Blakeley J.O.,Johns Hopkins University |
Evans D.G.,University of Manchester |
Adler J.,Stanford University |
Brackmann D.,House Research Institute |
And 20 more authors.
American Journal of Medical Genetics, Part A | Year: 2012
Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome characterized by bilateral vestibular schwannomas (VS) which often result in deafness despite aggressive management. Meningiomas, ependymomas, and other cranial nerve and peripheral schwannomas are also commonly found in NF2 and collectively lead to major neurologic morbidity and mortality. Traditionally, the overall survival rate in patients with NF2 is estimated to be 38% at 20 years from diagnosis. Hence, there is a desperate need for new, effective therapies. Recent progress in understanding the molecular basis of NF2 related tumors has aided in the identification of potential therapeutic targets and emerging clinical therapies. In June 2010, representatives of the international NF2 research and clinical community convened under the leadership of Drs. D. Gareth Evans (University of Manchester) and Marco Giovannini (House Research Institute) to review the state of NF2 treatment and clinical trials. This manuscript summarizes the expert opinions about current treatments for NF2 associated tumors and recommendations for advancing therapies emerging from that meeting. The development of effective therapies for NF2 associated tumors has the potential for significant clinical advancement not only for patients with NF2 but for thousands of neuro-oncology patients afflicted with these tumors. © 2011 Wiley Periodicals, Inc.
Becker A.,University of Munster |
Hokamp N.G.,University of Munster |
Zenker S.,University of Munster |
Flores-Borja F.,King's College London |
And 14 more authors.
Journal of Nuclear Medicine | Year: 2015
Tumors recruit and reprogram immune cells to support tumor development and spread, the most prominent among them being of monocytic origin such as tumor-associated macrophages (TAM) or myeloid-derived suppressor cells (MDSC). The alarmin S100A8/A9 has been implicated in the induction of TAM and MDSC. We assessed S100A9 as a molecular imaging marker for the activity of tumor-associated immune cells in a syngeneic murine breast cancer model. S100A9 could serve as a surrogate marker for tumor immune crosstalk as a function of malignancy, providing a tool with the potential for both basic research in tumor immunology and clinical stratification of patients. Methods: BALB/c mice were inoculated with murine breast cancer cells of common origin but different metastatic capability. At different times during tumor development, optical imaging was performed using a S100A9-specific probe to visualize activated monocytes. To further explore the impact of tumor-educated monocytes, splenic myeloid cells were isolated from either healthy or tumor-bearing animals and injected into tumor-bearing mice. We analyzed the effect of the cell transfer on immune cell activity and tumor development. Results: We could prove S100A9-driven imaging to sensitively and specifically reflect monocyte activity in primary tumor lesions. The imaging results were corroborated by histology and fluorescence-activated cell sorting analyses. In a prospective experiment, S100A9 imaging proved indicative of the individual tumor growth, with excellent correlation.Moreover, we could show that the monocyte activity as depicted by S100A9 activity in the primary tumor lesion mirrored the tumor's metastatic behavior. Treatment with tumor-primed splenic monocytes induced increased tumor growth, accompanied by an augmented infiltration of activated myeloid cells (MDSC and TAM) into the tumor. The consecutive S100A9 expression as depicted by in vivo imaging was significantly increased. Conclusion: S100A9 proved to be a sensitive and specific marker for the activity of tumor-associated immune cells. To our knowledge, S100A9 imaging represents a first in vivo imaging approach for the estimation of recruitment and activity of tumor-associated myeloid immune cells. We demonstrated the potential value of this imaging approach for prediction of local and systemic tumor development. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
Thurtle N.,Guys and St Thomas NHS Hospital Trust |
Banks C.,Townsville Hospital |
Banks C.,James Cook University |
Cox M.,University of Botswana |
And 4 more authors.
