• Framework to construct and interpret latent class trajectory modelling.

      Lennon, H; Kelly, S; Sperrin, M; Buchan, I; Cross, A; Leitzmann, M; Cook, M; Renehan, Andrew G; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK (2018-07-07)
      Latent class trajectory modelling (LCTM) is a relatively new methodology in epidemiology to describe life-course exposures, which simplifies heterogeneous populations into homogeneous patterns or classes. However, for a given dataset, it is possible to derive scores of different models based on number of classes, model structure and trajectory property. Here, we rationalise a systematic framework to derive a 'core' favoured model.
    • A framework to support the lung cancer nurse specialist in the development and evaluation of nurse-led clinics

      Morgan, S; Draffan, J; Bolton, S; Borthwick, D; Field, S; Morley, J; Rees, P; Roberts, J; Savory, S; Thomas, C; et al. (2016)
    • Free ALT-flap can treat chronic seroma: a case report

      Pham, Hien; Tsapralis, Nikolaos; Kosutic, Damir; Department of plastic and reconstructive surgery, The Christie Hospital NHS FT, Manchester (2020)
    • Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels.

      Russell, Wanda; Harrison, R F; Smith, N; Darzy, Ken H; Shalet, Stephen M; Weetman, A P; Ross, R J M; University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield, United Kingdom. (2008-06)
      CONTEXT: TSH is known to have a circadian rhythm, but the relationship between this and any rhythm in T(4) and T(3) has not been clearly demonstrated. OBJECTIVE: With a view to optimizing thyroid hormone replacement therapy, we have used modern assays for free T(4) (FT4) and free T(3) (FT3) to investigate circadian rhythmicity. SETTING: The study was performed at a university hospital. DESIGN AND SUBJECTS: This was a cross-sectional study in 33 healthy individuals with 24-h blood sampling (TSH in 33 and FT4 and FT3 in 29 individuals) and cosinor analysis. RESULTS: Of the individuals, 100% showed a sinusoidal signal in TSH, for FT4 76%, and for FT3 86% (P < 0.05). For FT4 and FT3, the amplitude was low. For TSH the acrophase occurred at a clock time of 0240 h, and for FT3 approximately 90 minutes later at 0404 h. The group cosinor model predicts that TSH hormone levels remain above the mesor between 2020 and 0820 h, and for FT3 from 2200-1000 h. Cross correlation of FT3 with TSH showed that the peak correlation occurred with a delay of 0.5-2.5 h. When time-adjusted profiles of TSH and FT3 were compared, there was a strong correlation between FT3 and TSH levels (rho = 0.80; P < 0.0001). In contrast, cross correlation revealed no temporal relationship between FT4 and TSH. CONCLUSIONS: FT3 shows a circadian rhythm with a periodicity that lags behind TSH, suggesting that the periodic rhythm of FT3 is due to the proportion of T(3) derived from the thyroid. Optimizing thyroid hormone replacement may need to take these rhythms into account.
    • The frequency of bleeding complications in patients with haematological malignancy following the introduction of a stringent prophylactic platelet transfusion policy.

      Callow, Colin R; Swindell, Ric; Randall, William; Chopra, Rajesh; Department of Haematological Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. Colin.Callow@christie-tr.nwest.nhs.uk (2002-08)
      Indications for platelet transfusion remain controversial and are frequently based on arbitrary numerical criteria. In October 2000, we introduced a stringent prophylactic-platelet transfusion policy < 10 x 109/l for stable patients and < 20 x 10(9)/l in the presence of major bleeding or additional risk factors. A trigger of < 50 x 10(9)/l was introduced for patients undergoing invasive procedures. A prospective analysis was performed measuring the frequency of minor and major bleeding events, morbidity, mortality and duration of pancytopenia. Blood product usage was assessed and health care savings measured. A total of 98 patients were evaluated on 2147 patient study days and 271 bleeding episodes were recorded. Major bleeding occurred on 1.39% (30/2147) of the study days when platelet counts were < 10 x 10(9)/l and 2.3% (50/2147) of the study days when platelet counts were 10-20 x 10(9)/l. In patients with platelets > 20 x 10(9)/l, there were 117 major bleeding episodes observed on 5.4% of the study days. In patients with no identified additional risk factors present, major haemorrhages were recorded in 0.51% (11/2147) of the study days in patients with platelet counts > or = 10 x 10(9)/l . There was a 36% reduction in platelet units transfused compared with retrospective data when an arbitrary transfusion trigger of 20 x 10(9)/l was in place (P = < 0.02). Of note, a 16% reduction in red cell transfusions was recorded. These data confirm that the introduction of a transfusion trigger of < 10 x 10(9)/l in the absence of fresh bleeding and sepsis (> 38 degrees C) is safe and has a significant impact on overall hospital transfusion costs.
    • Frequency of down-regulation of individual HLA-A and -B alleles in cervical carcinomas in relation to TAP-1 expression.

