Accumulating evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth. Recently, there have been efforts to explain drug resistance of cancer cells based on the concept of CSCs having an intrinsic detoxifying mechanism. In the present study, to investigate the role of CSCs in acquiring chemoresistance in pancreatic cancer, gemcitabine‐resistant cells were established by exposure to serially escalated doses of gemcitabine in HPAC and CFPAC‐1 cells. Gemcitabine‐resistant cells were more tumorigenic in vitro and in vivo, and had greater sphere‐forming activity than parental cells. After high‐dose gemcitabine treatment to eliminate most of the cells, CD44⁺ cells proliferated and reconstituted the population of resistant cells. CD44⁺CD24⁺ESA⁺ cells remained as a small subset in the resistant cell population. Among ATP‐binding cassette (ABC) transporters, which are known as the mechanism of drug resistance in CSCs, ABCB1 (MDR1) was significantly augmented during the acquisition of drug resistance. ABC transporter inhibitor verapamil resensitized the resistant cells to gemcitabine in a dose‐dependent manner and RNA interference of CD44 inhibited the clonogenic activity of resistant cells. In human pancreatic cancer samples, CD44 expression was correlated with histologic grade and the patients with CD44‐positive tumors showed poor prognosis. These data indicate that cancer stem‐like cells were expanded during the acquisition of gemcitabine resistance and in therapeutic application, targeted therapy against the CD44 or ABC transporter inhibitors could be applied to overcome drug resistance in the treatment of pancreatic cancer. © 2009 UICC

In this study, we aimed to assess the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) measured on ¹⁸F-FDG PET/CT in pancreatic cancer patients who underwent resection with curative intent. Methods: Eighty-seven patients with pancreatic ductal adenocarcinoma who underwent ¹⁸F-FDG PET/CT and subsequent surgical resection with curative intent with (30 patients) or without (57 patients) neoadjuvant therapy were retrospectively enrolled. The maximum standardized uptake value (SUVmax), MTV, and TLG were measured on ¹⁸F-FDG PET/CT in all patients. The prognostic significances of PET/CT parameters and tumor factors for recurrence-free survival (RFS) and overall survival (OS) were evaluated by univariate and multivariate analyses. Results: Of the 87 patients, 57 (64%) experienced recurrence during the follow-up period. The tumor size, pathologic T (pT) stage, SUVmax, MTV, and TLG were significant prognostic factors for both RFS and OS (P < 0.05) on univariate analyses, and the presence of lymph node metastasis showed significance only for predicting RFS (P < 0.05). On multivariate analyses, the tumor size, MTV, and TLG were independent prognostic factors for RFS, and pT stage, MTV, and TLG were independent prognostic factors for OS. For the 57 patients who did not undergo neoadjuvant treatment, MTV and TLG remained significant predictive factors for tumor recurrence, along with tumor size and SUVmax. Conclusion: MTV and TLG are independent prognostic factors for predicting RFS and OS in patients with pancreatic cancer. Thus, ¹⁸F-FDG PET/CT can provide useful prognostic information for patients undergoing resection of pancreatic cancer with curative intent irrespective of neoadjuvant treatment.

Goals The aims of this study were to determine the clinical use of 18-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) in the differential diagnosis of patients with suspected pancreatic cancer and in the determination of tumor response after concurrent chemoradiotherapy for pancreatic cancer. Background Despite advances in diagnostic tools for pancreatic cancer, it is difficult to differentiate pancreatic cancer from mass-forming pancreatitis. Even with current imaging modalities, it is also difficult to assess tumor response to therapeutic intervention. Study One hundred two patients with suspected pancreatic cancer were selected for this study. Dynamic computerized tomography (CT) scan and ¹⁸FDG-PET were used sequentially to diagnose pancreatic cancer. After diagnostic confirmation their diagnostic yields were compared. We also evaluated the treatment response in 15 patients who underwent chemoradiation therapy with dynamic CT scan and ¹⁸FDG-PET and compared their results. Results In 93 out of 102 patients, pancreatic cancer was confirmed. ¹⁸FDG-PET showed higher diagnostic accuracy than CT scan (95.1% vs. 76.5%). ¹⁸FDG-PET was also superior to CT in the detection of liver metastasis. ¹⁸FDG-PET detected treatment response in 5 out of 15 cases after chemoradiation therapy, whereas CT could not detect any treatment response. Comparing responder and nonresponder, ¹⁸FDG-PET was able to predict significantly different prognosis (399 vs. 233 d, P<0.05). Conclusions ¹⁸FDG-PET is a very useful tool in diagnosing pancreatic cancer. ¹⁸FDG-PET may be also used as an adjunct for determining the treatment modality of pancreatic cancer and evaluating tumor response to chemoradiation therapy.

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

[6]-Gingerol, a major phenolic compound derived from ginger, has anti-bacterial, anti-inflammatory and anti-tumor activities. While several molecular mechanisms have been described to underlie its effects on cells in vitro and in vivo, the underlying mechanisms by which [6]-gingerol exerts anti-tumorigenic effects are largely unknown. The purpose of this study was to investigate the action of [6]-gingerol on two human pancreatic cancer cell lines, HPAC expressing wild- type (wt) p53 and BxPC-3 expressing mutated p53. We found that [6]-gingerol inhibited the cell growth through cell cycle arrest at G1 phase in both cell lines. Western blot analyses indicated that [6]-gingerol decreased both Cyclin A and Cyclin-dependent kinase (Cdk) expression. These events led to reduction in Rb phosphorylation followed by blocking of S phase entry. p53 expression was decreased by [6]-gingerol treatment in both cell lines suggesting that the induction of Cyclin-dependent kinase inhibitor, p21cip1, was p53-independent. [6]-Gingerol induced mostly apoptotic death in the mutant p53-expressing cells, while no signs of early apoptosis were detected in wild type p53-expressing cells and this was related to the increased phosphorylation of AKT. These results suggest that [6]-gingerol can circumvent the resistance of mutant p53- expressing cells towards chemotherapy by inducing apoptotic cell death while it exerts cytostatic effect on wild type p53- expressing cells by inducing temporal growth arrest.