• No evidence of significant silencing of Fanconi genes FANCF and FANCB or Nijmegen breakage syndrome gene NBS1 by DNA hyper-methylation in sporadic childhood leukaemia.

      Meyer, Stefan; White, Daniel J; Will, Andrew M; Eden, Tim O B; Sim, Alyson; Brown, Robert; Strathdee, Gordon; Department of Paediatric Haematology and Oncology, Central Manchester and Manchester Children's University Hospitals NHS Trust, Manchester, UK. stefan.meyer-2@manchester.ac.uk (2006-07)
      Fanconi anaemia (FA) and Nijmegen breakage syndrome (NBS) carry a high risk of haematological cancer. Affected cellular pathways may be modulated in sporadic malignancies and silencing of FANCF through methylation has been shown to cause somatic disruption of the FA pathway. Combined bisulphite restriction analysis for methylation of FANCF, FANCB and NBS1 was used to investigate 81 sporadic acute childhood leukaemias. No methylation was detected at any associated CpG sites analysed. This does not exclude very low levels of FANCF, FANCB or NBS1 methylation, but suggests other factors are responsible for chemo-sensitivity and chromosomal instability in sporadic childhood leukaemia.
    • No longer an untreatable disease: How targeted and immunotherapies have changed the management of melanoma patients.

      Girotti, Maria Romina; Saturno, Grazia; Lorigan, Paul C; Marais, Richard; Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester, UK. (2014-09-12)
      The discovery that BRAF is a driver oncogene in cancer, and complementary improvements in our understanding of the immune system have resulted in new targeted and immune-therapies for metastatic melanoma. Targeted therapies achieve impressive clinical results in carefully selected patients but the development of resistance seems inevitable in most cases. Conversely, immune-checkpoints inhibitors can achieve long-term remission and cures, but in a smaller proportion of patients, and biomarkers to predict which patients will respond are not available. Nevertheless, melanoma has led the evolution of cancer treatment from relatively nonspecific cytotoxic agents to highly selective therapies and here we review the lessons from this paradigm shift in treatment and the opportunities for further improvements in outcomes for melanoma patients.
    • No mutation at codon 918 of the RET gene in a family with multiple endocrine neoplasia type 2B.

      Toogood, Andy; Eng, C; Smith, D P; Ponder, B A; Shalet, Stephen M; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK. (1995-12)
      Multiple endocrine neoplasia type 2B (MEN 2B) is a rare cancer syndrome which is inherited in an autosomal dominant manner. The molecular basis of this condition has recently been defined as a mutation of codon 918 of exon 16 of the RET proto-oncogene. The mutation in codon 918 has been described in 69 out of 72 families with MEN 2B. We have studied a brother and sister who undoubtedly have the features of MEN 2B as evidenced by medullary thyroid carcinoma, phaeochromocytoma, mucosal neuromas and skeletal abnormalities. Neither of these patients has the classic gene mutation at codon 918 of exon 16 of the RET proto-oncogene, and although exons 2-20 have also been sequenced, no abnormality has been found. DNA analysis is a sensitive method of screening families for the MEN 2 syndromes. The absence of the mutation at codon 918 in a phenotypically normal individual would refute the diagnosis of MEN 2B, but in an individual with some of the features of MEN 2B would make the clinician reconsider the diagnosis. This family demonstrates that, although it is rare, the absence of the mutation in codon 918 of exon 16 of the RET proto-oncogene does not always exclude the diagnosis of MEN 2B. In such families routine biochemical screening for medullary thyroid carcinoma and phaeochromocytoma must be maintained for all individuals at genetic risk.
    • No relationship between 18F-fluorodeoxyglucose positron emission tomography and expression of Glut-1 and -3 and hexokinase I and II in high-grade glioma.

