Antagonistic interactions between gemcitabine and 5-fluorouracil in the human pancreatic carcinoma cell line Capan-2.

Although the recently-developed Gemcitabine (GEM) has renewed interest in clinical research in pancreatic carcinoma, it offers modest improvement of tumor-related symptoms and marginal survival advantage, even when combined with other currently-available chemotherapeutic agents such as 5-Fluorouracil (5-FU). We hypothesized that this disappointing result could be due to an interaction between the two drugs affecting cytotoxic activity. We measured in-vitro growth inhibition, cell cycle distribution, gene and protein expression of apoptosis regulators bcl-2, bcl-x and survivin, NFkappaB and telomerase activities of human pancreatic carcinoma cell line Capan-2 following exposure to GEM and 5-FU singly or combined, by MTT assay and median effect analysis, flow cytometry, real-time RT-PCR, Western blotting, electrophoretic mobility shift assay (EMSA) and telomeric repeat amplification protocol (TRAP) assay, respectively. We found cell growth to be inhibited by both drugs, decreasing the percentage of cells in S and G2/M phases and inducing apoptosis, dependent on the levels of bcl-2, bcl-xL and survivin expression in the case of 5-FU, but not for GEM. Moreover, while telomerase activity was reduced equally by both drugs, 5-FU but not GEM effectively downregulated NFkappaB binding activity. Intriguingly, a substantial antagonistic effect was noticed when GEM was combined with 5-FU in the concentration range tested, with the exception of the TRAP assay. These indications of an antagonistic interaction between GEM and 5-FU in some pancreatic cancer context urge further investigation of both genetic and non-genetic differences to identify the variables most relevant for optimal selection and dosing of treatment for the individual patient

Different quality of treatment in retroperitoneal sarcomas (RPS) according to hospital-case volume and surgeon-case volume: a retrospective regional analysis in Italy

Abstract Background Retroperitoneal sarcomas (RPS) should be surgically managed in specialized sarcoma centers. However, it is not clearly demonstrated if clinical outcome is more influenced by Center Case Volume (CCV) or by Surgeon Case Volume (SCV). The aim of this study is to retrospectively explore the relationship between CCV and SCV and the quality of surgery in a wide region of Northern Italy. Methods We retrospectively collected data about patients M0 surgically treated for RPSs in 22 different hospitals from 2006 to 2011, dividing them in two hospital groups according to sarcoma clinical activity volume (HCV, high case volume or LCV, low case volume hospitals). The HCV group (> 100 sarcomas observed per year) included a Comprehensive Cancer Center (HVCCC) with a high sarcoma SCV (> 20 cases/year), and a Tertiary Academic Hospital (HVTCA) with multiple surgeon teams and a low sarcoma SCV (≤ 5 cases/year for each involved surgeon). All other hospitals were included in the LCV group (< 100 sarcomas observed per year). Results Data regarding 138 patients were collected. Patients coming from LCV hospitals (66) were excluded from the analysis as prognostic data were frequently not available. Among the 72 remaining cases of HCV hospitals 60% of cases had R0/R1 margins, with a more favorable distribution of R0/R1 versus R2 in HVCCC compared to HVTCA. Conclusions In HCV hospitals, sarcoma SCV may significantly influence RPS treatment quality. In low-volume centers surgical reports can often miss important prognostic issues and surgical quality is generally poor

Cooperative Induction of a Tolerogenic Dendritic Cell Phenotype by Cytokines Secreted by Pancreatic Carcinoma Cells

AbstractAg presentation by dendritic cells (DC) is essential to effective antitumor T cell responses in cancer patients. Depending on their origin, maturation state, and the ambient cytokine milieu, DC can differentiate into distinct subpopulations, which preferentially either induce Th1 cell activation (CD11c+,CD123− myeloid DC (MDC)) or immunosuppressive T cell development (CD11c−,CD123+ plasmacytoid DC (PDC)). The present study was undertaken to characterize the effects of pancreatic carcinoma cell-derived cytokines on immature monocyte-derived DC (iMo-DC) in vitro and in vivo. Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-γ. Moreover, in tumor-patient peripheral blood, the ratio of MDC to PDC cells was lower than in healthy controls due to reduced numbers of MDC CD11c+ cells. Importantly, rather than a single cytokine, a combination of tumor-derived cytokines was responsible for these effects; these were primarily TGF-β, IL-10, and IL-6, but not vascular endothelial growth factor. In summary, we have identified an array of pancreatic carcinoma-derived cytokines that cooperatively affect iMo-DC activation in a manner consistent with ineffective antitumor immune responses

Key performance indicators for monitoring the integrated care pathway in breast cancer: the E.Pic.A. project

