Research by staff affiliated to St. Luke's Radiation Oncology Network

Recent Submissions

  • Heterogeneity in high-risk prostate cancer treated with high-dose radiation therapy and androgen deprivation therapy.

    Cagney, Daniel N; Dunne, Mary; O'Shea, Carmel; Finn, Marie; Noone, Emma; Sheehan, Martina; McDonagh, Lesley; O'Sullivan, Lydia; Thirion, Pierre; Armstrong, John (2017-08-01)
    Our aim was to assess the heterogeneity of high-risk (HR) prostate cancer managed with high-dose external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT).
  • Monoamine oxidase inhibitors l-deprenyl and clorgyline protect nonmalignant human cells from ionising radiation and chemotherapy toxicity.

    Seymour, C B; Mothersill, C; Mooney, R; Moriarty, M; Tipton, K F (London, Lewis, 2003-11-17)
    l-Deprenyl (R-(-)-deprenyl, selegiline) is an inhibitor of monoamine oxidase-B (MAO-B) that is known to protect nerve cells from a variety of chemical and physical insults. As apoptosis is a common mechanism of radiation-induced cell death, the effect of l-deprenyl on the survival of cultured cells and tissue explants was studied following exposure to gamma radiation. The results obtained were compared with the effects of the less-selective MAO-B inhibitor pargyline and the MAO-A inhibitor clorgyline. l-Deprenyl at a concentration of 10(-9) M protected the nontumorigenic cell line (HaCaT) and normal human urothelial explants from the effects of cobalt-60 gamma radiation, but did not protect tumorigenic human cell lines HaCaT-ras, HPV-transfected human keratinocytes (HPV-G cells), or PC3. Human bladder carcinoma explants were not protected. Clorgyline showed a smaller protective effect of normal cells, whereas pargyline had no effect. Radiation-induced delayed effects (genomic instability measured as delayed cell death) were prevented in normal cells by l-deprenyl but, interestingly, deprenyl appeared to increase the amount of delayed death in the tumorigenic cell lines. Studies using l-deprenyl prior to the exposure of nonmalignant cells to cisplatin showed that cell death due to this agent was also reduced. Treatment of cultures of nontumorigenic cells with l-deprenyl or clorgyline significantly increased the levels of the protein Bcl-2 following irradiation, but there was no such effect on the already-elevated levels of this protein in the tumour samples. Since the Bcl-2 has been shown to be an inhibitor of apoptosis or programmed cell death, this would imply that the protective effects of l-deprenyl and clorgyline involve activation of antiapoptotic pathways within the normal cell. This hypothesis is supported by data showing reduced levels of apoptosis in HaCAT cells and in normal bladder explant cultures following treatment with l-deprenyl.
  • In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer.

    Perry, A S; Loftus, B; Moroose, R; Lynch, T H; Hollywood, D; Watson, R W G; Woodson, K; Lawler, M (2007-05-21)
    Promoter hypermethylation is central in deregulating gene expression in cancer. Identification of novel methylation targets in specific cancers provides a basis for their use as biomarkers of disease occurrence and progression. We developed an in silico strategy to globally identify potential targets of promoter hypermethylation in prostate cancer by screening for 5' CpG islands in 631 genes that were reported as downregulated in prostate cancer. A virtual archive of 338 potential targets of methylation was produced. One candidate, IGFBP3, was selected for investigation, along with glutathione-S-transferase pi (GSTP1), a well-known methylation target in prostate cancer. Methylation of IGFBP3 was detected by quantitative methylation-specific PCR in 49/79 primary prostate adenocarcinoma and 7/14 adjacent preinvasive high-grade prostatic intraepithelial neoplasia, but in only 5/37 benign prostatic hyperplasia (P < 0.0001) and in 0/39 histologically normal adjacent prostate tissue, which implies that methylation of IGFBP3 may be involved in the early stages of prostate cancer development. Hypermethylation of IGFBP3 was only detected in samples that also demonstrated methylation of GSTP1 and was also correlated with Gleason score > or =7 (P=0.01), indicating that it has potential as a prognostic marker. In addition, pharmacological demethylation induced strong expression of IGFBP3 in LNCaP prostate cancer cells. Our concept of a methylation candidate gene bank was successful in identifying a novel target of frequent hypermethylation in early-stage prostate cancer. Evaluation of further relevant genes could contribute towards a methylation signature of this disease.
  • Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition.

