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AJCC TNM stage and WHO grade (G) are two widely used staging systems to guide clinical management for pancreatic neuroendocrine neoplasms (panNENs), based on clinical staging and pathological grading information, respectively. We proposed to integrate TNM stage and G grade into one staging system (TNMG) and to evaluate its clinical application as a prognostic indicator for panNENs. Accordingly, 5254 patients diagnosed with panNENs were used to evaluate and to validate the applicability of TNMG to panNENs. The predictive accuracy of TNMG system was compared with that of each separate staging/grading system. We found that TNM stage and G grade were independent risk factors for survival in both the Surveillance, Epidemiology, and End Result (SEER) and multicenter series. The interaction effect between TNM stage and G grade was significant. Twelve subgroups combining the TNM stage and G grade were proposed in the TNMG stage, which were classified into five stages TNMG. According to the TNMG staging classification in the SEER series, the estimated median survival for stages I, II, III, IV, and V were 203, 174, 112, 61, and 8 months, respectively. The predictive accuracy of TNMG stage was higher than that of TNM stage and G grade used independently. The TNMG stage classification was more accurate in predicting panNEN patient's prognosis than either the TNM stage or G grade.

BACKGROUND Many clinicians and surgeons are unfamiliar with the sclerosing angiomatoid nodular transformation (SANT), which is gaining recognition as a benign splenic tumor. We challenge that SANT is rare and whether surgical intervention could be avoided through critical imaging review. AIM To evaluate the incidence of SANT among splenic tumors and the decision-making process of SANT management. METHODS Twenty hospitalized patients who underwent splenectomy in 2018 and 2019 in a tertiary university hospital were retrospectively reviewed, and their data on imaging, diagnosis, surgical indications, and courses were recorded. All pathology results were confirmed by pathologist. Discriminative features differentiating SANT from other non-SANT splenic tumors were descriptively analyzed in this case series. RESULTS Fourteen out of 20 patients who underwent splenectomy had splenic tumors, including 3 SANTs (21% splenic tumors), 6 non-SANT benign lesions (43%), 2 metastatic tumors, and 3 lymphomas. Hypointensity on T2-weighted magnetic resonance imaging (MRI), spoke wheel enhancing pattern in contrasted computed tomography or MRI, and cold spot (low fluorodeoxyglucose uptake) in positron emission tomography (PET) scan helped establish the diagnosis of SANT. Lymphoma, presenting with a hot spot on the PET scan were differentiated from SANT. Surgical indications were reformatted for splenic tumors. Splenectomy need not be performed in patients with typical imaging features of SANT. CONCLUSION SANT is not a rare disease entity in clinical practice. Splenectomy should not be routinely indicated as the only management option for SANT with typical imaging features.

Islets are thought to be stably present in the adult human pancreas to maintain glucose homeostasis. However, identification of the pancreatic intraepithelial neoplasia (PanIN)–islet complex in mice and the presence of PanIN lesions in adult humans suggest that similar remodelling of islet structure and environment may occur in the human pancreas. To identify islet remodelling in a clinically related setting, we examine human donor pancreases with 3D histology to detect and characterise the human PanIN–islet complex. Cadaveric donor pancreases (26–65 years old, n = 10) were fixed and sectioned (350 μm) for tissue labelling, clearing and microscopy to detect local islet remodelling for 3D analysis of the microenvironment. The remodelled microenvironment was subsequently examined via microtome-based histology for clinical assessment. In nine pancreases, we identified the unique peri-lobular islet aggregation associated with the PanIN lesion (16 lesion–islet complexes detected; size: 3.18 ± 1.34 mm). Important features of the lesion–islet microenvironment include: (1) formation of intra-islet ducts, (2) acinar atrophy, (3) adipocyte association, (4) inflammation (CD45+), (5) stromal accumulation (α-SMA+), (6) increase in Ki-67 proliferation index but absence of Ki-67+ alpha/beta cells and (7) in-depth and continuous duct–islet cell contacts, forming a cluster. The duct–islet cell cluster and intra-islet ducts suggest likely islet cell neogenesis but not replication. We identify local islet remodelling associated with PanIN–islet complex in the adult human pancreas. The tissue remodelling and the evidence of inflammation and stromal accumulation suggest that the PanIN–islet complex is derived from tissue repair after a local injury.

We sought to investigate whether preoperative dual-phase 2-[18F]FDG PET-CT identify predictors for poor survival in patients with ampullary carcinoma receiving pancreaticoduodenectomy. The preoperative PET-CT images of patients with resected ampullary carcinoma from June 2007 to July 2017 were analyzed. Survival curves were analyzed using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard model was used to identify potential prognostic factors associated with disease-free survival (DFS) and overall survival (OS). Fifty-four subjects (26 men, 28 women) were enrolled with a median tumor size of 20 mm. All patients were followed for a median period of 36.9 months with 3- and 5-year DFS of 50.3% and 44.2%, and OS of 77.0% and 68.2%, respectively. Parameters associated with DFS in multivariate analysis were lymphovascular invasion (hazard ratio [HR]: 9.45, p < 0.001), involved margin in pathology (HR: 7.67, p < 0.001), and tumor retention index (RI) from the dual-phase PET (HR: 2.41, p = 0.03), whereas involved margin (HR: 13.14, p < 0.001), post-recurrence chemotherapy (HR: 0.10, p < 0.001), and metabolic tumor volume (MTV) (HR: 4.62, p = 0.009) emerged as independent prognostic factors for OS. Preoperative 2-[18F]FDG PET-CT offered independent prognostic biomarkers in patients with ampullary carcinoma receiving standard surgical resection. • 2-[ 18 F]FDG PET-CT offers good survival prediction before operation in primary malignant neoplasms at ampulla of Vater. • Dual-phase PET scan with bowel distention can better delineate Ampulla of Vater and characterize tumor physiology. • Preoperative risk stratification might aid in better treatment planning.

To analyze the effect of preoperative body composition on survival in patients with pancreatic cancer following pancreaticoduodenectomy (PD). Between October 2005 and August 2018, 116 patients (68 men, 48 women, mean age 66.2 ± 11.9 years) diagnosed with pancreatic adenocarcinoma following PD were retrospectively enrolled. The preoperative CT on vertebral level L3 was assessed for total abdominal muscle area (TAMA), visceral adipose tissue area (VAT), subcutaneous adipose tissue area (SAT), and mean skeletal muscle attenuation (SMD). The clinical data and pathological findings of tumors were collected. The impact of these factors on disease-free survival (DFS) and overall survival (OS) was evaluated by the Kaplan–Meier method and by univariable and multivariable Cox proportional hazards models. The 3-year DFS and OS rates were 8% and 25%, respectively. Of 116 patients, 20 (17.2%), 3 (2.6%), and 46 (39.7%) patients were classified as having sarcopenia, sarcopenic obesity, and myosteatosis, respectively. The VAT–TAMA ratio (1.2 ± 0.7 vs 0.9 ± 0.5, p = 0.01) and the visceral to subcutaneous adipose tissue area ratio (1.3 ± 0.7 vs 0.9 ± 0.5, p = 0.04) were higher in sarcopenic patients than in the nonsarcopenic group. Preoperative sarcopenia and sarcopenic obesity were associated with shorter OS (p = 0.012 and p = 0.041, respectively), but not shorter DFS. Myosteatosis was neither associated with DFS nor OS. On multivariable analysis, sarcopenia was the only significant prognostic factor for OS (p = 0.039). Preoperative sarcopenia assessed by CT is a poor prognostic factor for OS in pancreatic cancer patients after PD. • Sarcopenia and sarcopenic obesity can be evaluated by abdominal CT on L3 level. • Patients with diabetes mellitus (DM) had lower sex-standardized subcutaneous adipose tissue area index and skeletal muscle density and higher visceral to subcutaneous adipose tissue area ratio than did those without DM. • Preoperative sarcopenia, sarcopenic obesity, and new-onset diabetes mellitus may predict poor overall survival in pancreatic cancer patients following pancreaticoduodenectomy.

