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International audience; Background: Experienced pancreatic surgeons, for whom complexity is not an issue, must decide at the end of neoadjuvant therapy whether to continue or discontinue surgery, when pancreatectomy with vascular resection is planned in patients with pancreatic ductal adenocarcinoma (PDAC). Objective: Our study aimed to determine preoperative factors that can predict short postoperative survival in such situations. Methods: Overall, 105 patients with borderline or locally advanced PDAC received neoadjuvant FOLFIRINOX (followed by chemoradiation in 22% of patients) and underwent pancreatectomy with segmental venous and/or arterial resection at two high-volume centers. The primary endpoint was overall survival (OS) of < 1 year after surgery for patients who did not die from the surgery. Results: Tumors were classified as borderline in 78% of cases and locally advanced in 22% of cases. Mean CA19-9 at diagnosis was 934 U/mL, which significantly decreased to 213 U/mL (p < 0.01) after a median of six cycles of FOLFIRINOX. Pancreaticoduodenectomy was performed most often (76%). The vast majority of patients underwent venous resection (92%), and a simultaneous arterial resection was performed in 16 patients (15%). The severe morbidity rate and 30- and 90-day mortality rates were 21%, 8.5%, and 10.4%, respectively. The median OS after surgery was 23 months. In the multivariate analysis, preoperative CA19-9 ≥ 450 U/mL was the only preoperative factor independently associated with OS of < 1 year (p = 0.044). Conclusion: The preoperative CA19-9 value should be considered in the clinical decision-making process when complex vascular resection is required. © 2021, Society of Surgical Oncology.

Increased risk of pancreatic cancer may be associated with consumption of sugar containing foods. The aim of this study was to evaluate the effect of peach nectar containing high fructose corn sirup (HFCS) consumption in a pancreatic carcinogenesis rat model induced by 7,12-Dimethyl benzanthracene (DMBA). Fifty-day-old male Sprague Dawley rats were fed with peach nectar containing HFCS + chow, peach nectar containing sucrose + chow and only chow. After 8 mo, feeding period, each group was divided into two subgroups, in which the rats were implanted with DMBA and no DMBA (sham). Histologic specimens were evaluated according to the routine tissue processing protocol. The animals withad libitumaccess to pn-HFCS, pn-sucrose and chow (only) showed significant differences in chow consumption and glucose level. Necropsy and histopathologic findings showed tumor formation in the entire group treated with DMBA. Excluding one rat in chow group, which was classified as poorly differentiated type, the others were classified as moderately differentiated pancreatic ductal adenocarcinoma (PDAC). This study demonstrated that daily intake of HFCS did not increase body weight and there was no effect of peach nectar consumption on the development of PDAC induced by DMBA in rats.

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give patients, health professionals, managers and policymakers a guide to essential care throughout the patient journey. Pancreatic cancer is an increasing cause of cancer mortality and has wide variation in treatment and care in Europe. It is a major healthcare burden and has complex diagnosis and treatment challenges. Care must be carried out only in pancreatic cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals detailed here. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.

Pancreatic tumors, except solid pseudopapillary tumors (SPTs), are rare in pediatric patients. Herein, we report various types of pancreatic tumors in pediatric patients and review the literature regarding their treatments and prognosis. We retrospectively reviewed the data of pediatric patients who underwent surgery for pancreatic tumors, excluding SPTs, between January 2009 and December 2019 at Seoul National University Children's Hospital. A total of 35 pediatric patients were identified as having undergone surgery for pancreatic tumors. Of these patients, 30 were excluded because the tumor was identified as an SPT. The diagnoses of the five remaining (non-SPT) pancreatic tumors were pancreatic neuroendocrine tumor, mixed acinar neuroendocrine carcinoma, kaposiform hemangioendothelioma, and intraductal papillary mucinous neoplasm. All five patients survived; however, recurrence and liver metastasis were observed in one patient. The detailed demographics, treatments, and prognosis of each patient were reviewed. Despite the rarity and low incidence of pancreatic tumors in pediatric patients, four types of non-SPT tumors are reported here. Hence, the possibility of these should not be overlooked, especially since the diagnosis and adjuvant treatment differ vastly between the tumor types.

