Publications (39)180.88 Total impact
-
Article: Effects of Radiation on Levels of DNA Damage in Normal Non-adjacent Mucosa from Colorectal Cancer Cases.
[show abstract] [hide abstract]
ABSTRACT: PURPOSE: Defects in DNA repair pathways have been linked with colorectal cancer (CRC). Adjuvant radiotherapy has become commonplace in the treatment of rectal cancer however it is associated with a higher rate of second cancer formation. It is known that radiation results in DNA damage directly or indirectly by radiation-induced bystander effect (RIBE) by causing double-strand breaks (DSBs). The majority of work in RIBE has been performed in cell lines and limited studies have been in or ex vivo. METHODS: The first study aim was to examine by immunohistochemistry, levels of DSB (expression of the protein MRE11) in normal colonic tissue outside the irradiated field post neo-adjuvant radiotherapy (group 1). These levels were compared to (a) irradiated tumour tissue post neo-adjuvant radiation within the same group, (b) a CRC patient group (group 2) who had not undergone neo-adjuvant radiotherapy and (c) a non-cancer patient group (group 3). The second aim was to determine if MRE11 expression levels were related to survival or radio-sensitivity post neo-adjuvant radiotherapy. RESULTS: There was a highly significant increase in MRE 11 expression in group 1 versus groups 2 and 3 (p < 0.001). There was no association between MRE11 levels and survival or radio-sensitivity. CONCLUSION: Our findings show radiotherapy causes DSBs at significantly higher levels in normal colonic mucosa of patients post neo-adjuvant treatment which may represent RIBE. If this damage remains unrepaired, increased levels of genomic instability may contribute to the higher occurrence of second cancers in patients treated post neo-adjuvant radiotherapy.Journal of Gastrointestinal Cancer 10/2012; -
Article: Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy.
[show abstract] [hide abstract]
ABSTRACT: Puppa G, Senore C, Sheahan K, Vieth M, Lugli A, Zlobec I, Pecori S, Wang L M, Langner C, Mitomi H, Nakamura T, Watanabe M, Ueno H, Chasle J, Conley S A, Herlin P, Lauwers G Y & Risio M (2012) Histopathology Diagnostic reproducibility of tumour budding in colorectal cancer: a multicentre, multinational study using virtual microscopy Aims: Despite the established prognostic relevance of tumour budding in colorectal cancer, the reproducibility of the methods reported for its assessment has not yet been determined, limiting its use and reporting in routine pathology practice. Methods and results: A morphometric system within telepathology was devised to evaluate the reproducibility of the various methods published for the assessment of tumour budding in colorectal cancer. Five methods were selected to evaluate the diagnostic reproducibility among 10 investigators, using haematoxylin and eosin (H&E) and AE1-3 cytokeratin-immunostained, whole-slide digital scans from 50 pT1-pT4 colorectal cancers. The overall interobserver agreement was fair for all methods, and increased to moderate for pT1 cancers. The intraobserver agreement was also fair for all methods and moderate for pT1 cancers. Agreement was dependent on the participants' experience with tumour budding reporting and performance time. Cytokeratin immunohistochemistry detected a higher percentage of tumour budding-positive cases with all methods compared to H&E-stained slides, but did not influence agreement levels. Conclusions: An overall fair level of diagnostic agreement for tumour budding in colorectal cancer was demonstrated, which was significantly higher in early cancer and among experienced gastrointestinal pathologists. Cytokeratin immunostaining facilitated detection of budding cancer cells, but did not result in improved interobserver agreement.Histopathology 07/2012; · 3.08 Impact Factor -
Article: Clusterin and Chemotherapy Sensitivity Under Normoxic and Graded Hypoxic Conditions in Colorectal Cancer
[show abstract] [hide abstract]
ABSTRACT: Background and AimsIn vitro studies have shown that clusterin modulates treatment sensitivity in a number of human cancers; however, the interaction between clusterin expression and hypoxia in controlling treatment response in CRC has not previously been examined. The aim of this study was to assess the effect of clusterin overexpression in CRC cells on sensitivity to 5-fluorouracil (5-FU), oxaliplatin and FOLFOX treatment under normoxic and graded hypoxic conditions. MethodsSW480 colon cancer cells were transfected with full length Clusterin cDNA to generate a clusterin overexpressing cell line. Overexpression was confirmed by western blot analysis. The response of parental and clusterin overexpressing cells to 5-FU, oxaliplatin and FOLFOX was examined using a crystal violet-based