    Baeyens, A; Thierens, H; Claes, K; Poppe, B; Messiaen, L; De Ridder, L; Vral, A (London, Lewis, 2002-12-02)
    The chromosomal radiosensitivity of breast cancer patients with a known or putative genetic predisposition was investigated and compared to a group of healthy women. The chromosomal radiosensitivity was assessed with the G2 and the G0-micronucleus assay. For the G2 assay lymphocytes were irradiated in vitro with a dose of 0.4 Gy (60)Co gamma-rays after 71 h incubation, and chromatid breaks were scored in 50 metaphases. For the micronucleus assay lymphocytes were exposed in vitro to 3.5 Gy (60)Co gamma-rays at a high dose rate or low dose rate. 70 h post-irradiation cultures were arrested and micronuclei were scored in 1000 binucleate cells. The results demonstrated that the group of breast cancer patients with a known or putative genetic predisposition was on the average more radiosensitive than a population of healthy women, and this with the G2 as well as with the high dose rate and low dose rate micronucleus assay. With the G2 assay 43% of the patients were found to be radiosensitive. A higher proportion of the patients were radiosensitive with the micronucleus assay (45% with high dose rate and 61% with low dose rate). No correlation was found between the G2 and the G0-micronucleus chromosomal radiosensitivity. Out of the different subgroups considered, the group of the young breast cancer patients without family history showed the highest percentage of radiosensitive cases in the G2 (50%) as well as in the micronucleus assay (75-78%).
  • MR vs CT imaging: low rectal cancer tumour delineation for three-dimensional conformal radiotherapy.

    O'Neill, B D P; Salerno, G; Thomas, K; Tait, D M; Brown, G (British Institute of Radiology, 2009-06)
    Modern three-dimentional radiotherapy is based upon CT. For rectal cancer, this relies upon target definition on CT, which is not the optimal imaging modality. The major limitation of CT is its low inherent contrast resolution. Targets defined by MRI could facilitate smaller, more accurate, tumour volumes than CT. Our study reviewed imaging and planning data for 10 patients with locally advanced low rectal cancer (defined as < 6 cm from the anal verge on digital examination). Tumour volume and location were compared for sagittal pre-treatment MRI and planning CT. CT consistently overestimated all tumour radiological parameters. Estimates of tumour volume, tumour length and height of proximal tumour from the anal verge were larger on planning CT than on MRI (p < 0.05). Tumour volumes defined on MRI are smaller, shorter and more distal from the anal sphincter than CT-based volumes. For radiotherapy planning, this may result in smaller treatment volumes, which could lead to a reduction in dose to organs at risk and facilitate dose escalation.
  • Primary thromboprophylaxis for cancer patients with central venous catheters--a reappraisal of the evidence.

    Cunningham, M S; White, B; Hollywood, D; O'Donnell, J (2006-01-30)
    Venous thromboembolism (VTE) is responsible for an estimated 25 000 deaths per annum in UK hospital practice. It is well established that many of these deaths could be prevented through the use of appropriate thromboprophylaxis. This issue is of particular relevance in oncology practice, where the risks of VTE and bleeding are both significantly higher than those observed in general medical patients. Cancer patients with in-dwelling central venous catheters (CVCs) are at particularly high risk of developing thrombotic complications. However, the literature has produced conflicting conclusions regarding the efficacy of using routine primary thromboprophylaxis in these patients. Indeed such is the level of confusion around this topic, that the most recent version of the American College of Chest Physicians (ACCP) guidelines published in 2004 actually reversed their previous recommendation (published in 2001). Nevertheless, minidose warfarin continues to be routinely used in many oncology centres in the UK. In this article, we have performed a systematic review of the published literature regarding the efficacy and the risks, associated with using thromboprophylaxis (either minidose warfarin or low-dose LMWH) in cancer patients with CVC. On the basis of this evidence, we conclude that there is no proven role for using such thromboprophylaxis. However, asymptomatic CVC-related venous thrombosis remains common, and further more highly powered studies of better design are needed in order to define whether specific subgroups of cancer patients might benefit from receiving thromboprophylaxis.
  • A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.

