• 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.
    • Molecular and therapeutic advances in the diagnosis and management of malignant pheochromocytomas and paragangliomas.

      Lowery, Aoife J; Walsh, Siun; McDermott, Enda W; Prichard, Ruth S; Department of Surgery, St. Vincent's University Hospital, Dublin, Ireland. (2013)
      Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare catecholamine-secreting tumors derived from chromaffin cells originating in the neural crest. These tumors represent a significant diagnostic and therapeutic challenge because the diagnosis of malignancy is frequently made in retrospect by the development of metastatic or recurrent disease. Complete surgical resection offers the only potential for cure; however, recurrence can occur even after apparently successful resection of the primary tumor. The prognosis for malignant disease is poor because traditional treatment modalities have been limited. The last decade has witnessed exciting discoveries in the study of PCCs and PGLs; advances in molecular genetics have uncovered hereditary and germline mutations of at least 10 genes that contribute to the development of these tumors, and increasing knowledge of genotype-phenotype interactions has facilitated more accurate determination of malignant potential. Elucidating the molecular mechanisms responsible for malignant transformation in these tumors has opened avenues of investigation into targeted therapeutics that show promising results. There have also been significant advances in functional and radiological imaging and in the surgical approach to adrenalectomy, which remains the mainstay of treatment for PCC. In this review, we discuss the currently available diagnostic and therapeutic options for patients with malignant PCCs and PGLs and detail the molecular rationale and clinical evidence for novel and emerging diagnostic and therapeutic strategies.
    • 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.
    • 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.
    • mTOR in breast cancer: differential expression in triple-negative and non-triple-negative tumors.

      Walsh, S; Flanagan, L; Quinn, C; Evoy, D; McDermott, E W; Pierce, A; Duffy, M J; UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin, Ireland. (Elsevier, 2012-04)
      Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptors (ER), progesterone receptors (PR) and overexpression of HER2. Targeted therapy is currently unavailable for this subgroup of breast cancer patients. mTOR controls cancer cell growth, survival and invasion and is thus a potential target for the treatment of patients with TNBC. Using immunohistochemistry, mTOR and p-mTOR were measured in 89 TNBCs and 99 non-TNBCs. While mTOR expression was confined to tumor cell cytoplasm, p-mTOR staining was located in the nucleus, perinuclear area and in the cytoplasm. Potentially important, was our finding that nuclear p-mTOR was found more frequently in triple-negative than non triple-negative cancers (p < 0.001). These results suggest that mTOR may play a more important role in the progression of TNBC compared to non-TNBC. Based on these findings, we conclude that mTOR may be a new target for the treatment of triple-negative breast cancer.
    • Multimodal management of retroperitoneal sarcoma

      Rangaswamy, Guhan; Gillham, Charles; St. Luke's Hospital, Rathgar, Dublin 6 (2012-05-03)
    • New targeted therapies for NSCLC.

      Carney, D (GreenCross Publishing, 2011)
    • 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.
    • Nursing recruitment and retention

      Dublin Academic Teaching Hospitals (DATHs); St. Luke's Hospital (Dublin Academic Teaching Hospitals (DATHs), 2000)
    • An overview of a prospective randomised phase II trial evaluating adjuvant pelvic radiotherapy using either IMRT or 2-dimensional virtual simulation planning for early stage endometrial cancer [ICORG 09-06]

      O'Sullivan, L.; Clayton-Lea, A.; McArdle, O.; Walsh, L.; Gilmore, J.; Gillham, C.; St Luke's Radiation Oncology Network (2010-03)
      Oral presentation - 10th All-Ireland Radiation Therapists Study Day, March 2010
    • Perforation of colon cancer into a benign ovarian cyst.

      Walsh, S; Evoy, D; Cantwell, C P; Kroon, N; Sheahan, K; Gibbons, D; McDermott, E W; St. Vincent's University Hospital, Dublin , Ireland. siunwalsh@gmail.com (Informa Healthcare, 2012-04)
    • Pilomatrix carcinoma presenting as an extra axial mass: clinicopathological features.

