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Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8 + T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge. Using PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with elimination of tumors. cDC1 vaccination coupled with iCBT identified specific CDR3 sequences in the tumor-infiltrating CD8 + T cells with potential therapeutic importance. This study identifies a fundamental difference in the immune microenvironment in PDAC concurrent with, or without, pancreatitis and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.

Oncogenic KRAS G12D (KRAS ∗ ) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS ∗ in genetic mouse models of PDAC leads to the reactivation of FAS, CD8 + T cell-mediated apoptosis, and complete eradication of tumors. KRAS ∗ elimination recruits activated CD4 + and CD8 + T cells and promotes the activation of antigen-presenting cells. Mechanistically, KRAS ∗ -mediated immune evasion involves the epigenetic regulation of Fas death receptor in cancer cells, via methylation of its promoter region. Furthermore, analysis of human RNA sequencing identifies that high KRAS expression in PDAC tumors shows a lower proportion of CD8 + T cells and demonstrates shorter survival compared with tumors with low KRAS expression. This study highlights the role of CD8 + T cells in the eradication of PDAC following KRAS ∗ elimination and provides a rationale for the combination of KRAS ∗ targeting with immunotherapy to control PDAC., Competing Interests: Declaration of interests Y.C. and K.M.M. received speaker honorarium from Stellanova Therapeutics. V.S.L. is a Scientific Advisory Board member and stockholder of Stellanova Therapeutics. R.A.D. is a founder, advisor, and director of Tvardi Therapeutics, Inc., cofounder and advisor to Asylia Therapeutics, Nirogy Therapeutics, Stellanova Therapeutics, and Sporos Bioventures. A.M. receives royalties from Cosmos Wisdom Biotechnology and is listed as an inventor of a patent licensed to Thrive Earlier Detection, an Exact Sciences Company. A.M. is a consultant for Freenome and Tezcat Biotechnology., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The KRAS G12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRAS G12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRAS G12D , on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRAS G12D -driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8 + effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRAS G12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8 + T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials., Competing Interests: Declaration of interests A.M. receives royalties for a pancreatic cancer biomarker test from Cosmos Wisdom Biotechnology, and this financial relationship is managed and monitored by the UTMDACC Conflict of Interest Committee. A.M. is also listed as an inventor on a patent that has been licensed by Johns Hopkins University to Thrive Earlier Detection and serves as a consultant for Freenome and Tezcat Biosciences., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In contrast to normal type I collagen (Col1) heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (α1/α1/α1). Col1 homotrimer results from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via α3β1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Col1 homotrimers increases overall survival of mice with pancreatic ductal adenocarcinoma (PDAC), associated with reprograming of the tumor microbiome with increased microaerophilic Campylobacterales, which can be reversed with broad-spectrum antibiotics. Deletion of Col1 homotrimers enhances T cell infiltration and enables efficacy of anti-PD-1 immunotherapy. This study identifies the functional impact of Col1 homotrimers on tumor microbiome and tumor immunity, implicating Col1 homotrimer-α3β1 integrin signaling axis as a cancer-specific therapeutic target., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of fibroblasts as part of the host response to cancer. Using single-cell RNA sequencing, multiplex immunostaining, and several genetic mouse models, we identify carcinoma-associated fibroblasts (CAF) with opposing functions in PDAC progression. Depletion of fibroblast activation protein (FAP)+ CAFs results in increased survival, in contrast to depletion of alpha smooth muscle actin (αSMA)+ CAFs, which leads to decreased survival. Tumor-promoting FAP+ CAFs (TP-CAF) and tumor-restraining αSMA+ CAFs (TR-CAF) differentially regulate cancer-associated pathways and accumulation of regulatory T cells. Improved efficacy of gemcitabine is observed when IL6 is deleted from αSMA+ CAFs but not from FAP+ CAFs using dual-recombinase genetic PDAC models. Improved gemcitabine efficacy due to lack of IL6 synergizes with anti-PD-1 immunotherapy to significantly improve survival of PDAC mice. Our study identifies functional heterogeneity of CAFs in PDAC progression and their different roles in therapy response., Significance: PDAC is associated with accumulation of dense stroma consisting of fibroblasts and extracellular matrix that regulate tumor progression. Here, we identify two distinct populations of fibroblasts with opposing roles in the progression and immune landscape of PDAC. Our findings demonstrate that fibroblasts are functionally diverse with therapeutic implications. This article is highlighted in the In This Issue feature, p. 1397., (©2022 American Association for Cancer Research.)

Stromal desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC) involves significant accumulation of type I collagen (Col1). However, the precise molecular and mechanistic contribution of Col1 in PDAC progression remains unknown. Activated pancreatic stellate cells/αSMA + myofibroblasts are major contributors of Col1 in the PDAC stroma. We use a dual-recombinase genetic mouse model of spontaneous PDAC to delete Col1 specifically in myofibroblasts. This results in significant reduction of total stromal Col1 content and accelerates the emergence of PanINs and PDAC, decreasing overall survival. Col1 deletion leads to Cxcl5 upregulation in cancer cells via SOX9. Increase in Cxcl5 is associated with recruitment of myeloid-derived suppressor cells and suppression of CD8 + T cells, which can be attenuated with combined targeting of CXCR2 and CCR2 to restrain accelerated PDAC progression in the setting of stromal Col1 deletion. Our results unravel the fundamental role of myofibroblast-derived Co1l in regulating tumor immunity and restraining PDAC progression., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Epithelial-to-mesenchymal transition (EMT) is a recognized eukaryotic cell differentiation program that is also observed in association with invasive tumors. Partial EMT program in carcinomas imparts cancer cells with mesenchymal-like features and is proposed as essential for metastasis. Precise determination of the frequency of partial EMT program in cancer cells in tumors and its functional role in metastases needs unraveling. Here, we employed mesenchymal cell reporter mice driven by αSMA-Cre and Fsp1-Cre with genetically engineered mice that develop spontaneous pancreatic ductal adenocarcinoma (PDAC) to monitor partial EMT program. Both αSMA - and Fsp1 - Cre -mediated partial EMT programs were observed in the primary tumors. The established metastases were primarily composed of cancer cells without evidence for a partial EMT program, as assessed by our fate mapping approach. In contrast, metastatic cancer cells exhibiting a partial EMT program were restricted to isolated single cancer cells or micrometastases (3-5 cancer cells). Collectively, our studies identify large metastatic nodules with preserved epithelial phenotype and potentially unravel a novel metastasis program in PDAC., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

Exosomes are extracellular vesicles produced by all cells with a remarkable ability to efficiently transfer genetic material, including exogenously loaded siRNA, to cancer cells. Here, we report on a bioreactor-based, large-scale production of clinical-grade exosomes employing good manufacturing practice (GMP) standards. A standard operating procedure was established to generate engineered exosomes with the ability to target oncogenic Kras (iExosomes). The clinical-grade GMP iExosomes were tested in multiple in vitro and in vivo studies to confirm suppression of oncogenic Kras and an increase in the survival of several mouse models with pancreatic cancer. We perform studies to determine the shelf life, biodistribution, toxicology profile, and efficacy in combination with chemotherapy to inform future clinical testing of GMP iExosomes. Collectively, this report illustrates the process and feasibility of generating clinical-grade exosomes for various therapies of human diseases.

