Human splenic TER cells: A relevant prognostic factor acting via the artemin-GFRα3-ERK pathway in pancreatic ductal adenocarcinoma.

Splenectomy is routinely performed during distal or total pancreatectomy (DP or TP) for pancreatic ductal adenocarcinoma (PDAC), but information about its oncological value is limited. TER cells, nonimmune cells discovered in the spleens of tumour-bearing mice, are elicited by tumours and promote tumour progression, while their role in the clinical outcomes of patients with PDAC remains unclear. In our study, postoperative specimens from 622 patients who underwent DP or TP with splenectomy were analysed by flow cytometry or immunofluorescence, and the relationship between splenic TER cell count and clinical parameters was calculated. We also purified human TER cells for functional experiments and mechanistic studies. We found that TER cell numbers were increased only in the spleens of patients with PDAC but not in PDAC tissue and adjacent pancreatic tissue. High splenic TER cell counts independently predicted poor prognosis (P < .001) and indicated large tumour size, lymph node metastasis, advanced 8th AJCC/mAJCC stage and high CA19-9 classification (all P < .050) in patients with PDAC. Mechanistic analysis showed that TER cells express artemin, which facilitates the proliferation and invasion of PDAC cells by activating GFRα3-ERK signalling. Our study reveals that TER cell count is an indicator of poor prognosis of PDAC, while splenectomy during pancreatic surgery might provide oncological benefits in addition to ensuring the radical resection of PDAC.

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.

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.

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.

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.

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

PURPOSE: Tumour 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 (18)F-FDG PET/CT in patients with resectable PDAC. METHODS: Included in the study were 122 PDAC patients who received preoperative (18)F-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). RESULTS: MTV and TLG were significantly associated with baseline serum CA19-9 level (P = 0.001 for MTV, P < 0.001 for TLG) and tumour size (P < 0.001 for MTV, P = 0.001 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 (P < 0.001 for all). CONCLUSION: MTV 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.

Stathmin destabilizing microtubule dynamics promotes malignant potential in cancer cells by epithelial-mesenchymal transition.

BACKGROUND: Stathmin is a ubiquitous cytosolic regulatory phosphoprotein and is overexpressed in different human malignancies. The main physiological function of stathmin is to interfere with microtubule dynamics by promoting depolymerization of microtubules or by preventing polymerization of tubulin heterodimers. Stathmin plays important roles in regulating many cellular functions as a result of its microtubule-destabilizing activity. Currently, the critical roles of stathmin in cancer cells, as well as in lymphocytes have been valued. This review discusses stathmin and microtubule dynamics in cancer development, and hypothesizes their possible relationship with epithelial-mesenchymal transition (EMT). DATA SOURCES: A PubMed search using such terms as "stathmin", "microtubule dynamics", "epithelial-mesenchymal transition", "EMT", "malignant potential" and "cancer" was performed to identify relevant studies published in English. More than 100 related articles were reviewed. RESULTS: The literature clearly documented the relationship between stathmin and its microtubule-destabilizing activity of cancer development. However, the particular mechanism is poorly understood. Microtubule disruption is essential for EMT, which is a crucial process during cancer development. As a microtubule-destabilizing protein, stathmin may promote malignant potential in cancer cells by initiating EMT. CONCLUSIONS: We propose that there is a stathmin-microtubule dynamics-EMT (S-M-E) axis during cancer development. By this axis, stathmin together with its microtubule-destabilizing activity contributes to EMT, which stimulates the malignant potential in cancer cells.

Ligamentum teres hepatis patch enhances the healing of pancreatic fistula after distal pancreatectomy.

