Changes over time in the course of advanced pancreatic cancer treatment with systemic chemotherapy: a pooled analysis of five clinical trials from two decades of the German AIO study group.

BACKGROUND: Over the past two decades, our group has conducted five multicenter trials focusing on first-line systemic therapy for patients with advanced pancreatic cancer. The current pooled analysis was designed to evaluate prognosis over time and the impact of clinical characteristics on survival. PATIENTS AND METHODS: Individual patient data were derived from five prospective, controlled, multicenter trials conducted by the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO): 'Gem/Cis', 'Ro96', 'RC57', 'ACCEPT' and 'RASH', which recruited patients between December 1997 and January 2017. RESULTS: Overall, 912 patients were included. The median overall survival (OS) for all assessable patients was 7.1 months. OS significantly improved over time, with a median OS of 8.6 months for patients treated from 2012 to 2017 compared with 7.0 months from 1997 to 2006 [hazard ratio (HR) 1.06; P < 0.004]. Eastern Cooperative Oncology Group performance status (HR 1.48; P < 0.001), use of second-line treatment (HR 1.51; P < 0.001), and Union for International Cancer Control (UICC) stage (III versus IV) (HR 1.34, P = 0.002) had a significant impact on OS. By contrast, no influence of age and gender on OS was detectable. Comparing combination therapy with single-agent chemotherapy did not demonstrate a survival benefit, nor did regimens containing epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as afatinib or erlotinib, compared with chemotherapy-only arms. Patients with early-onset pancreatic cancer (age at study entry of ≤50 years, n = 102) had a similar OS compared with those >50 years (7.1 versus 7.0 months; HR 1.13; P = 0.273). The use of a platinum-containing regimen was not associated with better outcomes in patients with early-onset pancreatic cancer. CONCLUSIONS: Within this selected group of patients treated within prospective clinical trials, survival has shown improvement over two decades. This effect is likely attributable to the availability of more effective combination therapies and treatment lines, rather than to any specific regimen, such as those containing EGFR-TKIs. In addition, concerning age and sex subgroups, the dataset did not provide evidence for distinct clinical behavior.

[Rate of thrombosis and bleeding after urological surgery under standardized anticoagulation]. / Thromboserate und Blutungen in der universitären operativen Urologie unter standardisierter Antikoagulation.

BACKGROUND: According to the current definition of the German guideline for prevention of venous thromboembolism, urological surgery includes a high number of high-risk patients. All patients undergoing urological surgery between 2012 and 2016 were analyzed with regard to complications (bleeding or thrombosis). MATERIALS AND METHODS: This study is a retrospective and monocentric cohort study. Included were all patients who underwent surgery between 2012 and 2016 at the Urological Department at the University Hospital of Luebeck. Information was collected relating to anticoagulation, patient-specific and surgery-specific risk factors, and complications. RESULTS: In all, 3609 surgeries were analyzed: 77.8% of patients received no medical prophylaxis, 10.2% received an aggregation inhibitor, and 8.5% synthetic, unfractionated or low molecular weight heparin. Heparin was administered to 80.4% of patients after surgery. During an average hospital stay of 4.5 days, 93.3% of the patients received no change in anticoagulation. Merely 0.8% of all patients suffered from clinical thomboembolic events within 28 days. In contrast the number of bleedings was higher with 20.3% (minor: 4.8%, major: 15.5%). CONCLUSION: We found a slight risk for postoperative thromboembolism (0.8%). The risk for postoperative bleeding in contrast was 20.3%, including 15.5% major bleedings. The results are discussed in relation to the current guidelines.

Prognostic relevance of topoisomerase II α and minichromosome maintenance protein 6 expression in colorectal cancer.

