Publications by authors named "John O Larkin"

24 Publications

  • Page 1 of 1

Sigmoid volvulus: definitive surgery is safe and should be considered in all instances.

Ir J Med Sci 2021 Jul 29. Epub 2021 Jul 29.

Department of Colorectal Surgery, St James's Hospital, Dublin 8, Ireland.

Background: Acute sigmoid volvulus (ASV) represents a small but significant portion of cases of large bowel obstruction, especially in the elderly and co-morbid. Given the characteristics of the patient cohort most commonly affected, a non-operative/conservative approach is often undertaken but is associated with a high rate of recurrence.

Objective: We sought to evaluate outcomes for those patients who underwent non-operative management, emergency surgery or staged, semi-elective surgery following decompression for ASV at our institution.

Methods: Hospital in-patient enquiry (HIPE) data were used to identify all patients who presented with sigmoid volvulus between January 2005 and June 2020 inclusive. Patient notes were interrogated, including surgical and endoscopic procedures performed. Patient demographics and co-morbidities were recorded.

Results: Thirty-nine patients were treated over a 15-year period with a mean age of 73 years at first presentation (range 36-93). Twenty-two patients (56%) had just a single admission for ASV with three deaths in this group. Seventeen patients (44%) had more than one admission with volvulus due to recurrence after a decompression-only strategy on the index admission. Of these, three succumbed to complications of their subsequent episodes of volvulus. Twenty-five patients underwent surgical intervention (fifteen on, or shortly following, their first admission and ten following at least two admissions for ASV). The overall mortality in the operative group was 2/25 (8%) with both deaths in those undergoing emergency surgeries. Five patients were treated successfully with endoscopic measures alone and had required no further interventions at the time of compiling data.

Conclusion: There is a high recurrence rate following non-operative management of acute sigmoid volvulus and consequently, a cumulative increase in the attendant significant morbidity and mortality with subsequent episodes. Given the relatively low complication rate of definitive surgery, even in those patients perceived to be high risk, we contend that all patients should be considered for early surgery to prevent the likely recurrence of sigmoid volvulus.
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http://dx.doi.org/10.1007/s11845-021-02713-0DOI Listing
July 2021

Obesity and anastomotic leak rates in colorectal cancer: a meta-analysis.

Int J Colorectal Dis 2021 Sep 1;36(9):1819-1829. Epub 2021 Apr 1.

Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland.

Purpose: Anastomotic leak (AL) following colorectal cancer resection is associated with considerable morbidity and mortality with an impact on recurrence rates and survival. The impact of obesity on AL rates is debated. This meta-analysis aims to investigate the relationship between obesity and AL.

Methods: A search was conducted of the PubMed/MEDLINE, and Web of Science databases and included studies were split into Western and Asian groups based on population-specific body mass index (BMI) ranges for obesity. A meta-analysis was performed to assess the impact of obesity on AL rate following colorectal cancer resection.

Results: Two thousand three hundred and four articles were initially screened. Thirty-one studies totaling 32,953 patients were included. Patients with obesity had a statistically significant increase in AL rate in all Western and Asian study groups. However, this increase was only clinically significant in the rectal anastomotic subgroups-Western: 10.8% vs 8.4%, OR 1.57 (1.01-2.44) and Asian: 9.4% vs 7.4%, OR 1.58 (1.07-2.32).

Conclusions: The findings of this analysis confirm that obesity is a significant risk factor for anastomotic leak, particularly in rectal anastomoses. This effect is thought to be primarily mediated via technical difficulties of surgery although metabolic and immunological factors may also play a role. Obesity in patients undergoing restorative CRC resection should be discussed and considered as part of the pre-operative counselling.
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http://dx.doi.org/10.1007/s00384-021-03909-7DOI Listing
September 2021

The Protein Secretome Is Altered in Rectal Cancer Tissue Compared to Normal Rectal Tissue, and Alterations in the Secretome Induce Enhanced Innate Immune Responses.

Cancers (Basel) 2021 Feb 2;13(3). Epub 2021 Feb 2.

Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin and St. James's Hospital, D08 W9RT Dublin 8, Ireland.

