Publications by authors named "John R McGregor"

12 Publications

  • Page 1 of 1

Analysis of lesion localisation at colonoscopy: outcomes from a multi-centre U.K. study.

Surg Endosc 2017 07 8;31(7):2959-2967. Epub 2016 Nov 8.

Department of Surgery, Royal Alexandra Hospital, Corsebar Road, Paisley, PA2 9PN, Scotland, UK.

Background: Colonoscopy is currently the gold standard for detection of colorectal lesions, but may be limited in anatomically localising lesions. This audit aimed to determine the accuracy of colonoscopy lesion localisation, any subsequent changes in surgical management and any potentially influencing factors.

Methods: Patients undergoing colonoscopy prior to elective curative surgery for colorectal lesion/s were included from 8 registered U.K. sites (2012-2014). Three sets of data were recorded: patient factors (age, sex, BMI, screener vs. symptomatic, previous abdominal surgery); colonoscopy factors (caecal intubation, scope guide used, colonoscopist accreditation) and imaging modality. Lesion localisation was standardised with intra-operative location taken as the gold standard. Changes to surgical management were recorded.

Results: 364 cases were included; majority of lesions were colonic, solitary, malignant and in symptomatic referrals. 82% patients had their lesion/s correctly located at colonoscopy. Pre-operative CT visualised lesion/s in only 73% of cases with a reduction in screening patients (64 vs. 77%; p = 0.008). 5.2% incorrectly located cases at colonoscopy underwent altered surgical management, including conversion to open. Univariate analysis found colonoscopy accreditation, scope guide use, incomplete colonoscopy and previous abdominal surgery significantly influenced lesion localisation. On multi-variate analysis, caecal intubation and scope guide use remained significant (HR 0.35, 0.20-0.60 95% CI and 0.47; 0.25-0.88, respectively).

Conclusion: Lesion localisation at colonoscopy is incorrect in 18% of cases leading to potentially significant surgical management alterations. As part of accreditation, colonoscopists need lesion localisation training and awareness of when inaccuracies can occur.
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http://dx.doi.org/10.1007/s00464-016-5313-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487844PMC
July 2017

A survey of morbidity and mortality review meetings in the general surgical units of the West of Scotland.

Scott Med J 2015 Nov 23;60(4):244-8. Epub 2015 Jul 23.

Consultant General and Colorectal Surgeon, Department of Surgery, Crosshouse Hospital, UK.

Background And Aims: There is little consensus as to the conduct of surgical morbidity and mortality review meetings. The aim of this survey was to determine how surgical morbidity and mortality meetings in the surgical units in the West of Scotland are carried out and to explore possible areas for improvement.

Methods And Results: Forty six surgical trainees distributed between the 15 general surgery units of the West of Scotland were asked to provide details of their surgical morbidity and mortality meetings for the training year 2012-2013. Twenty-five of 46 (54%) specialty trainees responded with all units being represented. All had designated time for surgical morbidity and mortality review. Meeting frequency varied as follows: weekly (3 units), fortnightly (1 unit), monthly (10 units), three monthly (1 unit). Fewer than half the units (6) included Foundation Trainees, and only one meeting was attended by nursing staff. Five units had clear criteria for morbidity, but only three included morbidity collected from outpatient follow-up. A standardised proforma was used to present the cases in only 2 units.

Conclusions: All 15 surgical units in the West of Scotland have a regular surgical morbidity and mortality meeting but significant variations were observed as to frequency and participating personnel. A more robust system for reporting morbidities should be considered.
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http://dx.doi.org/10.1177/0036933015597179DOI Listing
November 2015

Endothelial nitric oxide synthase is a key mediator of interleukin-2-induced hypotension and vascular leak syndrome.

J Immunother 2011 Jun;34(5):419-27

Section of Melanoma, Renal Cancer and Immunotherapy, Nevada Cancer Institute, Las Vegas, USA.