      Keating, P J; Cromme, F V; Duggan-Keen, Margaret F; Snijders, P J; Walboomers, Jan M; Hunter, Robin D; Dyer, P A; Stern, Peter L; Cancer Research Campaign Department of Immunology, Paterson Institute for Cancer Research, Manchester, UK. (1995-08)
      The development of cervical carcinoma is strongly associated with specific types of human papillomaviruses (HPVs). A role for cellular immunity in cervical disease is supported by the increased occurrence of HPV-associated lesions in immunosuppressed individuals. Upon viral infection or malignant transformation, ensuing alterations in gene expression result in the generation of novel sets of peptides which can form complexes with specific HLA class I heavy chains and beta 2-microglobulin. These are then expressed at the cell surface as potential targets for specific T cells. In this study of 100 carcinomas HLA-A and -B class I expression by the tumour cells was down-regulated at one or more alleles in at least 73% of cervical carcinomas. Interference with the transporter associated with antigen presentation (TAP), which translocates cytosolic peptides from endogenously synthesised proteins (e.g. viral) into the lumen of the endoplasmic reticulum was found in 38% of the HLA class I down-regulated tumours. Loss of expression for common HLA class I alleles ranged from 36% to 71%, and such changes might be expected to influence specific immunogenic peptide presentation and consequent immune recognition. These results underline the importance of single as well as multiple allelic loss in cervical neoplasia and have important implications for attempts to intervene immunologically in cervical cancer.
    • Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival.

      Griffiths, Richard W; Elkord, Eyad; Gilham, David E; Ramani, Vijay A C; Clarke, Noel W; Stern, Peter L; Hawkins, Robert E; Department of Medical Oncology, Christie Research Centre, Paterson Institute for Cancer Research, Manchester, UK. (2007-11)
      BACKGROUND: Regulatory T cells are important in maintaining immune homeostasis, mediating peripheral tolerance and preventing autoimmunity. Increased frequencies of CD4(+)CD25(high )T regulatory (T(Reg)) cells have been documented in the peripheral blood of patients with several types of cancer consistent with a role in tumour escape from immunological control. We have investigated the presence of T(Reg) cells systemically and in situ in previously untreated patients with renal cell carcinoma (RCC). RESULTS: We have shown that there is a significant increased frequency of CD4(+)CD25(high) T cells in RCC patients (n = 49) compared to normal donors (n = 38), respectively, 2.47% versus 1.50%; P < 0.0001. We confirmed these data using the FOXP3 marker of T(Reg) cells in a subset of these patients and normal donors. The population of T(Reg) cells identified showed the expected phenotype with CD4(+)CD25(high) population in both RCC patients and normal donors contained higher proportions of CD45RO and GITR than CD4(+)CD25(-/low) populations and exhibiting suppressive activity in an anti-CD3 and anti-CD28 induced proliferation assay. CD4(+)FOXP3(+) T cells were detected in the tumour microenvironment by immunofluorescence and the numbers enumerated in lymphocytes recovered following enzymatic disaggregations of biopsies; their frequency was higher in the tumour than the peripheral blood of the same patients. The early follow up data show an association between higher peripheral blood regulatory T-cell count and adverse overall survival. CONCLUSION: These data confirm the increase of T(Reg) cells in RCC patients and provide impetus to further investigate modulation of T(Reg) activity in RCC patients as part of therapy.
    • Frequent derepression of the mesenchymal transcription factor gene FOXC1 in acute myeloid leukemia.