proliferation assay under normoxic conditions, 3% and 1% hypoxic conditions. The levels of apoptosis and G2/M arrest in FOLFOX-treated cells were assessed by flow cytometry. ResultsUnder normoxic conditions, clusterin overexpressing cells were more sensitive to FOLFOX treatment (p = 0.01); under 3% and 1% hypoxic conditions, overexpressing clusterin cells were more sensitive to 5-FU, oxaliplatin and FOLFOX, p values <0.05 for all conditions. Under normoxic conditions, overexpressing clusterin cells showed significantly higher levels of apoptosis when treated with FOLFOX compared to untransfected cells; levels of G2M cells were not significantly different. Under both 3% and 1% hypoxia, the percentage of cells undergoing apoptosis following FOLFOX treatment was significantly higher in overexpressing clusterin cells. ConclusionThese in vitro findings suggest that tumours expressing high levels of clusterin, particularly if hypoxic in nature, may benefit from treatments such as FOLFOX. KeywordsClusterin–Colorectal cancer–Treatment sensitivity–HypoxiaJournal of Gastrointestinal Cancer 04/2012; -
Article: Mitochondrial mutagenesis induced by tumor-specific radiation bystander effects
[show abstract] [hide abstract]
ABSTRACT: The radiation bystander effect is a cellular process whereby cells not directly exposed to radiation display cellular alterations similar to directly irradiated cells. Cellular targets including mitochondria have been postulated to play a significant role in this process. In this study, we utilized the Random Mutation Capture assay to quantify the levels of random mutations and deletions in the mitochondrial genome of bystander cells. A significant increase in the frequency of random mitochondrial mutations was found at 24h in bystander cells exposed to conditioned media from irradiated tumor explants (p = 0.018). CG:TA mutations were the most abundant lesion induced. A transient increase in the frequency of random mitochondrial deletions was also detected in bystander cells exposed to conditioned media from tumor but not normal tissue at 24h (p = 0.028). The increase in both point mutations and deletions was transient and not detected at 72h. To further investigate mitochondrial dysfunction, mitochondrial membrane potential and reactive oxygen species were assessed in these bystander cells. There was a significant reduction in mitochondrial membrane potential and this was positively associated with the frequency of random point mutation and deletions in bystander cells treated with conditioned media from tumor tissue (r = 0.71, p = 0.02). This study has shown that mitochondrial genome alterations are an acute consequence of the radiation bystander effect secondary to mitochondrial dysfunction and suggests that this cannot be solely attributable to changes in ROS levels alone. KeywordsRadiation bystander-Mitchondrial genome-Random mutations-Reactive oxygen species-Mitochondrial membrane potentialJournal of Molecular Medicine 04/2012; 88(7):701-708. · 4.67 Impact Factor -
Article: Stage II colonic adenocarcinoma: a detailed study of pT4N0 with emphasis on peritoneal involvement and the role of tumour budding.
[show abstract] [hide abstract]
ABSTRACT: Evaluation of peritoneal involvement in colonic cancer (CC) can be difficult. We studied pT4N0 cancers and their association with pathological prognostic markers, including tumour budding. Tumours were classified as (i) at the peritoneal surface or free in the peritoneal cavity (pT4a subgroup n = 44); (ii) directly invading adjacent organ (pT4b subgroup n = 8); or (iii) showing inflammatory involvement of the peritoneum (pT4I subgroup n = 25). A published pT3N0 cohort was used to compare Stage II subgroups. Standard pathological markers including tumour budding were assessed. Elastin staining was performed in the pT4I subgroup. Seventy-seven Stage II CCs met inclusion criteria. There was no significant difference in survival across subgroups. pT4b tumours were larger than pT4a tumours (P < 0.001). Over-represented features in pT4a versus pT4b tumours were tumour budding (P = 0.02) and infiltrative margin (P = 0.02). Tumour budding did not predict survival. Using multivariate analysis, neural invasion was the only parameter predictive of survival (hazard ratio = 2.8; 95% CI 1.2-6.4; P = 0.02). Stage II pT4I CCs have a similar outcome to T4a/b tumours. Elastin staining is useful in defining this group. Tumour budding may facilitate peritoneal invasion in pT4a tumours, but does not predict outcome in pT4N0 disease. Only neural invasion independently predicted poor outcome.Histopathology 03/2012; 61(3):488-96. · 3.08 Impact Factor -
Article: A prospective analysis of patient outcome following treatment of T3 rectal cancer with neo-adjuvant chemoradiotherapy and transanal excision.