Background and Aim: The aim of this study is to elucidate the natural history of pancreatic cystic lesions (PCLs), including branch duct-type intraductal papillary mucinous neoplasm (BD-IPMN), via midterm follow-up analysis of a multicenter prospective observational study (NSPINAL study)., Methods: From July 2011 to October 2016, 881 patients with PCLs were enrolled in NSPINAL study, and 664 patients with > 12 months of follow up were analyzed. Every patient was asymptomatic, and endoscopic ultrasound was performed at the initial diagnosis to exclude high-risk individuals. Follow up included endoscopic ultrasound, computed tomography, or magnetic resonance imaging at least once a year. Serial morphological changes and the pancreatic cancer (PC) incidence, including malignant progression of PCLs, were evaluated., Results: The 664 patients (358 men) were followed for a median of 33.5 months (interquartile range 29). The cyst and main pancreatic duct sizes were 16.6 ± 9.3 and 2.3 ± 1.0 mm, respectively. Morphologically, 518 cases were multilocular, 137 were unilocular, and 9 had a honeycomb pattern; 269 cases involved multifocal lesions. Ninety-six patients (14.5%) showed worsening progression on imaging. There were two resectable and four unresectable cases of pancreatic ductal adenocarcinoma and three cases of malignant BD-IPMN. The 3-year risk of developing PC was 1.2%. The standardized incidence ratio for PC among PCLs was 10.0 (95% confidence interval 3.5-16.5), and the standardized incidence ratio among BD-IPMN was 16.6 (95% confidence interval 5.1-28.1). Multivariate analysis showed that development of symptoms and worsening progression were significant predictors of PC., Conclusions: Malignant progression of PCLs, including PC development, is not uncommon. Patients with PCLs should be carefully monitored to detect pancreatic ductal adenocarcinoma at early stages., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: The guidelines for the classification of the resectability of pancreatic cancer established by the National Comprehensive Cancer Network can be difficult to utilize in clinical practice. We evaluated novel criteria proposed by the Japan Pancreas Society., Methods: We analyzed 382 patients with pancreatic cancer between 2001 and 2015 for survival differences among subgroups classified according to the Japan Pancreas Society classification. Overall survival and disease-free survival were expressed as median values and compared with data based on the National Comprehensive Cancer Network classification, and differences in initial patterns of recurrence were analyzed., Results: Overall survival times according to the Japan Pancreas Society criteria were 34.2, 29.7, 17.3, 14.3, and 15.8 months for the groups defined as resectable, resectable with portal vein invasion, borderline resectable with portal vein invasion, borderline resectable with arterial invasion, and unresectable by locally advanced disease respectively. The overall survival of the resectable group was better than those of the borderline resectable with portal vein invasion or borderline resectable with arterial invasion groups (P < .0001); however, the borderline resectable with portal vein invasion, borderline resectable with arterial invasion, and unresectable by locally advanced groups showed no differences in overall survival. The resectable group showed a tendency toward better survival than the resectable with portal vein invasion group (P = .058). The median overall survival times according to the classic 2012 National Comprehensive Cancer Network criteria were 30.5, 20.5, 15.8, and 13.8 months for the resectable, portal invasion, common hepatic artery and superior mesenteric artery invasion groups, respectively. Each survival curve was clearly separate. The borderline resectable with arterial invasion and unresectable by locally advanced groups exhibited high local recurrence rates (42.0% and 44.8%, respectively)., Conclusion: The Japan Pancreas Society criteria, which are simpler, predicted survival differences between the resectable group and the other subgroups. Our data suggest that cancer patients with borderline resectable pancreatic cancer (borderline resectable with portal vein invasion and borderline resectable with arterial invasion) can be managed as a single subset., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes are extracellular vesicles generated by all cells, and are naturally present in the blood. Here we show that enhanced retention of exosomes, compared to liposomes, in the circulation of mice is likely due to CD47-mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry short interfering RNA or short hairpin RNA specific to oncogenic Kras G12D , a common mutation in pancreatic cancer. Compared to liposomes, the engineered exosomes (known as iExosomes) target oncogenic KRAS with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. Our results demonstrate an approach for direct and specific targeting of oncogenic KRAS in tumours using iExosomes.

Objectives: To investigate the impact of the body composition such as skeletal muscle, visceral fat and body mass index (BMI) on patients with resected pancreatic ductal adenocarcinoma (PDAC)., Methods: A total of 265 patients who underwent curative surgery for PDAC were examined in this study. The total skeletal muscle and fat tissue areas were evaluated in a single image obtained at the third lumber vertebra during a preoperative computed tomography (CT) scan. The patients were assigned to either the sarcopenia or non-sarcopenia group based on their skeletal muscle index (SMI) and classified into high visceral fat area (H-VFA) or low VFA (L-VFA) groups. The association of clinicopathological features and prognosis with the body composition were statistically analyzed., Results: There were 170 patients (64.2%) with sarcopenia. The median survival time (MST) was 23.7 months for sarcopenia patients and 25.8 months for patients without sarcopenia. The MST was 24.4 months for H-VFA patients and 25.8 months for L-VFA patients. However, sarcopenia patients with BMI ≥22 exhibited significantly poorer survival than patients without sarcopenia (MST: 19.2 vs. 35.4 months, P = 0.025). There was a significant difference between patients with and without sarcopenia who did not receive chemotherapy (5-year survival rate: 0% vs. 68.3%, P = 0.003). The multivariate analysis revealed that tumor size, positive dissected peripancreatic tissue margin, and sarcopenia were independent prognostic factors., Conclusions: Sarcopenia is an independent prognostic factor in PDAC patients with a BMI ≥22. Therefore, evaluating skeletal muscle mass may be a simple and useful approach for predicting patient prognosis., (Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: The Charlson age comorbidity index (CACI) is a useful measure of comorbidity to standardize the evaluation of surgical patients and has been reported to predict postoperative mortality in various cancers., Method: A total of 379 patients who underwent R0/R1 resection for pancreatic cancer between 2003 and 2014 were enrolled in this study. According to the CACI, the age-adjusted comorbidity index was calculated by weighting individual comorbidities; CACI<4 was considered the low-CACI group, whereas CACI≥4 was considered the high-CACI group. The correlations between the CACI and clinicopathologic features and survival outcomes were statistically analyzed., Results: The patients with a high CACI were more likely to be old and had higher CA19-9 levels and lower incidences of portal vein resection and blood transfusion. The rate of patients who received chemotherapy was significantly higher in the low-CACI group than in the high-CACI group (87% vs. 69%, P < 0.0001). The overall survival (OS) rate was significantly higher in the low-CACI group than in the high-CACI group (P = 0.047). Multivariable analysis showed that a high CACI was a predictor of poor survival (P = 0.024). In the high-CACI group, patients with high relative dose intensity (RDI) for postoperative adjuvant chemotherapy had significantly better relapse-free survival (RFS) and OS than those with low RDI (both P < 0.0001)., Conclusions: The CACI was a significant independent predictor of prognosis and compliance for postoperative adjuvant chemotherapy in the resected pancreatic cancer., (Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose: To determine which indicators, anatomical nodal metastasis (Japan Pancreas Society, JPS), number of positive lymph nodes (PLN), or lymph node ratio (LNR), is the best means of assessing lymph node involvement in pancreatic cancer., Methods: This retrospective study analyzed 275 patients with pancreatic cancer treated at a single institution. Survival curves according to the JPS, PLN, or LNR were assessed by the Kaplan-Meier method. Prognostic value of each classification was explored by Cox regression analysis after adjustments for clinical factors., Results: Multivariate analysis showed that, relative to n0 in the JPS, hazard ratios (HR) in n1, n2, and n3 were 1.72, 1.73, and 2.75, respectively, with no difference in survival between n1 and n2. Relative to PLN of 0, the HR in the PLN categories of 1∼2, 3, and >3 were 1.39, 1.65, and 3.03, respectively. Relative to LNR of 0, the HR in the categories of 0 < LNR ≤ 0.1, 0.1 < LNR ≤ 0.2, and LNR > 0.2 were 1.27, 2.00, and 5.58, respectively. An incremental increase in the HR was observed as the LNR category progressed, and differences between the survivals were distinct when stratified by the LNR., Conclusions: The LNR was an accurate predictor of survival among three assessment strategies and could be proposed as a candidate for use as N categories, pending validation studies.

