Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need.
...Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out.
The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P < 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC ≥ 7500 and dNLR ≥ 3 had a significantly and independently increased risk of death hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29–7.75 and of progression (HR = 4.10; 95% CI 3.08–5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC ≥ 7500 and dNLR ≥ 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR.
Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials.
The proliferation of smart meter data allows the application of new analytic methods to inform regulatory deliberations. The bill alignment test (BAT) method, which compares the costs allocated to ...each residential customer with their electric bill, is introduced to help regulators consider how a proposed rate design balances various regulatory criteria. The BAT requires an explicit statement of preferences by policymakers or stakeholders and choices about allocating residual costs unassociated with customer-level causality. The BAT is applied to more than 35,000 smart-meter customer load profiles to assess the trade-offs associated with proposed rate designs. This example demonstrates the impact of residual cost allocation preferences and tariff design choices on proposed tariff evaluation.
•Smart meter data enables new analytic methods to inform regulatory deliberations.•The bill alignment test evaluates how rate proposals balance regulatory criteria.•The method compares allocated costs to residential customer bills.•Case study uses method on 35,000 smart meter residential customer load profiles.•Demonstrates significance of residual allocation method choices.
Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of the combination of ipilimumab and fotemustine in metastatic melanoma patients with or without brain metastases. The ...addition of fotemustine to ipilimumab does not impair its immunomodulatory activity.
In the NIBIT-M1 study, we reported a promising activity of ipilimumab combined with fotemustine in metastatic melanoma (MM) patients with or without brain metastases. To corroborate these initial findings, we now investigated the long-term efficacy of this combination.
This analysis captured the 3-year outcome of MM patients who received ipilimumab combined with fotemustine as first- or second-line treatment. Median overall survival (OS), 3-year survival rates, immune-related (ir) progression-free survival (irPFS), brain PFS, and ir duration of response (irDOR) for the entire population and for patients with brain metastases were assessed. Clinical results were correlated with circulating CD3+CD4+ICOS+CD45RO+ or CD45RA+ T cells, neutrophil/lymphocyte (N/L) ratios, and tumorBRAF-V600 mutational status.
Eighty-six MM patients, including 20 with asymptomatic brain metastases that had been pre-treated with radiotherapy in 7 subjects, were enrolled in the study. With a median follow-up of 39.9 months, median OS and 3-year survival rates were 12.9 months 95% confidence interval (CI) 7.1–18.7 months and 28.5% for the whole study population, and 12.7 months (95% CI 2.7–22.7 months) and 27.8% for patients with brain metastases, respectively. Long-term ir adverse events consisting of G1 rush and pruritus occurred in 21% of patients. The absolute increase from baseline to week 12 in ‘memory’ but not in ‘naïve’ T cells identified patients with a better survival (P = 0.002). The N/L ratio correlated with a significantly better survival at early time points.BRAF status did not correlate with clinical outcome.
Long-term analysis of the NIBIT-M1 trial continues to demonstrate efficacy of ipilimumab combined with fotemustine in MM patients. Fotemustine does not seem to impair the immunologic activity of ipilimumab.
2010-019356-50.
NCT01654692.
Patients with advanced uveal melanoma have a poor prognosis and limited treatment options. Ipilimumab is approved for pre-treated adult patients with advanced melanoma. However, because previous ...clinical trials with ipilimumab have excluded patients with uveal melanoma, data in this patient population are limited.
Pre-treated patients with advanced uveal melanoma received ipilimumab 3 mg/kg through an expanded access programme, every 3 weeks for four doses. Tumour assessments were conducted at baseline and after completion of treatment and patients were monitored throughout for adverse events.
Among 82 assessable patients, 4 (5%) had an immune-related objective response and 24 (29%) had immune-related stable disease lasting ≥3 months for an immune-related disease control rate of 34%. With a median follow-up of 5.6 months, median overall survival (OS) was 6.0 months and median progression-free survival (PFS) was 3.6 months. The 1-year rates of OS and PFS were 31% and 11%, respectively. The safety profile of ipilimumab was similar to that in patients with cutaneous melanoma.
These data suggest ipilimumab 3 mg/kg is a feasible option in pre-treated patients with metastatic uveal melanoma. Evidence of disease control and a 1-year survival rate of 31% indicate the need for further investigation in randomised, controlled trials to determine the optimal timing and use of ipilimumab in this patient population.
