• 019 Chemotherapy-induced cardiotoxicity: could a translational cardiac MRI model help identify patients at risk?

      Cove-Smith, Laura; Schmitt, M; Dive, Caroline; Backen, Alison C; Mescallado, Nerissa; Roberts, R; Mellor, H; Morris, D; Naish, J; Jackson, A; et al. (2017-04-03)
    • 06-Methyldeoxyguanosine in oesophageal dna among individuals at high risk of oesophageal cancer

      Umbenhauer, D; Wild, C; Montesano, R; Saffhill, Roy; Boyle, John M; Huh, N; Kirstein, U; Thomale, Jürgen; Rajewsky, M; Lu, S; et al. (1985)
    • 1 versus 2-cm excision margins for pT2-pT4 primary cutaneous melanoma (MelMarT): a feasibility study.

      Moncrieff, M; Gyorki, D; Saw, R; Spillane, A; Peach, H; Oudit, Deemesh; Geh, J; Dziewulski, P; Wilson, E; Matteucci, P; et al. (2018-05-30)
      There is a lack of consensus regarding optimal surgical excision margins for primary cutaneous melanoma > 1 mm in Breslow thickness (BT). A narrower surgical margin is expected to be associated with lower morbidity, improved quality of life (QoL), and reduced cost. We report the results of a pilot international study (MelMarT) comparing a 1 versus 2-cm surgical margin for patients with primary melanoma > 1 mm in BT.
    • (1)H, (13)C, (15)N backbone resonance assignment for the 1-164 construct of human XRCC4

      Cabello-Lobato, Maria J; Schmidt, Christine K; Cliff, M. J.; Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, 555 Wilmslow Road, Manchester, M20 4GJ, UK. (2021)
      DNA double-strand breaks (DSBs) represent the most cytotoxic DNA lesions, as-if mis- or unrepaired-they can cause cell death or lead to genome instability, which in turn can cause cancer. DSBs are repaired by two major pathways termed homologous recombination and non-homologous end-joining (NHEJ). NHEJ is responsible for repairing the vast majority of DSBs arising in human cells. Defects in NHEJ factors are also associated with microcephaly, primordial dwarfism and immune deficiencies. One of the key proteins important for mediating NHEJ is XRCC4. XRCC4 is a dimer, with the dimer interface mediated by an extended coiled-coil. The N-terminal head domain forms a mixed alpha-beta globular structure. Numerous factors interact with the C-terminus of the coiled-coil domain, which is also associated with significant self-association between XRCC4 dimers. A range of construct lengths of human XRCC4 were expressed and purified, and the 1-164 variant had the best NMR properties, as judged by consistent linewidths, and chemical shift dispersion. In this work we report the 1H, 15 N and 13C backbone resonance assignments of human XRCC4 in the solution form of the 1-164 construct. Assignments were obtained by heteronuclear multidimensional NMR spectroscopy. In total, 156 of 161 assignable residues of XRCC4 were assigned to resonances in the TROSY spectrum, with an additional 11 resonances assigned to His-Tag residues. Prediction of solution secondary structure from a chemical shift analysis using the TALOS + webserver is in good agreement with the published X-ray crystal structures of this protein.
    • 1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice.