Background & Aims: There is no established non-invasive method for diagnosis of pancreatic fibrosis. Shear wave elastography (SW-EG) may be a candidate for this purpose. The aims of this study were to assess the reproducibility of SW-EG in the normal imaging pancreas (Phase 1) and to evaluate the diagnostic performance of SW-EG for pancreatic fibrosis classified histologically (Phase 2)., Methods: Phase 1: This included 127 cases that underwent SW-EG of the normal imaging pancreas. SW-EG was measured at least five times in the pancreatic parenchyma and the median of repeated measurements was defined as the pancreatic elastic modulus (PEM). Phase 2: This included 53 cases that underwent SW-EG of the pancreatic parenchyma preoperatively and in which pancreas parenchyma were evaluated histologically. Histological fibrosis was graded in 4 stages: normal, mild, moderate, and severe., Results: Phase 1: Median PEM in the head, body, and tail of the pancreas were 3.23, 3.17, and 2.91 kPa, respectively, with no significant difference among regions (P = 0.554). The intraclass correlation coefficient showed good reproducibility (ρ = 0.71) after 5 measurements. Phase 2: There was a significant positive correlation between PEM and the histological pancreatic fibrosis stage (r s  = 0.63, P < 0.001). Areas under the receiver operating characteristic curve for the accuracy of SW-EG for diagnosis of pancreatic fibrosis were 0.85 (≥mild), 0.84 (≥moderate), and 0.87 (severe)., Conclusion: SW-EG can be used to determine the stage of pancreatic fibrosis non-invasively with high accuracy and reproducibility., (Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Recently, it has been reported that the relative dose intensity (RDI) of adjuvant chemotherapy (AC) influences survival in various cancers, but there are very few reports about RDI in pancreatic ductal adenocarcinoma (PDAC). The optimal timing for initiation of AC for PDAC also remains unknown. The aim of this study was to identify the significance of RDI and the time interval between surgery and initiation of AC on survival of patients with PDAC. Clinicopathological factors that affect RDI were also investigated.A total of 311 consecutive PDAC patients who underwent curative resection between May 2005 and January 2015 were enrolled. Patients who underwent neoadjuvant chemoradiation, had UICC stage IV disease, or had early recurrences within 6 months were excluded, and the remaining 168 cases were analyzed.Patients with RDIs ≥80% (n = 79) showed significantly better overall survival (OS) compared to patients with RDIs <80% (n = 55) (median survival time (MST): 45.6 months, 26.0 months, P < 0.001). Patients with no AC (n = 34) showed the worst OS (MST: 20.8 months). Whether the AC was initiated earlier or later than 8 weeks after surgery did not influence survival, either in patients with RDIs ≥80% (P = 0.79) or in those with <80% (P = 0.73). Patients in the S-1 monotherapy group (n = 49) showed significantly better OS than patients in the gemcitabine monotherapy group (n = 51) (MST: 95.0 months, 26.0 months, respectively; P = 0.001). Univariate analysis conducted after adjusting for the chemotherapeutic drug used identified several prognostic factors; male gender (P = 0.01), intraoperative blood transfusion (P = 0.005), lymph node metastasis (P = 0.03), and postoperative WBC count (P = 0.03). Multivariate analysis identified intra-plus postoperative blood transfusion (P = 0.002) and high postoperative platelet-to-lymphocyte ratios (PLR) (P = 0.04) as independent predictors of poor RDI.Efforts to maintain RDI had a greater impact on survival than the struggle to start AC early after surgery. Intra-plus postoperative blood transfusion and a high postoperative PLR could be predictive markers of reduced RDI in AC of PDAC patients. Avoidance of perioperative blood transfusions where possible and nutritional support during the perioperative period could maintain adequate RDI and may lead to improved long-term outcome., Competing Interests: The authors report no conflicts of interest.

A variety of systemic inflammation-based prognostic scores have been explored; however, there has been no study to clarify which score could best reflect survival in resected pancreatic cancer patients.Between 2002 and 2014, 379 consecutive patients who underwent curative resection of pancreatic cancer were enrolled. The Glasgow Prognostic Score (GPS), modified GPS (mGPS), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), prognostic index (PI), and prognostic nutritional index (PNI) scores for each patient were calculated. Survival of each score was evaluated, and correlations between the score selected on the basis of the prognostic significance and various clinicopathological factors were analyzed.In the analysis of the GPS, the median survival time (MST) was 28.1 months for score 0, 25.6 for score 1, and 17.0 for score 2. As for mGPS, the MST was 25.8 months for score 0, 27.7 for score 1, and 17.0 for score 2. Both scores were found to be significant. On the contrary, there were no statistical differences in MST between various scores obtained using the NLR, PLR, PI, or PNI. Multivariate analysis revealed that lymph node metastasis, positive peritoneal washing cytology, and a GPS score of 2 were significant prognostic factors. There was also statistically significant correlation between the GPS score and tumor location (head), tumor size (≥2.0 cm), bile duct invasion, and duodenal invasion.Our study demonstrated that the GPS could be an independent predictive marker and was superior to other inflammation-based prognostic scores in patients with resected pancreatic cancer.

Background: This study sought to evaluate the predictors of malignancy in the 2012 international consensus guidelines for intraductal papillary mucinous neoplasms (IPMNs) and validate their diagnostic value relative to the 2006 guidelines., Methods: Between 2002 and 2014, 177 consecutive patients who underwent curative resection of IPMN were reviewed. Based on the 2012 guidelines, high-risk stigmata (mural nodule with enhancement, main pancreatic duct [MPD] ≥ 10 mm, and obstructive jaundice) and worrisome features (cyst size ≥ 30 mm, thickened cyst wall, mural nodule without enhancement, MPD 5-9 mm, an abrupt change in MPD diameter, and lymphadenopathy) were assessed, and predictive and diagnostic values were analyzed statistically., Results: Multivariate analysis identified obstructive jaundice (odds ratio [OR], 23.9; P < .0001), abrupt change in MPD diameter (OR, 3.01; P = .017) and lymphadenopathy (OR, 5.84; P = .027) as independent predictive factors, with an accuracy of 69.8, 67.4, and 66.3%, respectively. Operative intervention was indicated in 156 patients (94.0%) using the 2006 guidelines, and in 130 (78.3%) using the 2012 guidelines. The accuracy of the 2006 guidelines was 35.5% compared with 44.8% for the 2012 guidelines. The area under the curve (AUC) for the 2006 and 2012 guidelines was 0.65 and 0.67, respectively; ΔAUC was 0.02, which was not statistically significant. When the worrisome features were combined with high-risk stigmata, the AUC increased to 0.79., Conclusion: Obstructive jaundice, abrupt change in MPD diameter, and lymphadenopathy were independent predictive factors in the 2012 guidelines with high accuracy. Using the new guidelines, the number of patients with IPMN managed with observation and the predictive accuracy increased., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Aim: Patients with advanced pancreatic cancer have severe pain, anxiety, and depression, and these symptoms deteriorate quality of life (QOL). Previous study reported that early psychiatric intervention for advanced cancer patients may improve QOL. We evaluated the trajectory of health-related QOL (HRQOL) in patients with pancreatic cancer after an early psychiatric intervention., Methods: A prospective cohort study was performed in 108 pancreatic cancer patients who received consultation liaison psychiatry from November, 2011 to October, 2014 at Nagoya University Hospital. Longitudinal changes in HRQOL and the association between aspects of HRQOL and survival were evaluated using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 before treatment and every month after the start of treatment., Results: Physical functioning significantly decreased after 1, 3, and 6 months of treatment compared with baseline, but global health status (GHS), role functioning, emotional functioning, and social functioning showed a tendency to improve. Severe impairment of GHS, fatigue, and appetite loss were apparent at 3 months prior to death. In multivariate analysis, pain was a significant prognostic factor for survival (hazard ratio [HR], 1.109; 95% confidence interval [CI], 1.021-1.204; P = 0.013), in addition to poor performance status (HR, 5.473; 95%CI, 2.338-12.816; P < .0001) and distant metastases at diagnosis (HR, 3.274; 95%CI, 1.872-5.725; P < .0001)., Conclusions: Early psychiatric intervention in patients with pancreatic cancer may maintain HRQOL. More effective pain management and reduction of psychological distress are important for patients with pancreatic cancer., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: The aim of this study was to investigate the efficacy and mechanism of action of combined S-1 and nab-paclitaxel in pancreatic cancer., Methods: Three human pancreatic cancer cell lines were treated with S-1, nab-paclitaxel, alone or in combination. Mice bearing subcutaneous xenograft of the cell line, PANC-1, were treated with the same drugs., Results: The growth-inhibitory effect of combined S-1 and nab-paclitaxel was greater than that of the individual drugs, and the combination index value indicated that S-1 and nab-paclitaxel had a synergistic effect in vitro. The combination of S-1 and nab-paclitaxel showed greater efficacy in vivo than monotherapy, and the growth-inhibitory effect was significantly greater when compared with the controls (P = 0.009), although no significant reduction in body weight was observed. Fractional tumor volume analysis indicated that the combination had a synergistic effect. Tumor stroma staining with α-smooth muscle actin was significantly decreased by nab-paclitaxel (P < 0.001) while the number of CD31-stained microvessel lumina was significantly increased by the combination therapy when compared with the control (P = 0.046)., Conclusions: S-1 and nab-paclitaxel had a synergetic effect in preclinical studies with good tolerability, and may play a role in stromal depletion and tumor angiogenesis. J. Surg. Oncol. 2016;113:413-419. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objectives: To find predictive factors among computed tomography (CT) findings to identify pancreatic neuroendocrine tumors G2 of World Health Organization classification., Methods: Thirty-seven patients with pancreatic neuroendocrine tumors underwent multiphase contrast enhanced CT (unenhanced, arterial, pancreatic, portal and equilibrium phase), and attenuation values and imaging findings were examined. A receiver operating characteristic curve analysis was performed, and association between imaging findings and World Health Organization classification was evaluated., Results: Mean CT attenuation value of NET G1 was significantly higher than that of NET G2 throughout the arterial, pancreatic, and portal phases. Receiver operating characteristic analysis according to tumor size revealed sensitivity: 83.3%, specificity: 92.0% and area under the curve (AUC): 0.853, whereas that of corrected true enhancement values in the pancreatic phase revealed sensitivity: 91.7%, specificity: 84.0% and AUC: 0.897, which showed the highest AUC. Specific CT findings, such as irregular tumor contour, vessel involvement, and cystic degeneration/necrosis, were significantly associated with NET G2, but not to the extent of CT attenuation value and tumor size., Conclusions: The CT enhancement in the pancreatic phase, and irregularity, vessel involvement, and cystic degeneration/necrosis were significant predictors of NET G2. These parameters might help in differentiating between NET G1 and G2, providing a basis for appropriate treatment.

Diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis despite current best therapies; therefore new treatment strategies are urgently required. Numerous studies have suggested that epithelial-to-mesenchymal transition (EMT) contributes to early-stage dissemination of cancer cells and is pivotal for invasion and metastasis of PDAC. EMT is associated with phenotypic conversion of epithelial cells into mesenchymal-like cells in cell culture conditions, although such defined mesenchymal conversion (with spindle-shaped morphology) of epithelial cells in vivo is rare, with quasi-mesenchymal phenotypes occasionally observed in the tumour (partial EMT). Most studies exploring the functional role of EMT in tumours have depended on cell-culture-induced loss-of-function and gain-of-function experiments involving EMT-inducing transcription factors such as Twist, Snail and Zeb1 (refs 2, 3, 7-10). Therefore, the functional contribution of EMT to invasion and metastasis remains unclear, and genetically engineered mouse models to address a causal connection are lacking. Here we functionally probe the role of EMT in PDAC by generating mouse models of PDAC with deletion of Snail or Twist, two key transcription factors responsible for EMT. EMT suppression in the primary tumour does not alter the emergence of invasive PDAC, systemic dissemination or metastasis. Suppression of EMT leads to an increase in cancer cell proliferation with enhanced expression of nucleoside transporters in tumours, contributing to enhanced sensitivity to gemcitabine treatment and increased overall survival of mice. Collectively, our study suggests that Snail- or Twist-induced EMT is not rate-limiting for invasion and metastasis, but highlights the importance of combining EMT inhibition with chemotherapy for the treatment of pancreatic cancer.

Non-equilibrium atmospheric pressure plasma (NEAPP) has attracted attention in cancer therapy. We explored the indirect effect of NEAPP through plasma-activated medium (PAM) on pancreatic cancer cells in vitro and in vivo. In this study, four pancreatic cancer cell lines were used and the antitumor effects of PAM treatment were evaluated using a cell proliferation assay. To explore functional mechanisms, morphological change and caspase-3/7 activation in cells were also assessed. Furthermore, reactive oxygen species (ROS) generation in cells was examined and N-acetyl cysteine (NAC), an intracellular ROS scavenger, was tested. Finally, the antitumor effect of local injection of PAM was investigated in a mouse xenograft model. We found that PAM treatment had lethal effect on pancreatic cancer cells. Typical morphological findings suggestive of apoptosis such as vacuolization of cell membranes, small and round cells and aggregation of cell nuclei, were observed in the PAM treated cells. Caspase-3/7 activation was detected in accordance with the observed morphological changes. Additionally, ROS uptake was observed in all cell lines tested, while the antitumor effects of PAM were completely inhibited with NAC. In the mouse xenograft model, the calculated tumor volume on day 28 in the PAM treatment group was significantly smaller compared with the control group [28 ± 22 vs. 89 ± 38 (mm(3) ± SD), p=0.0031]. These results show that PAM treatment of pancreatic cancer might be a promising therapeutic strategy.

Objectives: The aim of this study was to investigate the relationship between pancreas and small intestine evaluating the endoscopic and histopathologic findings of the proximal small intestine in pancreatic diseases., Methods: Fifty patients (18 patients with chronic pancreatitis, 17 patients with pancreatic cancer, 15 control subjects) underwent enteroscopy using a prototype enteroscope. The villous height of the jejunum on bioptic specimens was measured, and the mean values of the villi were compared among the 3 groups. Exocrine function was calculated by the pancreatic function diagnostic test, and the correlation between the recovery rate of p-aminobenzoic acid and the villous height was assessed. Finally, the distribution of the K cells secreting glucose-dependent insulinotropic polypeptide and the L cells secreting glucagon-like peptide 1 in the duodenum and jejunum was investigated using immunohistochemistry for glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1., Results: The mean villous height in chronic pancreatitis (328 ± 67 μm) was significantly lower than that in pancreatic cancer (413 ± 57 μm) and control subjects (461 ± 97 μm) (P = 0.004 and P < 0.0001, respectively). A positive correlation was found between the recovery rate of p-aminobenzoic acid and the villous height (r = 0.52, P = 0.0001). The presence of K and L cells was verified in the duodenum and the jejunum., Conclusions: Close relationship between pancreas and small intestine was demonstrated.

Combined arterial resection during pancreatectomy can be a challenging treatment, and outcome would be more favorable if the tumor becomes technically removable from the artery. Neoadjuvant chemoradiotherapy (NACRT) is expected to achieve locoregional control and enable margin-negative resection. To investigate the effects of NACRT in patients with pancreatic adenocarcinoma (PDAC) which were deemed borderline resectable through preoperative imaging due to abutment of the major artery, including the superior mesenteric artery (SMA) or common hepatic artery (CHA), but were still considered to be technically removable. In the current study, comparisons were make between 71 patients who underwent upfront surgery and 21 patients who underwent NACRT followed by surgery in the strategy to preserve the artery, using unmatched and inverse probability of treatment weighting analysis (UMIN000017115). Fifty patients in the upfront surgery group and 18 in the NACRT group underwent curative resection (70% vs 86%, respectively; P = 0.16). The results of the propensity score weighted logistic regressions indicated that the incidences of pathological lymph node metastasis and a pathological positive resection margin were significantly lower in the NACRT group (odds ratio, 0.006; P < 0.001 and odds ratio, 0.007; P < 0.001, respectively). Among the propensity-score matched patients, the estimated 1- and 2-year survival rates in the upfront surgery group were 66.7% and 16.0%, respectively, and those in the NACRT group were 80.0% and 65.2%, respectively. In conclusion, it was suggested that chemoradiotherapy followed by surgery provided clinical benefits in patients with PDACs in contact with the SMA or CHA.

