Management of Cylindrical Battery Ingestion.

Presentation A female presented to the Emergency Department following ingestion of an unknown number of cylindrical batteries. Diagnosis Abdominal X-ray confirmed the presence of multiple batteries located throughout the abdomen. Treatment A trial of conservative management was pursued, and five AA batteries were successfully passed per rectum. Serial X-rays over three weeks revealed that the majority of batteries failed to pass. A decision was made to perform a laparotomy, and 46 cylindrical batteries were removed from the stomach through a small gastrotomy. Four batteries located in the colon were milked into the rectum and removed via the transanal route. Discussion Using daily clinical exams and weekly plain films of the abdomen, conservative management is possible if a small number of batteries are ingested and make it to the stomach. However, the potential of cylindrical batteries to result in acute surgical emergencies should not be underestimated.

Mucinous and non-mucinous colorectal cancers show differential expression of chemotherapy metabolism and resistance genes.

Previous research has identified differences in mutation frequency in genes implicated in chemotherapy resistance between mucinous and non-mucinous colorectal cancers (CRC). We hypothesized that outcomes in mucinous and non-mucinous CRC may be influenced by expression of genes responsible for chemotherapy resistance. Gene expression data from primary tumor samples were extracted from The Cancer Genome Atlas PanCancer Atlas. The distribution of clinical, pathological, and gene expression variables was compared between 74 mucinous and 521 non-mucinous CRCs. Predictors of overall survival (OS) were assessed in a multivariate analysis. Kaplan-Meier curves were constructed to compare survival according to gene expression using the log rank test. The median expression of 5-FU-related genes TYMS, TYMP, and DYPD was significantly higher in mucinous CRC compared to non-mucinous CRC (p < 0.001, p = 0.003, p < 0.001, respectively). The median expression of oxaliplatin-related genes ATP7B and SRPK1 was significantly reduced in mucinous versus non-mucinous CRC (p = 0.004, p = 0.007, respectively). At multivariate analysis, age (odds ratio (OR) = 0.96, p < 0.001), node positive disease (OR = 0.49, p = 0.005), and metastatic disease (OR = 0.32, p < 0.001) remained significant negative predictors of OS, while high SRPK1 remained a significant positive predictor of OS (OR = 1.59, p = 0.037). Subgroup analysis of rectal cancers demonstrated high SRPK1 expression was associated with significantly longer OS compared to low SRPK1 expression (p = 0.011). This study highlights that the molecular differences in mucinous CRC and non-mucinous CRC extend to chemotherapy resistance gene expression. SRPK1 gene expression was associated with OS, with a prognostic role identified in rectal cancers.

Microsatellite instability and response to neoadjuvant chemoradiotherapy in rectal cancer: A systematic review and meta-analysis.

BACKGROUND: Response to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer is variable. Identification of biomarkers to predict response is desirable in order to provide prognostic information and targeted therapy. Several studies have investigated microsatellite instability (MSI) as a predictor of response to CRT with contradictory results. This study aims to clarify the effect of MSI status on response to CRT in locally advanced rectal cancer through systematic review and meta-analysis. METHODS: A systematic search of PubMed, Embase and Cochrane databases was performed for all studies relating to MSI and response to CRT in rectal cancer using the search algorithm (Microsatellite Instability) AND (Chemoradiotherapy) AND (Rectal Cancer). From each included study the number of patients with MSI tumors and Microsatellite Stable (MSS) tumors and the numbers achieving pathological complete response (pCR) were recorded. Pooled outcome measures were determined using a random effects model and the odds ratio estimated with variance and 95% confidence interval. RESULTS: Nine published studies were identified reporting data on MSI and its effect on outcome after CRT for locally advanced rectal cancer. Five studies describing 5,877 patients included data on MSI and the number of patients achieving pCR. There was no significant association between MSI and pCR (MSI Vs MSS: 10.1% Vs 6.6%, OR 1.38, 95% CI: 0.7-2.72, p = 0.35). CONCLUSION: This meta-analysis concludes that there appears to be no significant difference in pCR rate following CRT in patients with MSI versus MSS rectal tumors.