Background The centralization of pancreatoduodenectomy (PD) has been shown to improve patient outcomes. The scheduling of two PDs in one day is one option to shorten the waiting time for patients referred to high volume centers. The effect on the surgical team or patient outcomes of such an approach have not previously been explored. This study aimed to investigate the effect of scheduling two PDs in one day on the surgeon's workload and patient outcomes. Methods A retrospective review of patients undergoing PD by a single surgeon between 2007 and 2018 was performed. Patients were allocated into: first PD (FIRSTPD group) or second PD (SECONDPD group) according to the position on the surgical operating list. The intraoperative, postoperative outcomes, and workload (the Surgery Task Load Index; SURG-TLX) were assessed between two groups. Results A total of 967 (91%) and 101 (9%) patients were included in the FIRSTPD and SECONDPD group, respectively. There were no differences in the duration of surgery (coefficient = −9.65; 95% confidence interval: −29.26 to 9.94; P = 0.334), incidence of major complications (odds ratio = 1.08; 95% confidence interval: 0.67–1.73; P = 0.739), or 90-day mortality (odds ratio = 1.03; 95% confidence interval: 0.12–8.53; P = 0.978) for those patients in the SECONDPD group as compared to the FIRSTPD group. The mean scores of two (physical and temporal demand) of the six SURG-TLX subscales of surgical workload were recorded as significantly higher by surgeons following two PD's as compared to one PD. Conclusions Although scheduling a second PD in one day shows no association with adverse patient outcomes, there is an increase in the physical and temporal subscales of surgical workload and consideration should be given to how this could be minimized.

Background: Heavily pretreated pancreatic cancer patients have a grave prognosis. In this case series study, we evaluated the safety and efficacy of nab-paclitaxel-based chemotherapy for such patients. Methods: The data of pancreatic adenocarcinoma patients (n = 40) treated with nab-paclitaxel after the failure of gemcitabine or fluoropyrimidines at our institution in 2013–2015 were reviewed. Results: The median number of prior chemotherapy regimens was two (range, 1–6). Eighteen patients had an Eastern Cooperative Oncology Group performance status of ≥2. The regimens comprised nab-paclitaxel combined with the following drugs: gemcitabine (n = 28), gemcitabine and fluoropyrimidine (n = 3), platinum and fluoropyrimidine (n = 4), fluoropyrimidine (n = 4), and irinotecan and fluoropyrimidine (n = 1). The median dose of nab-paclitaxel was 63 (range, 51–72) mg/m2/dose, with the schedule of D1/15, D1/8, and D1/8/15 followed in 23, 14, and 3 patients, respectively. The median overall survival was 5.1 (95% CI, 4.6–5.7) months. Among 32 evaluable patients, two partial responses and six stable diseases were observed. The median progression-free survival was 2.6 (95% CI, 1.9–3.2) months. Grade 3/4 leucopenia or neutropenia was observed in three and two patients, respectively. Grade 3/4 anemia was observed in four patients. Other significant (grade 3 or more) nonhematological toxicities were not frequent, except for sepsis/infection (n = 7). However, more severe anemia or sepsis/infection was significantly associated with disease control. Conclusion: In heavily pretreated pancreatic adenocarcinoma patients, low-dose nab-paclitaxel-based chemotherapy was fairly tolerable with modest efficacy. Keywords: Chemotherapy, Nab-paclitaxel, Pancreatic cancer, Pretreated, Prognosis

BackgroundPancreatic head ductal adenocarcinoma (PHDAC) patients with the same tumor-node-metastasis (TNM) stage may share different outcomes after pancreaticoduodenectomy (PD). Therefore, a novel method to identify patients with poor prognosis after PD is urgently needed. We aimed to develop a nomogram to estimate survival in PHDAC after PD.MethodsTo estimate survival after PD, a nomogram was developed using the Tongji Pancreatic cancer cohort comprising 355 PHDAC patients who underwent PD. The nomogram was validated under the same conditions in another cohort (N = 161) from the National Taiwan University Hospital. Prognostic factors were assessed using LASSO and multivariate Cox regression models. The nomogram was internally validated using bootstrap resampling and then externally validated. Performance was assessed using concordance index (c-index) and calibration curve. Clinical utility was evaluated using decision curve analysis (DCA), X-tile program, and Kaplan–Meier curve in both training and validation cohorts.ResultsOverall, the median follow-up duration was 32.17 months, with 199 deaths (64.82%) in the training cohort. Variables included in the nomogram were age, preoperative CA 19-9 levels, adjuvant chemotherapy, Tongji classification, T stage, N stage, and differentiation degree. Harrell’s c-indices in the internal and external validation cohorts were 0.79 (95% confidence interval [CI], 0.76–0.82) and 0.83 (95% CI, 0.78–0.87), respectively, which were higher than those in other staging systems. DCA showed better clinical utility.ConclusionThe nomogram was better than TNM stage and Tongji classification in predicting PHDAC patients’ prognosis and may improve prognosis-based selection of patients who would benefit from PD.

Background We previously demonstrated that nuclear BCL10 translocation participates in the instigation of NF-κB in breast cancer and lymphoma cell lines. In this study, we assessed whether nuclear BCL10 translocation is clinically significant in advanced and metastatic pancreatic ductal adenocarcinoma (PDAC). Method and materials We analyzed the expression of BCL10-, cell cycle-, and NF-κB- related signaling molecules, and the DNA-binding activity of NF-κB in three PDAC cell lines (mutant KRAS lines: PANC-1 and AsPC-1; wild-type KRAS line: BxPC-3) using BCL10 short hairpin RNA (shBCL10). To assess the anti-tumor effect of BCL10 knockdown in PDAC xenograft model, PANC-1 cells treated with or without shBCL10 transfection were inoculated into the flanks of mice. We assessed the expression patterns of BCL10 and NF-κB in tumor cells in 136 patients with recurrent, advanced, and metastatic PDAC using immunohistochemical staining. Results We revealed that shBCL10 transfection caused cytoplasmic translocation of BCL10 from the nuclei, inhibited cell viability, and enhanced the cytotoxicities of gemcitabine and oxaliplatin in three PDAC cell lines. Inhibition of BCL10 differentially blocked cell cycle progression in PDAC cell lines. Arrest at G1 phase was noted in wild-type KRAS cell lines; and arrest at G2/M phase was noted in mutant KRAS cell lines. Furthermore, shBCL10 transfection downregulated the expression of phospho-CDC2, phospho-CDC25C, Cyclin B1 (PANC-1), Cyclins A, D1, and E, CDK2, and CDK4 (BxPC-3), p-IκBα, nuclear expression of BCL10, BCL3, and NF-κB (p65), and attenuated the NF-κB pathway activation and its downstream molecule, c-Myc, while inhibition of BCL10 upregulated expression of p21, and p27 in both PANC-1 and BxPC-3 cells. In a PANC-1-xenograft mouse model, inhibition of BCL10 expression also attenuated the tumor growth of PDAC. In clinical samples, nuclear BCL10 expression was closely associated with nuclear NF-κB expression (p Conclusion Nuclear BCL10 translocation activates NF-κB signaling and contributes to tumor progression and poor prognosis of advanced/metastatic PDAC.

