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Adriana J Michielsen,
Sinead Noonan,
Petra Martin,
Miriam Tosetto,
Joseph Marry,
Monika Biniecka,
Aoife A Maguire, John M Hyland,
Kieran D Sheahan,
Diarmuid P O'Donoghue,
Hugh E Mulcahy,
David Fennelly,
Elizabeth J Ryan,
Jacintha N O'Sullivan
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ABSTRACT: Development of bevacizumab has improved survival in colorectal cancer, however, currently there are no biomarkers that predict response to bevacizumab and it is unknown how it influences the immune system in colorectal cancer patients. Dendritic cells are important for the induction of an antitumor immune response; however tumors are capable of disabling dendritic cells and escaping immune surveillance. The aim of this study was to assess the numbers of CD11c+ cells infiltrating tumor tissue and to examine the effects of tumor conditioned media (TCM) and bevacizumab conditioned media (BCM) on dendritic cell maturation and correlate our findings with patient survival. colorectal cancer explant tissues were cultured with or without bevacizumab, to generate BCM and TCM, which were used to treat dendritic cells. CD80, CD86, CD83, CD54, HLA-DR, and CD1d expression was measured by flow cytometry. Interleukin (IL)-10 and IL-12p70 were measured by ELISA. The Cox proportional hazards model was used to associate survival with dendritic cell inhibition. TCM and BCM inhibited lipopolysaccharide (LPS)-induced dendritic cell maturation and IL-12p70 secretion (P < 0.0001), while increasing IL-10 secretion (P = 0.0033 and 0.0220, respectively). Inhibition of LPS-induced CD1d (P = 0.021, HR = 1.096) and CD83 (P = 0.017, HR = 1.083) by TCM and inhibition of CD1d (P = 0.017, HR = 1.067), CD83 (P = 0.032, HR = 1.035), and IL-12p70 (P = 0.037, HR = 1.036) by BCM was associated with poor survival in colorectal cancer patients. CD11c expression was elevated in tumor tissue compared with normal tissue (P < 0.001), but this did not correlate with survival. In conclusion, TCM and BCM inhibit dendritic cells, and this inhibition correlates with survival of colorectal cancer patients receiving bevacizumab.
Molecular Cancer Therapeutics 06/2012; 11(8):1829-37. · 5.23 Impact Factor
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ABSTRACT: Omental torsion is an unusual and infrequently encountered cause of acute abdominal pain in adults. Computed tomography (CT) is a useful adjunct to clinical history and examination in establishing the diagnosis; however, definitive diagnosis is frequently established at the time of exploratory surgery. Treatment may be conservative or operative, with laparoscopic resection the surgical approach of choice. We report the case of a 60-year-old man who presented with a 3-day history of severe right-sided abdominal pain. Abdominal CT scan revealed a right upper quadrant mass with a whirl-like appearance, suspicious for omental infarction. Diagnostic laparoscopy was undertaken, the diagnosis confirmed and the diseased omentum resected. The patient was discharged the following day and made an uncomplicated recovery.
International journal of surgery case reports. 01/2011; 2(6):125-7.
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Adriana J Michielsen,
Andrew E Hogan,
Joseph Marry,
Miriam Tosetto,
Fionnuala Cox, John M Hyland,
Kieran D Sheahan,
Diarmuid P O'Donoghue,
Hugh E Mulcahy,
Elizabeth J Ryan,
Jacintha N O'Sullivan
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ABSTRACT: Inflammatory mediators in the tumour microenvironment promote tumour growth, vascular development and enable evasion of anti-tumour immune responses, by disabling infiltrating dendritic cells. However, the constituents of the tumour microenvironment that directly influence dendritic cell maturation and function are not well characterised. Our aim was to identify tumour-associated inflammatory mediators which influence the function of dendritic cells. Tumour conditioned media obtained from cultured colorectal tumour explant tissue contained high levels of the chemokines CCL2, CXCL1, CXCL5 in addition to VEGF. Pre-treatment of monocyte derived dendritic cells with this tumour conditioned media inhibited the up-regulation of CD86, CD83, CD54 and HLA-DR in response to LPS, enhancing IL-10 while reducing IL-12p70 secretion. We examined if specific individual components of the tumour conditioned media (CCL2, CXCL1, CXCL5) could modulate dendritic cell maturation or cytokine secretion in response to LPS. VEGF was also assessed as it has a suppressive effect on dendritic cell maturation. Pre-treatment of immature dendritic cells with VEGF inhibited LPS induced upregulation of CD80 and CD54, while CXCL1 inhibited HLA-DR. Interestingly, treatment of dendritic cells with CCL2, CXCL1, CXCL5 or VEGF significantly suppressed their ability to secrete IL-12p70 in response to LPS. In addition, dendritic cells treated with a combination of CXCL1 and VEGF secreted less IL-12p70 in response to LPS compared to pre-treatment with either cytokine alone. In conclusion, tumour conditioned media strongly influences dendritic cell maturation and function.
