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Introduction: SRPX2 and RAB31 play important roles in tumorigenesis and metastasis; however, their prognostic value in pancreatic cancer remains unclear. This study aimed to investigate the potential interactions and effects of SRPX2 and RAB31 on the diagnosis and prognosis of pancreatic cancer. Methods: The expression of SRPX2 and RAB31 in pancreatic tumor tissues and cells was evaluated through database mining of the Oncomine, Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, and validated the results through immunohistochemistry (IHC) and Western blot in our clinical database. Protein-protein interactions were explored by immunofluorescence and Co-immunoprecipitation (Co-IP). Two hundred tissue microarray specimens from patients (79 training and 121 validation), who underwent curative pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) were used. Additionally, the association between the SRPX2 and RAB31 and prognosis of PDAC patients after surgery was analyzed. Results: The expression of SRPX2 and RAB31 was highly increased in pancreatic cancer, and there was a significant positive correlation between these two proteins. Co-IP showed the direct interaction between SRPX2 and RAB31. Kaplan-Meier analysis showed that positive expression of SRPX2 and RAB31 was associated with reduced disease-free survival (DFS) and overall survival (OS) of PDAC patients in the training set and the validation sets. Furthermore, multivariate analysis indicated that the 8th edition TNM stage and combination of SRPX2 and RAB31 were independent prognostic factors that associated with OS and DFS in the training, and the validation sets, respectively. Conclusions: The combination of SRPX2 and RAB31 can be important markers for the prognosis of pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) progression is mediated by mutations in driver genes and a complex stroma that is mainly dependent on the Sonic hedgehog (Shh) signaling pathway. However, the association between driver genes and Shh-pathway proteins and their potential prognostic significance remain unclear. Methods: We analyzed protein expressions of the KRAS, TP53, SMAD4, and CDKN2A/P16 driver genes and the Shh-pathway molecules, including Shh, glioma-associated oncogene (Gli) 1, Gli2, and smoothened (SMO) by immunohistochemistry using tissue microarrays in 237 patients with resectable PDAC and statistically determined their prognostic significance. Results: SMAD4lost mutation was associated with shorter survival outcomes [overall survival (OS): Hazard ratio (HR) 1.887, p < 0.001]; recurrence-free survival (RFS): HR 1.886, p < 0.001) and abnormal p53 immunolabeling was associated with poor OS (HR 1.436, p = 0.011) in patients with PDAC. The mutational status of p16 had no effect on patient survival. High levels of SMO and Gli1 expression were associated with poor survival outcomes in both univariate and multivariate analyses. Pearson's χ2 test showed a medium correlation between the SMAD4lost mutation and Shh (R = 0.343) and Gli1 (R = 0.505) expression levels (p < 0.001). Patients with the SMAD4lost mutation and high levels of Shh and Gli1 expression showed the poorest survival outcomes (RFS: HR 2.976; OS: HR 3.598; p < 0.001 for both) compared with other patients in the study. Conclusion: Loss of SMAD4 associated with a strongly activated Shh pathway resulted in poor survival outcomes in patients with resected PDAC.

Background: Sorafenib has been recognized as the standard therapy for advanced hepatocellular carcinoma (HCC). Besides, efficacy of sorafenib was unsatisfactory and vast patients are resistant to sorafenib. Thus, molecular mechanisms underlying regulation of sorafenib resistance and seeking potential strategy to improve its efficacy have attracted much attention. As a small-molecule inhibitor of IGF-1R, NT157 has potent antitumor activity against some human cancers. However, whether NT157 has potential anti-tumor effects and its molecular mechanisms in HCC remain poorly understood. Methods: We assessed the effects and explored the mechanism of NT157 and sorafenib as single agents or in combination with sorafenib in HCC cells and mouse model. Further, we further demonstrated that NT157 reversed resistance to sorafenib in HCC.Results: Here, we found NT157 inhibited HCC growth and induced apoptosis in vitro and in vivo. In terms of mechanism, NT157 phosphorylated IRS-1 through ERK-MAPK signaling to be degraded by the ubiquitin-proteasome pathway, lowered p-AKT to deactivate IGF-1R signaling to inhibit proliferation and induce apoptosis. Surprisingly, we further demonstrated that NT157 acted synergistically with sorafenib to inhibit proliferation and contributed to sensitize HCC cells to sorafenib by down-regulation of p-AKT. Conclusions: Overall, our findings provide a translational rationale for inhibition of IGF-1R and downstream signaling pathways by NT157 as a novel targeted therapy alone or combined with sorafenib in HCC.

To evaluate the prediction of benefits from adjuvant chemoradiotherapy by postoperative serum CA19-9, CA125 and CEA.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.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).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.

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

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.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.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.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.

There are few data regarding the clinical and serologic features of chronic hepatitis B (CHB) infection among Hispanics in the United States. The aims of this study were to compare and contrast clinical characteristics of Hispanic and Asian CHB patients.Demographic, clinical, and laboratory data were collected from Hispanic and Asian CHB patients seen between January 2013 and May 2014 at Los Angeles County Hepatitis Clinic.A total of 55 Hispanic and 342 Asian CHB patients were identified. Almost all were foreign-born. Compared with Asians, Hispanics were more likely to report heterosexual transmission (P0.0001) and blood transfusion history (P0.0001) as risk factors. Overall, 31% of Hispanics had HBV2000 IU/mL compared with 54% of Asians (P=0.004).Significantly more Asian HBeAg-negative/anti-HBe-positive CHB patients had high HBV DNA levels (2000 IU/mL) with elevated ALT compared with Hispanic patients (P=0.04). Compared with Asians, Hispanic CHB patients were more likely to have elevated ALT and low HBV DNA levels (P=0.001). Among CHB patients who received antiviral therapy, response was comparable among Hispanics and Asians. There were no Hispanic CHB patients who experienced spontaneous reactivation or developed hepatocellular carcinoma.There were important differences in the clinical, demographic, and serologic characteristics between Hispanic and Asian CHB. Response rate to antiviral therapy was comparable. Further studies of Hispanic CHB patients in the United States are warranted.