Objective: The purpose of this study was to evaluate the prognostic relevance of SMAD4 expression in pancreatic cancer., Methods: We analyzed the correlations between SMAD4 expression and clinicopathological parameters and outcome in 174 patients with pancreatic cancer. Specimens were also classified into subtypes reflecting epithelial-to-mesenchymal transition, based on E-cadherin and vimentin., Results: We found that 59.8% (104/174) of patients were SMAD4 and 40.2% (70/174) were SMAD4. Disease-specific survival in patients with SMAD4 was significantly better than that in SMAD4. SMAD4 status was significantly correlated with portal vein invasion, lymph vessel invasion, and perineural invasion and was an independent prognostic factor. SMAD4 was significantly associated with mesenchymal phenotype. The loss of SMAD4 expression was found in 49.4% of patients with no vascular invasion, 61.9% with portal vein invasion, 76.5% with common hepatic artery invasion, and 80.8% with superior mesenteric artery invasion. In addition, the specimens from 59.0% of patients with local recurrence, 66.7% of those with both local and distant recurrence, and 73.7% of those with distant recurrence were SMAD4., Conclusions: The loss of SMAD4 expression is an independent prognostic factor and seems to be associated with tumor progression, pattern of failure, and epithelial-to-mesenchymal transition status. Preoperative stratification based on SMAD4 could lead to appropriate treatment strategy.

Objectives: The aim of this study was to evaluate the clinical relevance of vascular endothelial growth factor (VEGF) single nucleotide polymorphisms (SNPs) in intraductal papillary mucinous neoplasms (IPMNs)., Methods: A total of 169 IPMN and 108 pancreatic ductal adenocarcinoma patients who underwent curative resection were enrolled, and VEGF +405G/C and -460C/T SNPs were investigated., Results: Vascular endothelial growth factor +405C/C was found more frequently in malignant IPMNs compared with +405G/G (odds ratio [OR], 2.7; P = 0.04), and +405C allele was associated with malignant IPMNs compared with +405G (P = 0.055). In branch duct IPMNs, VEGF +405C/C was significantly associated with malignant transformation (CC vs GG: OR, 4.0; P = 0.03; CC vs CG + GG: OR, 3.3; P = 0.04), and there was a trend of VEGF +405C/C associated with malignant transformation of gastric-type IPMNs (CC vs GG: OR, 3.0; P = 0.07). When the survival outcomes were analyzed based on VEGF +405G/C SNPs, however, there was no relationship between VEGF SNPs and overall survival in patients with both IPMNs and pancreatic ductal adenocarcinomas., Conclusions: Vascular endothelial growth factor +405G/C SNP was significantly associated with malignant transformation in IPMNs, especially branch duct and gastric-type IPMNs. Vascular endothelial growth factor +405G/C SNP might be helpful in predicting clinical course in pancreatic disease with potential for malignant transformation.

Objectives: The objective of this study was to identify the most appropriate endoscopic biliary drainage method in patients with pancreatic head cancer., Methods: A prospectively collected database comprising 122 consecutive patients who underwent pancreatoduodenectomy, including 72 patients treated by endoscopic retrograde biliary drainage (ERBD) and 50 patients treated by endoscopic nasobiliary drainage (ENBD) procedures, was analyzed., Results: All bile cultures collected intraoperatively were positive in the ERBD group, and the positive rates of drainage fluid cultures on postoperative days 1, 3, and 5 and the incidence of postoperative abdominal abscess formation were significantly higher than those in the ENBD group. Moreover, ERBD was identified as an independent predictive factor for postoperative pancreatic fistula (POPF) formation (hazards ratio, 11.81; P < 0.001). The receiver operating characteristic curve analysis for the preoperative drainage period in the ERBD group revealed that the determined cutoff level for the onset of POPF was 29 days., Conclusions: Endoscopic retrograde biliary drainage resulted in more frequent postoperative complications, including POPF, compared with ENBD. Postoperative pancreatic fistula is more likely to occur if the ERBD period exceeds 1 month in patients scheduled to undergo pancreatoduodenectomy.

Background: Resection of the superior mesenteric vein (SMV) and portal vein (PV) involved in pancreatic neoplasms improves the chances of complete tumor removal. No consensus exists, however, on the optimal reconstructive approach, and postoperative venous stenosis in the first 6 months to 1 year can cause patient morbidity. We investigated medium-term patency after direct, end-to-end venous anastomosis and evaluate predictive factors for stenosis or occlusion., Methods: We analyzed retrospectively the records of 810 patients who underwent pancreatectomy at our institution from January 2000 through April 2014, and 197 patients who underwent concurrent SMV/PV resection were selected. The venous anastomosis was assessed every 4 or 6 months postoperatively by the use of portography with computed tomography. Preoperative and intraoperative variables were evaluated for their possible association with the development of severe anastomotic stenosis (≥70% occlusion)., Results: Among patients whose cancer did not recur during the 1-year follow-up period, 18 developed severe stenosis. Univariate analyses showed that operation time ≥520 minutes and length of SMV/PV resection ≥31 mm were associated with the development of severe anastomotic stenosis. Multivariate analysis showed that length of SMV/PV resection ≥31 mm was among independent predictors of medium-term, severe anastomotic stenosis (hazard ratio, 5.96; 95% confidence interval 1.79-22.69; P = .003)., Conclusion: Direct end-to-end anastomosis of the PV system is safe and offers patients with periampullary neoplasia improved chances of complete tumor excision. When tension-free anastomosis cannot be guaranteed, generally in cases requiring ≥31 mm of SMV/PV resection, venous autografting may decrease the likelihood of anastomotic stenosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background/aims: Pancreatic head carcinoma frequently invades the superior mesenteric vein (SMV) and/or portal vein (PV). We aimed to evaluate the outcome of transection of the splenic vein (SV) and inferior mesenteric vein (IMV) in pancreatoduodenectomy (PD) with SMV and/or PV resection., Methods: We retrospectively analyzed the records of 660 patients who had undergone pancreatectomy at our institution from January 2004 to October 2013, and selected 141 consecutive patients who had undergone PD with concurrent SMV/PV resection. Postoperative hypersplenism and the presence of remnant branches were evaluated., Results: The SV had been transected in 81 patients and preserved in 60. Postoperative complications and white blood cell counts were similar between the groups. The postoperative splenic volume was not significantly associated with the status of the SV or IMV on the transected SV. The platelet count was significantly lower, and the incidence of collateral veins was higher after SV transection than after SV preservation until 6 months after surgery; these variables were similar in the long term., Conclusion: SV reconstruction might be unnecessary when SV transection is required. Preservation of the IMV on the remnant SV might not prevent sinistral portal hypertension., (© 2015 S. Karger AG, Basel.)

Purpose: The aim of this study was to detect high-performance prognostic biomarkers of pancreatic cancer which would enable the identification of high-risk patients., Methods: The subjects were 324 patients who underwent radical surgery for pancreatic ductal adenocarcinoma without neoadjuvant therapy. We evaluated the prognostic impact of four perioperative serum tumor markers, including carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). We also evaluated the indices by multiplying the values of two tumor markers (e.g., CA19-9 × CEA)., Results: The preoperative CA19-9 × CEA index had a strong correlation with the prognosis of patients with pancreatic cancer, even when the cut-off was set at the median value. CA19-9 × CEA ≥500 was an independent predictor of mortality (hazard ratio: 1.642, p = 0.021). In the ROC curve analysis of early mortality after surgery, the CA19-9 × CEA index had the highest goodness of fit. The presence of CA19-9 × CEA ≥500 had the largest attributable risk proportion because of its combined high predictive performance and prevalence. The postoperative CA19-9 × CEA index was also a significant predictive marker of mortality., Conclusion: The CA19-9 × CEA index is a strong prognostic biomarker that could help identify pancreatic cancer patients expected to have a poor prognosis so that they can be administered appropriate multidisciplinary treatment.

