Publications by authors named "Omar Din"

17 Publications

  • Page 1 of 1

Improving the management of type 2 diabetes through large-scale general practice: the role of a data-driven and technology-enabled education programme.

BMJ Open Qual 2021 02;10(1)

AT Medics Ltd, London, London, UK

A quality improvement (QI) scheme was launched in 2017, covering a large group of 25 general practices working with a deprived registered population. The aim was to improve the measurable quality of care in a population where type 2 diabetes (T2D) care had previously proved challenging. A complex set of QI interventions were co-designed by a team of primary care clinicians and educationalists and managers. These interventions included organisation-wide goal setting, using a data-driven approach, ensuring staff engagement, implementing an educational programme for pharmacists, facilitating web-based QI learning at-scale and using methods which ensured sustainability. This programme was used to optimise the management of T2D through improving the eight care processes and three treatment targets which form part of the annual national diabetes audit for patients with T2D. With the implemented improvement interventions, there was significant improvement in all care processes and all treatment targets for patients with diabetes. Achievement of all the eight care processes improved by 46.0% (p<0.001) while achievement of all three treatment targets improved by 13.5% (p<0.001). The QI programme provides an example of a data-driven large-scale multicomponent intervention delivered in primary care in ethnically diverse and socially deprived areas.
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http://dx.doi.org/10.1136/bmjoq-2020-001087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871240PMC
February 2021

The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis.

Gastroenterology 2021 03 14;160(4):1224-1239.e30. Epub 2020 Nov 14.

Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York.

Background & Aims: Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored.

Methods: Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC.

Results: We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5 intestinal stem cell differentiation. Finally, adeno-associated virus 8 (AAV8)-mediated delivery of Islr to hepatocytes increased BMP signaling and improved survival in our mouse model of hepatic metastasis.

Conclusions: Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.
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http://dx.doi.org/10.1053/j.gastro.2020.11.011DOI Listing
March 2021

The Impact of Centralised Services on Metric Reflecting High-quality Performance: Outcomes from 1110 Consecutive Radical Cystectomies at a Single Centre.

Eur Urol Focus 2021 May 21;7(3):554-565. Epub 2020 Jun 21.

Academic Urology Unit, University of Sheffield, Sheffield, UK; Department of Urology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. Electronic address:

Background: The 2002 National Institute for Health and Care Excellence guidance on centralisation of radical cystectomy (RC) coincided with changes in practice: use of neoadjuvant chemotherapy (NAC) and pelvic lymph node dissection (PLND), and RC for high-risk non-muscle-invasive bladder cancer (HR-NMIBC).

Objective: To report the outcomes of RC at a single centre and to compare trends in survival with respect to centralisation and change in RC practice.

Design, Setting, And Participants: Data were collected retrospectively between 1 January 1994 and 31 December 2016. Patients with urothelial cell carcinoma (UCC) were selected. Outcomes from 1994 to 2007 (before centralisation, era 1) were compared with those from 2008 to 2016 (after centralisation, era 2).

Outcome Measurements And Statistical Analysis: The primary outcome was disease-specific mortality. Secondary outcomes were survival and use of NAC and PLND.

Results And Limitations: Overall, 1100 RCs (era 1, 316; era 2, 794) were performed for UCC. Median (interquartile range [IQR]) follow-up was 28.5 (11.9-57.4) mo. RC for NMIBC was 36.2% versus 51.3% (p<0.001), NAC use was 2.2% versus 31.6% (p<0.001), and PLND use was 59.7% versus 76.4% (p<0.001) in era 1 versus era 2. The 30-d (1.6% [era 1] vs 0.8% [era 2], p=0.21) and 90-d (4.1% vs 2.6%, p=0.2) mortality rates did not differ with respect to RC year. Five-year disease-specific survival (DSS) was 56.0% in era 1 versus 79.0% in era 2 (p<0.001). RC for patients aged ≥75 yr was 13.9% versus 28.1% (p<0.001) and 30-d mortality in this group was 4.5% versus 0% (p=0.001) in era 1 versus era 2. The study is limited by its retrospective design.