      Somerville, Tim D D; Wiseman, Daniel H; Spencer, Gary J; Huang, Xu; Lynch, James T; Leong, Hui Sun; Williams, Emma L; Cheesman, E; Somervaille, Tim C P; Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK (2015-09-14)
      Through in silico and other analyses, we identified FOXC1 as expressed in at least 20% of human AML cases, but not in normal hematopoietic populations. FOXC1 expression in AML was almost exclusively associated with expression of the HOXA/B locus. Functional experiments demonstrated that FOXC1 contributes to a block in monocyte/macrophage differentiation and enhances clonogenic potential. In in vivo analyses, FOXC1 collaborates with HOXA9 to accelerate significantly the onset of symptomatic leukemia. A FOXC1-repressed gene set identified in murine leukemia exhibited quantitative repression in human AML in accordance with FOXC1 expression, and FOXC1(high) human AML cases exhibited reduced morphologic monocytic differentiation and inferior survival. Thus, FOXC1 is frequently derepressed to functional effect in human AML.
    • Frequent elevation of tissue polypeptide antigen in the sera of workers exposed to bladder carcinogens.

      Kumar, Shant; Wilson, Philip B; Brenchley, Paul E C; Taylor, Geoffrey; Björklund, B; Eklund, G; Christie Hospital, Withington, Manchester, M20 4BX, UK (1978-11-15)
      A group of 108 male workers previously exposed to bladder carcinogens and a group of 26 patients with carcinoma of the bladder differed significantly from a control group comprising 63 healthy male donors with respect to their levels of tissue polypeptide antigen (TPA). The risk group exhibited 4-6 times more frequent elevations of TPA than did the group of healthy donors.
    • Frequent reconstitution of IDH2(R140Q) mutant clonal multilineage hematopoiesis following chemotherapy for acute myeloid leukemia.

      Wiseman, Daniel H; Williams, Emma L; Wilks, Deepti P; Leong, Hui Sun; Somerville, Tim D D; Dennis, Michael; Struys, E; Bakkali, A; Salomons, G; Somervaille, Tim C P; et al. (2016-05-13)
    • FROGG patterns of practice survey and consensus recommendations on radiation therapy for MIBC

      Cardoso, M.; Choudhury, Ananya; Christie, D.; Eade, T.; Foroudi, F.; Hayden, A.; Holt, T.; Kneebone, A.; Sasso, G.; Shakespeare, T. P.; et al. (2020)
      None
    • From biomarkers to medical tests: the changing landscape of test evaluation.

      Horvath, A; Lord, S; St John, A; Sandberg, S; Cobbaert, C; Lorenz, S; Monaghan, Phillip J; Verhagen-Kamerbeek, W; Ebert, C; Bossuyt, P; et al. (2014-01-01)
      Regulators and healthcare payers are increasingly demanding evidence that biomarkers deliver patient benefits to justify their use in clinical practice. Laboratory professionals need to be familiar with these evidence requirements to better engage in biomarker research and decisions about their appropriate use. This paper by a multidisciplinary group of the European Federation of Clinical Chemistry and Laboratory Medicine describes the pathway of a laboratory assay measuring a biomarker to becoming a medically useful test. We define the key terms, principles and components of the test evaluation process. Unlike previously described linearly staged models, we illustrate how the essential components of analytical and clinical performances, clinical and cost-effectiveness and the broader impact of testing assemble in a dynamic cycle. We highlight the importance of defining clinical goals and how the intended application of the biomarker in the clinical pathway should drive each component of test evaluation. This approach emphasizes the interaction of the different components, and that clinical effectiveness data should be fed back to refine analytical and clinical performances to achieve improved outcomes. The framework aims to support the understanding of key stakeholders. The laboratory profession needs to strengthen collaboration with industry and experts in evidence-based medicine, regulatory bodies and policy makers for better decisions about the use of new and existing medical tests.
    • From BRCA1 to polygenic risk scores: mutation-associated risks in breast cancer-related genes

      Woodward, E. R.; van Veen, E. M.; Evans, D Gareth R; Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, (2021)
      Background: There has been huge progress over the last 30 years in identifying the familial component of breast cancer. Summary: Currently around 20% is explained by the high-risk genes BRCA1 and BRCA2, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes ATM and CHEK2. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. Key-Messages: There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as CDH1 and TP53, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.
    • From BRCA1to polygenic risk scores: mutation-associated risks in breast cancer-related genes