Locally advanced rectal cancer is treated with neoadjuvant-chemoradiotherapy; however, only ~22% of patients achieve a complete response, and resistance mechanisms are poorly understood. The role of inflammation and immune cell biology in this setting is under-investigated. In this study, we profiled the inflammatory protein secretome of normal (non-cancer) ( = 8) and malignant rectal tissue ( = 12) pre- and post-radiation in human ex vivo explant models and examined the influence of these untreated and treated secretomes on dendritic cell biology ( = 8 for cancer and normal). These resultant profiles were correlated with patient clinical characteristics. Nineteen factors were secreted at significantly higher levels from the rectal cancer secretome when compared to the normal rectal secretome; Flt-1, P1GF, IFN-γ, IL-6, IL-10, CCL20, CCL26, CCL22, CCL3, CCL4, CCL17, GM-CSF, IL-12/IL-23p40, IL-17A, IL-1α, IL-17A/F, IL-1RA, TSLP and CXCL10 ( < 0.05). Radiation was found to have differential effects on normal rectal tissue and rectal cancer tissue with increased IL-15 and CCL22 secretion following radiation from normal rectal tissue explants ( < 0.05), while no significant alterations were observed in the irradiated rectal cancer tissue. Interestingly, however, the irradiated rectal cancer secretome induced the most potent effect on dendritic cell maturation via upregulation of CD80 and PD-L1. Patient's visceral fat area correlated with secreted factors including CCL20, suggesting that obesity status may alter the tumour microenvironment (TME). These results suggest that radiation does not have a negative effect on the ability of the rectal cancer TME to induce an immune response. Understanding these responses may unveil potential therapeutic targets to enhance radiation response and mitigate normal tissue injury. Tumour irradiation in this cohort enhances innate immune responses, which may be harnessed to improve patient treatment outcome.
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http://dx.doi.org/10.3390/cancers13030571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867296PMC
February 2021

Radiation-induced Bystander Effect (RIBE) alters mitochondrial metabolism using a human rectal cancer ex vivo explant model.

Transl Oncol 2021 Jan 23;14(1):100882. Epub 2020 Oct 23.

Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland. Electronic address:

Locally advanced rectal cancer is treated with neoadjuvant-chemoradiotherapy, however only 22% of patients achieve a complete response. Resistance mechanisms are poorly understood. Radiation-induced Bystander Effect (RIBE) describes the effect of radiation on neighbouring unirradiated cells. We investigated the effects of ex vivo RIBE-induction from normal and rectal cancer tissue on bystander cell metabolism, mitochondrial function and metabolomic profiling. We correlated bystander events to patient clinical characteristics. Ex vivo RIBE-induction caused metabolic alterations in bystander cells, specifically reductions in OXPHOS following RIBE-induction in normal (p = 0.01) and cancer tissue (p = 0.03) and reduced glycolysis following RIBE-induction in cancer tissue (p = 0.01). Visceral fat area correlated with glycolysis (p = 0.02) and ATP production (p = 0.03) following exposure of cells to TCM from irradiated cancer biopsies. Leucine levels were reduced in the irradiated cancer compared to the irradiated normal secretome (p = 0.04). ROS levels were higher in cells exposed to the cancer compared to the normal secretome (p = 0.04). RIBE-induction ex vivo causes alterations in the metabolome in normal and malignant rectal tissue along with metabolic alterations in bystander cellular metabolism. This may offer greater understanding of the effects of RIBE on metabolism, mitochondrial function and the secreted metabolome.
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http://dx.doi.org/10.1016/j.tranon.2020.100882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586242PMC
January 2021

Combining 1,4-dihydroxy quininib with Bevacizumab/FOLFOX alters angiogenic and inflammatory secretions in ex vivo colorectal tumors.

BMC Cancer 2020 Oct 2;20(1):952. Epub 2020 Oct 2.

Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.

Background: Colorectal cancer (CRC) is the second most common cause of cancer-related mortality worldwide with one in every five patients diagnosed with metastatic CRC (mCRC). In mCRC cases, the 5-year survival rate remains at approximately 14%, reflecting the lack of effectiveness of currently available treatments such as the anti-VEGF targeting antibody Bevacizumab combined with the chemotherapy folinic acid, fluorouracil and oxaliplatin (FOLFOX). Approximately 60% of patients do not respond to this combined treatment. Furthermore, Bevacizumab inhibits dendritic cell (DC) maturation in poor responders, a key process for tumor eradication.