    Walsh, T N; Noonan, N; Hollywood, D; Kelly, A; Keeling, N; Hennessy, T P (1996-08-15)
    Uncontrolled studies suggest that a combination of chemotherapy and radiotherapy improves the survival of patients with esophageal adenocarcinoma. We conducted a prospective, randomized trial comparing surgery alone with combined chemotherapy, radiotherapy, and surgery.
  • Nodular fasciitis: A pseudomalignant clonal neoplasm characterized by USP gene rearrangements and spontaneous regression

    Hennebry, Jennifer; Mulholland, Douglas; Tchrakian, Nairi; Martin Gillham, Charles; Julian Beddy, Peter; Mai O'Donnell, Dearbhaile; Eibhlín McMenamin, Máirín (Edorium Journals, 2017-01)
    Introduction: Nodular fasciitis (NF) is a rapidly growing, self-limited, myofibroblastic neoplasm that typically arises in subcutaneous tissues of young adults and regresses spontaneously. Nodular fasciitis mimics sarcoma on clinical, radiological, and histological grounds and is usually, diagnosed following excision. Case Report: A 26-year-old female presented at surveillance computed tomography (CT) scan one year post-treatment for stage 1c ovarian dysgerminoma with a 4 cm axillary soft tissue mass, radiologically suspicious for metastasis with subclavian vein invasion. Histopathology of core biopsies favored NF, confirmed by detection of USP6 gene rearrangements by FISH analysis. This case describes an unusual relatively deep NF, suspicious for metastasis on CT scan with confirmed spontaneous regression over two years. Conclusion: Nodular fasciitis should be considered in the differential diagnosis of rapidly growing enhancing soft tissue masses. Molecular cytogenetic testing of USP6 gene rearrangements allows definitive diagnosis on core biopsies in challenging cases, permitting a conservative approach and avoiding potentially radical and unnecessary surgery.
  • The involvement of calcium and MAP kinase signaling pathways in the production of radiation-induced bystander effects.

    Lyng, F M; Maguire, P; McClean, B; Seymour, C; Mothersill, C (2006-04)
    Much evidence now exists regarding radiation-induced bystander effects, but the mechanisms involved in the transduction of the signal are still unclear. The mitogen-activated protein kinase (MAPK) pathways have been linked to growth factor-mediated regulation of cellular events such as proliferation, senescence, differentiation and apoptosis. Activation of multiple MAPK pathways such as the ERK, JNK and p38 pathways have been shown to occur after exposure of cells to radiation and a variety of other toxic stresses. Previous studies have shown oxidative stress and calcium signaling to be important in radiation-induced bystander effects. The aim of the present study was to investigate MAPK signaling pathways in bystander cells exposed to irradiated cell conditioned medium (ICCM) and the role of oxidative metabolism and calcium signaling in the induction of bystander responses. Human keratinocytes (HPV-G cell line) were irradiated (0.005-5 Gy) using a cobalt-60 teletherapy unit. The medium was harvested 1 h postirradiation and transferred to recipient HPV-G cells. Phosphorylated forms of p38, JNK and ERK were studied by immunofluorescence 30 min-24 h after exposure to ICCM. Inhibitors of the ERK pathway (PD98059 and U0126), the JNK pathway (SP600125), and the p38 pathway (SB203580) were used to investigate whether bystander-induced cell death could be blocked. Cells were also incubated with ICCM in the presence of superoxide dismutase, catalase, EGTA, verapamil, nifedipine and thapsigargin to investigate whether bystander effects could be inhibited because of the known effects on calcium homeostasis. Activated forms of JNK and ERK proteins were observed after exposure to ICCM. Inhibition of the ERK pathway appeared to increase bystander-induced apoptosis, while inhibition of the JNK pathway appeared to decrease apoptosis. In addition, reactive oxygen species, such as superoxide and hydrogen peroxide, and calcium signaling were found to be important modulators of bystander responses. Further investigations of these signaling pathways may aid in the identification of novel therapeutic targets.
  • Preventing treatment errors in radiotherapy by identifying and evaluating near misses and actual incidents