[show abstract] [hide abstract]
ABSTRACT: Local excision is an alternative to anterior or abdomino-perineal resection in patients with early rectal cancer. In more advanced disease, neo-adjuvant therapy (CRXT) can result in significant disease regression such that local excision may be considered. The primary aim was to assess oncological outcome in patients with T3 rectal cancer treated with CRXT and local excision due to unsuitability for or aversion to anterior resection and stoma. The secondary aim was to examine oncological outcomes in patients treated in a similar way in the published literature. Between July 2006 and July 2009, patients with rectal cancer staged T3, N0/N1, M0 who were deemed unfit for or who refused anterior resection were offered long-course CRXT. Patients were restaged 8 weeks following completion. If there was a good response (regression grade 2 or 3 clinically and radiologically), full thickness transanal excision was performed. All patients were followed regularly (monthly CT abdomen/pelvis and annual endoscopy) to assess for recurrence of disease. A literature search of PubMed was performed to identify all prospective data available of T3 rectal cancers managed with CRXT and local excision. Ten patients were treated over 3 years. Six patients had complete pathological response, while four patients had a partial response. The resection margins following local excision were clear in all. There was no local recurrence (median follow-up 24 months, range 9-42 months). Neo-adjuvant chemoradiotherapy and local excision is an option in patients unfit for or averse to major surgical resection if there is a good response to CRXT.International Journal of Colorectal Disease 12/2011; 27(6):759-64. · 2.38 Impact Factor -
Article: Development and independent validation of a prognostic assay for stage II colon cancer using formalin-fixed paraffin-embedded tissue.
[show abstract] [hide abstract]
ABSTRACT: Current prognostic factors are poor at identifying patients at risk of disease recurrence after surgery for stage II colon cancer. Here we describe a DNA microarray-based prognostic assay using clinically relevant formalin-fixed paraffin-embedded (FFPE) samples. A gene signature was developed from a balanced set of 73 patients with recurrent disease (high risk) and 142 patients with no recurrence (low risk) within 5 years of surgery. The 634-probe set signature identified high-risk patients with a hazard ratio (HR) of 2.62 (P < .001) during cross validation of the training set. In an independent validation set of 144 samples, the signature identified high-risk patients with an HR of 2.53 (P < .001) for recurrence and an HR of 2.21 (P = .0084) for cancer-related death. Additionally, the signature was shown to perform independently from known prognostic factors (P < .001). This gene signature represents a novel prognostic biomarker for patients with stage II colon cancer that can be applied to FFPE tumor samples.Journal of Clinical Oncology 11/2011; 29(35):4620-6. · 18.37 Impact Factor -
Article: Pathology of oesophagitis.
[show abstract] [hide abstract]
ABSTRACT: Endoscopic oesophageal biopsies are common in daily pathology practice. Inflammation and damage of the oesophageal mucosa is known as oesophagitis and is common worldwide. A variety of physical, chemical and infectious agents cause oesophagitis. The oesophagus has a limited range of responses to a wide variety of injuries, and so histopathological features of different diseases often overlap. The pathologist is reliant on the endoscopist for the 'macroscopic description' of the oesophagus. Access to the endoscopic images enhances the pathologist's overall interpretation of the case. Correlating clinical, endoscopic and microscopic findings may be crucial in arriving at the correct diagnosis. In this review, we present clinicopathological descriptions of the major types of oesophagitis.Histopathology 08/2011; 60(6):864-79. · 3.08 Impact Factor -
Article: Epithelial-mesenchymal transition (EMT) protein expression in a cohort of stage II colorectal cancer patients with characterized tumor budding and mismatch repair protein status.
[show abstract] [hide abstract]
ABSTRACT: The relationship between tumor budding, epithelial-mesenchymal transition (EMT) protein expression, and survival has not been closely examined in stage II colorectal cancer (CRC). This study aimed to assess proteins implicated in EMT and to correlate their expression with tumor budding, microsatellite status, and survival. A total of 258 stage II CRCs were identified (tumor budding characterized in 122 cases). Immunohistochemistry for LAMC2, E cadherin, cathepsin L, and β catenin using tissue microarrays was performed. EMT and mismatch repair (MMR) protein expression were correlated with tumor budding and survival. LAMC2 positivity (P < .001) and low membranous β catenin (P = .056) were associated with tumor budding. In a univariate survival analysis, tumor budding (P < .001), LAMC2 positivity (P < .03), and stromal cytoplasmic cathepsin L (P = .025) predicted poorer prognosis. Multivariate analysis showed tumor budding to be the only variable independently associated with survival: hazard ratio = 7.9 (95% confidence interval = 3-21); P < .001. Tumor budding was more frequent in microsatellite-stable (MSS) versus microsatellite-instable (MSI) tumors: 48% versus 26%, respectively; P = .087. MSS cases exhibited reduced membranous β catenin (P = .002) and increased cytoplasmic and nuclear β catenin (P < .001) compared with MSI cases. Epithelial mesenchymal protein expression plays a key role in tumor budding and prognosis in early-stage colorectal cancer and requires further evaluation.International Journal of Surgical Pathology 07/2011; 19(6):751-60. · 1.00 Impact Factor -
Article: Cytomegalovirus-induced cutaneous vasculopathy and perianal ulceration.