PLoS ONE 01/2011; 6(11):e27944. · 4.09 Impact Factor
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ABSTRACT: Among the entero-urinary fistulae, those between the ureter and colon are rare. Most spontaneous ureterocolic fistulae are caused by urinary calculi. We report a case of a spontaneous ureterocolic fistula which occurred as a consequence of diverticular disease. This rare presentation was further complicated as it occurred in the presence of a solitary kidney. The patient underwent a laparoscopic defunctioning loop ileostomy and after 6 weeks underwent definitive surgical treatment of the ureterocolic fistula. We describe the presentation and management of this fistula and review the current literature.
Case Reports 01/2009; 2009.
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Alan Coss,
Miriam Tosetto,
Edward J Fox,
Beata Sapetto-Rebow,
Sheeona Gorman,
Breandán N Kennedy,
Andrew T Lloyd, John M Hyland,
Diarmuid P O'Donoghue,
Kieran Sheahan,
Dermot T Leahy,
Hugh E Mulcahy,
Jacintha N O'Sullivan
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ABSTRACT: Topoisomerase IIalpha is a nuclear enzyme that regulates the tertiary structure of DNA. The influence of topoisomerase IIalpha gene (TOP2A) or protein alterations on disease progression and treatment response in colorectal cancer (CRC) is unknown. The study investigated the clinical relevance of topoisomerase IIalpha in CRC using in vivo and in vitro models. Differentially expressed genes in early and late-stage CRC were identified by array comparative genomic hybridization (CGH). Cellular location of gene amplifications was determined by fluorescence in situ hybridization (FISH). Topoisomerase IIalpha levels, proliferation index, and HER2 expression were examined in 228 colorectal tumors by immunohistochemistry. Overexpression of topoisomerase IIalpha in vitro was achieved by liposome-based transfection. Cell growth inhibition and apoptosis were quantified using the crystal violet assay and flow cytometry, respectively, in response to drug treatment. Amplification of TOP2A was identified in 3 (7.7%) tumors using array CGH and confirmed using FISH. At the protein level, topoisomerase IIalpha staining was observed in 157 (69%) tumors, and both staining and intensity levels were associated with an aggressive tumor phenotype (p values 0.04 and 0.005, respectively). Using logistic regression analysis, topoisomerase IIalpha remained significantly associated with advanced tumor stage when corrected for tumor proliferation (p=0.007) and differentiation (p=0.001). No association was identified between topoisomerase IIalpha and HER2. In vitro, overexpression of topoisomerase IIalpha was associated with resistance to irinotecan (p=0.001) and etoposide chemotherapy (p=0.03), an effect mediated by inhibition of apoptosis. Topoisomerase IIalpha overexpression is significantly associated with alterations in tumor behavior and response to drug treatment in CRC. Our results suggest that gene amplification may represent an important mechanism underlying these changes.
Cancer letters 01/2009; 276(2):228-38. · 4.86 Impact Factor
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ABSTRACT: The efficacy of biologic agents in Crohn's disease (CD) has led to proposals that they be introduced early in the disease (top-down treatment) with the aim of reducing corticosteroid dependency and surgical resection. However, the long-term use of biologic agents in limited CD may be difficult to justify. The aims were to assess outcomes for ileocecal resection in CD and evaluate its role in the current era.
The study included 139 CD patients who underwent ileocecal resection between 1980 and 2000. Data were retrieved from a prospectively maintained database. Disease recurrence was defined as symptoms in addition to endoscopic or radiological evidence of disease activity. Severe disease recurrence was defined as a need for repeat resection surgery.
Seventy-two (52%) patients developed disease recurrence. Median (interquartile range) time to recurrence was 7.1 (5-10.6) years. Forty-nine (35%) patients required repeat resection surgery. Median (IQ range) time to repeat surgery was 7.2 (4.9-10.8) years. The presence of granulomas was associated with disease recurrence (P = 0.03) and repeat resection surgery (P = 0.01).
Long-term outcomes for ileocecal resection in CD are excellent with 48% of patients remaining symptom-free and only 35% requiring repeat resection surgery at 10 years. This should be borne in mind when considering biologic therapy.
Inflammatory Bowel Diseases 12/2007; 13(11):1369-73. · 4.86 Impact Factor
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ABSTRACT: Hypermethylation of CpG islands in gene promoter regions is an important mechanism of gene inactivation in cancer. Many cellular pathways, including DNA repair, are inactivated by this type of epigenetic lesion, resulting in proposed mutator phenotypes. Promoter hypermethylation of hMLH1 has been implicated in a subset of colorectal cancers that show microsatellite instability (MSI). Transcriptional silencing of O6-methylguanine DNA methyltransferase (MGMT) has also been described in a variety of neoplasms and has been associated with a consequent mutational spectrum. We investigated the relationship between hMLH1 promoter hypermethylation and MGMT promoter hypermethylation in 110 colorectal cancers using methylation-specific polymerase chain reaction. Expression of hMLH1 and MGMT was assessed by immunohistochemistry. MSI testing was performed using the National Cancer Institute consensus panel of five microsatellite markers. Promoter hypermethylation of hMLH1 was detected in 12% of tumors. This was significantly associated with the MSI-high phenotype (P < 0.01) and loss of hMLH1 expression (P < 0.01). Methylation of the MGMT promoter was detected in 43% of tumors, which were mostly microsatellite stable or MSI-low (P = 0.041) and showed loss of MGMT expression (P < 0.01). We demonstrated an inverse relationship between hMLH1 promoter hypermethylation and MGMT promoter hypermethylation (P = 0.041), suggesting that a number of distinct hypermethylation-associated pathways may exist in colorectal cancer.