Two experimental campaigns were performed with the aim to study the effect of two different bed materials, magnesite and olivine during steam–O2 biomass gasification. The test-rig consists of a ...100kWth atmospheric circulating fluidized-bed gasifier and a high temperature filter unit which contains 3 rigid ceramic candles with an outer diameter of 60mm, 10mm wall thickness and a length of 1520mm. Tests were performed with different fuels (A-wood, B-wood, miscanthus and straw). Two types of filter elements were used, Dia-Schumalith1 (DS3) and Dia-Schumalith1 N (DSN1), which operated at 800°C for 58h and 50h, respectively. The filtration performance was studied through continuous observation of the increasing pressure drop during the build-up of the dust cake. Gas face velocities ranged between 2.5 and 5cms−1. DSN1 elements showed longer steady filtration compared to DS3 candles with filtration efficiencies equal to 100%. Formation of calcium and potassium silicates resulted from filter cake analyses. The filtration process influenced gas and tar composition of the incoming gas flow. Hydrogen content increased about 10% (dry basis) and the heavier tar compounds appeared to be broken into lighter chains, such as naphthalene whose concentration increased.
Global trends toward urbanization will exacerbate traffic congestion, delays in economic productivity, and air pollution issues for growing cities. Traffic congestion pricing is one method available ...to help ameliorate these concerns. New York City is on the verge of implementing a cordon-based traffic congestion pricing policy around its central business district. For budget-constrained municipalities, evaluating implementation of such policy could be costly. This article proposes a sketch-planning methodology, called Cordon Screen, for major U.S. cities to evaluate the net income, traffic mitigation, and avoided pollution emissions from cordon-based traffic congestion pricing. This method relies on national datasets and limited user-specific data inputs, along with a range of user-selectable assumptions informed by academic literature to deliver order-of-magnitude results. The numerous limitations of this method are acceptable for preliminary policy evaluation to determine if greater financial investment to obtain more accurate results is justified. The Denver metropolitan area is used to demonstrate Cordon Screen capabilities, with mid-range assumption results suggesting the policy is most effective at generating net income and increasing vehicle speeds on major interstates. For Denver, the policy is comparably less effective at reducing air pollution and increasing speeds on minor roadways. Validation against early implementation results from the London cordon are acceptable. However, users should discount revenue generation projections. Choice of cordon area may be the most difficult obstacle when using the Cordon Screen. With refinement, Cordon Screen could serve as a low-cost, open-source planning evaluation tool for growing and congested U.S. cities.
Implications: As global urbanization trends continue, impacted local governments will be looking to explore policies to mitigate traffic congestion and reduce environmental emissions. Internationally, cordon-based traffic congestion pricing has been implemented in London, Singapore, and several other large cities. In America, New York City is implementing cordon-based congestion pricing around its central business district to reduce traffic and environmental emissions. Financial resource constraints, exacerbated by the COVID-19 pandemic, may limit the ability for local governments to invest in studying new policy options. The Cordon Screen method detailed in the manuscript presents a low-cost, open-source approach to assessing the potential benefits of cordon-based traffic congestion policy. The method utilizes national datasets to minimize user-specific data requirements and allows users to toggle between a range of values to test sensitivities to key assumptions. For example, emissions reductions are highly sensitive to how drivers respond to tolling. In this example, sensitivity testing enables users to understand how policy design can impact air quality goals. The Cordon Screen approach presented provides a strong platform for future stakeholder deliberation, refinement, and implementation.
We present an innovative satellite-based solar UV (ultraviolet) radiation dosimeter with a mobile app interface that has been validated by exploiting both ground-based measurements and an in vivo ...assessment of the erythemal effects on some volunteers having controlled exposure to solar radiation. The app with this satellite-based UV dosimeter also includes other related functionalities such as the provision of safe sun exposure time updated in real-time and end exposure visual/sound alert. Both validations showed that the system has a good accuracy and reliability needed for health-related applications. This app will be launched on the market by siHealth Ltd in May 2016 under the name of "HappySun" and is available for both Android and iOS devices (more info on ). Extensive R&D activities are on-going for the further improvement of the satellite-based UV dosimeter's accuracy.
The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks ...(FOLFOX-4 regimen) in patients with advanced gastric cancer (AGC). A total of 61 previously untreated AGC patients were treated with oxaliplatin 85 mg m(-2) on day 1, FA 200 mg m(-2) as a 2 h infusion followed by bolus 5-FU 400 mg m(-2) and a 22 h infusion of 5-FU 600 mg m(-2), repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and response to treatment. Four (7%) complete responses and 19 partial responses were observed (overall response rate, 38%). Stable disease was observed in 22 (36%) patients, with progressive disease in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. National Cancer Institute Common Toxicity Criteria grade 3 and 4 haematologic toxicities were neutropenia, anaemia and thrombocytopenia in 36, 10 and 5% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. FOLFOX-4 is an active and well-tolerated chemotherapy. Response rate (RR), TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer.
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