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Introduction: This study aimed to compare the long-term effects of neoadjuvant therapy and upfront surgery on overall survival (OS) and progression-free survival (PFS) in patients with resectable pancreatic ductal adenocarcinoma (PDAC)., Methods: We retrospectively analyzed 202 patients, including 167 who had upfront surgery and 35 who received neoadjuvant therapy followed by surgery. Surgical outcomes and survival rates were compared using propensity score matching to minimize selection bias., Results: Neoadjuvant therapy showed significantly longer 75% OS (72.7 months vs. 28.3 months, p = 0.032) and PFS (29.6 months vs. 13.2 months, p < 0.001) compared to upfront surgery. Additionally, neoadjuvant therapy demonstrated significant improvements in surgical outcomes, including higher R0 resection rates (74.3% vs. 49.5%, p = 0.034), reduced tumor size (22.0 mm vs. 28.0 mm, p = 0.001), and decreased lymphovascular invasion (20.0% vs. 52.4%, p = 0.001)., Conclusion: Our study demonstrates the potential benefits of neoadjuvant therapy for resectable PDAC. The improved survival rates, delayed disease progression, and enhanced surgical outcomes underscore the potential of neoadjuvant therapy in addressing this aggressive disease. Despite limitations such as the retrospective design and small sample size, these findings support the effectiveness of neoadjuvant therapy in improving treatment outcomes for PDAC patients in real-world settings. Further prospective studies are required to validate these results., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

To identify risk factors and biomarker for early recurrence in patients diagnosed with pancreatic cancer who undergo curative resection. Early recurrence after curative resection of pancreatic cancer is an obstacle to long-term survival. We retrospectively reviewed 162 patients diagnosed with pancreatic cancer who underwent curative resection. Early recurrence was defined as recurrence within 12 months of surgery. We selected S100A2 as a biomarker and investigated its expression using immunohistochemistry. Of the total, 79.6% (n = 129) of patients received adjuvant chemotherapy after surgery and 117 (72.2%) experienced recurrence, of which 73 (45.1%) experience early recurrence. In multivariate analysis, age < 60 years, presence of lymph node metastasis, and no adjuvant chemotherapy were significantly associated with early recurrence (all P < 0.05). The proportion of patients with high S100A2 expression (H-score > 5) was significantly lower in the early recurrence group (41.5% vs. 63.3%, P = 0.020). The cumulative incidence rate of early recurrence was higher in patients with an S100A2 H-score < 5 (41.5% vs. 63.3%, P = 0.012). The median overall survival of patients with higher S100A2 expression was longer than those with lower S100A2 expression (median 30.1 months vs. 24.2 months, P = 0.003). High-risk factors for early recurrence after surgery for pancreatic cancer include young age, lymph node metastasis, and no adjuvant therapy. Neoadjuvant treatment or intensive adjuvant therapy after surgery may improve the prognosis of patients with high-risk signatures. In patients who receive adjuvant therapy, high S100A2 expression is a good predictor., (© 2024. The Author(s).)

Background: Recent studies using single-cell transcriptomic analysis have reported several distinct clusters of neoplastic epithelial cells and cancer-associated fibroblasts in the pancreatic cancer tumor microenvironment. However, their molecular characteristics and biological significance have not been clearly elucidated due to intra- and inter-tumoral heterogeneity., Methods: We performed single-cell RNA sequencing using enriched non-immune cell populations from 17 pancreatic tumor tissues (16 pancreatic cancer and one high-grade dysplasia) and generated paired spatial transcriptomic data from seven patient samples., Results: We identified five distinct functional subclusters of pancreatic cancer cells and six distinct cancer-associated fibroblast subclusters. We deeply profiled their characteristics, and we found that these subclusters successfully deconvoluted most of the features suggested in bulk transcriptome analysis of pancreatic cancer. Among those subclusters, we identified a novel cancer cell subcluster, Ep&#95;VGLL1, showing intermediate characteristics between the extremities of basal-like and classical dichotomy, despite its prognostic value. Molecular features of Ep&#95;VGLL1 suggest its transitional properties between basal-like and classical subtypes, which is supported by spatial transcriptomic data., Conclusions: This integrative analysis not only provides a comprehensive landscape of pancreatic cancer and fibroblast population, but also suggests a novel insight to the dynamic states of pancreatic cancer cells and unveils potential therapeutic targets., (© 2024. The Author(s).)

Context: Considering the absence of methods to find pancreatic cancer early, surveillance of high-risk groups is needed for early diagnosis., Objective: The study aimed to investigate the effect in the incidence of pancreatic cancer and the differences between new-onset diabetes mellitus (NODM) and long-standing DM (LSDM) since NODM group is a representative high-risk group., Methods: The Korean National Health Insurance Service-National Sample Cohort between 2002 and 2013 data were used. Regarding 88 396 people with DM (case group), we conducted a 1:1 propensity score matching to select a matched non-DM population (control group). To investigate the interaction between DM and the time variable distinguishing NODM and LSDM, we performed a multivariate time-dependent Cox regression analysis., Results: The incidence of pancreatic cancer was higher in the DM group compared to the non-DM group (0.52% vs 0.16%; P < .001). The DM group had shown different risk of pancreatic cancer development according to the duration since the DM diagnosis (NODM hazard ratio (HR): 3.81; 95% CI, 2.97-4.88; P < .001; LSDM HR: 1.53; 95% CI, 1.11-2.11; P < .001). When the NODM and the LSDM groups were compared, the risk of pancreatic cancer was higher in the NODM group than in the LSDM group (HR: 1.55; P = .020). In subgroup analysis, NODM group showed that men (HR = 4.42; 95% CI, 3.15-6.19; P < .001) and patients who were in their 50 seconds (HR = 7.54; 95% CI, 3.24-17.56; P < .001) were at a higher risk of developing pancreatic cancer than matched same sex or age control group (non-DM population), respectively., Conclusion: The risk of pancreatic cancer was greater in people with DM than in a non-DM population. Among people with DM, NODM showed a higher risk of pancreatic cancer than LSDM., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This phase I/II study evaluated the safety and efficacy of a new histone deacetylase (HDAC) inhibitor, ivaltinostat, in combination with gemcitabine and erlotinib for advanced pancreatic ductal adenocarcinoma (PDAC). Patients diagnosed with unresectable, histologically confirmed PDAC who had not undergone previous therapy were eligible. Phase I had a 3 + 3 dose escalation design to determine the maximum tolerable dose (MTD) of ivaltinostat (intravenously on days 1, 8 and 15) with gemcitabine (1000 mg/m 2 intravenously on days 1, 8 and 15) and erlotinib (100 mg/day, orally) for a 28-day cycle. In phase II, patients received a six-cycle treatment with the MTD of ivaltinostat determined in phase I. The primary endpoint was the objective response rate (ORR). Secondary endpoints included overall survival (OS), disease control rate (DCR) and progression-free survival (PFS). The MTD of ivaltinostat for the phase II trial was determined to be 250 mg/m 2 . In phase II, 24 patients were enrolled. The median OS and PFS were 8.6 (95% confidence interval [CI]: 5.3-11.2) and 5.3 months (95% CI: 3.7-5.8). Of the 16 patients evaluated for response, ORR and DCR were 25.0% and 93.8% with a median OS/PFS of 10.8 (95% CI: 8.3-16.7)/5.8 (95% CI: 4.6-6.7) months. Correlative studies showed that mutation burden detected by cfDNA and specific blood markers such as TIMP1, pro-MMP10, PECAM1, proMMP-2 and IGFBP1 were associated with clinical outcomes. Although the result of a small study, a combination of ivaltinostat, gemcitabine and erlotinib appeared to be a potential treatment option for advanced PDAC., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background/aims: : Controversy regarding the effectiveness of neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDAC) still exists. Here, we aimed to identify the potential benefits of neoadjuvant therapy followed by surgery for resectable PDAC., Methods: We reviewed radiologically resectable PDAC patients who received resection with curative intent at a tertiary hospital in South Korea between January 2012 and August 2019. A total of 202 patients underwent curative resection for resectable PDAC: 167 underwent surgical resection first during this period, and 35 received neoadjuvant chemotherapy/chemoradiation therapy followed by surgery. Resectable PDAC patients were subdivided, and 1:3 propensity score matching (PSM) was performed to reduce selection bias., Results: Compared with the group that received surgery first, the group that received neoadjuvant treatment followed by surgery had significantly smaller tumors (22.0 mm vs 27.0 mm, p=0.004), a smaller proportion of patients with postoperative pathologic T stage (p=0.026), a smaller proportion of patients with lymphovascular invasion (20.0% vs 40.7%, p=0.022), and a larger proportion of patients with negative resection margins (74.3% vs 51.5%, p=0.049). After PSM, the group that received neoadjuvant therapy had a significantly longer progression-free survival than those in the group that underwent surgery first (29.6 months vs 15.1 months, p=0.002). Overall survival was not significantly different between the two groups after PSM analysis., Conclusions: We observed significantly better surgical outcomes and progression-free survival with the addition of neoadjuvant therapy to the management of resectable PDAC. However, despite PSM, there was still selection bias due to the use of different regimens between the groups receiving surgery first and neoadjuvant therapy. Large homogeneous samples are needed in the future prospective studies.

