Irreversible electroporation for metastatic pancreatic carcinoma with liver metastasis:What does the evidence say

Irreversible electroporation is a promising non-thermal ablation method that has been shown to increase overall survival in locally advanced pancreatic cancer in some studies.However,higher quality studies with proper controls and randomization are required to establish its superiority when added with neoadjuvant chemotherapy over the current management of choice,which is chemotherapy alone.Further studies are required before establishment of any survival benefit in metastatic pancreatic carcinoma,and such evidence is lacking at present.

Advancements of molecular imaging and radiomics in pancreatic carcinoma

Despite the recent progress of medical technology in the diagnosis and treatment of tumors,pancreatic carcinoma remains one of the most malignant tumors,with extremely poor prognosis partly due to the difficulty in early and accurate imaging evaluation.This paper focuses on the research progress of magnetic resonance imaging,nuclear medicine molecular imaging and radiomics in the diagnosis of pancreatic carcinoma.We also briefly described the achievements of our team in this field,to facilitate future research and explore new technologies to optimize diagnosis of pancreatic carcinoma.

Value of three-dimensional reconstructions in pancreatic carcinoma using multidetector CT:Initial results

AIM:To evaluate the use of three-dimensional imaging of pancreatic carcinoma using multidetector computed tomography(CT)in a prospective study.METHODS:Ten patients with suspected pancreatic tumors were examined prospectively using multidetec-tor CT(Somatom Sensation 16,Siemens,Erlangen,Germany).The images were evaluated for the pres-ence of a pancreatic carcinoma and invasion of the peripancreatic vessels and surrounding organs.Using the isotropic CT data sets,a three-dimensional image was created with automatic vascular analysis and semi-automatic segmentation of the organs and pancreatic tumor by a radiologist.The CT examinations and the three-dimensional images were presented to the sur-geon directly before and during the patient's operation using the Medical Imaging Interaction Toolkit-based software "ReLiver".Immediately after surgery,the value of the two images was judged by the surgeon.The operation and the histological results served as the gold standard.RESULTS:Nine patients had a pancreatic carcinoma(all pT3),and one patient had a serous cystadenoma.One tumor inf iltrated the superior mesenteric vein.The inf iltration was correctly evaluated.All carcinomas were resectable.In comparison to the CT image with axial and coronal reconstructions,the three-dimensional image was judged by the surgeons as better for operation planning and consistently described as useful.CONCLUSION:A 3D-image of the pancreas repre-sents an invaluable aid to the surgeon.However,the 3D-software must be further developed in order to be integrated into daily clinical routine.

Pancreatic carcinoma coexisting with chronic pancreatitis versus tumor-forming pancreatitis:Diagnostic utility of the time-signal intensity curve from dynamic contrast-enhanced MR imaging

AIM: To evaluate the ability of the time-signal intensity curve (TIC) of the pancreas obtained from dynamic contrast-enhanced magnetic resonance imaging (MRI) for differentiation of focal pancreatic masses, especially pancreatic carcinoma coexisting with chronic pancreatitis and tumor-forming pancreatitis. METHODS: Forty-eight consecutive patients who underwent surgery for a focal pancreatic mass, including pancreatic ductal carcinoma (n = 33), tumor-forming pancreatitis (n = 8), and islet cell tumor (n = 7), were reviewed. Five pancreatic carcinomas coexisted with longstanding chronic pancreatitis. The pancreatic TICs were obtained from the pancreatic mass and the pancreatic parenchyma both proximal and distal to the mass lesion in each patient, prior to surgery, and were classified into 4 types according to the time to a peak: 25 s and 1, 2, and 3 min after the bolus injection of contrast material, namely, type-Ⅰ, Ⅱ, Ⅲ, and Ⅳ, respectively, and were then compared to the corresponding histological pancreatic conditions. RESULTS: Pancreatic carcinomas demonstrated type-Ⅲ (n = 13) or Ⅳ (n = 20) TIC. Tumor-forming pancreatitis showed type-Ⅱ (n = 5) or Ⅲ (n = 3) TIC. All islet cell tumors revealed type-Ⅰ. The type-Ⅳ TIC was only recognized in pancreatic carcinoma, and the TIC of carcinoma always depicted the slowest rise to a peak among the 3 pancreatic TICs measured in each patient, even in patients with chronic pancreatitis.CONCLUSION: Pancreatic TIC from dynamic MRI provides reliable information for distinguishing pancreatic carcinoma from other pancreatic masses, and may enable us to avoid unnecessary pancreatic surgery and delays in making a correct diagnosis of pancreatic carcinoma, especially, in patients with longstanding chronic pancreatitis.

