• X-linked inhibitor of apoptosis protein as a therapeutic target.

      Dean, Emma J; Ranson, Malcolm R; Blackhall, Fiona H; Dive, Caroline; Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. emma.dean@christie.nhs.uk (2007-11)
      Dysregulation of apoptosis has been shown to contribute to many diseases, including cancer formation, development and resistance, as well as neurodegenerative and autoimmune disorders. One mechanism through which tumour cells are believed to acquire resistance to apoptosis is by overexpression of X-linked inhibitor of apoptosis protein (XIAP), which belongs to a family of inhibitor of apoptosis proteins. When XIAP is overexpressed, cancer cells are rendered resistant to apoptosis, both intrinsically and in response to chemotherapy and radiotherapy. Significant progress has been made in targeting XIAP therapeutically, both directly and indirectly through the modulation of other molecules involved in the apoptotic pathway. This review introduces XIAP from its molecular origins, discusses its modulation and potential as a novel drug target, and considers future therapeutic perspectives.
    • X-ray protection considerations for mammography screening centres.

      Walker, Anne; Hounsell, Alan R; Regional Department of Medical Physics and Bioengineering, Christie Hospital, Manchester. (1989-06)
    • X-ray refraction effects: application to the imaging of biological tissues.

      Lewis, R A; Hall, C J; Hufton, Alan P; Evans, S; Menk, R H; Arfelli, F; Rigon, L; Tromba, G; Dance, D R; Ellis, I O; et al. (2003-05)
      The purpose of this study was to explore the potential of refraction contrast X-ray imaging of biological tissues. Images of dissected mouse lungs, heart, liver and legs were produced using the medical beamline at the Elettra Synchrotron at Trieste, Italy. The technique used was diffraction enhanced imaging. This utilizes a silicon crystal positioned between the tissue sample and the detector to separate refracted X-rays from transmitted and scattered radiation by Bragg diffraction. The contrast in the images produced is related to changes in the X-ray refractive index of the tissues, resulting in remarkable clarity compared with conventional X-ray images based on absorption effects. These changes were greatest at the boundaries between different tissues, giving a marked edge enhancement effect and three-dimensional appearance to the images. The technique provides a way of imaging a property of biological tissues not yet exploited, and further studies are planned to identify specific applications in medical imaging.
    • The x-ray treatment of ovarian tumours

      Tod, Margaret C; Holt Radium Institute, Manchester (1944-10)
    • X-ray volume imaging in bladder radiotherapy verification.

      Henry, Ann M; Stratford, Julia; McCarthy, Claire; Davies, Julie; Sykes, Jonathan R; Amer, Ali M; Marchant, Thomas E; Cowan, Richard A; Wylie, James P; Logue, John P; et al. (2006-03-15)
      PURPOSE: To assess the clinical utility of X-ray volume imaging (XVI) for verification of bladder radiotherapy and to quantify geometric error in bladder radiotherapy delivery. METHODS AND MATERIALS: Twenty subjects undergoing conformal bladder radiotherapy were recruited. X-ray volume images and electronic portal images (EPIs) were acquired for the first 5 fractions and then once weekly. X-ray volume images were co-registered with the planning computed tomography scan and clinical target volume coverage assessed in three dimensions (3D). Interfraction bladder volume change was described by quantifying changes in bladder volume with time. Bony setup errors were compared from both XVI and EPI. RESULTS: The bladder boundary was clearly visible on coronal XVI views in nearly all images, allowing accurate 3D treatment verification. In 93.5% of imaged fractions, the clinical target volume was within the planning target volume. Most subjects displayed consistent bladder volumes, but 25% displayed changes that could be predicted from the first three XVIs. Bony setup errors were similar whether calculated from XVI or EPI. CONCLUSIONS: Coronal XVI can be used to verify 3D bladder radiotherapy delivery. Image-guided interventions to reduce geographic miss and normal tissue toxicity are feasible with this technology.
    • X-ray volumetric imaging in image-guided radiotherapy: the new standard in on-treatment imaging.