      Charnley, Natalie; Airley, R; Du Plessis, D; West, Catharine M L; Brock, Cathryn S; Barnett, C; Matthews, Julian C; Symonds, Kirsten; Bottomly, M; Swindell, Ric; et al. (2008-09)
      The purpose of this study was to compare glucose metabolism, measured using 18F-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET), with the expression of Glut-1 and -3 and hexokinase I (Hex I) and II in high-grade glioma. The retrospective study involved 27 patients with WHO classification grade III and IV glioma, with either newly diagnosed or recurrent tumours. Patients underwent dynamic and static [18F]FDG-PET to glucose metabolic rate (MRGlu) and standardised uptake value (SUV), respectively. Tumour biopsies were obtained and stained using immunohistochemistry for the expression of Glut-1, -3, Hex I and II. Relationships between variables were studied using Spearman's rank correlation test. Results showed that the expression of Glut-1, Glut-3, Hex I and Hex II varied between and within the tumour samples. The mean of MRGlu was 0.2 (range 0.09-0.25) micromol/min/ml and that of SUV was 4.2 (range 3.2-5.2). There were no significant relationships among the tumour expression of any of the proteins studied with either MRGlu or SUV (p>0.21 for all). In conclusion, the lack of relationship between the immunohistochemical expression of Glut-1, -3, Hex I or II and glucose metabolism measured using [18F]FDG-PET in patients with high-grade glioma may be due to the tissue heterogeneity and presence of necrosis in high-grade tumours.
    • No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix.

      Kabuubi, Paul; Loncaster, Juliette A; Davidson, Susan E; Hunter, Robin D; Kobylecki, Christopher; Stratford, Ian J; West, Catharine M L; Academic Department of Radiation Oncology, The University of Manchester, Christie Hospital NHS Trust, Manchester M20 4BX, UK. (2006-01-16)
      The expression of hypoxia-regulated genes promotes an aggressive tumour phenotype and is associated with an adverse cancer treatment outcome. Thymidine phosphorylase (TP) levels increase under hypoxia, but the protein has not been studied in association with hypoxia in human tumours. An investigation was made, therefore, of the relationship of tumour TP with hypoxia, the expression of other hypoxia-associated markers and clinical outcome. This retrospective study was carried out in patients with locally advanced cervical carcinoma who underwent radiotherapy. Protein expression was evaluated with immunohistochemistry. Hypoxia was measured using microelectrodes and the level of pimonidazole binding. There was no relationship of TP expression with tumour pO(2) (r=-0.091, P=0.59, n=87) or pimonidazole binding (r=0.13, P=0.45, n=38). There was no relationship between TP and HIF-1alpha, but there was a weak borderline significant relationship with HIF-2alpha expression. There were weak but significant correlations of TP with the expression of VEGF, CA IX and Glut-1. In 119 patients, the presence of TP expression predicted for disease-specific (P=0.032) and metastasis-free (P=0.050) survival. The results suggest that TP is not a surrogate marker of hypoxia, but is linked to the expression of hypoxia-associated genes and has weak prognostic power.
    • No strong evidence for increased risk of breast cancer 8-26 years after multiple mammograms in their 30s in females at moderate and high familial risk.

      Evans, D Gareth R; Kotre, C John; Harkness, E; Wilson, M; Maxwell, A; Howell, Anthony; Genesis Prevention Centre and Nightingale Breast Screening Centre, University Hospital of South Manchester, Wythenshawe, Manchester, UK (2016-03)
      To assess the risks of induction of breast tumours from frequent screening mammography in younger females.
    • No study left behind: a network meta-analysis in non-small-cell lung cancer demonstrating the importance of considering all relevant data.