Antiangiogenic therapy for human pancreatic carcinoma xenografts in nude mice

AIM: To investigate the anti-tumor effects of antiangiogenic therapy (a combination of TNP-470, an antiangiogenic compound, with gemcitabine, an antimetabolite) on human pancreatic carcinoma xenografts and its mechanism. METHODS: A surgical orthotopic implantation (SOI) model was established by suturing small pieces of SW1990 pancreatic carcinoma into the tail of pancreas in nude male mice. Mice then received either single therapy (n = 24) or combined therapy (n = 32). Mice receiving single therapy were randomly divided into control group, G100 group receiving 100 mg/kg gemcitabine IP on d O, 3, 6 and 9 after transplantation, and T30 group receiving 30 mg/kg TNP-470 s.c on alternate days for 8 wk. Mice receiving combined therapy were randomly divided into control group, T15 group, G50 group and combination group (TNP-470 30 mg/kg and gemcitabine 50 mg/kg). Animals were killed 8 wk after transplantation. Transplanted tumors, liver, lymph node and peritoneum were removed. Weight of transplanted tumors, the T/C rate (the rate of mean treated tumor weight to mean control tumor weight), change of body weight, metastasis rate, and 9-wk survival rate were investigated. Tumor samples were taken from the control group, T30 group, G100 group and combination group. PCNA index (PI) and microvessel density (MVD) were investigated by immunohistochemical staining for PCNA and factor VIII, respectively. RESULTS: There was a significant inhibitory effect on primary tumor growth of pancreatic carcinoma in G100 group, compared to T30 group, whereas tumor metastasis was significantly inhibited in T30 group compared to G100 group. There was no significant improvement in survival rate in these two groups. No significant inhibitory effect on tumor growth and metastasis in T15 group and G50 group. However, significant anti-tumor and anti-metastatic effects were observed in the combination group with a significant improvement in survival rate. The inhibitory effect on tumor growth in combination group enhanced 2 times in comparison with G50 group and 5 times in comparison with T15 group. Moreover, 25% of the animals hearing tumors were cured by the combination therapy. The levels of MVD and PI were 14.50±5.93 and 0.41±0.02,12.38±1.60 and 0.30±0.07, 7.13±2.99 and 0.37±0.03, and 5.21±1.23 and 0.23±0.02 respectively in the control group, G100 group, T30 group and combination group. A significant inhibitory effect on PI level and MVD level was observed in G100 group and T30 group respectively whereas both MVD and PI levels were significantly inhibited in the combination group (P<0.05). CONCLUSION: Antiangiogenic therapy shows significant anti-tumor and anti-metastatic effects, and is helpful to reduce the dosage of cytotoxic drugs and the side effects. These effects are related to the antiangiogenic effect of TNP-470 and cytotoxic effect of gemcitabine.

Clinical value of serum CA19-9 levels in evaluating resectability of pancreatic carcinoma

AIM:To evaluate the clinical value of serum CA19-9 levels in predicting the respectability of pancreatic carcinoma according to receiver operating characteristic(ROC) curve analysis. METHODS:Serum CA19-9 levels were measured in 104 patients with pancreatic cancer which were possible to be resected according to the imaging. ROC curve was plotted for the CA19-9 levels. The point closest to the upper left-hand corner of the graph were chosen as the cut-off point. The sensitivity,specificity,positive and negative predictive values of CA19-9 at this cut-off point were calculated. RESULTS:Resectable pancreatic cancer was detected in 58(55.77%) patients and unresectable pancreatic cancer was detected in 46(44.23%) patients. The area under the ROC curve was 0.918 and 95% CI was 0.843-0.992. The CA19-9 level was 353.15 U/mL,and the sensitivity and specificity of CA19-9 at this cut-off point were 93.1% and 78.3%,respectively. The positive and negative predictive value was 84.38% and 90%,respectively. CONCLUSION:Preoperative serum CA19-9 level is a useful marker for further evaluating the resectability of pancreatic cancer. Obviously increased serum levels of CA19-9(> 353.15 U/mL) can be regarded as an ancillary parameter for unresectable pancreatic cancer.

Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor γ involves angiogenesis inhibition

AIM： TO Study the possible actions and mechanisms or peroxisome proliferator-activated receptor γ （PPARγ）, a ligand-activated transcription factor, in pancreatic car- cinogenesis, especially in angiogenesis. METHODS： Expressions of PPARy and retinoid acid receptor （RXRα） were examined by reverse-transcription polymerase chain reaction （RT-PCR） with immunocyto- chemical staining. Pancreatic carcinoma cells, PANC-1, were treated either with 9-cis-RA, a ligand of RXRα, or with 15-deoxy-△12,14 prostaglandin J2 （15d-PGJ2）, a ligand of PPART, or both. Antiproliferative effect was evaluated by cell viability using methyltetrazolium （MTT） assay. A pancreatic carcinoma xenograft tumor model of nude mice was established by inoculating PANC-1 cells subcutaneously. Rosiglitazone, a specific ligand of PPARy, was administered via water drinking in experimental group of nude mice. After 75 d, all mice were sacrificed. Expression of proliferating cell nuclear antigen （PCNA） in tumor tissue was examined with immunohistochemical staining. Expression of vascular endothelial growth factor （VEGF） mRNA in PANC-1 cells, which were treated with 15d-PGJ2 or 9-cis-RA at various concentrations or different duration, was detected by semi-quantitative RT-PCR. Effects of Rosi- glitazone on changes of microvascular density （MVD） and VEGF expression were investigated in xenograft tumor tissue. Neovasculature was detected with immu- nohistochemistry staining labeled with anti-Ⅳ collagen antibody, and indicated by MVD. RESULTS： RT-PCR and immunocytochemical stain- ing showed that PPARγ and RXRα were expressed in PANC-1 cells at both transcription level and translation level. MTT assay demonstrated that 15d-PGJ2, 9-cis-RA and their combination inhibited the growth of PANC-1 cells in a dose-dependent manner. 9-cis-RA had a com- bined inhibiting action with 15d-PGJ2 on the growth of pancreatic carcinoma. In vivo studies revealed that Rosiglitazone significantly suppressed the growth of pancreatic carcinoma as compared to control group （0.48 ± 0.23 cm^3 vs 2.488 ± 0.59 cm^3, P 〈 0.05）, and the growth inhibition rate was 80.7%. Immuno- histochemistry study showed that PCNA was down regulated in Rosiglitazone-treated group compared to the control group. 15d-PGJ2, 9-cis-RA and their com- bination inhibited the expression of VEGF mRNA in PANC-1 cells in a dose- and time-dependent manner. MVD was decreased more significantly in Rosiglitazone- treated mice （10.67±3.07） than in the control group （31.44±6.06） （P 〈 0.01）. VEGF expression in xeno- graft tumor tissue was also markedly down-regulated in Rosiglitazone-treated mice. CONCLUSION： Activation of PPARγ, inhibits the growth of pancreatic carcinoma both in vitro and in vivo. Sup- pression of tumor angiogenesis by down-regulating the expression of VEGF may be one of the mechanisms by which PPARγ, activation inhibits the growth of pancre- atic carcinoma.

Proteomic analysis of pancreatic intraepithelial neoplasia and pancreatic carcinoma in rat models

AIM:To detect the proteomic variabilities of pancreatic intraepithelial neoplasia(PanIN)and pancreatic carcinoma(PC)induced by 7,12-dimethylbenzanthracene(DMBA) in rat models and to identify potential biomarkers.METHODS:Sixty adult male Sprague Dawley rats were randomized into three groups.The rats had DMBA implanted into their pancreas for one(n=20)or two months(n=20)or assigned to the normal group(n =20).The rats were killed after one or two months,and were evaluated histopathologically.Three tissue samples from each group of rats with either normal pancreas,PanIN(PanIN-2)or PC were examined by 2D-DIGE.The different expression spot features were analyzed by matrix-assisted laser desorption/ionizationtime of flight/time of flight(MALDI-TOF/TOF)tandem mass spectrometry.The expression of enolase 1,a differentially expressed protein,was identified by immu-nohistochemistry.RESULTS:There was significant difference in the proportions of neoplastic changes between the 1-and 2-mogroups(P=0.0488).There was an increase in the frequency of adenocarcinomas in the 2-mo group compared with the 1-mo group(P=0.0309).No neoplastic changes were observed in any of the animals in the normal group.Enolase 1,pancreatic ELA3B,necdin,Hbp23,CHD3,hnRNP A2/B1,Rap80,and Gnb2l1 were up-regulated in the PanIN and PC tissues,and CEL,TPT1,NME2,PCK2,an unnamed protein product,and glycine C-acetyltransferase were down-regulated in the PanIN and PC tissues.The immunohistochemical results showed that enolase 1 expression was up-regulated in the pancreatic cancer tissues of rats and humans.CONCLUSION:The pancreatic protein expression changes induced by DMBA suggest potential molecular targets for the early diagnosis and treatment of PC.

