Never let it go: Stopping key mechanisms underlying metastasis to fight pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive neoplasm, predicted to become the second leading cause of cancer-related deaths before 2030. This dismal trend is mainly due to lack of effective treatments against its metastatic behavior. Therefore, a better understanding of the key mechanisms underlying metastasis should provide new opportunities for therapeutic purposes. Genomic analyses revealed that aberrations that fuel PDAC tumorigenesis and progression, such as SMAD4 loss, are also implicated in metastasis. Recently, microRNAs have been shown to play a regulatory role in the metastatic behavior of many tumors, including PDAC. In particular, miR-10 and miR-21 have appeared as master regulators of the metastatic program, while members of the miR-200 family are involved in the epithelial-to-mesenchymal switch, favoring cell migration and invasiveness. Several studies have also found a close relationship between cancer stem cells (CSCs) and biological features of metastasis, and the CSC markers ALDH1, ABCG2 and c-Met are expressed at high levels in metastatic PDAC cells. Emerging evidence reveals that exosomes are involved in the modulation of the tumor microenvironment and can initiate PDAC pre-metastatic niche formation in the liver and lungs. In this review, we provide an overview of the role of all these pivotal factors in the metastatic behavior of PDAC, and discuss their potential exploitation in the clinic to improve current therapeutics and identify new drug targets.

Contaminated area instability along Ångermanälven River, northern Sweden.

Industrially utilized river basins are frequently exposed to contaminants originating from polluting activities. However, the physical instability and probability of mass movement mobilization of contaminated soil into rivers have only received little attention. In this study, we present a GIS-based method to produce a regional overview of where and how contaminated areas are potentially exposed to slope instability. A landslide susceptibility-index was used to study the degree and distribution of overlap between contaminated sites and unstable ground. A contaminated area instability hazard classification was produced integrating slope instability and contamination risk classification. Our results indicate that mass movement can be tied mainly to a slope gradient ≥16°, a proximity to the river that is <500 m, a distance of <500 m from roads, concave surface curvature, and sand- and silt soils. Forty-six (22%) of all considered contaminated sites are located within areas with a non-negligible slope instability, of which a majority, 30 sites (14%) are situated on ground with a low or moderate instability. Three sites with a class 2 contamination risk (the 2nd highest class) are located on ground with a very high slope instability.

Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in ß-adrenergic signaling and enhances apoptosis.

The use of anthracyclines such as doxorubicin (DOX) has improved outcome in cancer patients, yet associated risks of cardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity is frequently irreversible and typically progresses to heart failure (HF) but our understanding of molecular mechanisms underlying this and essential for development of cardioprotective strategies remains largely obscure. As microRNAs (miRNAs) have been shown to play potent regulatory roles in both cardiovascular disease and cancer, we investigated miRNA changes in DOX-induced HF and the alteration of cellular processes downstream. Myocardial miRNA profiling was performed after DOX-induced injury, either via acute application to isolated cardiomyocytes or via chronic exposure in vivo, and compared with miRNA profiles from remodeled hearts following myocardial infarction. The miR-30 family was downregulated in all three models. We describe here that miR-30 act regulating the ß-adrenergic pathway, where preferential ß1- and ß2-adrenoceptor (ß1AR and ß2AR) direct inhibition is combined with Giα-2 targeting for fine-tuning. Importantly, we show that miR-30 also target the pro-apoptotic gene BNIP3L/NIX. In aggregate, we demonstrate that high miR-30 levels are protective against DOX toxicity and correlate this in turn with lower reactive oxygen species generation. In addition, we identify GATA-6 as a mediator of DOX-associated reductions in miR-30 expression. In conclusion, we describe that DOX causes acute and sustained miR-30 downregulation in cardiomyocytes via GATA-6. miR-30 overexpression protects cardiac cells from DOX-induced apoptosis, and its maintenance represents a potential cardioprotective and anti-tumorigenic strategy for anthracyclines.

A Study of Clinical Coding Accuracy in Surgery: Implications for the Use of Administrative Big Data for Outcomes Management.