Background: Approximately 80% of pancreatic ductal adenocarcinoma (PDAC) patients suffer from anorexia, weight loss, and asthenia. Most PDAC patients receive chemotherapy, which often worsens their nutritional status owing to the adverse effects of chemotherapy. Malnutrition of PDAC patients is known to be associated with poor prognosis; therefore, nutritional management during chemotherapy is a key factor influencing the outcome of the treatment. Mobile apps have the potential to provide readily accessible nutritional support for patients with PDAC., Objective: We aimed to evaluate the efficacy of a mobile app-based program, Noom, in patients receiving chemotherapy for PDAC., Methods: We prospectively enrolled 40 patients who were newly diagnosed with unresectable PDAC from a single university-affiliated hospital in South Korea, and randomly assigned them into a Noom user group (n=20) and a non-Noom user group (n=20). The 12-week in-app interventions included meal and physical activity logging as well as nutritional education feedback from dietitians. The non-Noom user group did not receive any nutrition intervention. The primary outcomes were the changes in the nutritional status and quality of life (QoL) from the baseline to 12 weeks. The secondary outcomes included the changes in the skeletal muscle index (SMI) from the baseline to 12 weeks. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and the Patient-Generated Subjective Global Assessment (PG-SGA) were used as paper questionnaires to assess the QoL and nutritional status of the patients. Intention-to-treat and per-protocol analyses were conducted. Regarding the study data collection time points, we assessed the nutritional status and QoL at the baseline (T0), and at 4 (T1), 8 (T2), and 12 (T3) weeks. Abdominal computed tomography (CT) imaging was conducted at the baseline and after 8 weeks for tumor response and SMI evaluation. The skeletal muscle area (cm 2 ) was calculated using routine CT images. The cross-sectional areas (cm 2 ) of the L3 skeletal muscles were analyzed., Results: Between February 2017 and January 2018, 48 patients were assessed for eligibility. Totally 40 patients with pancreatic cancer were included by random allocation. Only 17 participants in the Noom user group and 16 in the non-Noom user group completed all follow-ups. All the study participants showed a significant improvement in the nutritional status according to the PG-SGA score regardless of Noom app usage. Noom users showed statistically significant improvements on the global health status (GHS) and QoL scales compared to non-Noom users, based on the EORTC QLQ (P=.004). The SMI decreased in both groups during chemotherapy (Noom users, 49.08±12.27 cm 2 /m 2 to 46.08±10.55 cm 2 /m 2 ; non-Noom users, 50.60±9.05 cm 2 /m 2 to 42.97±8.12 cm 2 /m 2 ). The decrement was higher in the non-Noom user group than in the Noom user group, but it was not statistically significant (-13.96% vs. -3.27%; P=.11)., Conclusions: This pilot study demonstrates that a mobile app-based approach is beneficial for nutritional and psychological support for PDAC patients receiving chemotherapy., Trial Registration: ClinicalTrials.gov NCT04109495; https://clinicaltrials.gov/ct2/show/NCT04109495., (©Jiyoung Keum, Moon Jae Chung, Youngin Kim, Hyunyoung Ko, Min Je Sung, Jung Hyun Jo, Jeong Youp Park, Seungmin Bang, Seung Woo Park, Si Young Song, Hee Seung Lee. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 31.08.2021.)

Background: The establishment of patient-derived models for pancreatic ductal adenocarcinoma (PDAC) using conventional methods has been fraught with low success rate, mainly because of the small number of tumour cells and dense fibrotic stroma. Here, we sought to establish patient-derived model of PDAC and perform genetic analysis with responses to anticancer drug by using the conditionally reprogrammed cell (CRC) methodology., Methods: We performed in vitro and in vivo tumourigenicity assays and analysed histological characteristics by immunostaining. We investigated genetic profiles including mutation patterns and copy number variations using targeted deep sequencing and copy-number analyses. We assessed the responses of cultured CRCs to the available clinical anticancer drugs based on patient responsiveness., Findings: We established a total of 28 CRCs from patients. Of the 28 samples, 27 showed KRAS mutations in codon 12/13 or codon 61. We found that somatic mutations were shared in the primary-CRC pairs and shared mutations included key oncogenic mutations such as KRAS (9 pairs), TP53 (8 pairs), and SMAD4 (3 pairs). Overall, CRCs preserved the genetic characteristics of primary tumours with high concordance, with additional confirmation of low-AF NPM1 mutation in CRC (35 shared mutations out of 36 total, concordance rate=97.2%). CRCs of the responder group were more sensitive to anticancer agents than those of the non-responder group (P < 0.001)., Interpretation: These results show that a pancreatic cancer cell line model can be efficiently established using the CRC methodology, to better support a personalized therapeutic approach for pancreatic cancer patients., Funding: 2014R1A1A1006272, HI19C0642-060019, 2019R1A2C2008050, 2020R1A2C209958611, and 2020M3E5E204028211., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aim: We aimed to measure the natural killer (NK) cell activity and pro-inflammatory cytokine levels in the peripheral blood of pancreatic cancer patients and investigate the correlation of NK cell activity and cytokines with cancer status and clinical outcomes., Methods: We prospectively enrolled patients who were pathologically diagnosed with pancreatic ductal adenocarcinoma (PDAC) between 2016 and 2017 at a tertiary hospital in Seoul, South Korea. As a control group, healthy participants were enrolled by mobile application recruitment., Results: A total of 203 patients were enrolled for this study (PDAC, n = 102; healthy participants, n = 101). The peripheral blood NK cell activity of PDAC patients was significantly lower than that of healthy participants (median level, 95 pg/mL vs 2000 pg/mL, P < 0.001), and decreased NK cell activity was correlated to poor clinical outcome in terms of response to chemotherapy, tumor progression, and survival. The pro-inflammatory cytokine interleukin-6 had a strong negative correlation with NK cell activity., Conclusions: In pancreatic cancer patients, NK cell activity decreased as cancer progressed, and decreased NK cell activity was associated with poor clinical outcomes., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: The association of Lewis antigen phenotype with survival of patients with pancreatic ductal adenocarcinoma was investigated., Methods: A total of 1187 patients diagnosed with pancreatic ductal adenocarcinoma were evaluated in a prospective cohort. Patients were classified into 3 different groups according to Lewis antigen phenotype: Lewis antigen (1) A positive [Le(a+b-)], (2) B positive [Le(a-b+)], and (3) negative [Le(a-b-)]. Risk of mortality was analyzed with Cox regression after adjusting for other predictors., Results: The risk of mortality increased in the order of Le(a+b-), Le(a-b+), and Le(a-b-) [reference; hazard ratio (HR), 1.27; 95% confidence interval (CI)], 1.03-1.57; P = 0.02; and HR, 1.65; 95% CI, 1.31-2.09; P < 0.001] after adjusting for other predictors. Among patients with serum carbohydrate antigen (CA) 19-9 lower than 37 U/mL, the association seemed more apparent (reference; HR, 1.50; 95% CI, 0.77-2.29; P = 0.22; and HR, 2.10; 95% CI, 1.10-4.02; P < 0.02)., Conclusions: The risk of mortality increased in the order of Le(a+b-), Le(a-b+), and Le(a-b-). The difference in prognosis according to the Lewis antigen phenotype was more pronounced in the low CA 19-9 group, which suggests that the Lewis antigen phenotype works as a biomarker predicting the prognosis of patients with pancreatic cancer with undetectable CA 19-9 level.

