Kaizhou Jin

Modified Staging Classification for Pancreatic Neuroendocrine Tumors on the Basis of the American Joint Committee on Cancer and European Neuroendocrine Tumor Society Systems

Purpose The European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC) staging classifications are two widely used systems in managing pancreatic neuroendocrine tumors. However, there is no universally accepted system. Methods An analysis was performed to evaluate the application of the ENETS and AJCC staging classifications using the SEER registry (N = 2,529 patients) and a multicentric series (N = 1,143 patients). A modified system was proposed based on analysis of the two existing classifications. The modified system was then validated. Results The proportion of patients with AJCC stage III disease was extremely low for both the SEER series (2.2%) and the multicentric series (2.1%). For the ENETS staging system, patients with stage I disease had a similar prognosis to patients with stage IIA disease, and patients with stage IIIB disease had a lower hazard ratio for death than did patients with stage IIIA disease. We modified the ENETS staging classification by maintaining the ENETS T, N, and M definitions and adopting the AJCC staging definitions. The proportion of patients with stage III disease using the modified ENETS (mENETS) system was higher than that of the AJCC system in both the SEER series (8.9% v 2.2%) and the multicentric series (11.6% v 2.1%). In addition, the hazard ratio of death for patients with stage III disease was higher than that for patients with stage IIB disease. Moreover, statistical significance and proportional distribution were observed in the mENETS staging classification. Conclusion An mENETS staging classification is more suitable for pancreatic neuroendocrine tumors than either the AJCC or ENETS systems and can be adopted in clinical practice.

FBW7 (F-box and WD repeat domain-containing 7) negatively regulates glucose metabolism by targeting the c-Myc/TXNIP (thioredoxin binding protein) axis in pancreatic cancer

Purpose: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras–Raf–MEK–ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy. Experimental Design: Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo. Finally, gene expression profiling was performed to identify core signaling pathways. Results: The expression level of FBW7 was negatively associated with SUVmax in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro. Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose (18F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a c-Myc target gene and that FBW7 regulated TXNIP expression in a c-Myc–dependent manner. Conclusions: Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer. Clin Cancer Res; 22(15); 3950–60. ©2016 AACR.

ALDOA functions as an oncogene in the highly metastatic pancreatic cancer

Pancreatic cancer is an aggressive and devastating disease that is characterized by uncontrolled progression, invasiveness and resistance to conventional treatment. In the past decades, much effort has been given to cancer genetics and pathological classification of this disease. Our previous study has uncovered a subgroup of patients with poor outcome, which is characterized by serum signature of CEA(+)/CA125(+)/CA19-9 ≥ 1000 U/mL; however, the underlying biology mechanism remains poorly understood. By using high-throughput screening analysis, we analyzed gene expression signature in highly malignant patients with serum markers of CEA(+)/CA125(+)/CA19-9 ≥ 1000 U/mL. Multiple differentially expressed genes were identified, many of which were closely related with cancer metabolic changes. Treatment of pancreatic cancer cell lines PANC-1 with transforming growth factor-β (TGF-β), which was commonly used to induce metastasis, has uncovered that the glycolytic process and antioxidant response was up-regulated upon TGF-β stimulation. These results were consistent with the high-throughput screening analysis. Subsequent analysis indicated that among glycolytic genes, aldolase A (ALDOA) increased the most significantly upon TGF-β treatment. Further in vitro and in vivo results demonstrated that ALDOA was associated with proliferation and metastasis of pancreatic cancer cells. Moreover, ALDOA predicted poor prognosis of pancreatic cancer, partially due to its role in E-cadherin expression regulation, and the results were further validated by analysis of the correlation between ALDOA and E-cadherin expression in pancreatic cancer tissue samples. Mechanistically, the role of ALDOA in pancreatic cancer might attribute to its regulation of c-Myc, HIF1α and NRF2 (Nuclear Factor, Erythroid 2-Like 2), which were key regulators of glycolysis and antioxidant response control.

Noncoding RNAs as potential biomarkers to predict the outcome in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC), a common digestive system cancer, is highly malignant and has a poor disease outcome. Currently, all available examination and detection methods cannot accurately predict the clinical outcome. Therefore, it is extremely important to identify novel molecular biomarkers for personalized medication and to significantly improve the overall outcome. The “noncoding RNAs” (ncRNAs) are a group of RNAs that do not code for proteins, and they are categorized as structural RNAs and regulatory RNAs. It has been shown that microRNAs and long ncRNAs function as regulatory RNAs to affect the progression of various diseases. Many studies have confirmed a role for ncRNAs in the progression of PDAC during the last few years. Because of the significant role of ncRNAs in PDAC, ncRNA profiling may be used to predict PDAC outcome with high accuracy. This review comprehensively analyzes the value of ncRNAs as potential biomarkers to predict the outcome in PDAC and the possible mechanisms thereof.