      Colussi, Claudia; Fiumicino, Silvia; Giuliani, Alessandro; Rosini, Sandra; Musiani, Piero; Macrí, Caterina; Potten, Christopher S; Crescenzi, Marco; Bignami, Margherita; Laboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanitá, Rome, Italy. (2001-10-17)
      BACKGROUND: Defective mismatch repair (MMR) in humans is particularly associated with familial colorectal cancer, but defective repair in mice is generally associated with lymphoma in the absence of experimental exposure to carcinogens. Loss of MMR also confers resistance to the toxic effects of methylating agents. We investigated whether resistance to methylation contributes to increased susceptibility to colorectal cancer in mice by exposing mice with defects in the MMR gene msh2 to a methylating agent. METHODS: Tumor incidence and time of death in msh2(+/+), msh2(+/-), and msh2(-/-) mice were analyzed after weekly exposure (until tumor appearance) to the methylating agent 1,2-dimethylhydrazine (DMH). Chemically induced and spontaneous tumors were characterized by frequency, type, and location. The tumor incidence in untreated and treated mice of each genotype was compared by a Mann-Whitney U test. Carcinogen-induced apoptosis in histologic sections of small and large intestines was also determined. All statistical tests were two-sided. RESULTS: Homozygous inactivation of the msh2 gene statistically significantly accelerated (P<.0001) death due to the development of DMH-induced colorectal tumors and lymphomas. Rates of death from DMH-induced colorectal adenocarcinoma were similar in msh2 heterozygous and wild-type mice, but only msh2 heterozygotes (msh(+/-)) developed additional, noncolorectal malignancies (notably trichofolliculoma [two of 21], angiosarcoma of the kidney capsule [two of 21], and lymphoma [one of 21]), suggesting that heterozygosity for msh2 slightly increases DMH susceptibility. DMH induced apoptosis in small intestinal and colonic epithelial crypts that was dependent on active msh2. CONCLUSIONS: Inactivation of msh2 allows the proliferation of gastrointestinal tract cells damaged by methylating agents. Furthermore, MMR constitutes a powerful defense against colorectal cancer induced by DNA methylation.
    • 1,N(2)-ethenoguanine, a mutagenic DNA adduct, is a primary substrate of Escherichia coli mismatch-specific uracil-DNA glycosylase and human alkylpurine-DNA-N-glycosylase.

      Saparbaev, Murat K; Langouët, Sophie; Privezentzev, Cyril V; Guengerich, F Peter; Cai, Hongliang; Elder, Rhoderick H; Laval, Jacques; Cancer Research United Kingdom Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. M20 4BX (2002-07-26)
      The promutagenic and genotoxic exocyclic DNA adduct 1,N(2)-ethenoguanine (1,N(2)-epsilonG) is a major product formed in DNA exposed to lipid peroxidation-derived aldehydes in vitro. Here, we report that two structurally unrelated proteins, the Escherichia coli mismatch-specific uracil-DNA glycosylase (MUG) and the human alkylpurine-DNA-N-glycosylase (ANPG), can release 1,N(2)-epsilonG from defined oligonucleotides containing a single modified base. A comparison of the kinetic constants of the reaction indicates that the MUG protein removes the 1,N(2)-epsilonG lesion more efficiently (k(cat)/K(m) = 0.95 x 10(-3) min(-1) nm(-1)) than the ANPG protein (k(cat)/K(m) = 0.1 x 10(-3) min(-1) nm(-1)). Additionally, while the nonconserved, N-terminal 73 amino acids of the ANPG protein are not required for activity on 1,N(6)-ethenoadenine, hypoxanthine, or N-methylpurines, we show that they are essential for 1,N(2)-epsilonG-DNA glycosylase activity. Both the MUG and ANPG proteins preferentially excise 1,N(2)-epsilonG when it is opposite dC; however, unlike MUG, ANPG is unable to excise 1,N(2)-epsilonG when it is opposite dG. Using cell-free extracts from genetically modified E. coli and murine embryonic fibroblasts lacking MUG and mANPG activity, respectively, we show that the incision of the 1,N(2)-epsilonG-containing duplex oligonucleotide has an absolute requirement for MUG or ANPG. Taken together these observations suggest a possible role for these proteins in counteracting the genotoxic effects of 1,N(2)-epsilonG residues in vivo.
    • 10-year results of the International Breast Cancer Intervention Study II (IBIS-II)

      Cuzick, J; Sestak, I; Forbes, JF; Dowsett, M; Cawthorn, S; Mansel, RE; Loibl, S; Bonanni, B; Howell, Anthony; Centre for Cancer Prevention, Queen Mary University of London, London (2020)
    • 10-Year results of UK childhood cancer and leukaemia group's (CCLG) UK relapsed Wilms tumour (UKWR) trial

      Moroz, V; Hale, J; Pavasovic, V; Hobson, R; Sartori, P; Saunders, Daniel; Powis, M; Vujanic, G; Pritchard-Jones, K; Vaidya, S; et al. (2019)
    • 11 beta-Hydroxysteroid dehydrogenase activity in Cushing's syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome.