Background/aims: The aim of this study was to evaluate patterns of the initial recurrence after pancreatectomy for pancreatic cancer and risk factors in each pattern., Methodology: This study included 209 pancreatic cancer patients who underwent pancreatectomy and of whom the detailed information on the first recurrent lesions detected by imaging during postoperative followup were available. Relapse patterns were classified into 4 groups: liver, peritoneal, local and extra-abdominal recurrences. We evaluated their associations with prognosis and various clinicopathological factors to identify relevant risk factors., Results: Cumulative numbers of patients with liver, peritoneal, local, and extra-abdominal recurrences were 81, 70, 98 and 22, respectively, for the first recurrences. Hepatic relapse was associated with significantly shorter overall survival than other sites (p<0.001) and was an independent prognostic factor in multivariate analysis (p<0.001). Pathological portal vein invasion was the only independent risk factor for hepatic relapse (p=0.045). There was no significant correlation between the depth of invasion and prevalence of hepatic relapse., Conclusions: Hepatic relapse was associated with a dismal prognosis and with pathological portal vein invasion. Novel therapeutic strategies are therefore required to reduce the incidence of hepatic relapse, especially in patients with portal vein invasion.

Objectives: We aimed to evaluate the feasibility and clinical benefit of pancreatoduodenectomy (PD) with portal vein resection (PVR) in elderly patients., Methods: This retrospective study enrolled 272 consecutive patients with pancreatic ductal adenocarcinoma who underwent PD between 2000 and 2012. The patients were categorized into 4 groups: elderly (≥70 years) and younger (<70 years) PD-PVR groups as well as elderly and younger PD groups. Preoperative patient background, postoperative course, and overall survival were compared., Results: Among the patients who underwent PD-PVR, the elderly group had significantly higher prevalence of comorbidity compared with the younger group (77% and 52%, respectively; P = 0.003), whereas there were no differences in the intraoperative and pathological characteristics. Postoperatively, morbidity and length of hospital stay were similar between the elderly and younger groups. Despite the fact that the proportion of patients who underwent adjuvant chemotherapy was lower in the elderly group (62% vs 83%; P = 0.005), the overall survival of the elderly group was comparable with that of the younger group, and both groups had a significantly more favorable prognosis than that of 36 patients with unresected tumors (P = 0.006 and P < 0.001, respectively)., Conclusions: Pancreatoduodenectomy with portal vein resection is safe and potentially beneficial for elderly patients with pancreatic cancer.

Purpose: Morphological subtypes of intraductal papillary mucinous neoplasm (IPMN) have been established. Invasive IPMNs include colloid carcinoma and tubular carcinoma. Few studies have explored the association between the morphological and invasive subtypes in a large population. Clinical relevance of the morphological subtypes remains unclear., Methods: One hundred sixty-nine consecutive patients who underwent curative resection of IPMN were enrolled. The intraductal components were classified into four distinct epithelial subtypes: gastric, intestinal, pancreatobiliary, and oncocytic. The invasive components were classified as colloid or tubular., Results: The numbers of patients with gastric, intestinal, pancreatobiliary, and oncocytic subtypes were 123, 42, 3, and 1, respectively. Fifty-six patients had invasive cancer (tubular type, 42; colloid type, 14). The proportions of gastric type IPMN within each histological grade were 88 % among adenomas, 43 % among noninvasive carcinomas, 41 % among minimally invasive carcinomas, and 74 % among invasive carcinomas. Gastric subtype was more commonly associated with branch duct type and intestinal subtype with main duct type, and these tendencies were statistically significant (P = 0.0131). Furthermore, there was a strong correlation between gastric and tubular types and between intestinal and colloid types (P < 0.0001). The 5-year survival rate among the 56 invasive cancers was 52.7 % for gastric type and 89.7 % for intestinal type, which was statistically significant (P = 0.030)., Conclusions: Gastric type IPMN is mostly derived from branch duct IPMN and often demonstrates benign behavior, as seen with adenomas. However, once gastric type IPMN develops into invasive carcinoma, the survival rate is significantly lower than other types.

Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Postoperative pancreatic fistula (POPF) is the main cause of fatal complications after pancreatoduodenectomy. There is still no universally accepted technique for pancreaticoenterostomy, especially in patients with soft pancreas., Methods: Between July 2008 and June 2013, 240 patients who underwent pancreatoduodenectomy were enrolled in this single-institution matched historical control study. To approximate the pancreatic parenchyma to the jejunal seromuscular layer, 120 patients underwent anastomosis using the Kakita method (three or four interrupted penetrating sutures) and 120 underwent anastomosis using the modified Blumgart anastomosis (m-BA) method (one to three transpancreatic/jejunal seromuscular sutures to completely cover the pancreatic stump with jejunal serosa)., Results: The rate of clinically relevant POPF formation was significantly lower in the m-BA group than that in the Kakita group (2.5 vs 36 %; p < 0.001). The duration of drain placement and the length of postoperative hospital stay were significantly shorter in the m-BA group. Multivariate analysis showed that m-BA was an independent predictor of non-formation of POPF (hazard ratio, 0.02; 95 % confidence interval, 0.01-0.08; p < 0.001)., Conclusion: The m-BA method is safe and simple and improves postoperative outcomes. We suggest that the m-BA is suitable for use as a standard method of pancreaticojejunostomy after pancreatoduodenectomy.

Background: There is the potential to use replication-competent oncolytic viruses to treat cancer. We evaluated the efficacy of HF10, a herpes simplex virus type 1 (HSV-1) mutant, in combination with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in human pancreatic cancer xenograft models., Methods: The viability of human pancreatic cancer cell lines (BxPC-3 and PANC-1) treated with HF10 and erlotinib, on their own or in combination, was determined. Effects of erlotinib on HF10 entry into tumor cells were also investigated. BxPC-3 subcutaneous tumor-bearing mice were treated with HF10 and erlotinib, on their own or in combination, with effects on tumor volume determined. Immunohistochemical examination of HSV-1 and CD31 was conducted to assess virus distribution and angiogenesis within tumors. A peritoneally disseminated BxPC-3 xenograft model was evaluated for survival., Results: HF10 combined with erlotinib demonstrated the highest cytotoxicity against BxPC-3. A combination effect was not observed in PANC-1 cells, and erlotinib did not affect virus entry into tumor cells. In the peritoneally disseminated model, HF10 combined with erlotinib had no beneficial effect on survival. In the subcutaneous tumor model, combination therapy resulted in the inhibition of tumor growth to a greater extent than using each agent on its own. Immunohistochemistry revealed that virus distribution within the tumor persisted in the combination therapy group., Conclusions: Combination therapy with HF10 and erlotinib warrants further investigation to establish a new treatment strategy against human pancreatic cancers.

Background: Peritoneal lavage cytology (CY) is used in the diagnosis and staging of various cancers. The clinical significance of positive cytology results in patients with pancreatic cancer is yet to be determined., Methods: Peritoneal washing samples were collected from consecutive patients with pancreatic cancer between July 1991 and December 2012. The correlations between cytology results, clinicopathological parameters and recurrence patterns were evaluated. The prognostic impact of CY status, regarding resectability and the effectiveness of adjuvant chemotherapy, were analysed., Results: Of 523 included patients, 390 underwent resection. Patients with tumours at least 2 cm in diameter were more likely to have CY+ status than patients with tumours smaller than 2 cm (48 of 312 versus 3 of 78 respectively; P = 0·005) and there was a significant correlation between CY+ status and tumour invasion of the anterior pancreatic capsule (43 of 276 versus 8 of 113 with no invasion of the capsule; P = 0·030). Although the overall survival of patients with resected CY+ tumours was worse than that of patients with resected CY- tumours, it was significantly better than the survival of unresected patients regardless of CY status. Multivariable analysis of all patients who had pancreatectomy did not identify CY+ as an independent prognostic factor. Patients with CY+ tumours tended to develop peritoneal metastasis more often than those with CY- tumours, although not significantly so. The median survival time of 34 patients with resected CY+ tumours who received adjuvant chemotherapy was better than that of 17 patients who had surgery alone, although this was not statistically significant (15·3 versus 10·0 months; P = 0·057)., Conclusion: CY+ status is not clinically equivalent to gross peritoneal metastasis in patients with pancreatic cancer. Curative resection is still recommended regardless of CY status., (© 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd.)