    Holmberg, Ola; McClean, Brendan (Cambridge University Press, 2002-06)
    When preparing radiation treatment, the prescribed dose and irradiation geometry must be translated into physical machine parameters. An error in the calculations or machine settings can negatively affect the intended treatment outcome. Analysing incidents originating in the treatment preparation chain makes it possible to find weak links and prevent treatment errors. The aim of this work is to study the effectiveness of a multilayered error prevention system by analysing both near misses and actual treatment errors.
  • Increased mitochondrial mass in cells with functionally compromised mitochondria after exposure to both direct gamma radiation and bystander factors.

    Nugent, Sharon M E; Mothersill, Carmel E; Seymour, Colin; McClean, Brendan; Lyng, Fiona M; Murphy, James E J (2007-07)
    The bystander effect describes radiation-like damage in unirradiated cells either in the vicinity of irradiated cells or exposed to medium from irradiated cells. This study aimed to further characterize the poorly understood mitochondrial response to both direct irradiation and bystander factor(s) in human keratinocytes (HPV-G) and Chinese hamster ovarian cells (CHO-K1). Oxygen consumption rates were determined during periods of state 4, state 3 and uncoupled respiration. Mitochondrial mass was determined using MitoTracker FM. CHO-K1 cells showed significantly reduced oxygen consumption rates 4 h after exposure to 5 Gy direct radiation and irradiated cell conditioned medium (ICCM) and an apparent recovery 12-24 h later. The apparent recovery was likely due to the substantial increase in mitochondrial mass observed in these cells as soon as 4 h after exposure. HPV-G cells, on the other hand, showed a sustained increase in oxygen consumption rates after ICCM exposure and a transient increase 4 h after exposure to 5 Gy direct radiation. A significant increase in mitochondrial mass per HPV-G cell was observed after exposure to both direct radiation and ICCM. These findings are indicative of a stress response to mitochondrial dysfunction that increases the number of mitochondria per cell.
  • Modulation of Radiation responses by pre-exposure to irradiated Cell conditioned medium.

    Maguire, Paula; Mothersill, Carmel; McClean, Brendan; Seymour, Colin; Lyng, Fiona M (Radiation Research Society, 2007-04)
    The aim of this study was to investigate whether exposure of HPV-G cells to irradiated cell conditioned medium (ICCM) could induce an adaptive response if the cells were subsequently challenged with a higher ICCM dose. Clonogenic survival and major steps in the cascade leading to apoptosis, such as calcium influx and loss of mitochondrial membrane potential, were examined to determine whether these events could be modified by giving a priming dose of ICCM before the challenge dose. Clonogenic survival data indicated an ICCM-induced adaptive response in HPV-G cells "primed" with 5 mGy or 0.5 Gy ICCM for 24 h and then exposed to 0.5 Gy or 5 Gy ICCM. Reactive oxygen species (ROS) were found to be involved in the bystander-induced cell death. Calcium fluxes varied in magnitude across the exposed cell population, and a significant number of the primed HPV-G cells did not respond to the challenge ICCM dose. No significant loss of mitochondrial membrane potential was observed when HPV-G cells were exposed to 0.5 Gy ICCM for 24 h followed by exposure to 5 Gy ICCM for 6 h. Exposure of HPV-G cells to 5 mGy ICCM for 24 h followed by exposure to 0.5 Gy ICCM for 18 h caused a significant increase in mitochondrial mass and a change in mitochondrial location, events associated with the perpetuation of genomic instability. This study has shown that a priming dose of ICCM has the ability to induce an adaptive response in HPV-G cells subsequently exposed to a challenge dose of ICCM.
  • Review of surface dose detectors in radiotherapy