Meta-analysis of the molecular associations of mucinous colorectal cancer.

BACKGROUND: Mucinous differentiation occurs in 5-15 per cent of colorectal adenocarcinomas. This subtype of colorectal cancer responds poorly to chemoradiotherapy and has a worse prognosis. The genetic aetiology underpinning this cancer subtype lacks consensus. The aim of this study was to use meta-analytical techniques to clarify the molecular associations of mucinous colorectal cancer. METHODS: This study adhered to MOOSE guidelines. Databases were searched for studies comparing KRAS, BRAF, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), p53 and p27 status between patients with mucinous and non-mucinous colorectal adenocarcinoma. A random-effects model was used for analysis. RESULTS: Data from 46 studies describing 17 746 patients were included. Mucinous colorectal adenocarcinoma was associated positively with KRAS (odds ratio (OR) 1·46, 95 per cent c.i. 1·08 to 2·00, P = 0·014) and BRAF (OR 3·49, 2·50 to 4·87; P < 0·001) mutation, MSI (OR 3·98, 3·30 to 4·79; P < 0·001) and CIMP (OR 3·56, 2·85 to 4·43; P < 0·001), and negatively with altered p53 expression (OR 0·46, 0·31 to 0·67; P < 0·001). CONCLUSION: The genetic origins of mucinous colorectal adenocarcinoma are predominantly associated with BRAF, MSI and CIMP pathways. This pattern of molecular alterations may in part explain the resistance to standard chemotherapy regimens seen in mucinous adenocarcinoma.

Thirty-seven-year Population-based Study of Colorectal Cancer Rates in Renal Transplant Recipients in Ireland.

BACKGROUND: Renal transplantation is associated with an increased risk of neoplasia, including colorectal cancer (CRC). Advances in surgical techniques and immunosuppressive medications have resulted in increased survival rates of both patients and grafts, but the incidence of CRC in the Irish renal transplant population is currently unknown. The aim of this study is to review the incidence of CRC in the Irish renal transplant population and compare it to the general population. METHODS: A retrospective review of a prospectively maintained database of all renal transplant recipients in Ireland between January 1980 and July 2017 was performed. RESULTS: Thirty-three out of 4230 transplant recipients (men = 20, women = 13) developed CRC subsequent to transplantation and were eligible for inclusion in the series. The mean age at transplantation was 51.5 years, with patients developing CRC on average 10.9 years post-transplantation; 6.1% (n = 2/33) had stage IV disease at diagnosis. The majority of patients (87.8%) had a pathologic T stage of T3/T4 and 45.5% had involvement of locoregional lymph nodes (N1/N2); 42.4% also had a mucinous component at histopathologic assessment. The incidence of CRC was higher in the transplant population compared to the general population. CONCLUSION: This is the first population-based assessment of CRC development in the Irish renal transplant population. Our data suggest that Irish transplant recipients have an increased risk of being diagnosed with a more advanced tumor than the general population, with most being diagnosed almost a decade after transplantation. This highlights the need for increased awareness among patients and clinicians and the potential need for coordinated lifelong surveillance of this patient population to ensure early detection and treatment.

Drug repurposing from the perspective of pharmaceutical companies.