Background: Venous invasion is not included in the pancreatic ductal adenocarcinoma (PDAC) staging, and its correlation with prognosis remains unclear. We evaluated the prognostic impact of radiographic portal/superior mesenteric vein (PV/SMV) invasion, and its possibility of complementing T staging., Methods: We identified patients with non-metastatic PDAC using our institutional cohort, and divided them according to PV/SMV invasion at imaging, defined as >180-degree tumor-vessel interface or contour deformity. We conducted Cox proportional hazard regression, and compared survival in the original and 1:1 propensity score matched datasets., Results: We identified 454 patients [PV/SMV(+): 172; PV/SMV(-): 282]. In the multivariate analysis, PV/SMV invasion, age (≥70 years), performance status, tumor size (2-4, >4 cm), lymph nodes >4, and arterial invasion was correlated with prognosis. The PV/SMV(+) group had a shorter overall survival (OS) than the PV/SMV(-) group in the original (14.4 vs. 20.9 months; P < 0.001) and matched datasets (14.3 vs. 17.2 months; P = 0.009). Among patients without arterial invasion (cT1-cT3), the PV/SMV(+) group had a shorter OS (15.9 vs. 21.2 months; P = 0.002). Moreover, their OS did not differ from that of patients with arterial invasion (cT4) (15.9 vs. 14.4 months; P = 0.907). Patients with vessel (artery/vein) invasion had a shorter OS than those without vessel invasion (14.5 vs. 21.2 months; P < 0.001)., Conclusions: Radiographic PV/SMV invasion in non-metastatic PDAC was correlated with a poor prognosis. It could identify a group with shorter OS among patients without arterial invasion (cT1-cT3). It is suggested that inclusion of PV/SMV invasion in clinical T4 criteria should be considered., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: FOLFIRINOX is the standard therapy in patients with unresectable pancreatic cancer (PC). However, FOLFIRINOX frequently induces febrile neutropenia (FN) and neutropenia. The purpose of this study was to explore risk factors for FN and grade 4 neutropenia (NP G4) in patients receiving FOLFIRINOX for PC., Methods: We collected data on 106 patients with PC treated with first-line FOLFIRINOX between 2015 and 2017 using the Pancreatic Cancer Cohort Registry of Severance Hospital in Seoul, Korea., Results: Multivariate logistic regression analysis showed that female (OR, 3.24; P = 0.023), Eastern Cooperative Oncology Group performance status (OR, 3.70; P = 0.024), overweight (OR, 4.25; P = 0.022), and initial biliary stent insertion (OR, 4.22; P = 0.008) were significantly related to a high risk of FN. Time-dependent bias was reduced using Cox regression analysis, which revealed that female (OR, 2.29; P = 0.041), overweight (OR, 2.67; P = 0.022), and initial biliary stent insertion (OR, 2.59; P = 0.016) were statistically significant predictors. Regarding NP G4, female sex (OR, 2.90; P = 0.016) and overweight (OR, 4.07; P = 0.033) were identified as risk factors in multivariate analysis; however, in Cox regression analysis, tumor in the head of the pancreas (OR, 1.96; P = 0.027) and hemoglobin (g/dL < 12) (OR, 1.87; P = 0.049) were also identified as risk factors., Conclusion: Female sex, overweight, and initial biliary stent insertion were independent risk factors for the occurrence of FN in patients with unresectable PC treated with FOLFIRINOX.

Background and Aim: The aim of this study is to identify the predictive factors for futile surgery in patients with radiologically resectable or borderline resectable pancreatic cancer and to develop a prediction model., Methods: This retrospective study included patients who underwent pancreatic surgery for pancreatic cancer between 2006 and 2017. To identify independent risk factors for futile surgery, logistic regression and random forest analyses were performed in the training cohort, based on which a nomogram was established. The predictive accuracy and discriminative ability of the nomogram were validated in the validation cohort., Results: Of 389 patients who underwent pancreatic surgery, the laparotomy was futile in 40 patients (10.3%). In the training cohort, the univariate and multivariate logistic regression analyses revealed that serum carbohydrate antigen 19-9 level of ≥ 150 U/mL (P = 0.003), the presence of suspicious lymph node (P = 0.013), and more extensive peripancreatic tumor infiltration (P < 0.001) were independent predictive factors for futile surgery. The bootstrap-corrected concordance index of the nomogram was high in the training cohort, 0.826 with a 95% confidence interval of 0.745-0.907. This model also showed a good discriminative performance in the validation cohort, with a concordance index of 0.831., Conclusions: We established and validated a novel nomogram that predicts the risk of futile surgery due to occult distant metastasis in patients with radiologically resectable or borderline resectable pancreatic cancer., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background/Aims: The benefit of second-line chemotherapy (SL) after failed first-line chemotherapy (FL) in patients with advanced pancreatic cancer has not yet been established. We evaluated the clinical characteristics affecting the benefits of SL compared to best supportive care (BSC), identified the prognostic factors, and ultimately devised a model of clinical parameters to assist in making decision between SL and BSC after the failure of gemcitabine-based FL. Methods: The records of patients who received gemcitabinebased FL for advanced pancreatic cancer at Yonsei University Hospital between January 2010 and December 2015 were retrospectively reviewed. Significant clinical parameters were assessed for their potential as predictive factors. Results: SL patients received a longer duration of FL compared with BSC patients with median duration being 16.0 weeks (range, 8.0 to 26.0 weeks) and 8.0 weeks (range, 4.0 to 16.0 weeks), respectively (p<0.001). When the SL group was stratified by their modified overall survival (mOS) (longer and shorter than 6 months), we found significant differences for several clinical factors, namely, metastasis to the peritoneum (p<0.001), number of metastases (p<0.001), thrombotic events (p=0.003), and level of carbohydrate antigen 19-9 (CA19- 9; p=0.011). In multivariate analysis, more than one site of metastasis, occurrence of thrombotic event during FL, and a CA19-9 level above 90 U/mL were significant independent prognostic factors for mOS in the SL group (p<0.05). When an attempt was made to devise a prognostic nomogram, Harrell's C-index of the final prognosis prediction model was 0.62. Conclusions: SL may be beneficial for patients without peritoneal metastasis or thrombotic events who have a single metastasis and a level of CA19-9 less than 90 U/mL. This prognostic nomogram can be used to predict mOS before the administration of SL after the failure of gemcitabinebased FL.

Recent studies have identified the mutational landscape of pancreatic cancer and suggested tumor-specific subtypes. However, the major hurdle against personalized treatment is the difficulty to obtain sufficient cancer tissues from most inoperable cases. We investigated whether patient-derived conditionally reprogrammed cells (CRCs) can be constructed using a small piece of tumor tissue using endoscopic ultrasound (EUS)-guided fine needle biopsy (FNB). Thirty patients with pancreatic solid mass (mean size, 34.6 mm) were enrolled prospectively. Among 22 patients who were diagnosed with pancreatic ductal adenocarcinoma, we established patient-derived pancreatic cancer cell lines from eight patients (36.4%). Immunofluorescence colony staining for CRCs showed that the cytoplasm of cancer cells was clearly stained with anti-cytokeratin 19 monoclonal antibody. In the soft agar colony formation assay, CRCs formed colonies compared with the negative control by day 15. In vivo, implanted CRCs showed tumor engraftment and hematoxylin and eosin staining showed pancreatic cancer ductal structure. All established CRCs showed a KRAS mutation. In conclusion, we established patient-derived pancreatic cancer cell lines with a small tumor tissue obtained by EUS-FNB. With in vitro drug sensitivity and genomic studies, established patient-derived cell lines can be used in identification of new targets for diagnosis and treatment of pancreatic cancer., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: Neuroendocrine differentiation in pancreatic ductal adenocarcinoma (PDAC) is known, but its clinical significance still remains uncertain. The clinical role of chromogranin A (CgA), a marker of neuroendocrine tumor, was evaluated in patients with PDAC., Methods: We retrospectively analyzed 350 patients with PDAC. All patients had plasma CgA levels at diagnosis. Patients were classified as normal and high CgA groups according to the upper limit of plasma CgA., Results: There were 202 patients (57.7%) in the normal CgA group and 148 patients (42.3%) in the high CgA group. High CgA group presented higher rate of metastatic disease (61.5% vs 45.0%; P = 0.002) and shorter median overall survival (OS) (8.2 vs 11.6 months; P = 0.015). Upon grouping patients based on clinical stages, OS was significantly different between the CgA groups only in metastatic disease (6.6 vs 7.2 months; P = 0.022). Multivariate analysis showed no association between high CgA and OS (hazard ratio, 1.22; 95% confidence interval, 0.97-1.54; P = 0.090). However, high CgA was associated with poor OS in patients with metastatic disease (hazard ratio, 1.37; 95% confidence interval, 1.01-1.87; P = 0.047)., Conclusions: High CgA levels may predict poor prognosis in patients with pancreatic cancer, especially during metastatic stages.

Objectives: Although the significance of skeletal muscle mass has been investigated in pancreatic cancer, there are no reports regarding the impact of skeletal muscle mass on prognosis in patients who have undergone second-line chemotherapy. We aimed to identify prognostic factors in patients with advanced pancreatic cancer treated with second-line FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin). Methods: We retrospectively reviewed the data of 57 pancreatic cancer patients treated with second-line FOLFIRINOX. Age, sex, body mass index, Eastern Cooperative Oncology Group (ECOG) performance status, carbohydrate antigen 19-9 levels, skeletal muscle area, skeletal muscle index (SMI), progression free survival (PFS), and overall survival (OS) were analyzed. Results: The median age of the 57 patients (male, 56.1%) was 60.4 years (38-78). Median PFS and OS were 2.6 and 6.6 months. On Kaplan-Meier curves, high SMI was associated with prolonged OS and PFS ( P value = 0.003 and 0.015). In multivariate analysis, baseline SMI was significant independent prognostic factor in patients treated with second-line FOLFIRINOX. Conclusion: Baseline SMI has an impact on prognosis in patients who undergoing second-line chemotherapy for pancreatic cancer. Skeletal muscle mass may warrant consideration as a predictive factor with which to identify candidates for second-line chemotherapy for advanced pancreatic cancer.