Method: Following drug treatment, secreted expression levels of angiogenic and inflammatory markers in tumor conditioned media generated from human ex vivo colorectal tumors were measured by ELISA. Dendritic cell phenotypic and maturation markers were assessed by flow cytometry.

Results: Our novel compound, 1,4-dihydroxy quininib, acts in an alternative pathway compared to the approved therapy Bevacizumab. 1,4-dihydroxy quininib alone, and in combination with Bevacizumab or FOLFOX significantly reduced TIE-2 expression which is involved in the promotion of tumor vascularization. Combination treatment with 1,4-dihydroxy quininib significantly increased the expression level of DC phenotypic and maturation markers.

Conclusion: Our results indicate the anti-angiogenic small molecule 1,4-dihydroxy quininib could be an alternative novel treatment in combination therapy for CRC patients.
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http://dx.doi.org/10.1186/s12885-020-07430-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532092PMC
October 2020

Prophylactic negative pressure wound therapy for closed laparotomy wounds: a systematic review and meta-analysis of randomised controlled trials.

Ir J Med Sci 2021 Feb 25;190(1):261-267. Epub 2020 Jun 25.

Department of Colorectal Surgery, St James's Hospital, Dublin, 8, Ireland.

Surgical site infections are a common source of post-operative morbidity and contribute significantly to healthcare costs. Patients undergoing emergency laparotomy and/or bowel surgery are particularly at risk. Prophylactic negative pressure wound therapy (NPWT) has been shown to reduce wound infection. However, to date, there has been a lack of consensus around its use for closed laparotomy wounds. We conducted a systematic review of randomised controlled trials comparing the use of prophylactic negative pressure wound therapy with standard dressings for closed laparotomy incisions. The primary outcome was incidence of incisional surgical site infection (SSI) at 30 days post-operatively. Secondary outcomes included superficial and deep SSI, skin dehiscence, fascial dehiscence and length of stay. A total of 2182 publications were identified, of which, following review of titles, abstracts and full texts, five studies met the criteria for inclusion. Across these studies, 467 patients were randomised to NPWT and 464 to standard dressings. Overall SSI rate was 18.6% (n = 87/467) versus 23.9% (n = 111/464) in the NPWT and standard dressing groups, respectively (Odds ratio 0.71, 95% CI 0.52-0.99, p = 0.04*). Deep SSI incidence was the same in both groups (2.6%). Both skin dehiscence and fascial dehiscence were slightly higher in the standard dressing group ((4.2%, n = 11/263 versus 3.1% (n = 8/261) and (0.9% (n = 3/324) versus 0.6% (n = 2/323)), respectively. This study observed that NPWT reduces the overall SSI for closed laparotomy wounds. It supports data recommending the use of prophylactic NPWT dressings, especially in high-risk patients in both emergency and elective circumstances.
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http://dx.doi.org/10.1007/s11845-020-02283-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315908PMC
February 2021

Effective treatment of intractable cutaneous metastases of breast cancer with electrochemotherapy: Ten-year audit of single centre experience.

Breast Cancer Res Treat 2017 01 22;161(2):289-297. Epub 2016 Nov 22.

Cork Cancer Research Centre, Mercy University Hospital and Leslie C. Quick Jnr. Laboratory, Biosciences Institute, University College Cork, Cork, Ireland.

Purpose: Electrochemotherapy (ECT) is the application of electric pulses to tumour tissue to render the cell membranes permeable to usually impermeant hydrophilic anti-cancer drugs, thereby enhancing cytotoxic effects. We sought to ascertain whether ECT can be an effective palliative treatment for cutaneous metastases of breast cancer.

Methods: This work reports data from the European Standard Operating Procedures for Electrochemotherapy trial (EudraCT Number: 2004-002183-18). In combination with systemic and/or intratumoural bleomycin, optimised electric pulses were delivered to locally recurrent or metastatic cutaneous breast cancer lesions. Follow-up continued until December 2014.