Journal of the American Academy of Dermatology 06/2011; 64(6):1216-8. · 3.99 Impact Factor -
Article: Primary intrahepatic small-cell carcinoma arising from combined hepatocellular and cholangiocarcinomas.
Journal of Clinical Oncology 05/2011; 29(21):e630-3. · 18.37 Impact Factor -
Article: Clusterin and chemotherapy sensitivity under normoxic and graded hypoxic conditions in colorectal cancer.
[show abstract] [hide abstract]
ABSTRACT: In vitro studies have shown that clusterin modulates treatment sensitivity in a number of human cancers; however, the interaction between clusterin expression and hypoxia in controlling treatment response in CRC has not previously been examined. The aim of this study was to assess the effect of clusterin overexpression in CRC cells on sensitivity to 5-fluorouracil (5-FU), oxaliplatin and FOLFOX treatment under normoxic and graded hypoxic conditions. SW480 colon cancer cells were transfected with full length Clusterin cDNA to generate a clusterin overexpressing cell line. Overexpression was confirmed by western blot analysis. The response of parental and clusterin overexpressing cells to 5-FU, oxaliplatin and FOLFOX was examined using a crystal violet-based proliferation assay under normoxic conditions, 3% and 1% hypoxic conditions. The levels of apoptosis and G2/M arrest in FOLFOX-treated cells were assessed by flow cytometry. Under normoxic conditions, clusterin overexpressing cells were more sensitive to FOLFOX treatment (p = 0.01); under 3% and 1% hypoxic conditions, overexpressing clusterin cells were more sensitive to 5-FU, oxaliplatin and FOLFOX, p values <0.05 for all conditions. Under normoxic conditions, overexpressing clusterin cells showed significantly higher levels of apoptosis when treated with FOLFOX compared to untransfected cells; levels of G2M cells were not significantly different. Under both 3% and 1% hypoxia, the percentage of cells undergoing apoptosis following FOLFOX treatment was significantly higher in overexpressing clusterin cells. These in vitro findings suggest that tumours expressing high levels of clusterin, particularly if hypoxic in nature, may benefit from treatments such as FOLFOX.Journal of Gastrointestinal Cancer 04/2011; 43(2):305-13. -
Article: Multiple facial white papules. Birt-Hogg-Dubé syndrome (BHDS).
Archives of dermatology 04/2011; 147(4):499-504. · 4.76 Impact Factor -
Article: Peritoneal elastic lamina invasion in colorectal cancer: the answer to a controversial area of pathology?
The American journal of surgical pathology 03/2011; 35(3):465-8; author reply 468-9. · 4.06 Impact Factor -
Article: Residual tumor (R) classification in colorectal cancer: reduced, expanded, or not uniform?
Archives of pathology & laboratory medicine 03/2011; 135(3):288; author reply 289. · 2.58 Impact Factor -
Article: Standardization of whole slide image morphologic assessment with definition of a new application: Digital slide dynamic morphometry.
[show abstract] [hide abstract]
ABSTRACT: In histopathology, the quantitative assessment of various morphologic features is based on methods originally conceived on specific areas observed through the microscope used. Failure to reproduce the same reference field of view using a different microscope will change the score assessed. Visualization of a digital slide on a screen through a dedicated viewer allows selection of the magnification. However, the field of view is rectangular, unlike the circular field of optical microscopy. In addition, the size of the selected area is not evident, and must be calculated. A digital slide morphometric system was conceived to reproduce the various methods published for assessing tumor budding in colorectal cancer. Eighteen international experts in colorectal cancer were invited to participate in a web-based study by assessing tumor budding with five different methods in 100 digital slides. The specific areas to be tested by each method were marked by colored circles. The areas were grouped in a target-like pattern and then saved as an .xml file. When a digital slide was opened, the .xml file was imported in order to perform the measurements. Since the morphometric tool is composed of layers that can be freely moved on top of the digital slide, the technique was named digital slide dynamic morphometry. Twelve investigators completed the task, the majority of them performing the multiple evaluations of each of the cases in less than 12 minutes. Digital slide dynamic morphometry has various potential applications and might be a useful tool for the assessment of histologic parameters originally conceived for optical microscopy that need to be quantified.Journal of pathology informatics. 01/2011; 2:48. -
Article: Reproducibility of the rapid bud count method for assessment of tumor budding in stage II colorectal cancer.