Drug repurposing holds the potential to bring medications with known safety profiles to new patient populations. Numerous examples exist for the identification of new indications for existing molecules, most stemming from serendipitous findings or focused recent efforts specifically limited to the mode of action of a specific drug. In recent years, the need for new approaches to drug research and development, combined with the advent of big data repositories and associated analytical methods, has generated interest in developing systematic approaches to drug repurposing. A variety of innovative computational methods to enable systematic repurposing screens, experimental as well as through in silico approaches, have emerged. An efficient drug repurposing pipeline requires the combination of access to molecular data, appropriate analytical expertise to enable robust insights, expertise and experimental set-up for validation and clinical development know-how. In this review, we describe some of the main approaches to systematic repurposing and discuss the various players in this field and the need for strategic collaborations to increase the likelihood of success in bringing existing molecules to new indications, as well as the current advantages, considerations and challenges in repurposing as a drug development strategy pursued by pharmaceutical companies. LINKED ARTICLES: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.

Adherence to clinical guidelines and the potential economic benefits of admission avoidance for acute uncomplicated diverticulitis.

BACKGROUND: The treatment paradigm for acute diverticulitis is changing. There is an increasing trend towards managing patients with uncomplicated diverticulitis in the community. AIMS: The aim of this study was to analyse how acute diverticulitis is managed in our institution and also to analyse national data pertaining to treatment of acute diverticulitis. METHODS: A prospective database of all patients admitted to our institution over a 2-year period (2014-2016) with acute diverticulitis was maintained. Severity of disease, treatment received and average length of stay (LOS) were analysed for all patients. Contemporaneous hospital inpatient enquiry (HIPE) data was interrogated to analyse current management for acute diverticulitis at a national level. RESULTS: One hundred twenty-six patients were admitted to our institution with acute diverticulitis during the study period (inpatient stay = €1277/night). Of patients, 59.5% had uncomplicated diverticulitis while 40.5% had complicated disease. The median LOS was 4 (range 1-34) days and 8 (range 2-51) days in the uncomplicated and complicated group, respectively. Based on HIPE data, there were 11,357 patients with uncomplicated diverticulitis and 526 patients with complicated diverticulitis admitted to Irish hospitals in the year 2015. Nationally, the median LOS for those with uncomplicated diverticulitis was 3 (range 1-142) days and for those with complicated diverticulitis the median LOS was 7 (range 1-308) days. Projected total cost for hospital stay nationally for uncomplicated diverticulitis amounted to €43.5 million for the year 2015. CONCLUSIONS: At present, uncomplicated diverticulitis in Ireland is not being managed as per evidence-based guidelines. Changing practice could result in significant cost savings for surgical departments.

C-reactive protein as a predictor of anastomotic leak in the first week after anterior resection for rectal cancer.

AIM: Anastomotic leak (AL) after anterior resection results in increased morbidity, mortality and local recurrence. The aim of this study was to assess the ability of C-reactive protein (CRP) to predict AL in the first week after anterior resection for rectal cancer. METHOD: A retrospective review of a prospectively maintained database that included all patients undergoing anterior resection between January 2008 and December 2013 was performed. The ability of CRP to predict AL was assessed using area under the receiver-operating characteristics (AUC) curves. The severity of AL was defined using the International Study Group of Rectal Cancer (ISREC) grading system. RESULTS: Two-hundred and eleven patients were included in the study. Statistically significant differences in mean CRP values were found between those with and without an AL on postoperative days 5, 6 and 7. A CRP value of 132 mg/l on postoperative day 5 had an AUC of 0.75, corresponding to a sensitivity of 70%, a specificity of 76.6%, a positive predictive value of 16.3% and a negative predictive value of 97.5%. Multivariable analysis found that a CRP of > 132 mg/l on postoperative day 5 was the only statistically significant patient factor that was linked to an increased risk of AL (HR = 8.023, 95% CI: 1.936-33.238, P = 0.004). CONCLUSION: Early detection of AL may minimize postoperative complications. CRP is a useful negative predictive test for the development of AL following anterior resection.

Magnitude of non-operative surgical emergency admissions; service implications for surgical and radiological practice.