Inhibition of pancreatic carcinoma cell growth in vitro by DPC4 gene transfection

AIM: To detect the expression of DPC4 in malignant and non-malignant specimens of human pancreas,and observe the inhibition of retroviral pLXSN containing DPC4 on pancreatic carcinoma cells in vitro.METHODS: The expression of DPC4 was determined in 40 pancreatic adenocarcinoma and 36 non-malignant pancreatic specimens by reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohisto-chemistry.Furthermore,we constructed retroviral vectors containing DPC4,which then infected the pancreatic carcinoma cell line BxPC-3.Cell growth in vitro after being infected was observed,and the vascular endothelial growth factor (VEGF) mRNA level in the daughter cells was determined by semi-quantitative PCR assay.RESULTS: The RT-PCR assay showed a positive rate of DPC4 mRNA in 100% (36/36) of normal specimens,compared to 40% (16/40) in adenocarcinoma specimens.The regional and intense positive cases of DPC4 expression in adenocarcinoma detected by immunohistochemistry were 10 and four,whereas it was all positive expression in normal tissues.There was a significant difference of DPC4 expression between them.The stable expression of DPC4 in the pancreatic carcinoma cells BxPC-3 could be resumed by retroviral vector pLXSN transfection,and could inhibit cell growth in vitro.Rather,DPC4 could decrease VEGF mRNA transcription levels.CONCLUSION: The deletion of DPC4 expression in pancreatic carcinoma suggests that loss of DPC4 may be involved in the development of pancreatic carcinoma.The retroviral vector pLXSN containing DPC4 can inhibit the proliferation of pancreatic carcinoma cells,and down-regulate the level of VEGF.

Effect of antidepressants on body weight, ethology and tumor growth of human pancreatic carcinoma xenografts in nude mice

AIM: To investigate the effects of mirtazapine and fluoxetine, representatives of the noradrenergic and specific serotonergic antidepressant (NaSSA) and se- lective serotonin reuptake inhibitor (SSRI) antidepres- sant respectively, on body weight, ingestive behavior, locomotor activity and tumor growth of human pancre- atic carcinoma xenografts in nude mice. METHODS: A subcutaneous xenograft model of hu- man pancreatic cancer cell line SW1990 was estab- lished in nude mice. The tumor-bearing mice were ran- domly divided into mirtazapine group [10 mg/(kg·d)], fluoxetine group [10 mg/(kg·d)] and control group (an equivalent normal saline solution) (7 mice in each group). Doses of all drugs were administered orally, once a day for 42 d. Tumor volume and body weight were measured biweekly. Food intake was recorded once a week. Locomotor activity was detected weekly using an open field test (OFT). RESULTS: Compared to the fluoxetine, mirtazapine significantly increased food intake from d 14 to 42 and attenuated the rate of weight loss from d 28 to 42 (t = 4.38, P < 0.05). Compared to the control group, food intake was significantly suppressed from d 21 to 42 and weight loss was promoted from d 35 to 42 in the fluoxetine group (t = 2.52, P < 0.05). There was a significant difference in body weight of the mice after removal of tumors among the three groups. The body weight of mice was the heaviest (13.66 ± 1.55 g) in the mirtazapine group and the lightest (11.39 ± 1.45 g) in the fluoxetine group (F(2,12) = 11.43, P < 0.01). The behavioral test on d 7 showed that the horizontal and vertical activities were significantly increased in the mirtazapine group compared with the fluoxetine and control groups (F(2,18) = 10.89, P < 0.01). These effects disappeared in the mirtazapine and fluoxetine groups during 2-6 wk. The grooming activity was higher in the mirtazapine group than in the fluoxetine group (10.1 ± 2.1 vs 7.1 ± 1.9 ) (t = 2.40, P < 0.05) in the second week. There was no significant difference in tumor vol- ume and tumor weight of the three groups. CONCLUSION: Mirtazapine and fluoxetine have no effect on the growth of pancreatic tumor. However, mirtazapine can significantly increase food intake and improve nutrition compared with fluoxetine in a pan- creatic cancer mouse model.

