• Transformed diffuse large B-cell lymphomas with gains of the discontinuous 12q12-14 amplicon display concurrent deregulation of CDK2, CDK4 and GADD153 genes.

      Al-Assar, Osama; Rees-Unwin, Karen S; Menasce, Lia P; Hough, Rachael E; Goepel, John R; Hammond, David W; Hancock, Barry W; Yorkshire Cancer Research Institute for Cancer Studies, Division of Genomic Medicine, University of Sheffield, Sheffield, UK. o.al.assar@sheffield.ac.uk (2006-06)
      Transformation of the indolent follicular lymphoma (FL) to the aggressive diffuse large B-cell lymphoma (DLBCL) results in resistance to therapy with shortened survival. It has been demonstrated that the 12q12-14 region was mainly amplified in DLBCL cases but not in their FL counterparts. Therefore, we examined the DNA copy number and protein expression profiles for CDK2, CDK4 and GADD153, three genes that map to 12q12-14, in a set of 44 paired FL/DLBCL samples from 22 patients. The concordant amplification of these genes occurred in seven of 22 (32%) of FL cases, compared with 15 of 22 (68%) of DLBCL cases. At the protein level, 15 of 22 of the DLBCL samples (68%) showed strong staining for the CDK2 protein, compared with five of 21 of FL samples (24%). The majority of the DLBCL samples (16/22, 72%) expressed the CDK4 protein, whereas the majority of the FL samples (12/21, 57%) showed no expression of this protein. Except for one DLBCL case, no expression of the GADD153 protein could be detected. The deregulation of the CDK2 and CDK4 genes at the genetic and protein levels suggest a functional role for these genes in the transformation process and could potentially provide targets for prognostic tests or therapeutic interventions.
    • Transforming cancer outcomes in England: earlier and faster diagnoses, pathways to success, and empowering alliances

      Harrison, Christopher J; Spencer, Roger G; Shackley, David C; University of Manchester Division of Cancer Sciences, The Christie NHS Foundation Trust, Manchester, UK (2019)
      Cancer outcomes and patient experience in England have never been better but survival remains worse than in comparable countries. Differences in stage at diagnosis and, to a lesser extent, access to optimal treatments are likely to be the most important factors. The national cancer plan emphasizes earlier and faster diagnosis and the creation of cancer alliances providing strategic leadership and coordination. Earlier diagnosis is being promoted by national awareness campaigns designed to overcome fatalism and perceived barriers to consulting a general practitioner as well as improvements to existing screening programs and the introduction of more targeted screening such as Lung Health Checks. These are supported by local social marketing campaigns in which trained volunteers support and advise others about cancer and cancer care. The epidemiology of symptoms in general practice provides an organizing framework for cancer diagnostic pathways. Alliances are implementing a broader model of cancer diagnostic clinics at a larger scale taking into account the different needs of patients with 1) obvious alert symptoms, 2) low risk but not no risk symptoms, and 3) serious but not specific symptoms. Faster diagnosis is being promoted by the introduction of a Faster Diagnosis Standard requiring patients are given a diagnosis of cancer or have it ruled out within 28 days of referral. The three cancer alliances forming the National Cancer Vanguard together with NHS England are publishing clinically led evidence-based Timed Diagnostic Pathways which show how the drastic changes needed can be achieved. Cancer alliances have been successful in developing clinical cancer pathways which need support by improved commissioning and regulatory approaches which align clinical pathways with financial and performance ratings. Clinical leadership has been essential but further focus is needed on making sure that performance and regulatory approaches give proper attention and encouragement to earlier and faster diagnosis.
    • Transforming growth factor beta 1 expression in human colorectal tumours: an independent prognostic marker in a subgroup of poor prognosis patients.

      Robson, Helen; Anderson, Elizabeth; James, Roger D; Schofield, Philip F; Tumour Biochemistry Department, Christie Hospital NHS Trust, Manchester, UK. (1996-09)
      Members of the transforming growth factor beta (TGF-beta family, in particular TGF-beta 1, are some of the most potent inhibitory growth factors in a variety of cell types. Resistance to TGF-beta 1-induced growth inhibition is frequently observed in colorectal carcinomas and is associated with tumour progression. Perturbations of TGF-beta 1 expression and function, therefore, may contribute to the loss of some constraints on tumour cell growth. In this study we have examined the expression of TGF-beta 1 and its precursor latency-associated peptide (LAP)-TGF-beta in human colorectal tumours using immunohistochemical techniques. In 86% of the tumours the LAP-TGF-beta complex was present in both the stromal and epithelial cells, whereas the mature TGF-beta 1 peptide was expressed in the glandular epithelium of 58.3% of these tumours. Intense staining for TGF-beta 1 was positively associated with advanced Dukes' stage. Furthermore, there was a significant correlation between the presence of TGF-beta 1 in the tumours and a shorter post-operative survival. This was most significant in a subgroup of patients who had received only a palliative operation. These results suggest that TGF-beta 1 expression may be useful as an independent prognostic indicator for a subgroup of patients who have a particularly poor prognosis.
    • Transforming growth factor beta 1 promotes the differentiation of endothelial cells into smooth muscle-like cells in vitro.