    O'Shea, E.; McCavana, P. (2006-11-20)
    Several instruments have been used to measure absorbed radiation dose under non-electronic equilibrium conditions, such as in the build-up region or near the interface between two different media, including the surface. Many of these detectors are discussed in this paper. A common method of measuring the absorbed dose distribution and electron contamination in the build-up region of high-energy beams for radiation therapy is by means of parallel-plate ionisation chambers. Thermoluminescent dosimeters (TLDs), diodes and radiographic film have also been used to obtain surface dose measurements. The diamond detector was used recently by the author in an investigation on the effects of beam-modifying devices on skin dose and it is also described in this report
  • Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer.

    Thirion, P; Piedbois, P; Buyse, M; O'Dwyer, P J; Cunningham, D; Man, A; Greco, F A; Colucci, G; Köhne, C H; Di Constanzo, F; Piga, A; Palmeri, S; Dufour, P; Cassano, A; Pajkos, G; Pensel, R A; Aykan, N F; Marsh, J; Seymour, M T (2001-03-02)
    Two meta-analyses were conducted to quantify the benefit of combining alpha-IFN to 5FU in advanced colorectal cancer in terms of tumour response and survival. Analyses were based on a total of 3254 individual patient data provided by principal investigators of each trial. The meta-analysis of 5FU +/- LV vs. 5FU +/- LV + alpha-IFN combined 12 trials and 1766 patients. The meta-analysis failed to show any statistically significant difference between the two treatment groups in terms of tumour response or survival. Overall tumour response rates were 25% for patients receiving no alpha-IFN vs. 24% for patients receiving alpha-IFN (relative risk, RR = 1.02), and median survivals were 11.4 months for patients receiving no alpha-IFN vs. 11.5 months for patients receiving alpha-IFN (hazard ratio, HR = 0.95). The meta-analysis of 5FU + LV vs. 5FU + alpha-IFN combined 7 trials, and 1488 patients. This meta-analysis showed an advantage for 5FU + LV over 5FU + alpha-IFN which was statistically significant in terms of tumour response (23% vs. 18%; RR = 1.26;P = 0.042), and of a borderline significance for overall survival (HR = 1.11;P = 0.066). Metastases confined to the liver and primary rectal tumours were independent favourable prognostic factors for tumour response, whereas good performance status, metastases confined to the liver or confined to the lung, and primary tumour in the rectum were independent favourable prognostic factors for survival. We conclude that alpha-IFN does not increase the efficacy of 5FU or of 5FU + LV, and that 5FU + alpha-IFN is significantly inferior to 5FU + LV, for patients with advanced colorectal cancer.
  • A prospective randomised controlled clinical trial to evaluate three immobilisation devices for intra-thoracic radiation therapy