BACKGROUND: Clinical coding is the translation of clinical activity into a coded language. Coded data drive hospital reimbursement and are used for audit and research, and benchmarking and outcomes management purposes. METHODS: We undertook a 2-center audit of coding accuracy across surgery. Clinician-auditor multidisciplinary teams reviewed the coding of 30,127 patients and assessed accuracy at primary and secondary diagnosis and procedure levels, morbidity level, complications assignment, and financial variance. Postaudit data of a randomly selected sample of 400 cases were reaudited by an independent team. RESULTS: At least 1 coding change occurred in 15,402 patients (51%). There were 3911 (13%) and 3620 (12%) changes to primary diagnoses and procedures, respectively. In 5183 (17%) patients, the Health Resource Grouping changed, resulting in income variance of £3,974,544 (+6.2%). The morbidity level changed in 2116 (7%) patients (P < 0.001). The number of assigned complications rose from 2597 (8.6%) to 2979 (9.9%) (P < 0.001). Reaudit resulted in further primary diagnosis and procedure changes in 8.7% and 4.8% of patients, respectively. CONCLUSIONS: The coded data are a key engine for knowledge-driven health care provision. They are used, increasingly at individual surgeon level, to benchmark performance. Surgical clinical coding is prone to subjectivity, variability, and error (SVE). Having a specialty-by-specialty understanding of the nature and clinical significance of informatics variability and adopting strategies to reduce it, are necessary to allow accurate assumptions and informed decisions to be made concerning the scope and clinical applicability of administrative data in surgical outcomes improvement.

Neoadjuvant chemotherapy and primary-first approach for rectal cancer with synchronous liver metastases.

AIM: Up to a quarter of patients with rectal cancer have synchronous liver metastases at the time of diagnosis. This is a predictor of poor outcome. There are no standardized guidelines for treatment. We reviewed the outcomes of our patients with synchronous rectal liver metastases treated with a curative intent by neoadjuvant chemotherapy with or without chemoradiotherapy followed by resection of the primary tumour and then liver metastases. METHOD: Between 2004 and 2012, patients who presented with rectal cancer and synchronous liver metastasis were treated with curative intent with peri-operative systemic chemotherapy as the first line of treatment. Responders to chemotherapy underwent resection of the primary tumour with or without preoperative chemoradiotherapy followed by hepatic resection. RESULTS: Fifty-three rectal cancer patients with 152 synchronous liver lesions were identified. After a median follow-up of 29.6 months, the median survival was 41.4 months. Overall survival was 59.0% at 3 years and 39.0% at 5 years. CONCLUSION: Rectal resection before hepatic resection combined with neoadjuvant chemotherapy is associated with promising clinical outcome. It allows downstaging of liver lesions and removal of the primary tumour before the progression of further micrometastases. Furthermore, patients who do not respond to chemotherapy can be identified and may avoid major surgical intervention.

The efficacy of tacrolimus and sirolimus in heavily pre-treated unresectable thymic malignancies.

BACKGROUND: Thymomas and thymic carcinomas, although uncommon, constitute a significant proportion of anterior mediastinal tumours. Systemic chemotherapy is the mainstay of treatment for inoperable or recurrent disease, but immunosuppressive therapy may provide an alternative treatment strategy. PATIENTS AND METHODS: We present a series of 18 patients diagnosed with unresectable thymic tumours, of which eight received immunosuppressive therapy following relapse after chemotherapy. RESULTS: Eight individuals were treated with primary immunotherapy after a median of 3.5 lines of chemotherapy (range 2-6 lines), of which 3 had confirmed myasthenia gravis (MG). After 3 months, 2 patients achieved a radiological partial response and 4 had stable disease. The median time to progression measured 6.8 months (CI 1.4-19.3 months). Two of the 4 patients who progressed on tacrolimus and prednisolone received sirolimus. One of these patients has stable disease (SD) at 21 months, and the other has SD at 3 months. CONCLUSIONS: Although previous case reports have related tacrolimus therapy with tumour shrinkage in patients with MG-associated invasive thymomas, these data are the first to demonstrate the efficacy of such immunosuppressive agents in a larger cohort of heavily pre-treated patients with thymic tumours. Our experience adds to the limited anecdotal evidence in the literature, and suggests that immunosuppressive agents represent a valuable additional treatment for thymic tumours.

The histone deacetylase inhibitor valproic acid enhances equine herpesvirus type 1 (EHV-1)-mediated oncolysis of human glioma cells.