Pancreatic fistula is one of the most common complications after the distal pancreatectomy. Many methods have been tried to solve the problem, but no one is optimal, especially for the soft pancreatic stump cases. This study used ligamentum teres hepatis as a patch to cover the pancreatic stump. Between October 2010 and December 2012, seventy-seven patients who had undergone distal pancreatectomy with a soft pancreatic stump were divided into two groups: group A (n=39, patients received conventional ligated main pancreatic duct method) and group B (n=38, patients underwent a coverage procedure). Patients in group A had a longer recovery from postoperative pancreatic fistula than those in group B (16.4+/-3.5 vs 10.8+/-1.6 days, P<0.05). The coverage procedure with ligamentum teres hepatis is a safe, effective and convenient method for patients with a soft pancreas remnant during distal pancreatectomy.

Interventions to promote the implementation of pressure injuries prevention measures in nursing homes: a scoping review protocol.

INTRODUCTION: Currently, various guidelines and documents on the prevention of pressure injuries have been published, but there are many serious lags in the actual practice in nursing homes. So some interventions are required to promote the implementation of normative practices. There was a review of preventive interventions for pressure injuries in long-term care facilities, but there is no systematic review of how to promote the implementation of preventive measures. This review aims to summarise interventions that promote the implementation of pressure injuries prevention measures in nursing homes, explore the research scope and gaps in this field and provide evidence and striving direction for global nursing homes to improve existing preventive behaviours. METHODS AND ANALYSIS: This scoping review will combine the Arksey and O'Malley framework with further clarification and advice of the scoping review by Levac et al as methodological guidance. Systematic retrieval of relevant literature databases, grey literature and references included studies will be conducted. Two reviewers will screen titles and abstracts independently, and then screen the full text of potentially relevant articles to determine final inclusion. After that, two reviewers will extract data based on a predesigned data extraction table independently. Inductive analysis and narrative analysis will be used to collate, summarise and report the results. Finally, managers of nursing homes in China will be consulted for additional information and their viewpoints on the research findings. ETHICS AND DISSEMINATION: Since the scoping review is a secondary analysis of the literature, there is no need to apply for ethical approval. Our goal is to share the results with key stakeholders to help them find the direction of effort and improve clinical practice. Therefore, dissemination plans include publication in international journals and sharing it at conferences to inform more healthcare workers about the scope and gaps of the studies.

NK cells adjuvant therapy shows survival benefits in a gastric mixed signet ring cell carcinoma patient: A case report.

RATIONALE: Advanced signet ring cell (SRC) carcinoma has a worse prognosis. Therefore, early diagnosis and prevention is particularly important; SRC tumors have lower R0 resection rate and are thought to be less chemosensitive than non-SRCC. Consequently, a novel postoperative adjuvant treatment is urgently needed to improve clinical outcomes. PATIENT CONCERNS: A 41-year-old female with advanced gastric SRC carcinoma was treated with radical gastrectomy and oxaliplatin-based regimen for 6 cycles after surgery. She was suspected of recurrence with the high level of carbohydrate antigen (CA) 72-4. DIAGNOSES: The gastroscopy revealed SRC carcinoma of gastric antrum and poorly differentiated adenocarcinoma in some areas. The diagnosis of postoperative pathology report was gastric cancer with stage III C (T4a, N3a, M0). INTERVENTIONS: The level of CA72-4 rapidly increased during the 2 follow-up after the completion of conventional treatment, ex vivo-cultured allogeneic natural killer (NK) cell infusion was offered to prevent recurrence. OUTCOMES: Intravenous injections of NK cells combination with surgical treatment and chemotherapy showed therapeutic effects in this patient with possible relapse. The patient remained disease-free 46 months after the infusion of NK cells until the latest follow-up. LESSONS: CA72-4 appeared to be the most sensitive and specific marker in the gastric cancer patient, and the high level of CA72-4 may indicate the risk of recurrence. This case report provide rationale for NK cell infusion following the rapid increase of CA72-4 to prevent recurrence.

Neutrophil Extracellular Traps and Macrophage Extracellular Traps Predict Postoperative Recurrence in Resectable Nonfunctional Pancreatic Neuroendocrine Tumors.