BACKGROUND: Despite rising incidence rates of colorectal malignancies, only a few prognostic tools have been implemented in proven clinical routine. Cell division and proliferation play a significant role in malignancies. In terms of colorectal cancer, the impact of proliferation associated proteins is controversially debated. The aim of our study was to examine the expression of topoisomerase II α and minichromosome maintenance protein 6 and to correlate these findings with the clinical data. METHODS: Tissue samples of 619 patients in total were stained using the antibodies Ki-S4 and Ki-MCM6 targeting topoisomerase II α as well as minichromosome maintenance protein 6. The median rate of proliferation was correlated with clinical and follow up data. RESULTS: The expression rate of minichromosome maintenance protein 6 is significantly higher than the proportion of topoisomerase II α in tumour cells (p < 0.001). A high expression of both proteins coincides with a beneficial outcome for the patient, indicating a favourable prognostic marker (p < 0.001 and p = 0.008). CONCLUSIONS: We have demonstrated that high expression rates of proliferative markers is linked to a beneficial patient outcome. According to the general opinion, a high expression rate correlates with a poor patient outcome. In this study, we were able to refute this assertion.

PO-18 - Fibronectin EDA/EDB is expressed in adherent SCLC NCI-H69 cells and in pleural effusions of lung cancer patients: possible implication for drug resistance.

INTRODUCTION: Small cell lung cancer (SCLC) is an extremely aggressive tumour which metastasizes early. Even if chemotherapy can achieve an initial regression, relapses due to chemo-resistance are almost inevitable. Sethi et al (Nat Med. 1999;5:662-668) reported that matrix proteins are essentially involved in the development of drug resistance. SCLC cells in suspension culture secrete negligible amounts of matrix proteins AIM: For a more detailed study of the SCLC ability to produce matrix proteins we applied a recently introduced cell culture model of adherence selected SCLC (Salge et al. J Cancer Res Clin Oncol. 2001;127(2):139-411) and analysed pleural effusions form lung cancer patients. MATERIALS AND METHODS: Adherent cells were selected from the SCLC cell line NCI-H69 after exposure to cellular stress. Pleural effusion were obtained from lung cancer patients (SCLC and NSCLC) and from pleural effusions (PE) with congestive heart failure Protein expression was analysed by western blotting (WB) and flow cytometry using specific antibodies against the fibronectin extra domain A (FnEDA) and B (FnEDB) (Sirius, Italy), and for integrins alpha 1-5 and beta 1-3. Drug resistance was assessed with the metabolic stain MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromid). RESULTS: SCLC suspension cells expressed negligible amounts of fibronectin. In contrast, adherent H69 cells, which showed a significantly reduced chemo-sensitivity against carboplatin and doxorubicin, strongly expressed FnEDA and to a lesser extent FnEDB. Furthermore, in adherent cells expression of various integrins was up-regulated, in particular integrins alpha5/beta3, representing potential binding sites for FnEDA/FnEDB. Analysis of pleural effusions clearly showed the presence of FnEDA/ FnEDB in those of lung cancer patients, whereas in benign pleural effusion almost no FnEDA/ FnEDB was found. CONCLUSIONS: Our data reveal the presence of Fn, and its splice variants FnEDA/EDB in particular, in adherent SCLC cells as well as in malignant PE. We assume that the splice variants FnEDA/ FnEDB are linked to cancer progression and chemo-resistance in this tumour type.

Tissue invasion and metastasis: Molecular, biological and clinical perspectives.

Cancer is a key health issue across the world, causing substantial patient morbidity and mortality. Patient prognosis is tightly linked with metastatic dissemination of the disease to distant sites, with metastatic diseases accounting for a vast percentage of cancer patient mortality. While advances in this area have been made, the process of cancer metastasis and the factors governing cancer spread and establishment at secondary locations is still poorly understood. The current article summarizes recent progress in this area of research, both in the understanding of the underlying biological processes and in the therapeutic strategies for the management of metastasis. This review lists the disruption of E-cadherin and tight junctions, key signaling pathways, including urokinase type plasminogen activator (uPA), phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT), focal adhesion kinase (FAK), ß-catenin/zinc finger E-box binding homeobox 1 (ZEB-1) and transforming growth factor beta (TGF-ß), together with inactivation of activator protein-1 (AP-1) and suppression of matrix metalloproteinase-9 (MMP-9) activity as key targets and the use of phytochemicals, or natural products, such as those from Agaricus blazei, Albatrellus confluens, Cordyceps militaris, Ganoderma lucidum, Poria cocos and Silybum marianum, together with diet derived fatty acids gamma linolenic acid (GLA) and eicosapentanoic acid (EPA) and inhibitory compounds as useful approaches to target tissue invasion and metastasis as well as other hallmark areas of cancer. Together, these strategies could represent new, inexpensive, low toxicity strategies to aid in the management of cancer metastasis as well as having holistic effects against other cancer hallmarks.