      McBain, Catherine A; Henry, Ann M; Sykes, Jonathan R; Amer, Ali M; Marchant, Thomas E; Moore, Christopher J; Davies, Julie; Stratford, Julia; McCarthy, Claire; Porritt, Bridget; et al. (2006-02-01)
      PURPOSE: X-ray volumetric imaging (XVI) for the first time allows for the on-treatment acquisition of three-dimensional (3D) kV cone beam computed tomography (CT) images. Clinical imaging using the Synergy System (Elekta, Crawley, UK) commenced in July 2003. This study evaluated image quality and dose delivered and assessed clinical utility for treatment verification at a range of anatomic sites. METHODS AND MATERIALS: Single XVIs were acquired from 30 patients undergoing radiotherapy for tumors at 10 different anatomic sites. Patients were imaged in their setup position. Radiation doses received were measured using TLDs on the skin surface. The utility of XVI in verifying target volume coverage was qualitatively assessed by experienced clinicians. RESULTS: X-ray volumetric imaging acquisition was completed in the treatment position at all anatomic sites. At sites where a full gantry rotation was not possible, XVIs were reconstructed from projection images acquired from partial rotations. Soft-tissue definition of organ boundaries allowed direct assessment of 3D target volume coverage at all sites. Individual image quality depended on both imaging parameters and patient characteristics. Radiation dose ranged from 0.003 Gy in the head to 0.03 Gy in the pelvis. CONCLUSIONS: On-treatment XVI provided 3D verification images with soft-tissue definition at all anatomic sites at acceptably low radiation doses. This technology sets a new standard in treatment verification and will facilitate novel adaptive radiotherapy techniques.
    • X-ray volumetric imaging in paediatric radiotherapy--a case study.

      McCarthy, Claire; Davies, Julie; Stratford, Julia; Duffy, Michelle; Gattamaneni, Rao; Wade Centre for Radiotherapy Research, Christie Hospital, Withington, Manchester, UK. claire.mccarthy@christie-tr.nwest.nhs.uk (2007-04)
    • Xeroderma pigmentosum group D haplotype predicts for response, survival, and toxicity after platinum-based chemotherapy in advanced nonsmall cell lung cancer.

      Booton, Richard; Ward, Timothy H; Heighway, Jim; Taylor, Pat; Power, Fiona; Ashcroft, Linda; Morris, Julie; Thatcher, Nick; Christie Hospital National Health Service Trust, Manchester, United Kingdom. r.booton@btopenworld.com (2006-06-01)
      BACKGROUND: The treatment of lung cancer has reached a therapeutic plateau. Several mechanisms of platinum resistance have been described, including the removal of platinum-DNA adduct by nucleotide excision repair (NER). Polymorphisms within the Xeroderma pigmentosum Group D protein (XPD), a member of the NER pathway, are associated with alterations in enzyme activity and may change sensitivity to platinum-based chemotherapy. The authors investigated the relation between XPD polymorphisms and treatment response, toxicity, and overall survival in patients who received platinum-based chemotherapy for advanced nonsmall cell lung cancer (NSCLC). METHODS: Between 2001 and 2002, 108 patients with chemotherapy-naive, advanced NSCLC were recruited. Associations between XPD312/751 polymorphisms and XPD haplotype and treatment response, toxicity. and survival were evaluated. RESULTS: Significant correlations were observed between XPD haplotype and Grade 4 neutropenia and overall survival together with a greater response to platinum-based chemotherapy for the XPD *A haplotype. CONCLUSIONS: The XPD haplotype may represent a useful pharmacogenomic marker of platinum-based chemotherapy in patients with advanced NSCLC and requires prospective validation.
    • XRCC1 polymorphism associated with late toxicity after radiation therapy in breast cancer patients.

      Seibold, P; Behrens, S; Schmezer, P; Helmbold, I; Barnett, G; Coles, C; Yarnold, J; Talbot, C; Imai, T; Azria, D; et al. (2015-08-01)
      To identify single-nucleotide polymorphisms (SNPs) in oxidative stress-related genes associated with risk of late toxicities in breast cancer patients receiving radiation therapy.
    • XVI. Early stage Hodgkin lymphoma.