Analysis of ctDNA to predict prognosis and monitor treatment responses in metastatic pancreatic cancer patients

Cell‐free circulating tumor DNA (ctDNA) in plasma has been used as a potential noninvasive biomarker for various tumors. Our study was performed to evaluate the clinical implications of ctDNA detection in patients with metastatic pancreatic cancer. First, we attempted to prospectively screen a panel of 60 genes in cell‐free DNA (cfDNA) from ten metastatic pancreatic cancer patients via exome sequencing. Second, droplet digital PCR (ddPCR) was used to identify potential mutations in a cohort of 188 patients with metastatic pancreatic cancer. Finally, to preliminary evaluate the potential role of ctDNA in monitoring tumor responses following chemotherapy, we detected the presence of ctDNA in serial plasma samples from 13 metastatic pancreatic cancer patients (Clinical trial: NCT02017015). The analysis revealed five somatic mutations at BRCA2, EGFR, KDR and ERBB2 gene loci. The frequencies of ctDNA mutation at BRCA2, KDR, EGFR, ERBB2 exon17 and ERBB2 exon27 were 11.7%, 13.8%, 13.3%, 13.3% and 6.4% respectively. Univariate and multivariate analyses identified the ERBB2 exon17 mutation (p = 0.035, HR = 1.61) as an independent factor associated with overall survival among metastatic pancreatic cancer patients. Furthermore, the rate of coincident detection of ctDNA and response to treatment as assessed by CT imaging was 76.9% (10 of 13 cases), and the presence of ctDNA provided the earliest measure of treatment in 6 of 10 patients (60%). ctDNA sequencing may have clinical value for determining metastatic pancreatic cancer treatment and monitoring the tumor response.

Potential Biomarkers in Lewis Negative Patients With Pancreatic Cancer

Objective: To examine potential biomarkers in Lewis negative patients with pancreatic cancer. Background: Carbohydrate antigen 19–9 (CA19–9) is currently the most important and widely used biomarker in pancreatic cancer. However, approximately 5 to 10% of the population are Lewis negative individuals, and they are documented to have scarce or no CA19–9 secretion. Therefore, it is necessary to explore potential biomarkers to compensate for this drawback. Methods: Lewis genotypes were determined in a large cohort of patients with pancreatic cancer (682 cases) and controls (525 cases) by sequencing the Fucosyltransferase 3 (FUT3) gene from genomic DNA. Potential biomarkers were examined in patients with Lewis negative genotypes and normal subjects. The impact of potential biomarkers on tumor burden and survival was analyzed. Results: Forty-seven (6.9%) patients with pancreatic cancer had Lewis negative genotypes. Carcinoembryonic antigen (CEA) and CA125 had greater sensitivity than other biomarkers in Lewis negative patients with pancreatic cancer [CEA, 63.8%; CA125, 51.1%; CA72–4, 25.5%; CA15–3, 21.3%; CA19–9, 19.1%; CA50, 12.8%; CA242, 10.6%; and alpha-fetoprotein (AFP), 0.0%]. In addition, both CEA (98.0%) and CA125 (93.8%) showed a high specificity. Compared with other biomarkers, CEA (60.9%) was sensitive for stage I, II diseases and CA125 (75.0%) was sensitive for stage III, IV diseases. CEA and CA125 were associated with tumor metastasis and therapeutic response. Conclusions: CEA and CA125 have the potential to be applied as biomarkers in Lewis negative patients with pancreatic cancer. CEA and CA125 should be routinely measured for all patients with pancreatic cancer.

Pancreatic cancer: BRCA mutation and personalized treatment

The highly heterozygous nature of pancreatic cancer is partially responsible for its therapeutic ineffectiveness and resistance. Therefore, the ability to identify subgroups of pancreatic cancer with unique biological characteristics and treatment response is urgently needed. In addition to breast and ovarian cancer, pancreatic cancer is the third most common cancer type that is related to the early onset (BRCA) gene mutation in breast cancer. Mounting evidence has demonstrated that BRCA1/2-mutant breast and ovarian cancers are highly sensitive to DNA damage-related treatment, including poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum-based agents. Preliminary evidence also showed promising results for DNA damage-related treatment in BRCA1/2-mutant pancreatic cancer. Importantly, several prospective clinical trials of PARPi-based regimens are underway for BRCA1/2-mutated pancreatic cancer. Pancreatic cancer with a BRCA1/2 mutation is a small subgroup with a promising therapeutic strategy.