BACKGROUND: Financial sustainability is an area of sharp ongoing focus across the broad spectrum of the Irish Health Service. Recent attention has been drawn to the financial implications of non-operative surgical admissions, suggesting that some of these may be unnecessary. AIMS: In this study, we aim to determine the volume of emergency surgical admissions to Mayo University Hospital (MUH), in particular, to identify the scale of non-operative admissions and to assess the wider inherent implications for acute hospital services. METHODS: An electronic handover system for emergency surgical admissions was introduced in MUH in September 2014. All surgical admissions from September 1st 2014 to August 31st 2015 were identified from this prospectively maintained database. HIPE (Hospital Inpatient Enquiry) data were not used in this study. Theatre logbooks confirmed those patients who required operative intervention. RESULTS: 1466 patients were admitted as emergencies during the study period. 58 % (850) were male and median age was 48 years (0-100). Average length of stay was 5 days (range 1-125). 327 patients (22.3 %) required operative intervention. The most commonly performed procedure was appendicectomy (52.5 %). 48 (3.3 %) patients were transferred to other hospitals. 131 (8.9 %) admissions related to the acute urological conditions. Of the 1466 admissions, 546 underwent a CT scan, while 342 patients proceeded to ultrasound. CONCLUSION: Almost 80 % of all surgical emergency admissions were discharged without undergoing a formal operative procedure while generating a significant workload for the radiology department. Changes in working practices and hospital network structures will be required to reduce the burden of non-operative emergency admissions.

Endoscopic tattooing to aid tumour localisation in colon cancer: the need for standardisation.

BACKGROUND/AIMS: An increasing number of colon and rectal tumours are being resected using laparoscopic techniques. Identifying these tumours intraoperatively can be difficult. The use of tattooing can facilitate an easier resection; however, the lack of standardised guidelines can potentially lead to errors intraoperatively and potentially result in worse outcomes for patients. The aim of this study was to identify the most reliable method of preoperative tumour localisation from the available literature to date. METHODS: A literature review was undertaken to identify any articles related to endoscopic tattooing and tumour localisation during colorectal surgery. RESULTS: To date there is still mixed evidence regarding tattooing techniques and the choice of ink that should be used. There are numerous studies demonstrating safe tattooing techniques and highlighting the risks and benefits of different types of ink available. CONCLUSION: Based on the available studies we have recommended a standardised approach to endoscopic tattooing of colorectal tumours prior to laparoscopic resection.

Liberal perioperative fluid administration is an independent risk factor for morbidity and is associated with longer hospital stay after rectal cancer surgery.

INTRODUCTION Recent studies have advocated the use of perioperative fluid restriction in patients undergoing major abdominal surgery as part of an enhanced recovery protocol. Series reported to date include a heterogenous group of high- and low-risk procedures but few studies have focused on rectal cancer surgery alone. The aim of this study was to assess the effects of perioperative fluid volumes on outcomes in patients undergoing elective rectal cancer resection. METHODS A prospectively maintained database of patients with rectal cancer who underwent elective surgery over a 2-year period was reviewed. Total volume of fluid received intraoperatively was calculated, as well as blood products required in the perioperative period. The primary outcome was postoperative morbidity (Clavien-Dindo grade I-IV) and the secondary outcomes were length of stay and major morbidity (Clavien-Dindo grade III-IV). RESULTS Over a 2-year period (2012-2013), 120 patients underwent elective surgery with curative intent for rectal cancer. Median total intraoperative fluid volume received was 3680ml (range 1200-9670ml); 65/120 (54.1%) had any complications, with 20/120 (16.6%) classified as major (Clavien-Dindo grade III-IV). Intraoperative volume >3500ml was an independent risk factor for the development of postoperative all-cause morbidity (P=0.02) and was associated with major morbidity (P=0.09). Intraoperative fluid volumes also correlated with length of hospital stay (Pearson's correlation coefficient 0.33; P<0.01). CONCLUSIONS Intraoperative fluid infusion volumes in excess of 3500ml are associated with increased morbidity and length of stay in patients undergoing elective surgery for rectal cancer.