African Journal of Emergency Medicine | Year: 2016
Introduction. Free Open Access Medical Education encompasses a broad array of free online resources and discussion fora. The aim of this paper was to describe whether Emergency Medicine trainees in different contexts know about Free Open Access Medical Education, whether or not they know about its different platforms, which ones they use, and what the major barriers to regular usage are.Methods. A convenience sample was surveyed on awareness and use of Free Open Access Medical Education blogs, podcasts, websites and Twitter at three institutions (in Australia, Botswana and Papua New Guinea) and one deanery (United Kingdom) between June 2013 and June 2014 using an online survey tool or via hand-distributed survey.Results. 44 trainees responded: four from Botswana, seven from Papua New Guinea, ten from the United Kingdom and 23 from Australia. 82% were aware of blogs, 80% of websites, 75% of podcasts and 61% of Twitter as resources in Emergency Medicine. Awareness and use of specific resources were lower in Botswana and Papua New Guinea. For blogs, podcasts and websites, trainees who had looked at a resource at least once were neutral or agreed that it was relevant. For Twitter, some trainees found it difficult to navigate or not relevant. Lack of awareness of resources rather than lack of internet access was the main barrier to use.Conclusion. The Emergency Medicine trainees in both developed and low resource settings studied were aware that Free Open Access Medical Education resources exist, but trainees in lower income settings were generally less aware of specific resources. Lack of internet and device access was not a barrier to use in this group. © 2015.
Huson S.M.,University of Manchester |
Acosta M.T.,Childrens National Medical Center |
Belzberg A.J.,Johns Hopkins Hospital |
Bernards A.,Harvard University |
And 20 more authors.
American Journal of Medical Genetics, Part A | Year: 2011
The neurofibromatoses (NF) encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect 100,000 Americans; over 2 million persons worldwide; and are caused by mutation of tumor suppressor genes. Individuals with NF1 in particular may develop tumors anywhere in the nervous system; additional manifestations can include learning disabilities, bone dysplasia, cardiovascular defects, unmanageable pain, and physical disfigurement. Ultimately, the NFs can cause blindness, deafness, severe morbidity, and increased mortality and NF1 includes a risk of malignant cancer. Today there is no treatment for the NFs (other than symptomatic); however, research efforts to understand these genetic conditions have made tremendous strides in the past few years. Progress is being made on all fronts, from discovery studies-understanding the molecular signaling deficits that cause the manifestations of NF-to the growth of preclinical drug screening initiatives and the emergence of a number of clinical trials. An important element in fuelling this progress is the sharing of knowledge, and to this end, for over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share ideas and build collaborations. The 2010 NF Conference held in Baltimore, MD June 5-8, 2010 hosted over 300 NF researchers and clinicians. This paper provides a synthesis of the highlights presented at the Conference and as such, is a "state-of-the-field" for NF research in 2010. © 2010 Wiley-Liss, Inc.
Laird A.,Western General Hospital |
Fowler S.,British Association of Urological Surg. |
Good D.W.,Western General Hospital |
Stewart G.D.,Western General Hospital |
And 4 more authors.
BJU International | Year: 2015
Objective To determine current radical prostatectomy (RP) practice in the UK and compare surgical outcomes between techniques. Patients and Methods All RPs performed between 1 January 2011 and 31 December 2011 in the UK with data entered into the British Association of Urological Surgeons (BAUS) database, were identified for analysis. Overall surgical outcomes were assessed and subgroup analyses of these outcomes, based on operative technique [open RP (ORP), laparoscopic RP (LRP) and robot-assisted laparoscopic RP (RALP)], were made. Continuous variables were compared using the Mann-Whitney U-test and categorical variables using the Pearson chi-squared test. Univariate and multivariate binary regression analyses were performed to assess the effect of patient, surgeon and technique-related variables on surgical outcomes. Results During the study period 2163 RPs were performed by 115 consultants with a median (range) of 11 (1-154) cases/consultant. Most RPs were performed laparoscopically (ORP 25.8%, LRP 54.6%, RALP 19.6%) and those performing minimally invasive techniques are more likely to have a higher annual case volume with <1% ORP, 39% LRP and 62% RALP being performed by consultants with an annual caseload of >50 cases/year. Most patients were classified as having intermediate- or high-risk disease preoperatively (1596 patients, 82.5%) and this increased to 97.2% (1649) on postoperative risk stratification. The overall intraoperative complication rate was 14.2% and was significantly greater for LRP (17.8%) vs ORP (8.2%) and RALP (12.4%), (P < 0.001). In all, 71% of patients had an estimated blood loss (EBL) of <500-mL, although there were significantly more patients undergoing ORP with >500, > 1000 and >2000-mL EBL compared with the other techniques (P < 0.001). The postoperative complication rate was 10.7% overall, with a significantly greater postoperative complication rate in the LRP group (LRP 14.6%, ORP 8.8% and RALP 10.3% respectively, P = 0.007). Positive surgical margin (PSM) rates were 17.5% for pT2 disease and 42.3% for pT3 disease. The PSM rate was significantly lower in the RALP patients compared with the ORP patients for those with pT2 disease (P = 0.025), while there was no difference between ORP and LRP (ORP 21.7%, LRP 18.1% and RALP 13.0%). There was no significant difference in the PSM rate in pT3 disease between surgical techniques. Conclusion Most RPs in the UK are performed using minimally invasive techniques, which offer reduced blood loss and transfusion rates compared with ORP. The operation time, complication rate, PSM rates, and association with higher volume practice support RALP as the minimally invasive technique of choice, which could have implications for regions without access to such services. The disparity in outcomes between this national study and high-volume single centres, most probably reflects the low median national case volume, and combined with the positive effect of high case volume on multivariate analysis of surgical outcomes and PSM rates, strengthens the argument for centralisation of services. © 2014 The Authors. BJU International © 2014 BJU International.