The American journal of surgical pathology 05/2010; 34(5):746-8. · 4.06 Impact Factor -
Article: Clinical and pathological factors associated with colorectal cancer at the upper extreme of life.
Journal of the American Geriatrics Society 04/2010; 58(4):794-5. · 3.74 Impact Factor -
Article: Mitochondrial mutagenesis induced by tumor-specific radiation bystander effects.
[show abstract] [hide abstract]
ABSTRACT: The radiation bystander effect is a cellular process whereby cells not directly exposed to radiation display cellular alterations similar to directly irradiated cells. Cellular targets including mitochondria have been postulated to play a significant role in this process. In this study, we utilized the Random Mutation Capture assay to quantify the levels of random mutations and deletions in the mitochondrial genome of bystander cells. A significant increase in the frequency of random mitochondrial mutations was found at 24 h in bystander cells exposed to conditioned media from irradiated tumor explants (p = 0.018). CG:TA mutations were the most abundant lesion induced. A transient increase in the frequency of random mitochondrial deletions was also detected in bystander cells exposed to conditioned media from tumor but not normal tissue at 24 h (p = 0.028). The increase in both point mutations and deletions was transient and not detected at 72 h. To further investigate mitochondrial dysfunction, mitochondrial membrane potential and reactive oxygen species were assessed in these bystander cells. There was a significant reduction in mitochondrial membrane potential and this was positively associated with the frequency of random point mutation and deletions in bystander cells treated with conditioned media from tumor tissue (r = 0.71, p = 0.02). This study has shown that mitochondrial genome alterations are an acute consequence of the radiation bystander effect secondary to mitochondrial dysfunction and suggests that this cannot be solely attributable to changes in ROS levels alone.Journal of Molecular Medicine 03/2010; 88(7):701-8. · 4.67 Impact Factor -
Article: Collagenous sprue: a clinicopathologic study of 12 cases.
[show abstract] [hide abstract]
ABSTRACT: Collagenous sprue is a rare form of small bowel enteropathy characterized by chronic diarrhea and progressive malabsorption with little data available on its natural history. The pathologic lesion consists of subepithelial collagen deposition associated with variable alterations in villous architecture. The small bowel biopsies of 12 cases were reviewed. Clinical details, celiac serology, and T-cell receptor gene rearrangement study results, when available, were collated. There were 8 females and 4 males (age ranged from 41 to 84 y) who presented with chronic diarrhea and weight loss. Small intestinal biopsies showed subepithelial collagen deposition with varying degrees of villous atrophy and varying numbers of intraepithelial lymphocytes. Four patients had previous biopsies showing enteropathic changes without collagen deposition. Seven cases were associated with collagenous colitis and 1 also had features of lymphocytic colitis. Three patients also had collagen deposition in gastric biopsies. One case was associated with lymphocytic gastritis. Celiac disease (CD, gluten-sensitive enteropathy) was documented in 4 patients. Five patients made a clinical improvement with combinations of a gluten-free diet and immunosuppressive therapy. Two patients died of complications of malnutrition and 1 of another illness. Clonal T-cell populations were identified in 5 of 6 cases tested. Four of these patients improved clinically after treatment but 1 has died. Collagenous sprue evolved on a background of CD in 4 cases. There was no history of CD in others and these cases may be the result of a biologic insult other than gluten sensitivity. None has developed clinical evidence of lymphoma to date.The American journal of surgical pathology 08/2009; 33(10):1440-9. · 4.06 Impact Factor
Top co-authors
Top Journals
Institutions
-
2006–2012
-
St Vincent's University Hospital
Dublin, L, Ireland (Republic of Ireland) -
University College Dublin
Dublin, L, Ireland (Republic of Ireland)
-
-
2011
-
Università degli Studi dell'Insubria
Varese, Lombardy, Italy
-