Background: Pancreatic cancer has a dismal prognosis that is attributed to common local invasiveness and metastasis. Epithelial-to-mesenchymal transition (EMT) plays an important role in cancer invasion and metastasis and is associated with early dissemination. The aim of this study was to evaluate the association between EMT and the prognoses for patients with pancreatic cancer., Methods: Immunohistochemistry of E-cadherin and vimentin was performed on surgical specimens from 174 patients who underwent resection of their pancreatic cancers. Tumoral stainings of E-cadherin and vimentin were graded, and EMT statuses were determined by calculating the ratio of vimentin to E-cadherin, whereby patients were categorized into 3 groups: epithelial, intermediate, and mesenchymal. The correlations between EMT statuses and clinicopathologic factors and prognoses were analyzed., Results: There was a significant correlation between EMT status and CA19-9 levels (P = .020); peritoneal washing cytology (P = .025); portal vein invasion (P = .038); and lymph node metastasis (P = .030). The median survival for patients with epithelial tumors was 40.2 months as compared to 13.7 months for patients with mesenchymal tumors. Multivariate analysis demonstrated that perineural invasion (P = .024); lymph node metastasis (P = .033); and EMT status (P < .0001) were significant prognostic factors. It is interesting that adjuvant chemotherapy (gemcitabine and/or S-1) improved the median survival time from 10.8 to 16.1 months in patients with mesenchymal tumors (P = .002); however, no significant difference was seen in patients with epithelial tumors., Conclusion: EMT status is an important prognostic factor for pancreatic cancer and is associated with portal vein invasion and lymph node metastasis., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objectives: The objective of this study was to evaluate the relevance of defining borderline resectable (BR) pancreatic cancer as a distinct entity in the treatment scheme of pancreatic cancer as proposed by the National Comprehensive Cancer Network., Methods: Among 375 patients with pancreatic cancer, 137 patients were deemed to have resectable disease (R) by preoperative imaging studies, whereas 96 were found to have an unresectable disease during surgery. The remaining 142 patients fulfilled the definition of BR and were further classified into 3 subgroups based on the National Comprehensive Cancer Network guidelines: portal vein invasion (PV[+]), common hepatic artery invasion (CHA[+]), and superior mesenteric artery invasion (SMA[+]). PV(+) was subdivided into types B, C, and D according to the degree of portal vein invasion., Results: Patients in the R group had significantly better survival than those in the PV(+) group (P = 0.0038), who in turn survived significantly longer than those classified as SMA(+) (P = 0.041). Type B patients survived significantly longer than did types C and D patients (P = 0.013 and P = 0.030, respectively). In PV(+) patients, compliance with postoperative chemotherapy at 3 and 6 months was 56.9% and 44.6%, respectively, substantially inferior to patients with resectable disease (72.6% and 54.7%, respectively)., Conclusions: The optimal treatment strategy may differ among various subgroups within the BR category.

A 65-year-old man was referred to our hospital due to epigastric pain. Abdominal enhanced computed tomography (CT) demonstrated marked dilatation of the main pancreatic duct (MPD) and communication to the gastric and duodenal lumen was suspected. Esophagogastroduodenoscopy (EGD) showed a villous tumor with white mucous discharge in the posterior wall of the gastric corpus and duodenal bulb. Pathological specimens showed mucin-producing epithelium with nuclear atypia that had developed in a papillary form. Based on these findings, we diagnosed intraductal papillary mucinous neoplasm (IPMN) arising in the MPD with penetration into the gastric and duodenal lumen. Magnetic resonance cholangiopancreatography (MRCP) with an oral negative contrast agent (manganese chloride tetrahydrate) showed a fistulous tract not only to the stomach and duodenum, but also to the jejunum. MRCP demonstrated mucous streaming with remarkably high intensity. In this case, an oral negative contrast agent was useful to distinguish mucous discharge from gastric fluid, facilitating the diagnosis of penetration to the jejunum. This finding was unobtainable by CT or EGD. When IPMN penetrating to other organs is suspected, MRCP with an oral negative contrast agent may provide important information., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: The aims of this study were to clarify the type of intrapancreatic spread of cancer of the pancreatic body and tail and to assess whether a 2-cm transection margin is adequate to ensure negative margins., Methods: We selected 66 patients who underwent distal pancreatectomy for cancer of the pancreatic body and tail. We investigated intrapancreatic cancer spread in these patients histopathologically and analyzed the relationship between 2-cm-margin positivity and other clinicopathological characteristics., Results: Two-centimeter-margin positivity was observed in 17 cases. In these, tumors had a tendency to spread toward the pancreatic head along the main pancreatic duct. As a result of statistical analysis, we considered venous invasion (odds ratio [OR], 15.48; 95% confidence interval [CI], 1.61-148.94; P = 0.0177), 2-cm-margin fibrosis (OR, 173.88; 95% CI, 8.96-3375.03; P = 0.0007), and 2-cm-margin hardness (OR, 5.97; 95% CI, 1.07-33.46; P = 0.0420) as being independently related to 2-cm-margin positivity., Conclusions: The results suggest that 2 cm is not a safe length to ensure a negative margin. In the future, preoperative and intraoperative evaluation of the degree of fibrosis of pancreatic parenchyma could lead to cancer-free pancreatic cut-end margins.

Objectives: Pancreaticoduodenectomy is performed for pancreatic head cancer that originated from the dorsal or ventral primordium. Although the extent of lymph node (LN) dissection is the same irrespective of the origin, the lymphatic continuities may differ between the 2 primordia., Methods: Between March 2003 and September 2010, 152 patients underwent pancreaticoduodenectomy for pancreatic cancer. One hundred six patients were assigned into 2 groups according to tumor location on preoperative computed tomography, and their clinical and pathological features were retrospectively analyzed in view of the embryonic development of the pancreas., Results: Sixty of 106 patients were classified with tumors that were derived from the dorsal pancreas (D group) and 46 from the ventral pancreas (V group). The frequency of LN involvement around the middle colic artery (LN 15) in the D group was higher than in the V group (P = 0.008). The rate of additional resection of the pancreas tended to be higher in the D group (P = 0.067)., Conclusions: The present study showed the detailed pattern of spread of pancreatic ductal carcinoma to the LNs and provided important information for determining the optimal surgical strategy.

Objectives: A retrospective study was performed to clarify the correlation between radiographic type of portal vein (PV) invasion and pathological grade of PV wall invasion, and their correlation with postoperative prognosis., Background: In many patients with pancreatic cancer, PV resection is necessary to increase resectability and obtain cancer-free margins., Methods: We analyzed 671 patients who had undergone surgery for invasive adenocarcinoma of the pancreas between July 1981 and June 2010. Radiographic types of PV invasion of pancreatic head cancer were classified into A (normal), B (unilateral narrowing), C (bilateral narrowing), or D (complete obstruction with collateral veins), by portography or computed tomography. Pathological grades of PV wall invasion were classified as 0 (no invasion), 1 (tunica adventitia), 2 (tunica media), or 3 (tunica intima)., Results: Four hundred and sixty-three patients underwent resection, and PV resection was performed in 297. Combined arterial vessel resection was performed in 16 cases. No significant difference in operative mortality was observed between PV preservation (0.6%) and PV-only resection (2.1%), and no operative deaths occurred after 1999. Radiographic classification of PV invasion correlated with incidence of pathological PV wall invasion. In pancreatic head carcinoma, no pathological PV wall invasion was observed in type A (n = 111). Pathological PV invasion was observed in 51% of type B (42/82), 74% of type C (72/97), and 93% of type D (63/68). Long-term survival (>5 years) was observed in types A and B, and grades 0 and 1 subgroups., Conclusions: Pancreatectomy with PV resection can be performed safely. Even in radiographic classification type B, pathological PV wall invasion was observed in 51% of patients. Long-term survival was observed in types A and B, and grades 0 and 1.