Results: Between February 2004 and December 2014, twenty-four patients were treated. All patients had received prior multimodal therapy. In total, the patient cohort had, or developed, 242 lesions. Two hundred and 36 lesions were treated, with 34 lost to follow-up. An objective response was seen in 161 of 202 lesions (79.7%), with a complete response observed in 130 (64.3%). Thirty-nine lesions (19.3%) did not respond, while 2 (1%) progressed following ECT. 17 (73.9%) patients received two or fewer treatments. A minimum of a partial response was seen in at least 50% of treated lesions in 18 of the 24 (75%) patients. Smaller lesions were more likely to have an objective response (Chi-square test for trend, p < 0.001).

Conclusions: Electrochemotherapy is an effective treatment for cutaneous breast cancer lesions that have proven refractory to standard therapies. As smaller lesions were found to be more responsive, we suggest that ECT should be considered as an early treatment modality, within multimodal treatment strategies.
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http://dx.doi.org/10.1007/s10549-016-4046-yDOI Listing
January 2017

Activated systemic inflammatory response at diagnosis reduces lymph node count in colonic carcinoma.

World J Gastrointest Oncol 2016 Aug;8(8):623-8

Rory P Kennelly, Brenda Murphy, John O Larkin, Brian J Mehigan, Paul H McCormick, Department of Colorectal Surgery, St James Hospital, Dublin 8, Ireland.

Aim: To investigate a link between lymph node yield and systemic inflammatory response in colon cancer.

Methods: A prospectively maintained database was interrogated. All patients undergoing curative colonic resection were included. Neutrophil lymphocyte ratio (NLR) and albumin were used as markers of SIR. In keeping with previously studies, NLR ≥ 4, albumin < 35 was used as cut off points for SIR. Statistical analysis was performed using 2 sample t-test and χ(2) tests where appropriate.

Results: Three hundred and two patients were included for analysis. One hundred and ninety-five patients had NLR < 4 and 107 had NLR ≥ 4. There was no difference in age or sex between groups. Patients with NLR of ≥ 4 had lower mean lymph node yields than patients with NLR < 4 [17.6 ± 7.1 vs 19.2 ± 7.9 (P = 0.036)]. More patients with an elevated NLR had node positive disease and an increased lymph node ratio (≥ 0.25, P = 0.044).

Conclusion: Prognosis in colon cancer is intimately linked to the patient's immune response. Assuming standardised surgical technique and sub specialty pathology, lymph node count is reduced when systemic inflammatory response is activated.
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http://dx.doi.org/10.4251/wjgo.v8.i8.623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980653PMC
August 2016

Sigmoid volvulus causing displacement of the liver and gastric outlet obstruction.

BMJ Case Rep 2015 Jul 16;2015. Epub 2015 Jul 16.

Department of Surgery, St James Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1136/bcr-2015-210317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513522PMC
July 2015

Oral tolerance to cancer can be abrogated by T regulatory cell inhibition.

PLoS One 2014 15;9(5):e97602. Epub 2014 May 15.

Cork Cancer Research Centre, BioSciences Institute, University College Cork, Cork, Ireland.

Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue--JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups--this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097602PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022586PMC
January 2015

Spontaneous perforation of the esophagus in a patient with achalasia.

Ann Thorac Surg 2013 Oct;96(4):1456-1457

Department of Surgery, St. James's Hospital and Trinity Center for Health Sciences, Dublin, Ireland.

Esophageal perforation in achalasia is rare. The risk would mainly follow pneumatic dilatation, and spontaneous perforation has not been described. We report a case of spontaneous rupture of the midesophagus in a 56-year-old woman with treated achalasia in whom the perforation occurred during a meal and was not preceded by emesis. A gastrografin swallow confirmed extravasation of contrast medium from the esophagus, and endoscopy revealed significant esophageal food stasis, consistent with achalasia, with a large tear in the midesophagus and gross mediastinal contamination. She subsequently underwent a three-stage esophagectomy with an uneventful recovery.
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http://dx.doi.org/10.1016/j.athoracsur.2013.01.091DOI Listing
October 2013

A 10-step intraoperative surgical checklist (ISC) for laparoscopic cholecystectomy-can it really reduce conversion rates to open cholecystectomy?

J Gastrointest Surg 2012 Jul 20;16(7):1318-23. Epub 2012 Apr 20.

