Introducing in vivo pancreatic cancer models for the study of new therapeutic regimens
T SychraR. VáclavíkováÁrpád SzabóAlžběta SpálenkováKarolína ŠeborováStepan BalatkaTereza TesařováKristaq KociR GürlichPavel SoučekM Oliverius
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Introduction: Pancreatic cancer is a severe oncological disease with an ever-increasing incidence and a high rate of morbidity and mortality. Therapeutic options are limited and the five-year overall survival rate is 7–20%, depending on the possibility of surgical resection and the earliness of detection. Most patients with this diagnosis die due to the resistance of tumour cells and their microenvironment to the used treatment regimes. Methods: In our study, we focused on the implementation of two in vivo models, which are the cell-line derived xenograft (CDX) and the patient-derived xenograft (PDX). These two models differ significantly from each other methodologically, technically, financially, but also in their achieved results. Results: In a pilot study, we managed to successfully implement the CDX model with a very aggressive and resistant PaCa-44 line of pancreatic cancer in a total of 30 NU/NU strain mice. Furthermore, we created three PDX models with various subtypes of pancreatic cancer from patients operated at the University Hospital Kralovske Vinohrady, Department of General Surgery. These tumours were re-transplanted into subsequent generations of 23 individuals of NOD/SCID strain and 47 NU/NU strain mice. The established CDX and PDX models are then used to compare conventional and experimental chemotherapy regimens. Conclusion: The next steps will be to evaluate the effects of treatment regimens by using imaging and molecular genetic methods and to optimise the entire process for further use in precise personalised medicine for patients with pancreatic cancer. The upcoming goal is to create a library of PDX models of the most common pancreatic ductal adenocarcinoma and other rare subtypes of pancreatic cancerPancreatic cancer is the fourth leading cause of cancer‑associated deaths in Western countries, and ranks sixth among cancer‑associated diseases, with the highest mortality rate in China. Deregulation of micro (miR) RNA may contribute to the occurrence and progression of numerous cancers, including pancreatic cancer. In particular, deregulation of microRNA‑720 (miR‑720) has been reported in various types of human cancer. However, the expression and biological role of miR‑720 in pancreatic cancer remains to be elucidated. The present study aimed to investigate the expression and functional role of miR‑720 in pancreatic cancer and determine the underlying regulatory mechanism. The results demonstrated that miR‑720 was expressed at low levels in pancreatic cancer tissue samples and cell lines. Upregulating miR‑720 suppressed pancreatic cancer cell proliferation and invasion in vitro. Additionally, cyclin D1 (CCND1) was identified as the direct target gene of miR‑720 in pancreatic cancer. Furthermore, CCND1 was significantly upregulated in pancreatic cancer tissues and inversely correlated with miR‑720 expression. Furthermore, CCND1 re‑expression partially abrogated the inhibitory effects of miR‑720 on pancreatic cancer cells. Overall, miR‑720 may act as a tumor suppressor by directly targeting CCND1 in pancreatic cancer.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extraordinarily aggressive cancer that arises in the context of a unique tumor microenvironment. Molecularly, PDAC involves a combination of undruggable cancer drivers, including activating mutations in the KRAS oncogene and disruption of tumor suppressors such a TP53, SMAD4, and CDKN2A together with poorly characterized epigenetic changes that correlate with metastatic progression. Histologically, PDAC arises within a heterogeneous tissue microenviroment characterized by dense fibroinflammatory stroma that influences disease progression and limits therapy response. Our laboratory has developed genetically engineered mouse models based on ES cells (GEMMESCs) of pancreas cancer, where chimeric mice are produced directly from multiallelic ES cells harboring a latent KrasG12D oncogene together with all the genetic elements needed for Kras activation in the together with those needed for tetracycline-inducible (and reversible) regulation of short hairpin RNAs targeting capable of suppressing any gene of interest at any time after pancreas cancer initiation. Using this system, we have probed the epigenetic requirements for pancreas cancer initiation and compare them to those required for pancreatic regeneration following tissue damage; in addition, we have explored the metabolic programs needed for p53 to suppress tumorigenesis. Our studies have identified elements of cellular plasticity that act at multiple points that suppress pancreas cancer progression and identify actionable intervention points required for these transitions. Citation Format: Scott W. Lowe. Understanding and exploiting natural barriers to pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I25.
Tumor initiation
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With a high invasive ability and poor prognosis, the morbidity of pancreatic cancer is about 98%. Combination of chemotherapy and radiotherapy is the primary management for locoregionally advanced pancreatic cancer, but its effi cacy is limited. Results from a number of meta-analysis have confi rmed that gemcitabine is associated with signifi cantly better clinical response and one-year overall survival rates; therefore, currently gemcitabine is the standard chemotherapy for advanced pancreatic cancer. Gemcitabine-based multi-drug regimens may have potentially favorable effects on patients’ survival. However, evidence from phase Ⅲ clinical trials is lacking. Newer chemotherapy and targeted therapy agents are clearly needed for patients with advanced pancreatic cancer.
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Tumor progression
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[Objective]Explore Breast cancer surgery Kangai injection Chemotherapy combined application of the clinical curative effect.[Methods]Breast cancer surgery will be 60 cases were randomly divided into trial group and control group each 30 cases,the observation group application Kangai injection combination Chemotherapy treatment,the control group limited to Chemotherapy treatment,compared between the two groups of patients with clinical symptoms improved.[Results]The observation group of patients GaiShanLv for 90.00%,in the patients in the GaiShanLv is 73.33%,the observation group significantly better than control group,two groups of comparisons,the difference was statistically significant(P 0.05).[Conclusion]Breast cancer postoperative Chemotherapy combined application Kangai injection treatment,curative effect is distinct,Chemotherapy drugs significantly reduce the side effects on the body,increase the body's immune function,and can effectively improve the quality of life of the patients,and the use of safe,convenient.