      Hawkins, Neil; Scott, David A; Woods, Beth S; Thatcher, Nick; Oxford Outcomes Ltd., Oxford, UK. neil.hawkins@oxfordoutcomes.com (2009-09)
      OBJECTIVE: To demonstrate the importance of considering all relevant indirect data in a network meta-analysis of treatments for non-small-cell lung cancer (NSCLC). METHODS: A recent National Institute for Health and Clinical Excellence appraisal focussed on the indirect comparison of docetaxel with erlotinib in second-line treatment of NSCLC based on trials including a common comparator. We compared the results of this analysis to a network meta-analysis including other trials that formed a network of evidence. We also examined the importance of allowing for the correlations between the estimated treatment effects that can arise when analysing such networks. RESULTS: The analysis of the restricted network including only trials of docetaxel and erlotinib linked via the common placebo comparator produced an estimated mean hazard ratio (HR) for erlotinib compared with docetaxel of 1.55 (95% confidence interval [CI] 0.72-2.97). In contrast, the network meta-analysis produced an estimated HR for erlotinib compared with docetaxel of 0.83 (95% CI 0.65-1.06). Analyzing the wider network improved the precision of estimated treatment effects, altered their rankings and also allowed further treatments to be compared. Some of the estimated treatment effects from the wider network were highly correlated. CONCLUSIONS: This empirical example shows the importance of considering all potentially relevant data when comparing treatments. Care should therefore be taken to consider all relevant information, including correlations induced by the network of trial data, when comparing treatments.
    • No useful role for fine needle aspiration as a marker for familial breast cancer.

      Teraifi, Hassan E; Evans, D Gareth R; Mohammad, Z; Howell, Anthony; Department of Cytology, Christie Hospital, Manchester, UK. (2000-08)
      A study of a single fine needle aspiration taken from the upper outer quadrant of 228 asymptomatic women attending a family history clinic has been performed. No abnormalities were detected. This is not a useful screening tool in asymptomatic women at risk of breast cancer.
    • Nodal stage migration and prognosis in anal cancer: a systematic review, meta-regression, and simulation study.

      Sekhar, Hema; Zwahlen, M; Trelle, S; Malcomson, Lee; Kochhar, Rohit; Saunders, Mark P; Sperrin, M; van Herk, Marcel; Sebag-Montefiore, D; Egger, M; et al. (2017-08-09)
      In patients with squamous cell carcinoma of the anus (SCCA), lymph node positivity (LNP) indicates poor prognosis for survival and is central to radiotherapy planning. Over the past three decades, LNP proportion has increased, mainly reflecting enhanced detection with newer imaging modalities; a process known as nodal stage migration. If accompanied by constant T stage distributions, prognosis for both lymph node-positive and lymph node-negative groups may improve without any increase in overall survival for individual patients; a paradox termed the Will Rogers phenomenon. Here, we aim to systematically evaluate the impact of nodal stage migration on survival in SCCA and address a novel hypothesis that this phenomenon results in reduced prognostic discrimination.
    • Nodular basal cell carcinoma in Gorlin's syndrome treated with systemic photodynamic therapy and interstitial optical fiber diffuser laser.

      Madan, Vishal; Loncaster, Juliette A; Allan, Donald; Lear, John T; Sheridan, Linda; Leach, Catherine; Allan, Ernest; Dermatology Centre, Hope Hospital, Salford, Manchester, M6 8HD, UK. (2006-11)
      Nodular basal cell carcinomas resistant to multiple forms of treatment in two patients with nevoid basal cell carcinoma syndrome (Gorlin's syndrome) were treated with systemic porfimer sodium-based photodynamic therapy. Interstitially placed optical diffuser fibers were used to deliver light. Good response to treatment was seen on clinical evaluation and on measurement by a 20-MHz high-resolution ultrasound.
    • Nodular erythema elevatum diutinum mimicking cutaneous neoplasms.