      Woodward, E. R.; van Veen, E. M; Evans, D Gareth R; Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester (2021)
      Background: There has been huge progress over the last 30 years in identifying the familial component of breast cancer. Summary: Currently around 20% is explained by the high-risk genes BRCA1 and BRCA2, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes ATM and CHEK2. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40-90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace. Key-messages: There is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as CDH1 and TP53, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.
    • From presentation to paper: gender disparities in oncological research

      Dijksterhuis, WPM; Stroes, CI; Tan, WL; Ithimakin, S; Calles, A; van Oijen, MGH; Verhoeven, RHA; Barriuso, Jorge; Oosting, SF; Kolarevic, ID; et al. (2019)
      Gender disparities in scientific publications have been identified in oncological research. Oral research presentations at major conferences enhance visibility of presenters. The share of women presenting at such podia is unknown. We aim to identify gender-based differences in contributions to presentations at two major oncological conferences. Abstracts presented at plenary sessions of the American Society of Clinical Oncology (ASCO) Annual Meetings and European Society for Medical Oncology (ESMO) Congresses were collected. Trend analyses were used to analyze female contribution over time. The association between presenter's sex, study outcome (positive/negative) and journals' impact factors of subsequently published papers was assessed using Chi-square and Mann-Whitney U tests. Of 166 consecutive abstracts presented at ASCO in 2011-2018 (n =?34), and ESMO in 2008-2018 (n =?132), 21% had female presenters, all originating from Northern America (n =?17) or Europe (n =?18). The distribution of presenter's sex was similar over time (P =?0.70). Of 2,425 contributing authors to these presented abstracts, 28% were women. The proportion of female abstract authors increased over time (P <?0.05), and was higher in abstracts with female (34%) compared to male presenters (26%; P <?0.01). Presenter's sex was not associated with study outcome (P =?0.82). Median journals' impact factors were lower in papers with a female first author (P <?0.05). In conclusion, there is a clear gender disparity in research presentations at two major oncological conferences, with 28% of authors and 21% of presenters of these studies being female. Lack of visibility of female presenters could impair acknowledgement for their research, opportunities in their academic career, and even hamper heterogeneity in research.
    • FTIR microscopy of biological cells and tissue: data analysis using resonant Mie scattering (RMieS) EMSC algorithm.

      Bassan, P; Sachdeva, A; Kohler, A; Hughes, C; Henderson, A; Boyle, J; Shanks, Jonathan H; Brown, Michael D; Clarke, Noel W; Gardner, P; et al. (2012-03-21)
      Transmission and transflection infrared microscopy of biological cells and tissue suffer from significant baseline distortions due to scattering effects, predominantly resonant Mie scattering (RMieS). This scattering can also distort peak shapes and apparent peak positions making interpretation difficult and often unreliable. A correction algorithm, the resonant Mie scattering extended multiplicative signal correction (RMieS-EMSC), has been developed that can be used to remove these distortions. The correction algorithm has two key user defined parameters that influence the accuracy of the correction. The first is the number of iterations used to obtain the best outcome. The second is the choice of the initial reference spectrum required for the fitting procedure. The choice of these parameters influences computational time. This is not a major concern when correcting individual spectra or small data sets of a few hundred spectra but becomes much more significant when correcting spectra from infrared images obtained using large focal plane array detectors which may contain tens of thousands of spectra. In this paper we show that, classification of images from tissue can be achieved easily with a few (<10) iterations but a reliable interpretation of the biochemical differences between classes could require more iterations. Regarding the choice of reference spectrum, it is apparent that the more similar it is to the pure absorption spectrum of the sample, the fewer iterations required to obtain an accurate corrected spectrum. Importantly however, we show that using three different non-ideal reference spectra, the same unique correction solution can be obtained.
    • A FTIR microspectroscopic study of the uptake and metabolism of isotopically labelled fatty acids by metastatic prostate cancer.

      Gazi, Ehsan; Harvey, Tim J; Brown, Michael D; Lockyer, Nicholas P; Gardner, Peter; Clarke, Noel W; Genito Urinary Cancer research Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK (2009)
    • FTIR microspectroscopy of selected rare diverse sub-variants of carcinoma of the urinary bladder.