Breaking Barriers to Successful Implementation of Day Case Laparoscopic Cholecystectomy.

Laparoscopic cholecystectomy is a common procedure performed in both emergency and elective settings. Our aim was to analyse the trends in laparoscopic surgery in Ireland in the public and private healthcare systems. In particular we studied the trend in day case laparoscopic cholecystectomy. National HIPE data for the years 2010-2012 was obtained. Similar datasets were obtained from the three main health insurers. 19,214 laparoscopic cholecystectomies were carried out in Ireland over the 3-year period. More procedures were performed in the public system than the private system from 2010-2012. There was a steady increase in surgeries performed in the public sector, while the private sector remained static. Although the ALOS was significantly higher in the public sector, there was an increase in the rate of day case procedures from 416 (13%) to 762 (21.9%). The day case rates in private hospitals increased only slightly from 29 (5.1%) in 2010 to 40 (5.9%) in 2012. Day case laparoscopic cholecystectomy has been shown to be a safe procedure, however significant barriers remain in place to the implementation of successful day case units nationwide.

Health-related quality of life of HIV-infected intravenous drug users.

To investigate health-related quality of life in HIV-infected intravenous drug users registered but not engaged in HIV outpatient care (missing ≥2 outpatient appointments over 1 year or non-attendance for ≥6 months) we conducted a cross-sectional study to examine health-related quality of life of HIV-infected intravenous drug users registered for care at an inner city HIV unit. EQ-5D, SF-36, SF-6D, mood disorder, clinical and substance misuse data were collected. Mean scores and preference derived utility scores were calculated. Statistical relationships between health-related quality of life and other variables were explored using univariate and multivariate analysis. Fifty-five patients were recruited, 64% were males. The mean anxiety value was 11.44 (anxious) and mean depression score was 9.3 (borderline depressed). The mean EQ-5D utility was 0.45 (95% CI 0.35, 0.55) and mean SF-6D utility was 0.52 (95% CI 0.48, 0.55). There was no statistical relationship between HIV indices, substance misuse and EQ-5D and SF-6D utility. Anxiety and depression were significantly correlated with EQ-5D and SF-6D utility values on univariate and multivariate analysis. Health-related quality of life was reduced in this HIV-infected intravenous drug user population. Whilst hepatitis C co-infection and substance misuse did not affect health-related quality of life, anxiety and depression had a significant impact on it.

Tissue and corneal donation and transplantation in the UK.

NHS Blood and Transplant (NHSBT) was established in 2005 as a Special Health Authority when the National Blood Authority and UK Transplant merged. This helped to bring tissue banking and organ transplantation services under one umbrella organization. This merger means that ~!95% of all deceased donors (whether tissue, organ or both) are now facilitated by one organization. NHSBT Tissue Services is the largest tissue establishment in the UK, and is a multi-tissue bank that specializes in the consent, retrieval, processing, storage, and dispatch of donated tissue coordinated from a purpose built, state-of-the-art tissue bank in Liverpool. Tissue donations can come from either tissue-only donors or solid organ donors who also donate tissue. Annually there are ~450 multi-tissue donors and 2500 eye donors in the UK, resulting in many thousands of transplants, including 3564 cornea transplants in 2010-2011. The separation of tissue- and organ-specific donors is largely artificial, and while organ transplantation can be life-saving, tissue transplantation can also have a dramatic effect on a patient's quality of life. It is hoped that all donors, both organ and tissue, will be recognized for the gift they make to society after their death.

Differences in mitochondrial movement and morphology in young and mature primary cortical neurons in culture.