Introduction: Due to its high incidence, evaluating performance of care delivered to breast cancer patients is a crucial issue. The multidisciplinary panel E.Pic.A. (Economic Appropriateness of an Integrated Care Pathway) defined a set of key performance indexes (KPIs) to evaluate economic waste in breast cancer healthcare interventions. Methods: The E.Pic.A. panel identified the principal KPIs that are crucial within the breast cancer care pathway to evaluate the performance of care. KPIs were defined taking into account their reliability, validity, usability and feasibility of measurement through the linkage between multiple routine healthcare data sources. Results: 7 KPIs were identified: 3 on instrumental diagnostics, 2 on surgery and 2 on treatment. The 3 KPIs regarding instrumental diagnostics are aimed at assessing the inappropriateness of diagnostic tests performed before and after the index surgery. The 2 KPIs regarding surgery measure the inappropriateness of possible repeated interventions considering the time elapsed from the index surgery. The 2 KPIs regarding oncologic therapy measure the inappropriateness about the administration time of adjuvant therapy and radiotherapy considering the time elapsed from the index surgery. Conclusion: E.Pic.A methodology could help to evaluate economic waste in healthcare interventions with the objective of redirecting resources to interventions with greater value

Variability of clinical target volume delineation for rectal cancer patients planned for neoadjuvant radiotherapy with the aid of the platform Anatom-e

Objective: Delineation of treatment volumes is a major source of uncertainties in radiotherapy (RT). This is also true for rectal cancer patients undergoing neoadjuvant RT, with a potential impact on treatment quality. We investigated the role of the digital platform Anatom-e (Anatom-e Information Sytems Ltd., Houston, Texas) in increasing the compliance to follow a specific treatment protocol in a multicentric setting. Materials and methods: Two clinical cases of locally advanced rectal cancer were chosen. Participants were instructed to follow the 2009 Radiation Therapy Oncology Group consensus atlas and asked to manually segment clinical target volumes (CTVs), for both patient 1 and 2, on day 1 with and without the use of Anatom-e. After one week (day 2), the same radiation oncologist contoured again, with and without Anatom-e, the same CT series. Intraobserver (Intra-OV) and interobserver (Inter-OV) variability were evaluated with the Dice similarity coefficient (DSC), the Hausdorff distance (HD) and mean distance to agreement (MDA). Results: For clinical case 1, no significant difference was found for Intra-OV and Inter-OV. For clinical case 2, no significant difference was found for Intra-OV but a statistically significant difference was found for Inter-OV in DSC when using or not the platform. Mean DCS was 0.65 (SD: ±0.64; range: 0.58–0.79) for day 1 vs reference volume without Anatom-e and 0.72 (SD: ±0.39; range: 0.67–0.77) (p = 0.03) with it. Mean MDA was lower with Anatom-e (3.61; SD: ±1.33; range: 2.85–4.78) than without (4.14; SD: ±2.97; range: 2.18–5.21), with no statistical significance (p = 0.21) The use of Anatom-e decreased the SD from 2.97 to 1.33. Mean HD was lower with Anatom-e (26.06; SD: ±2.05; range: 24.08–32.62), with no statistical significance (p = 0.14) compared to that without (31.39; SD: ±1.31; range: 26.14–48.72). Conclusions: The use of Anatom-e decreased the Inter-OV in the CTV delineation process for locally advanced rectal cancer with complex disease presentation planned for neoadjuvant RT. This system may be potentially helpful in increasing the compliance to follow shared guidelines and protocols. Keywords: Rectal cancer, Neoadjuvant radiotherapy, Interobserver variability, Contouring, Target volume delineatio

Continuous 5-fluorouracil infusion plus long acting octreotide in advanced well-differentiated neuroendocrine carcinomas. A phase II trial of the Piemonte Oncology Network

<p>Abstract</p> <p>Background</p> <p>Well-differentiated neuroendocrine carcinomas are highly vascularized and may be sensitive to drugs administered on a metronomic schedule that has shown antiangiogenic properties. A phase II study was designed to test the activity of protracted 5-fluorouracil (5FU) infusion plus long-acting release (LAR) octreotide in patients with neuroendocrine carcinoma.</p> <p>Methods</p> <p>Twenty-nine patients with metastatic or locally advanced well-differentiated neuroendocrine carcinoma were treated with protracted 5FU intravenous infusion (200 mg/m²daily) plus LAR octreotide (20 mg monthly). Patients were followed for toxicity, objective response, symptomatic and biochemical response, time to progression and survival.</p> <p>Results</p> <p>Assessment by Response Evaluation Criteria in Solid Tumors (RECIST) criteria showed partial response in 7 (24.1%), stable disease in 20 (69.0%), and disease progression in 2 patients. Response did not significantly differ when patients were stratified by primary tumor site and proliferative activity. A biochemical (chromogranin A) response was observed in 12/25 assessable patients (48.0%); symptom relief was obtained in 9/15 symptomatic patients (60.0%). There was non significant decrease in circulating vascular epithelial growth factor (VEGF) over time. Median time to progression was 22.6 months (range, 2.7-68.5); median overall survival was not reached yet. Toxicity was mild and manageable.</p> <p>Conclusion</p> <p>Continuous/metronomic 5FU infusion plus LAR octreotide is well tolerated and shows activity in patients with well-differentiated neuroendocrine carcinoma. The potential synergism between metronomic chemotherapy and antiangiogenic drugs provides a rationale for exploring this association in the future.</p> <p>Trial registration</p> <p>NCT00953394</p