      Radford, John A; "Institute of Cancer Sciences, University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK. " (2015-06)
    • XVII. Radiotherapy in early stage Hodgkin lymphoma.

      Illidge, Timothy M; Institute of Cancer Sciences University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester, UK. (2013-06)
    • YoDA BRCA: views and experiences around genetic testing for young women with breast cancer: developing a decision aid

      Grimmett, C; Brooks, C; Recio-Saucedo, A; Cutress, R; Copson, E; Evans, G; Gerty, S; Armstrong, Anne C; Turner, L; Mason, S; et al. (2016)
    • Young adulthood body mass index, adult weight gain and breast cancer risk: the PROCAS Study (United Kingdom)

      Renehan, Andrew G; Pegington, Mary; Harvie, MH; Sperrin, M; Astley, SM; Brentnall, AR; Howell, Anthony; Cusick, J; Evans, D Gareth R; Manchester Cancer Research Centre and NIHR Manchester Biomedical Research Centre, Manchester, UK (2020)
    • Young age at first pregnancy does protect against early onset breast cancer in BRCA1 and BRCA2 mutation carriers.

      Evans, D; Harkness, E; Howell, Sacha J; Woodward, E; Howell, Anthony; Lalloo, F; Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre (MAHSC), Institute of Human Development, St Mary's Hospital, University of Manchester, Manchester (2017-11-07)
      Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies.
    • Yttrium-90 radioembolization in intrahepatic cholangiocarcinoma: a multicenter retrospective analysis

      Buettner, S.; Braat, A.; Margonis, G. A.; Brown, D. B.; Taylor, K. B.; Borgmann, A. J.; Kappadath, S. C.; Mahvash, A.; JNM, I. J.; Weiss, M. J.; et al. (2020)
      PURPOSE: To report outcomes of yttrium-90 ((90)Y) radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: Retrospective review was performed of 115 patients at 6 tertiary care centers; 92 were treated with resin microspheres (80%), 22 were treated with glass microspheres (19%), and 1 was treated with both. Postintervention outcomes were compared between groups with chi(2) tests. Survival after diagnosis and after treatment was assessed by Kaplan-Meier method. RESULTS: Grade 3 laboratory toxicity was observed in 4 patients (4%); no difference in toxicity profile between resin and glass microspheres was observed (P = .350). Clinical toxicity per Society of Interventional Radiology criteria was noted in 29 patients (25%). Partial response per Response Evaluation Criteria In Solid Tumors 1.1 was noted in 25% of patients who underwent embolization with glass microspheres and 3% of patients who were treated with resin microspheres (P = .008). Median overall survival (OS) from first diagnosis was 29 months (95% confidence interval [CI], 21-37 mo) for all patients, and 1-, 3-, and 5-year OS rates were 85%, 31%, and 8%, respectively. Median OS after treatment was 11 months (95% CI, 8-13 mo), and 1- and 3-year OS rates were 44% and 4%, respectively. These estimates were not significantly different between resin and glass microspheres (P = .730 and P = .475, respectively). Five patients were able to undergo curative-intent resection after (90)Y radioembolization (4%). CONCLUSIONS: This study provides observational data of treatment outcomes after (90)Y radioembolization in patients with unresectable ICC.
    • Yttrium-90 transarterial radioembolization for chemotherapy-refractory intrahepatic cholangiocarcinoma: a prospective, observational study