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The material forming the basis of this report was obtained from my records of cases at the Mayo Clinic and my service at Augustana Hospital, Chicago. Of the 712 cases studied, all had been operatively and pathologically proved to be gastric cancer. Doubtful cases were excluded.
Sex.
—The sex ratio was approximately that of gastric ulcer; namely, 483 males and 229 females, or 2.1 to 1.Age.
—While instances were recorded at as low as 20 years, the age of more than three-fourths of the patients ranged between the fifth and the eighth decades.Etiologic Factors.
—A family or blood-relationship history was proved in 9.4 per cent. of cases. A history of trauma was demonstrated in 3.1 per cent. of instances. In 2.2 per cent, the trauma appeared to precipitate symptoms. With respect todefinite symptomatology, it is well to admit here that 1.9 per cent. of cases gave absolutelyGeneral hospital
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Objective To improve the patients with advanced lung cancer quality of life,reduce the chemotherapy-induced side effects,thereby enhancing immune function. Methods The treatment group Kangai injection 60 ml in 5% glucose or 0.9% NS 250~500 ml diluted intravenous drip,once/d,30 d for a course of treatment,combined with chemotherapy. The control group alone with chemotherapy. Results 47.5% effective in the treatment group,37.5% effective in the control group. Conclusion Kangai injection combined with chemotherapy can improve the quality of life of patients and reduce the toxicity,and enhance immune function in patients.
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4189 Background: Radiologic evaluation of the efficacy of chemotherapy regimens in pancreatic cancer is difficult. The aim of this study was to evaluate the role of baseline CA 19–9 and the decrease in CA 19–9 after one cycle of chemotherapy as predictors of response, time to progression, and survival. Methods: Three consecutive phase II trials evaluating the role of gemcitabine and cisplatin based chemotherapy have been conducted by our group between 1997 and 2004. A total of 111 patients (pts) were enrolled on the trials. A retrospective chart review was performed for demographic data, best response status, time to progression, survival, and CA19–9 levels. Response by CA 19–9 (R-CA19–9) was defined as a decrease of ≥ 50% in CA 19–9 after the completion of the first cycle of chemotherapy. Results: The median age was 59 years with 60% males. Median performance status was 1. No significant difference was observed across the three trials with respect to age, sex, or performance status. Baseline CA19–9 was known for 102 pts, and was grouped into tertiles: < 300; 300–4,499; and ≥ 4,500 ng/mL. Lower baseline CA19–9 levels were not associated with higher response rate (p = 0.7568): 18%; 26%, and 21%, respectively. Lower baseline CA19–9 was weakly associated with longer overall survival (OS), but not significantly so (p = 0.1011). Median OS was 9.2, 6.9, and 5.9 months, respectively. Similar results were observed for time to progression (TTP), with p = 0.0977, and median TTP of 6.3, 5.3, and 4.2 months, respectively. The change in CA19–9 from baseline to the end of treatment cycle 1 was available for 68 pts. The pts with R-CA19–9 had a higher radiologic response rate (29%) than did the other pts (24%), but not significantly so (p = 0.7495). The pts with R-CA19–9 had longer OS (median 8.7 vs 7.1 months) and longer TTP (median 7.1 vs 5.4 months), but not significantly so (p > 0.42 for each endpoint). Conclusions: Both lower baseline CA19–9 and R-CA19–9 after treatment cycle 1 were each weakly but negatively associated with prognosis in our patient population. These data suggest that a 50% decrease in CA19–9 after the first cycle of chemotherapy is not a useful predictor of response, time to progression, or survival. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Aventis, Lilly Oncology
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Surgical treatment has improved the prognosis of resectable pancreatic cancer considerably de-spite the generally aggressive behavior of its malignancy. Neoadjuvant therapy for pancreatic cancer has been shown effective in improving a survival benefit. Few prospective randomized controlled clinical trials (RCTs) on the use of neoadjuvant chemotherapy and chemoradiation has been done tp show the survival advantage of systemic chemotherapy (5-FU/FA or gemcitabine) following surgical resection. Up to now, there is no high-level evidence of any benefit deriving from neoadjuvant chemo therapy for pancreatic cancer. Well designed trials are needed to compare neoadjuvant chemotherapy with surgery to judge the value of neoadjuvant cherqo-therapy in multimodal treatment concepts of pancreatic cancer.
Key words:
pancreatic cancer; neoadjuvant chemotherapy
Neoadjuvant Therapy
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Individualized chemotherapy is important in the treatment of pancreatic cancer. Therefore, markers for predicting a patient response to treatment must be identified. We studied the relationship between human equilibrative nucleoside transporter 1 (hENT1) expression in tumor cells and the Asian patient response to gemcitabine-based chemotherapy. The aim of the study was to identify markers for individualized chemotherapy in Asian patients with pancreatic cancer.Specimens from 44 Asian patients diagnosed with pancreatic adenocarcinoma were analyzed by immunohistochemistry for hENT1 expression in tumor cells. The correlations between hENT1 expression and various clinicopathological factors, including survival status, were studied.The overall survival (OS) and disease-free survival (DFS) in the hENT1 high-expression group were significantly longer than those of the hENT1 low or no-expression group: OS 21.75 months (95%CI=18.45-25.04 months) vs. 12.48 months (95%CI=10.12-14.85 months); DFS 15.44 months (95%CI=11.26-19.62 months) vs. 8.24 months (95%CI=8.69-9.78 months), respectively.Our studies suggest that hENT1 expression is related to the patient response to gemcitabine-based chemotherapy in Asian patients with pancreatic cancer. Therefore, hENT1 may be a valuable prognostic marker for individualized chemotherapy in pancreatic cancer.
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