Ultrasonic interventional analgesia in pancreatic carcinoma with chemical destruction of celiac ganglion

AIM： To detect the therapeutic effects of chemical destruction of celiac ganglion in patients with pancreatic carcinoma with intractable pain. METHODS： Ninety-seven cases with advanced pancreatic carcinoma received chemical destruction of celiac ganglion-5 mL pure alcohol injection around celiac artery under ultrasonic guidance. The changes of visual analogue scale （VAS）, serum substance P （Sub P）, β-endopeptide （β-EP） and T-lymphocyte subtypes level were compared between pre- and post-therapy. RESULTS： Successful rate of puncture was 98.7%, with one failure. No serious complications such as traumatic pancreatitis, pancreatic fistula, abdominal cavity hemorrhage or peritoneal infection occurred. VAS, serum Sub P and β-EP level significantly changed after treatment （8.0 ± 2.3 vs 4.6 ± 2.1, 254.1 ± 96.7 vs 182.4 ± 77.6, 3.2 ± 0.8 vs 8.8 ± 2.1, P 〈 0.01, P 〈 0.05, P 〈 0.01） with complete relief rate 54.2%, partial relief rate 21.9%, ineffective rate 12.5% and recurrent rate 10.7%. The T-lymphocyte subtypes level remarkably increased when compared with that of pre-therapy （46.7 ± 3.7 vs 62.5 ± 5.5, P 〈 0.01）. CONCLUSION： Our study suggests that chemical destruction of celiac ganglion under ultrasonic guidance is highly safe, and can evidently relieve cancer pain and improve the cellular immunity in patients with advanced pancreatic carcinoma.

Recombinant adenovirus-p53(Gendicine) sensitizes a pancreatic carcinoma cell line to radiation

Objective： In this study, we examine the effects of recombinant adenovirus-p53 （rAd-p53） on the pancreatic carcinoma cell line SW1990. Specifically, we determine if expression of rAd-p53 sensitizes these cells to radiation. Methods： Following transfection of SW1990 cells with rAd-p53, we measured expression of P53, P21 and Bax by immunocytochemistry. Both transfected and control cell lines were irradiated with a range of doses, and the survival fractions （SF） were calculated. Dose survival cttrves were constructed and modeled for comparison. Results： Transfection of SW1990 cells with rAd-p53 resulted in increased expression of P53, P21 and Bax in a time-dependent manner. At 96 h after transfection, 89.92% of cells expressed P53, 56.8% expressed P21, and 76.50% expressed Bax. The SF following radiation was lower in the rAd-p53 transfected cells compared to the control cells, suggesting that rAd-p53 sensitizes SW1990 cells to radiation （Do for the experimental and control groups was 2.199 and 2.462, respectively）. Conclusions： Use of the adenoviral vector is an effective means of transfecting SW1990 cells with wild-type P53, and this sensitizes the cell line to irradiation. This work suggests that combining rAd-p53 with radiation therapy in pancreatic cancer may be therapeutically beneficial.

Analysis of gene expression profiles in pancreatic carcinoma by using cDNA microarray

OBJECTIVES: To survey the gene expression profiles in pancreatic carcinoma by using cDNA microarray and detect target genes for further study. METHODS: Three mixed samples from 2 cases of normal pancreatic tissue and 4 cases of moderate-differentiated pancreatic carcinoma were studied by means of cDNA microarray consisting of 18 000 genes. RESULTS: 1484 and 1353 different expressed genes were observed in two cancer samples respectively. We identified 455 genes altered with the same tendency in both samples, including 102 up-regulated and 353 down-regulated genes. There were 274 known genes and 181 unknown genes; 27.8% and 52.0% genes respectively had an expression level in cancer that was 2-fold higher or lower than that in normal samples. Tumor suppressor genes, growth factors and receptor genes, signal conduction genes, transcription factor genes were identified. CONCLUSIONS: cDNA microarray is an efficient and high-throughout method to investigate gene expression profiles in pancreatic carcinoma. MBD1, EDG1 and gene hypermethylation mechanism would play an important role in the pathogenesis of pancreatic carcinoma.