International audience; [No abstract available]

Purpose: NRG Oncology RTOG 9704 was the first adjuvant trial to validate the prognostic value of postresection CA19-9 levels for survival in patients with pancreatic carcinoma. The data resulting from this study also provide information about predictors of recurrence that may be used to tailor individualized management in this disease setting. This secondary analysis assessed the prognostic value of postresection CA19-9 and surgical margin status (SMS) in predicting patterns of disease recurrence. Methods and materials: This multicenter cooperative trial included participants who were enrolled as patients at oncology treatment sites in the United States and Canada. The study included 451 patients analyzable for SMS, of whom 385 were eligible for postresection CA19-9 analysis. Postresection CA19-9 was analyzed at cut points of 90, 180, and continuously. Patterns of disease recurrence included local/regional recurrence (LRR) and distant failure (DF). Multivariable analyses included treatment, tumor size, and nodal status. To adjust for multiple comparisons, a P value of ≤ .01 was considered statistically significant and > .01 to ≤ .05 to be a trend. Results: For CA19-9, 132 (34%) patients were Lewis antigen–negative (no CA19-9 expression), 200 (52%) had levels

Targeting the rich extracellular matrix of desmoplastic tumors has been successfully shown to normalize collagen and hyaluronan levels and re-engineer intratumoral mechanical forces, improving tumor perfusion and chemotherapy. As far as targeting the abundant cancer-associated fibroblasts (CAFs) in desmoplastic tumors is concerned, while both pharmacologic inhibition of the sonic-hedgehog pathway and genetic depletion of fibroblasts have been employed in pancreatic cancers, the results between the two methods have been contradictory. In this study, we employed vismodegib to inhibit the sonic-hedgehog pathway with the aim to i) elucidate the mechanism of how CAFs depletion improves drug delivery, ii) extent and evaluate the potential use of sonic-hedgehog inhibitors to breast cancers, and iii) investigate whether sonic-hedgehog inhibition improves not only chemotherapy, but also the efficacy of the most commonly used breast cancer nanomedicines, namely Abraxane® and Doxil®. We found that treatment with vismodegib normalizes the tumor microenvironment by reducing the proliferative CAFs and in cases the levels of collagen and hyaluronan. These modulations re-engineered the solid and fluid stresses in the tumors, improving blood vessel functionality. As a result, the delivery and efficacy of chemotherapy was improved in two models of pancreatic cancer. Additionally, vismodegib treatment significantly improved the efficacy of both Abraxane and Doxil in xenograft breast tumors. Our results suggest the use of vismodegib, and sonic hedgehog inhibitors in general, to enhance cancer chemo- and nanotherapy. © 2017 Elsevier B.V. 261 105 112 105-112

症例は70歳代の女性．7年前に膵尾部単純性嚢胞と診断され，経過観察中であった．4ヶ月持続する発熱と心窩部痛の精査を目的として入院した．入院時のCTでは多発肝腫瘍を認め，嚢胞内には結節病変を，嚢胞周囲には出血・感染を示唆する所見を認めた．以上より，嚢胞性病変が癌化して転移・浸潤をきたし，嚢胞周囲に膿瘍を形成したものと考えて対症的に治療したが，第15病日に死亡した．剖検所見から嚢胞の癌化は否定され，嚢胞に近接して発生した膵未分化癌と，肝転移，肺転移等の多臓器転移，腹膜播種と診断された．

Metronomic dosing of chemotherapy - defined as frequent administration at lower doses - has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor-drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy. © 2017, National Academy of Sciences. All rights reserved. 114 1994 1999 1994-1999

PubMed ID: 30104029 Purpose: Solid pseudopapillary neoplasm (SPN) is a rare, low-grade neoplasm with excellent prognosis. In this study, we evaluated clinicopathological characteristics of patients diagnosed with SPN retrospectively. Methods: This is a retrospective study intended to characterize patients with the diagnosis of SPN between 2005 and 2015. Clinicopathological features, recurrence rate, and overall survival of 28 patients were recorded. Malignant SPN criteria were defined as the presence of distant metastasis (developed at diagnosis or during follow up) or lymph node involvement. Results: The mean age at diagnosis was 42 (range: 17-41). Among patients, 82% (n = 23) were female and 17.9% (n = 5) were male. The mean size of tumor was 5.81 cm (range: 2-15). The mean follow up period was 55.6 months, 1-year survival was 96.5% and 5-year survival rate was 88%. A total of 25 patients were alive at the end of follow-up period and 3 of the patients became exitus due to disease. Two patients had a metastatic presentation in livers at the diagnosis and metastasis developed in 3 patients during follow-up (liver of 1 patient, peritoneum in 1 patient and liver and peritoneum in 1 patient). The reason of admission was headache in 68% patients. The type of operation was frequently subtotal pancreatectomy (n = 11, 39.3%) and distal pancreatectomy (n = 10, 35.7%). Tumors were located frequently in body and tail regions (n = 18, 64.3%) and the number of patients with malignant criteria was 6 (21.4%). Although the mean age of malignant patients was significantly higher than benign patients (P = 0.046), there was no significant difference between 2 groups in terms of gender, tumor size, capsule invasion, perineural invasion, vascular invasion, and margin status. Conclusion: SPN is a rarely seen tumor with low malignity potential. Surgical resection provides long-term survival rate even in local invasion or metastasis conditions. © 2018 Elsevier Inc.

