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Turney B.W.,Molecular Oncology Laboratories | Turner G.D.H.,Molecular Oncology Laboratories | Brewster S.F.,Molecular Oncology Laboratories | MacAulay V.M.,Cancer and Haematology Center | MacAulay V.M.,Weatherall Institute of Molecular Medicine
BJU International | Year: 2011

What's known on the subject? and What does the study add? In a previous study of diagnostic prostate biopsies, we showed that the insulin-like growth factor (IGF) receptor is up-regulated in primary prostate cancers. In this study we identified prostate cancer cases in which multiple transurethral resections had been performed, and showed that IGF receptor expression increased or remained high with disease progression. Thus, the IGF receptor is an attractive therapeutic target for patients with advanced prostate cancer. Objective: To compare immunostaining protocols using different antibodies for the type 1 insulin-like growth factor receptor (IGF-1R) in channel transurethal resection of the prostate (chTURP) chips, and to investigate how IGF-1R expression varies with time in serial prostate cancer specimens from individual patients. METHODS We studied IGF-1R expression in 44 prostate cancer specimens from 18 patients who had undergone serial chTURP at least 3 months apart. Retrospective analysis of the hospital notes was undertaken to obtain clinical information, including age, Gleason score, prostate-specific antigen (PSA) level, hormone treatment and metastatic disease status at the time of each operation. After an optimization process using three commercially-available IGF-1R antibodies, we used two antibodies for semiquantititve immunostaining of serial chTURP chips. Results: Santa Cruz antibody sc713 gave positive staining in IGF-1R null R- cells, and was not used further. Antibodies from Cell Signaling Technology (Beverly, MA, USA) (CS) and NeoMarkers Inc. (Fremont, CA, USA) (NM) did not stain R- cells and, in prostate tissue, showed staining of the glandular epithelium, with negligible stromal staining. All 44 chTURP samples contained identifiable malignant tissue and, of these, 73% and 64% scored moderately or strongly (score 3 or 4) with the CS and NM antibodies respectively. There was significant correlation of IGF-1R scores of malignant tissue between the two antibodies (P < 0.001). By contrast, staining of benign glands showed poor correlation between antibodies: CS gave significantly weaker staining than malignant epithelium in the same sections (P < 0.001), whereas NM showed poor discrimination between malignant and benign glands. IGF-1R staining scores generated by the CS antibody were used to analyze the clinical data. Most patients (six of seven) with falling IGF-1R staining scores were responding to androgen deprivation therapy (confirmed by PSA response) between operations. Conversely, in seven of eight patients who had progression to androgen-independence between procedures, IGF-1R levels increased or remained high. Finally, seven of 11 patients who developed radiologically confirmed metastases between procedures showed stable or increasing IGF-1R staining scores. Conclusion: The present study is the first to assess changes in IGF-1R expression in serial prostate cancer samples. The results obtained indicate that IGF-1R expression usually remains high throughout the course of histologically-proven disease progression in serial specimens, suggesting that the IGF-1R remains a valid treatment target for advanced prostate cancer. © 2010 BJU International.

Chitnis M.M.,Weatherall Institute of Molecular Medicine | Lodhia K.A.,Weatherall Institute of Molecular Medicine | Aleksic T.,Weatherall Institute of Molecular Medicine | Gao S.,Weatherall Institute of Molecular Medicine | And 2 more authors.
Oncogene | Year: 2013

Inhibition of type 1 insulin-like growth factor receptor (IGF-1R) enhances tumor cell sensitivity to ionizing radiation. It is not clear how this effect is mediated, nor whether this approach can be applied effectively in the clinic. We previously showed that IGF-1R depletion delays repair of radiation-induced DNA double-strand breaks (DSBs), unlikely to be explained entirely by reduction in homologous recombination (HR) repair. The current study tested the hypothesis that IGF-1R inhibition induces a repair defect that involves non-homologous end joining (NHEJ). IGF-1R inhibitor AZ12253801 blocked cell survival and radiosensitized IGF-1R-overexpressing murine fibroblasts but not isogenic IGF-1R-null cells, supporting specificity for IGF-1R. IGF-1R inhibition enhanced radiosensitivity in DU145, PC3 and 22Rv1 prostate cancer cells, comparable to effects of Ataxia Telangiectasia Mutated inhibition. AZ12253801-treated DU145 cells showed delayed resolution of γH2AX foci, apparent within 1 h of irradiation and persisting for 24 h. In contrast, IGF-1R inhibition did not influence radiosensitivity or γH2AX focus resolution in LNCaP-LN3 cells, suggesting that radiosensitization tracks with the ability of IGF-1R to influence DSB repair. To differentiate effects on repair from growth and cell-survival responses, we tested AZ12253801 in DU145 cells at sub-SF50 concentrations that had no early (≤48 h) effects on cell cycle distribution or apoptosis induction. Irradiated cultures contained abnormal mitoses, and after 5 days IGF-1R-inhibited cells showed enhanced radiation-induced polyploidy and nuclear fragmentation, consistent with the consequences of entry into mitosis with incompletely repaired DNA. AZ12253801 radiosensitized DNA-dependent protein kinase (DNA-PK)-proficient but not DNA-PK-deficient glioblastoma cells, and did not radiosensitize DNA-PK-inhibited DU145 cells, suggesting that in the context of DSB repair, IGF-1R functions in the same pathway as DNA-PK. Finally, IGF-1R inhibition attenuated repair by both NHEJ and HR in HEK293 reporter assays. These data indicate that IGF-1R influences DSB repair by both major DSB repair pathways, findings that may inform clinical application of this approach.Oncogene advance online publication, 4 November 2013; doi:10.1038/onc.2013.460.