Conclusions: Centralisation was associated with higher rates of NAC and PLND use, and increased RC performed for older patients and patients with HR-NMIBC. DSS was higher and RC appeared to be safer for older patients (fewer postoperative mortalities) after centralisation.

Patient Summary: We looked at outcomes from bladder removal for bladder cancer. Survival outcomes improved following centralisation of services. Surgery appeared to be safer for older patients, as there were fewer postoperative mortalities after centralisation. Centralisation of radical cystectomy (RC) services was associated with higher rates of neoadjuvant chemotherapy and pelvic lymph node dissection use, and increased usage of RC for older patients with high-risk non-muscle-invasive bladder cancer. Survival outcomes from RC were superior after centralisation and safer for older patients undergoing RC (fewer postoperative mortalities).
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http://dx.doi.org/10.1016/j.euf.2020.05.011DOI Listing
May 2021

Interfacing gene circuits with microelectronics through engineered population dynamics.

Sci Adv 2020 May 22;6(21):eaaz8344. Epub 2020 May 22.

BioCircuits Institute, University of California, San Diego, La Jolla, CA, USA.

While there has been impressive progress connecting bacterial behavior with electrodes, an attractive observation to facilitate advances in synthetic biology is that the growth of a bacterial colony can be determined from impedance changes over time. Here, we interface synthetic biology with microelectronics through engineered population dynamics that regulate the accumulation of charged metabolites. We demonstrate electrical detection of the bacterial response to heavy metals via a population control circuit. We then implement this approach to a synchronized genetic oscillator where we obtain an oscillatory impedance profile from engineered bacteria. We lastly miniaturize an array of electrodes to form "bacterial integrated circuits" and demonstrate its applicability as an interface with genetic circuits. This approach paves the way for new advances in synthetic biology, analytical chemistry, and microelectronic technologies.
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http://dx.doi.org/10.1126/sciadv.aaz8344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244307PMC
May 2020

Rock-paper-scissors: Engineered population dynamics increase genetic stability.

Science 2019 09;365(6457):1045-1049

Department of Bioengineering, University of California-San Diego, La Jolla, CA, USA.

Advances in synthetic biology have led to an arsenal of proof-of-principle bacterial circuits that can be leveraged for applications ranging from therapeutics to bioproduction. A unifying challenge for most applications is the presence of selective pressures that lead to high mutation rates for engineered bacteria. A common strategy is to develop cloning technologies aimed at increasing the fixation time for deleterious mutations in single cells. We adopt a complementary approach that is guided by ecological interactions, whereby cyclical population control is engineered to stabilize the functionality of intracellular gene circuits. Three strains of were designed such that each strain could kill or be killed by one of the other two strains. The resulting "rock-paper-scissors" dynamic demonstrates rapid cycling of strains in microfluidic devices and leads to an increase in the stability of gene circuit functionality in cell culture.
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http://dx.doi.org/10.1126/science.aaw0542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988775PMC
September 2019

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.

Lancet 2018 12 21;392(10162):2353-2366. Epub 2018 Oct 21.

Department of Health Services Research, London School of Hygiene & Tropical Medicine, London, UK.

Background: Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy.

Methods: We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476.

Findings: Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63-73) and median amount of prostate-specific antigen of 97 ng/mL (33-315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68-0·84; p<0·0001) but not overall survival (0·92, 0·80-1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3-4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy).

Interpretation: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer.

Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.
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http://dx.doi.org/10.1016/S0140-6736(18)32486-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269599PMC
December 2018

Rational engineering of synthetic microbial systems: from single cells to consortia.

Curr Opin Microbiol 2018 10 22;45:92-99. Epub 2018 Mar 22.

