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.

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.

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.

Nitric oxide-induced changes in intracellular zinc homeostasis are mediated by metallothionein/thionein.

We hypothesized that metallothionein (MT), a cysteine-rich protein with a strong affinity for Zn(2+), plays a role in nitric oxide (NO) signaling events via sequestration or release of Zn(2+) by the unique thiolate clusters of the protein. Exposing mouse lung fibroblasts (MLF) to the NO donor S-nitrosocysteine resulted in 20-30% increases in fluorescence of the Zn(2+)-specific fluorophore Zinquin that were rapidly reversed by the Zn(2+) chelator N,N,N',N'-tetrakis-(2-pyridylmethyl)ethylenediamine. The absence of a NO-mediated increase in labile Zn(2+) in MLF from MT knockouts and its restoration after MT complementation by adenoviral gene transfer inferred a critical role for MT in the regulation of Zn(2+) homeostasis by NO. Additional data obtained in sheep pulmonary artery endothelial cells suggested a role for the apo form of MT, thionein (T), as a Zn(2+)-binding protein in intact cells, as overexpression of MT caused inhibition of NO-induced changes in labile Zn(2+) that were reversed by Zn(2+) supplementation. Furthermore, fluorescence-resonance energy-transfer data showed that overexpression of green fluorescent protein-modified MT prevented NO-induced conformational changes, which are indicative of Zn(2+) release from thiolate clusters. This effect was restored by Zn(2+) supplementation. Collectively, these data show that MT mediates NO-induced changes in intracellular Zn(2+) and suggest that the ratio of MT to T can regulate Zn(2+) homeostasis in response to nitrosative stress.

Fas mRNA expression in blood is reduced during episodes of human corneal graft rejection.

BACKGROUND: Our purpose is to examine levels of Fas mRNA expression in blood during human corneal transplant rejection. METHODS: Fas mRNA expression was detected by reverse transcription-PCR in blood from normal controls, corneal recipients at the time of transplantation and during episodes of rejection. RESULTS: Samples taken at the time of a corneal rejection episode showed Fas mRNA levels were significantly lower in these patients than either normal controls (P = 0.017) or corneal transplant recipients not undergoing graft rejection (P = 0.00052). Serial samples from five patients who suffered an episode of rejection showed that the level of Fas mRNA is reduced during the rejection episode and subsequently recovers. CONCLUSIONS: These results indicate low levels of Fas mRNA in blood may have a role in corneal transplant rejection.

Pharmacological investigation of mitochondrial ca(2+) transport in central neurons: studies with CGP-37157, an inhibitor of the mitochondrial Na(+)-Ca(2+) exchanger.

Mitochondria buffer large changes in [Ca(2+)](i)following an excitotoxic glutamate stimulus. Mitochondrial sequestration of [Ca(2+)](i)can beneficially stimulate oxidative metabolism and ATP production. However, Ca(2+)overload may have deleterious effects on mitochondrial function and cell survival, particularly Ca(2+)-dependent production of reactive oxygen species (ROS) by the mitochondria. We recently demonstrated that the mitochondrial Na(+)-Ca(2+)exchanger in neurons is selectively inhibited by CGP-37157, a benzothiazepine analogue of diltiazem. In the present series of experiments we investigated the effects of CGP-37157 on mitochondrial functions regulated by Ca(2+). Our data showed that 25 microM CGP-37157 quenches DCF fluorescence similar to 100 microM glutamate and this effect was enhanced when the two stimuli were applied together. CGP-37157 did not increase ROS generation and did not alter glutamate or 3mM hydrogen-peroxide-induced increases in ROS as measured by DHE fluorescence. CGP-37157 induces a slight decrease in intracellular pH, much less than that of glutamate. In addition, CGP-37157 does not enhance intracellular acidification induced by glutamate. Although it is possible that CGP-37157 can enhance mitochondrial respiration both by blocking Ca(2+)cycling and by elevating intramitochondrial Ca(2+), we did not observe any changes in ATP levels or toxicity either in the presence or absence of glutamate. Finally, mitochondrial Ca(2+)uptake during an excitotoxic glutamate stimulus was only slightly enhanced by inhibition of mitochondrial Ca(2+)efflux. Thus, although CGP-37157 alters mitochondrial Ca(2+)efflux in neurons, the inhibition of Na(+)-Ca(2+)exchange does not profoundly alter glutamate-mediated changes in mitochondrial function or mitochondrial Ca(2+)content.

Induction of neuronal apoptosis by thiol oxidation: putative role of intracellular zinc release.