Mitochondria have many roles critical to the function of neurons including the generation of ATP and regulation of intracellular Ca2+. Mitochondrial movement is highly dynamic in neurons and is thought to direct mitochondria to specific cellular regions of increased need and to transport damaged or old mitochondria to autophagosomes. Morphology also varies between individual mitochondria and is modulated by fusion and fission proteins such as mitofusin-1 and dynamin-related protein-1, respectively. Although mitochondrial movement and morphology are thought to be modulated to best meet cellular demands, few regulatory signals have been identified. In this study, we examined how the different cellular environments of synaptically immature and mature rat cortical neurons affect mitochondrial movement, morphology, distribution and function. In younger cells, mitochondria were more mobile, were shorter, occupied a smaller percentage of neuronal processes, and expressed greater mitofusin-1 and lower dynamin-related protein-1 protein levels compared with older cells. However, the number of mitochondria per mum of neuronal process, mitochondrial membrane potential and the amount of basally sequestered mitochondrial Ca2+ were similar. Our results suggest that while mitochondria in young neurons are functionally similar to mature neurons, their enhanced motility may permit faster energy dispersal for cellular demands, such as synaptogenesis. As cells mature, mitochondria in the processes may then elongate and reduce their motility for long-term support of synaptic structures.

Epidermal growth factor activates m-calpain (calpain II), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.

How m-calpain is activated in cells has challenged investigators because in vitro activation requires near-millimolar calcium. Previously, we demonstrated that m-calpain activation by growth factors requires extracellular signal-regulated kinase (ERK); this enables tail deadhesion and allows productive motility. We now show that ERK directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (EGF)-induced calpain activation in vitro and in vivo. Replacing the serine with alanine limits activation by EGF and subsequent cell deadhesion and motility. A construct with the serine converted to glutamic acid displays constitutive activity in vivo; expression of an estrogen receptor fusion construct produces a tamoxifen-sensitive enzyme. Interestingly, EGF-induced m-calpain activation occurs in the absence of increased intracellular calcium levels; EGF triggers calpain even in the presence of intracellular calcium chelators and in calcium-free media. These data provide evidence that m-calpain can be activated through the ERK cascade via direct phosphorylation and that this activation may occur in the absence of cytosolic calcium fluxes.

Elevated intracellular zinc and altered proton homeostasis in forebrain neurons.

Using the H(+)-sensitive fluorophore 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) and microfluorimetry, we investigated how elevated intracellular free zinc ([Zn(2+)](i)) altered intracellular proton concentration (pH(i)) in dissociated cultures of rat forebrain neurons. Neurons exposed to extracellular zinc (3 microM) in the presence of the Zn(2+)-selective ionophore pyrithione (20 microM) underwent intracellular acidification that was not reversed upon washout of the stimulus. Application of a membrane-permeant Zn(2+) chelator, but not an impermeant chelator, partially restored pH(i). Removal of extracellular Ca(2+) greatly inhibited [Zn(2+)](i)-induced acidification, suggesting that acidification was a secondary consequence of Ca(2+) entry. Additional experiments suggested that Ca(2+) entered through the plasma membrane sodium/calcium exchanger (NCE), because a specific inhibitor of reverse mode NCE operation, KB-R7943 (1 microM), significantly inhibited Zn(2+)-induced acidification. In addition to the phenomenon of [Zn(2+)](i)-induced acidification, we found that elevated [Zn(2+)](i) inhibited neuronal recovery from low pH(i). Neurons exposed to a protonophore underwent robust acidification, and pH(i) recovery ensued upon protonophore washout. In contrast, neurons acidified by the protonophore in the presence of Zn(2+) (3 microM) and pyrithione (20 microM) showed no ability to recover from low pH(i). Application of a membrane-permeant Zn(2+) chelator partially restored pH(i) to pre-stimulus values. Experiments designed to elucidate mechanisms responsible for pH(i) regulation revealed that neurons relied primarily on bicarbonate exchange for proton export, suggesting that elevated [Zn(2+)](i) might impede pH(i) by inhibiting proton efflux via bicarbonate exchange. These results provide novel insights into the physiological effects of raising [Zn(2+)](i), and may help illuminate the mechanisms by which Zn(2+) injures neurons.