BioCircuits Institute, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Molecular Biology Section, Division of Biological Science, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

One promise of synthetic biology is to provide solutions for biomedical and industrial problems by rational design of added functionality in living systems. Microbes are at the forefront of this biological engineering endeavor due to their general ease of handling and their relevance in many potential applications from fermentation to therapeutics. In recent years, the field has witnessed an explosion of novel regulatory tools, from synthetic orthogonal transcription factors to posttranslational mechanisms for increased control over the behavior of synthetic circuits. Tool development has been paralleled by the discovery of principles that enable increased modularity and the management of host-circuit interactions. Engineered cell-to-cell communication bridges the scales from intracellular to population-level coordination. These developments facilitate the translation of more than a decade of circuit design into applications.
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http://dx.doi.org/10.1016/j.mib.2018.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151159PMC
October 2018

A stabilized microbial ecosystem of self-limiting bacteria using synthetic quorum-regulated lysis.

Nat Microbiol 2017 Jun 12;2:17083. Epub 2017 Jun 12.

Department of Bioengineering, University of California, La Jolla, San Diego, California 92093, USA.

Microbial ecologists are increasingly turning to small, synthesized ecosystems as a reductionist tool to probe the complexity of native microbiomes. Concurrently, synthetic biologists have gone from single-cell gene circuits to controlling whole populations using intercellular signalling. The intersection of these fields is giving rise to new approaches in waste recycling, industrial fermentation, bioremediation and human health. These applications share a common challenge well-known in classical ecology-stability of an ecosystem cannot arise without mechanisms that prohibit the faster-growing species from eliminating the slower. Here, we combine orthogonal quorum-sensing systems and a population control circuit with diverse self-limiting growth dynamics to engineer two 'ortholysis' circuits capable of maintaining a stable co-culture of metabolically competitive Salmonella typhimurium strains in microfluidic devices. Although no successful co-cultures are observed in a two-strain ecology without synthetic population control, the 'ortholysis' design dramatically increases the co-culture rate from 0% to approximately 80%. Agent-based and deterministic modelling reveal that our system can be adjusted to yield different dynamics, including phase-shifted, antiphase or synchronized oscillations, as well as stable steady-state population densities. The 'ortholysis' approach establishes a paradigm for constructing synthetic ecologies by developing stable communities of competitive microorganisms without the need for engineered co-dependency.
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http://dx.doi.org/10.1038/nmicrobiol.2017.83DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603288PMC
June 2017

Synchronized cycles of bacterial lysis for in vivo delivery.

Nature 2016 08 20;536(7614):81-85. Epub 2016 Jul 20.

Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.

The widespread view of bacteria as strictly pathogenic has given way to an appreciation of the prevalence of some beneficial microbes within the human body. It is perhaps inevitable that some bacteria would evolve to preferentially grow in environments that harbor disease and thus provide a natural platform for the development of engineered therapies. Such therapies could benefit from bacteria that are programmed to limit bacterial growth while continually producing and releasing cytotoxic agents in situ. Here we engineer a clinically relevant bacterium to lyse synchronously ata threshold population density and to release genetically encoded cargo. Following quorum lysis, a small number of surviving bacteria reseed the growing population, thus leading to pulsatile delivery cycles. We used microfluidic devices to characterize the engineered lysis strain and we demonstrate its potential as a drug delivery platform via co-culture with human cancer cells in vitro. Asa proof of principle, we tracked the bacterial population dynamics in ectopic syngeneic colorectal tumours in mice via a luminescent reporter. The lysis strain exhibits pulsatile population dynamics in vivo, with mean bacterial luminescence that remained two orders of magnitude lower than an unmodified strain. Finally, guided by previous findings that certain bacteria can enhance the efficacy of standard therapies, we orally administered the lysis strain alone or in combination with a clinical chemotherapeutic to a syngeneic mouse transplantation model of hepatic colorectal metastases. We found that the combination of both circuit-engineered bacteria and chemotherapy leads to a notable reduction of tumour activity along with a marked survival benefit over either therapy alone.Our approach establishes a methodology for leveraging the tools of synthetic biology to exploit the natural propensity for certain bacteria to colonize disease sites.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048415PMC
http://dx.doi.org/10.1038/nature18930DOI Listing
August 2016

A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer.

Eur Urol 2016 Mar 11;69(3):450-6. Epub 2015 Sep 11.

St. James's University Hospital, University of Leeds, Leeds, UK.

Background: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2).

Objective: The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC.

Design, Setting, And Participants: Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial.