Despite increasing use of "targeted therapy," interleukin-2 (IL-2) is unique, because this cytokine can induce long-term remissions in 5% to 7% of patients with metastatic melanoma and renal cancer. Clinical use of IL-2 is limited by severe toxicities, such as hypotension and vascular leak syndrome (VLS). Nitric oxide seems to be involved in the pathogenesis of these toxicities. On the basis of previous studies, we hypothesized that the endothelial nitric oxide synthase (eNOS) is the major source of nitric oxide. Mice with a knockout of the eNOS isoenzyme were treated with IL-2 (800,000 IU twice daily for 5 d). Blood pressure and vascular leak were measured. Inhibitors of superoxide, nitric oxide, and soluble guanylate cyclase were used to probe the mechanism. These experiments showed that IL-2 treatment increased eNOS messenger ribonucleic acid expression and nitric oxide metabolite excretion in eNOS knockout mice. Unlike normal and inducible nitric oxide synthase knockout mice, eNOS knockout mice proved resistant to IL-2-induced hypotension and vascular leak. Although hypotension seems to be mediated by superoxide or peroxynitrite, vascular leak seemed to be mediated by nitric oxide. Inhibition of guanylate cyclase and cyclic guanylate monophosphate formation during IL-2 treatment using methylene blue (MB)-inhibited vascular leak. MB treatment did not interfere with IL-2-induced antitumor mechanisms. Our experiments established that eNOS is a key mediator of IL-2-induced VLS and hypotension. A clinical trial of MB infusion during IL-2 therapy is currently being planned.
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http://dx.doi.org/10.1097/CJI.0b013e31821dcb50DOI Listing
June 2011

Cancer of the proximal colon after a "normal" colonoscopy.

Biosci Trends 2009 Aug;3(4):158-60

Colorectal Unit, Department of General Surgery, Crosshouse Hospital, Kilmarnock Road, Kilmarnock, Scotland, UK.

In common with other diagnostic tests, colonoscopy has a false negative rate which is infrequently assessed. The available literature suggests that lesion miss rate is higher for proximal colonic tumors. A total of 367 patients were diagnosed with cancer of the colon and rectum over a period of 2 years. Ninety-two of these patients had tumors proximal to the splenic flexure. Their 5-year pre-diagnosis colonoscopic exposure was analyzed. The primary end-point of this study was to confirm the false negative colonoscopy rate in patients subsequently diagnosed with cancer of the proximal colon. The secondary endpoint was to assess the effects of diagnostic delay on tumor stage and presentation. In the group of patients with proximal colon cancer (n = 92) we identified 10 patients (11%) who, as a result of incomplete (2 cases) or falsely negative (8 cases) colonoscopies, suffered a median diagnostic delay of 17 months (range 3-60). At diagnosis, 4 of these patients had Dukes' D caecal cancer, 4 had Dukes' C caecal cancer and 2 had Dukes' B transverse colon cancer; 3 presented with perforated tumours and 1 with intestinal obstruction. In this small subgroup of patients therefore 40% presented with emergency complications compared to 8% in the rest of the group with proximal cancers (p < 0.01). Missed cancers are more likely to present with complications. This study highlights the importance of recognition of an incomplete examination and the adverse impact of missed diagnosis on subsequent presentation.
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August 2009

Quantitative analysis of cytokine-induced vascular toxicity and vascular leak in the mouse brain.

J Immunol Methods 2009 Sep 5;349(1-2):45-55. Epub 2009 Aug 5.

Section of Melanoma, Renal Cancer and Immunotherapy, Nevada Cancer Institute, Las Vegas, NV 89135, United States of America.

A storm of inflammatory cytokines is released during treatment with pro-inflammatory cytokines, such as interleukin-2 (IL-2), closely approximating changes initially observed during sepsis. These signals induce profound changes in neurologic function and cognition. Little is known about the mechanisms involved. We evaluated a number of experimental methods to quantify changes in brain blood vessel integrity in a well-characterized IL-2 treatment mouse model. Measurement of wet versus dry weight and direct measurement of small molecule accumulation (e.g. [(3)H]-H(2)O, sodium fluorescein) were not sensitive or reliable enough to detect small changes in mouse brain vascular permeability. Estimation of brain water content using proton density magnetic resonance imaging (MRI) measurements using a 7T mouse MRI system was sensitive to 1-2% changes in brain water content, but was difficult to reproduce in replicate experiments. Successful techniques included use of immunohistochemistry using specific endothelial markers to identify vasodilation in carefully matched regions of brain parenchyma and dynamic contrast enhanced (DCE) MRI. Both techniques indicated that IL-2 treatment induced vasodilation of the brain blood vessels. DCE MRI further showed a 2-fold increase in the brain blood vessel permeability to gadolinium in IL-2 treated mice compared to controls. Both immunohistochemistry and DCE MRI data suggested that IL-2 induced toxicity in the brain results from vasodilation of the brain blood vessels and increased microvascular permeability, resulting in perivascular edema. These experimental techniques provide us with the tools to further characterize the mechanism responsible for cytokine-induced neuropsychiatric toxicity.
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http://dx.doi.org/10.1016/j.jim.2009.07.014DOI Listing
September 2009

Inducible nitric oxide synthase (iNOS) is not required for IL-2-induced hypotension and vascular leak syndrome in mice.