Department of Surgery, Mayo General Hospital, Castlebar, Co. Mayo, Republic of Ireland.

Introduction: The recent introduction of a Surgical Safety Checklist has significantly reduced the morbidity and mortality of surgery. Such a simple measure that can impact so highly on surgical outcomes causes all surgeons to pause for thought. This paper documents the introduction of a 10-step intraoperative surgical checklist (ISC) to standardize performance, decision-making, and training during laparoscopic cholecystectomy (LC). The checklist's impact on conversion rates to open cholecystectomy (OC) is presented.

Methods: In 2004, a 10-step ISC was introduced by a single consultant surgeon for the performance of LCs. Data were collected comparing LCs between 1999-2003 (period 1) and 2004-2008 (period 2). Data on sex, age, American Society of Anesthesiology grade, previous abdominal surgery, severity of gallbladder pathology, and conversion to OC were recorded. The chi-squared test with Yates correction was used to compare groups.

Results: In total, 637 LCs were performed, 277 during period 1 and 360 during period 2. Risk factors for conversion (gender, age, previous abdominal surgery, and severity of gallbladder pathology) were not significantly different in the two periods studied. The overall conversion rate to OC fell significantly in period 2 (p=0.001). Subgroup analysis also showed a significant reduction in conversion rates in female patients (p=0.002) and patients with grades III and IV gallbladder disease (p=0.001).

Conclusions: The introduction of a 10-step ISC was temporally related to reduced conversion rates to OC. The standardization of a frequently performed operation such as a LC that could potentially lead to an impact as great the one we observed warrants further attention in prospective, appropriately designed studies.
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http://dx.doi.org/10.1007/s11605-012-1886-6DOI Listing
July 2012

Necrotizing pancreatitis presenting with pneumatosis coli and hepatic portal venous gas.

ANZ J Surg 2011 Jun;81(6):467-8

Department of Clinical Surgery, St James’s Hospital and Trinity College, Dublin, Ireland.

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http://dx.doi.org/10.1111/j.1445-2197.2011.05760.xDOI Listing
June 2011

Partial herniation through the peritoneal defect of a pfannenstiel incision: a rare complication of non-closure.

J Obstet Gynaecol Can 2011 Jun;33(6):625-627

Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland.

Background: The Pfannenstiel incision is used almost invariably in Caesarean section. With Caesarean section rates increasing, the Pfannenstiel is a commonly performed incision. The prevailing recommendation is not to close the peritoneum when closing a Pfannenstiel incision, and peritoneal non-closure does not appear to statistically influence postoperative complication rates.

Case: A 33-year-old woman presented with severe, intermittent lower abdominal pain one year after a Caesarean section. Laparoscopy showed a hernial defect at the Pfannenstiel incision, between the left rectus abdominis muscle and the anterior rectus sheath. Mesh repair was performed with uncomplicated postoperative outcome.

Conclusion: The current case illustrates that complications specific to non-closure of the peritoneum do arise. We advocate that laparoscopy should be considered for any patient with persistent, severe, or atypical pain following a Pfannenstiel incision.
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http://dx.doi.org/10.1016/S1701-2163(16)34912-XDOI Listing
June 2011

Gallstone ileus in evolution.

ANZ J Surg 2011 Apr;81(4):287-8

Department of Clinical Surgery, St. James's Hospital, Trinity College Dublin, Ireland.

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http://dx.doi.org/10.1111/j.1445-2197.2011.05691.xDOI Listing
April 2011

Recurrent melaena in a 21-year-old female.

ANZ J Surg 2011 Mar;81(3):181-2

Department of Clinical Surgery, St. James's Hospital and Trinity College Dublin, Dublin, Ireland.

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http://dx.doi.org/10.1111/j.1445-2197.2010.05550.xDOI Listing
March 2011

Differential pathologic variables and outcomes across the spectrum of adenocarcinoma of the esophagogastric junction.

World J Surg 2010 Dec;34(12):2821-9

Department of Surgery, St. James's Hospital and Trinity College Dublin, Trinity Center, Dublin 8, Ireland.