      Stewart, P M; Walker, B R; Holder, G; O'Halloran, Domhnall J; Shackleton, C H; Department of Medicine, Queen Elizabeth Hospital, Birmingham, United Kingdom. (1995-12)
      A characteristic feature of the ectopic ACTH syndrome is a state of mineralocorticoid excess, although the etiology remains obscure. Some forms of endocrine hypertension, such as licorice ingestion, have been explained by cortisol acting as a mineralocorticoid in the setting of inhibition or deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). This enzyme is responsible for the conversion of cortisol (F) to hormonally inactive cortisone, and its activity in vivo can be inferred from the ratio of the urinary excretion of tetrahydrocortisol (THF) and its isomer (5 alpha THF) to tetrahydrocortisone. Twenty-two patients with Cushing's syndrome (11 pituitary dependent, 9 ectopic, and 2 adrenal adenomas) and 13 controls were studied. Compared to controls. Cushing's patients had a significant increase (P < 0.001) in the excretion of all principal metabolites of F, secondary to a 5- to 6-fold increase in the cortisol secretion rate [median, 34.0 (range, 13.3-327) mg/day in Cushing's vs. 6.1 (range, 2.5-10.3) mg/day in controls]. The THF plus 5 alpha THF/tetrahydrocortisone ratio was significantly increased in Cushing's syndrome regardless of etiology [mean, 1.81 (range, 1.09-9.99) in Cushing's vs. 0.81 (range, 0.51-1.47) in controls; P < 0.001), indicative of defective 11 beta HSD activity. Furthermore, compared to patients with pituitary-dependent Cushing's, this ratio was significantly higher in patients with the ectopic ACTH syndrome (4.12 vs. 1.49; P < 0.01) and was inversely correlated with serum potassium levels (r = -0.57; P = 0.01; n = 22). One explanation for the mineralocorticoid excess state of the ectopic ACTH syndrome appears to be that cortisol gains inappropriate access to the mineralocorticoid receptor through failure of its normal metabolism by 11 beta HSD. The reason for the defective 11 beta HSD activity is unclear, but it may be secondary to substrate saturation, inhibition by other adrenal steroids, or product inhibition.
    • 11-week course of sequential methotrexate, thoracic irradiation, and moderate-dose cyclophosphamide for "limited"-stage small-cell bronchogenic carcinoma. A study from the Manchester Lung Tumour Group.

      Thatcher, Nick; Barber, Philip V; Hunter, Robin D; Carroll, K B; Jegarajah, S; Wilkinson, Peter M; Crowther, Derek (1982-05-08)
      55 patients with inoperable but "limited"-stage small-cell carcinoma were treated sequentially with methotrexate, radiotherapy, and high doses of cyclophosphamide. The treatment was completed over 11 weeks and no maintenance chemotherapy was given. Follow-up lasted 9-29 months. Toxicity was acceptable, despite doses of cyclophosphamide of 1.5-3.5 g/m2. The complete response rate was 53%. Median survival for the total patient group was 12 months, range 2-29+. Patients who attained a complete response had a 17 month median survival; 17 patients remained in complete remission, 9 of whom first underwent treatment 14-29 months previously. Karnofsky performance scores improved after treatment and most patients were able to resume normal activity. The results are similar to those obtained with prolonged combination chemotherapy.
    • 111: How good is lung cancer education in primary care and how can the Christie Lung Cancer Group improve this?

      Coote, Joanna H; Harris, Maggie A; Summers, Yvonne J; Neocleous, M; Hill, T; Dhamrait, B; Clinical Oncology, The Christie NHS Foundation Trust, Manchester (2017-01)
    • 1133P Non-elective admissions in cancer care - a review of acute oncology services (AOS) implementation in a north-west region of England.

      Chow, Shien; Leach, Rebecca; Mitchell, Claire L; Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK (2017-09)
    • 114Inm oxine-labelled lymphocytes--therapeutic applications.