Objective: To compare the metabolites of in vivo 1H- MRS in pancreatic cancer with normal pancreas, and correlate these metabolites with Positron Emission Tomography (PET) metabolic activity, clinical stages, and survival outcomes. Methods: The prospective study included 58 patients (mean age 62.7 ± 12.1 years, range 34–81 years; 36 men, 22 women) with pathological proof of pancreatic adenocarcinoma, and all of them received 18F-fluorodeoxyglucose (FDG) PET/MRI before treatment. The single-voxel MRS with a point-resolved selective spectroscopy sequence was used to measure metabolites (creatine, Glx (glutamine and glutamate), N-acetylaspartate (NAA), and lipid) of pancreatic cancer and adjacent normal parenchyma, respectively. FDG-PET parameters included SUVmax, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Non-parametric tests were used to evaluate the differences of MRS metabolites between pancreatic cancer and those in normal pancreas, and their correlation with PET parameters and clinical stages. The correlation with progression-free survival (PFS) and overall survival (OS) was measured using the Kaplan–Meier and Cox proportional hazard models. Results: When compared with normal pancreas, the Glx, NAA, and lipid levels were significantly decreased in pancreatic cancer (all p < 0.05). Creatine, Glx, and lipid levels were all inversely correlated with both MTV (rho = −0.405~−0.454) and TLG (rho = −0.331~−0.441). For correlation with clinical stages, lower lipid levels were found in patients with T4 (vs. p = 0.038) and lower creatine levels were found in N1 (vs. N0, p = 0.019). Regarding survival outcomes, high TNM stage, low creatine, low Glx, and low lipid levels were associated with both poor PFS and OS (all p < 0.05). Additionally, creatine remained an independent factor for PFS and OS after adjusting for age, sex, tumor size, stages, and other metabolites levels. Conclusions: Decreased MRS metabolites in pancreatic cancer were associated with poor survival outcome, and may be used as prognostic image biomarkers for these patients.

Objectives To explore the associations among clinical characteristics, fatigue, diabetes mellitus (DM) self-care activities, and quality of life (QOL) in individuals with resectable pancreatic cancer and DM. Sample & setting 57 individuals with resectable pancreatic cancer and DM from an outpatient pancreatic surgical department in Taiwan were included in the final analysis. Methods & variables A cross-sectional, correlational design was used. QOL, fatigue, and DM self-care were measured by the European Organisation for Research and Treatment of Cancer QOL Questionnaire-Core 30, the Fatigue Symptom Inventory, and the Summary of Diabetes Self-Care Activities. Results Participants who had a shorter duration of DM and higher levels of fatigue (including intensity, duration, and interference) reported lower QOL scores. Participants who performed more DM self-care activities and physical activity per week had higher QOL scores. Fatigue, DM self-care activities, and DM duration were significant factors related to QOL. Implications for nursing Shorter DM duration, increased fatigue, and fewer DM self-care activities were determinants of worse QOL in individuals with resectable pancreatic cancer and DM.

Background Delayed postpancreatectomy hemorrhage (PPH) is a fatal complication caused by arterial erosion. This study reports a single-center experience of managing delayed PPH with different endovascular treatment approaches. Methods We reviewed the data of patients who had delayed PPH due to hepatic artery or gastroduodenal artery stump perforation and underwent endovascular treatment between 2003 and 2018. We categorized endovascular treatment approaches involving hepatic artery sacrifice, superselective pseudoaneurysm embolization with hepatic artery preservation, and covered stent placement. Technical success rates, hemorrhage recurrence rates, major and minor hepatic complication rates, and 30-day and 1-year mortality rates were assessed. Results A total of 18 patients were reviewed; 11 (61%), 4 (22%), and 3 (17%) delayed PPH cases were managed through hepatic artery sacrifice, superselective pseudoaneurysm embolization, and hepatic artery stenting, respectively. Multidetector computed tomography was performed in 14 (78%) patients. The technical success rate was 100%. The overall hemorrhage recurrence rate was 39%, with superselective pseudoaneurysm embolization having a 100% hemorrhage recurrence rate—much higher than that of hepatic artery sacrifice or stent graft placement. The overall major and minor hepatic complication rates were 56% and 83%, respectively. The overall 30-day and 1-year mortality rates were 11% and 25%, respectively. The 30-day and 1-year mortality rates and minor and major hepatic complication rates were similar in each group. Conclusion Hepatic artery sacrifice is more effective than superselective pseudoaneurysm embolization in the management of delayed PPH. Covered stent placement may be a reasonable alternative treatment to hepatic artery sacrifice.

Objectives To compare fatigue and quality of life (QOL) between individuals with pancreatogenic diabetes after total pancreatectomy (TP) and pancreaticoduodenectomy (PD). Sample & setting 50 individuals (14 after TP and 36 after PD) were recruited from a pancreatic surgical outpatient department. A final sample of 39 matched individuals (13 after TP and 26 after PD) were included in the final analysis. Methods & variables A comparative cross-sectional approach was used. Variables were fatigue and QOL. The Fatigue Symptom Inventory and European Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 were used. Data went through propensity score one-to-two matching. Generalized estimating equation was used to compare fatigue and QOL. Results The groups showed no statistically significant difference in fatigue intensity and overall QOL. The TP group had significantly longer fatigue duration, perceived higher interference of functioning, lower physical function, and a higher level of insomnia. Implications for nursing Future studies with a larger sample and longitudinal design will help identify the trajectory of fatigue and QOL in individuals with pancreatogenic diabetes post-TP and PD.

Background The lymphatic system is involved in metastasis in pancreatic cancer progression. In cancer staging, lymphatic spread has been used to assess the invasiveness of tumor cells. However, from the endothelium's perspective, the analysis downplays the peri-lesional activities of lymphatic vessels. This unintended bias is largely due to the lack of 3-dimensional (3-D) tissue information to depict the lesion microstructure and vasculature in a global and integrated fashion. Methods We targeted the pancreas as the model organ to investigate lymphatic vessel remodeling in cancer lesion progression. Transparent pancreases were prepared by tissue clearing to facilitate deep-tissue, tile-scanning microscopy for 3-D lymphatic network imaging. Findings In human pancreatic ductal adenocarcinoma, we identify the close association between the pancreatic intraepithelial neoplasia (PanIN) lesions and the lymphatic network. In mouse models of PanIN (elastase-CreER;LSL-KrasG12D and elastase-CreER;LSL-KrasG12D;p53+/-), the 3-D image data reveal the peri-lesional lymphangiogenesis, endothelial invagination, formation of the bridge/valve-like luminal tubules, vasodilation, and luminal invasion. In the orthotopic mouse model of pancreatic cancer, we identify the localized, graft-induced lymphangiogenesis and the peri- and intra-tumoral lymphatic vessel invasion. Interpretation The integrated view of duct lesions and vascular remodeling suggests an active role, rather than a passive target, of lymphatic vessels in the metastasis of pancreatic cancer. Our 3-D image data provide insights into the pancreatic cancer microenvironment and establish the technical and morphological foundation for systematic detection and 3-D analysis of lymphatic vessel invasion. FUND: Taiwan Academia Sinica (AS-107-TP-L15 and AS-105-TP-B15), Ministry of Science and Technology (MOST 106-2321-B-001-048, 106-0210-01-15-02, 106-2321-B-002-034, and 106-2314-B-007-004-MY2), and Taiwan National Health Research Institutes (NHRI EX107-10524EI).