Background: Extracellular traps (ETs) and tumor-infiltrating immune cells can contribute to disease progression. The clinical significance of tumor-infiltrating neutrophils and macrophages and related extracellular traps in pancreatic neuroendocrine tumors (pNETs) has not been fully elucidated. This study aimed to explore the prognostic value of tumor infiltration and ET formation by neutrophils and macrophages in pNETs. Methods: A total of 135 patients with radical resection of nonfunctional pNETs were analyzed retrospectively. Immunohistochemistry and immunofluorescence were utilized to stain tumor tissue sections. The recurrence-free survival (RFS) of subgroups determined by Kaplan-Meier analysis was compared with the log-rank test. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. A nomogram was established to predict 3-year RFS. Results: Patients with high tumor-infiltrating neutrophils or macrophages or positive expression of neutrophils ETs or macrophage ETs displayed worse RFS (all p<0.05). Moreover, univariate and multivariate Cox regression analyses showed that neutrophil and macrophage infiltration and ETs were independent prognostic factors for RFS (all p<0.05). A combined parameter including WHO grade, TNM stage, tumor-infiltrating neutrophils and macrophages, and neutrophil and macrophage ETs had the highest C-index (0.866) and lowest Akaike information criteria (326.557). The calibration plot of nomogram composed of the combined parameter exhibited excellent prognostic values for 3-year RFS. Conclusions: Infiltration and ETs by neutrophils and macrophages can be used as biological indicators of patient prognosis, suggesting the treatment potential for targeting those in nonfunctional pNETs.

A novel risk factor panel predicts early recurrence in resected pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are indolent pancreatic tumors derived from neuroendocrine cells in pancreatic islets. To date, reliable predictors for identifying patients at high risk for recurrence after curative cancer resection are lacking. We aimed to determine independent predictors for high-risk PanNETs and patient outcomes after surgery. METHODS: We analyzed relevant clinicopathological parameters in 319 consecutive patients of derivation cohort 1 and 106 patients of validation cohort 2 who underwent pancreatectomy and were diagnosed with PanNETs. Association of tumor characteristics with recurrence-free survival (RFS) and overall survival (OS) was evaluated using Cox regression. RESULTS: PanNET grade 3 (G3), pancreatic duct dilatation, and perineural invasion were independent prognostic factors for RFS and were significantly associated with early recurrence (within 1.5 years) of PanNETs after curative resection (P = 0.019, P < 0.001, and P < 0.001, respectively). Using these factors, we established a novel risk factor panel (R-panel), which predicted early recurrence (P < 0.001, HR = 15.02, 95% CI 5.76-39.19). Predictive accuracy of this R-panel was favorable, with a C-index of 0.853, higher than AJCC TNM staging (0.713). We further built an integrated staging system combining R-panel scoring and TNM staging, which improved predictive probability of TNM staging. Finally, we showed that adjuvant therapy with long-acting somatostatin analogs (SSAs) significantly reduced postoperative recurrence (P < 0.001) and prolonged long-term survival (P = 0.021) in patients with the above risk factors. CONCLUSION: We identified a novel risk factor panel, which includes PanNET G3, pancreatic duct dilatation, and perineural invasion; this panel predicted early recurrence of PanNETs after curative resection. Patients with these risk factors can benefit from adjuvant therapy with SSAs.

[Feasibility study of preserving intercostobrachial nerve during dissection for breast carcinoma: evidences from a preliminary pathologic exploration].

OBJECTIVE: To determine the feasibility of preservation of intercostobrachial nerve (ICBN) in breast cancer. METHODS: During June 2004 to June 2006, 99 patients with operable breast cancer receiving an axillary lymph node dissection at our department were analyzed. The extirpated ICBN and ambient tissues were tested by HE staining to observe the pathological changes. RESULTS: In 96 (96.97%) cases with ICBN sacrificing, the nerves were not violated microscopically and the nerve cells remained intact. Of 28 patients with axillary lymphadenectasis, only 3 cases (10.71%) were found to have tumor emboli in the peri-neural vessels. CONCLUSION: The preservation of ICBN is a feasible and safe technique. The operative approach should be advocated. If at all possible, a surgeon should identify ICBN and preserve it.