Background: Pylorus-preserving pancreatoduodenectomy (PPPD) has replaced conventional pancreatoduodenectomy with a distal gastrectomy (cPD) as the most commonly performed procedure. However, there has been no evidence from prospective studies to indicate the overwhelming superiority of PPPD over cPD. A recent report revealed that resection of the pyloric ring reduced the incidence of delayed gastric emptying (DGE) in a randomized controlled trial., Methods: In 158 patients with pancreatic head cancer, the perioperative outcomes and long-term nutritional consequences were retrospectively compared among three types of pancreatoduodenectomy: cPD; PPPD; and subtotal stomach-preserving pancreatoduodenectomy (SSPPD), in which the pyloric ring and duodenum were removed and more than 90% of the stomach was preserved., Results: The incidence of DGE was significantly higher in the PPPD group than in the cPD and SSPPD groups (27.3 vs. 5.8 and 5.4%, respectively; P = 0.0012). The serum albumin concentration and total lymphocyte count at 1 year postoperatively were significantly higher in the SSPPD group than in the PPPD group (P = 0.0303 and P = 0.0203, respectively). The patients in the SSPPD group showed longer survival times than the patients in the cPD and PPPD groups (median survival times, 21.3, 17.1, and 17.7 months, respectively), although the differences did not reach statistical significance., Conclusions: Our results suggest that preservation of the pyloric ring without vagal innervation has little significance, and that SSPPD with better perioperative and long-term outcomes is more suitable as a standard procedure for patients with pancreatic head cancer.

Objective: The aim of this study was to investigate the clinical benefits of pancreatic head resection with segmental duodenectomy (PHRSD) with a particular emphasis on the long-term outcome., Methods: A retrospective analysis of PHRSD (77 patients) and pylorus-preserving pancreatoduodenectomy (PPPD; 55 patients) was performed for benign and low-grade malignant neoplasms of the pancreatic head. The zintraoperative and postoperative courses and long-term nutritional statuses were compared., Results: The mean operative time and blood loss were significantly less in the PHRSD group than in the PPPD group (351 vs 395 minutes, P = 0.005; and 474 vs 732 mL, P < 0.0001, respectively). Fewer overall postoperative complications occurred in the PHRSD group than in the PPPD group (33.8% vs 52.7%, respectively, P = 0.03). Postoperative weight loss and changes in the serum total protein and albumin levels were significantly milder in the PHRSD group than in the PPPD group (P = 0.04, P = 0.04, and P = 0.046, respectively). The overall recurrence-free survival rates in patients with noninvasive intraductal papillary mucinous neoplasms were equivalent in both groups., Conclusions: The present results suggest that PHRSD fulfills the operative safety, long-term nutritional status, and curative goals and could be the best option for patients with benign or low-grade malignant pancreatic lesions.

Objective: The current classification of pancreatic cancer is based only on anatomic location of metastatic lymph nodes (LNs). On the other hand, the number of metastatic LNs has been used in staging of colorectal, esophageal, and gastric cancers. The aim of this study was to assess the prognostic impact of the number or ratio of the metastatic LNs in pancreatic body and tail carcinoma., Methods: Eighty-five patients with pancreatic body and tail adenocarcinoma who underwent pancreatectomy were included. Location, number, ratio of metastatic LNs, and the survival of patients were analyzed., Results: Forty patients with LN metastasis had poor prognosis (P = 0.007). The prognoses of patients with 5 or more metastatic LNs were poorer than those with less than 5 metastatic LNs (P = 0.046), and patients with a metastatic LN ratio of 0.2 or more had the worst prognosis. Multivariate analysis revealed that 5 or more metastatic LNs and metastatic LN ratio of 0.2 or more were independent prognostic factors for survival (P = 0.0015 and P = 0.014, respectively)., Conclusion: These results indicate that the number and the ratio of metastatic LNs can be used to predict poor patient survival and as a staging strategy.

Objectives: We aimed to clarify the detailed pattern of lymph node (LN) metastasis spread in patients with pancreatic cancer., Methods: This retrospective study enrolled 429 patients who underwent pancreatectomy with extended lymphadenectomy for pancreatic cancer. The prognostic implications of LN metastasis were evaluated, and the position, frequency, and association with other clinicopathologic factors were investigated., Results: Lymph node metastasis was confirmed pathologically in 289 patients (67.4%). The prognosis of patients with LN metastasis was significantly poorer than that of patients without LN metastasis (P < 0.001). Distant LN metastasis occurred frequently, regardless of the tumor site. Patients classified with T1 or T2 only had regional LN metastasis, whereas there was a high rate of distant LN metastasis, including the para-aortic LNs, in patients with T3 or higher-stage tumors. Para-aortic LN metastasis was significantly associated with arterial and perineural invasion (P = 0.006 and P < 0.001, respectively). Lymph node metastasis in the hepatic portal region was a strong predictor of para-aortic LN metastasis in pancreatic head cancer., Conclusions: Pancreatic cancer frequently metastasized to distant LNs via a complex pathway and developed into systemic disease. Aggressive multimodality therapy, including neoadjuvant therapy, is essential to improve the long-term survival of patients at substantial risk of distant LN metastasis.

Background: The negative impact of anastomotic leakage on cancer-specific survival and recurrence patterns has been recognized in colorectal cancer. In pancreatic cancer, pancreatic fistula (PF) is a serious morbidity, but its negative effect on long-term outcome remains to be elucidated. The aim of this study was to determine the impact of PF on pancreatic cancer recurrence., Methods: The medical records of 184 patients with curative pancreatectomy for pancreatic cancer were reviewed. PF was scored on the basis of the International Study Group of Pancreatic Fistula classification. Overall and disease-free survivals and recurrence patterns were analyzed. Grade A PF was excluded because the negative effects can be negligible., Results: PF occurred in 51 of the 184 patients (27.7%). The mortality related to PF was 0.5% (1 of 184). PF was an independent risk factor for peritoneal recurrence (hazard ratio 3.974; 95% confidence interval 1.345-11.737; P = 0.013). According to the analysis of disease-free survival in patients with peritoneal recurrence, time to recurrence was shorter and the survival rate was worse in patients with PF than in those without PF (5.6 vs. 8.2 months; 6-month survival, 40 vs. 71%; 1-year survival, 7 vs. 19%; P = 0.053). PF was an independent prognostic factor after multivariate analysis (hazard ratio 3.257; 95% confidence interval 1.201-8.828; P = 0.020)., Conclusions: PF was statistically significantly related to peritoneal recurrence, and patients with PF developed peritoneal recurrence earlier than those without PF. With regard to the development of peritoneal recurrence, PF may be considered to be a negative prognostic factor.

In 2005, we initiated a clinical trial that examined the efficacy of the oncolytic virus HF10 to treat pancreatic cancer. Pancreatic cancer continues to have a high mortality rate, despite multimodal treatments for patients, and new therapeutic methods are greatly needed. The current mainstream methods for cancer treatment include biological therapeutics such as trastuzumab (Herceptin) for breast cancer or erlotinib (Tarceva) for non-small cell lung cancer. Oncolytic virus therapy is a new and promising treatment strategy for cancer. Oncolytic viruses are novel biological therapeutics for advanced cancer that appear to have a wide spectrum of anticancer activity with minimal human toxicity. To examine the efficacy of oncolytic virus therapy for pancreatic cancer, we initiated pilot studies by injecting six patients with non-resectable pancreatic cancer with three doses of HF10. All patients were monitored for 30 days for local and systemic adverse effects and were not administered any other therapeutics during this period. There were no adverse side-effects, and we observed some therapeutic potential based on tumor marker levels, survival, pathological findings and diagnostic radiography. The tumors were classified as stable disease in three patients, partial response in one patient and progressive disease in two patients.