Welcome to The Christie Research Publications Repository

The repository contains the research outputs from staff and students at The Christie NHS Foundation Trust and Cancer Research UK Manchester Institute.

Current Repository Content:

Over 7000 peer reviewed articles, reviews and selected publications from 1933 onwards.

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  • Risk of melanoma recurrence After diagnosis of a high-risk primary tumor

    von Schuckmann, LA; Hughes, MCB; Ghiasvand, R; Malt, M; van der Pols, JC; Beesley, VL; Khosrotehrani, K; Smithers, BM; Green, Adele C; Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia (2019)
    Importance: With emerging new systemic treatments for metastatic melanoma, early detection of disease recurrence is increasingly important. Objective: To investigate the risk of melanoma recurrence in patients with a localized melanoma at a high risk of metastasis. Design, Setting, and Participants: A total of 1254 patients with newly diagnosed, histologically confirmed tumor category T1b to T4b melanoma in Queensland, Australia, were recruited prospectively between October 1, 2010, and October 1, 2014, for participation in a cohort study. Data analysis was conducted from February 8, 2018, to February 20, 2019. We used Cox proportional hazards regression analysis to examine associations between patient and tumor factors and melanoma recurrence. Exposures: Disease-free survival (DFS) by melanoma tumor category defined by the 7th vs 8th editions of the AJCC Cancer Staging Manual (AJCC 7 vs AJCC 8). Main Outcomes and Measures: Melanoma recurrences were self-reported through follow-up questionnaires administered every 6 months and confirmed by histologic or imaging findings. Results: Of 1254 patients recruited, 825 individuals (65.8%) agreed to participate. Thirty-six were found to be ineligible after providing consent and a further 89 patients were excluded after reclassifying tumors using AJCC 8, leaving 700 participants with high-risk primary melanoma (mean [SD] age, 62.2 [13.5] years; 410 [58.6%] men). Independent predictors of recurrence were head or neck site of primary tumor, ulceration, thickness, and mitotic rate greater than 3/mm2 (hazard ratio, 2.36; 95% CI, 1.19-4.71). Ninety-four patients (13.4%) developed a recurrence within 2 years of diagnosis: 66 tumors (70.2%) were locoregional, and 28 tumors (29.8%) developed at distant sites. After surgery for locoregional disease, 37 of 64 patients (57.8%) remained disease free at 2 years, 7 patients (10.9%) developed new locoregional recurrence, and 20 patients (31.3%), developed distant disease. Two-year DFS was similar when comparing AJCC 7 and AJCC 8, for T1b (AJCC 7, 253 [93.3% DFS]; AJCC 8, 242 [93.0% DFS]) and T4b (AJCC 7 and AJCC 8, 50 [68.0% DFS] category tumors in both editions. Patients with T2a to T4a tumors who did not have a sentinel lymph node biopsy (SLNB) at diagnosis had lower DFS than patients with the same tumor category and a negative SLNB (T2a: 136 [91.1%; 95% CI, 86.4-95.9] vs 96 [96.9%; 95 % CI, 93.4-100.0]; T4a: 33 [78.8%; 95% CI, 64.8-92.7] vs 6 [83.3; 95% CI, 53.5-100.0]). Conclusions and Relevance: These findings suggest that 13.4% of patients with a high-risk primary melanoma will experience disease recurrence within 2 years. Head or neck location of initial tumor, SLNB positivity, and signs of rapid tumor growth may be associated with primary melanoma recurrence.
  • Histologic features associated with an invasive component in lentigo maligna lesions