Lymph node status predicts the benefit of adjuvant chemoradiotherapy for patients with resected pancreatic cancer

BACKGROUND The role of adjuvant chemoradiotherapy in pancreatic cancer remains limited. The primary aim of this study was to determine the prediction of lymph node (LN) status to the benefit of adjuvant chemoradiotherapy for patients with resected pancreatic adenocarcinoma. METHODS Between December 2010 and December 2012, a total of 152 patients undergoing curative R0 resection for pancreatic adenocarcinoma from multi-institutions were retrospectively analyzed. RESULTS Overall median survival was 16.3 months. Sixty-four patients (42.1%) received adjuvant chemoradiotherapy, whereas 88 (57.9%) did not receive adjuvant therapy after surgery. Patients who received chemoradiotherapy could achieve an improved median OS compared with surgery alone (20.3 versus 13.9 months, p=0.027). Stratified by different lymph node status, multivariate analysis demonstrated the benefit of adjuvant chemoradiotherapy was only seen among patients with lymphatic positive disease (HR = 0.54, 95% CI, 0.33-0.88; p=0.014), not lymphatic negative disease (HR = 0.80, 95% CI, 0.44-1.46; p=0. 468). CONCLUSIONS This study suggests adjuvant chemoradiotherapy is associated with a significant improvement of survival only in patients with LN-positive disease, while the effects of chemoradiotherapy on patients with LN-negative disease may be limited. This study may add incremental knowledge of the role of lymph node status in offering treatment with adjuvant chemoradiotherapy.

Neutrophil-lymphocyte ratio predicts survival in pancreatic neuroendocrine tumors

Although the prognostic role of neutrophil-lymphocyte ratio (NLR) has been confirmed in a variety of tumors, the prognostic role of NLR in pancreatic neuroendocrine tumors (PNETs) has not been examined. The present study was performed to assess the role of NLR as a prognostic factor in patients with PNETs. Clinical data were retrospectively retrieved from a single institution. The best cut-off value for baseline NLR levels was determined by the receiver operating characteristic (ROC) curve and area under the ROC curve. The primary event was overall survival and event times were assessed by the Kaplan-Meier method. Potential factors associated with the elevation of NLR in PNETs were examined. A total of 165 consecutive patients with pathologically confirmed PNETs were included in this study. The cutoff value of NLR was 2.4 by ROC curve (area under ROC curve, 0.70). NLR >2.4 was found to be a poor prognostic factor in the univariate and multivariate analyses. Patients with a NLR value >2.4 had a higher proportion of tumor size at >3 cm (P=0.001), TNM stage III or IV (P=0.019), and G2/G3 (P=0.003). We concluded that NLR is an independent predictor of overall survival for patients with PNETs. Aberrant elevation of NLR identifies high-risk patients with aggressive characteristics.

Surgical management for non-functional pancreatic neuroendocrine neoplasms with synchronous liver metastasis: A consensus from the Chinese Study Group for Neuroendocrine Tumors (CSNET)

Pancreatic neuroendocrine neoplasms (p-NENs) are slowly growing tumors with frequent liver metastasis. There is a variety of approaches to treat non-functional p-NENs with synchronous liver metastasis (LM) which complicates the determination of optimal treatment. Based on updated literature review, we discussed the treatment strategy determinants for p-NEN with LM. According to the resectability of primary tumor, the WHO 2010 grade classification and the radiological type of liver metastasis, the CSNET group reached agreements on a number of issues, including the following. Prior to treatment, biopsy is required to confirm pathology. Liver biopsy is important for more accurate grading of tumor and percutaneous core needle biopsy is more available than EUS-FNA. In patients with unresectable primary, surgical resection for liver-metastatic lesions should be avoided. Curative surgery is recommended for G1/G2 p-NET with type I LM and R1 resection also seems to improve overall survival rate. Cytoreductive surgery is recommended for G1/G2 p-NET with type II LM in select patients, and should meet stated requirements. Surgical resection for G1/G2 p-NET with type III LM and p-NEC with LM should be avoided, and insufficient evidence exists to guide the surgical treatment of G3 p-NET with LM. Liver transplantation may be an option in highly select patients. In addition, the optimal time for surgical approach is still required for more evidence.