J Immunother 2008 May;31(4):325-33

Division of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Dose limiting side effects of interleukin-2 (IL-2) include severe hypotension and vascular leak syndrome (VLS). Previous studies have shown that nitric oxide (NO) synthesis is strongly induced after IL-2 treatment of C3H/HeN mice (180,000 IU b.i.d. for 5 d). We employed knockout mice (on C57BL/6 background) to test the role of the inducible NO synthase (iNOS) in mediating IL-2 toxicity. In contrast to C3H/HeN mice, which developed hypotension and VLS after 10 doses of only 180,000 IU IL-2, C57BL/6 mice were far more resistant requiring increased doses of 800,000 IU IL-2 (b.i.d., 5 d) to induce hypotension and VLS. Serum interferon-gamma levels were significantly more elevated by IL-2 treatment in C3H/HeN mice than in C57BL/6, correlating with the severity of hypotension and VLS. Urinary excretion of NO metabolites was markedly reduced in iNOS knockout mice (C57BL/6 iNOS) after IL-2 treatment. A surprising finding was that these mice still developed profound hypotension and VLS. Similar findings were observed after administration of a iNOS specific inhibitor, L-N[6]-(1-iminoethyl)lysine (L-NIL). In contrast, a general NOS inhibitor, N-monomethyl-L-arginine, prevented both hypotension and vascular leak. The superoxide dismutase mimetic, M40403, reversed IL-2-induced hypotension but not VLS in knockout mice. Thus, peroxynitrite-mediated mechanisms are likely responsible for hypotension, whereas NO-induced changes in vascular permeability result in VLS. The iNOS enzyme is not necessary for pathogenesis of IL-2-induced cardiovascular toxicity. These results imply that other NOS isoforms, such as endothelial NOS, may play a major role in the development of IL-2-induced cardiovascular toxicity.
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http://dx.doi.org/10.1097/CJI.0b013e31816112e8DOI Listing
May 2008

ReGel polymer-based delivery of interleukin-2 as a cancer treatment.

J Immunother 2006 Sep-Oct;29(5):524-35

Multidisciplinary Melanoma Program, Huntsman Cancer Institute, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA.

ReGel is an aqueous, filter sterilizable ABA tri-block polymer consisting of poly-(lactide-co-glycolide) and polyethylene glycol. We tested the suitability of this polymer to provide sustained interleukin-2 (IL-2) delivery for cancer immunotherapy. ReGel/IL-2 is liquid at or below room temperature, and is easily injectable through narrow gauge needles, but undergoes a reversible thermal transition into a bioerodible depot at body temperature. We demonstrated that ReGel/IL-2 releases IL-2 over 72 to 96 hours in vitro, without loss of bioactivity. Pharmacokinetic studies after peritumoral injection of 0.1 mL ReGel/IL-2 in mice demonstrated an early burst of IL-2 release, followed by more sustained release kinetics over 96 hours (T(1/2)beta 48 h). Less than 1.5% of the injected dose was detectable in blood or kidneys during the first 48 hours. A single peritumoral dose of ReGel/IL-2 [1 to 4 million international units (MIU) ReGel/IL-2, split into 4 quadrant injections] was administered to mice bearing subcutaneous RD-995 spindle cell carcinoma. Only the highest dose of ReGel/IL-2 tested (4.0 MIU) resulted in significant hypotension on day 3 after injection. Weekly treatment of Meth A fibrosarcoma and RENCA renal carcinoma with ReGel/IL-2 (2 MIU/dose) induced a significant reduction in tumor growth and improved survival. Reduction in tumor growth at implants remote from treated lesions was also observed, suggesting systemic activation of antitumor immunity. These findings establish that peritumoral injection of ReGel/IL-2 is an effective delivery system for cancer immunotherapy, while decreasing IL-2 toxicity. This polymer delivery system is likely to be broadly applicable for sustained delivery of other cytokines and peptides.
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http://dx.doi.org/10.1097/01.cji.0000211306.05869.25DOI Listing
November 2006

Training for educational supervision.

Med Teach 2005 Aug;27(5):474

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August 2005

Suppression of cytokine-inducible nitric oxide synthesis during intraperitoneal Meth A tumor growth.

J Vet Med Sci 2004 May;66(5):357-65

University of Utah Cancer Immunotherapy Program, Department of Internal Medicine of the University of Utah School of Medicine, Salt Lake City, 84132, USA.

