J T Lear

The University of Manchester, Manchester, England, United Kingdom

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Publications (145)810.82 Total impact

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    ABSTRACT: Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053. Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1-17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79 patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3-4 adverse events were raised creatine kinase (five [6%] in the 200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four [5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. Novartis Pharmaceuticals Corporation. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 05/2015; 16(6). DOI:10.1016/S1470-2045(15)70100-2 · 24.73 Impact Factor
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    ABSTRACT: While actinic keratoses (AKs) have a known association with cutaneous squamous cell carcinoma (SCC), the relation of actinic field change to SCC has not been quantified. This study investigated the presence of field change and AKs in renal transplant recipients (RTRs) and estimated SCC risk. May 2010 to October 2011, a dermatologist examined 452 white RTRs (mean age 53 years) at two hospitals in Manchester, UK, counting AKs and recording field change presence by body site and SCCs arising during the study period. Of the participants 130 (29%) had AKs at examination. In 60 (13%) RTR patients with AKs but no field change, 4 (7%) developed SCCs, compared with 15 (21%) of the 70 (15%) with AKs and field change. SCCs developed directly within field change areas in 11/15 (73%) RTRs. This study confirms that RTRs with widespread confluent actinic skin damage are at very high risk of SCC and should be monitored closely.
    Acta Dermato-Venereologica 03/2015; DOI:10.2340/00015555-2098 · 4.24 Impact Factor
  • F. R. Ali, A. Aslam, L. Motta, J. T. Lear
    Clinical and Experimental Dermatology 03/2015; DOI:10.1111/ced.12615 · 1.23 Impact Factor
  • Journal of the European Academy of Dermatology and Venereology 10/2014; DOI:10.1111/jdv.12796 · 3.11 Impact Factor
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    ABSTRACT: Basal cell carcinoma (BCC) is a common malignancy with a good prognosis in the majority of cases. However, some BCC patients develop a more advanced disease that poses significant management challenges. Such cases include locally advanced, recurrent or metastatic BCC, or tumours that occur in anatomical sites where surgical treatment would result in significant deformity. Until recently, treatment options for these patients have been limited, but increased understanding of the molecular basis of BCC has enabled potential therapies, such as hedgehog signalling pathway inhibitors, to be developed. A clear definition of advanced BCC as a distinct disease entity and formal management guidelines have not previously been published, presumably because of the rarity, heterogeneity and lack of treatment options available for the disease. Here we provide a UK perspective from a multidisciplinary group of experts involved in the treatment of complex cases of BCC, addressing the key challenges associated with the perceived definition and management of the disease. With new treatments on the horizon, we further propose a definition for advanced BCC that may be used as a guide for healthcare professionals involved in disease diagnosis and management.British Journal of Cancer advance online publication, 11 September 2014; doi:10.1038/bjc.2014.270 www.bjcancer.com.
    British Journal of Cancer 09/2014; 111(8). DOI:10.1038/bjc.2014.270 · 4.82 Impact Factor
  • 15th World Congress on Cancers of the Skin; 09/2014
  • 15th World Congress on Cancers of the Skin; 09/2014
  • 15th World Congress on Cancers of the Skin; 09/2014
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    ABSTRACT: Gorlin syndrome is an autosomal dominant disorder, characterized by multiple early-onset basal cell carcinomas (BCCs) and jaw keratocysts. Through association studies in cohorts of sporadic BCC, nine genetic variants have previously been identified to increase the risk of BCC. The nine SNPs were genotyped by Taqman allelic discrimination in 125 individuals with Gorlin syndrome. Kaplan-Meier survival curves and Cox proportional-Hazard regression analysis were applied to determine the association between genotypes and age of first BCC in individuals with Gorlin syndrome. The p.