Intervention: Starting in February 2013, patients were randomised (1:1) to AZD2014 (50 mg twice daily) or everolimus (10 mg once daily) until progression of disease at 10 centres across the United Kingdom.

Outcome Measurements And Statistical Analysis: Progression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients.

Results And Limitations: Recruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 [95% confidence interval (CI), 1.2-6.5]; p=0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p<0.001). Grade 3-4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p=0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1-8.4; p<0.02).

Conclusions: The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles.

Patient Summary: There is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.
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http://dx.doi.org/10.1016/j.eururo.2015.08.035DOI Listing
March 2016

Accelerated hypo-fractionated radiotherapy for non small cell lung cancer: results from 4 UK centres.

Radiother Oncol 2013 Oct 3;109(1):8-12. Epub 2013 Oct 3.

Dept. of Clinical Oncology, Weston Park Hospital, Sheffield, UK.

Background And Purpose: A variety of radiotherapy fractionations are used as potentially curative treatments for non-small cell lung cancer. In the UK, 55 Gy in 20 fractions over 4 weeks (55/20) is the most commonly used fractionation schedule, though it has not been validated in randomized phase III trials. This audit pooled together existing data from 4 UK centres to produce the largest published series for this schedule.

Materials And Methods: 4 UK centres contributed data (Cambridge, Cardiff, Glasgow and Sheffield). Case notes and radiotherapy records of radically treated patients between 1999 and 2007 were retrospectively reviewed. Basic patient demographics, tumour characteristics, radiotherapy and survival data were collected and analysed.

Results: 609 patients were identified of whom 98% received the prescribed dose of 55/20. The median age was 71.3 years, 62% were male. 90% had histologically confirmed NSCLC, 49% had stage I disease. 27% had received chemotherapy (concurrent or sequential) with their radiotherapy. The median overall survival from time of diagnosis was 24.0 months and 2 year overall survival was 50%.

Conclusion: These data show respectable results for patients treated with accelerated hypo-fractionated radiotherapy for NSCLC with outcomes comparable to those reported for similar schedules and represent the largest published series to date for 55/20 regime.
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http://dx.doi.org/10.1016/j.radonc.2013.07.014DOI Listing
October 2013

Palliative radiotherapy in patients with esophageal carcinoma: A retrospective review.

Pract Radiat Oncol 2012 Oct-Dec;2(4):257-264. Epub 2012 Feb 10.

Department of Clinical Oncology, Weston Park Hospital, Sheffield, United Kingdom.

Purpose: Palliative radiotherapy has traditionally been used as a noninvasive means of palliating dysphagia in patients with incurable esophageal cancer. Insertion of an esophageal stent is a traditional alternative and newer treatment modalities such as brachytherapy and laser therapy are being increasingly investigated and employed. There are few large series in the literature which examine the role of short palliative radiotherapy regimens in this patient group. This retrospective review aims to demonstrate the useful role that external beam radiotherapy can have in the palliation of patients with incurable esophageal carcinoma.

Methods And Materials: One hundred forty-eight patients with histologically proven esophageal cancer, who were unsuitable for radical treatment, were identified. Notes were reviewed to determine baseline characteristics, indications for radiotherapy, response to treatment, need for further intervention, time to further intervention, and survival.

Results: The median age of patients who received palliative radiotherapy was 74 years (range, 31-91). Forty-nine percent of patients (n = 73) were performance status 2 or 3, 70% (n = 103) had adenocarcinoma, 58% (n = 86) had locally advanced disease, and 28% (n = 41) had metastatic disease. Ninety-three percent of patients (n = 138) complained of dysphagia prior to radiotherapy. Eighty-nine percent of patients (n = 132) received a dose of 20 Gy in 5 fractions. Only 2 patients (1%) failed to complete the prescribed course of treatment. Following radiotherapy, 75% of patients experienced an improvement in dysphagia and 25% of patients gained weight. Twenty-six percent of patients (n = 38) required subsequent insertion of an esophageal stent and a further 3% (n = 5) received retreatment with radiotherapy. The median stent (and retreatment)-free survival was 4.9 months. Median overall survival was 6.1 months.