Expression of regenerating islet-derived protein 4 (REG4), a secretory protein involved in cell differentiation and proliferation, is upregulated in inflammatory bowel diseases and in many gastrointestinal malignancies. The prognostic significance of its expression in pancreatic ductal adenocarcinoma is unknown. Our aim was to investigate tumor tissue and serum REG4 expression in pancreatic ductal adenocarcinoma patients. We also evaluated as a control the diagnostic value of serum REG4 level in patients with chronic pancreatitis. Immunohistochemical expression of REG4 was evaluated in 154 surgical specimens and serum REG4 level in 130 samples from pancreatic ductal adenocarcinoma patients treated at Helsinki University Hospital, Finland, in 2000–2011. REG4 tissue and serum expression was assessed in relation to clinicopathological parameters and patient survival. A chronic pancreatitis control group comprised 34 patients who underwent pancreatic resection because of suspicion of malignancy. Significant survival differences were detectable in subgroups: in tumor stages IA–IIA, high serum REG4 level predicted worse survival (p=0.046). In patients with grade I tumor, positive tissue REG4 expression predicted better survival (p=0.006). In multivariate analysis, neither tissue nor serum REG4 expression was independent prognostic factors. Serum REG4 levels were higher in pancreatic ductal adenocarcinoma than in chronic pancreatitis (p=0.002), with diagnostic sensitivity of 45% and specificity of 91%. In logistic regression analysis, a multivariate model with REG4, CA19-9, and age provided sensitivity of 82% and specificity of 79%. REG4 tissue expression is a prognostic marker in subgroups of pancreatic ductal adenocarcinoma patients. Serum REG4 level might be useful in differential diagnosis between pancreatic ductal adenocarcinoma and chronic pancreatitis. © 2018, © The Author(s) 2018.

Background/objectives: Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) for low-grade malignant pancreas tumors was recently demonstrated. Although the procedure with splenic vessel preservation (SVP) is optimal for LSPDP, SVP is not always possible in patients with a large tumor or a tumor attached to splenic vessels. This study aimed to analyze the safety of two procedures: LSPDP without SVP, known as the Warshaw technique (lap-WT), and LSPDP with SVP (lap-SVP). Methods: Seventeen patients who underwent a lap-WT and seven patients who underwent a lap-SVP were investigated retrospectively. Results: The median follow-up duration was 45 (range 17-105) months. In the lap-WT and lap-SVP patients, the sizes of the tumors were 5 (1.3-12) and 1.5 (1-4) cm; the operative times were 304 (168-512) and 319 (238-387) min; the blood loss was 210 (5-3250) and 60 (9-210) gr; the length of the postoperative hospital stay was 15 (8-29) and 18 (5-24) days; the peak platelet counts were 37.2 (14.6 -65.2) and 26.4 (18.8-41) × 104/μL, and splenomegaly was observed in 10 (59%) and three (43%) patients, respectively. In both procedures, there was no local recurrence. In the lap-WT group, splenic infarctions were seen in four (24%) patients and perigastric varices were seen in two (12%) patients. All of these patients were observed conservatively. Conclusions: Both the lap-WT and lap-SVP were found to be safe and effective, and in cases in which the tumor is relatively large or close to the splenic vessels, lap-WT can be used as the more appropriate procedure., Pancreatology, 14(6), pp.530-535; 2014