    Moreno, A; Manrique-Silva, E; Viros, Amaya; Requena, C; Sanmartin, O; Traves, V; Nagore, E; School of Medicine, Universidad Catolica de Valencia San Vicente Martir, Valencia, Spain (2019)
    Importance: Lentigo maligna (LM) presents an invasive component in up to 20% of biopsied cases, but to date the histologic features useful in detecting this invasive component have not been described. Some histologic characteristics are hypothesized to contribute to the progression of LM invasion. Objective: To identify the histologic characteristics associated with lentigo maligna melanoma (LMM) in patients with LM diagnosed by a partial diagnostic biopsy. Design, Setting, and Participants: A retrospective cross-sectional study of patients treated between January 1, 2000, and December 31, 2017, was conducted in a referral oncology center in València, Spain. Data and specimens of patients (n?=?96) with a diagnosis of primary cutaneous melanoma in the form of either LM or LMM who had undergone surgical treatment, a complete histologic examination of the whole tumor, and an initial diagnostic partial biopsy of LM were included in the study. Histologic assessment was blinded to the presence of an invasive component. Interventions: All biopsy specimens were evaluated for the presence of certain histologic characteristics. Main Outcomes and Measures: Comparisons between invasive samples and samples without an invasive component were performed. The differences in the distribution of variables between the groups were assessed using the ?2 and Fisher exact tests, and the degree of association of the relevant variables was quantified by logistic regression models. A classification and regression tree analysis was performed to rank the variables by importance. Results: In total, 96 patients had sufficient histologic material that could be evaluated. The patients were predominantly male (56 [58.3%]) and had a mean (SD) age at diagnosis of 72 (12) years. Of these patients, 63 (65.6%) had an LM diagnosis and 33 (34.4%) had an LMM diagnosis (an invasive component). The histologic variables associated with the presence of an invasive component were melanocytes forming rows (odds ratio [OR], 11.5; 95% CI, 1.4-94.1; P?=?.02), subepidermal clefts (OR, 2.8; 95% CI, 1.0-7.9; P?=?.049), nests (OR, 3.0; 95% CI, 1.1-8.6; P?=?.04), and a lesser degree of solar elastosis (OR, 0.4; 95% CI, 0.1-1.1; P?=?.07). A classification and regression tree analysis of the relevant histologic features was able to accurately identify lentigo maligna with an invasive component (LMM) in more than 60% of patients. Conclusions and Relevance: These findings may be useful in classifying early LM specimens at higher risk of invasion, which may eventually be relevant in identifying the most appropriate management for LM.
  • Hypoxia and angiogenic biomarkers in prostate cancer after external beam radiotherapy (EBRT) alone or combined with high-dose-rate brachytherapy boost (HDR-BTb)

    Bhattacharya, IS; Taghavi, Azar SM; Alonzi, R; Hoskin, Peter J; Institute of Cancer Research Clinical Trials and Statistics Unit (ICR-CTSU), London, United Kingdom (2019)
    PURPOSE: To investigate angiogenic and hypoxia biomarkers to predict outcome in patients receiving external beam radiotherapy (EBRT) alone or combined with high-dose-rate brachytherapy boost (HDR-BTb) for localised prostate cancer. METHODS: Prostate biopsy samples were collected prospectively in patients entered into a phase 3 randomised controlled trial of patients receiving EBRT or EBRT?+?HDR-BTb. Univariate and multivariate analyses using Cox proportional hazards model were performed to identify associations between immunohistochemical staining of hypoxia inducible factor 1 alpha (HIF1?), glucose transporter 1 (GLUT1), osteopontin (OPN) and microvessel density (MVD) using CD-34 antibody with clinical outcome. The primary endpoint was biochemical relapse free survival (BRFS) and secondary endpoint was distant metastasis free survival (DMFS). RESULTS: Immunohistochemistry was available for 204 patients. Increased OPN (Hazard ratio [HR] 2.38, 95% Confidence Interval [CI] 1.06-5.34, p?<?0.036) and GLUT1 (HR 2.36, 95%CI 1.39-4.01, p?<?0.001) expression were predictive of worse BRFS. Increased GLUT1 expression (HR 2.22, 1.02-4.84, p?=?0.045) was predictive of worse DMFS. Increased MVD (CD-34) (HR 1.82, 95%CI 1.06-3.14, p?=?0.03) and OPN (HR 1.82, 95%CI 1.06-3.14, p?=?0.03) but reduced GLUT1 expression (HR 0.40, 95%CI 0.20-0.79, p?=?0.009) were predictive of improved BRFS in patients receiving EBRT?+?HDR-BTb. CONCLUSION: Our data suggest angiogenic and hypoxia biomarkers may predict outcome and benefit of dose escalation, however further validation in prospective studies including hypoxia modification is needed. Trial registration number ISRCTN98241100, registered with ISRCTN at http://www.controlled-trials.com/isrctn/.
  • Hypoxia-induced secretion stimulates breast cancer stem cell regulatory signalling pathways