Nitric oxide (NO*) synthesis is induced within many tumors. The time course of NO* synthesis was evaluated during intra-peritoneal Meth A fibrosarcoma progression. While increasing macrophage recruitment into ascites was noted, inducible nitric oxide synthase (iNOS) antigen and function peaked between days 3-6 after tumor implantation. The capacity of cells to respond to LPS and IFNgamma stimulation was markedly depressed on day 9 and 11. Cellular proliferation correlated in an inverse fashion with levels of NO* synthesis. Electron paramagnetic resonance spectroscopy and nitrotyrosine immunostaining failed to show accumulation of characteristic target cell lesions induced by NO*. These findings lead us to conclude that NO* production was increasingly suppressed during Meth A tumor progression. Depression of NO* production did not correlate with levels of the inhibitory cytokines TGFbeta and IL-10, but could be partially overcome by addition of sepiapterin (a tetrahydrobiopterin prodrug). Thus, depletion of essential co-factors necessary for iNOS function may contribute to depressed NO* responses during cancer progression.
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May 2004

Suppression of cytokine-inducible nitric oxide synthesis during intraperitoneal meth a tumor growth.

J Vet Med Sci 2004 Apr;66(4):357-65

University of Utah Cancer Immunotherapy Program, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City 84132, USA.

Nitric oxide (NO*) synthesis is induced within many tumors. The timecourse of NO* synthesis was evaluated during intraperitoneal Meth A fibrosarcoma progression. While increasing macrophage recruitment into ascites was noted, inducible nitric oxide synthase (iNOS) antigen and function peaked between days 3-6 after tumor implantation. The capacity of cells to respond to LPS and IFNgamma stimulation was markedly depressed on day 9 and 11. Cellular proliferation correlated in an inverse fashion with levels of NO* synthesis. Electron paramagnetic resonance spectroscopy and nitrotyrosine immunostaining failed to show accumulation of characteristic target cell lesions induced by NO*. These findings lead us to conclude that NO* production was increasingly suppressed during Meth A tumor progression. Depression of NO* production did not correlate with levels of the inhibitory cytokines TGFbeta and IL-10, but could be partially overcome by addition of sepiapterin (a tetrahydrobiopterin prodrug). Thus, depletion of essential co-factors necessary for iNOS function may contribute to depressed NO* responses during cancer progression.
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April 2004

Dorsal urethral fistula: case report and review of literature.

Urology 2004 Jan;63(1):175-6

Department of General Surgery, Crosshouse Hospital, Kilmarnock, Scotland, United Kingdom.

Urethral fistula is a rare, but recognized, entity. We report the case of a young diabetic patient who developed urethral fistula on the dorsum of penis after debridement for necrotizing fasciitis. This cause and location for urethral fistula is extremely rare, and we were unable to find a similar case in published studies. A brief literature search for various causes of urethral fistula was made, and the likely mechanisms for the cause of the fistula were explored.
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http://dx.doi.org/10.1016/j.urology.2003.09.031DOI Listing
January 2004

A nonpeptidyl mimic of superoxide dismutase, M40403, inhibits dose-limiting hypotension associated with interleukin-2 and increases its antitumor effects.

Nat Med 2003 Jun 5;9(6):750-5. Epub 2003 May 5.

Melanoma Program, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, Utah 84112, USA.

Interleukin-2 (IL-2) is used to treat metastatic renal cell carcinoma and malignant melanoma, but its use is limited by the severe hypotension it produces. We have shown here that M40403, a superoxide dismutase (SOD) mimetic, blocked IL-2-induced hypotension and allowed the dose of IL-2 to be increased in mice. The reversal of IL-2-mediated hypotension was associated with an increase in plasma catecholamines. In addition, M40403 increased lymphokine-activated killer (LAK) cell cytotoxicity in vitro and in vivo, through inhibition of macrophage superoxide production. Treatment of methylcholanthrene-induced (Meth A) ascites tumors with IL-2 and > or =3 mg per kg body weight M40403 induced 50% complete remissions lasting for more than 200 d, which was longer than those of untreated mice (15-d median survival) or mice treated with IL-2 alone (22-d median). Growth of subcutaneous implants of RENCA renal carcinoma was also inhibited by the combination of IL-2 and M40403. These results established that M40403 prevented IL-2 from causing dose-limiting hypotension, while enhancing its anticancer activity.
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http://dx.doi.org/10.1038/nm874DOI Listing
June 2003
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