    O'Shea, Evelyn; Armstrong, John; Gillham, Charles; McCloy, Roisin; Murrells, Rachel; O'Hara, Tom; Clayton-Lea, Angela; Murphy, Michael; Browne, Patricia; Booth, Catherine; Thirion, Pierre (2010-07-07)
    Purpose: To determine the optimal of three immobilisation devices for lung radiotherapy in terms of set-up reproducibility, patient comfort, radiation therapists’ (RTs) satisfaction and cost-effectiveness. Materials and methods: A total of 30 lung CRT patients were randomised to one of three immobilisation techniques – Arm A, headsponge; Arm B, BreastBoard dedicated immobilisation device; and Arm C, LungBoard dedicated immobilisation device. Results: Random errors were larger for Arm A versus C in all directions ( p < 0.05). Random errors were larger for Arm A versus B for y and z directions ( p < 0.05). When the data for the immobilisation devices (Arms B+C) were pooled and compared with Arm A (no dedicated device), the systematic errors were larger in the z direction for A ( p < 0.05). Arm C was cheaper and was more comfortable for patients. Therapists preferred this device (Arm C) and treatment times were less ( p < 0.05). Conclusion: This is the first prospective randomised controlled lung immobilisation trial, based on 3-DCRT, that takes into account treatment accuracy, users satisfaction and resource implications. It suggests that the LungBoard immobilisation device is optimal.
  • The Role of Proteomics in Biomarker Development for Improved Patient Diagnosis and Clinical Decision Making in Prostate Cancer.

    Tonry, Claire L; Leacy, Emma; Raso, Cinzia; Finn, Stephen P; Armstrong, John; Pennington, Stephen R (2016-07-18)
    Prostate Cancer (PCa) is the second most commonly diagnosed cancer in men worldwide. Although increased expression of prostate-specific antigen (PSA) is an effective indicator for the recurrence of PCa, its intended use as a screening marker for PCa is of considerable controversy. Recent research efforts in the field of PCa biomarkers have focused on the identification of tissue and fluid-based biomarkers that would be better able to stratify those individuals diagnosed with PCa who (i) might best receive no treatment (active surveillance of the disease); (ii) would benefit from existing treatments; or (iii) those who are likely to succumb to disease recurrence and/or have aggressive disease. The growing demand for better prostate cancer biomarkers has coincided with the development of improved discovery and evaluation technologies for multiplexed measurement of proteins in bio-fluids and tissues. This review aims to (i) provide an overview of these technologies as well as describe some of the candidate PCa protein biomarkers that have been discovered using them; (ii) address some of the general limitations in the clinical evaluation and validation of protein biomarkers; and (iii) make recommendations for strategies that could be adopted to improve the successful development of protein biomarkers to deliver improvements in personalized PCa patient decision making.
  • Stereotactic Radiosurgery (SRS) / Stereotactic body radiotherapy (SBRT): Benefit to Irish patients and Irish Healthcare Economy

    Cagney, DN; Armstrong, JG (Irish Medical Journal, 2017-01)
    Cancer incidence across Europe is projected to rise rapidly over the next decade. This rising cancer incidence is mirrored by increasing use of and indications for stereotactic radiation. This paper seeks to summarize the exponential increase in indications for stereotactic radiotherapy as well as the evolving economic advantages of stereotactic radiosurgery and stereotactic body radiotherapy
  • Small-cell carcinoma of the cervix at 23 weeks gestation.

    Smyth, Elizabeth C; Korpanty, Grzegorz; McCaffrey, John A; Mulligan, Niall; Carney, Desmond N (2010-06-20)
  • Attitudes and experiences towards setting up a bibliotherapy service for the bereavement support service (EAHIL Conference)

    Callinan, Joanne. (2011)
    Oral presentation at Best Posters Session at EAHIL Conference, Istanbul, Turkey, 2011.
  • A randomized trial comparing bladder volume consistency during fractionated prostate radiation therapy

    Mullaney, L.; O'Shea, E.; Dunne, M.; Finn, M.; Thirion, P.; Cleary, L. A.; McGarry, M.; O'Neill, L.; Armstrong, J.G. (2014-01-10)
    Organ motion is a contributory factor to the variation in location of the prostate and organs at risk during a course of fractionated prostate radiation therapy (RT). A prospective randomized controlled trial was designed with the primary endpoint to provide evidence-based bladder-filling instructions to achieve a consistent bladder volume (BV) and thus reduce the bladder-related organ motion. The secondary endpoints were to assess the incidence of acute and late genitourinary (GU) and gastrointestinal (GI) toxicity for patients and patients’ satisfaction with the bladder-filling instructions.

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