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No reliable predictors of susceptibility to gemcitabine chemotherapy exist in pancreatic ductal adenocarcinoma (PDAC). MicroRNAs (miR) are epigenetic gene regulators with tumorsuppressive or oncogenic roles in various carcinomas. This study assesses chemoresistant PDAC for its specific miR expression pattern. Gemcitabine-resistant variants of two mutant p53 human PDAC cell lines were established. Survival rates were analyzed by cytotoxicity and apoptosis assays. Expression of 1733 human miRs was investigated by microarray and validated by qRT-PCR. After in-silico analysis of specific target genes and proteins of dysregulated miRs, expression of MRP-1, Bcl-2, mutant p53, and CDK1 was quantified by Western blot. Both established PDAC clones showed a significant resistance to gemcitabine (p<0.02) with low apoptosis rate (p<0.001) vs. parental cells. MiR-screening revealed significantly upregulated (miR-21, miR-99a, miR-100, miR-125b, miR-138, miR-210) and downregulated miRs (miR-31*, miR-330, miR-378) in chemoresistant PDAC (p<0.05). Bioinformatic analysis suggested involvement of these miRs in pathways controlling cell death and cycle. MRP-1 (p<0.02) and Bcl-2 (p<0.003) were significantly overexpressed in both resistant cell clones and mutant p53 (p = 0.023) in one clone. Consistent miR expression profiles, in part regulated by mutant TP53 gene, were identified in gemcitabine-resistant PDAC with significant MRP-1 and Bcl-2 overexpression. These results provide a basis for further elucidation of chemoresistance mechanisms and therapeutic approaches to overcome chemoresistance in PDAC.

Abstract Study Objectives In patients with heart failure (HF) and reduced left ventricular ejection fraction (HFrEF), stroke volume (SV) falls during hyperpnea of Cheyne-Stokes respiration with central sleep apnea (CSR-CSA). We have identified two distinct patterns of hyperpnea: positive, in which end-expiratory lung volume (EELV) remains at or above functional residual capacity (FRC), and negative, in which EELV falls below FRC. The increase in expiratory intrathoracic pressure generated by the latter should have effects on the heart analogous to external chest compression. To test the hypotheses that in HFrEF patients, CSR-CSA with the negative pattern has an auto-resuscitation effect such that compared with the positive pattern, it is associated with a smaller fall in SV and a smaller increase in cardiac workload (product of heart rate and systolic blood pressure). Methods In 15 consecutive HFrEF patients with CSR-CSA during polysomnography, hemodynamic data derived from digital photoplethysmography during positive and negative hyperpneas were compared. Results Compared to the positive, negative hyperpneas were accompanied by reductions in the maximum and mean relative fall in SV of 30% (p = 0.002) and 10% (p = 0.031), respectively, and by reductions in the degree of increases in heart rate and rate pressure product during hyperpnea of 46% (p < 0.001) and 13% (p = 0.007), respectively. Conclusions Our findings suggest the novel concept that the negative pattern of CSR-CSA may constitute a form of auto-resuscitation that acts as a compensatory mechanism to maintain SV in patients with severe HF.

Background Gastrectomy is associated with relevant postoperative morbidity. However, outcome of surgery can be improved by careful selection of patients. The objective of the current study was therefore to identify preoperative risk factors that might impact on patients’ further outcome after surgical resection. Methods Preoperative risk factors having respectively different surgical risk scores for major complex surgery (including Cologne Risk Score, p-/o-POSSUM, and NSQIP risk score) of patients that underwent gastrectomy for AEG II/III tumors and gastric cancer were correlated with complications according to Clavien-Dindo and outcome. Patients who underwent surgery in palliative intention were excluded from further analysis. Results Subtotal gastrectomy was performed in 23%, gastrectomy in 59%, and extended gastrectomy in 18% in a total of 139 patients (mean age: 64 years old). Thirty six percent experienced a minor complication (Dindo I-II) and 24% a major complication (Dindo III-V), which resulted in a prolonged hospital stay ( p < 0.001). In-hospital mortality (=Dindo V) was 2.5%. Besides age, type of surgical procedure impacted on complications with extended gastrectomy showing the highest risk ( p = 0.005). The o-POSSUM score failed to predict mortality accurately. We observed a highly positive correlation between predicted morbidity respectively mortality and occurrence of complications estimated by p-POSSUM ( p = 0.005), Cologne Risk ( p = 0.007), and NSQIP scores ( p < 0.001). Conclusion The results demonstrate a significant association between different risk scores and occurrence of complications following gastrectomy. The p-POSSUM, Cologne Risk, and NSQIP score exhibited superior performance than the o-POSSUM score. Therefore, these scores might allow identification and selection of high-risk patients and thus might be highly useful for clinical decision making.