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. 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). NETs were associated with OS (both, P

Hepatitis B immune globulin (HBIg) in combination with a nucleos(t)ide analog is the mainstay of prophylactic regimen to prevent recurrence of hepatitis B following orthotopic liver transplantation (OLT). HBIg therapy is costly and inconvenient for the patients. There is a growing experience converting HBIg/nucleos(t)ide to combination nucleotide/nucleoside analogs from. Twenty-six patients that underwent OLT between March 2001 and July 2011 who had received at least 12 months of HBIg and single nucleos(t)ide were enrolled. HBsAg and HBV DNA were undetectable, and anti-HBs were detectable at the time of switch. HBV DNA and HBsAg were measured every 3 months following discontinuation of HBIg and addition of nucleos(t)ide. Patients included 23 Asians/3 Caucasian, 21 males/5 females. Mean time of conversion from HBIg/nucleos(t)ide to nucleoside/nucleotide combination was 77.5 (range 11–132) months after OLT. Mean duration of follow-up after conversion was 31.9 (range 14–70) months. All patients had undetectable HBV DNA, and 24 patients remained HBsAg negative during follow-up. Two patients recurred 7 and 9 months later, respectively, with detectable HBsAg. Both patients continued to have undetectable HBV DNA and normal ALT. HBsAg was neutralized by reinfusion of HBIg. Nucleoside/nucleotide combination is an effective alternative to HBIg/nucleos(t)ide to prevent recurrence of hepatitis B after OLT.

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.

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.

To the Editor, Insulin autoimmune syndrome (IAS) showed hypoglycemia, hyperinsulinemia, positive insulin antibodies without insulin injection history. Some patients with diabetes, treated with insulin, also showed these signs. The first case of IAS was reported in 1970s. [1, 2]. IAS can be induced by autoimmune diseases, some drugs, such as methimazole [3]. Here we report one case of special IAS, who suffered from type 2 diabetes concomitant with Graves’ disease. This an 85-year-old woman diagnosed with type 2 diabetes 30 years ago. She accepted oral antidiabetic drugs initially, and switched to insulin injection therapy (Novolin 30R 12 u/day) 5 years ago. About 1 year ago, she began to experiencing recurrent cold sweat, hunger, palpitation, and other symptoms of hypoglycemia, with her peripheral blood glucose ranged from 3.0–4.0 mmol/L during the night and morning. Hypoglycemia episodes still occurred after insulin treatment was suspended. Meanwhile she appeared weight loss, palpitation, chest tightness, fatigue, and lower extremity edema. One month prior to admission, the patient began to appearing eyelid edema, proptosis, photophobia, tearing, redness and pain of eye, polyphagia, heat intolerance, sweating, irritability, and stool frequency. She has hypertension and dyslipidemia history. Physical examination revealed a thinly built woman, BMI 20.7 kg/m, BP 160/70 mmHg, pulse 106/min. Her skin appeared sweeting and hot. She appeared wider palpebral fissures, proptosis, limited eye movements, conjunctival edema, and hyperemia. The movements of the lids were jerky and spasmodic, and the lightly closed lids tremor. Thyroid examination revealed II degrees of goiter with marked tremor and vascular murmur. Thyroid function tests revealed that TSH 0.01 lU/mL, T4 223.18 nmol/l, FT4 34.8 pmol/l, rT3 0.58 ng/ml, thyroglobulin 27.73 ng/ml, Anti-Tg 906.1 IU/ml, TPO [ 600 IU/ml, TRAB 20.8 IU/ml, ESR 64 mm/h. Serum total insulin concentration was 552.3 uU/ml, free insulin concentration 394.4 uU/ml, and Iab binding rate 70.6 %. Scatchard analysis revealed that the serum Iab constituted by two types binding sites which were high-affinity with low capacity (k1 = 3.125 9 10 mol/l, b1 = 37.5 9 10 mol/l) and low-affinity with high capacity (k2 = 1.0 9 10 mol/l, b2 = 5.918 9 10 mol/l), (Fig. 1). Insulin binding antibodies analysis suggested that it was IgG with k light chains. Ultrasound showed bilateral thyroid swelling, diffuse lesions. Abdominal magnetic resonance imaging revealed no abnormalities. The patient was diagnosed with Grave’s diseases, Grave’s ophthalmopathy and IAS, and start receiving prednisone (20 mg/day) and methimazole (10 mg qd) treatment. The insulin injection treatment (Novolin 30R) continued and the dose increased along with blood glucose change. After treatment for 1 month, symptoms including palpitation, heat intolerance, fatigue relieved, photophobia and tearing relieved, meanwhile hypoglycemia attack disappeared. After 2 months of treatment, her serum insulin levels returned to normal range and insulin antibody became X. Wang X. Xu X. Zhao X. Ma H. Yu H. Gong F. Chen (&) No. 3 People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China 280# MoHe Road, Shanghai 201900, People’s Republic of China e-mail: 903561138@qq.com; fengling_chen@hotmail.com