Background: We developed a nomogram for predicting survival of patients with locally advanced pancreatic cancer (LAPC) after concurrent chemoradiotherapy (CRT) using 18 F-flurodeoxyglucose-positron emission tomography (FDG-PET) parameters and CA 19-9 levels., Methods: Based on 426 patients with LAPC who received concurrent CRT between 2004 and 2015, we investigated significant prognostic factors for survival to build a nomogram, including the maximum standardized uptake value (SUV max ) and CA 19-9 levels. Predictive accuracy and discriminative ability were then measured., Results: Median progression-free survival and overall survival (OS) were 9.4 and 15.4 months, respectively, at a median 15-month follow-up. High-dose radiation (EQD2, ≥61 Gy), initial SUV max <3.5 and CA 19-9 ≤400 U/mL, and surgical resection after CRT were significantly related to prolonged OS by multivariate analysis (p < 0.05). A nomogram model for OS was established and showed good calibration and acceptable discrimination (c-index 0.656). Using the nomogram, 3 different prognosis groups could be identified with a median OS of 25, 15, and 11 months (p < 0.001)., Conclusion: A nomogram was developed with high-dose radiation (EQD2, ≥61 Gy), initial SUV max <3.5, CA 19-9 ≤400 U/mL, and surgical resection after CRT for patients with LAPC. This will help in clinical decision-making and in selecting patients for CRT., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Carbohydrate antigen (CA) 19-9 is the only diagnostic marker used in pancreatic cancer despite its limitations. Here, we aimed to identify the diagnostic role of CEMIP (also called KIAA1199) combined with CA 19-9 in patients with pancreatic cancer. A retrospective analysis of prospectively collected patient samples was performed to determine the benefit of diagnostic markers in the diagnosis of pancreatic cancer. We investigated CEMIP and CA 19-9 levels in 324 patients with pancreatic cancer and 49 normal controls using serum enzyme-linked immunosorbent assay. Median CA 19-9 and CEMIP levels were 410.5 U/ml (40.8-3342.5) and 0.67 ng/ml (0.40-1.08), respectively, in patients with pancreatic cancer. The AUROC for CA 19-9 and CEMIP were 0.847 (95% confidence interval [CI]: 0.806-0.888) and 0.760 (95% CI: 0.689-0.831), respectively. Combination of CA 19-9 with CEMIP showed markedly improved AUROC over CA 19-9 alone in pancreatic cancer diagnosis (0.94 vs. 0.89; P < 0.0001). CEMIP showed a diagnostic yield of 86.1% (68/79) in CA 19-9 negative pancreatic cancer. Combined use with CEMIP showed significantly improved diagnostic value compared with CA 19-9 alone in pancreatic cancer. Especially, CEMIP may be a complementary marker in pancreatic cancer patients with normal CA 19-9 levels.

Pancreatic cancer has poor prognosis because of its rapid progression and treatment resistance. Based on the results of the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), a combination regimen of gemcitabine with nab-paclitaxel is currently used as standard therapy for the treatment of metastatic pancreatic cancer. However, because studies in Asian populations are lacking, we investigated the treatment efficacy and safety of this combination therapy in Korean population. Patients with metastatic pancreatic cancer (n=81) treated with gemcitabine and nab-paclitaxel (1,000 and 125 mg/m 2 , respectively) as the first-line chemotherapy from January 2016 were identified using the Severance Hospital Pancreatic Cancer Cohort Registry. Treatment efficacy and treatment-related adverse events (AEs) were analyzed. The median follow-up period was 10.7 months (range, 1.5-23.3 months). Median overall survival, progression-free survival, and objective response rates were 12.1 months (95% confidence interval [CI], 10.7-not estimable), 8.4 months (95% CI, 5.0-11.8), and 46.9%, respectively. The incidence of grade ≥3 neurotoxicity and neutropenia were 18.5% and 46.9%, respectively. Febrile neutropenia and grade ≥3 gastrointestinal AEs occurred in 13 (16.0%) and 16 (19.8%) patients, respectively. Dose reductions because of AEs were required in 60.5% of patients. The combination of gemcitabine with nab-paclitaxel is an effective anti-cancer regimen in Korean population of patients with metastatic pancreatic adenocarcinoma. However, careful monitoring and management are required because of occurrence of treatment-related AEs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background/aims: We aimed to investigate the incidence of second primary pancreatic cancer (PC) after colorectal cancer (CRC) and to identify risk factors associated with subsequent PC., Methods: The observed incidence of a subsequent PC in patients with CRC was standardized using a population with CRC from the Korean Central Cancer Registry (KCCR). The expected incidence rate of PC was obtained by assuming that the select group experienced the same cancer incidence as the corresponding general population in the KCCR., Results: The registry included 4,822 patients with CRC aged 45 to 74 years, representing 16,725.1 person-years of follow-up. Thirteen patients (0.3%) were diagnosed with a subsequent PC, and the overall age-adjusted incidence of second primary PC was 269.6 per 100,000 cases. In contrast, the overall incidence of primary PC in the general population was 18.68 per 100,000 individuals. The standardized incidence ratio of subsequent PC was 14.44, which was significantly higher in patients with CRC than in the general population. Sex, diabetes mellitus, smoking, body mass index, and a history of receiving chemotherapy as a treatment for CRC did not increase the risk of subsequent development of PC., Conclusions: The risk of a second primary PC was higher in patients with CRC. Further studies are needed to identify the risk factors and generate a screening strategy for cancer survivors.

Background and Aims: A biliary self-expandable metal stent (SEMS) is commonly used to relieve malignant biliary obstruction. The aim of this study was to compare the efficacy of a conventional uncovered SEMS with that of a newly developed uncovered double bare metal stent in reducing the risk of stent occlusion caused by tumor ingrowth., Patients and Methods: We performed a prospective, open-labeled, randomized trial in 71 patients at Severance Hospital, Yonsei University College of Medicine from June 2013 to June 2014. Patients with inoperable malignant biliary obstruction were included and randomized to receive an uncovered single bare metal stent (SBSs; S&G Biotech Inc.), an uncovered single bare metal stent (SBSt; Taewoong Medical), or an uncovered double bare metal stent (DBS; S&G Biotech Inc.)., Results: The mean age was 66.6 years (range, 35-83), and 42 (59.2%) were male. The mean duration of stent patency was 212 days (±152) in the DBS group (n = 24) compared with 124 days (±98) in the SBSs group (n = 23; P = 0.022 for noninferiority) and 116 days (±79) in the SBSt group (n = 24; P = 0.010 for noninferiority). There were no differences in the incidences of early and delayed complications or migration., Conclusions: The newly developed DBS is noninferior to the conventional uncovered SEMSs on duration of stent patency and tumor ingrowth occurred less frequently in the DBS group. This might decrease the need for reintervention and offer a better quality of life. The trial is registered with Clinicaltrials.gov no: NCT01869894.

Purpose: Several studies reported the increased risk of second primary pancreatic ductal adenocarcinoma (2nd PDAC) in cancer survivors. However, data on the characteristics of 2nd PDAC are insufficient., Methods: This retrospective cohort study included 1759 patients with PDAC. They were classified as having 2nd PDAC or first primary PDAC (1st PDAC) according to a prior diagnosed cancer of different origin, at least 6 months before PDAC diagnosis., Results: There were 110 patients (6.4%) with 2nd PDAC and 1606 (93.6%) patients with 1st PDAC. Patients with 2nd PDAC presented with older age (66.5 vs. 62.2 years, p < 0.001) and higher rate of resectability (26.4% vs. 15.9%, p = 0.004) at diagnosis than those with 1st PDAC. Multivariate analysis without considering resectable status showed that 2nd PDAC (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.56-0.94, p = 0.016) was associated with better overall survival. After adjusting for resectable status, however, 2nd PDAC (HR 0.85, 95% CI 0.66-1.09, p = 0.198) was no longer associated with overall survival. When subgroups were separately analyzed according to initial treatment modality, the effectiveness of surgery and chemotherapy were similar between 2nd and 1st PDAC (33.1 vs. 28.5 months, p = 0.860 and 10.8 vs. 10.7 months, p = 0.952)., Conclusions: The proportion of resectable cases was significantly higher in 2nd PDAC. When surgery with curative aim was possible, the overall survival was increased even in patients with 2nd PDAC. These results suggest the importance of screening for second primary cancer in cancer survivors.

Nutritional status affects the prognosis of various tumors. The prognostic nutritional index (PNI) is the known predictor of postoperative outcome in resectable pancreatic cancer patients. This study aimed to validate the prognostic value of PNI in all stages of pancreatic cancer. We retrospectively reviewed 499 patients with pancreatic cancer who were diagnosed at Severance Hospital between January 2006 and December 2011. The PNI value was calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (/mm 3 ) at initial diagnosis. The median patient age was 62 yr, and 289 were men. The study group comprised resectable disease (n = 121), locally advanced disease (n = 118), and metastatic disease (n = 260). Univariate and multivariate analysis revealed that PNI ≤ 49.5 at initial diagnosis, together with performance status, platelet count, and clinical stage, was significantly associated with overall survival (hazard ratio, 1.562; all P < 0.05). Patients with PNI ≤ 49.5 (n = 208) had shorter median overall survival compared to patients with high PNI (9.8 vs. 14.2 mo; log rank, P < 0.001). In clinical stage subgroup analysis, initial PNI ≤49.5 independently predicted shorter overall survival, especially in resectable and metastatic disease (P = 0.041, P = 0.002, respectively).