(Arg151Cys) variant in MC1R (rs1805007) was associated with an earlier median age of onset of BCC of 27 years (95% CI: 20-34) compared with 34 years (95% CI: 30-40) for wild-type individuals (hazard ratio (HR)=1.64, 95% CI: 1.04-2.58, P=0.034). The risk allele of the variant at the chromosome 5p15 locus encompassing TERT-CLPTM1L (rs401681) was also associated with an earlier median onset of BCC, 31 years (95% CI: 28-37) compared with 41 years (95% CI: 32-48, HR=1.44, 95% CI: 1.08-1.93, P=0.014). In individuals with a risk allele at either rs1805007 or rs401681 the median time to BCC was 31 years of age (95% CI: 28-34) compared with 44 years of age (95% CI: 38-53) in wild-type individuals (HR=2.48, 95% CI: 1.47-4.17, P=0.0002). Our findings may have implications for future personalized risk estimates and BCC screening strategies in individuals with Gorlin syndrome.European Journal of Human Genetics advance online publication, 27 August 2014; doi:10.1038/ejhg.2014.167.
    European journal of human genetics: EJHG 08/2014; 23(5). DOI:10.1038/ejhg.2014.167 · 4.23 Impact Factor
  • F R Ali, A Aslam, J T Lear
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    ABSTRACT: Sattler and colleagues' paper exploring the factors underlying lack of patient adherence to sun protective measures (1) overlooks a potentially critical facet, that of patient preference. Shared decision-making and promotion of patient choice are requisite to good practice, as discussed in a recent editorial (2) and stipulated in the UK dermatology specialty training curriculum. (3) This is perhaps best illustrated in dermatology by the realm of emollients, where patient concordance with prescribed therapy is greater when patients are encouraged to select the emollient of their choice, with patients often preferring lighter cream-based emollients to greasier ointments. This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 05/2014; 171(6). DOI:10.1111/bjd.13136 · 4.10 Impact Factor
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    Thomas Dirschka, John T Lear
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    ABSTRACT: Interest is increasing in the use of sequential or combined therapeutic modalities for spot or area treatment of actinic keratoses (AKs) to achieve complete sustained remission. For multiple lesions in a contained area, topical treatment offers less discomfort, better cosmesis and greater patient convenience than destructive/ablative techniques. Twelve patients with multiple grade I and II AK lesions of the scalp (cases 1-10) or the dorsum of the hand (cases 11 and 12), most with a history of recurrence, were treated with Solaraze gel (3% diclofenac sodium in 2.5% hyaluronic acid) twice daily for 12 weeks, followed by a 2-week treatment-free interval, then Actikerall cutaneous solution (5-fluorouracil 5 mg/g and salicylic acid 100 mg/g) once daily for up to 6 weeks as required. Sequential treatment provided complete (clinical and histological) clearance in 8/10 male patients. Two patients with numerous lesions had partial clearance (significant improvement) and the remaining few lesions were treated with erbium laser. Both female patients achieved complete clinical clearance with sequential treatment. Solaraze/Actikerall were well tolerated. A case of contact dermatitis with Solaraze resolved after discontinuation and the patient progressed to treatment with Actikerall. Local application site reactions resolved upon treatment completion. Topical lesion-directed sequential treatment with Solaraze/Actikerall is a rational approach to treat patients with multiple AKs. Sequential treatment produces excellent clearance rates which are accompanied by relevant improvement in patients' quality of life.
    Case Reports in Dermatology 05/2014; 6(2):164-8. DOI:10.1159/000365070
  • 05/2014; 11(3):295-306. DOI:10.2217/cpr.14.13
  • Transplantation 04/2014; 97(8):e48-50. DOI:10.1097/TP.0000000000000084 · 3.78 Impact Factor
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    ABSTRACT: Actinic keratosis (AK) is a common skin disease seen in daily practice. It is associated with a risk of progression to invasive squamous cell carcinoma and can be regarded as a marker of increased risk for non-melanoma skin cancer. The use of a field-directed treatment approach reflects the need to initiate early treatment over an affected area to prevent tumour development and local recurrence. Candidate field-directed treatments require a mechanism of action compatible with an effect on field cancerisation, immediate and long-term efficacy against visible lesions and efficacy against subclinical AK. Applicability to large treatment areas, tolerability compatible with long-term use, utility in organ transplant patients and, ideally, evidence of extended long-term activity may also be desirable. We review the