      White, J; Carolan-Rees, G; Dale, M; Patrick, H; See, T; Bell, Jon; Manas, D; Crellin, A; Slevin, Nicholas J; Sharma, R; et al. (2019)
      PURPOSE: To evaluate the safety and efficacy of yttrium-90 transarterial radioembolization (TARE) for the treatment of unresectable, chemotherapy-refractory intrahepatic cholangiocarcinoma (ICC). METHODS: A prospective, observational study was carried out in 10 centers between 2013 and 2017. TARE plus standard care was delivered to patients with unresectable, chemotherapy-refractory or chemotherapy-intolerant ICC. Primary outcome was overall survivaL Secondary outcomes included safety, progression-free survival (PFS), and liver-specific progression-free survival (LPFS). RESULTS: Sixty-one patients were treated with TARE Patients were 53% male; median age was 64 years; 91% had performance status 0/1; 92% had received prior chemotherapy; and 59% had no extrahepatic disease. Median follow-up was 13.9 months (95% confidence interval [CI], 9.6-18.1). Overall survival was 8.7 months (95% CI, 5.3-12.1), and 37% of patients survived to 12 monthS PFS was 2.8 months (95% CI, 2.6-3.1), and LPFS was 3.1 months (95% CI, 1.3-4.8). One severe complication (abdominal pain) occurred at the time of the TARE procedure. Thirty patients experienced a total of 49 adverse events, of which 8% were grade >/=3; most common were grade 1-2 fatigue and abdominal pain. A total of 77 abnormal laboratory value events were recorded, of which 4% were grade >/=3. CONCLUSIONS: Patients with advanced ICC have limited therapeutic options and a poor prognosis. This prospective study examined the survival of patients with unresectable, chemotherapy-refractory primary ICC treated with TARE in real-world practice. The results demonstrate that this treatment merits further investigation in this patient cohort in a larger study, including collection of patient-reported outcomes.
    • YY1 expression predicts favourable outcome in follicular lymphoma.

      Naidoo, Khimara; Clay, V; Hoyland, J A; Swindell, Ric; Linton, Kim M; Illidge, Timothy M; Radford, John A; Byers, RJ; School of Cancer and Enabling Sciences, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, UK. (2011-02)
      Follicular lymphoma is the second most common type of non-Hodgkin's lymphoma worldwide. The majority of patients diagnosed as having follicular lymphoma have an indolent form of the disease, but a subset of patients have aggressive disease with a shorter survival interval. Optimal treatment stratification requires a distinction between these two groups, though there are presently few prognostic biomarkers available. The transcription factor YY1 has been shown to play an important role in cancer biology. The authors have previously reported a correlation of Yin Yang 1 (YY1) mRNA levels with survival in FL. This study aimed to validate these findings at the protein level.
    • ZD1839 (IRESSA): a selective EGFR-TK inhibitor.

      Ranson, Malcolm R; Mansoor, Was; Jayson, Gordon C; Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester, UK. malcolm.ranson@amn.ac.uk (2002-04)
      The recent development of highly selective, target-based cancer therapeutics, such as ZD1839 has resulted from a greater understanding of tumor biology. Amongst the most promising of new target-based agents are inhibitors of the epidermal growth factor receptor. ZD 1839 is a potent, selective epidermal growth factor receptor tyrosine kinase inhibitor that has demonstrated promising results in early clinical trials.
    • ZD1839 (Iressa): for more than just non-small cell lung cancer.

      Ranson, Malcolm R; Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom. malcolm.ranson@man.ac.uk (2002)
      ZD1839 (Iressa) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor that blocks signal transduction pathways involved in cell proliferation. Preclinical studies demonstrated that ZD1839 is a promising agent for the treatment of a wide range of tumors and has additive-to-synergistic effects when combined with radiation or chemotherapy in various cell lines and xenografts. Phase I clinical trials have reported that ZD1839 has acceptable tolerability and antitumor activity. In addition to non-small cell lung cancer, phase II/III studies are currently investigating ZD1839 as monotherapy or in combination therapy against prostate, breast, head and neck, gastric, and colorectal tumors.
    • ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.

      Ranson, Malcolm R; Hammond, Lisa A; Ferry, David R; Kris, Mark; Tullo, Andrew; Murray, Philip I; Miller, Vince; Averbuch, Steven D; Ochs, Judith; Morris, Charles; et al. (2002-05-01)
      PURPOSE: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non-small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for > or = 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for > or = 6 months. CONCLUSION: ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.