Chemoradiotherapy combined with NK cell transfer in a patient with recurrent and metastatic nasopharyngeal carcinoma inducing long-term tumor control: A case report.

RATIONALE: Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in Southern China. Although combined chemotherapy with radiotherapy has been widely used in treating locally advanced lesions, relapse and metastases remain the primary cause of treatment failure, and are associated with an extremely poor prognosis. Therefore, more efficient and milder therapies are needed. PATIENT CONCERNS: Herein, we report a patient with advanced NPC with intracranial metastases who showed progression during conventional treatment. DIAGNOSES: Nonkeratinizing undifferentiated nasopharyngeal carcinoma (stage IV). INTERVENTIONS: After the completion of initial chemoradiotherapy and targeted therapy, metastases to brain occurred during follow-up. Ex vivo-cultured allogeneic NK cell infusion was offered. OUTCOMES: Although the intracranial metastases did not decrease 10 months after the NK cell treatment, they decreased significantly at 31 months after the treatment and partially disappeared. The tumor response indicated partial response. Furthermore, all of the intracranial metastases continued to decrease at about 42 months after treatment. LESSONS: The brain metastases of NPC are rare with poor prognosis. Radiotherapy in NPC can disrupt the blood-brain barrier, which may contribute to the metastases of brain. This case report will provide rationale for NK cell infusion following regular chemoradiotherapy.

Active surveillance in metastatic pancreatic neuroendocrine tumors: A 20-year single-institutional experience.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are heterogeneous and indolent; systemic therapy is not essential for every patient with metastatic PanNET. The National Comprehensive Cancer Network guidelines state that delaying treatment is an option for PanNET with distant metastasis, if the patient has stable disease. However, specific factors that influence surveillance were not mentioned. In addition, data regarding the period of active surveillance in patients with metastatic PanNET are lacking. AIM: To specifically determine factors influencing active surveillance in patients with liver metastatic nonfunctioning PanNETs (NF-PanNETs). METHODS: Seventy-six patients with liver metastatic NF-PanNETs who received active surveillance from a high-volume institution were enrolled. Time to disease progression (TTP) and time to initiation of systemic therapy were determined. RESULTS: Thirty-one (40.8%) patients had recurrent liver disease after R0 resection; 45 (59.2%) were diagnosed with liver metastasis. The median follow-up period was 42 mo and 90.7% patients were observed to have disease progression. The median TTP (mTTP) was 10 mo. Multivariate analysis showed that the largest axis of the liver metastasis > 5 mm (P = 0.04), non-resection of the primary tumor (P = 0.024), and T3-4 stage (P = 0.028) were associated with a shorter TTP. The mTTP in patients with no risk factors was 24 mo, which was significantly longer than that in patients with one (10 mo) or more (6 mo) risk factors (P < 0.001). A nomogram with three risk factors showed reasonable calibration, with a C-index of 0.603 (95% confidence interval: 0.47-0.74). CONCLUSION: Active surveillance may only be safe for metastatic NF-PanNET patients with favorable risk factors, and other patients progressed rapidly without treatment. Further studies with a larger sample size and a control group are needed.

TET1 downregulates epithelial-mesenchymal transition and chemoresistance in PDAC by demethylating CHL1 to inhibit the Hedgehog signaling pathway.