Background: This phase III trial compared the efficacy and safety of gemcitabine plus capecitabine (GemCap) versus single-agent gemcitabine (Gem) in advanced pancreatic cancer as first-line chemotherapy., Methods: A total of 214 advanced pancreatic cancer patients were enrolled from 16 hospitals in South Korea between 2007 and 2011. Patients were randomly assigned to receive GemCap (oral capecitabine 1660 mg/m plus Gem 1000 mg/m by 30-minute intravenous infusion weekly for 3 weeks followed by a 1-week break every 4 weeks) or Gem (by 30-minute intravenous infusion weekly for 3 weeks every 4 weeks)., Results: Median overall survival (OS) time, the primary end point, was 10.3 and 7.5 months in the GemCap and Gem arms, respectively (P = 0.06). Progression-free survival was 6.2 and 5.3 months in the GemCap and Gem arms, respectively (P = 0.08). GemCap significantly improved overall response rate compared with Gem alone (43.7% vs 17.6%; P = 0.001). Overall frequency of grade 3 or 4 toxicities was similar in each group. Neutropenia was the most frequent grade 3 or 4 toxicity in both groups., Conclusion: GemCap failed to improve OS at a statistically significant level compared to Gem treatment. This study showed a trend toward improved OS compared to Gem alone. GemCap and Gem both exhibited similar safety profiles., Competing Interests: The authors have no conflicts of interest to disclose.

Purpose: Erlotinib-gemcitabine combined chemotherapy is considered as the standard treatment for unresectable pancreatic cancer. This study aimed to determine the clinical factors associated with response to this treatment., Materials and Methods: This retrospective study included 180 patients with unresectable pancreatic cancer who received ≥2 cycles of gemcitabine-erlotinib combination therapy as first-line palliative chemotherapy between 2006 and 2014. "Long-term response" was defined as tumor stabilization after >6 chemotherapy cycles., Results: The median progression-free survival (PFS) and overall survival (OS) were 3.9 and 8.1 months, respectively. On univariate analysis, liver metastasis (p=0.023) was negatively correlated with long-term response. Locally advanced stage (p=0.017), a history of statin treatment (p=0.01), and carcinoembryonic antigen levels <4.5 (p=0.029) had a favorable effect on long-term response. On multivariate analysis, a history of statin treatment was the only independent favorable factor for long-term response (p=0.017). Prognostic factors for OS and PFS were significantly correlated with liver metastasis (p=0.031 and 0.013, respectively). A history of statin treatment was also significantly associated with OS after adjusting for all potential confounders (hazard ratio, 0.48; 95% confidence interval, 0.26-0.92; p=0.026)., Conclusion: These results suggest that statins have a favorable effect on "long-term response" to gemcitabine-erlotinib chemotherapy in unresectable pancreatic cancer patients. Statins may have a chemoadjuvant role in stabilizing long-term tumor growth.

Pancreatic cancer remains one of the most lethal cancers. These patients often have multiple symptoms, and integrated supportive care is critical in helping them remain well for as long as possible. Fluorouracil-based chemotherapy is known to improve overall survival (OS) by approximately 3 months, compared to the best supportive care alone. A 1997 study comparing gemcitabine and fluorouracil treatment of advanced pancreatic cancer patients showed an improvement in OS of 1 month in patients receiving gemcitabine. Over the next 10 years, multiple randomized studies compared singleagent gemcitabine with combination chemotherapy and showed no effective survival improvement. However, the addition of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, was associated with a significant improvement in OS of approximately 2 weeks. However, adoption of this regimen has not been widespread because of its limited effect and added toxicity. Two clinical trials have recently prolonged OS in advanced pancreatic cancer patients by almost 1 year. The first compared FOLFIRINOX with gemcitabine alone, and was associated with a significant improvement in median survival. The second compared gemcitabine and nabpaclitaxel with gemcitabine alone, and was associated with improvements in OS. At present, these regimens are considered standard treatment for patients with good performance statuses.

Statins are cholesterol-lowering medications that are associated with a number of signaling pathways involved in carcinogenesis. Recent observational studies raised the possibility that the use of statins may reduce overall mortality in various types of cancer. We investigated whether statins used after pancreatic cancer diagnosis are associated with longer survival in pancreatic cancer patients.We retrospectively analyzed data from 1761 patients newly diagnosed with pancreatic adenocarcinoma between January 1, 2006, and December 31, 2014. We used the time-dependent Cox proportional hazards regression model to estimate mortality among pancreatic cancer patients according to statin use.Among the 1761 pancreatic cancer patients, 118 patients had used statins. During the study period, 1176 patients (66.7%) died. After adjusting for age, sex, location of cancer, cancer stage, diabetes mellitus, hypertension, dyslipidemia, smoking, alcohol use, body mass index, and CA 19-9, statin use was associated with a lower risk of cancer death (hazard ratio [HR], 0.780; 95% confidence interval [CI], 0.617-0.986), especially among simvastatin users (HR, 0.554; 95% CI, 0.312-0.982) and atorvastatin users (HR, 0.636; 95% CI, 0.437-0.927). Subgroup analysis showed that overall survival was statistically significantly longer in patients with nonmetastatic pancreatic cancer (log-rank P = 0.024).We found that the use of simvastatin and atorvastatin after cancer diagnosis is associated with longer survival in patients with nonmetastatic pancreatic adenocarcinoma.

Backgrounds: The effect of metformin on survival in patients with pancreatic cancer is controversial., Aims: To investigate the beneficial effect of metformin in pancreatic cancer patients., Methods: We retrospectively analyzed patients with pancreatic cancer and pre-existing diabetes mellitus type 2 who were treated at Severance Hospital (Seoul, South Korea) between May 2005 and December 2013., Results: Among 237 enrolled patients, 117 patients (49.4%) were exposed to metformin. The median overall survival was 13.7 months for the metformin group versus 8.9 months for the non-metformin group (P=0.001) In univariate analysis, metformin exposure, low serum carbohydrate antigen 19-9 levels (<1000 U/mL), small tumor size (≤20 mm), no tail involvement, good performance status (ECOG 0 vs. 1 or 2), and resectable cancer stage were associated with favorable survival outcomes (all P<0.05). In multivariate analysis, in addition to low serum carbohydrate antigen 19-9 levels (<1000 U/mL) and resectable cancer stage, metformin exposure was significantly associated with longer survival with a hazard ratio of 0.61 (P=0.001). Additionally, the cumulative duration of metformin use was significantly correlated with a favorable survival outcome., Conclusion: Our findings supported that metformin exposure was associated with survival benefits in patients with pancreatic cancer and pre-existing type 2 diabetes mellitus, especially among those with an advanced cancer stage., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background/aims: Concurrent chemoradiotherapy (CCRT) is considered the treatment option for locally advanced pancreatic cancer, but accompanying gastrointestinal toxicities are the most common complication. With the introduction of three-dimensional conformal radiotherapy (3-D CRT) and intensity-modulated radiotherapy (IMRT), CCRT-related adverse events are expected to diminish. Here, we evaluated the benefits of radiation modalities by comparing gastrointestinal toxicities between 3-D CRT and IMRT., Methods: Patients who received CCRT between July 2010 and June 2012 in Severance Hospital, Yonsei University College of Medicine, were enrolled prospectively. The patients underwent upper endoscopy before and 1 month after CCRT., Results: A total of 84 patients were enrolled during the study period. The radiotherapy modalities delivered included 3D-CRT (n=40) and IMRT (n=44). The median follow-up period from the start of CCRT was 10.6 months (range, 3.8 to 29.9 months). The symptoms of dyspepsia, nausea/vomiting, and diarrhea did not differ between the groups. Upper endoscopy revealed significantly more gastroduodenal ulcers in the 3-D CRT group (p=0.003). The modality of radiotherapy (3D-CRT; odds ratio [OR], 11.67; p=0.011) and tumor location (body of pancreas; OR, 11.06; p=0.009) were risk factors for gastrointestinal toxicities., Conclusions: IMRT is associated with significantly fewer gastroduodenal injuries among patients treated with CCRT for pancreatic cancer.

An association between obesity and unfavorable outcomes for various types of malignancy has been established. Nevertheless, the impact of visceral obesity (VO) on outcomes in pancreatic cancer is still unknown and controversial. The aim of this study was to uncover an association between VO and pancreatic cancer outcomes. We retrospectively reviewed 499 patients with pancreatic cancer who were diagnosed and treated in Severance Hospital from January 2006 to December 2011. Compared to the low-VO group (n = 260), the high-VO group (n = 239) was mostly male (68.2% vs. 31.8%, P < 0.001) and was more likely to have current smoking status (29.7% vs. 17.7%, P < 0.001), current alcohol intake status (52.3% vs. 26.4%, P < 0.001) and diabetes mellitus (54.4% vs. 31.9%, P = 0.028). The progression free survival (PFS) and overall survival (OS) were found to be significantly shorter by the Kaplan-Meier method in the high-VO group than in the low-VO group (PFS; P = 0.044, OS: P = 0.013). In addition, the higher percentage of visceral fat was correlated with more lymph node metastasis and shorter OS (P = 0.011 and P = 0.017, respectively). In patients with pancreatic cancer, VO at the time of diagnosis is associated with negative outcomes, such as shorter PFS and OS.

