Randomized controlled trial of fractionated laser resurfacing on aged skin as prophylaxis against actinic neoplasia.

BACKGROUNDThe loss of insulin-like growth factor 1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of nonmelanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin, which upregulates dermal IGF-1 levels, can prevent the occurrence of actinic keratosis (AK) and NMSC.METHODSA human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation. Subsequently, the durability of FLR treatment was tested on a cohort of human participants aged 65 years and older. Finally, 48 individuals aged 60 years and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion.RESULTSXenografting studies revealed that chronic UVB treatment with a topical IGF-1R inhibitor resulted in a procarcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least 2 years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSCs in the treated arm (2 NMSCs) versus the untreated arm (24 NMSCs).CONCLUSIONThe elimination of senescent fibroblasts via FLR reduced the procarcinogenic UVB response of aged skin. Thus, wounding therapies are a potentially effective prophylaxis for managing high-risk populations.TRIAL REGISTRATIONClinicalTrials.gov (NCT03906253).FUNDINGNational Institutes of Health, Veterans Administration.

A discrete event simulation model to evaluate the treatment pathways of patients with cataract in the United Kingdom.

BACKGROUND: The number of people affected by cataract in the United Kingdom (UK) is growing rapidly due to ageing population. As the only way to treat cataract is through surgery, there is a high demand for this type of surgery and figures indicate that it is the most performed type of surgery in the UK. The National Health Service (NHS), which provides free of charge care in the UK, is under huge financial pressure due to budget austerity in the last decade. As the number of people affected by the disease is expected to grow significantly in coming years, the aim of this study is to evaluate whether the introduction of new processes and medical technologies will enable cataract services to cope with the demand within the NHS funding constraints. METHODS: We developed a Discrete Event Simulation model representing the cataract services pathways at Leicester Royal Infirmary Hospital. The model was inputted with data from national and local sources as well as from a surgery demand forecasting model developed in the study. The model was verified and validated with the participation of the cataract services clinical and management teams. RESULTS: Four scenarios involving increased number of surgeries per half-day surgery theatre slot were simulated. Results indicate that the total number of surgeries per year could be increased by 40% at no extra cost. However, the rate of improvement decreases for increased number of surgeries per half-day surgery theatre slot due to a higher number of cancelled surgeries. Productivity is expected to improve as the total number of doctors and nurses hours will increase by 5 and 12% respectively. However, non-human resources such as pre-surgery rooms and post-surgery recovery chairs are under-utilized across all scenarios. CONCLUSIONS: Using new processes and medical technologies for cataract surgery is a promising way to deal with the expected higher demand especially as this could be achieved with limited impact on costs. Non-human resources capacity need to be evenly levelled across the surgery pathway to improve their utilisation. The performance of cataract services could be improved by better communication with and proactive management of patients.

A simulation tool for better management of retinal services.

BACKGROUND: Advances in the management of retinal diseases have been fast-paced as new treatments become available, resulting in increasing numbers of patients receiving treatment in hospital retinal services. These patients require frequent and long-term follow-up and repeated treatments, resulting in increased pressure on clinical workloads. Due to limited clinic capacity, many National Health Service (NHS) clinics are failing to maintain recommended follow-up intervals for patients receiving care. As such, clear and robust, long term retinal service models are required to assess and respond to the needs of local populations, both currently and in the future. METHODS: A discrete event simulation (DES) tool was developed to facilitate the improvement of retinal services by identifying efficiencies and cost savings within the pathway of care. For a mid-size hospital in England serving a population of over 500,000, we used 36 months of patient level data in conjunction with statistical forecasting and simulation to predict the impact of making changes within the service. RESULTS: A simulation of increased demand and a potential solution of the 'Treat and Extend' (T&E) regimen which is reported to result in better outcomes, in combination with virtual clinics which improve quality, effectiveness and productivity and thus increase capacity is presented. Without the virtual clinic, where T&E is implemented along with the current service, we notice a sharp increase in the number of follow-ups, number of Anti-VEGF injections, and utilisation of resources. In the case of combining T&E with virtual clinics, there is a negligible (almost 0%) impact on utilisation of resources. CONCLUSIONS: Expansion of services to accommodate increasing number of patients seen and treated in retinal services is feasible with service re-organisation. It is inevitable that some form of initial investment is required to implement service expansion through T&E and virtual clinics. However, modelling with DES indicates that such investment is outweighed by cost reductions in the long term as more patients receive optimal treatment and retain vision with better outcomes. The model also shows that the service will experience an average of 10% increase in surplus capacity.

Insulin-like growth factor-1 receptor regulates repair of ultraviolet B-induced DNA damage in human keratinocytes in vivo.

The activation status of the insulin-like growth factor-1 receptor (IGF-1R) regulates the cellular response of keratinocytes to ultraviolet B (UVB) exposure, both in vitro and in vivo. Geriatric skin is deficient in IGF-1 expression resulting in an aberrant IGF-1R-dependent UVB response which contributes to the development of aging-associated squamous cell carcinoma. Furthermore, our lab and others have reported that geriatric keratinocytes repair UVB-induced DNA damage less efficiently than young adult keratinocytes. Here, we show that IGF-1R activation influences DNA damage repair in UVB-irradiated keratinocytes. Specifically, in the absence of IGF-1R activation, the rate of DNA damage repair following UVB-irradiation was significantly slowed (using immortalized human keratinocytes) or inhibited (using primary human keratinocytes). Furthermore, inhibition of IGF-1R activity in human skin, using either ex vivo explant cultures or in vivo xenograft models, suppressed DNA damage repair. Primary keratinocytes with an inactivated IGF-1R also exhibited lower steady-state levels of nucleotide excision repair mRNAs. These results suggest that deficient UVB-induced DNA repair in geriatric keratinocytes is due in part to silenced IGF-1R activation in geriatric skin and provide a mechanism for how the IGF-1 pathway plays a role in the initiation of squamous cell carcinoma in geriatric patients.