Chemoresistance is a major obstacle to prolonging pancreatic ductal adenocarcinoma (PDAC) patient survival. TET1 is identified as the most important epigenetic modification enzyme that facilitates chemoresistance in cancers. However, the chemoresistance mechanism of TET1 in PDAC is unknown. This study aimed to determine the role of TET1 in the chemoresistance of PDAC. TET1-associated chemoresistance in PDAC was investigated in vitro and in vivo. The clinical significance of TET1 was analyzed in 228 PDAC patients by tissue microarray profiling. We identified that TET1 downregulation is caused by its promoter hypermethylation and correlates with poor survival in PDAC patients. In vitro and in vivo functional studies performed by silencing or overexpressing TET1 suggested that TET1 is able to suppress epithelial-mesenchymal transition (EMT) and sensitize PDAC cells to 5FU and gemcitabine. Then RNA-seq, whole genome bisulfite sequencing (WGBS) and ChIP-seq were used to explore the TET1-associated pathway, and showed that TET1 promotes the transcription of CHL1 by binding and demethylating the CHL1 promoter, which consequently inhibits the Hedgehog pathway. Additionally, inhibiting Hedgehog signaling by CHL1 overexpression or the Hedgehog pathway inhibitor, GDC-0449, reversed the chemoresistance induced by TET1 silencing. Regarding clinical significance, we found that high TET1 and high CHL1 expression predicted a better prognosis in resectable PDAC patients. In summary, we demonstrated that TET1 reverses chemoresistance in PDAC by downregulating the CHL1-associated Hedgehog signaling pathway. PDAC patients with a high expression levels of TET1 and CHL1 have a better prognosis.

Advances on diagnostic biomarkers of pancreatic ductal adenocarcinoma: A systems biology perspective.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is usually diagnosed at an advanced stage when curative surgery is no longer an option. Robust diagnostic biomarkers with high sensitivity and specificity for early detection are urgently needed. Systems biology provides a powerful tool for understanding diseases and solving challenging biological problems, allowing biomarkers to be identified and quantified with increasing accuracy, sensitivity, and comprehensiveness. Here, we present a comprehensive overview of efforts to identify biomarkers of PDAC using genomics, transcriptomics, proteomics, metabonomics, and bioinformatics. Systems biology perspective provides a crucial "network" to integrate multi-omics approaches to biomarker identification, shedding additional light on early PDAC detection.

Infiltrating pattern and prognostic value of tertiary lymphoid structures in resected non-functional pancreatic neuroendocrine tumors.

BACKGROUND: Tertiary lymphoid structures (TLS) are associated with favorable survival and play a critical role in most solid tumors. However, investigations of TLS are lacking in patients with grade 1 or grade 2 (G1/G2) non-functional pancreatic neuroendocrine tumors (NF-PanNETs). This study aimed to investigate the presence, cellular composition, association with tumor-infiltrating immune cells, and prognostic value of TLS in G1/G2 NF-PanNETs. METHODS: Tumor tissues from a 182-patient Fudan cohort and a 125-patient external validation set were assessed by H&E staining, immunohistochemistry, and/or multispectral fluorescent immunohistochemistry. RESULTS: TLS were identified in more than one-third of patients with G1/G2 NF-PanNETs and were located peritumorally, either just outside the tumor tissue or in the stromal area. TLS were mainly composed of B-cell follicles with germinal centers and T-cell zones with dendritic cells. Kaplan-Meier analyses showed that the presence of TLS correlated with both longer recurrence-free survival (RFS, p<0.001) and overall survival (OS, p=0.001), but the number of TLS had no prognostic significance. Multivariate Cox-regression analyses demonstrated that the presence of TLS, WHO classification, and 8th edition American Joint Committee on Cancer (AJCC8th) tumor-node-metastasis (TNM) stage were independent prognostic factors for RFS (p=0.004, p=0.001, and p<0.001, respectively) and OS (p=0.009, p=0.008, and p=0.019, respectively). These results were confirmed using an external validation set. Finally, a nomogram incorporating the presence of TLS was constructed to predict the probability of 5-year RFS of resected G1/G2 NF-PanNETs, which improved on the current WHO classification and AJCC8th TNM stage. CONCLUSIONS: The presence of TLS is an independent and favorable predictor of resected G1/G2 NF-PanNETs, which may play a role in cancer immunobiology.