evidence of a role for topical diclofenac sodium 3% administered in a 2.5% hyaluronic acid gel (diclofenac/HA) as field-directed treatment. Diclofenac/HA directly targets AK pathophysiology through multiple mechanisms, including induction of apoptosis, inhibition of angiogenesis and reduced inflammation. Clearance of visible field cancerisation is safely and rapidly achieved with a 90-day treatment course in patients with affected areas of up to 50 cm(2) and is associated with a ≥75% reduction in target lesion number score in 85% and 91% of patients, respectively, at 30 days and 1 year post-treatment. Following treatment of AK in high-risk transplant patients, 45% remained free of lesions in the treatment area at 2 years post-treatment. We conclude that diclofenac/HA fulfils most criteria necessary to be considered an appropriate candidate for a field-directed treatment in AK.
    04/2014; 24(2). DOI:10.1684/ejd.2014.2286
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    ABSTRACT: ANCA-associated vasculitis (AAV) encompasses a heterogeneous group of autoimmune inflammatory disorders, including Granulomatosis with Polyangiitis (GPA, previously Wegener's granulomatosis), Microscopic Polyangiitis (MPA) and Eosinophilic Granulomatosis with Polyangiitis (EGPA, previously Churg-Strauss syndrome). (1) AAV patients typically receive induction therapy with cyclophosphamide and corticosteroids, followed by long-term maintenance immunosuppression. A multi-disciplinary group including clinicians, research methodologists and patient representatives developed a self-report questionnaire for AAV patients, which sought to establish immunosuppression exposure, patients' knowledge of side-effects of these medications and previous diagnoses of skin malignancies together with skin surveillance uptake, dermatological follow-up and use of sun protective measures. This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 02/2014; 171(1). DOI:10.1111/bjd.12861 · 4.10 Impact Factor
  • Faisal R Ali, John T Lear, Neel Sharma
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    ABSTRACT: Mitigating the risk of skin cancer associated with thiopurine use.
    British journal of hospital medicine (London, England: 2005) 01/2014; 75(1):55-Unknown. · 0.37 Impact Factor
  • Faisal R Ali, John T Lear
    British journal of hospital medicine (London, England: 2005) 01/2014; 75(1):55-55. DOI:10.12968/hmed.2014.75.1.55 · 0.37 Impact Factor
  • John T Lear
    The Lancet Oncology 12/2013; 15(1). DOI:10.1016/S1470-2045(13)70582-5 · 24.73 Impact Factor
  • N J Collier, F R Ali, J T Lear
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    ABSTRACT: Photodynamic therapy (PDT) is an established treatment for superficial basal cell carcinoma (BCC). Organ transplant recipients (OTRs) are at increased risk of BCC. We investigated the efficacy of PDT in OTRs and compared the recurrence rate to the non-transplanted population. We conducted a retrospective casenote review of all patients undergoing PDT for the treatment of BCC in our centre from 2003 to 2013. Three hundred and twenty-two BCCs from 103 patients underwent PDT during this period. There is no significant difference in BCC recurrence following PDT in OTRs (22.6 %) versus non-transplant patients (15.2 %) (p = 0.18). PDT is an efficacious treatment for BCC in OTRs with no significant evidence of inferiority compared to non-transplanted patients. Our findings require corroboration in a larger study.
    Lasers in Medical Science 10/2013; DOI:10.1007/s10103-013-1454-7 · 2.42 Impact Factor

Publication Stats

3k Citations
810.82 Total Impact Points

Institutions

  • 2000–2015
    • The University of Manchester
      • Centre for Dermatology
      Manchester, England, United Kingdom
  • 2007–2014
    • Central Manchester University Hospitals NHS Foundation Trust
      • Department of Dermatology
      Manchester, England, United Kingdom
  • 2009–2012
    • Salford Royal NHS Foundation Trust
      Salford, England, United Kingdom
  • 2005–2006
    • University Hospital Of North Staffordshire NHS Trust
      • Department of Dermatology
      Stoke-upon-Trent, England, United Kingdom
  • 1996–2003
    • Keele University
      • Institute for Science and Technology in Medicine
      Newcastle-under-Lyme, England, United Kingdom
  • 1995–2002
    • Staffordshire and Stoke-On-Trent Partnership NHS Trust
      Newcastle-under-Lyme, England, United Kingdom
  • 1999
    • Heinrich-Heine-Universität Düsseldorf
      • Institut für Physikalische Chemie
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1998–1999
    • University of Bristol
      Bristol, England, United Kingdom