Volume–outcome relationship has been demonstrated extensively for short-term outcomes for oncological surgery. However, its effect on long-term surgical outcomes or in one universal health care (UHC) system is unknown. This retrospective population-based study aims to validate the correlation between the increased hospital volume and better short- and long-term outcomes in patients who underwent total gastrectomy (TG) for gastric cancer. From the Taiwan National Health Insurance Research Database, we examined 7905 patients who underwent TG between 2000 and 2010. The surgical outcomes of this study were defined as death within 30, 60, and 180 days after TG. A total of 7905 subjects were included for analysis. The mean age was 65.8 years, and 68.8% were males. The 30-, 60-, and 180-day mortality rates after TG for gastric cancer were 2.7%, 6.2%, and 18.2%, respectively. On the multivariate analysis, TG at high-volume hospitals significantly contributed to lower 30-day (odds ratio 0.64; 95% confidence interval 0.48–0.85; P

Patients with periampullary cancer frequently suffer obstructive jaundice and commonly require preoperative biliary drainage (PBD) for relief and to avoid related complications. Although research has established a correlation between PBD and surgical wound infection, the impact of PBD on major infectious complications (intra-abdominal abscess [IAA]) and overall mortality remains debatable. We hypothesized that PBD could lead to IAA and mortality, and evaluated their correlation in patients undergoing pancreaticoduodenectomy (PD). We enrolled patients undergoing PD at an Asian academic medical center between 2007 and 2016. The types of PBD included endoscopic retrograde biliary drainage (ERBD) and percutaneous transhepatic cholangiography and drainage (PTCD). The primary outcome was IAA, defined as the presence of pus or infected fluid inside the abdominal cavity and with documented infectious pathogens. There was one (0.1%) 30-day mortality and eight (0.9%) 90-day mortalities among 899 consecutive patients examined. More than one-quarter of patients had PBD (n = 237, 26.4%; 165 ERBD, 72 PTCD). In the ERBD, PTCD, and non-PBD groups, the IAA rates were 37.0%, 16.7%, and 10.6%, respectively. On multivariate analysis, ERBD (odds ratio 3.67; 95% confidence interval 2.22–6.06; p

(4S)-4-(3-18F-Fluoropropyl)-l-glutamate (FSPG) positron emission tomography (PET) reflects system xC− transporter (xCT) expression. FSPG PET has been used to detect brain, lung, breast and liver cancer with only modest success. There is no report on the use of FSPG PET in pancreatic ductal adenocarcinoma (PDAC), presumably because of normal xCT expression in the pancreas. Nonetheless, the tissue-specific expression of xCT in the pancreas suggests that FSPG PET may be ideal for identifying metastasized PDAC. The performance of FSPG in detecting PDAC metastases was compared with that of 18F-fluorodeoxyglucose (FDG) in small-animal PET studies in seven PDAC tumour-bearing mice and in prospective PET/computed tomography (CT) studies in 23 patients with tissue-confirmed PDAC of stage III or stage IV. All PET/CT results were correlated with the results of histopathology or contrast-enhanced CT (ceCT) performed 3 and 6 months later. In the rodent model, FSPG PET consistently found more PDAC metastases earlier than FDG PET. FSPG PET showed a trend for a higher sensitivity, specificity and diagnostic accuracy than FDG PET in detecting PDAC metastases in a patient-based analysis: 95.0%, 100.0% and 95.7%, and 90.0%, 66.7% and 90.0%, respectively. In a lesion-based analysis, FSPG PET identified significantly more PDAC metastases, especially in the liver, than FDG PET (109 vs. 95; P = 0.0001, 95% CI 4.9–14.6). The tumour-to-background ratios for FSPG and FDG uptake on positive scans were similar (FSPG 4.2 ± 4.3, FDG 3.6 ± 3.0; P = 0.44, 95% CI −1.11 to 0.48), despite a lower tumour maximum standardized uptake value in FSPG-avid lesions (FSPG 4.2 + 2.3, FDG 7.7 + 5.7; P = 0.002, 95% CI 0.70–4.10). Because of the lower physiological activity of FSPG in the liver, FSPG PET images of the liver are more easy to interpret than FDG PET images, and therefore the use of FSPG improves the detection of liver metastasis. FSPG PET is superior to FDG PET in detecting metastasized PDAC, especially in the liver.

Aptamer-based nanovectors that actively bind to circulating monocytes enhance drug delivery to the heart and to cancer., The delivery of therapeutics through the circulatory system is one of the least arduous and less invasive interventions; however, this approach is hampered by low vascular density or permeability. In this study, by exploiting the ability of monocytes to actively penetrate into diseased sites, we designed aptamer-based lipid nanovectors that actively bind onto the surface of monocytes and are released upon reaching the diseased sites. Our method was thoroughly assessed through treating two of the top causes of death in the world, cardiac ischemia-reperfusion injury and pancreatic ductal adenocarcinoma with or without liver metastasis, and showed a significant increase in survival and healing with no toxicity to the liver and kidneys in either case, indicating the success and ubiquity of our platform. We believe that this system provides a new therapeutic method, which can potentially be adapted to treat a myriad of diseases that involve monocyte recruitment in their pathophysiology.

Purpose Pancreatic cancer is one of the most malignant cancers with poor survival. The latest edition of the American Joint Committee on Cancer (AJCC) staging system classifies the majority of operable pancreatic cancer patients as stage-III, while dramatic heterogeneity is observed among these patients. Therefore, subgrouping is required to accurately predict their prognosis and define a treatment plan. This study conducts a cohort study to provide a more precise classification system for stage-III pancreatic cancer patients by utilizing clinical variables. Methods We analyzed survival using log-rank tests, univariate Cox-regression models, and Kaplan-Meier survival curves for stage-III pancreatic ductal adenocarcinoma (PDAC) patients from the Taiwan Cancer Registry (TCR). Patients were further divided into subgroups using classification and regression tree (CART) algorithm. All results were validated using the SEER database. Results Among stage-III PDAC patients, lymph node and tumor grade showed significant association with survival. Patients with N2 stage had higher mortality risks (hazard ratio [HR] = 2.30, 95% confidence interval [CI] 1.71–3.08, p p p Conclusions Lymph node involvement and tumor grade are predictive factors for survival in stage-III PDAC patients. This new precise classification system can be used to guide treatment planning in advanced-stage pancreatic cancer.

Immune checkpoint inhibitors have limited efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). We investigated prognostic markers for nivolumab-based therapy in advanced or recurrent PDAC. Consecutive patients receiving nivolumab-based therapy at our institution between 2015 and 2020 were evaluated. Overall survival (OS) was analyzed through univariate and multivariate analyses. Spleen volume was estimated from the width, thickness, and length of the spleen. A total of 45 patients were identified. Biweekly nivolumab was administered as monotherapy (n = 5) or in combination with chemotherapy or targeted therapy (n = 40). Among 31 evaluable patients, the response and disease control rates were 7% and 36%, respectively. The baseline median spleen volume was 267 (110–674) mL. Patients with spleens ≥267 mL had significantly shorter median OS (1.9 months, 95% confidence interval [CI], 1.0–2.7) than did those with smaller spleens (8.2 months, 95% CI, 5.6–10.8; P = .003). In the multivariate analysis, spleen volume of

Background A major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the significant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis. Methods We analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found candidate genes that were differentially expressed in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and verified our finding with the survival data of patients with PDAC from the website of The Human Protein Atlas. Results We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC. Conclusions PSCs stimulated PDAC cells to secrete S100A9, which acts as a chemoattractant to attract circulatory monocytes into cancer microenvironment and induces expression of PD-L1 on macrophages. High expression of S100A9 and PD-L1 was associated with worse overall survival in a cohort of patients with PDAC.

Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related death. Altered glycosylation contributes to tumor progression and chemoresistance in many cancers. C1GALT1 is the key enzyme controlling the elongation of GalNAc-type O-glycosylation. Here we showed that C1GALT1 was overexpressed in 85% (107/126) of PDAC tumors compared with adjacent non-tumor tissues. High expression of C1GALT1 was associated with poor disease-free and overall survival (n = 99). C1GALT1 knockdown using siRNA suppressed cell viability, migration, and invasion as well as increased gemcitabine sensitivity in PDAC cells. In contrast, C1GALT1 overexpression enhanced cell migration and invasion. In subcutaneous and pancreatic orthotopic injection models, C1GALT1 knockdown decreased tumor growth and metastasis of PDAC cells in NOD/SCID mice. Mechanistically, C1GALT1 knockdown dramatically suppressed cell-extracellular matrix (ECM) adhesion, which was associated with decreased phosphorylation of FAK at Y397/Y925 and changes in O-glycans on integrins including the β1, αv, and α5 subunits. Using functional blocking antibodies, we identified integrin αv as a critical factor in C1GALT1-mediated invasiveness of PDAC cells. In conclusion, this study not only reveals that C1GALT1 could be a potential therapeutic target for PDAC but also provides novel insights into the role of O-glycosylation in the α subunits of integrins.

The members of the interleukin-17 (IL-17) cytokine family and their receptors were identified decades ago. Unlike IL-17 receptor A (IL-17RA), which heterodimerizes with IL-17RB, IL-17RC, and IL-17RD and mediates proinflammatory gene expression, IL-17RB plays a distinct role in promoting tumor growth and metastasis upon stimulation with IL-17B. However, the molecular basis by which IL-17RB promotes oncogenesis is unknown. Here, we report that IL-17RB forms a homodimer and recruits mixed-lineage kinase 4 (MLK4), a dual kinase, to phosphorylate it at tyrosine-447 upon treatment with IL-17B in vitro. Higher amounts of phosphorylated IL-17RB in tumor specimens obtained from patients with pancreatic cancer correlated with worse prognosis. Phosphorylated IL-17RB recruits the ubiquitin ligase tripartite motif containing 56 to add lysine-63–linked ubiquitin chains to lysine-470 of IL-17RB, which further assembles NF-κB activator 1 (ACT1) and other factors to propagate downstream oncogenic signaling. Consequentially, IL-17RB mutants with substitution at either tyrosine-447 or lysine-470 lose their oncogenic activity. Treatment with a peptide consisting of amino acids 403 to 416 of IL-17RB blocks MLK4 binding, tyrosine-477 phosphorylation, and lysine-470 ubiquitination in vivo, thereby inhibiting tumorigenesis and metastasis and prolonging the life span of mice bearing pancreatic tumors. These results establish a clear pathway of how proximal signaling of IL-17RB occurs and provides insight into how this pathway provides a therapeutic target for pancreatic cancer.

The effect of a harmonic scalpel on postoperative pancreatic fistula (POPF) has not been addressed. This study assessed the effect of pancreatic neck transection using a harmonic scalpel on rate and severity of POPF after pancreaticoduodenectomy (PD).This retrospective analysis included patients who underwent PD at National Taiwan University Hospital between July 2015 and March 2019. We compared rate and severity of POPF between patients who underwent pancreatic neck transection using a harmonic scalpel versus electrosurgical unit.Of 422 consecutive PDs, the pancreatic neck was transected using a harmonic scalpel or electrosurgical unit in 144 and 278 patients, respectively. Use of a harmonic scalpel significantly increased risk of biochemical leak (25.7% versus [vs] 10.8%; P 0.05) but not clinically relevant POPF (CR-POPF; 30.2% vs 26.4%; P = 0.41). Harmonic transection was an independent predictor of biochemical leak (odds ratio [OR] = 2.93; P 0.05) but not CR-POPF (OR = 0.83; P = 0.41) or other major complications (OR = 0.72; P = 0.27). There was no significant intergroup difference in postoperative hospital stay.Pancreatic neck transection using a harmonic scalpel increased risk of biochemical leak but not CR-POPF or other major complications.

(4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) is a positron emission tomography (PET) imaging agent for measuring the system xC− transporter activity. It has been used for the detection of various cancers and metastasis in clinical trials. [18F]FSPG is also a promising diagnostic tool for evaluation of multiple sclerosis, drug resistance in chemotherapy, inflammatory brain diseases, and infectious lesions. Due to the very short half-life (110 min) of 18F nuclide, [18F]FSPG needs to be produced on a daily basis; therefore, fast and efficient synthesis and analytical methods for quality control must be established to assure the quality and safety of [18F]FSPG for clinical use. To manufacture cGMP-compliant [18F]FSPG, all four nonradioactive stereoisomers of FSPG were prepared as reference standards for analysis. (2S,4S)-1 and (2R,4R)-1 were synthesized starting from protected L- and D-glutamate derivatives in three steps, whereas (2S,4R)-1 and (2R,4S)-1 were prepared in three steps from protected (S)- and (R)-pyroglutamates. A chiral HPLC method for simultaneous determination of four FSPG stereoisomers was developed by using a 3-cm Chirex 3126 column and a MeCN/CuSO4(aq) mobile phase. In this method, (2R,4S)-1, (2S,4S)-1, (2R,4R)-1, and (2S,4R)-1 were eluted in sequence with sufficient resolution in less than 25 min without derivatization. Scale-up synthesis of intermediates for the production of [18F]FSPG in high optical purity was achieved via stereo-selective synthesis or resolution by recrystallization. The enantiomeric excess of intermediates was determined by HPLC using a Chiralcel OD column and monitored at 220 nm. The nonradioactive precursor with >98% ee can be readily distributed to other facilities for the production of [18F]FSPG. Based on the above accomplishments, cGMP-compliant [18F]FSPG met the acceptance criteria in specifications and was successfully manufactured for human use. It has been routinely prepared and used in several pancreatic ductal adenocarcinoma metastasis-related clinical trials.

Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies. Pancreatic ductal adenocarcinoma (PDAC) is characterised by the aberrant expression of mucins. However, the role of mucin (MUC) 20 in PDAC remains unclear. PDAC is usually surrounded by a dense fibrotic stroma consisting of an extracellular matrix and pancreatic stellate cells (PSCs). The stroma creates a nutrient-deprived, hypoxic, and acidic microenvironment, and promotes the malignant behaviours of PDAC cells. In this study, immunohistochemical staining demonstrated that high MUC20 expression correlated with poor progression-free survival and high local recurrence rate of PDAC patients (n = 61). The expression of MUC20 was induced by serum deprivation, hypoxia, and acidic pH in PDAC cells. MUC20 knockdown with siRNA decreased cell viability, as well as migration and invasion induced by PSCs in HPAC and HPAF-II cells. In intraperitoneal, subcutaneous, and orthotopic injection models, MUC20 knockdown decreased tumour growth in immunodeficient mice. Phospho-RTK array and western blot analysis indicated that MUC20 knockdown decreased HGF-mediated phosphorylation of MET in PDAC cells. Moreover, HGF-induced malignant phenotypes could be suppressed by MUC20 knockdown. Co-immunoprecipitation revealed the physical association of MUC20 and MET. These findings suggest that MUC20 knockdown suppresses the malignant phenotypes of PDAC cells at least partially through the inhibition of the HGF/MET pathway and that MUC20 could act as a potential therapeutic target.