Proukakis C.,University College London |
Moore D.,Guys And St Thomas Nhs Hospital Trust |
Labrum R.,University College London |
Wood N.W.,University College London |
Houlden H.,University College London
Journal of the Neurological Sciences | Year: 2011
Background: Hereditary spastic paraplegia (HSP) is characterised in its pure form by slowly progressive spastic paraparesis. Around 40% of autosomal dominant (AD) cases are caused by mutations in SPAST, encoding spastin. Patients and methods: The clinical and investigation details of all patients with a SPAST mutation identified through our centre were reviewed. All published reports of SPAST mutations where the sex of patients was given were subsequently analysed in order to determine whether there is evidence of one sex being preferentially affected. Results: In total 22 probable pathogenic changes were detected, including 11 novel ones. One patient carried two adjacent missense mutations. The pathogenicity of a further novel missense mutation is uncertain. Most patients had a pure phenotype, although mild peripheral neuropathy was sometimes present. The total number of patients with SPAST mutations was 27, as three of the previously known mutations were present in more than one person. The excess of males over females in our population (17:10) prompted us to review all published studies where the sex of the patients was given (n = 31). A significant excess of males was identified (ratio 1.29, p = 0.0007). Conclusions: Our results are consistent with data suggesting that SPAST mutations mostly cause a pure HSP phenotype. The excess of males in our sample and in published reports suggests that penetrance or severity may be sex-dependent, and merits further investigation as it may have important implications for counselling. © 2011 Elsevier B.V. All rights reserved.
PubMed | Guys and St Thomas NHS Hospital Trust
Type: Journal Article | Journal: Journal of communication disorders | Year: 2010
Non-word repetition (NWR) was investigated in adolescents with typical development, Specific Language Impairment (SLI) and Autism Plus language Impairment (ALI) (n=17, 13, 16, and mean age 14;4, 15;4, 14;8 respectively). The study evaluated the hypothesis that poor NWR performance in both groups indicates an overlapping language phenotype (Kjelgaard & Tager-Flusberg, 2001). Performance was investigated both quantitatively, e.g. overall error rates, and qualitatively, e.g. effect of length on repetition, proportion of errors affecting phonological structure, and proportion of consonant substitutions involving manner changes. Findings were consistent with previous research (Whitehouse, Barry, & Bishop, 2008) demonstrating a greater effect of length in the SLI group than the ALI group, which may be due to greater short-term memory limitations. In addition, an automated count of phoneme errors identified poorer performance in the SLI group than the ALI group. These findings indicate differences in the language profiles of individuals with SLI and ALI, but do not rule out a partial overlap. Errors affecting phonological structure were relatively frequent, accounting for around 40% of phonemic errors, but less frequent than straight Consonant-for-Consonant or vowel-for-vowel substitutions. It is proposed that these two different types of errors may reflect separate contributory mechanisms. Around 50% of consonant substitutions in the clinical groups involved manner changes, suggesting poor auditory-perceptual encoding. From a clinical perspective algorithms which automatically count phoneme errors may enhance sensitivity of NWR as a diagnostic marker of language impairment.Readers will be able to (1) describe and evaluate the hypothesis that there is a phenotypic overlap between SLI and Autism Spectrum Disorders (2) describe differences in the NWR performance of adolescents with SLI and ALI, and discuss whether these differences support or refute the phenotypic overlap hypothesis, and (3) understand how computational algorithms such as the Levenshtein Distance may be used to analyse NWR data.