A multicenter phase 4 geriatric assessment directed trial to evaluate gemcitabine +/− nab-paclitaxel in elderly pancreatic cancer patients (GrantPax)

Background: In the group of elderly patients (≥70 years) with metastatic pancreatic ductal adenocarcinoma (mPDAC), it is not known who benefits from intensive 1st line nab-paclitaxel/gemcitabine (nab-p/gem) combination chemotherapy or who would rather suffer from increased toxicity. We aim to determine whether treatment individualization by comprehensive geriatric assessments (CGAs) improves functional outcome of the patients. Methods/Design: GrantPax is a multicenter, open label phase 4 interventional trial. We use a CGA to stratify elderly patients into three parallel treatment groups (n = 45 per arm): 1) GOGO (nab-p/gem), 2) SLOWGO (gem mono) or 3) FRAIL (best supportive care). After the 1st cycle of chemotherapy (or 4 weeks in FRAIL group) another CGA and safety assessment is performed. CGA-stratified patients may not decline in their CGA performance in response to the first cycle of chemotherapy (primary objective), measured as a loss of 5 points or less in Barthels activities of daily living. Based on the second CGA, patients are re-assigned to their definite treatment arm and undergo further CGAs to monitor the course of treatment. Secondary endpoints include CGA scores during the course of therapy (CGA1–4), response rates, safety and survival rates. Discussion: GrantPax is the first trial implementing a CGA-driven treatment to personalize therapy for elderly patients with pancreatic cancer. This may lead to standardization of therapy decisions for elderly patients and may optimize standard of care for this increasing group of patients. Trial registration: NCT02812992 , registered 24.06.2016

Gene expression analysis of pancreatic cell lines reveals genes overexpressed in pancreatic cancer

Background: Pancreatic cancer is one of the leading causes of cancer-related death. Using DNA gene expression analysis based on a custom made Affymetrix cancer array, we investigated the expression pattern of both primary and established pancreatic carcinoma cell lines. Methods: We analyzed the gene expression of 5 established pancreatic cancer cell lines (AsPC-1, BxPC-3, Capan-1, Capan-2 and HPAF II) and 5 primary isolates, 1 of them derived from benign pancreatic duct cells. Results: Out of 1,540 genes which were expressed in at least 3 experiments, we found 122 genes upregulated and 18 downregulated in tumor cell lines compared to benign cells with a fold change > 3. Several of the upregulated genes (like Prefoldin 5, ADAM9 and E-cadherin) have been associated with pancreatic cancer before. The other differentially regulated genes, however, play a so far unknown role in the course of human pancreatic carcinoma. By means of immunohistochemistry we could show that thymosin [β-10 (TMSB10), upregulated in tumor cell lines, is expressed in human pancreatic carcinoma, but not in non-neoplastic pancreatic tissue, suggesting a role for TMSB10 in the carcinogenesis of pancreatic carcinoma. Conclusion: Using gene expression profiling of pancreatic cell lines we were able to identify genes differentially expressed in pancreatic adenocarcinoma, which might contribute to pancreatic cancer development.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Chronic hyperglycemia induces trans-differentiation of human pancreatic stellate cells and enhances the malignant molecular communication with human pancreatic cancer cells

BACKGROUND: Diabetes mellitus is linked to pancreatic cancer. We hypothesized a role for pancreatic stellate cells (PSC) in the hyperglycemia induced deterioration of pancreatic cancer and therefore studied two human cell lines (RLT-PSC, T3M4) in hyperglycemic environment. METHODOLOGY/PRINCIPAL FINDINGS: The effect of chronic hyperglycemia (CHG) on PSCs was studied using mRNA expression array with real-time PCR validation and bioinformatic pathway analysis, and confirmatory protein studies. The stress fiber formation (IC: αSMA) indicated that PSCs tend to transdifferentiate to a myofibroblast-like state after exposure to CHG. The phosphorylation of p38 and ERK1/2 was increased with a consecutive upregulation of CDC25, SP1, cFOS and p21, and with downregulation of PPARγ after PSCs were exposed to chronic hyperglycemia. CXCL12 levels increased significantly in PSC supernatant after CHG exposure independently from TGF-β1 treatment (3.09-fold with a 2.73-fold without TGF-β1, p<0.05). The upregualtion of the SP1 transcription factor in PSCs after CHG exposure may be implicated in the increased CXCL12 and IGFBP2 production. In cancer cells, hyperglycemia induced an increased expression of CXCR4, a CXCL12 receptor that was also induced by PSC's conditioned medium. The receptor-ligand interaction increased the phosphorylation of ERK1/2 and p38 resulting in activation of MAP kinase pathway, one of the most powerful stimuli for cell proliferation. Certainly, conditioned medium of PSC increased pancreatic cancer cell proliferation and this effect could be partially inhibited by a CXCR4 inhibitor. As the PSC conditioned medium (normal glucose concentration) increased the ERK1/2 and p38 phosphorylation, we concluded that PSCs produce other factor(s) that influence(s) pancreatic cancer behaviour. CONCLUSIONS: Hyperglycemia induces increased CXCL12 production by the PSCs, and its receptor, CXCR4 on cancer cells. The ligand-receptor interaction activates MAP kinase signaling that causes increased cancer cell proliferation and migration