Transforming growth factor [31 (TGF beta 1) is a well -established inducer of the epithelial-mesenchymal transition (EMT) that is essential for the acquisition of malignant properties, such as invasion, in tumor cells. Although recent studies suggest that the EMT in tumor cells is associated with reprogramming of energy metabolism and TGF beta 1 has been shown to stimulate glycolysis in multiple primary cell lines, little is known about TGF beta l 's effect on glycolysis and glycolytic regulators in transformed cells. Given the known regulatory role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-3 (PFKFB3) in glycolysis and association of glycolytic activity with malignant features such as invasion, we sought to investigate whether TGF beta 1 regulates PFKFB3 expression and if PFKFB3 is involved in the TGF beta l -mediated increase in the invasive ability of the Panc1 cell cline a well -established model of TGF beta 1 -initiated EMT. Herein we demonstrate that TGF beta 1 induces PFKFB3 expression and stimulates glycolysis in Panci cells. We also show that s1RNA silencing of PFKFB3 prevents the stimulation of glycolysis and in vitro invasive ability of Panci cells by TGF beta 1. Furthermore, PFKFB3 silencing suppresses the TGFfil -mediated induction of the Snail protein, suggesting that PFKFB3 is required for the regulation of Snail expression by TGFfil. Taken together, our study identifies PFKFB3 as a key TGF beta 1 effector protein that mediates TGF beta 1's effect on Snail expression, invasion, and glycolysis.

Von Hippel-Lindau syndrome (VHL) is an autosomal dominant inherited disease associated with mutations in the VHL tumour suppressor gene located on chromosome 3p25. VHL is characterized by the development of multiple malignant and benign tumours in the central nervous system and internal organs, including liver, pancreas and the adrenal gland. More than 823 different mutations of the VHL gene have currently been identified. In the present study we describe the case of a family affected by VHL treated at the University Hospital of La Ribera and the results of the genetic analysis of three relatives, identifying the mutation R167G in exon 3 of VHL gene as the cause of VHL syndrome in this family. © 2016 Sociedad Española de Anatomía Patológica

Background: Occupational exposure to acrylamide was associated with excess mortality from pancreatic cancer, though in the absence of dose-risk relationship. Few epidemiological studies have examined the association between acrylamide from diet and pancreatic cancer risk. Patients and methods: We considered this issue in a combined set of 1975 cases of pancreatic cancer and 4239 controls enrolled in six studies of the Pancreatic Cancer Case-Control Consortium (PanC4). We calculated pooled odds ratios (ORs) and their 95% confidence intervals (CI) by estimating study-specific ORs through multivariate unconditional logistic regression models and pooling the obtained estimates using random-effects models. Results: Compared with the lowest level of estimated dietary acrylamide intake, the pooled ORs were 0.97 (95% CI, 0.79-1.19) for the second, 0.91 (95% CI, 0.71-1.16) for the third, and 0.92 (95% CI, 0.66-1.28) for the fourth (highest) quartile of intake. For an increase of 10 mg/day of acrylamide intake, the pooled OR was 0.96 (95% CI, 0.87-1.06), with heterogeneity between estimates (I2 = 67%). Results were similar across various subgroups, and were confirmed when using a one-stage modelling approach. Conclusions: This PanC4 pooled-analysis found no association between dietary acrylamide and pancreatic cancer. © The Author 2016.

Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm that accounts for 2-3% of all primary pancreatic neoplasms. This study aimed to characterize clinicopathological features associated with SPNs and to retrospectively evaluate the relationship of these features with predictive parameters associated with aggressive behavior. We reviewed 16 cases of SPN of the pancreas that had been diagnosed between 2005 and 2014 at our pathology department. A total of 16 cases, 15 female and one male, were evaluated in this study. The patient age ranged from 13 years to 63 years with a median of 35.70 years. The mean tumor diameter ranged from 2 cm to 18 cm with a mean diameter of 5.90 cm. We identified a significant association between the presence of clear cells and perineural invasion (p = 0.019), which was considered to be a predictive factor for aggressive behavior. Other features (i.e., localization, nuclear grooves, central hyalinization, myxoid stroma, eosinophilic bodies, foamy histiocyte aggregates, multinucleated cells, and calcification) were not significantly associated with predictive factors for aggressive behavior. One patient died as a result of a pancreatic fistula that developed as a postoperative complication. The remaining 15 patients are alive and have not demonstrated any signs of recurrence or metastasis. The current study suggested that the presence of clear cells might serve as a possible prognostic indicator of perineural invasion, which is a predictive parameter associated with aggressive behavior in SPN. Copyright