      Arciniegas, E; Sutton, Andrew B; Allen, Terence D; Schor, Ana M; CRC Department of Medical Oncology, Christie Hospital, Manchester, UK. (1992-10)
      Alpha-smooth muscle actin is considered a reliable marker for distinguishing between arterial smooth muscle and endothelial cells. Several authors have reported heterogeneity in the expression of this actin isoform in atherosclerotic lesions. Such heterogeneity appears to result from the presence of different smooth muscle cell phenotypes (contractile and synthetic) in these lesions. In the present study, we show that bovine aortic endothelial cells, which are characterised by the presence of Factor VIII-related antigen (FVIII) and by the absence of alpha-smooth muscle actin (alpha-SM actin) may be induced to express the latter when exposed to TGF-beta 1. FVIII was detected by immunofluorescence, alpha-SM actin was detected by immunofluorescence and immunoblotting. The number of cells expressing alpha-SM actin increased with time of incubation with TGF-beta 1, and this increase occurred concomitantly with a decrease in the expression of FVIII. Double immunofluorescence demonstrated the presence of cells that expressed both FVIII and alpha-SM actin after 5 days of incubation with TGF-beta 1. With longer incubation times (10-20 days) the loss of FVIII expression was complete and over 90% of the cells expressed alpha-SM actin. Ultrastructurally, cells in control cultures showed the typical features of endothelial cells. In the TGF-beta 1-treated cultures, cells which appeared indistinguishable from contractile and synthetic smooth muscle cells were observed. Withdrawal of TGF-beta 1 after 10 days incubation resulted in the re-appearance of polygonal cells which were FVIII-positive and alpha-SM actin-negative.(ABSTRACT TRUNCATED AT 250 WORDS)
    • Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation.

      O'Brien, Stephen G; Vieira, Sara A D; Connors, Samantha; Bown, Nick; Chang, James; Capdeville, Renaud; Melo, Junia V; School of Clinical and Laboratory Sciences and the School of Biochemistry and Genetics, University of Newcastle, United Kingdom. s.g.o'brien@ncl.ac.uk (2002-05-01)
      We report the transient response of a patient with the ETV6-ABL fusion gene to imatinib mesylate (STI571). A 38-year-old man was referred with an erroneous diagnosis of Philadelphia-positive chronic myeloid leukemia in blastic transformation for treatment with the ABL tyrosine kinase inhibitor, STI571. Further investigation indicated that the patient in fact had acute myeloid leukemia; no evidence of the Philadelphia translocation or BCR-ABL was found using fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction. Detailed FISH analysis identified a cryptic t(9;12) translocation, and molecular studies confirmed the presence of the ETV6-ABL fusion transcript. Because the patient was gravely ill at presentation, treatment was commenced immediately with STI571 monotherapy, resulting in considerable initial improvement. However within 10 days the patient's condition again deteriorated, and he required conventional chemotherapy. This case has implications for the design of future studies using STI571 in leukemias involving ABL-encoded fusion proteins other than BCR-ABL.
    • Transitioning adolescent and young adult cancer care research out of its adolescence.

      Stark, D; Fern, LA; Gibson, F; Hawkins, M; Hough, R; McCabe, Martin; Taylor, R; Department of Cancer Medicine, Leeds, UK (2018)
    • Translating prognostic prostate cancer gene signatures into the clinic.

      Choudhury, Ananya; West, Catharine M L; Division of Cancer Sciences, The University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Manchester, UK (2017-03)
    • Translation of cure for acute lymphoblastic leukaemia to all children.

      Eden, Tim O B; Academic Unit of Paediatric Oncology Central Manchester and Manchester Children's University Hospitals NHS Trust and Christie NHS Trust, Manchester, UK. tim.eden@christie-tr.nwest.nhs.uk (2002-09)
    • Translational research in radiotherapy trials.

      West, Catharine M L; McKeown, S; Academic Department of Radiation Oncology, The University of Manchester, Christie Hospital, Manchester M20 4BX, UK. (2006-09)
    • Translocations involving 12p in acute myeloid leukemia: association with prior myelodysplasia and exposure to mutagenic agents.

