The miR-371∼373 Cluster Represses Colon Cancer Initiation and Metastatic Colonization by Inhibiting the TGFBR2/ID1 Signaling Axis.

The vast majority of colorectal cancer-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different colorectal cancer cell lines and recently established primary cultures enriched in colon cancer stem cells, also known as tumor-initiating cells (TIC), to identify genes and miRNAs with regulatory functions in colorectal cancer progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, TGFß signaling activity, and reduced expression of the miR-371∼373 cluster compared with nonmetastatic cultures. TGFß receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371∼373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371∼373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371∼373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371∼373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371∼373 and ID1. Altogether, our results establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization.Significance: These findings establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel mechanism regulating self-renewal of tumor-initiating cell and metastatic colonization, potentially opening new concepts for therapeutic targeting of cancer metastasis.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3793/F1.large.jpg Cancer Res; 78(14); 3793-808. ©2018 AACR.

Lean processes for optimizing OR capacity utilization: prospective analysis before and after implementation of value stream mapping (VSM).

BACKGROUND: The decision to optimize the processes in the operating tract was based on two factors: competition among clinics and a desire to optimize the use of available resources. The aim of the project was to improve operating room (OR) capacity utilization by reduction of change and throughput time per patient. SETTING: The study was conducted at Centre Hospitalier Emil Mayrisch Clinic for specialized care (n = 618 beds) Luxembourg (South). METHOD: A prospective analysis was performed before and after the implementation of optimized processes. Value stream analysis and design (value stream mapping, VSM) were used as tools. VSM depicts patient throughput and the corresponding information flows. Furthermore it is used to identify process waste (e.g. time, human resources, materials, etc.). For this purpose, change times per patient (extubation of patient 1 until intubation of patient 2) and throughput times (inward transfer until outward transfer) were measured. VSM, change and throughput times for 48 patient flows (VSM A(1), actual state = initial situation) served as the starting point. Interdisciplinary development of an optimized VSM (VSM-O) was evaluated. Prospective analysis of 42 patients (VSM-A(2)) without and 75 patients (VSM-O) with an optimized process in place were conducted. RESULTS: The prospective analysis resulted in a mean change time of (mean ± SEM) VSM-A(2) 1,507 ± 100 s versus VSM-O 933 ± 66 s (p < 0.001). The mean throughput time VSM-A(2) (mean ± SEM) was 151 min (±8) versus VSM-O 120 min (±10) (p < 0.05). This corresponds to a 23% decrease in waiting time per patient in total. CONCLUSION: Efficient OR capacity utilization and the optimized use of human resources allowed an additional 1820 interventions to be carried out per year without any increase in human resources. In addition, perioperative patient monitoring was increased up to 100%.

Predictive relevance of clinical scores and inflammatory parameters in secondary peritonitis.

HYPOTHESIS: To measure and evaluate clinical scores and various inflammation parameters for providing a better outcome assessment of patients with secondary peritonitis. DESIGN: Prospective study. SETTING: ICU of a university and a university affiliated hospital. PATIENTS: Fifty-six patients with severe secondary peritonitis were enrolled in this study executed within 4 years. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken preoperatively and 2, 6, 8, 12, 18, 24, 30, 36, 42 and 48 hours post operation, thereafter every 12th hour until day 5 respectively once daily until day 14. Etiology of peritonitis, clinical score systems (APACHE II, MOF and SOFA), and 27 mainly with activity tests or enzyme-immunoassays measurable inflammation parameters were simultaneously analyzed and stratified into lethal outcome (n = 11) or survival (n = 45), respectively. The etiological distribution of peritonitis was identical among both groups. Proportion of intraperitoneal fungi, E. coli, and bacteroids was substantially higher during the primary operation in the group with lethal outcome. With increasing significance initial and follow-up APACHE II, MOF and SOFA scores provided higher values in this group. Various plasma/serum parameters of hemostasis, leukocyte proteolytic system, acute phase reaction, cytokine system, cell adhesion, opsonization, and main organ functions showed significantly different values between both groups at the preoperative stage and/or during observation period I (day 0-4). Logistic regression analysis revealed the SOFA score and neopterin concentration as the combination with the best sensitivity (63.6%) and specificity (93.2%) for predicting the patients' survival even at the preoperative stage. For the observation period I, the combination of SOFA score and TNF receptor II showed the highest predictive sensitivity (72.7%) and specificity (95.6%). CONCLUSION: Evaluation of the severity of secondary peritonitis using a scoring system with high prognostic relevance could conceivably result in an earlier and adequate application of intensive care such as hemofiltration, administration of immunoglobulins and serial abdominal lavage to improve successful outcome.