Chronic inflammation has been known to be a risk for many kinds of cancers, including pancreatic and biliary tract cancer. Recently, inflammatory process has emerged as a key mediator of cancer development and progression. Many efforts with experimental results have been given to identify the underlying mechanisms that contribute to inflammation-induced tumorigenesis. Diverse inflammatory pathways have been investigated and inhibitors for inflammation-related signaling pathways have been developed for cancer treatment. This review will summarize recent outcomes about this distinctive process in pancreatic and biliary tract cancer. Taking this evidence into consideration, modulation of inflammatory process will provide useful options for pancreatic and biliary tract cancer treatment.

Objectives: Inoperable pancreatic ductal adenocarcinoma is known to have an extremely poor prognosis. Although rare, there are some patients who have unexpected long-term survival, but the reason is not yet clear., Methods: A total of 482 inoperable pancreatic ductal adenocarcinoma of 1602 patients diagnosed at Severance Hospital between 2002 and 2009 were evaluated, who were selected statistically with a retrospective cohort study. They were divided into locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC). Short-term survivors (SS group) were defined as patients who survived less than 9 months with LAPC and 6 months with MPC. Patients who survived 3 times longer than the SS group were classified as long-term survivors (LS group). Predictive factors of long-survival were identified by comparing the 2 groups, and effects of these factors on survival were investigated statistically., Results: In multivariate analysis, better performance status and lower CA19-9 were related to overall survival in LAPC. In MPC, younger age, better performance status, peritoneal metastasis, higher serum albumin, lower CA19-9, and CA19-9 variation were related to overall survival., Conclusions: These parameters related to long-term survivors of advanced pancreatic cancer can be useful for the expectation of survival. In the near future, conjunction of these clinical factors and novel molecular biologic characteristics of individual patients can be used for the personalized therapy.

Second-line chemotherapy in patients with gemcitabine-refractory advanced pancreatic cancer has shown disappointing survival outcomes due to rapid disease progression and performance deterioration. The aim of this phase II trial was to evaluate the efficacy and safety of adoptive immunotherapy using ex vivo-expanded, cytokine-induced killer (CIK) cells in gemcitabine-refractory advanced pancreatic cancer. Patients with advanced pancreatic cancer who showed disease progression during gemcitabine-based chemotherapy were enrolled in this study. For generation of CIK cells, peripheral blood samples were collected from each patient and cultured with anti-CD3 monoclonal antibody and IL-2. Patients received CIK cells intravenously 10 times, every week for 5 weeks and then every other week for 10 weeks. Twenty patients were enrolled between November 2009 and September 2010. The disease control rate was 25 % (4/16 patients). The median progression-free survival (PFS) was 11.0 weeks (95 % CI 8.8-13.2), and the median overall survival (OS) was 26.6 weeks (95 % CI 8.6-44.6). Grade 3 toxicities included general weakness in two patients and thrombocytopenia in one patient. Grade 4 hematologic or non-hematologic toxicity was not observed. Patients showed improvement in pancreatic pain, gastrointestinal distress, jaundice, body image alterations, altered bowel habits, health satisfaction, and sexuality when assessing quality of life (QoL). Adoptive immunotherapy using CIK cells showed comparable PFS and OS to survival data of previous trials that assessed conventional chemotherapies while maintaining tolerability and showing encouraging results in terms of patient QoL in gemcitabine-refractory advanced pancreatic cancer (clinicalTrials.gov number NCT00965718).

Background/aims: Among borderline resectable pancreatic cancer (BRPC), group B BRPC patients have findings that are suggestive but not diagnostic of metastasis. In this study, we attempted to validate whether group B could truly be categorized as a borderline resectable group., Methods: We placed the BRPC patients into group A or group B. The survival outcomes were compared between the groups., Results: A total of 53 patients with pancreatic adenocarcinoma was classified as either group A or B borderline resectable. In group A, 23 (60.5%) of 38 patients underwent pancreatectomy after concurrent chemoradiotherapy or chemotherapy, but in group B, only five (33.3%) of 15 patients underwent pancreatectomy, mainly because of the progression of suspected distant metastasis. There was a significant difference in overall survival (OS) between group A and B patients (median OS, 21.2 months vs 10.2 months, respectively; p=0.007). Of the patients who underwent pancreatectomy, group B had a higher recurrence rate compared to group A (recurrence rate: 11 of 23 patients [47.8%] vs five of five patients [100%], respectively; p=0.033)., Conclusions: This report is the first to validate the definition of BPRC. Group B had much worse outcomes, and whether group B BRPC can be categorized as BRPC together with group A is questionable.

Objectives: To compare the efficacy of full-dose gemcitabine-based concurrent chemoradiotherapy (FG-CCRT) and conventional 5-fluorouracil CCRT (5FU-CCRT) for locally advanced pancreatic cancer (LAPC)., Methods: 109 LAPC cases treated with FG-CCRT (n = 89) or 5FU-CCRT (n = 20) were reviewed retrospectively. The FG-CCRT group was composed of a full-dose gemcitabine monotherapy (1,000 mg/m(2)) arm and a combination therapy with cisplatin (70 mg/m(2)) arm. The 5FU-CCRT group used a radiosensitizing dose of 5-FU (500 mg/m(2)) plus leucovorin (20 mg/m(2)). Concurrent radiotherapy was targeted at the tumor with a 5-mm margin without lymph node irradiation., Results: Objective response rate (ORR) and disease control rate (DCR) was significantly higher in the FG-CCRT group (ORR: 32.6 vs. 5%, p = 0.013; DCR: 79.8 vs. 50.0%, p = 0.006). FG-CCRT showed remarkable superiority to 5FU-CCRT for suppressing distant metastasis (18.0 vs. 45.0%, p = 0.017). Neutropenia (34.8 vs. 10%, p = 0.032) and thrombocytopenia (21.3 vs. 0.0%, p = 0.021) were more frequent in the FG-CCRT group as originally expected. When dividing the FG-CCRT group to gemcitabine monotherapy (GEM) and gemcitabine plus cisplatin, toxicities of the GEM subgroup were not different than those of the 5FU-CCRT group., Conclusion: FG-CCRT, especially full-dose gemcitabine monotherapy-based CCRT was more effective for the initial control of LAPC than 5FU-CCRT, and also relatively safe.

Background: Surgical resection is the only curative treatment for pancreatic cancer, but surgical outcomes for borderline resectable pancreatic cancer (BRPC) are generally poor because of the complexity of the surgery and the advanced nature of the tumor. The aim of this study was to evaluate whether neoadjuvant concurrent chemoradiation therapy (CCRT) in BRPC patients could improve surgical outcome., Methods: Baseline characteristics and treatment outcomes for patients who underwent surgery for BRPC with (CCRT (+) group) and without neoadjuvant treatment (CCRT (-) group) were retrospectively compared. Treatment outcomes measured included overall survival, recurrence-free survival, and perioperative complications., Results: A total of 30 patients were included in the CCRT (+) group and 21 patients in the CCRT (-) group. Baseline characteristics were not different before CCRT, but pathological examination after resection revealed reduced tumor size and a lower neurovascular invasion rate in the CCRT (+) group. Overall median survival time was 45.0 months in the CCRT (+) group and 23.5 months in the CCRT (-) group (p = 0.045). The CCRT (+) group had a lower recurrence rate (50.0% vs. 81.0%; p = 0.024) and a longer median disease-free survival period (21.0 months vs. 10.6 months; p = 0.004) than the CCRT (-) group. Perioperative complication rates were not different between the two groups., Conclusions: Neoadjuvant chemoradiation therapy combined with surgical resection yielded better treatment outcomes in patients with BRPC compared with surgery alone. Further larger prospective clinical trials with well defined enrollment criteria and treatment plan are needed., (Copyright © 2013 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Purpose: To investigate the use of pretreatment carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) as prognostic factors to determine survival in pancreatic adenocarcinoma., Materials and Methods: A retrospective review of the medical records of patients who were diagnosed with pancreatic adenocarcinoma and received surgery, chemoradiotherapy or chemotherapy was performed. Factors, including CA 19-9 and CEA, associated with the survival of pancreatic cancer patients were analyzed., Results: Patients with the median age of 65 years were included (n=187). Elevated serum CA 19-9 levels and CEA levels were observed in 75.4% and 39% of patients at diagnosis, respectively. CEA was correlated with tumor stages (p=0.005), but CA 19-9 was not. CA 19-9 and CEA were elevated in 69.0% and 33.3% of patients with resectable pancreatic cancer, and elevated in 72.9% and 47.2% of patients with advanced pancreatic cancer, respectively. The median overall survival of the normal serum CEA group was longer than that of the elevated serum CEA group (16.3 months vs. 10.2 months, p=0.004). However, the median overall survival of the normal serum CA 19-9 group was not different from that of the elevated serum CA 19-9 group (12.4 months vs. 13.5 months, p=0.969). The independent factors associated with overall survival were advanced pancreatic cancer [harzard ratio (HR) 4.33, p=0.001] and elevated serum CEA level (HR 1.52, p=0.032)., Conclusion: Patients with elevated serum CEA level at diagnosis demonstrated poor overall survival. Pretreatment CEA level may predict the prognosis of patients with pancreatic adenocarcinoma.