Background: Adenocarcinoma of the esophagogastric junction (AEG) as described by Siewert et al. is classified as one entity in the latest (7th Edition) American Joint Cancer Committee/International Union Against Cancer (AJCC/UICC) manual, compared with the previous mix of esophageal and gastric staging systems. The origin of AEG tumors, esophageal or gastric, and their biology remain controversial, particularly for AEG type II (cardia) tumors.

Methods: We adapted a large prospective database (n = 520: 180 type I, 182 type II, 158 type III) to compare AEG tumors under the new TNM system Pathological variables associated with prognosis were compared (pT, pN, stage, differentiation, R status, lymphovascular invasion, perineural involvement, number of positive nodes, percent of positive nodes, and tumor length), as well as overall survival.

Results: Compared with AEG type I tumors, type II and type III tumors had significantly (p < 0.05) more advanced pN stages, greater number and percentage of positive nodes, poorer differentiation, more radial margin involvement, and more perineural invasion. In AEG type I, 14/180 patients (8%) had >6 involved nodes (pN3), compared with 16 and 30% of patients classified type II and III, respectively. Median survival was significantly (p = 0.03) improved for type I patients (38 months) compared with those with tumors classified as type II (28 months) and type III (24 months). In multivariate analysis node positivity and pN staging but not AEG site had an impact on survival.

Conclusions: In this series AEG type I is associated with more favorable pathologic features and improved outcomes compared with AEG type II and III. This may reflect earlier diagnosis, but an alternative possibility, that type I may be a unique paradigm with more favorable biology, requires further study.
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http://dx.doi.org/10.1007/s00268-010-0783-yDOI Listing
December 2010

Sonoporation mediated immunogene therapy of solid tumors.

Ultrasound Med Biol 2010 Mar 4;36(3):430-40. Epub 2010 Feb 4.

Cork Cancer Research Centre, Mercy University Hospital, University College Cork, Cork, Ireland.

Development of gene-based therapies for the treatment of inherited and acquired diseases, including cancer, has seen renewed interest in the use of nonviral vectors coupled to physical delivery modalities. Low-frequency ultrasound (US), with a well-established record in a clinical setting, has the potential to deliver DNA efficiently, accurately and safely. Optimal in vivo parameters for US-mediated delivery of naked plasmid DNA were established using the firefly luciferase reporter gene construct. Optimized parameters were used to administer a therapeutic gene construct, coding for granulocyte-macrophage colony-stimulating factor (GM-CSF) and B7-1 costimulatory molecule, to growing murine fibrosarcoma tumors. Tumor progression and animal survival was monitored throughout the study and the efficacy of the US-mediated gene therapy determined and compared with an electroporation-based approach. Optimal parameters for US-mediated delivery of plasmid DNA to tumors were deduced to be 1.0 W/cm(2) at 20% duty cycle for 5 min (60 J/cm(2)). In vivo US-mediated gene therapy resulted in a 55% cure rate in tumor-bearing animals. The immunological response invoked was cell mediated, conferring resistance against re-challenge and resistance to tumor challenge after transfer of splenocytes to naïve animals. US treatment was noninjurious to treated tissue, whereas therapeutic efficacy was comparable to an electroporation-based approach. US-mediated delivery of an immune-gene construct to growing tumors was therapeutically effective. Sonoporation has the potential to be a major factor in the development of nonviral gene delivery approaches.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2009.11.005DOI Listing
March 2010

Management of gastro-bronchial fistula complicating a subtotal esophagectomy: a case report.

BMC Surg 2009 Dec 24;9:20. Epub 2009 Dec 24.

Department of Clinical Surgery, St James's Hospital and Trinity College Dublin, Dublin, Ireland.

Background: The development of a fistula between the tracheobronchial tree and the gastric conduit post esophagectomy is a rare and often fatal complication.