      Aherne, Noel J; Fitzpatrick, David A; Gibbons, David; Armstrong, John G; Department of Radiation Oncology, St. Luke's Hospital, Dublin, Ireland. naherne@gmail.com (BioMed Central, 2008)
      Pilomatrix carcinoma is the rare malignant counterpart of pilomatrixoma, a skin adnexal tumour originating from hair matrix cells. Pilomatrix carcinoma can arise as a solitary lesion de novo, or through transformation of a pilomatrixoma. Pilomatrixoma was first described erroneously as being of sebaceous gland origin but was later discovered to be derived from hair matrix cells. They are rare, slow growing tumours of the skin found in the lower dermis and subcutaneous fat and are predominantly found in the neck and the scalp. While known to be locally aggressive, no malignant form was thought to exist until it was described relatively recently. Since then, approximately ninety cases of pilomatrix carcinoma have been reported.We report the case of a 41 year old mentally retarded male who had a longstanding lesion in the left neck for approximately fifteen years previously diagnosed as a pilomatrixoma. He presented with severe headache, falls and visual disturbance and a biopsy showed pilomatrix carcinoma of the occipital region which, on computed tomography ( CT ) invaded the occipital bone, the cerebellum and the left temporal lobe. At his initial presentation he had a craniotomy and subtotal excision of the lesion but received no adjuvant therapy. After an early intracranial recurrence he had further debulking and adjuvant external beam radiotherapy. He has had no further intracranial recurrence after three and a half years of follow-up. Here we present the pathological features of this uncommon tumour.
    • PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer.

      van den Heerik, Anne Sophie V M; Horeweg, Nanda; Nout, Remi A; Lutgens, Ludy C H W; van der Steen-Banasik, Elzbieta M; Westerveld, G Henrike; van den Berg, Hetty A; Slot, Annerie; Koppe, Friederike L A; Kommoss, Stefan; et al. (2020-10-12)
      Background: Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics. Primary objectives: To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy STUDY HYPOTHESIS: Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs. Trial design: A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm). Major inclusion/exclusion criteria: Women aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1). Endpoints: The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs. Sample size: 500 eligible and evaluable patients. Estimated dates for completing accrual and presenting results: Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023. Trial registration: The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025). Keywords: endometrium; radiation oncology.
    • 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.
    • 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 prospective randomised controlled clinical trial investigating patient-customised headrest versus standard (non-patient specific) headrests in the immobilisation of head and neck radiotherapy patients. [ICORG 08-09]

      Mullaney, L.; O'Shea, E.; Carter, P.; Garret, B.; Kenny, J.; Clayton-Lea, A.; Howlin, C.; Thirion, P.; St Luke's Radiation Oncology Network (2010-03)
      Oral presemtation - 10th Annual All-Ireland Radiation Therapists Study Day March 2010.
    • 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; et al. (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.
    • A prospective study of patients with impending spinal cord compression treated with palliative radiotherapy alone

      O'Sullian, L.; Clayton-Lea, A.; McArdle, O.; McGarry, M.; Kenny, J.; Dunne, M.; O'Shea, E.; Small, C.; Moriarty, M.; Thirion, P. (Cambridge University Press, 2013)
      mpending malignant spinal cord compression (IMSCC) may be defined as compression of the thecal sac, without any visible pressure on the spinal cord itself. Although there is a perception that IMSCC patients have a better prognosis and less severe clinical symptoms than true malignant spinal cord compression (MSCC) patients, these factors have never been documented in the literature.
    • Prostate cancer in a male with Holt-Oram syndrome: first clinical association of the TBX5 mutation.

      Aherne, Noel J; Rangaswamy, Guhan; Thirion, Pierre; Department of Radiation Oncology, North Coast Cancer Institute, Coffs Harbour, NSW 2450, Australia. (Hindawi Publishing Corp., 2013-08-05)
      Holt-Oram syndrome is an autosomal dominant disorder which is caused by mutations of TBX5 and is characterised by cardiac and skeletal abnormalities. TBX5 is part of the T-box gene family and is thought to upregulate tumour cell proliferation and metastasis when mutated. We report the first clinical case of prostate cancer in an individual with Holt Oram syndrome.