Histone deacetylase (HDAC) inhibitors represent a promising new therapy against malignant glioma. When used in conjunction with oncolytic viral vectors, these compounds have been shown to augment virotherapy. In the current study, we examined the antitumor effect of combining the lytic animal virus equine herpesvirus type 1 (EHV-1) with the HDAC inhibitor valproic acid (VPA). Pretreatment of two human glioblastoma cell lines (U251 and SNB19) with VPA resulted in a significant increase in virus entry, replication, cell to cell spread and cell lysis. Overall, these data indicate that VPA significantly improves EHV-1-mediated oncolysis of human glioma cells that are only moderately killed by EHV-1 alone.

The good, the bad and the ugly: a tale of miR-101, miR-21 and miR-155 in pancreatic intraductal papillary mucinous neoplasms.

BACKGROUND: This multicenter study evaluated three candidate microRNAs (miRNAs) (miR-21, miR-155 and miR-101) as potential biomarkers in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. PATIENTS AND METHODS: miRNA expression was quantified by quantitative RT-PCR in 86 laser-microdissected specimens, including 65 invasive IPMNs, 16 non-invasive IPMNs and 5 normal pancreatic ductal tissues. Univariate and multivariate analyses compared miRNAs and clinical parameters with overall (OS) and disease-free survival (DFS). RESULTS: miR-21 and miR-155 were up-regulated in invasive IPMNs compared with non-invasive IPMNs, as well as in non-invasive IPMNs compared with normal tissues. Conversely, miR-101 levels were significantly higher in non-invasive IPMNs and normal tissues compared with invasive IPMNs. High levels of miR-21 were associated with worse OS [hazard ratio (HR) = 2.47, 95% confidence interval (CI) = 1.37-5.65, P = 0.0047]. Patients with high-miR-21 expression also had a shorter median DFS (10.9 versus 29.9 months, P = 0.01). Multivariate analysis confirmed miR-21 as independently prognostic for mortality and disease progression (death risk: HR = 3.3, 95% CI = 1.5-7.0, P = 0.02; progression risk: HR = 2.3, 95% CI = 1.2-4.8, P = 0.02), as well as positive lymph-node status (death risk: HR = 2.6, 95% CI = 1.1-6.3, P = 0.03; progression risk: HR = 2.2, 95% CI = 1.0-4.8, P = 0.04). CONCLUSIONS: miR-21, miR-155 and miR-101 showed significant differences in invasive versus non-invasive IPMNs. miR-21 emerged as an independent prognostic biomarker in invasive IPMNs and should be validated in prospective studies.

Operative fixation for complex tibial fractures.

INTRODUCTION: The management of open tibial shaft fractures remains challenging. Intramedullary nailing and external fixation are the most commonly used fixation techniques although the optimal fixation technique remains unresolved. In this article the outcomes of these two surgical techniques are compared. METHODS: A comprehensive literature search was conducted through MEDLINE(®) using Ovid(®) and MeSH (Medical Subject Heading) terms for articles published in the English literature between 1999 and 2009. The outcome measures compared were time to fracture union, infection rates and complications. RESULTS: Forty-one studies were identified, of which only three met the inclusion criteria. The average time to union was variable. Delayed union and non-union appeared to be more prevalent in the external fixator group although this was not statistically significant. Both techniques were associated with secondary procedures as well as infection. CONCLUSIONS: The current literature indicates little evidence to suggest the superiority of one fixation technique over another for open tibial fractures.

Radiofrequency assisted liver resection: analysis of 604 consecutive cases.

BACKGROUND: Intraoperative blood loss is an important factor contributing to morbidity and mortality in liver surgery. To address this we developed a bipolar radiofrequency (RF) device, the Habib 4X, used specifically for hepatic parenchymal transection. The aim of this study was to prospectively assess the peri-operative data using this technique. METHODS: Between 2001 and 2010, 604 consecutive patients underwent liver resections with the RF assisted technique. Clinico-pathological and outcome data were collected and analysed. RESULTS: There were 206 major and 398 minor hepatectomies. Median intraoperative blood loss was 155 (range 0-4300)ml, with a 12.6% rate of transfusion. There were 142 patients (23.5%) with postoperative complications; none had bleeding from the resection margin. Only one patient developed liver failure and the mortality rate was 1.8%. CONCLUSIONS: RF assisted liver resection allows major and minor hepatectomies to be performed with minimal blood loss, low blood transfusion requirements, and reduced mortality and morbidity rates.