      Shanks, Jonathan H; Banerjee, Saumitra S; Bishop, P W; Pearson, J M; Eyden, Brian P; Department of Histopathology, Christie Hospital NHS Trust, UK. (1997-07)
      AIMS: We describe the cutaneous pseudoneoplastic lesions in two patients with nodular erythema elevatum diutinum, a rare chronic disorder in which polymorph nuclear fragmentation (leukocytoclasis) is present within dermal nodules showing spindle cells and fibrosis. In both cases diagnostic difficulty was encountered clinically and pathologically and various benign and malignant neoplasms were considered in the differential diagnosis. METHODS AND RESULTS: Immunohistochemically the spindle cells were negative for CAM5.2, AE1/3, S100 protein and desmin (D33). They were positive for vimentin and focally positive for CD34 and alpha-smooth muscle actin. Some of the spindle cells were positive for Mac 387 and KP1(CD68). By electron microscopy, the lesions were shown to consist of fibroblasts/myofibroblasts and fusiform macrophages. CONCLUSIONS: Increased awareness of the features described will help to avoid misdiagnosis as a neoplastic process.
    • Nodular fasciitis of the head and neck.

      Silva, Priyamal; Bruce, Iain A; Malik, Tass; Homer, Jarrod J; Banerjee, Saumitra S; Department of Head and Neck Surgery, Christie Hospital, Manchester M20 4BX, UK. Priyamal.Silva@Christie-tr.nwest.nhs.uk (2005-01)
      Nodular fasciitis is an unusual benign reactive process affecting superficial and deep fascia. Its rapid growth, rich cellularity, high mitotic activity and poorly circumscribed nature result in it being easily misdiagnosed as a sarcomatous lesion. Three cases of nodular fasciitis presenting as neck lumps are reported. They were successfully treated with local excision, with no signs of recurrence following two years of follow up. This paper describes the clinical presentation and microscopic features of this rare benign lesion and it emphasizes the need for accurate histopathology and clinical suspicion, if inappropriate aggressive management is to be avoided.
    • Noise and contrast detection in computed tomography images.

      Faulkner, K; Moores, B M; Regional Department of Medical Physics and Bioengineering, Christie Hospital and holt Radium Institute, Withington, Manchester M20 9BX, England (1984-04)
      A discrete representation of the reconstruction process is used in an analysis of noise in computed tomography (CT) images. This model is consistent with the method of data collection in actual machines. An expression is derived which predicts the variance on the measured linear attenuation coefficient of a single pixel in an image. The dependence of the variance on various CT scanner design parameters such as pixel size, slice width, scan time, number of detectors, etc., is then described. The variation of noise with sampling area is theoretically explained. These predictions are in good agreement with a set of experimental measurements made on a range of CT scanners. The equivalent sampling aperture of the CT process is determined and the effect of the reconstruction filter on the variance of the linear attenuation coefficient is also noted, in particular, the choice and its consequences for reconstructed images and noise behaviour. The theory has been extended to include contrast detail behaviour, and these predictions compare favourably with experimental measurements. The theory predicts that image smoothing will have little effect on the contrast-detail detectability behaviour of reconstructed images.
    • Noise transfer in screen-film subtraction radiography.

      Shaw, A; Moores, B M; Regional Department of Medical Physics and Bioengineering, CHristie Hospital and Holt Radium Institute, Withington, Manchester M20 9BX, England (1985-03)
      The transfer of noise through the stages of a screen-film subtraction process was investigated. In particular the effect of measuring aperture size and film density on the measured noise granularity was studied. The relative contributions of quantum noise and film grain noise were found to depend on both aperture and density. Noise measurements are presented for a medium speed screen-film combination and also for a low noise alpha 16-Kodak Industrex C system. The effect of grain mottle and film blur on noise transfer through the multiple print process employed in subtraction radiography is demonstrated.
    • Non-bacterial thrombotic endocarditis in pancreatic cancer and other high-risk malignancies: the case for prophylactic treatment

      Spurgeon, Laura; Ispoglou, S.; The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK (2021)
    • Non-conventional therapies in childhood cancer: guidelines for distinguishing non-harmful from harmful therapies: a report of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology.