Prevalence of familial pancreatic cancer in Germany.

Based on several case-control studies, it has been estimated that familial aggregation and genetic susceptibility play a role in up to 10% of patients with pancreatic cancer, although conclusive epidemiologic data are still lacking. Therefore, we evaluated the prevalence of familial pancreatic cancer and differences to its sporadic form in a prospective multicenter trial. A total of 479 consecutive patients with newly diagnosed, histologically confirmed adenocarcinoma of the pancreas were prospectively evaluated regarding medical and family history, treatment and pathology of the tumour. A family history for pancreatic cancer was confirmed whenever possible by reviewing the tumour specimens and medical reports. Statistical analysis was performed by calculating odds ratios, regression analysis with a logit-model and the Kaplan-Meier method. Twenty-three of 479 (prevalence 4.8%, 95% CI 3.1-7.1) patients reported at least 1 first-degree relative with pancreatic cancer. The familial aggregation could be confirmed by histology in 5 of 23 patients (1.1%, 95% CI 0.3-2.4), by medical records in 9 of 23 patients (1.9%, 95% CI 0.9-3.5) and by standardized interviews of first-degree relatives in 17 of 23 patients (3.5%, 95% CI 2.1-5.6), respectively. There were no statistical significant differences between familial and sporadic pancreatic cancer cases regarding sex ratio, age of onset, presence of diabetes mellitus and pancreatitis, tumour histology and stage, prognosis after palliative or curative treatment as well as associated tumours in index patients and families, respectively. The prevalence of familial pancreatic cancer in Germany is at most 3.5% (range 1.1-3.5%) depending on the mode of confirmation of the pancreatic carcinoma in relatives. This prevalence is lower than so far postulated in the literature. There were no significant clinical differences between the familial and sporadic form of pancreatic cancer.

Circulating mediators and organ function in patients undergoing planned relaparotomy vs conventional surgical therapy in severe secondary peritonitis.

HYPOTHESIS: Planned relaparotomy (PRL) has been suggested to have detrimental effects on the systemic activation of inflammation mediators, thereby enhancing organ dysfunctions as assessed by clinical scores in secondary peritonitis. DESIGN: Prospective, nonrandomized control trial. SETTING: Intensive care units of an urban and a university teaching hospital. PATIENTS: Twenty-nine patients with secondary peritonitis. INTERVENTIONS: Of the 29 patients with comparable initial peritonitis conditions, 11 underwent PRL and 18 obtained primary abdominal closure. Blood samples were obtained preoperatively and at 2, 6, 8, 12, 18, 24, 30, 36, 42, and 48 hours after the primary operation, then every 12th hour until day 5 and once daily until day 8. MAIN OUTCOME MEASURES: Quantification of circulating inflammation parameters (coagulation, acute-phase proteins, cytokine system, cell adhesion, opsonization) in correlation with Acute Physiology and Chronic Health Evaluation II, multiple organ failure, and Sepsis-Related Organ Failure Assessment scores. RESULTS: Preoperatively, the patient groups did not differ in mean age, cause of peritonitis, or clinical scores. On average, 5.1 (SEM, +/- 0.7; range, 3-11) lavage treatments were performed in the PRL group, with 90% of the procedures executed during the first 6 days. The PRL treatment resulted in a significantly higher need of blood components and an increased inflammation mediator response, especially concerning coagulation factors, proinflammatory cytokines, adhesion molecules, and opsonic parameters. During PRL, clinical score systems showed higher values and a delayed decline compared with primary abdominal closure treatment. Incidence of multiorgan failure, mortality, and the mean intensive care unit hospitalization period were clearly more pronounced in the PRL group. CONCLUSION: In our pilot study, additional lavage treatment of secondary peritonitis resulted in an enhancement of systemic inflammatory mediator response (in particular interleukin 8), which may contribute to a further impairment of organ function.