The membrane-permeant oxidizing agent 2,2'-dithiodipyridine (DTDP) can induce Zn(2+) release from metalloproteins in cell-free systems. Here, we report that brief exposure to DTDP triggers apoptotic cell death in cultured neurons, detected by the presence of both DNA laddering and asymmetric chromatin formation. Neuronal death was blocked by increased extracellular potassium levels, by tetraethylammonium, and by the broad-spectrum cysteine protease inhibitor butoxy-carbonyl-aspartate-fluoromethylketone. N,N,N', N'-Tetrakis-(2-pyridylmethyl)ethylenediamine (TPEN) and other cell-permeant metal chelators also effectively blocked DTDP-induced toxicity in neurons. Cell death, however, was not abolished by the NMDA receptor blocker MK-801, by the intracellular calcium release antagonist dantrolene, or by high concentrations of ryanodine. DTDP generated increases in fluorescence signals in cultured neurons loaded with the zinc-selective dye Newport Green. The fluorescence signals following DTDP treatment also increased in fura-2- and magfura-2-loaded neurons. These responses were completely reversed by TPEN, consistent with a DTDP-mediated increase in intracellular free Zn(2+) concentrations. Our studies suggest that under conditions of oxidative stress, Zn(2+) released from intracellular stores may contribute to the initiation of neuronal apoptosis.

Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures.

Oxidative stress can trigger neuronal cell death and has been implicated in several chronic neurological diseases and in acute neurological injury. Oxidative toxicity can be induced by glutamate treatment in cells that lack ionotrophic glutamate receptors, such as the immortalized HT22 hippocampal cell line and immature primary cortical neurons. Previously, we found that neuroprotective effects of geldanamycin, a benzoquinone ansamycin, in HT22 cells were associated with a down-regulation of c-Raf-1, an upstream activator of the extracellular signal-regulated protein kinases (ERKs). ERK activation, although often attributed strictly to neuronal cell survival and proliferation, can also be associated with neuronal cell death that occurs in response to specific insults. In this report we show that delayed and persistent activation of ERKs is associated with glutamate-induced oxidative toxicity in HT22 cells and immature primary cortical neuron cultures. Furthermore, we find that U0126, a specific inhibitor of the ERK-activating kinase, MEK-1/2, protects both HT22 cells and immature primary cortical neuron cultures from glutamate toxicity. Glutamate-induced ERK activation requires the production of specific arachidonic acid metabolites and appears to be downstream of a burst of reactive oxygen species (ROS) accumulation characteristic of oxidative stress in HT22 cells. However, inhibition of ERK activation reduces glutamate-induced intracellular Ca(2+) accumulation. We hypothesize that the precise kinetics and duration of ERK activation may determine whether downstream targets are mobilized to enhance neuronal cell survival or ensure cellular demise.

Inhibition of glutamate-induced mitochondrial depolarization by tamoxifen in cultured neurons.

In central neurons, glutamate receptor activation causes massive calcium influx and induces a mitochondrial depolarization, which is partially blocked by cyclosporin A, suggesting a possible activation of the mitochondrial permeability transition pore (PTP) as a mechanism. It has been recently reported that tamoxifen (an antiestrogen chemotherapeutic agent) blocks the PTP in isolated liver mitochondria, similar to cyclosporin A. In this study, we tested whether tamoxifen inhibits the mitochondrial depolarization induced by glutamate receptor activation in intact cultured neurons loaded with the fluorescent dye 5,5',6,6'-tetrachloro-1,1',3, 3'-tetraethylbenzimidazolylcarbocyanine iodide. This dye reports disruptions in mitochondrial membrane potential, which can be caused by PTP activation. We found that glutamate (100 microM for 10 min) causes a robust mitochondrial depolarization that is partially inhibited by tamoxifen. The maximum inhibitory concentration of tamoxifen was 0.3 microM, with concentrations higher and lower than 0.3 microM being less effective. However, although tamoxifen (0.3 microM) blocked glutamate-induced mitochondrial depolarization, it did not inhibit glutamate-induced neuronal death, in contrast to the PTP inhibitor cyclosporin A. A relatively high concentration of tamoxifen (100 microM) caused mitochondrial depolarization itself and was neurotoxic. These data suggest that tamoxifen may be an inhibitor of the PTP in intact neurons. However, the lack of specificity of most PTP inhibitors, and the difficulty in measuring PTP in intact cells, preclude definite conclusions about the role of PTP in excitotoxic injury.