Rescue of an axillary-axillary arteriovenous graft not amenable to endovascular intervention by formation of an axillary loop: a case report.

Central venous obstruction associated with a distal arteriovenous fistula can result in massive swelling of the affected extremity and venous hypertension. We present the surgical rescue of an axillary-axillary arteriovenous access ((necklace graft) between the left axillary artery to the contralateral axillary vein), compromised by central venous stenosis, by conversion into an arteriovenous axillary loop graft (AVALG) as an additional 'exotic' grafting procedure in the anterior chest. This procedure resulted in the salvage of the patient's access and rapid resolution of the associated upper extremity swelling.

High dose methylprednisolone in the immediate management of acute, blunt spinal cord injury: what is the current practice in emergency departments, spinal units, and neurosurgical units in the UK?

BACKGROUND: The National Acute Spinal Cord Injuries Studies and the Cochrane Review advocate the administration of high dose methylprednisolone following acute traumatic spinal cord injury. However, controversy surrounds its use and approaches between different units are often inconsistent. METHODS: A questionnaire was sent to all emergency departments receiving major trauma and all specialist neurosurgical and spinal units in the UK to determine the current practice regarding the use of high dose methylprednisolone in the immediate management of acute, blunt spinal cord injuries. RESULTS: Of 250 emergency departments, 187 replied to the questionnaire. Twelve of the 26 departments with a neurosurgical or spinal service on site stated they received consistent advice from specialist teams. Sixty four departments had a written policy regarding the treatment of spinal injuries, which in 51 departments contained advice about the administration of methylprednisolone. Of the 128 departments who gave methylprednisolone, 88 did so only on the advice of a specialist team, with the remaining 40 giving steroids immediately on identification of the injury. Ten out of 11 spinal units replied, of whom only two advised the used of steroids. Of the 34 neurosurgical units approached, seven out of 17 responders had a policy recommending the use of steroids. Of the 10 units who did not consistently recommend the use of steroids, seven had practise that varied between consultants. CONCLUSION: Currently practice varies in the UK regarding the immediate use of methylprednisolone after spinal injury. Clear guidelines need to be established to achieve a more consistent approach.

Does meta-chlorophenylpiperazine (mCPP) activate human platelets?

mCPP (meta-chlorophenylpiperazine), an agonist at serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 receptors, has been used as a probe of serotonergic function. We assessed its effect on platelet activation by measuring median platelet volume (MPV), the Sonoclot (SCT) pattern and plasma and intraplatelet serotonin. (a) In vitro study: MPV was measured (n = 7) using a high-resolution channelyzer: Saline (median and range (5.23 fl; 5.10-6.18) vs. mCPP (5.36; 5.10-6.44) P = 0.03; ADP (5.42; 5.29-6.44) vs. ADP + mCPP (5.67; 5.42-6.63) P = 0.02; mCPP (5.36; 5.10-6.44) vs. ADP + mCPP (5.67; 5.42-6.63) P = 0.02. Therefore, mCPP increases the MPV and enhances the effect of ADP. (b) In vivo study: The SCT time to inflection (TI) and time to peak (TP) were measured following the oral administration of mCPP (0.5 mg/kg) or aspirin (300 mg) (n = 10). Ingestion of mCPP significantly shortened TI and TP indicating platelet activation. TI: 0 h (mean +/- SD: 10.2 +/- 2.0 min) vs. 6 h (9.3 +/- 1.5) P = 0.03; TP: 0 h (31.9 +/- 7.6) vs. 6 h (23.1 +/- 2.9) P = 0.01. Aspirin had no effect on TI or TP. There were no significant changes in plasma and intraplatelet 5-HT. It is concluded that mCPP activates human platelets via 5-HT receptors.

HSV trafficking and development of gene therapy vectors with applications in the nervous system.