      Harrison, Christine J; UKCCG, Dept. of Haematology, The Royal Free Hospital and School of Medicine, Pond St,. London NW3 2QG, UK. (1992-10)
      Six cases of acute myeloid leukemia (AML) with translocations involving 12p are described. The patients were one child age 7 yrs and five adults with an age range of 20-66 yrs (median 46 yrs). In two patients AML followed treatment for acute lymphoblastic leukemia (ALL), in one case after 11 years disease-free survival. Of the remaining four patients, two had been occupationally exposed to possible mutagens and three had a previous myelodysplastic phase. Two patients achieved complete remission; survival for the six cases was between 1 and 24 months (median 6.5 months). The breakpoints in 12p occurred in p11, p12, and p13, indicating that several sites are important in these rearrangements, and it is suggested that t(12;17)(p11;q11) is a new nonrandom abnormality in AML.
    • Translocations involving 9p and/or 12p in acute lymphoblastic leukemia. United Kingdom Cancer Cytogenetics Group (UKCCG).

      Harrison, Christine J; UKCCG, Dept. of Haematology, The Royal Free Hospital and School of Medicine, Pond St., London NW3 2QG, UK. (1992-10)
      Fifteen cases of acute lymphoblastic leukemia (ALL) with translocations involving 9p and/or 12p are described. Four children, three males and one female, age range 1-8 yrs, had translocations involving 9p but not 12p. Of these, three had B-lineage ALL and one had biphenotypic T-ALL/acute myeloid leukemia. Six patients, three males and three females, age range 1-49 yrs, had translocations involving 12p but not 9p. Five had B-lineage ALL and one had T-ALL. One patient had dic(7;12)(p11;p11), confirming that this previously reported translocation is nonrandom in ALL. One patient had t(2;12)(q14;p13), and it is suggested that this may also be a new nonrandom abnormality. Five patients, four males and one female, age range 11-21 yrs, had common ALL and dic(9;12). The dic(9;12) appears to confer a better prognosis than do other translocations involving 9p or 12p.
    • Transplant preparation

      Bompoint, C; Castagna, A; Hutt, D; Leather, Angela; Stenvall, M; Schroder, T; Arjona, E; Van Boxtel, T; Department of Haematological Medicine, King’s College Hospital NHS Foundation Trust, London, United Kingdom (2018)
    • Transplantation potential of hematopoietic cells released into the circulation during routine chemotherapy for non-Hodgkin's lymphoma.

      Pettengell, Ruth; Testa, Nydia G; Swindell, Ric; Crowther, Derek; Dexter, T Michael; Department of Experimental Haematology, Paterson Institute for Cancer Research and Christie Hospital, Manchester, UK. (1993-10-01)
      Primitive hematopoietic cells released into the peripheral blood (PB) were studied in 50 patients with high-grade non-Hodgkin's lymphoma enrolled in a phase III trial of intensive weekly chemotherapy (VAPEC-B) alone or with granulocyte colony-stimulating factor (G-CSF). Mononuclear cells numbers were monitored and their in vitro growth potential assessed in clonogenic progenitor cell assays and in long-term culture. Total colony-forming cells (granulocyte-macrophage [GM], burst-forming unit, erythroid [BFU-E], Mix-CFC) were increased 40-fold (median) over baseline with chemotherapy alone and 106-fold with chemotherapy and G-CSF after the final dose. CD34+ cells were increased to a median of 4%, equivalent to that in normal bone marrow (BM) controls. Circulating colony-forming cell levels were maximal when the recovering total white blood cell (WBC) count reached 5 to 10 x 10(9)/L. The timing of the maximum was reproducible in individual patients. Therefore the WBC count can be used as a guide to the timing of leukapheresis. PB cells from normal controls' and patients' prechemotherapy were unable to sustain hemopoiesis in two-stage long-term cultures. In contrast, PB cells collected from patients primed with chemotherapy alone or chemotherapy with G-CSF at the time of predicted maximal colony-forming cell release were able to generate and sustain hematopoiesis in long-term cultures at a level comparable or superior to normal BM. These findings indicate that the use of G-CSF after routine outpatient chemotherapy stimulates maximal release of primitive hemopoietic cells into the circulation, including colony-forming cells and long-term culture-initiating cells. Their numbers are comparable with those in normal BM and are such that a single leukapheresis will usually yield enough cells for hemopoietic reconstitution after myeloablative chemotherapy.
    • TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer.

      James, N; Pirrie, S; Pope, A; Barton, D; Andronis, L; Goranitis, I; Collins, S; McLaren, D; O'Sullivan, J; Parker, C; et al. (2016-07)
      Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking. Sr-89, approved for controlling metastatic pain and reducing need for subsequent bone treatments, is generally palliatively used in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine the clinical effectiveness and cost-effectiveness of each agent.
    • Trapezius placement of implanted ports: understanding the procedure.