[Obesity and cancer]. / Adipositas und Krebs.

The incidence of obesity in the western world has increased dramatically during recent decades. Epidemiological data suggest that obesity is associated with an increased risk of several but not all types of cancers, with clear sex-specific differences. The underlying mechanisms are still a matter of debate. This review focuses on the potential factors linking obesity to cancer. Current experimental evidence suggests that insulin resistance and a chronic, subclinical inflammation in the visceral fat are the major metabolic events causing alterations in the levels of insulin, glucose, free fatty acids, insulin-like growth factor 1 (IGF-1) and 2, adipose tissue-derived proinflammatory cytokines and other bioactive molecules, such as adipokines (e.g. leptin and adiponectin), vascular endothelial growth factor (VEGF), sex hormones, gut microbiota and secondary bile acids. All these factors may act directly or indirectly on the tumor microenvironment to drive tumor progression via stimulation of cell survival/antiapoptosis, cell proliferation, angiogenesis and invasion/metastasis of the cancer cells. Therapeutic strategies that target dysfunctional or inflamed fat and have been shown to benefit patients include bariatric surgery, while other cell or hormone-directed interventions, such as conversion of visceral fat macrophages to an anti-inflammatory M2 phenotype or the pharmacological modulation of serum adipokine levels are still theoretical and need to be clinically evaluated for their ability to successfully treat or prevent obesity-related cancers.

Adult mesenchymal stem cells explored in the dental field.

During the last decade it was realized that stem cell-based therapies hold an enormous therapeutic potential, improving the life of patients with conditions ranging from neurodegenerative and traumatic diseases to regenerative medicine requiring replacement of complex structures such as bones and teeth. Based on their ability to regenerate and/or repair damaged tissue and eventually restore organ function, multiple types of stem/progenitor cells have been discovered. In the field of periodontal regeneration and tooth engineering, several types of adult multipotent mesenchymal stem cells from various sources are currently being investigated. These include the bone marrow stromal stem cells (BMSSCs), adipose-derived stromal cells (ADSCs), dental pulp stem cells (DPSCs), dental follicle stem cells (DFSCs), stem cells from human exfoliated deciduous teeth (SHEDs), stem cells from the apical papilla (SCAP), periodontal ligament stem cells (PDLSCs), alveolar bone proper-derived stem cells, and gingival stem cells. The potential of these different MSCs as precursors for regenerative purposes in the dental field is discussed in this chapter.

Temperature corrected transepithelial electrical resistance (TEER) measurement to quantify rapid changes in paracellular permeability.

Determining the transepithelial electrical resistance (TEER) is a widely used method to functionally analyze tight junction dynamics in cell culture models of physiological barriers. Changes in temperature are known to have strong effects on TEER and can pose problems during the process of TEER measurements in cell culture vessels, complicating comparisons of TEER data across different experiments and studies. Here, we set out to devise a strategy to obtain temperature-independent TEER values based on the physical correlation between parameters such as TEER, temperature, medium viscosity and pore size of the cell culture inserts. By measuring the impact of temperature and different electrode types on TEER measurements on Caco-2 and HPDE (normal human pancreatic ductal epithelium) monolayers, we were able to derive a mathematical method that is suitable for the correction of TEER values for temperature changes. Applying this method to raw TEER values yields temperature-corrected TEER (tcTEER) values. Validity of tcTEER was demonstrated by showing a direct correlation with permeability of monolayers as determined by flux of RITC dextran. Taken together, the mathematical solution presented here allows for a simple and accurate determination of paracellular permeability independent of temperature variation during the process of TEER recording.