Inhibition of Metastatic Progression of SSTR2 Gene Transfection Mediated by Adenovirus in Human Pancreatic Carcinoma Cells

The inhibition of metastatic progression of Somatostatin receptor type 2 （SSTR2） gene transfection mediated by adenovirus in human pancreatic carcinoma cells and the mechanisms involved in this effect were studied. The full-length human SSTR2 cDNA was introduced into the pancreatic cancer cell line BXPC-3 by adenovirus-mediated transfection. Stable expression of mRNAs and protein of SSTR2 was detected by RT-PCR and Western-blot. The Matrigel-coated Transwell was used to detect the migratory and invasive ability of SSTR2-expressing cells, Adv-GFP control cells and mock control cells. Furthermore, the expression of matrix metalloproteinase-2 （MMP-2） and tissue inhibitor of metalloproteinase-2 （TIMP-2） was detected by RT-PCR in these cells. The stable expression of SSTR2 was detected in BXPC-3 transfected by Adv-GFP-SSTR2. A dramatic decrease of BXPC-3 expressing sst2 cells migrating through a Matrigel-coated filter was observed, as compared with Adv-GFP control and mock control cells （P〈0. 01）. Moreover, the expression of MMP-2 mRNA was significantly reduced in the SSTR2-expressing cells and converse- ly the expression of TIMP-2 mRNA was significantly increased in the SSTR2-expressing cells when compared with the Adv-GFP control and mock control （P〈0. 01）. The expression of reintroduced human SSTR2 gene in BXPC-3 cells by Adv-GFP-SSTR2 had the anti-migratory and anti-invasive effects, and the mechanisms involved in this effect may be due to the down-regulated expression of MMP-2 and up-regulated expression of TIMP-2.

Diagnostic accuracy of K-ras mutation for pancreatic carcinoma:a meta-analysis

BACKGROUND:The conventional tests for the diagnosis of early stage pancreatic carcinoma are not acceptable.This metaanalysis is to evaluate the accuracy of K-ras mutation for the diagnosis of pancreatic carcinoma.DATA SOURCES:A systemic search of all relevant literature was performed in Web of Science,EMBASE,Cochrane Database,and MEDLINE(PubMed as the search engine) prior to June 1,2011.Thirty-four studies fulfilled the inclusion criteria and data were pooled for analysis.RESULTS:The pooled estimates for K-ras mutation in diagnosis of pancreatic carcinoma were as follows:sensitivity 0.68(95% CI:0.66-0.71),specificity 0.87(95% CI:0.85-0.88),positive likelihood ratio 4.54(95% CI:3.47-5.94),negative likelihood ratio 0.37(95% CI:0.30-0.44) and diagnostic odds ratio 14.90(95% CI:10.02-22.15).Summary receiver operating characteristic analysis demonstrated that the maximum joint sensitivity and specificity was 0.79,and the overall area under the curve was 0.86.CONCLUSIONS:Diagnostic accuracy of K-ras mutation was not superior to that of conventional tests.Therefore,K-ras mutation analysis alone is not recommended for the diagnosis of pancreatic carcinoma.

Utility of fusion CT-PET in the diagnosis of small pancreatic carcinoma

Pancreatic carcinoma has a poor prognosis and early detection is essential for potentially curative resection. Despite the wide array of diagnostic tools, preoperative detection of small pancreatic carcinomas remains difficult. We report a case of small pancreatic carcinoma of the head of pancreas with indeterminate findings on US, ERCP, MRI and EUS which was successfully diagnosed via fusion CT-PET. This case illustrates the utility of CT-PET in the diagnosis of patients with small pancreatic carcinoma with equivocal findings on conventional diagnostic modalities.

Chromic-P32 phosphate treatment of implanted pancreatic carcinoma: Mechanism involved