      Hill, Steve; Procedure Team Manager, The Christie NHS Foundation Trust, Manchester (2016-01-27)
      Totally implantable vascular access devices (TIVADs) are indicated for intermittent long-term intravenous access. It is widely accepted within medical literature that TIVADs are associated with statistically significant lower infection rates than other central venous access devices. Typical sites for implantation are on the anterior chest wall, using the internal jugular, axillary, cephalic or a subclavian vein. This article follows on from a previous discussion of the benefits of this approach, which illustrated and examined clinical outcomes of trapezius-placement versus anterior chest wall placed ports, for patients with metastatic subcutaneous disease on the anterior chest wall. The procedure provides a unique challenge for the clinician. This article focuses on the process of trapezius port implantation, providing an illustrative guide to understand the procedure. Trapezius port placement is a viable option for patients for whom routine sites are excluded and who require long-term intermittent vascular access.
    • Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study

      Banerji, U; van Herpen, C; Saura, C; Thistlethwaite, Fiona C; Lord, S; Moreno, V; Macpherson, I; Boni, V; Rolfo, C; de Vries, E; et al. (2019)
      BACKGROUND: Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies showed promising antitumour activity in various modelS In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. METHODS: We did a phase 1 dose-escalation and dose-expansion studY The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0.3 mg/kg to 2.4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrialSgov, number NCT02277717, and is fully recruited. FINDINGS: Between Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2.4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1.5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3-4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1.2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two [1%]) and dyspnoea (two [1%]). The most common treatment-related adverse events (grades 1-4) were fatigue (48 [33%] of 146 patients), conjunctivitis (45 [31%]), and dry eye (45 [31%]). Most patients (104 [71%] of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patientS No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20.4-48.4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13.8-46.8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16.3-67.6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0.2-30.2) of 16 patients with gastric cancer, four (25%, 7.3-52.4) of 16 patients with urothelial cancer, and five (39%, 13.9-68.4) of 13 patients with endometrial cancer. INTERPRETATION: Trastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profilE Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparatioN FUNDING: Synthon BiopharmaceuticalS
    • Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study.

      Thuss-Patience, P; Shah, M; Ohtsu, A; Van Cutsem, E; Ajani, J; Castro, H; Mansoor, Was; Chung, H; Bodoky, G; Shitara, K; et al. (2017-03-23)
      Although trastuzumab plus chemotherapy is the standard of care for first-line treatment of HER2-positive advanced gastric cancer, there is no established therapy in the second-line setting. In GATSBY, we examined the efficacy and tolerability of trastuzumab emtansine in patients previously treated for HER2-positive advanced gastric cancer (unresectable, locally advanced, or metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction).
    • Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study.

      Kaufman, Bella; Mackey, John R; Clemens, Michael R; Bapsy, Poonamalle P; Vaid, Ashok; Wardley, Andrew M; Tjulandin, Sergei; Jahn, Michaela; Lehle, Michaela; Feyereislova, Andrea; et al. (2009-11-20)
      PURPOSE: TAnDEM is the first randomized phase III study to combine a hormonal agent and trastuzumab without chemotherapy as treatment for human epidermal growth factor receptor 2 (HER2)/hormone receptor-copositive metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women with HER2/hormone receptor-copositive MBC were randomly assigned to anastrozole (1 mg/d orally) with or without trastuzumab (4 mg/kg intravenous infusion on day 1, then 2 mg/kg every week) until progression. The primary end point was progression-free survival (PFS) in the intent-to-treat population. Results Overall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in PFS compared with patients receiving anastrozole alone (hazard ratio = 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4 months; log-rank P = .0016). In patients with centrally confirmed hormone receptor positivity (n = 150), median PFS was 5.6 and 3.8 months in the trastuzumab plus anastrozole and anastrozole alone arms, respectively (log-rank P = .006). Overall survival in the overall and centrally confirmed hormone receptor-positive populations showed no statistically significant treatment difference; however, 70% of patients in the anastrozole alone arm crossed over to receive trastuzumab after progression on anastrozole alone. Incidence of grade 3 and 4 adverse events was 23% and 5%, respectively, in the trastuzumab plus anastrozole arm, and 15% and 1%, respectively, in the anastrozole alone arm; one patient in the combination arm experienced New York Heart Association class II congestive heart failure. CONCLUSION: Trastuzumab plus anastrozole improves outcomes for patients with HER2/hormone receptor-copositive MBC compared with anastrozole alone, although adverse events and serious adverse events were more frequent with the combination.
    • Trastuzumab-associated cardiac events in the Persephone trial.

      Earl, H; Vallier, A; Dunn, J; Loi, S; Ogburn, E; McAdam, K; Hughes-Davies, L; Harnett, A; Abraham, J; Wardley, Andrew M; et al. (2016-12-06)
      We report cardiac events in the Persephone trial which compares 6-12 months of adjuvant trastuzumab in women with confirmed HER2-positive, early-stage breast cancer.
    • Treating bony metastases.

      Dodwell, David J; Howell, Anthony (1991-08-24)