Conclusions: Despite a lack of randomized comparison to other modalities, external beam radiotherapy remains an effective, noninvasive, and generally well-tolerated means to palliate dysphagia in selected patients with incurable esophageal carcinoma.
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http://dx.doi.org/10.1016/j.prro.2011.12.002DOI Listing
March 2014

Detection of radiation-induced lung injury in non-small cell lung cancer patients using hyperpolarized helium-3 magnetic resonance imaging.

Radiother Oncol 2010 Nov 17;97(2):244-8. Epub 2010 Aug 17.

Academic Unit of Clinical Oncology, University of Sheffield, UK.

Purpose: To compare hyperpolarized helium-3 magnetic resonance imaging ((3)He-MRI) acquired from non-small cell lung cancer (NSCLC) patients before and after external beam radiotherapy (EBRT).

Methods And Materials: In an Ethics Committee-approved prospective study, five patients with histologically confirmed NSCLC gave written informed consent to undergo computed tomography (CT) and (3)He-MR ventilation imaging 1 week prior to and 3 months after radiotherapy. Images were registered to pre-treatment CT using anatomical landmark-based rigid registration to enable comparison. Emphysema was graded from examination of the CT. MRI-defined ventilation was calculated as the intersection of (3)He-MRI and CT lung volume as a percentage of the CT lung volume for the whole lung and regions of CT-defined pneumonitis.

Results: On pre-treatment images, there was a significant correlation between the degree of CT-defined emphysema and (3)He-MRI whole lung ventilation (Spearman's rho=0.90, p=0.04). After radiation therapy, pneumonitis was evident on CT for 3/5 patients. For these cases, (3)He-MRI ventilation was significantly reduced within the regions of pneumonitis (pre: 94.1±2.2%, post: 73.7±4.7%; matched pairs Student's t-test, p=0.02, mean difference=20.4%, 95% confidence interval 6.3-34.6%).

Conclusions: This work demonstrates the feasibility of detecting ventilation changes between pre- and post-treatment using hyperpolarized helium-3 MRI for patients with NSCLC. Pre-treatment, the degree of emphysema and (3)He-MRI ventilation were correlated. For three cases of radiation pneumonitis, (3)He-MRI ventilation changes between pre- and post-treatment imaging were consistent with CT evidence of radiation-induced lung injury.
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http://dx.doi.org/10.1016/j.radonc.2010.07.013DOI Listing
November 2010

Aromatase inhibitor-induced arthralgia in early breast cancer: what do we know and how can we find out more?

Breast Cancer Res Treat 2010 Apr 16;120(3):525-38. Epub 2010 Feb 16.

Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, S10 2SJ, UK.

Aromatase inhibitors (AIs) are a standard of care for the adjuvant treatment of hormone responsive early carcinoma of the breast as demonstrated in a number of large international phase III randomised trials. Arthralgia was a somewhat unexpected side effect of this class of agents and has proven to be potentially problematic in clinical practice. Although rates of up 35% have been reported in the randomised trials, the figure has been much higher in subsequent case series. There is concern that these symptoms are significant and may affect compliance and thus the overall efficacy of treatment. It is therefore extremely important that we evaluate this syndrome with a view to gaining more information regarding its clinical features and possible aetiological mechanism. The potential aetiological mechanisms and evidence for aromatase inhibitor-induced arthralgia (AIA) are reviewed in this article. Looking forward, it is now important that prospective clinical trials are well designed to evaluate this syndrome and potential therapeutic strategies to circumvent it. Radiological imaging and biochemical analyses may help our understanding of AIA and these are discussed.
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http://dx.doi.org/10.1007/s10549-010-0757-7DOI Listing
April 2010

Palliative prostate radiotherapy for symptomatic advanced prostate cancer.

Radiother Oncol 2009 Nov 21;93(2):192-6. Epub 2009 May 21.

Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK.

Background And Purpose: To report the results for the use of short-course palliative radiotherapy to the prostate for localised symptoms.

