+/cancer antigen (CA)125+/CA19-9 ≥1,000 U/ml. In this study, by using high-throughput screening analysis, we found that receptor-interacting protein kinases 4 (RIPK4) may be a key molecule involved in the high metastatic potential of this subgroup of patients with pancreatic cancer. A high RIPK4 expression predicted a poor prognosis and promoted pancreatic cancer cell migration and invasion via the RAF1/MEK/ERK pathway. Moreover, RIPK4 activated the RAF1/MEK/ERK pathway by regulating proteasome-mediated phosphatidylethanolamine binding protein 1 (PEBP1) degradation. The suppression of PEBP1 degradation eliminated the RIPK4-induced activation of RAF1/MEK/ERK signaling and pancreatic cancer cell migration or invasion. Thus, on the whole, the findings of this study indicated that RIPK4 was upregulated in the subgroup of pancreatic cancer with a high metastatic potential. RIPK4 overexpression promoted pancreatic cancer cell migration and invasion via the PEBP1 degradation-induced activation of the RAF1/MEK/ERK pathway.

Intrinsic Contact Between T and N Classifications in Resected Well-Moderately Differentiated Locoregional Pancreatic Neuroendocrine Neoplasms.

BACKGROUND: The role of N classification is controversial in several prognostication systems proposed for pancreatic neuroendocrine neoplasms (pNENs). The widely accepted modified European Neuroendocrine Tumor Society (mENETS) system suggests this contradiction may be related to T classification. METHODS: Data were collected retrospectively from 981 patients in the Surveillance, Epidemiology, and End Results (SEER) database (1973-2012; cohort 1) and 140 patients from the Pancreatic Cancer Institute of Fudan University (2006-2016; cohort 2). All patients had resected well- to moderately differentiated locoregional pNENs, whereby the mENETS system was adopted. Factors related to N1 classification and the association between N and T classifications were analyzed, and N classification prognosis based on T classification was assessed. RESULTS: In cohorts 1 and 2, tumor size (2-4 cm: p < 0.001 and p = 0.037, respectively; > 4 cm: p < 0.001 and p = 0.012, respectively) and tumors extending beyond the pancreas (p < 0.001 and p = 0.016, respectively), which are factors for T classification, affected N1 classification. For tumors limited to the pancreas, the N1 classification was associated with tumor size (p < 0.001 and p = 0.046, respectively) and predicted poor disease-specific survival (DSS), while for tumors extending beyond the pancreas, the N1 classification did not affect patient outcomes. Findings obtained with data from the SEER database were reproducible with our institutional data. CONCLUSIONS: N classification is associated with T classification, limiting the value of N1 classification for the pNENs tumor-node-metastasis system. A new risk model is necessary to predict patient outcomes and guide clinical practice for the prognosis of pNENs.

Postoperative serum CEA and CA125 levels are supplementary to perioperative CA19-9 levels in predicting operative outcomes of pancreatic ductal adenocarcinoma.

BACKGROUND: Carbohydrate antigen (CA19-9) is a well-established marker to monitor disease status after resection of pancreatic cancer. However, few serum markers have been reported to improve the prognostic ability of postoperative CA19-9, especially in patients with normal postoperative CA19-9. METHODS: A total of 353 patients with pancreatic ductal adenocarcinoma treated by radical resection were reviewed retrospectively, and a prospective cohort including 142 patients with resectable pancreatic head carcinoma was analyzed as a validation cohort. Perioperative CA19-9 and postoperative serum markers (CEA, CA242, CA72-4, CA50, CA125, CA153, and AFP) were investigated. RESULTS: Patients with postoperative normalization of CA19-9 had improved survival times (recurrence-free survival: 11.9 months; overall survival: 22.5 months) compared with those with decreased but still elevated postoperative CA19-9 (recurrence-free survival: 6.8 months, P < .001; overall survival: 13.5 months, P < .001) or those with increased postoperative CA19-9 (recurrence-free survival: 3.5 months, P < .001; overall survival: 7.9 months, P < .001), which was similar to those with consistently normal CA19-9 during perioperative periods (recurrence-free survival: 10.6 months, P = .799; overall survival: 24.1 months, P = .756). Normal postoperative CA19-9 levels were an independent indicator for a positive outcome after operation, regardless of preoperative CA19-9 levels. Elevated postoperative CEA and CA125 were identified further as independent risk factors for patients with normal postoperative CA19-9, while elevated postoperative CA125 and nondecreased postoperative CA19-9 were independent prognostic markers for patients with elevated postoperative CA19-9. CONCLUSION: The postoperative monitoring of CEA and CA125 provided prognostic significance to the measurement of CA19-9 in pancreatic cancer after resection.