Desmoplasia and Chemoresistance in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) occurs mainly in people older than 50 years of age. Although great strides have been taken in treating PDAC over the past decades its incidence nearly equals its mortality rate and it was quoted as the 4th leading cause of cancer deaths in the U.S. in 2012. This review aims to focus on research models and scientific developments that help to explain the extraordinary resistance of PDAC towards current therapeutic regimens. Furthermore, it highlights the main features of drug resistance including mechanisms promoted by cancer cells or cancer stem cells (CSCs), as well as stromal cells, and the acellular components surrounding the tumor cells—known as peritumoral desmoplasia—that affects intra-tumoral drug delivery. Finally, therapeutic concepts and avenues for future research are suggested, based on the topics discussed

PCR in Helicobacter spp. diagnostic in extragastric malignancies of digestive system

Recognition of Helicobacter pylori as an important factor in genesis of gastric adenocarcinoma lead to a large number of studies concerning potential role of Helicobacter spp. in the development of extragastric digestive malignancies. The serological studies indicated possible localizations in the digestive system being from interest in enlightening Helicobacter spp. carcinogenic potential. The PCR obtruded itself as a gold standard in proving existence of actual correlation. In this review, the authors have examined studies conducted in the last 10 years examining Helicobacter spp. correlation with extragastric digestive carcinogenesis. Studies have been observed in four groups referring to hepatic carcinoma, bile duct cancer, pancreatic cancer, and colon cancer. The results of these researches have shown that there is a strong correlation between Helicobacter spp. colonization and primary liver tumors as well as bile duct tumors, whereas conclusions made by authors examining pancreatic cancer are contradictory and demands further investigation. No correlation between Helicobacter spp. and colon cancer have been proven. The PCR subtype most widely used in studies included in this review was nested PCR, whereas genes targeted most frequently for amplification are 16S rDNA of Helicobacter spp. and UreA gene or cagA gene of H. pylori. During the last 10 years PCR has proven itself as a sovereign method for Helicobacter spp. diagnostic in extragastric organs in the digestive system. Knowledge and experiences obtained in this domain could be encouraging for researchers in analogous fields of interest

Immunocytochemistry <i>(a)</i> and ELISA assessment <i>(b)</i> of PSC activation.

<p>Increased α-SMA and type-1 collagen protein expression was found on immunocytochemistry after PSCs were exposed both to 21 days of hyperglycemia or 48h of TGF-β1 <b><i>(a)</i>.</b> Increased type-1 and type-3 collagen levels were observed in PSC cell culture supernatant in the ELISA studies, however the increases were statistically only significant after the TGF-β1 treatments both with and without prior CHG exposure, but not after CHG exposure alone <b><i>(b)</i>.</b> Significant differences (p<0.05) are indicated *</p

Proliferation and migration assays of T3M4 cells and the Western blot analyses of key signaling molecules: <i>(a)</i> Sulphorodamine B test.

<p>Proliferation of T3M4 cells incubated with different conditioned PSC culture medium and the CXCR4 inhibitor AMD3100 after 24, 48, 72 and 96 hours of treatment. T3M4 cell proliferation (solid line; untreated control) was increased significantly after incubation with PSC supernatant (dotted line) provided that PSC were prior exposed to CHG. The presence of the CXCR4 inhibitor AMD3100 (dashed line) could partially antagonize this proliferation induction after 96h. <b><i>(b)</i> Migration of T3M4 cancer cells in a wound-healing assay.</b> Substantial effect of hyperglycemia on the migration of cancer cells: a rapid direct effect of elevated glucose level was found. There was no striking effect of conditioned PSC culture mediums on T3M4 cell migration. <b><i>(c)</i> Western blot analyses of key signaling molecules in T3M4 cells.</b> Cancer cells were exposed to hyperglycemia or different conditioned PSC culture medium. Best representative images of key signaling molecules of the cancer cells are indicated in WB membranes. Ponceau staining was used to assess the equal loading of gels. Significant (p<0.05) differences are indicated.*</p

CXCL12 (<i>a</i>) and IGFBP2 (<i>b</i>) protein levels in RLT-PSC cell culture supernatant with ELISA assesment after exposure to hyperglycemia and/or subsequent TGF-β1 treatment.

<p>CXCL12 level was significantly increased in PSC cell culture after exposure to CHG while 48h TGF-β1 treatment with normal glucose concentration also resulted in more than 2-fold increase <b><i>(a</i>)</b>. IGFBP2 protein level was increased in the cell culture medium after exposure to either CHG or TGF-β1. This alteration was only significant when PSCs were exposed to TGF-β1 subsequently after the CHG exposure. <b><i>(b)</i>.</b> Significant differences (p<0.05) are indicated*</p