Hua Xiang Xu

Metabolic tumour burden assessed by 18F-FDG PET/CT associated with serum CA19-9 predicts pancreatic cancer outcome after resection

PurposeTumour burden is one of the most important prognosticators for pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate the predictive significance of metabolic tumour burden measured by 18F-FDG PET/CT in patients with resectable PDAC.MethodsIncluded in the study were 122 PDAC patients who received preoperative 18F-FDG PET/CT examination and radical pancreatectomy. Metabolic tumour burden in terms of metabolic tumour volume (MTV) and total lesion glycolysis (TLG), pathological tumour burden (tumour size), serum tumour burden (baseline serum CA19-9 level), and metabolic activity (maximum standard uptake value, SUVmax) were determined, and compared for their performance in predicting overall survival (OS) and recurrence-free survival (RFS).ResultsMTV and TLG were significantly associated with baseline serum CA19-9 level (Pu2009=u20090.001 for MTV, Pu2009<u20090.001 for TLG) and tumour size (Pu2009<u20090.001 for MTV, Pu2009=u20090.001 for TLG). Multivariate analysis showed that MTV, TLG and baseline serum CA19-9 level as either categorical or continuous variables, but not tumour size or SUVmax, were independent risk predictors for both OS and RFS. Time-dependent receiving operating characteristics analysis further indicated that better predictive performances for OS and RFS were achieved by MTV and TLG compared to baseline serum CA19-9 level, SUVmax and tumour size (Pu2009<u20090.001 for all).ConclusionMTV and TLG showed strong consistency with baseline serum CA19-9 level in better predicting OS and RFS, and might serve as surrogate markers for prediction of outcome in patients with resectable PDAC.

Intratumoral α-SMA Enhances the Prognostic Potency of CD34 Associated with Maintenance of Microvessel Integrity in Hepatocellular Carcinoma and Pancreatic Cancer

Microvessel density (MVD) as an angiogenesis predictor is inefficient per se in cancer prognosis. We evaluated prognostic values of combining intratumoral alpha-smooth muscle actin (α-SMA)-positive stromal cell density and MVD after curative resection in hypervascular hepatocellular carcinoma (HCC) and hypovascular pancreatic cancer (PC). Tissue microarrays were constructed from tumors of 305 HCC and 57 PC patients who underwent curative resection and analyzed for α-SMA and CD34 expression by immunostaining. Prognostic values of these two proteins and other clinicopathological features were examined. Both low α-SMA density and high MVD-CD34 were associated in HCC with the presence of intrahepatic metastasis and microvascular invasion, and they were related to lymph node involvement and microvascular invasion in PC (p<0.05). Although CD34 alone, but not α-SMA, was an independent prognostic factor for overall survival and recurrence-free survival, the combination of low α-SMA and high CD34 was a predictor of worst prognosis for both types of tumors and had a better power to predict patient death and early recurrence (p<0.01). Furthermore, the results show that distribution of most of the α-SMA-positive cells and vascular endothelial cells overlap, showing major colocalization on vascular walls. Poor microvessel integrity, as indicated by high MVD, together with low perivascular α-SMA-positive cell coverage is associated with early recurrence, unfavorable metastasis, and short survival after tumor resection. This finding highlights the significance of vascular quality in tumor progression, which provides an optimized complement to vascular quantity in prognosis of postoperative patients.

Serum CA125 is a novel predictive marker for pancreatic cancer metastasis and correlates with the metastasis-associated burden

This study evaluated potential of serum tumor markers to predict the incidence and intensity of pancreatic cancer metastasis as well as patient survival. Retrospective records from 905 patients and prospective data from 142 patients were collected from two high-volume institutions. The levels of eight serum tumor markers (CA19-9, CEA, CA242, CA72-4, CA50, CA125, CA153, and AFP) commonly used in gastroenterological cancer were analyzed in all stages of pancreatic cancer. Serum CA125 levels were the most strongly associated with pancreatic cancer metastasis and were higher in patients with metastatic disease than those without. CA125 levels increased with increasing metastasis to lymph nodes and distant organs, especially the liver. High baseline CA125 levels predicted early distant metastasis after pancreatectomy and were associated with the presence of occult metastasis before surgery. An optimal CA125 cut-off value of 18.4 U/mL was identified; patients with baseline CA125 levels of 18.4 U/mL or higher had poor surgical outcomes. In addition, high serum CA125 levels coincided with the expression of a metastasis-associated gene signature and with alterations in “driver” gene expression involved in pancreatic cancer metastasis. CA125 may therefore be a promising, noninvasive, metastasis-associated biomarker for monitoring pancreatic cancer prognosis.