Background The rate of preoperative biliary drainage for pancreaticoduodenectomy has been increasing despite most recent evidence that favors avoiding it. Only a few studies have focused on late surgical complications - biliary stricture after pancreaticoduodenectomy and have produced only inconclusive results. We evaluate the role of preoperative biliary drainage in the formation of biliary stricture after pancreaticoduodenectomy. Methods The Taiwan National Health Insurance Program is a mandatory health care plan that covers nearly the entire population of 23 million in this country. A retrospective study was conducted to analyze the database compiled by the Taiwan National Health Insurance between January 2000 and December 2011. We included only patients with at least 2 years of follow-up. A cohort of 2,087 patients with preoperative diagnosis of biliary obstruction that underwent pancreaticoduodenectomy was evaluated. Results A total of 212 (10.1%) of the 2,087 studied patients needed intervention for biliary stricture after pancreaticoduodenectomy. The median time to biliary stricture formation was 15.2 months (range: 1.2-89.7 months). The cumulative biliary stricture rate was 6.9% (1 year), 15.8% (5 years), and 18.5% (10 year). Multivariate analysis showed preoperative biliary drainage (hazard ratio 1.78, 95% CI 1.27-2.50, P = 0.001) associated with biliary stricture after pancreaticoduodenectomy. Conclusions Preoperative biliary drainage increases biliary stricture rate after pancreaticoduodenectomy.

The aim of the present study was to evaluate the clinical utility of plasma chromogranin A (CgA) in patients diagnosed with early-stage pancreatic neuroendocrine tumors (PNETs) in terms of diagnostic value and treatment response. A total of 35 patients with PNETs were prospectively enrolled from August 2010 to April 2014. Demographic and clinicopathological data were collected, and serial plasma CgA levels were measured. Tumor responses were defined by the Response Evaluation Criteria In Solid Tumors criteria. Pearson's χ2 test was used for the analysis of the association between the plasma CgA level and various factors. Plasma CgA level was significantly associated with the size (P=0.03), metastasis (P=0.02) and tumor stage (P=0.03) of the PNETs. Using 126 U/l as the optimal cutoff value, the sensitivity and specificity were 87.5 and 81.5%, respectively. For localized tumors, the sensitivity of CgA for diagnosing PNETs was relatively low, even following a lowering of the cutoff values (29.6-51.9%). Plasma CgA level was correlated with therapeutic response in those patients with high baseline CgA levels (P=0.025), but not in the patients with low baseline CgA levels (P=0.587). In conclusion, plasma CgA level was associated with tumor size, metastasis and tumor stage in patients with PNET. For early-stage PNETs, CgA exhibited a limited role in diagnosis and treatment response evaluation in the population of the present study.

To correlate the overall survival (OS) with the imaging biomarkers of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), diffusion-weighted imaging (DWI), magnetic resonance spectroscopy, and glucose metabolic activity derived from integrated fluorine 18 fluorodeoxyglucose positron emission tomography (18F–FDG PET)/MRI in patients with pancreatic cancer. This prospective study was approved by the institutional review board and informed consent was obtained from all participants. Sixty-three consecutive patients (mean age, 62.7 ± 12 y; men/women, 40/23) with pancreatic cancer underwent PET/MRI before treatment. The imaging biomarkers were comprised of DCE-MRI parameters (peak, IAUC 60 , K trans , k ep , v e ), the minimum apparent diffusion coefficient (ADCmin), choline level, standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) of the tumors. The relationships between these imaging biomarkers with OS were evaluated with the Kaplan-Meier and Cox proportional hazard models. Seventeen (27%) patients received curative surgery, with the median follow-up duration being 638 days. Univariate analysis showed that patients at a low TNM stage (≦3, P = 0.041), high peak (P = 0.006), high ADCmin (P = 0.002) and low TLG (P = 0.01) had better OS. Moreover, high TLG/peak ratio was associated with poor OS (P = 0.016). Multivariate analysis indicated that ADCmin (P = 0.011) and TLG/peak ratio (P = 0.006) were independent predictors of OS after adjustment for age, gender, tumor size, and TNM stage. The TLG/peak ratio was an independent predictor of OS in a subgroup of patients who did not receive curative surgery (P = 0.013). The flow-metabolism mismatch reflected by the TLG/peak ratio may better predict OS than other imaging biomarkers from PET/MRI in pancreatic cancer patients.

Autoimmune pancreatitis (AIP) shares overlapping clinical features with pancreatic cancer (PC). Importantly, treatment of the two conditions is different. We investigated the clinical usefulness of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with suspected AIP before treatment. From September 2008 to July 2016, 53 patients with suspected AIP at National Taiwan University Hospital had PET/CT prior to therapy to exclude malignancy and evaluate the extent of inflammation. Their scans were compared with those from 61 PC patients. PET imaging features were analyzed using logistic regression. Significant differences in pancreatic tumor uptake morphology, maximum standardized uptake value, high-order primary tumor texture feature (i.e. high-gray level zone emphasis value), and numbers and location of extrapancreatic foci were found between AIP and PC. Using the prediction model, the area under curve of receiver-operator curve was 0.95 (P

Which patients with pancreatic intraductal papillary mucinous neoplasms (IPMNs) should undergo surgical intervention remains a controversial issue. The aim of this retrospective study was to validate the new European evidence-based guidelines on pancreatic cystic neoplasms (EEBGPCN) for the management of IPMNs.One hundred fifty-eight patients with resected IPMNs at National Taiwan University Hospital between January 1994 and December 2016 were enrolled. Clinical information, including new-onset diabetes mellitus (DM) and preoperative CA 19-9 levels, were collected. All patients were stratified into three groups-absolute, relative indications, and conservative approach-according to EEBGPCN. The performance characteristics of EEBGPCN for high-grade dysplasia (HGD)/invasive carcinoma (IC) of IPMNs were calculated.One hundred seven (67.7%) patients with low-grade dysplasia and 51 patients with HGD/IC, including 10 HGD and 41 IC, were analyzed. The missed rate for HGD/IC by EEBGPCN was 1.9% (3/158). The sensitivity, specificity, positive and negative predictive values, and accuracy of the absolute or relative indications for resecting IPMN according to EEBGPCN were 94.1%, 28.0%, 38.4%, 90.9%, and 49.4%. Jaundice, enhancing mural nodule5 mm, cyst diameter40 mm, increased levels of serum CA 19-9, new-onset DM, and main pancreatic duct dilation were associated with HGD/IC.The missed rate for HGD/IC is low by EEBGPCN. Increased serum CA 19-9 and new-onset DM in EEBGPCN were verified as the indications for the surgical resection of IPMNs.

The pancreas consists of both the exocrine (acini and ducts) and endocrine (islets) compartments to participate in and regulate the body’s digestive and metabolic activities. These activities are subjected to neural modulation, but characterization of the human pancreatic afferent and efferent nerves remains difficult because of the lack of three-dimensional (3-D) image data. Here we prepare transparent human donor pancreases for 3-D histology to reveal the pancreatic microstructure, vasculature, and innervation in a global and integrated fashion. The pancreatic neural network consists of the substance P (SP)-positive sensory (afferent) nerves, the vesicular acetylcholine transporter (VAChT)-positive parasympathetic (efferent) nerves, and the tyrosine hydroxylase (TH)-positive sympathetic (efferent) nerves. The SP+ afferent nerves were found residing along the basal domain of the interlobular ducts. The VAChT+ and TH+ efferent nerves were identified at the peri-acinar and perivascular spaces, which follow the blood vessels to the islets. In the intrapancreatic ganglia, the SP+ (scattered minority, ~7%) and VAChT+ neurons co-localize, suggesting a local afferent-efferent interaction. Compared with the mouse pancreas, the human pancreas differs in 1) the lack of SP+ afferent nerves in the islet, 2) the lower ganglionic density, and 3) the obvious presence of VAChT+ and TH+ nerves around the intralobular adipocytes. The latter implicates the neural influence on the pancreatic steatosis. Overall, our 3-D image data reveal the human pancreatic afferent and efferent innervation patterns and provide the anatomical foundation for future high-definition analyses of neural remodeling in human pancreatic diseases. NEW & NOTEWORTHY Modern three-dimensional (3-D) histology with multiplex optical signals identifies the afferent and efferent innervation patterns of human pancreas, which otherwise cannot be defined with standard histology. Our 3-D image data reveal the unexpected association of sensory and parasympathetic nerves/neurons in the intrapancreatic ganglia and identify the sympathetic and parasympathetic nerve contacts with the infiltrated adipocytes. The multiplex approach offers a new way to characterize the human pancreas in remodeling (e.g., fatty infiltration and duct lesion progression).

