Long-term outcomes to neoadjuvant pembrolizumab based on pathological response for patients with resectable stage III/IV cutaneous melanoma.

BACKGROUND: While neoadjuvant immunotherapy for melanoma has shown promising results, the data have been limited by a relatively short follow-up time, with most studies reporting 2-year outcomes. The goal of this study was to determine long-term outcomes for stage III/IV melanoma patients treated with neoadjuvant and adjuvant programmed cell death receptor 1 (PD-1) inhibition. PATIENTS AND METHODS: This is a follow-up study of a previously published phase Ib clinical trial of 30 patients with resectable stage III/IV cutaneous melanoma who received one dose of 200 mg IV neoadjuvant pembrolizumab 3 weeks before surgical resection, followed by 1 year of adjuvant pembrolizumab. The primary outcomes were 5-year overall survival (OS), 5-year recurrence-free survival (RFS), and recurrence patterns. RESULTS: We report updated results at 5 years of follow-up with a median follow-up of 61.9 months. No deaths occurred in patients with a major pathological response (MPR, <10% viable tumor) or complete pathological response (pCR, no viable tumor) (n = 8), compared to a 5-year OS of 72.8% for the remainder of the cohort (P = 0.12). Two of eight patients with a pCR or MPR had a recurrence. Of the patients with >10% viable tumor remaining, 8 of 22 patients (36%) had a recurrence. Additionally, the median time to recurrence was 3.9 years for patients with ≤10% viable tumor and 0.6 years for patients with >10% viable tumor (P = 0.044). CONCLUSIONS: The 5-year results from this trial represent the longest follow-up of a single-agent neoadjuvant PD-1 trial to date. Response to neoadjuvant therapy continues to be an important prognosticator with regard to OS and RFS. Additionally, recurrences in patients with pCR occur later and are salvageable, with a 5-year OS of 100%. These results demonstrate the long-term efficacy of single-agent neoadjuvant/adjuvant PD-1 blockade in patients with a pCR and the importance of long-term follow-up for these patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02434354.

Mathematical modelling of Pseudomonas aeruginosa biofilm growth and treatment in the cystic fibrosis lung.

Lung failure due to chronic bacterial infection is the leading cause of death for patients with cystic fibrosis (CF). It is thought that the chronic nature of these infections is, in part, due to the increased tolerance and recalcitrant behaviour of bacteria growing as biofilms. Inhalation of silver carbene complex (SCC) antimicrobial, either encased in polymeric biodegradable particles or in aqueous form, has been proposed as a treatment. Through a coordinated experimental and mathematical modelling effort, we examine this proposed treatment of lung biofilms. Pseudomonas aeruginosa biofilms grown in a flow-cell apparatus irrigated with an artificial CF sputum medium are analysed as an in vitro model of CF lung infection. A 2D mathematical model of biofilm growth within the flow-cell is developed. Numerical simulations demonstrate that SCC inactivation by the environment is critical in aqueous SCC, but not SCC-polymer, based treatments. Polymer particle degradation rate is shown to be an important parameter that can be chosen optimally, based on environmental conditions and bacterial susceptibility.

Nanoparticle deposition onto biofilms.

We develop a mathematical model of nanoparticles depositing onto and penetrating into a biofilm grown in a parallel-plate flow cell. We carry out deposition experiments in a flow cell to support the modeling. The modeling and the experiments are motivated by the potential use of polymer nanoparticles as part of a treatment strategy for killing biofilms infecting the deep passages in the lungs. In the experiments and model, a fluid carrying polymer nanoparticles is injected into a parallel-plate flow cell in which a biofilm has grown over the bottom plate. The model consists of a system of transport equations describing the deposition and diffusion of nanoparticles. Standard asymptotic techniques that exploit the aspect ratio of the flow cell are applied to reduce the model to two coupled partial differential equations. We perform numerical simulations using the reduced model. We compare the experimental observations with the simulation results to estimate the nanoparticle sticking coefficient and the diffusion coefficient of the nanoparticles in the biofilm. The distributions of nanoparticles through the thickness of the biofilm are consistent with diffusive transport, and uniform distributions through the thickness are achieved in about four hours. Nanoparticle deposition does not appear to be strongly influenced by the flow rate in the cell for the low flow rates considered.

Development of the Pseudomonas aeruginosa mushroom morphology and cavity formation by iron-starvation: a mathematical modeling study.

We present a mathematical model of mushroom-like architecture and cavity formation in Pseudomonas aeruginosa biofilms. We demonstrate that a proposed disparity in internal friction between the stalk and cap extracellular polymeric substances (EPS) leads to spatial variation in volumetric expansion sufficient to produce the mushroom morphology. The capability of diffusible signals to induce the formation of a fluid-filled cavity within the cap is then investigated. We assume that conversion of bacteria to the planktonic state within the cap occurs in response to the accumulation or depletion of some signal molecule. We (a) show that neither simple nutrient starvation nor signal production by one or more subpopulations of bacteria is sufficient to trigger localized cavity formation. We then (b) demonstrate various hypothetical scenarios that could result in localized cavity formation. Finally, we (c) model iron availability as a detachment signal and show simulation results demonstrating cavity formation by iron starvation. We conclude that iron availability is a plausible mechanism by which fluid-filled cavities form in the cap region of mushroom-like structures.