Journal of Molecular Diagnostics 02/2006; 8(1):68-75. · 3.58 Impact Factor
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ABSTRACT: T cells expressing NK cell receptors (NKR) display rapid MHC-unrestricted cytotoxicity and potent cytokine secretion and are thought to play roles in immunity against tumors. We have quantified and characterized NKR+ T cells freshly isolated from epithelial and lamina propria layers of duodenum and colon from 16 individuals with no evidence of gastrointestinal disease and from tumor and uninvolved tissue from 19 patients with colorectal cancer. NKR+ T cell subpopulations were differentially distributed in different intestinal compartments, and CD161+ T cells accounted for over one half of T cells at all locations tested. Most intestinal CD161+ T cells expressed alpha beta TCR and either CD4 or CD8. Significant proportions expressed HLA-DR,CD69 and Fas ligand. Upon stimulation in vitro, CD161+ T cells produced IFN-gamma and TNF-alpha but not IL-4. NKT cells expressing the Valpha24Vbeta11 TCR, which recognizes CD1d,were virtually absent from the intestine, but colonic cells produced IFN-gamma in response to the NKT cell agonist ligand alpha-galactosylceramide. NKR+ T cells were not expanded in colonic tumors compared to adjacent uninvolved tissue. The predominance, heterogeneity and differential distribution of NKR+ T cells at different intestinal locations suggests that they are central to intestinal immunity.
European Journal of Immunology 09/2004; 34(8):2110-9. · 5.10 Impact Factor
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ABSTRACT: Cyclosporin is advocated in the treatment of acute severe ulcerative colitis that has failed to respond to high-dose corticosteroid therapy. This approach is controversial, with critics highlighting the temporary nature of remissions and the potential for adverse effects. There have been few reports of the long-term outcome of those patients who do respond. The purpose of this study was to investigate the clinical outcome of all patients treated with cyclosporin at our institution over the past five years.
We conducted a retrospective study of 46 patients who presented to a tertiary referral center. Initial responders were those who avoided colectomy; a sustained response was defined as a remission that lasted while the patient was taking oral cyclosporin and for three months after this therapy was discontinued.
Thirty-two (69 percent) of 46 patients had an initial response to therapy, and 50 percent met criteria for a sustained response. Eleven of 23 sustained responders subsequently relapsed. At a mean of 22 months' follow-up, 26 percent of patients remain well and have never relapsed. Serious infective complications occurred in two patients, possibly attributable to therapy. No factors predictive of a likely response were identifiable on retrospective analysis.
This study confirms the efficacy of cyclosporin in the management of severe ulcerative colitis. Although many initial responders subsequently relapse, such patients may benefit from having even a short time to adjust to the need for surgery. A substantial minority (26 percent) of all patients treated remain in long-term remission.
Diseases of the Colon & Rectum 10/2002; 45(9):1200-5. · 3.13 Impact Factor
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ABSTRACT: PURPOSE: Cyclosporin is advocated in the treatment of acute severe ulcerative colitis that has failed to respond to high-dose corticosteroid therapy. This approach is controversial, with critics highlighting the temporary nature of remissions and the potential for adverse effects. There have been few reports of the long-term outcome of those patients who do respond. The purpose of this study was to investigate the clinical outcome of all patients treated with cyclosporin at our institution over the past five years.
METHODS: We conducted a retrospective study of 46 patients who presented to a tertiary referral center. Initial responders were those who avoided colectomy; a sustained response was defined as a remission that lasted while the patient was taking oral cyclosporin and for three months after this therapy was discontinued.
RESULTS: Thirty-two (69 percent) of 46 patients had an initial response to therapy, and 50 percent met criteria for a sustained response. Eleven of 23 sustained responders subsequently relapsed. At a mean of 22 months follow-up, 26 percent of patients remain well and have never relapsed. Serious infective complications occurred in two patients, possibly attributable to therapy. No factors predictive of a likely response were identifiable on retrospective analysis.
CONCLUSIONS: This study confirms the efficacy of cyclosporin in the management of severe ulcerative colitis. Although many initial responders subsequently relapse, such patients may benefit from having even a short time to adjust to the need for surgery. A substantial minority (26 percent) of all patients treated remain in long-term remission.
Diseases of the Colon & Rectum 08/2002; 45(9):1200-1205. · 3.13 Impact Factor