    Jacobsson, H; Harrison, Hannah; Hughes, E; Persson, E; Rhost, S; Fitzpatrick, P; Gustafsson, A; Andersson, D; Gregersson, P; Magnusson, Y; Stahlberg, A; Landberg, Goran; Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Medicinaregatan 1F, 413 90, Gothenburg, Sweden (2019)
    It is well known that tumor cells are dependent on communication with the tumor microenvironment. Previously, it has been shown that hypoxia induces pronounced, diverse and direct effects on cancer stem cell (CSC) qualities in different breast cancer subtypes. Here, we describe the mechanism by which hypoxia-induced secretion influence CSC spreading. Conditioned media from estrogen receptor (ER)-? positive hypoxic breast cancer cell cultures increased the fraction of CSCs compared to normal growth conditions, as determined using sets of CSC assays and model systems. In contrast, media from ER?-negative hypoxic cell cultures instead decreased this key subpopulation of cancer cells. Further, there was a striking overrepresentation of JAK-STAT-associated cytokines in both the ER?-positive and ER?-negative linked hypoxic responses as determined by a protein screen of the conditioned media. JAK-STAT inhibitors and knockdown experiments further supported the hypothesis that this pathway is critical for the CSC activating and inactivating effects induced by hypoxic secretion. We also observed that the interleukin (IL)-6 -JAK2-STAT3 axis was specifically central for the ER?-negative hypoxic behaviour. Our results underline the importance of considering breast cancer subtypes in treatments targeting JAK-STAT or hypoxia-associated processes, and indicate that hypoxia is not only a confined tumor biological event, but also influences key tumor properties in widespread normoxic microenvironments. This article is protected by copyright. All rights reserved.
  • Optical coherence tomography to detect acute esophageal radiation-induced damage in mice: a validation study

    Jelvehgaran, P; de Bruin, DM; Khmelinskii, A; Borst, G; Steinberg, JD; Song, JY; de Vos, J; van Leeuwen, TG; Alderliesten, T; de Boer, JF; van Herk, Marcel; Department of Biomedical Engineering and Physics, Cancer Center Amsterdam, Amsterdam UMC (2019)
    Radiation therapy for patients with non-small-cell lung cancer is hampered by acute radiation-induced toxicity in the esophagus. This study aims to validate that optical coherence tomography (OCT), a minimally invasive imaging technique with high resolution (~10 ?m), is able to visualize and monitor acute radiation-induced esophageal damage (ARIED) in mice. We compare our findings with histopathology as the gold standard. Irradiated mice receive a single dose of 40 Gy at proximal and distal spots of the esophagus of 10.0 mm in diameter. We scan mice using OCT at two, three, and seven days post-irradiation. In OCT analysis we define ARIED as a presence of distorted esophageal layering, change in backscattering signal properties, or change in the esophageal wall thickness. The average esophageal wall thickness is 0.53 mm larger on OCT when ARIED is present based on histopathology. The overall sensitivity and specificity of OCT to detect ARIED compared to histopathology are 94 % and 47 %, respectively. However, the overall sensitivity of OCT to assess ARIED is 100% seven days post-irradiation. We validated the capability of OCT to detect ARIED induced by high doses in mice. Nevertheless, clinical studies are required to assess the potential role of OCT to visualize ARIED in humans. This article is protected by copyright. All rights reserved.

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