Microhotplate Temperature Sensor Calibration and BIST.

In this paper we describe a novel long-term microhotplate temperature sensor calibration technique suitable for Built-In Self Test (BIST). The microhotplate thermal resistance (thermal efficiency) and the thermal voltage from an integrated platinum-rhodium thermocouple were calibrated against a freshly calibrated four-wire polysilicon microhotplate-heater temperature sensor (heater) that is not stable over long periods of time when exposed to higher temperatures. To stress the microhotplate, its temperature was raised to around 400 °C and held there for days. The heater was then recalibrated as a temperature sensor, and microhotplate temperature measurements were made based on the fresh calibration of the heater, the first calibration of the heater, the microhotplate thermal resistance, and the thermocouple voltage. This procedure was repeated 10 times over a period of 80 days. The results show that the heater calibration drifted substantially during the period of the test while the microhotplate thermal resistance and the thermocouple-voltage remained stable to within about plus or minus 1 °C over the same period. Therefore, the combination of a microhotplate heater-temperature sensor and either the microhotplate thermal resistance or an integrated thin film platinum-rhodium thermocouple can be used to provide a stable, calibrated, microhotplate-temperature sensor, and the combination of the three sensor is suitable for implementing BIST functionality. Alternatively, if a stable microhotplate-heater temperature sensor is available, such as a properly annealed platinum heater-temperature sensor, then the thermal resistance of the microhotplate and the electrical resistance of the platinum heater will be sufficient to implement BIST. It is also shown that aluminum- and polysilicon-based temperature sensors, which are not stable enough for measuring high microhotplate temperatures (>220 °C) without impractically frequent recalibration, can be used to measure the silicon substrate temperature if never exposed to temperatures above about 220 °C.

Reducing children's injection pain: lidocaine patches versus topical benzocaine gel.

PURPOSE: The purpose of this study was to compare the effectiveness of lidocaine patches and topical anesthetic gel in reducing injection pain in children. METHODS: Thirty-two children received bilateral greater palatine injections of 0.2 cc of 2% lidocaine with 1:100,000 epinephrine at the same visit. Injections followed a 15 minute application of DentiPatch (20% lidocaine) or a 1 minute application of topical anesthetic gel (Topex, 20% benzocaine). Each child completed a Faces Pain Scale and Visual Analog Scale after each injection and was asked which injection hurt more. Injections were videotaped and two independent evaluators, using the Sounds, Eyes, and Motor Scale, rated observed pain-related behavior. Inter-rater reliability was established at 96%. RESULTS: A significant difference was shown in observed pain-sounds favoring use of the DentiPatch (P < .003, Wilcoxon Sign Rank Test). Using Wilcoxon Sign Rank Test and paired t-tests, no significant differences were shown in either reported pain or observed pain-motor. CONCLUSIONS: A statistically significant decrease in observed verbal indicators of injection pain was found when the DentiPatch was used 20%: compared to a 1 minute application of topical anesthetic gel. However, no significant difference was found between the two study groups in either reported pain or observed pain-motor responses.

The Kelvin and Temperature Measurements.

The International Temperature Scale of 1990 (ITS-90) is defined from 0.65 K upwards to the highest temperature measurable by spectral radiation thermometry, the radiation thermometry being based on the Planck radiation law. When it was developed, the ITS-90 represented thermodynamic temperatures as closely as possible. Part I of this paper describes the realization of contact thermometry up to 1234.93 K, the temperature range in which the ITS-90 is defined in terms of calibration of thermometers at 15 fixed points and vapor pressure/temperature relations which are phase equilibrium states of pure substances. The realization is accomplished by using fixed-point devices, containing samples of the highest available purity, and suitable temperature-controlled environments. All components are constructed to achieve the defining equilibrium states of the samples for the calibration of thermometers. The high quality of the temperature realization and measurements is well documented. Various research efforts are described, including research to improve the uncertainty in thermodynamic temperatures by measuring the velocity of sound in gas up to 800 K, research in applying noise thermometry techniques, and research on thermocouples. Thermometer calibration services and high-purity samples and devices suitable for "on-site" thermometer calibration that are available to the thermometry community are described. Part II of the paper describes the realization of temperature above 1234.93 K for which the ITS-90 is defined in terms of the calibration of spectroradiometers using reference blackbody sources that are at the temperature of the equilibrium liquid-solid phase transition of pure silver, gold, or copper. The realization of temperature from absolute spectral or total radiometry over the temperature range from about 60 K to 3000 K is also described. The dissemination of the temperature scale using radiation thermometry from NIST to the customer is achieved by calibration of blackbody sources, tungsten-strip lamps, and pyrometers. As an example of the research efforts in absolute radiometry, which impacts the NIST spectral irradiance and radiance scales, results with filter radiometers and a high-temperature blackbody are summarized.