Materials And Methods: Fifty-eight patients were identified from radiotherapy records between 2003 and 2007. Data were collected retrospectively on patients' demographics, radiotherapy details and response. Symptoms and toxicity were scored, retrospectively, according to the following scale: 0=no symptoms, 1=mild symptoms, 2=moderate symptoms, and 3=severe symptoms.

Results: All the 58 patients had advanced prostate carcinoma. The median age at radiotherapy was 76.6 years (range 54-91). Fifty-six patients (97%) had hormone refractory disease. Twenty-seven patients (47%) had evidence of metastatic disease. 20 Gy in 5 fractions was the most commonly used fractionation. The most frequent baseline symptom was haematuria (54%). Eighty-nine percent (31/35) of the patients had a complete or partial resolution of symptoms at 4 months. Response rates for individual symptoms (including unknown responses) were: rectal symptoms (75%), pelvic pain (69%), urinary obstruction (54%) and haematuria (42%). A >50% reduction in PSA occurred in five patients. Toxicity was mild to moderate only and was self-limiting.

Conclusion: Palliative radiotherapy to the prostate gland for local symptoms appears to be an effective means of palliation with minimal toxic side effects. Prospective studies are now required to assess its benefits in more detail.
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http://dx.doi.org/10.1016/j.radonc.2009.04.017DOI Listing
November 2009

Treatment of gastrointestinal stromal tumor: focus on imatinib mesylate.

Ther Clin Risk Manag 2008 Feb;4(1):149-62

Academic Department of Clinical Oncology, University of Sheffield Weston Park Hospital, Sheffield, UK.

Gastrointestinal stromal tumor (GIST) is a rare primary neoplasm of the gastrointestinal tract, mesentery, or omentum. In the past, surgery has been the only effective treatment. The diagnosis and treatment of GIST has been revolutionized over the past decade, since expression of the receptor tyrosine kinase KIT was shown to occur on these tumors. Mutations in this proto-oncogene commonly cause constitutive activation of the KIT tyrosine kinase receptor, an important factor in the pathogenesis of the disease. The development of specific tyrosine kinase inhibitors, such as imatinib mesylate, has led to a breakthrough in the treatment of advanced GIST. Treatment with this drug has led to significant improvements in survival, with overall response rates in excess of 80%. Side effects are common, but usually manageable. The success of this drug has led to further trials investigating its use in the pre- and postoperative situation. This review summarizes the current knowledge of GIST and imatinib treatment and possible future developments.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2503651PMC
http://dx.doi.org/10.2147/tcrm.s1526DOI Listing
February 2008

Routine use of continuous, hyperfractionated, accelerated radiotherapy for non-small-cell lung cancer: a five-center experience.

Int J Radiat Oncol Biol Phys 2008 Nov 20;72(3):716-22. Epub 2008 Mar 20.

Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK.

Purpose: To report the results from continuous, hyperfractionated, accelerated radiotherapy (CHART) used as the standard fractionation for radical RT in the management of non-small cell lung cancer (NSCLC) in five United Kingdom centers.

Methods And Materials: In 2005, the CHART consortium identified six U.K. centers that had continued to use CHART after the publication of the CHART study in 1997. All centers had been using CHART for >5 years and agreed to use a common database to audit their results. Patients treated with CHART between 1998 and December 2003 were identified to allow a minimum of 2 years of follow-up. Patient demographics, tumor characteristics, treatment details, and survival were recorded retrospectively. Five centers completed the data collection.

Results: A total of 583 patients who had received CHART were identified. Of these patients, 69% were male, with a median age of 68 years (range, 31-89); 83% had performance status 0 or 1; and 43% had Stage I or II disease. Of the 583 patients, 99% received the prescribed dose. In only 4 patients was any Grade 4-5 toxicity documented. The median survival from the start of RT was 16.2 months, and the 2-year survival rate of 34% was comparable to that reported in the original study.

Conclusion: The results of this unselected series have confirmed that CHART is deliverable in routine clinical practice, with low levels of toxicity. Importantly, this series has demonstrated that the results of CHART reported from the randomized trial can be reproduced in routine clinical practice.
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http://dx.doi.org/10.1016/j.ijrobp.2008.01.033DOI Listing
November 2008
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