Medd P.,Center for Clinical Haematology | Medd P.,Cancer and Haematology Center | Nagra S.,Center for Clinical Haematology | Hollyman D.,Birmingham Center | And 2 more authors.
Bone Marrow Transplantation | Year: 2013

Cryopreservation of PBSC for allo-SCT offers potential advantages; however, its impact on engraftment and outcomes remains unclear. A total of 76 allo-SCT performed using cryopreserved PBSC from HLA identical related (n=57) and unrelated donors (n=19) were compared with 123 fresh PBSC allo-SCT. Median neutrophil engraftment was on day 12 for both cryopreserved and fresh PBSC; in multivariate analysis, there was a slight but significant delay in neutrophil engraftment after the median date (hazard ratio (HR)=1.44, P=0.003). Platelet engraftment was significantly delayed in cryopreserved PBSC recipients (median time 19 vs 14 days). In multivariate analysis cryopreservation (HR=1.85, P<0.001), earlier date of transplant and lower CD34 + cell dose were associated with delayed platelet engraftment. Two-year OS and relapse and 1-year TRM rates did not differ significantly. Acute GVHD incidence was comparable, and extensive chronic GVHD at 1 year was higher in cryopreserved PBSC recipients (40.3 vs 28.3%), but not significantly so (P=0.13). Cryopreservation of related and unrelated donor allogeneic PBSC is safe and effective where its benefits outweigh the risks of delayed platelet engraftment; its impact on chronic GVHD incidence requires further assessment. © 2013 Macmillan Publishers Limited All rights reserved.

Clarke R.T.,John Radcliffe Hospital | Warnick J.,John Radcliffe Hospital | Stretton K.,John Radcliffe Hospital | Littlewood T.J.,Cancer and Haematology Center
British Journal of Haematology | Year: 2011

Recent disquiet at inadequacies in the immediate management of neutropenic sepsis in the UK led to a new, gold standard 'door-to-needle' time of 1h for the administration of intravenous antibiotics. The aim of this audit was to identify whether that target is being met nationally, the potential barriers to its achievement, and concrete recommendations for how to overcome these. We also sought to establish the degree of regional heterogeneity in current local management protocols. Questionnaires were sent to haematologists across the UK to determine their unit's immediate management of patients presenting from the community with possible neutropenic sepsis. Local protocols and audits were also requested. Data covering 95 different hospitals were received, covering a combined catchment area of nearly 30million people. There were marked regional inconsistencies in the definition of 'neutropenic sepsis' and almost every aspect of its immediate management. Only 26% of audited patients (n=627) received intravenous antibiotics within the target time of 1h. Median door-to-needle times ranged from 30min to 4h. Long delays of over 5h were not uncommon. © 2011 Blackwell Publishing Ltd.

Clarke R.T.,Cancer and Haematology Center | Bird S.,Middlesex University | Kakuchi I.,University of Oxford | Littlewood T.J.,Cancer and Haematology Center | van Hamel Parsons V.,Kings College Hospital Nhs Foundation Trust
Supportive Care in Cancer | Year: 2015

Purpose: Neutropenic sepsis (NS) is a medical emergency in which urgent treatment with antibiotics is known to improve outcomes, yet there are minimal data about what happens to patients with NS before they reach hospital. We aimed to examine the pre-hospital experiences of patients with NS, identifying its early presenting features and exploring the factors potentially delaying patients’ arrival at hospital. Methods: We conducted in-depth, qualitative interviews with 22 cancer patients admitted to hospital for treatment of NS and 10 patient carers. The setting was a tertiary referral centre in Southern England. Results: Thirty seven percent of patients took over 12 h to present to hospital after symptom onset. The mean delay in presentation was 11 h (range 0–68 h). Thematic analysis of the interviews, using grounded theory, revealed wide-ranging, potentially modifiable factors delaying patients’ presentation to hospital. For example, information provided to patients about NS from different sources was inconsistent, with ‘mixed messages’ about urgency triggering delays. All patients self-monitored their temperature and understood the implication of a fever but few appreciated the potential significance of feeling unwell in the absence of fever. Attempts to obtain treatment were sometimes thwarted by nonspecialists’ failure to recognise possible neutropenia in a patient with apparently mild signs, and several patients with NS were discharged without treatment. Some patients denied their symptoms to themselves and others to avoid hospital admission; palliative patients seemed particularly prone to these attitudes, while their carers were keen to seek medical attention. Conclusions: This investigation of patients’ and carers’ experiences of NS identifies numerous strategies for improving patient education, support and pre-hospital management, all of which may reduce pre-hospital delays and consequently decrease morbidity and mortality from NS. © 2015, Springer-Verlag Berlin Heidelberg.

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