Background/aims: This phase II study assessed the efficacy and safety of FOLFOX4 as a rescue therapy in patients with gemcitabine-refractory pancreatic cancer., Methodology: The study included patients with advanced pancreatic cancer who had failed gemcitabine-based chemotherapy. FOLFOX4 was administered biweekly as follows: oxaliplatin, 85 mg/m² as a 2-hour infusion (day 1); leucovorin, 200 mg/m²/day as a 2-hour infusion (days 1 and 2); 5-fluorouracil, bolus 400 mg/m²/day and 600 mg/m²/day as a 22-hour infusion (days 1 and 2)., Results: Forty-four patients received a total of 264 cycles of chemotherapy. There was 1 complete response (2.2%), 4 partial responses (9.1%), and 13 stable diseases (29.5%). The objective response rate was 11.4% and the tumor stabilization rate was 40.9%. The median time to progression was 9.9 weeks (95%CI: 8.2-11.5) and the median overall survival was 31.1 weeks (95%CI: 24.4-37.9). The common adverse events were hematologic toxicities: grade 3 or 4 neutropenia in 19 patients (43.2%), anemia in 9 patients (20.5%), and thrombocytopenia in 6 patients (13.5%). Grade 3 or 4 neuropathy occurred in 4 patients (9.1%)., Conclusions: In gemcitabine-refractory pancreatic cancer, FOLFOX4 showed encouraging activity and was generally well-tolerated. However, careful attention needs to be paid to hematologic toxicities.

Objective: Pancreatic cysts are being detected more frequently with advances in abdominal imaging. We designed this study to identify the characteristics of pancreatic cysts upon long-term follow-up and to define the proper management of them., Methods: We identified 1386 patients diagnosed with pancreatic cysts at our hospital from 1999 to 2010 and analyzed clinicopathologic data including radiological findings., Results: At initial diagnosis, 515 patients (37.2%) were classified as being at high-risk for malignancy, and 247 patients (17.8%) underwent surgery identifying 128 borderline or malignant cysts (51.8%). Borderline or malignant cysts were associated with older age, male sex, elevated serum level of lipase, carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA 19-9), and a dilated pancreatic duct. Long-term follow-up for at least 24 months revealed that most of cystic lesions unchanged in size but malignant transformation was observed in 7 patients., Conclusions: Most lesions with low or indeterminate risk did not changed in size during follow-up period, but one fifth of high-risk lesions were identified as borderline or malignant after surgery. Surgical resection should be performed in patients with high-risk cysts considering their clinical condition, and radiological follow-up of nonsurgically managed cysts should be continued for more than 6 years.

Purpose: Pancreatic neuroendocrine tumors (PNET) are a rare subgroup of tumors. For PNETs, the predictive factors for survival and prognosis are not well known. The purpose of our study was to evaluate the predictive factors for survival and disease progression in PNETs., Materials and Methods: We retrospectively analyzed 37 patients who were diagnosed with PNET at Severance Hospital between November 2005 and March 2010. Prognostic factors for survival and disease progression were evaluated using the Kaplan-Meier method., Results: The mean age of the patients was 50.0±15.0 years. Eight cases (21.6%) were described as functioning tumors and 29 cases (78.4%) as non-functioning tumors. In univariate analysis of clinical factors, patients with liver metastasis (p=0.002), without resection of primary tumors (p=0.002), or American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) stage III/IV (p=0.002) were more likely to demonstrate shorter overall survival (OS). Patients with bile duct or pancreatic duct invasion (p=0.031), sized-lesions larger than 20 mm (p=0.036), liver metastasis (p=0.020), distant metastasis (p=0.005), lymph node metastasis (p=0.009) or without resection of primary tumors (p=0.020) were more likely to demonstrate shorter progression-free survival (PFS). In multivariate analysis of clinical factors, bile duct or pancreatic duct invasion [p=0.010, hazard ratio (HR)=95.046] and tumor location (non-head of pancreas) (p=0.036, HR=7.381) were confirmed as independent factors for predicting shorter PFS., Conclusion: Patients with liver metastasis or without resection of primary tumors were more likely to demonstrate shorter OS. Patients with bile duct or pancreatic duct invasion or tumors located at body or tail of pancreas were more likely to demonstrate shorter PFS.

Introduction: Protein profiles of endoscopically collected pancreatic juice from normal, chronic pancreatitis patients and pancreatic cancer patients were compared to identify diagnostic biomarkers of pancreatic cancer., Methods: Secretin was injected intravenously and pancreatic juice was collected via selective cannulation of the pancreatic duct during endoscopic retrograde cholangiopancreatography. Pancreatic juices consisting of three pooled samples for normal control, chronic pancreatitis, and pancreatic cancer patients were compared using two-dimensional gel electrophoresis, and the proteins were subsequently identified using MALDI-TOF-MS., Results: Thirty-five protein spots were up-regulated twofold in pancreatic cancer compared with the levels in the normal controls, and 85 protein spots were present in pancreatic cancer samples but not in normal controls. After excluding spots that were also expressed in chronic pancreatitis, 26 protein spots that were up-regulated or only expressed in pancreatic cancer samples were identified. Among the identified proteins, we confirmed the expressions of BIG2, PRDX6, and REG1α in pancreatic cancer tissue using immunohistochemistry. ELISA showed that the serum level of REG1α was significantly higher in patients with pancreatic cancer than it was in the normal controls (P = 0.023). With the best cut-off value, the sensitivity and specificity of REG1α to differentiate normal and pancreatic cancer were 82.6 and 81.8%, compared with 69.6 and 100% for CA19-9., Conclusions: We have shown that pancreatic juice is a good source of pancreatic cancer tumor markers. Further studies are needed to determine the clinical implications of REG1α and other markers.

Aberrant expression of the claudin family of proteins has been reported in many human cancers, including pancreatic ductal carcinoma. Intraductal papillary mucinous neoplasms of the pancreas (IPMN) and mucinous cystic neoplasms (MCN) are considered precancerous lesions that are able to progress towards pancreatic ductal adenocarcinoma. We analyzed the expression of several claudin family members using surgical IPMN and MCN specimens to clarify the relationships between claudin expression and clinicopathological features. Twenty-nine and 25 consecutive cases of IPMN and MCN were selected and the expression of claudin-2, -4 and -18 was analyzed by immunohistochemistry. In addition, IPMN and MCN histological grade as well as IPMN subtypes were analyzed in relation to claudin expression. The 29 cases of IPMN comprised of 3 (10.3%) adenomas, 18 (62.1%) borderline malignancies and 8 (27.6%) carcinomas. The 25 cases of MCN comprised of 13 (52%) adenomas, 5 (20%) borderline malignancies and 7 (28%) carcinomas. Claudin-2, -4 and -18 showed strong expression both in IPMN and MCN, with the exception of claudin-4 in MCN. The expression grades of claudin-2 in both IPMN and MCN became weaker with increased histological grade. On the other hand, the expression grades of claudin-4 and -18 became stronger with increased histological grade in both IPMN and MCN. With regard to histological subtype, claudin-4 expression was the strongest in pancreatobiliary type IPMN, and claudin-18 expression was the strongest in gastric type IPMN. The distinct expression patterns of claudin-2, -4 and -18 suggest that claudins may serve as useful molecular markers for tumor differentiation and progression in IPMN and MCN.

Background/aims: Capsule endoscopy may be a useful diagnostic tool for radiation enteritis in select situations. We conducted this pilot study to test feasibility of capsule endoscopy in the diagnosis of radiation enteritis., Methodology: Patients who received chemoradiotherapy to treat pancreatic cancer were enrolled. To increase the diagnostic yield of radiation enteritis, capsule endoscopy was performed in patients having anemia or chronic abdominal pain after chemoradiotherapy., Results: Fifteen patients were enrolled between June 2007 and December 2008. The mean age was 63.4 +/- 8.0 years. The median radiation dose was 5040cGy with range of 4500-5994cGy. The mean total operating time of capsule was 10h 12 min +/- 2h 37 min, and the complete examination rate to the cecum was 93.3%. Nine patients (60%) were suspected to have radiation enteritis, and of these, five (33.3%) had abnormal findings that strongly suggested radiation enteritis. Congested mucosa and erythematous mucosa were the most frequent abnormal lesions. No capsule retention or other complications occurred., Conclusions: Capsule endoscopy may safely and effectively diagnose radiation enteritis in patients previously treated with chemoradiotherapy on the upper abdomen, although a larger trial is needed to confirm this.