      Hughes, Caryn; Iqbal-Wahid, Junaid; Brown, Michael D; Shanks, Jonathan H; Eustace, Amanda; Denley, H; Hoskin, P; West, Catharine M L; Clarke, Noel W; Gardner, P; et al. (2012-11-02)
      Urothelial carcinomas of the bladder are a heterogeneous group of tumours, although some histological sub-variants are rare and sparsely reported in the literature. Diagnosis of sub-variants from conventional urothelial carcinoma can be challenging, as they may mimic the morphology of other malignancies or benign tumours and therefore their distinction is important. For the first time, the spectral pathology of some of these sub-variants has been documented by infrared microspectroscopy and an attempt made to profile their biochemistry. It is important not only to identify and separate the cancer-associated epithelial tissue spectra from common tissue features such as stroma or blood, but also to detect the signatures of tumour sub-variants. As shown, their spectroscopic signals can change dramatically as a consequence of differentiation. Example cases are discussed and compared with histological evaluations. (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim).
    • Full 3D position reconstruction of a radioactive source based on a novel hyperbolic geometrical algorithm

      Panaino, C. M. V.; Mackay, Ranald I; Sotiropoulos, M.; Kirkby, Karen J; Taylor, Michael J; Division of Cancer Sciences, University of Manchester,The Christie NHS Foundation Trust, M20 4BX, Manchester, UK. (2020)
      A new method to locate, with millimetre uncertainty, in 3D, an x-ray source emitting multiple X-rays in a cascade, employing conventional LaBr3(Ce) scintillation detectors, has been developed. Using 16 detectors in a symmetrical configuration the detector energy and time signals, resulting from the X-ray interactions, are fed into a new source position reconstruction algorithm. The Monte-Carlo based Geant4 framework has been used to simulate the detector array and a 60Co source located at two positions within the spectrometer central volume. For a source located at (0,0,0) the algorithm reports X, Y, Z values of -0.3 ± 2.5, -0.4 ± 2.4, and -0.6 ± 2.5 mm, respectively. For a source located at (20,20,20) mm, with respect to the array centre, the algorithm reports X, Y, Z values of 20.2 ± 1.0, 20.2 ± 0.9, and 20.1 ± 1.2 mm. The resulting precision of the reconstruction means that this technique could find application in a number of areas including nuclear medicine, national security, radioactive waste assay and proton beam therapy. Keywords: Gamma-ray spectroscopy; Reconstruction algorithm; Source emission position reconstruction.
    • Fulvestrant ("Faslodex"): clinical experience from the Compassionate Use Programme.

      Steger, Guenther G; Gips, Maya; Simon, Sergio D; Lluch, Ana; Vinholes, Jefferson; Kaufman, Bella; Wardley, Andrew M; Mauriac, Louis; Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, 18-20 Währinger Gürtel, A-1090 Vienna, Austria. guenther.steger@meduniwien.ac.at (2005)
      Fulvestrant ("Faslodex") is a new oestrogen receptor (ER) antagonist with no agonist effects that is licensed in the USA, Brazil, Europe and elsewhere for the treatment of advanced breast cancer (ABC) in postmenopausal women following progression on other endocrine agents. This report consolidates clinical experience from the "Faslodex" Compassionate Use Programme, including a total of 339 patients treated at eight cancer centres. Patients received fulvestrant as first- (n=22), second- (n=125), third- (n=105), fourth- (n=58), fifth- (n=22) or sixth-line (n=5) hormonal treatment for ABC, with two patients receiving fulvestrant after more than six other endocrine therapies. Objective response was achieved by 40 patients and stable disease lasting 6 months by 92 patients, giving overall clinical benefit (CB) in 132/339 patients (39%). The CB rate decreased as fulvestrant was used later in the sequence of endocrine treatments, from 46% (10/22) with first-line fulvestrant to 27% (6/22) with fifth-line fulvestrant. Increased benefit was found in patients with tumours expressing both ER and progesterone receptor (PgR) compared with other combinations, although good activity was reported in patients expressing either ER or PgR as well as in tumours expressing human epidermal growth factor receptor 2. Fulvestrant was well tolerated; adverse events were noted in 18/339 patients (5%). These findings concur with data from the clinical-trial setting and further support the assertion that greater benefit is derived when fulvestrant is used early in the treatment sequence.