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 CA19-9u2009≥u20091,000u2009U/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 (Pu2009<u20090.01). Furthermore, mutant p53R172H 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 (Pu2009<u20090.001). 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.

Preoperative serum CA125 levels predict the prognosis in hyperbilirubinemia patients with resectable pancreatic ductal adenocarcinoma.

AbstractSerum carbohydrate antigen 19-9 (CA19-9) is widely used to predict the prognosis for pancreatic ductal adenocarcinoma (PDAC). However, hyperbilirubinemia and the CA19-9 nonsecretor phenotype restrict the usage of serum CA19-9 alone. The goal of this study was to confirm the prognostic role of preoperative serum CA125 in PDAC, especially in patients with jaundice.A total of 211 patients with resected PDAC were eligible for this retrospective study, and were classified into 2 groups based on serum bilirubin levels. The prognostic significance of all clinicopathologic factors was evaluated by univariate and multivariate analyses, and the performance of each factor in predicting overall survival (OS) and recurrence-free survival (RFS) was compared.High preoperative CA125, high TNM stage, and lymph node metastasis were independent risk predictors for OS and RFS in all patients and the 2 subgroups, but high CA19-9 was only significant when considering all patients and those with nonelevated bilirubin. Using time-dependent receiver-operating characteristic analysis, better predictive performance for OS and RFS was observed for serum CA19-9 as compared to serum CA125 in these patients.High serum CA125 can independently predict poor prognosis. Importantly, in PDAC patients with hyperbilirubinemia, preoperative serum CA125 can predict the prognosis, whereas CA19-9 cannot. Preoperative CA19-9 had better predictive performance for survival than CA125, and the performance of CA19-9 did not decline between all patients and those with nonelevated bilirubin, but was significantly affected by hyperbilirubinemia.

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.

Significance of caveolin-1 regulators in pancreatic cancer.

Caveolin-1 is a scaffold protein on the cell membrane. As the main component of caveolae, caveolin-1 is involved in many biological processes that include substance uptake and transmembrane signaling. Many of these processes and thus caveolin-1 contribute to cell transformation, tumorigenesis, and metastasis. Of particular interest are the dual rolesof tumor suppressor and oncogene that caveolin-1 appear to play in different malignancies, including pancreatic cancer. Therefore, analyzing caveolin-1 regulators and understanding their mechanisms of actionis key to identifying novel diagnostic and therapeutic tools for pancreatic cancer. This review details the mechanisms of action of caveolin-1 regulators and the potential significance for pancreatic cancer treatment.

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

BACKGROUNDnImmunotherapy 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.nnnDATA SOURCESnElectronic 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).nnnRESULTSnNine 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) (Pu202f<u202f0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS (HRu202f=u202f2.34; 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 (ORu202f=u202f0.37; Pu202f=u202f0.001).nnnCONCLUSIONSnHigh 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

BackgroundThe 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.MethodsData 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.ResultsIn cohorts 1 and 2, tumor size (2–4 cm: pxa0<xa00.001 and pxa0=xa00.037, respectively; >xa04 cm: pxa0<xa00.001 and pxa0=xa00.012, respectively) and tumors extending beyond the pancreas (pxa0<xa00.001 and pxa0=xa00.016, respectively), which are factors for T classification, affected N1 classification. For tumors limited to the pancreas, the N1 classification was associated with tumor size (pxa0<xa00.001 and pxa0=xa00.046, 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.ConclusionsN 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.