      Jankovic, Momcilo; Spinetta, John J; Martins, Antonio Gentil; Pession, Andrea; Sullivan, Michael; D'Angio, Giulio J; Eden, Tim O B; Ben Arush, Myriam Weyl; X, Sutaryo; Punkko, Leena-Riitta; et al. (2004-01)
      This is the 11th official document of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology, instituted in 1991. There is a tendency for some physicians to make blanket statements against the use of non-proven, non-conventional therapies, even when these therapies are not harmful. There is an equal and opposite tendency on the part of many parents to do all that they possibly can for their children, including using any non-conventional therapy they feel might do some good. The health care team must open a healthy dialogue with parents that will lead to a clear distinction between those complementary therapies that are harmful and those that are not, indeed, might even be helpful psychologically if not therapeutically.
    • Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

      Tesileanu, C. M. S.; Vallentgoed, W. R.; Sanson, M.; Taal, W.; Clement, P. M.; Wick, W.; Brandes, A. A.; Baurain, J. F.; Chinot, O. L.; Wheeler, H.; et al. (2021)
      Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.
    • Non-invasive pulsed ultrasound quantification of the resolution of basal cell carcinomas after photodynamic therapy.

      Allan, Ernest; Pye, David A; Levine, Edward; Moore, James V; Dept of Clinical Oncology, Christie Hospital, Manchester, UK. (2002)
      The probability of local control of basal cell carcinomas (BCC) treated by photodynamic therapy (PDT) depends strongly on lesion thickness, thicker lesions often requiring two treatments. We examine the utility of 20 MHz pulsed ultrasound (US) for the non-invasive measurement of thickness and rate of regression after PDT treatment. PDT was by topically applied 20% aminolaevulinic acid, followed at 6 h by a standard 100 J/cm(2) of 630 nm light. Patients ( n=60) were selected as being difficult to treat with existing modalities for reasons of likely poor quality of healing or of cosmesis in this very largely elderly population. Ultrasound 'A' scans were made immediately before treatment, and at first and subsequent follow-ups. Parameters measured non-invasively for BCC, adjacent normal skin, and for fibroses after previous conventional therapies, were (a) thickness of skin or lesion, (b) linear density of ultrasound echoes and (c) linear density of high-amplitude echoes. Prior to treatment, median skin thickness (to the dermal/subcutaneous boundary) was 2.6 mm (range 1.2-5.7), fibroses 2.5 mm (1.4-5.6) and BCC 1.5 mm (0.5-4.4). Median linear density of echoes for normal skin, fibroses and BCC plus underlying tissue were 5.6, 5.5 and 4.5, respectively, the BCC values being significantly lower ( p=0.002). The corresponding medians for high-amplitude echoes were 1.9, 1.9 and 1.1 (skin or fibrosis versus BCC, p=0.001). Patients whose BCCs appeared clinically to be controlled at up to 220 days after a single treatment, all had values of ultrasound parameters corresponding to skin/fibrosis and were significantly different from measurements on the same site prior to treatment. Patients whose tumours appeared to be reverting to the original BCC ultrasound pattern were subsequently found to be recurring as judged clinically. Non-invasive pulsed ultrasound indicates that rates of resolution vary widely between BCC of similar initial thickness and that the probability of clearance of BCC by PDT is determined largely by the deepest, sometimes small, regions within a lesion, with the overall area being relatively unimportant.
    • Non-linear registration improves statistical power to detect hippocampal atrophy in aging and dementia