Cold atmospheric plasma (CAP) has shown promising potential in promoting wound healing. This case report presents the successful application of CAP in a 42-year-old female patient with extensive wound healing disorders and superinfections following the excision of an abscess in the left thoracic region. After several failed split skin graft attempts, the implementation of CAP led to significant improvements in wound healing. This report highlights the wound healing-promoting effects of CAP and discusses its potential mechanisms of action.

(1) Background: The aim of this study is to assess perioperative therapy in stage IA-III pancreatic cancer cross-validating the German Cancer Registry Group of the Society of German Tumor Centers—Network for Care, Quality, and Research in Oncology, Berlin (GCRG/ADT) and the National Cancer Database (NCDB). (2) Methods: Patients with clinical stage IA-III PDAC undergoing surgery alone (OP), neoadjuvant therapy (TX) + surgery (neo + OP), surgery+adjuvantTX (OP + adj) and neoadjuvantTX + surgery + adjuvantTX (neo + OP + adj) were identified. Baseline characteristics, histopathological parameters, and overall survival (OS) were evaluated. (3) Results: 1392 patients from the GCRG/ADT and 29,081 patients from the NCDB were included. Patient selection and strategies of perioperative therapy remained consistent across the registries for stage IA-III pancreatic cancer. Combined neo + OP + adj was associated with prolonged OS as compared to neo + OP alone (17.8 m vs. 21.3 m, p = 0.012) across all stages in the GCRG/ADT registry. Similarly, OS with neo + OP + adj was improved as compared to neo + OP in the NCDB registry (26.4 m vs. 35.4 m, p < 0.001). (4) Conclusion: The cross-validation study demonstrated similar concepts and patient selection criteria of perioperative therapy across clinical stages of PDAC. Neoadjuvant therapy combined with adjuvant therapy is associated with improved overall survival as compared to either therapy alone.

Background Ulceration of the oesophageal squamous mucosa (ulcerative oesophagitis) is a pathological manifestation of gastro-oesophageal reflux disease, and is a major risk factor for the development of Barrett’s oesophagus. Barrett’s oesophagus is characterised by replacement of reflux-damaged oesophageal squamous epithelium with a columnar intestinal-like epithelium. We previously reported discovery of microRNAs that are differentially expressed between oesophageal squamous mucosa and Barrett’s oesophagus mucosa. Now, to better understand early steps in the initiation of Barrett’s oesophagus, we assessed the expression, location and function of these microRNAs in oesophageal squamous mucosa from individuals with ulcerative oesophagitis. Methods Quantitative real-time PCR was used to compare miR-21, 143, 145, 194, 203, 205 and 215 expression levels in oesophageal mucosa from individuals without pathological gastro-oesophageal reflux to individuals with ulcerative oesophagitis. Correlations between microRNA expression and messenger RNA differentiation markers BMP-4, CK8 and CK14 were analyzed. The cellular localisation of microRNAs within the oesophageal mucosa was determined using in-situ hybridisation. microRNA involvement in proliferation and apoptosis was assessed following transfection of a human squamous oesophageal mucosal cell line (Het-1A). Results miR-143, miR-145 and miR-205 levels were significantly higher in gastro-oesophageal reflux compared with controls. Elevated miR-143 expression correlated with BMP-4 and CK8 expression, and elevated miR-205 expression correlated negatively with CK14 expression. Endogenous miR-143, miR-145 and miR-205 expression was localised to the basal layer of the oesophageal epithelium. Transfection of miR-143, 145 and 205 mimics into Het-1A cells resulted in increased apoptosis and decreased proliferation. Conclusions Elevated miR-143, miR-145 and miR-205 expression was observed in oesophageal squamous mucosa of individuals with ulcerative oesophagitis. These miRNAs localised to the basal layer of the oesophageal epithelium. They reduced proliferation and increased apoptosis, and may play roles in regulating epithelial restoration in response to injury caused by gastro-oesophageal reflux.