AIM: To study the effects of chromic-P32 phosphate (32p colloids) interstitial administration in Pc-3 implanted pancreatic carcinoma, and investigate its anticancer mechanism.METHODS: Ninety-eight tumor bearing nude mice werekilled at different time points after the injection of 32Pcolloids to the tumor core with observed radioactivity. The light microscopy, transmission electron microscopy (TEM) and immuno-histochemistry and flow cytometry were used to study the rates of tumor cell necrosis, proliferating cell nuclear antigen index, the micro vessel density (MVD). The changes of the biological response to the lymphatic transported 32p colloids in the inguinal lymph node (ILN) were dynamically observed, and the percentage of tumor cell apoptosis, and Apo2.7, caspase-3, Bcl-2, Baxrelated gene expression were observed too.RESULTS: The half-life of effective medication is 13 dafter injection of 32P colloids to the tumor stroma, in 1-6groups, the tumor cell necrosis rates were 20%, 45%,65%, 70%, 95% and 4%, respectively (F= 4.14-105.36, P＜0.01). MVD were 38.5±4.0, 28.0±2.9, 17.0±2.9, 8.8±1.5,5.7±2.3 and 65.0±5.2 (t= 11.9-26.1, P＜0.01), respectively.Under TEM fairly differentiated Pc-3 cells were found. Thirty days after medication, tumors were shrunk and dried with scabs detached, and those in control group increased in size prominently with plenty of hypodermic blood vessels. In all animals the ILN were enlarged but in medicated animals they appeared later and smaller than those in control group. The extent of irradiative injury in ILN was positively correlated to the dosage of medication. Typical tumor cell apoptosis could be found under TEM inanimals with intra-tumoral injection of low dosed 32P colloids. The peak of apoptosis occurred in 2.96 MBq group and 24 h after irradiation. In the course of irradiationinduced apoptosis, the value of Bcl-2/Bax was down regulated; Apo2.7 and caspase-3 protein expression were prominently increased dose dependently. CONCLUSION: 32p colloids intra-tumor injection having prominent anticancer effectiveness may reveal the ability of promoting cell differentiation. The low dose 32P colloids may induce human pancreatic carcinoma Pc-3 implanted tumor cell apoptosis; Apo2.7, caspase-3, Bcl-2 and Bax protein participated in regulating the process of irradiation induced cell apoptosis.

Celecoxib Inhibits Proliferation and Induces Apoptosis via Cyclooxygenase-2 Pathway in Human Pancreatic Carcinoma Cells

In order to evaluate the effects and mechanisms of celecoxib in inhibiting proliferation and inducing apoptosis on human pancreatic carcinoma cells, the anti-proliferative effect was measured by using methabenzthiazuron (MTT) assay. Cell cycle and apoptosis were analyzed by using flow cytometry (FCM), and the PGE 2 levels in the supernatant of cultured pancreatic carcinoma cells were quantitated by enzyme-linked immunoabsordent assay (ELISA). Our results showed that celecoxib suppressed the production of PGE 2 and inhibited the growth of JF-305 cells, and the anti-proliferative effect of celecoxib could be abolished by addition of PGE 2. FCM revealed that celecoxib could inhibit proliferation and induce apoptosis by G 1-S cell cycle arrest. It was concluded that cyclooxygenase-2 specific inhibitor celecoxib could inhibit proliferation and induced apoptosis of human pancreatic carcinoma cells via suppression of PGE 2 production in vitro.

Negative methylation status of Vimentin predicts improved prognosis in pancreatic carcinoma

AIM: To determine the existence of a potential relationship between the methylation state of the Vimentin gene and its prognostic value in pancreatic cancer.

Bacteriolytic therapy of experimental pancreatic carcinoma

AIM:To investigate the effectiveness of Clostridium novyi(C.novyi)-NT spores for the treatment of established subcutaneous pancreatic tumor in the syngeneic,immunocompetent Panc02/C57Bl/6 model. METHODS:C.novyi-NT spores were applied intravenously to animals carrying established pancreatic tumors of three different sizes.Systemic immune responses in peripheral blood and spleen were examined by flow cytometry.Supplementary,cytotoxic activity of lymphocytes against syngeneic tumor targets was analyzed. RESULTS:Application of spores identified,that(1) small tumors(<150 mm 3 )were completely unaffected (n=10);(2)very large tumors(>450 mm3)responded with substantial necrosis followed by shrinkage and significant lethality most likely due to tumor lysis syndrome (n=6);and(3)an optimal treatment window exists for tumors of approximately 250 mm 3 (n=21).In this latter group,all tumor-bearing animals had complete tu-mor regression and remained free of tumor recurrence. In subsequent tumor rechallenge experiments a significant delay in tumor growth compared to the initial tumor cell inoculation was observed(tumor volume at day 28:197.8±87.3 mm 3 vs 500.1±50.9 mm3,P<0.05). These effects were accompanied by systemic activation of immune response mechanisms predominantly mediated by the innate arm of the immune system. CONCLUSION:The observed complete tumor regression is encouraging and shows that immunotherapy with C.novyi-NT is an interesting strategy for the treatment of pancreatic carcinomas of defined sizes.