Herpes simplex virus type 1 (HSV-1) is a neurotropic double-stranded DNA virus that causes cold sores, keratitis, and rarely encephalitis in humans. Nonpathogenic HSV-1 gene transfer vectors have been generated by elimination of viral functions necessary for replication. The life cycle of the native virus includes replication in epithelial cells at the site of initial inoculation followed by retrograde axonal transport to the nuclei of sensory neurons innervating the area of cutaneous primary infection. In this review, we summarize the current understanding of the molecular basis for HSV cell entry, nuclear transport of the genome, virion egress following replication, and retrograde and anterograde axonal transport in neurons. We discuss how each of these properties has been exploited or modified to allow the generation of gene transfer vectors with particular utility for neurological applications. Recent advances in engineering virus entry have provided proof of principle that vector targeting is possible. Furthermore, significant and potentially therapeutic modifications to the pathological responses to various noxious insults have been demonstrated in models of peripheral nerve disease. These applications exploit the natural axonal transport mechanism of HSV, allowing transgene expression in the cell nucleus within the inaccessible trigeminal ganglion or dorsal root ganglion, following the noninvasive procedure of subcutaneous vector inoculation. These findings demonstrate the importance of understanding basic virology in the design of vector systems and the powerful approach of exploiting favorable properties of the parent virus in the generation of gene transfer vectors.

Reporting of gunshot wounds by doctors in emergency departments: a duty or a right? Some legal and ethical issues surrounding breaking patient confidentiality.

Recent guidelines have been produced advising doctors working in emergency departments that they should report all gunshot injuries to the police (albeit with consent in all but very limited circumstances). This article will discuss some of the legal and ethical issues that surround breaking patient confidentiality in relation to gunshot wounds and other potentially dangerous patients; and looks at some cases from the UK and the USA where such issues have been ruled on. Finally, the issue of whether physicians do, or should, have a duty to warn when they feel that their patient may be dangerous will be discussed.

Who can drive home from the emergency department? A questionnaire based study of emergency physicians' knowledge of DVLA guidelines.

OBJECTIVE: To determine whether doctors working in emergency departments are aware which of the common conditions seen have driving restrictions associated with them and whether they routinely advise patients of these restrictions. METHODS: 200 questionnaires were distributed to all grades of doctor currently working in 15 emergency departments in Wessex and the south west. The survey was anonymous so follow up of non-responders was not possible. Doctors were asked to indicate which of the 20 commonly seen conditions listed had DVLA guidelines restricting driving activity at least temporarily, and in which of these conditions they actually advised patients appropriately about their driving. In addition the MDU, GMC, and the Department of Transport web site were contacted to establish what they considered to be good medical practice regarding issuing advice about driving. RESULTS: 102 doctors (51%) responded to the survey. Knowledge regarding restrictions for various conditions varied, with 87.5% responding correctly about a first fit to only 7.8% regarding a collapse query cause. With regard to advising patients, 79.4% of doctors responding said that they routinely advised patients about stopping driving after a first fit, 32% advised patients after a single transient ischaemic attack, and only 7% after a collapse query cause. CONCLUSIONS: Doctors working in emergency departments are aware of conditions that lead to an inpatient admission that have driving restrictions. However, knowledge of conditions where patients are likely to be discharged was not as complete and advice was less likely to be given to patients. Emergency department doctors need to be more aware of restrictions that apply to conditions where patients are to be discharged.

Nurse administered relative analgesia using high concentration nitrous oxide to facilitate minor procedures in children in an emergency department.

AIMS: To describe the experience of using high concentration nitrous oxide (N(2)O) relative analgesia administered by nursing staff in children undergoing minor procedures in the emergency department (ED) and to demonstrate its safety. METHOD: Data were collected over a 12 month period for all procedures in the ED performed under nurse administered N(2)O sedation. All children greater than 12 months of age requiring a minor procedure who had no contraindication to the use of N(2)O were considered for sedation by this method. The primary outcome measure was the incidence of a major complication namely respiratory distress or hypoxia during the procedure. Secondary outcome measures were minor complications and the maximum concentration of N(2)O used. RESULTS: Data were collected for a total of 224 episodes of nurse administered N(2)O sedation over a 12 month period. In 73.2% of children no complications were recorded. One major complication was recorded (respiratory distress) and the most common minor complication was mask intolerance in 17%. The mean maximum concentration of N(2)O used was 60.2%. CONCLUSIONS: N(2)O is a safe analgesic in children over the age of 1 year undergoing painful or stressful procedures in the ED. It may safely be administered in concentrations of up to 70% by nursing staff after appropriate training.