Background: The link of pancreatic cancer to diabetes (type 3c) suggests that islets are influenced by the cancer lesion progression. However, at an early stage, i.e., when the pancreas appears to be normal, how the endocrine pancreas is affected by the initial duct lesion formation remains unclear. Aims. To apply panoramic 3-D histology to detect early duct lesions in human cadaveric donor pancreases and examine the peri-lesional islet environment. Methods: Tissue clearing was applied to the freshly perfused donor pancreases (target) and cancer surgical biopsies (malignant control) for 3-D microscopy. Results: Large-scale tissue scanning detects early duct lesions (PanIN 1A/B) in three donor pancreases (3/5; nondiabetic; age (yr)/BMI: 40/24, 53/28, and 51/20). High-definition 3-D fluorescence and 2-D transmitted-light and H&E images reveal: 1) peri-lesional islet aggregation, 2) epithelium-islet complex (e.g., intra-islet duct), 3) adipocyte association, 4) inflammation, 5) stromal activation, and 6) Ki-67+ ductal and stromal cells but not the β- or α-cells. Conclusions: We systematically developed a 3-D/2-D integrative imaging approach to detect and characterize the islet microenvironment around early duct lesions. Our data indicate a proliferative setting, but the islet aggregation appears not to arise from β- or α-cell division; instead, it may be due to lobular atrophy and/or evolve from duct-to-islet differentiation. Disclosure H. Chien: None. T. Chiang: None. S. Peng: None. M. Chung: None. C. Lee: None. Y. Tien: None. S. Tang: None.

Pancreatic stromal cells especially pancreatic stellate cells (PSCs) play a critical role in the progression of human pancreatic ductal adenocarcinoma (PDAC). However, the exact interaction between cancer cells and PSCs remains to be elucidated in order to develop more effective therapeutic approaches to treat PDAC. The microenvironment of PDAC shows higher hyaluronan (HA) levels, which is associated with poor prognosis of PDAC patients. In the current study, an efficient three-dimensional tumor spheroid model for PDAC was established. The pancreatic cancer cells and PSCs were co-cultured on hyaluronan grafted chitosan (CS-HA) coated plates to generate 3D tumor-like co-spheroids. The pancreatic cancer cells and PSCs (1:9 ratio) co-cultured on CS-HA coated plates were assembled into tumor-like co-spheroids with 3D core-shell structure in 48 h. These spheroids displayed potent in vitro tumorigenicity such as up-regulated expression of stemness and migration markers. The migration rate of cancer cells in spheroids (from 1:9 cell ratio) was much faster (3.2-fold) than that of cancer cells alone. Meanwhile, this unique co-spheroidal cancer cell structure with the outer wrap of PSCs contributed to the chemo-resistance of pancreatic cancer cells to gemcitabine as well as sensitivity to the combined gemcitabine and Abraxane treatment in vitro. The metastatic nature of the spheroids was confirmed by the zebrafish xenograft model in vivo. The compact and dynamic pancreatic cancer-PSC co-spheroids generated by the unique 3D co-culture platform on CS-HA biomaterials can mimic the PSC-constituting microenvironment of PDAC and demonstrate the chemo-resistant, invasive, and metastatic phenotypes. They have potential applications in personalized and high-throughput drug screening.

Background The pancreatoenteric anastomotic stricture (PEAS) is a common long-term complication after pancreaticoduodenectomy (PD), some of which present as acute pancreatitis requiring emergency care. This important topic has never been reported. In this study, we focus on the incidence, radiological features, clinical outcome, and risk factors of late-occurring acute pancreatitis (LAP) after PD. Methods We retrospectively reviewed a prospectively collected database of 539 patients who underwent PD at a single tertiary referral center between June 2005 and December 2014. Only patients with at least 3 years of follow-up and available pre- and post-operative images were included. Results Of the 539 patients, 23 (15 [65%] with and eight [35%] without PEAS) were diagnosed with LAP after PD. The cumulative incidence of LAP was 3.6% (1-year), 4.4% (2-year), and 5.1% (5-year). The median time to the first LAP episode was 22 months (range 8-38 months) after PD. All the first and recurrent LAP events were mild in severity and resolved after conservative treatment. Multivariate analysis showed that a history of acute pancreatitis before PD (P = 0.001, HR 5.24, 95% CI 1.95-14.10) and PEAS (P = 0.047, HR 2.75, 95% CI 1.01-7.49) were two significant risk factors. Conclusions We propose using a more conservative treatment for patients who experience LAP after PD.

The blood-brain barrier (BBB) selectively controls the passage of endogenous and exogenous molecules between systemic circulation and the brain parenchyma. Nanocarrier-based drugs such as liposomes and nanoparticles are an attractive prospect for cancer therapy since they can carry a drug payload and be modified to improve targeting and retention at the desired site. However, the BBB prevents most therapeutic drugs from entering the brain, including physically restricting the passage of liposomes and nanoparticles. In this paper, we show that a low dose of systemically injected recombinant human vascular endothelial growth factor induces a short period of increased BBB permeability. We have shown increased delivery of a range of nanomedicines to the brain including contrast agents for imaging, varying sizes of nanoparticles, small molecule chemotherapeutics, tracer dyes, and liposomal chemotherapeutics. However, this effect was not uniform across all brain regions, and permeability varied depending on the drug or molecule measured. We have found that this window of BBB permeability effect is transient, with normal BBB integrity restored within 4 h. This strategy, combined with liposomal doxorubicin, was able to significantly extend survival in a mouse model of human glioblastoma. We have found no evidence of systemic toxicity, and the technique was replicated in pigs, demonstrating that this technique could be scaled up and potentially be translated to the clinic, thus allowing the use of nanocarrier-based therapies for brain disorders.

BACKGROUND AND AIM Radiotherapy (RT) with or without chemotherapy is currently used in definitive therapy for advanced pancreatic cancer. We sought to evaluate the prognostic significance, pattern of care, and use of RT in locally advanced and metastatic pancreatic cancer. METHODS Between 2002 and 2011, patients with invasive pancreatic carcinoma and prior exposure to systemic chemotherapy were included. We used Cox regression model and propensity score matching for prognostic analyses and logistic regression for analyzing the factors impacting the use of RT. RESULTS We identified 217 pancreatic cancer patients (74 with unresectable stage II or III and 143 with stage IV). Of all patients, 90.8% had adenocarcinoma, and only 19.2% (42/217) received RT with doses ranging from 50 to 55 Gy in 25 to 28 fractions using modern RT techniques. Logistic regression showed stage (P

The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) remains dismal despite current chemotherapeutic agents and inhibitors of molecular targets. As the incidence of PDAC constantly increases, more effective multidrug approaches must be made. Here, we report a novel method of delivering antitumorigenic therapy in PDAC by upregulating the transcriptional factor CCAAT/enhancer-binding protein-α (C/EBPα), recognized for its antiproliferative effects. Small activating RNA (saRNA) duplexes designed to increase C/EBPα expression were linked onto PDAC-specific 2'-Fluropyrimidine RNA aptamers (2'F-RNA) - P19 and P1 for construction of a cell type-specific delivery vehicle. Both P19- and P1-C/EBPα-saRNA conjugates increased expression of C/EBPα and significantly suppressed cell proliferation. Tail vein injection of the saRNA/aptamer conjugates in PANC-1 and in gemcitabine-resistant AsPC-1 mouse-xenografts led to reduced tumor size with no observed toxicity. To exploit the specificity of the P19/P1 aptamers for PDAC cells, we also assessed if conjugation with Cy3 would allow it to be used as a diagnostic tool on archival human pancreatic duodenectomy tissue sections. Scoring pattern from 72 patients suggested a positive correlation between high fluorescent signal in the high mortality patient groups. We propose a novel aptamer-based strategy for delivery of targeted molecular therapy in advanced PDAC where current modalities fail.