Objective: To characterize the role of Oct4 and Nanog, two important homeobox transcription factors of embryonic development, in pancreatic carcinogenesis., Methods: Using a tissue microarray of human pancreatic carcinoma and adjacent noncancerous tissues as well as the N-nitrosobis(2-oxopropyl)amine-induced Syrian golden hamster pancreatic cancer model, we characterized the expression of Oct4 and Nanog. The presence of K-ras mutation with the time course of carcinogenesis in hamster model was also evaluated., Results: Oct4 expression in metaplastic ducts was significantly stronger than in normal acini and pancreatic carcinoma (P < 0.05). Of 24 cases, 19 (79.2%) showed a strong Oct4 expression in metaplastic ducts. In contrast, only 6 (19.4%) of 31 cancer tissues and 3 (16.7%) of 18 noncancer tissues showed a strong Oct4 expression. Nanog also showed similar patterns as Oct4. Restriction fragment length polymorphism-polymerase chain reaction showed the overt K-ras mutation after the expression of Oct4 in the hamster model., Conclusions: The strong expression of Oct4 and Nanog in metaplastic ducts and Oct4 expression preceding Ras mutation suggests that these homeobox transcription factors are associated with the early stage of pancreatic cancer carcinogenesis and may play an important role in that process.

Purpose: To examine STI-571-induced radiosensitivity in human pancreatic cancer cells in vitro., Methods and Materials: Three human pancreatic cancer cell lines (Bxpc-3, Capan-1, and MiaPaCa-2) exhibiting different expression levels of c-Kit and platelet-derived growth factor receptor beta (PDGFRbeta) and showing different K-ras mutation types were used. For evaluation of the antitumor activity of STI-571 in combination with radiation, clonogenic survival assays, Western blot analysis, and the annexin V/propidium iodide assay with microscopic evaluation by 4',6-diamidino-2-phenylindole were conducted., Results: Dramatic phosphorylated (p)-c-Kit and p-PDGFRbeta attenuation, a modest dose- and time-dependent growth inhibition, and significant radiosensitization were observed after STI-571 treatment in view of apoptosis, although the levels of growth inhibition and increased radiosensitization were different according to cell lines. The grades of radiosensitivity corresponded to the attenuation levels of p-c-Kit and p-PDGFRbeta by STI-571, particularly to those of p-c-Kit, and the radiosensitivity was partially affected by K-ras mutation in pancreatic cancer cells. Among downstream pathways associated with c-Kit or PDGFRbeta, p-PLCgamma was more closely related to radiosensitivity compared with p-Akt1 or p-extracellular signal-regulated kinase 1., Conclusion: STI-571 enhances radiation response in pancreatic cancer cells. This effect is affected by the attenuation levels of p-c-Kit or p-PDGFRbeta, and K-ras mutation status. Among them, p-c-Kit plays more important roles in the radiosensitivity in pancreatic cancer compared with p-PDGFRbeta or K-ras mutation status.

Background/aims: Thymidine phosphorylase (TP) has an angiogenic activity, but the prognostic value of TP has not been fully validated for pancreatic cancer. The aim of this study was to evaluate TP expression according to clinicopathological parameters to define its prognostic value for pancreatic cancer., Methodology: Forty-three patients with pancreatic ductal adenocarcinoma were examined retrospectively. TP expression and intratumoral microvessel density (IMD) were evaluated by immunohistochemistry. TP expression was analyzed according to clinicopathological parameters., Results: Twenty-eight (65%) of 42 cases showed diffuse cytoplasmic and nucleic TP staining. IMD was significantly higher in TP-positive tumors than in TP-negative tumors (27.7 +/- 8.9 vs. 18.1 +/- 4.4, p < 0.01). TP levels were significantly higher in T3 and T4 tumors than in T1 and T2 tumors (56% vs. 9.3%, respectively, p < 0.05). Patients with TP-positive tumors more frequently developed hepatic recurrence than those with TP-negative tumors after resection (p < 0.01). Patients with TP-positive tumors had a shorter survival than patients with TP-negative tumors (p < 0.05)., Conclusion: TP expression can be used as a predictor of hepatic recurrence and as an unfavorable prognostic factor for pancreatic cancer.

Purpose: There is no effective salvage regimen for failed gemcitabine-based chemotherapy. This study evaluated the efficacy and toxicity of 5-fluorouracil and paclitaxel in patients with gemcitabine-refractory pancreatic cancer., Methods: Between January 2004 and December 2007, 28 patients with pancreatic cancer previously treated with gemcitabine-based chemotherapy were enrolled. 5-Fluorouracil 1,000 mg/m(2) was infused (days 1, 2, and 3) and paclitaxel 175 mg/m(2) (day 1) was administered every 4 weeks. The primary endpoint of this study was efficacy and toxicity and the secondary endpoint was time to progression and overall survival., Results: A total of 75 cycles were given, for a mean of 2.68 cycles per patient. The response could be evaluated in 20 patients. Two patients (10%) obtained a partial response, and four patients (20%) had stable disease. The median time to progression and overall survival was 2.5 and 7.6 months, respectively. Grade 3/4 hematological toxicity included neutropenia in six patients (21.4%), anemia in one (3.6%), and thrombocytopenia in one (3.6%). One (3.6%) patient experienced grade 4 neuropathy, and two (7.2%) patients experienced grade 3 diarrhea., Conclusion: The 5-fluorouracil and paclitaxel combination treatment seems to be effective in patients with advanced pancreatic cancer that did not respond to a gemcitabine-based regimen.

Purpose: S-1 has a favorable effect in unresectable pancreatic cancer and a potential radiosensitizer. In addition, daily oral administration of S-1 is more convenient than continuous infusion of 5-fluorouracil. This study was designed to evaluate the efficacy and safety of S-1 and concurrent radiotherapy in patients with locally advanced pancreatic cancer., Methods: Eligibility criteria were histologically proven pancreatic adenocarcinoma, locally advanced disease, and no previous treatment. S-1 was administered orally at a dose of 40 mg/m(2) twice daily from day 1 to 14 and from day 22 to 35, and concurrent radiotherapy (a total dose of 50.4 Gy) was delivered in 28 fractions. One month after treatment completion, tumor response was evaluated by computed tomography (CT)., Results: A total of 25 patients were evaluable for efficacy and toxicity on the basis of the intention-to-treat analysis. The response rate and disease control rate were 24.0 and 68.0%, respectively. There was no treatment-related death or grade 4 toxicity. The most common grade 3 hematologic and non-hematologic toxicities were thrombocytopenia (4.0%) and anorexia (20%), respectively. All toxicities were tolerable and transient. The median time-to-progression and median overall survival were 6.5 months (95% confidence interval, 4.1-9.0 months) and 12.9 months (95% confidence interval, 6.7-19.0 months), respectively, and the 1-year survival rate was estimated to be 43%., Conclusions: S-1 and concurrent radiotherapy shows favorable efficacy for disease control against locally advanced pancreatic cancer and was well tolerated with no severe toxicities.

Purpose: To prospectively determine whether perfusion computed tomography (CT) parameters, such as volume transfer constant (K(trans)) between blood plasma and extracellular extravascular space (EES) and blood volume calculated from dynamic CT data, can be used to predict response of pancreatic cancer to concurrent chemotherapy and radiation therapy (CCRT)., Materials and Methods: This prospective study was institutional review board approved, and written informed consent was obtained. Thirty patients with pancreatic cancer underwent perfusion CT with 64-detector row CT before gemcitabine-based CCRT. Two perfusion parameters (K(trans) and blood volume) measured before treatment were compared between patients who responded to treatment and those who did not, as determined with World Health Organization criteria from first and second posttherapeutic follow-up CT examinations, which were performed at 3- and 6-month follow-up. Statistical analysis was performed with the two-sample t test. A receiver operating characteristic curve was used to determine the best cutoff value of perfusion parameters for differentiation of responders from nonresponders., Results: Twenty of 30 patients examined at 3-month follow-up responded to therapy. Their pretreatment K(trans) value was significantly higher than that of nonresponders (50.8 mL/100 mL/min +/- 30.5 [standard deviation] vs 19.0 mL/100 mL/min +/- 10.8, P = .001). The best cutoff value for differentiating between responders and nonresponders was 31.8 mL/100 mL/min, which yielded 75.0% sensitivity and 90.0% specificity. Ten of 18 patients examined at 6-month follow-up responded to therapy. Their pretreatment K(trans) value was significantly higher than that of nonresponders (58.6 mL/100 mL/min +/- 43.2 vs 19.8 mL/100 mL/min +/- 10.9, P = .002). Responders also had higher blood volume values, but this difference was not significant., Conclusion: Tumors with a high pretreatment K(trans) value tended to respond better to CCRT than did tumors with a low pretreatment K(trans) value. Perfusion CT may be used to predict tumor response to CCRT in patients with pancreatic cancer. This might aid in development of a tailored approach to therapy in these patients., ((c) RSNA, 2008.)