Objectives: The success of gemcitabine plus radiotherapy is dependent on the mutation status of pancreatic ductal adenocarcinoma (PDAC) tumors in the EGFR and KRAS genes; however, radiotherapy resistance may also be modulated epigenetically by microRNA (miRNA) regulation. In this study, we examined the potential effect of miRNAs on the resistance to radiotherapy in cases without EGFR or KRAS mutation. Methods: The association of EGFR and KRAS mutation status and different expression patterns of 6 selected miRNAs related to the EGFR/KRAS signaling pathway were evaluated in the tumors of 42 patients with PDAC. Results: Reduced miR-216b and miR-217 expression was associated with aggressive tumor characteristics and shortened disease-free survival. In addition, miR-216b expression was reduced 2.7-fold in the cases that did not benefit from therapy, although they did not demonstrate EGFR or KRAS expression (P = 0.0316). A negative correlation between FGFR1 and miR-216b expression (r = -0.355) was found in the tumors of these cases. Conclusions: Further studies and validations are required; in the tumors of patients with PDAC without activating mutations and induced expression of EGFR/KRAS genes, down-regulated miR-216b expression may be associated with a poor response to radiotherapy via deregulation of another signaling pathway related to FGFR1 signaling.

Novel and combinatorial treatment methods are becoming sought after entities in cancer treatment and these treatments are even more valuable for pancreatic cancer. The scientists are always on the lookout for new chemicals to help them in their fight against cancer. In this study, we examine the effects of ferulic acid (FA), a phenolic compound, on gene expression, viability, colony formation and migration/invasion in the cultured MIA PaCa-2 human pancreatic cancer cell. Cytotoxic effects of FA were determined by using trypan blue dye exclusion test and Cell TiterGlo (CTG) assay. IC50 dose in MIA PaCa-2 cells was detected as 500μM/ml at the 72nd hour. Expression profiles of certain cell cycle and apoptosis genes such as CCND1 (cyclin D1),CDK4, CDK6, RB, p21, p16, p53, caspase-3, caspase-9, caspase-8, caspase-10, Bcl-2, BCL-XL,BID, DR4,DR5,FADD,TRADD,PARP, APAF, Bax, Akt, PTEN, PUMA, NOXA, MMP2, MMP9, TIMP1 and TIMP2 were determined by real-time PCR. The effect of FA on cell viability was determined by CellTiter-Glo® Luminescent Cell Viability Assay. Additionally, effects of FA on colony formation and invasion were also investigated. It was observed that FA caused a significant decrease in the expression of CCND1, CDK 4/6, Bcl2 and caspase 8 and 10 in the MIA PaCa-2 cells while causing an increase in the expression of p53, Bax, PTEN caspase 3 and 9. FA was observed to decrease colony formation while inhibiting cell invasion and migration as observed by the BioCoat Matrigel Invasion Chamber guide and colony formation assays. In conclusion, FA is thought to behave as an anti-cancer agent by affecting cell cycle, apoptotic, invasion and colony formation behavior of MIA PaCa-2 cells. Therefore, FA is placed as a strong candidate for further studies aimed at finding a better, more effective treatment approach for pancreatic cancer. © 2015 Elsevier B.V.

Background/objectives Cachexia affects ∼80% of pancreatic cancer patients. An international consensus defines cachexia as an ongoing loss of skeletal muscle mass (sarcopenia) with or without loss of fat, which impairs body functioning and cannot be reversed by conventional nutritional measures. Weight loss percentage and elevated inflammation markers have been employed to define this condition earlier. This review aimed to assess the prevalence and consequences of cachexia and sarcopenia on survival in patients with pancreatic ductal adenocarcinoma. Methods The systematic review was performed by searching the articles with preset terms published in PubMed and Cochrane Database until December 2013. After identifying relevant titles, abstracts were read and eligible articles data retrieved on preformatted sheets. The prevalence and impact of sarcopenia/cachexia on survival was evaluated. Results In total 1145 articles were retrieved, only 10 were eligible. Definitions of cachexia and sarcopenia were heterogeneous. In patients with normal weight (BMI 18.5-24.9 kg/m2) the prevalence of sarcopenia ranged from 29.7 to 65%. In overweight or obese patients (BMI >25 kg/m2) were 16.2%-67%. Sarcopenia alone was not demonstrated to be an independent factor of decreased survival, although obese sarcopenic patients were shown to have significantly worse survival in two studies. Conclusions Impact of cachexia and sarcopenia on survival in pancreatic ductal adenocarcinoma is currently understudied in the available literature. Definitive association between cachexia and survival cannot be drawn from available studies, although weight loss and sarcopenic obesity might be considered as poor prognostic factors. Further prospective trials utilizing the consensus definition of cachexia and including other confounding factors are needed to investigate the impact of cachexia and sarcopenia on survival in pancreatic adenocarcinoma. © 2014 IAP and EPC.