To correlate the clinical stage and prognosis of pancreatic or periampullary cancer with the imaging biomarkers on diffusion-weighted imaging, magnetic resonance spectroscopy and glucose metabolic activity derived from integrated PET/MRI. This prospective study was approved by the institutional review board and informed consent was obtained. The study group comprised 60 consecutive patients with pancreatic or periampullary cancer who underwent PET/MRI before treatment. The imaging biomarkers were the minimal apparent diffusion coefficient (ADCmin), choline levels, standardized uptake values, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) of the tumours. The relationships between these biomarkers and clinical TNM stage were evaluated using the Pearson test and the Mann-Whitney U test. The area under the receiver operating characteristic curve (AUROC) was used to evaluate accuracy. The correlation between the imaging biomarker and progression-free survival (PFS) was investigated using the Cox proportional hazards model. ADCmin was significantly lower in N1 and TNM stage 3+ tumours. Choline levels significantly higher in T4 tumours. TLG was significantly higher in T4, N1 and TNM stage 3+ tumours. MTV was significantly higher in T4, N1, M1, and TNM stage 3+ tumours (all P

BACKGROUND Characterization of circulating tumor cells (CTCs) has been used to provide prognostic, predictive, and pharmacodynamic information in many different cancers. However, the clinical significance of CTCs and circulating tumor microemboli (CTM) in patients with pancreatic ductal adenocarcinoma (PDAC) has yet to be determined. METHODS In this prospective study, CTCs and CTM were enumerated in the peripheral blood of 63 patients with PDAC before treatment using anti-EpCAM (epithelial cell adhesion molecule)–conjugated supported lipid bilayer–coated microfluidic chips. Associations of CTCs and CTM with patients' clinical factors and prognosis were determined. RESULTS CTCs were abundant [mean (SD), 70.2 (107.6)] and present in 81% (51 of 63) of patients with PDAC. CTM were present in 81% (51 of 63) of patients with mean (SD) 29.7 (1101.4). CTM was an independent prognostic factor of overall survival (OS) and progression free survival (PFS). Patients were stratified into unfavorable and favorable CTM groups on the basis of CTM more or less than 30 per 2 mL blood, respectively. Patients with baseline unfavorable CTM, compared with patients with favorable CTM, had shorter PFS (2.7 vs 12.1 months; P < 0.0001) and OS (6.4 vs 19.8 months; P < 0.0001). Differences persisted if we stratified patients into early and advanced diseases. The number of CTM before treatment was an independent predictor of PFS and OS after adjustment for clinically significant factors. CONCLUSIONS The number of CTM, instead of CTCs, before treatment is an independent predictor of PFS and OS in patients with PDAC.

Importance: While laparoscopic pancreaticoduodenectomy (LPD) is being adopted with increasing enthusiasm worldwide, it is still challenging for both technical and anatomical reasons. Currently, there is no consensus on the technical standards for LPD.Objective: The aim of this consensus statement is to guide the continued safe progression and adoption of LPD.Evidence Review: An international panel of experts was selected based on their clinical and scientific expertise in laparoscopic and open pancreaticoduodenectomy. Statements were produced upon reviewing the literature and assessed by the members of the expert panel. The literature search and its critical appraisal were limited to articles published in English during the period from 1994 to 2019. The Web of Science, Medline, and Cochrane Library and Clinical Trials databases were searched, The search strategy included, but was not limited to, the terms 'laparoscopic', 'pancreaticoduodenectomy, 'pancreatoduodenectomy', 'Whipple's operation', and 'minimally invasive surgery'. Reference lists from the included articles were manually checked for any additional studies, which were included when appropriate. Delphi method was used to establish expert consensus and the AGREE II-GRS Instrument was applied to assess the methodological quality and externally validate the final statements. The statements were further discussed during a one-day face-to-face meeting at the 1st Summit on Minimally Invasive Pancreatico-Biliary Surgery in Wuhan, China.Findings: Twenty-eight international experts from 8 countries constructed the expert panel. Sixteen statements were produced by the members of the expert panel. At least 80% of responders agreed with the majority (80%) of statements. Other than three randomized controlled trials published to date, most evidences were based on level 3 or 4 studies according to the AGREE II-GRS Instrument.Conclusions and Relevance: The Wuhan international expert consensus meeting on LPD has produced a set of clinical practice statements for the safe development and progression of LPD. LPD is currently in its development and exploration stages, as defined by the international IDEAL framework for surgical innovation. More robust randomized controlled trial and registry study are essential to proceed with the assessment of LPD.

BackgroundWhether continued oral feeding may have a negative impact on healing of postoperative pancreatic fistula (POPF) is unclear. The aim was to test the hypothesis that oral feeding is non-inferior to enteral feeding in closure of POPF after pancreatoduodenectomy, and to clarify the effects of oral feeding on the duration and grade of POPF.MethodsThis multicentre, non-inferiority randomized trial of oral or enteral feeding of patients with POPF after pancreatoduodenectomy recruited patients between August 2013 and September 2016. The primary efficacy outcome was the 30-day fistula closure rate. The prespecified non-inferiority margin was 15 per cent. Other efficacy outcomes included grade of fistula, and hospital stay and costs.ResultsA total of 114 patients were included, and received oral (57) or enteral (57) feeding. The two groups were balanced in baseline characteristics and no patient was lost to follow-up. In intention-to-treat analysis, oral feeding was non-inferior to enteral feeding in terms of 30-day fistula closure rate (88 versus 89 per cent respectively; difference –1·8 per cent, lower limit of 95 per cent c.i. –14·4 per cent; P = 0·020 for non-inferiority). Compared with enteral feeding, oral feeding significantly reduced hospital costs and duration of stay. No significant differences were noted in the number of patients whose POPF evolved into grade B/C, or other outcomes.ConclusionOral feeding in patients with POPF after pancreatoduodenectomy did not increase the duration or grade of POPF, and was associated with reduced duration of stay and hospital costs. Registration number: NCT01755260 (http://www.clinicaltrials.gov).

Background Autoimmune pancreatitis (AIP) is a distinct type of chronic pancreatitis. To date, the association of CFTR gene variants with AIP has not been studied. Methods The entire coding and intronic regions of the CFTR gene were examined using next-generation sequencing in 89 AIP patients. Clinical features, including imaging, histology, serology, steroid treatment response and extra-pancreatic involvement, were compared between AIP patients with and without CFTR gene variants. Results A total of 28.1% (25/89) of the AIP patients carried 26 CFTR variants, including nine with I556V, seven with 5T, four with S42F, two with I125T, and one each with R31C, R553X, S895N, and G1069R. The presence of CFTR variants and age was independent predictors of the response to steroid treatment, as shown by multivariate analysis. Conclusions CFTR variants are associated with AIP. Because AIP patients with CFTR variants show slower and reduced steroid treatment responses, different treatments should be considered in AIP patients with CFTR variants.