Case Presentation: A 68 year old man underwent radical esophagectomy for esophageal adenocarcinoma. On postoperative day 14 the nasogastric drainage bag dramatically filled with air, without deterioration in respiratory function or progressive sepsis. A fiberoptic bronchoscopy was performed which demonstrated a gastro-bronchial fistula in the posterior aspect of the left main bronchus. He was managed conservatively with antibiotics, enteral nutrition via jejunostomy, and non-invasive respiratory support. A follow- up bronchoscopy 60 days after the diagnostic bronchoscopy, confirmed spontaneous closure of the fistula

Conclusions: This is the first such case where a conservative approach with no surgery or endoprosthesis resulted in a successful outcome, with fistula closure confirmed at subsequent bronchoscopy. Our experience would suggest that in very carefully selected cases where bronchopulmonary contamination from the fistula is minimal or absent, there is no associated inflammation of the tracheobronchial tree and the patient is stable from a respiratory point of view without evidence of sepsis, there may be a role for a trial of conservative management.
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http://dx.doi.org/10.1186/1471-2482-9-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803445PMC
December 2009

Bilateral adrenal haemorrhage secondary to intra-abdominal sepsis: a case report.

Cases J 2009 Jun 9;2:6894. Epub 2009 Jun 9.

Department of Surgery, Mayo General Hospital, Castlebar, Co. Mayo, Ireland and 2Department of Radiology, Mayo General Hospital,Castlebar, Co. Mayo, Ireland.

Introduction: Bilateral adrenal haemorrhage is a rare cause of adrenal failure. Clinical features are non-specific and therefore a high index of suspicion must be maintained in patients at risk. Predisposing factors include infection, malignancy and the post-operative state.

Case Presentation: We report the case of a patient who underwent a left hemicolectomy with primary anastomosis and formation of a defunctioning loop ileostomy for an obstructing colon carcinoma at the splenic flexure. En-bloc splenectomy was performed to ensure an oncologic resection. The patient developed a purulent abdominal collection post-operatively and became septic with hypotension and pyrexia. This precipitated acute bilateral adrenal haemorrhage with consequent adrenal insufficiency. Clinical suspicion was confirmed by radiological findings and a co-syntropin test. Following drainage of the collection, antibiotic therapy and corticosteroid replacement, the patient made an excellent recovery.

Conclusion: This case highlights the importance of prompt diagnosis and treatment of adrenal failure. In their absence, this condition can rapidly lead to death of the patient.
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http://dx.doi.org/10.4076/1757-1626-2-6894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2740141PMC
June 2009

Management of the acute scrotum in a district general hospital: 10-year experience.

ScientificWorldJournal 2009 Apr 28;9:281-6. Epub 2009 Apr 28.

Department of Surgery, Mayo General Hospital, Castlebar, Co. Mayo, Republic of Ireland.

The acutely painful scrotum is a common urologic emergency. The primary objective of management is to avoid testicular loss. This requires a high index of clinical suspicion and prompt surgical intervention. In our series conducted between January 1996 and December 2005, 119 patients (age range: 4-62 years) underwent emergency operative exploration for acute scrotal pain. The most common finding was torted cyst of Morgagni (63/119, 52.9%), followed by testicular torsion (41/119, 34.4%). The majority of testicular torsions occurred in the pubertal group (22/41, 53.6%). Only one patient in this group had an unsalvageable testis necessitating orchidectomy, a testicular loss rate in torsion of 2.4%. There were no postoperative wound infections or scrotal haematomas. Testicular salvage depends critically on early surgical intervention, so the delay incurred in diagnostic imaging may extend the period of ischaemia. Furthermore, all radiological investigations have a certain false-negative rate. We advocate immediate surgical exploration of the acute scrotum. We report a low orchidectomy rate (2.4%) in testicular torsion.
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http://dx.doi.org/10.1100/tsw.2009.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823175PMC
April 2009

Effective tumor treatment using optimized ultrasound-mediated delivery of bleomycin.

Ultrasound Med Biol 2008 Mar 7;34(3):406-13. Epub 2007 Nov 7.

Cork Cancer Research Centre, Leslie C. Quick Laboratory, University College Cork, Cork, Ireland.

Bleomycin is a nonpermeant, hydrophilic macromolecule with a high intrinsic anticancer cytotoxicity. However, the cytotoxic potential of the drug is restricted by its low membrane permeability. Application of low-intensity ultrasound to growing tumors enhances intracellular delivery of bleomycin after IP or intratumoral administration, thereby potentiating its cytotoxicity. Optimization of ultrasound parameters for in-vivo bleomycin delivery was undertaken, and an effective antitumor effect was demonstrated in solid tumors of both murine and human cell lines. Cell death after treatment was shown to occur by an apoptotic mechanism. The results achieved in these experiments were equivalent to those achieved using electroporation to mediate delivery of bleomycin-electrochemotherapy. We found that, although temperature rises of up to 5 degrees C occur using the optimized ultrasound conditions, this effect is not responsible for the potentiated drug cytotoxicity. This technique could be used with focused ultrasound or with endoscopic ultrasound probes to develop a localized and effective anticancer treatment with little or no systemic toxicity. (E-mail: [email protected]).
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http://dx.doi.org/10.1016/j.ultrasmedbio.2007.09.005DOI Listing
March 2008

Electrochemotherapy: aspects of preclinical development and early clinical experience.