[Antitumor Effect of Ganoderma lipsiense Extract on Triple-negative Breast Cancer Model Mice and Mechanism Study].

OBJECTIVE: To study the inhibitory effect and mechanism of Ganoderma lipsiense extract (GLE) on the growth of triple-negative breast cancer (TNBC) cell line MDA-MB-231-HM in a mouse model. METHODS: The mouse model of TNBC was established by subcutaneous injection of 1.5 x 10(6) of MDA-MB-231-HM cells into BALB/c-nu mouse. Twenty successfully modeled mice were divided into the GLE group and the negative control group according to random digit table, 10 in each group. GLE (0.2 mL 100 mg/mL) was peritoneally injected to mice in the GLE group, while equal dose of normal saline was peritoneally injected to mice in the negative control group. The medication was administered once per 3 days and discontinued after 45 days. The CD34 expression was detected using immunohistochemical assay for counting microvessels. Meanwhile, expressions of thrombospondin 1 (TSP-1) and cyclin D1 were detected using immunohistochemical assay. RESULTS: The average weight was obviously lower in the GLE group than in the negative control group [(0.33 ± 0.16) g vs (0.68 ± 0.37)g, P < 0.05]. The tumor inhibition rate was 51.4% in the GLE group. The volume of transplanted tumor was obviously lesser in the GLE group than in the negative control group (P < 0.05). Results of immunohistochemical staining showed, the microvessel density (MVD) under every field was (20.7 ± 2.1), TSP-1 positive cell count was (66.2 ± 9.2), cyclin D1 positive cell count was (33.8 ± 16.4) in the GLE group, and they were 34.0 ± 2.0, 24.0 ± 6.6, and 168.2 ± 32.6, respectively in the negative control group. There was statistical difference in all indices between the two groups (P < 0.05). CONCLUSION: GLE could inhibit malignant proliferation of tumor cells by suppressing angiogenesis of blood vessels in tumor tissues and regulating cell cycles, thereby inhibiting TNBC.

Mutant p53 determines pancreatic cancer poor prognosis to pancreatectomy through upregulation of cavin-1 in patients with preoperative serum CA19-9 ≥ 1,000 U/mL.

Patients with pancreatic ductal adenocarcinoma (PDAC) and preoperative CA19-9 ≥ 1,000 U/mL that does not decrease postresection have the worst prognosis, but the mechanism is unclear. Here, we elucidated the relationship between this signature and driver-gene mutations, and the cavins/caveolin-1 axis. Four major driver-genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4) that are associated with PDAC and five critical molecules (cavin-1/-2/-3/-4 and caveolin-1) in the cavins/caveolin-1 axis were screened by immunohistochemistry in tumor tissue microarrays. Additionally, six pancreatic cancer cell lines and a spleen subcapsular inoculation nude mouse model were also used. Overexpression of mutant p53 was the major mutational event in patients with the CA19-9 signature. Cavin-1 was also overexpressed, and mutant p53 correlated directly with high cavin-1 expression in pancreatic cancer cell lines and tumor specimens (P < 0.01). Furthermore, mutant p53(R172H) upregulated cavin-1 and promoted invasiveness and metastasis of pancreatic cancer cells in vitro and in vivo. Finally, combination of mutant p53 and high cavin-1 density indicated the shortest survival for patients with PDAC after resection (P < 0.001). Mutant p53-driven upregulation of cavin-1 represents the major mechanism of poor outcome for PDAC patients with the CA19-9 signature after resection, indicating that inhibition of cavin-1 may improve the long-term efficacy of pancreatectomy.