The indications for surgical treatment of hiatus hernias differentiate between type I and types II, III and IV hernias. The indications for a type I hernia should include a proven reflux disease but the indications for surgical treatment of types II, III and IV hernias are mandatory due to the symptoms with problems in the passage of food and due to the sometimes very severe possible complications. The primary aims of surgery are the repositioning of the herniated contents and a hiatoplasty, which includes a surgical narrowing of the esophageal hiatus by suture implantation. In addition, depending on the clinical situation other procedures, such as hernia sac removal, mesh implantation, gastropexy and fundoplication can be considered. There are various approaches to the repair, all of which have individual advantages and disadvantages. An adaptation to the specific needs situation of the patient and the expertise of the surgeon is therefore essential.

MicroRNAs (miRNAs, miRs) are small, non-coding RNA molecules that regulate gene expression posttranscriptionally. Although discovered only recently in the early 1990s, this relatively new group of molecules has already been proven to play an essential role in the regulation of many physiological and, most importantly, pathological processes such as cancer. A large number of miRNAs has been found to be involved in the pathogenesis of various human malignancies, and expression of miRNAs has been demonstrated to correlate with clinic and outcome. In tumors of the brain, however, the investigations on the role of miRNAs are still in its infancy, and most publications refer to the most common primary brain tumor, the glioma (mostly glioblastoma). But despite the fact that there is only limited data available so far, these first results are very promising and implicate that miRNAs might open a new perspective for diagnostics and treatment of this disease. With this review article, we aim to provide a short overview of miRNA biogenesis, function and regulation in general. Thereafter, the clinical relevant data about miRNAs in the two most common primary malignant brain tumors in adults (glioblastomas) and children (medulloblastomas) will be summarized, and their potential impact on diagnostics and treatment will be highlighted.[PUBLICATION ABSTRACT]

Background As esophagectomy is associated with a considerable complication rate, the aim of this study was to assess the impact of postoperative complications and neoadjuvant treatment on long-term outcome of adenocarcinoma (EAC) and squamous cell carcinoma (SCC) patients. Methods Altogether, 134 patients undergoing transthoracic esophagectomy between 2005 and 2010 with intrathoracic stapler anastomosis were included in the study. Postoperative complications were allocated into three main categories: overall complications, acute anastomotic insufficiency, and pulmonary complications. Data were collected prospectively and reviewed retrospectively for the purpose of this study. Results SCC patients suffered significantly more often from overall and pulmonary complications (SCC vs. EAC: overall complications 67 vs. 45 %, p  = 0.044; pulmonary complications 56 vs. 34 %, p  = 0.049). The anastomotic insufficiency rates did not differ significantly (SCC 11%, EAC 15%, p  = 0.69). Long-term survival of EAC and SCC patients was not affected by perioperative ( overall/pulmonary) complications or by the occurrence of anastomotic insufficiency. Also, neoadjuvant treatment did not influence the incidence of complications or long-term survival. Conclusions This is the first time the patient population of a center experienced with esophageal cancer surgery was assessed for the occurrence of general and esophageal cancer surgery-specific perioperative complications. Our results indicated that these complications did not affect long-term survival of EAC and SCC patients. Our data support the hypothesis that neoadjuvant treatment might not affect the incidence of perioperative complications or long-term survival after treatment of these tumor subtypes.