Ann Surg 2007 Mar;245(3):469-79

Cork Cancer Research Centre, Leslie C. Quick Jr. Cancer Laboratory, Biosciences Institute & Mercy University Hospital, National University of Ireland, Cork, Ireland.

Objective: To develop an optimized, reproducible system of electrochemotherapy, and to investigate its clinical application in patients with cutaneous or subcutaneous recurrences of inoperable or progressive disease recalcitrant to current anticancer treatments.

Background: Electrochemotherapy is the application of electric pulses to tumor tissue, rendering the cell membranes permeable to otherwise impermeant or poorly permeant anticancer drugs. This facilitates a potent local cytotoxic effect.

Study Design: The optimal parameters for electrical pulses and bleomycin concentration were obtained in vitro and then applied to tumors derived from 4 histologically distinct human cancer cell lines (7860, PC3, OE19, MCF-7) established in athymic nude mice. Comparison was made with tumors that received bleomycin alone, electric pulses alone, and untreated controls. The optimized electrochemotherapy was then applied to patients with cutaneous or subcutaneous tumors, of any histologic type, recurrent or metastatic and unresponsive to standard chemotherapy and/or radiotherapy regimens. Tumors were assessed at monthly intervals to determine response to the treatment.

Results: In vivo: Using the optimal parameters ascertained in vitro, all tumors treated by electrochemotherapy with bleomycin (n = 24) had significantly regressed (P < 0.001, all 4 lines) compared with control tumors (n = 72). Twelve tumors completely regressed (50%) following a single application, with 12 partial regressions (50%). Clinical: In 30 patients (111 tumors), none of the treated tumors progressed. Sixty percent of tumors (66 of 111) showed complete regression, 22% (24 of 111) partial response, and 18% (21 of 111) no change. Electrochemotherapy was more effective in smaller tumors (<3 cm), 71% (64 of 90) showing complete regression, 20% (18 of 90) partial response, and 9% (8 of 90) no change.

Conclusions: Electrochemotherapy parameters optimized in vitro are applicable in vivo. This treatment is effective in athymic nude mice for all histologic types indicating a nonimmunologic mode of action. In clinical application, electrochemotherapy is an effective, safe, and reproducible therapy. Patients with cutaneous or subcutaneous tumors previously refractory to surgical intervention, systemic chemotherapy, and/or radiotherapy responded successfully irrespective of histologic type.
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http://dx.doi.org/10.1097/01.sla.0000250419.36053.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1877027PMC
March 2007

Successful application of targeted electrochemotherapy using novel flexible electrodes and low dose bleomycin to solid tumours.

Cancer Lett 2006 Feb 16;232(2):300-10. Epub 2005 Jun 16.

Cork Cancer Research Centre, Mercy University Hospital and Leslie C. Quick Jnr Laboratory, Grenville Place, Cork, Ireland.

Electroporation is the application of very brief electric pulses to cells or tissues to render the cell membranes transiently and reversibly permeable, facilitating cellular uptake of otherwise impermeant molecules. Flexible electrode arrays were developed which may be used with endoscopic and laparoscopic devices for delivery of therapeutic electroporation. Their efficacy in enhancing the delivery of bleomycin, an impermeant drug, was assessed in vitro and in vivo in both human and murine cancer cell lines, and growing tumours (xenografts). These flexible electrodes consistently and predictably deliver the permeabilising electric pulses requisite for in vivo electroporation, and would be suitable for electrochemotherapy of endoluminal tumours when incorporated into an endoscopic delivery system.
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http://dx.doi.org/10.1016/j.canlet.2005.03.057DOI Listing
February 2006
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