      Bartel, F; Visser, M; de Ruiter, M; Belderbos, J; Barkhof, F; Vrenken, H; de Munck, J; van Herk, Marcel; Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands (2019)
      OBJECTIVE: To compare the performance of different methods for determining hippocampal atrophy rates using longitudinal MRI scans in aging and Alzheimer's disease (AD). BACKGROUND: Quantifying hippocampal atrophy caused by neurodegenerative diseases is important to follow the course of the disease. In dementia, the efficacy of new therapies can be partially assessed by measuring their effect on hippocampal atrophy. In radiotherapy, the quantification of radiation-induced hippocampal volume loss is of interest to quantify radiation damage. We evaluated plausibility, reproducibility and sensitivity of eight commonly used methods to determine hippocampal atrophy rates using test-retest scans. MATERIALS AND METHODS: Manual, FSL-FIRST, FreeSurfer, multi-atlas segmentation (MALF) and non-linear registration methods (Elastix, NiftyReg, ANTs and MIRTK) were used to determine hippocampal atrophy rates on longitudinal T1-weighted MRI from the ADNI database. Appropriate parameters for the non-linear registration methods were determined using a small training dataset (N?=?16) in which two-year hippocampal atrophy was measured using test-retest scans of 8 subjects with low and 8 subjects with high atrophy rates. On a larger dataset of 20 controls, 40 mild cognitive impairment (MCI) and 20? AD patients, one-year hippocampal atrophy rates were measured. A repeated measures ANOVA analysis was performed to determine differences between controls, MCI and AD patients. For each method we calculated effect sizes and the required sample sizes to detect one-year volume change between controls and MCI (NCTRL_MCI) and between controls and AD (NCTRL_AD). Finally, reproducibility of hippocampal atrophy rates was assessed using within-session rescans and expressed as an average distance measure DAve, which expresses the difference in atrophy rate, averaged over all subjects. The same DAve was used to determine the agreement between different methods. RESULTS: Except for MALF, all methods detected a significant group difference between CTRL and AD, but none could find a significant difference between the CTRL and MCI. FreeSurfer and MIRTK required the lowest sample sizes (FreeSurfer: NCTRL_MCI?=?115, NCTRL_AD?=?17 with DAve?=?3.26%; MIRTK: NCTRL_MCI?=?97, NCTRL_AD?=?11 with DAve?=?3.76%), while ANTs was most reproducible (NCTRL_MCI?=?162, NCTRL_AD?=?37 with DAve?=?1.06%), followed by Elastix (NCTRL_MCI?=?226, NCTRL_AD?=?15 with DAve?=?1.78%) and NiftyReg (NCTRL_MCI?=?193, NCTRL_AD?=?14 with DAve?=?2.11%). Manually measured hippocampal atrophy rates required largest sample sizes to detect volume change and were poorly reproduced (NCTRL_MCI?=?452, NCTRL_AD?=?87 with DAve?=?12.39%). Atrophy rates of non-linear registration methods also agreed best with each other. DISCUSSION AND CONCLUSION: Non-linear registration methods were most consistent in determining hippocampal atrophy and because of their better reproducibility, methods, such as ANTs, Elastix and NiftyReg, are preferred for determining hippocampal atrophy rates on longitudinal MRI. Since performances of non-linear registration methods are well comparable, the preferred method would mostly depend on computational efficiency.
    • Non-linearity in the cost-effectiveness frontier.

      Lord, Joanne; Laking, George R; Fischer, Alastair; National Institute for Health and Clinical Excellence (NICE), London, UK. joanne.lord@nice.org.uk (2006-06)
      Conventional cost-effectiveness decision rules rely on the assumptions that all health care programmes are divisible and exhibit constant returns to scale for a homogeneous population; hence, the path between adjacent programmes on a cost-effectiveness frontier must be linear. In this paper we build a framework to analyse non-linear 'expansion' paths. We model the impact of two key sources of non-linearity: economies of scale or scope in the production of health care; and prioritisation of patients who are most likely to benefit from more expensive and more effective treatments. We conclude that the expansion path might be linear, convex or concave, depending on the situation. The path might also exhibit vertical discontinuity due to fixed costs or horizontal discontinuity due to indivisibility. The efficiency of resource allocation might be improved by empirical estimation of expansion paths. We discuss the advantages and disadvantages of this approach compared with a standard stratified analysis.