      Hamilton, D; Cowan, Richard A; Drayson, M; Sharma, H; Cummins, P; Nuttall, Pamela M; Deakin, David P; Wagstaff, John; Crowther, Derek; Regional Department of Medical Physics and Bioengineering, Christie Hospital and Holt Radium Institute, Manchester, UK. (1988-10)
      It has shown that, after intravenous administration of autologous lymphocytes labelled with the beta-emitting radionuclide 114Inm, the cells initially migrate normally before succumbing to the toxic effects of the radiation. The radioactive material is then released from the cell and taken up by neighbouring radioresistant macrophages, thereby localizing a field of radiation to the site of lymphocyte death. Using this technique, lymphocytopoenia has been produced in rats. We have measured the whole-body distribution and excretion of radioactivity in patients who received escalating activities of 114Inm-labelled lymphocytes. All patients had active non-Hodgkin's lymphoma involving the spleen and liver which proved resistant to combination chemotherapy and conventional radiotherapy. Following intravenous administration, the labelled cells cleared rapidly from the vasculature with only 15% remaining in the peripheral blood at 30 min. The radioactivity continued to fall over the next 5 days to approximately 3% and was maintained at approximately 2% for up to 90 days. There was an almost immediate uptake of radioactivity by the spleen and liver which reached approximately 85% of the injected dose by 48 h. The localization of radioactivity stabilized by 48 h and thereafter the whole-body content fell by approximately 0.8% per day. Up to 5% of the administered radioactivity accumulated in the bone marrow. The activities administered were too low to produce a therapeutic response and no toxicity was experienced by the patients. A therapeutic study at higher activities is now underway.
    • 117: Organ at risk inter- and intra-observer contour variation for lung patients on average versus motion compensated 4DCT.

      McWilliam, Alan; Lee, Lip W; Harris, Maggie A; Sheikh, Hamid Y; Pemberton, Laura S; Faivre-Finn, Corinne; van Herk, Marcel; University of Manchester, Division of Molecular and Clinical Cancer Science, Faculty of Biology, Medicine and Health, Manchester (2017-01)
    • 118: Accelerated hypofractionated intensity modulated radiotherapy (IMRT) for early stage non-small cell lung cancer (NSCLC) in patients not suitable for conventional stereotactic ablative radiotherapy (SABR).

      Lavin, Victoria; Whitehurst, Philip; Harris, Catherine; Goldstraw, Rhiannon; Bayman, Neil A; Chan, Clara; Coote, J.; Harris, Maggie A; Pemberton, Laura S; Sheikh, Hamid Y; et al. (2017-01)
    • 118 Multiparametric Cardiovascular Magnetic Resonance Surveillance of Acute Cardiac Allograft Rejection and Characterisation of Transplantation-associated Myocardial Injury.

      Miller, C; Naish, J; Shaw, S; Yonan, N; Williams, S; Clark, D; Bishop, P; Ainslie, M; Borg, A; Coutts, Glyn; et al. (2014-06)
      Acute cardiac allograft rejection (ACAR) affects approximately 20% of patients in the first year post-transplantation, represents a leading cause of death during this period and confers higher mortality in patients surviving beyond the first year. Clinical features of ACAR are unreliable, therefore serial surveillance endomyocardial biopsies are performed in order to detect ACAR at an early stage. However the procedure is invasive, is associated with uncommon but significant complications and expensive, factors which prevent more frequent monitoring thus limiting optimal immunosuppression titration. This study aimed to prospectively and longitudinally evaluate the performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting and monitoring ACAR in the early phase post-transplant, and characterise graft recovery following transplantation.
    • 120: Impact of introducing intensity modulated radiotherapy (IMRT) on curative-intent radiotherapy for lung cancer – a ‘big data’ analysis.

      Chan, Clara; Woolf, David K; Kennedy, Jason; Whitehurst, Philip; Harris, Catherine; Goldstraw, R.; Bayman, Neil A; Coote, J.; Harris, Maggie A; Pemberton, Laura S; et al. (2017-01)
    • 126: Automated classification of radiation oesophagitis from free text clinical narratives.

      Dehghan, Azad; Ala-Aldeen, K; Blaum, C; Liptrot, Tom; Kennedy, Jason; Tibble, Daniel; Barker-Hewitt, Matthew; Faivre-Finn, Corinne; Data Science, Informatics, The Christie NHS Foundation Trust, Manchester (2017-01)