Therapeutic drug monitoring of neoadjuvant mFOLFIRINOX in resected pancreatic ductal adenocarcinoma.

BACKGROUND: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer. METHODS: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated. RESULTS: By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg·h/mL or CPT-11 AUC values below 10 mcg·h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC ≥28 mcg·h/mL [HR = 0.251, 95% CI 0.096-0.656; p = 0.005] and CPT-11 AUC <10 mcg·h/mL [HR = 0.189, 95% CI 0.073-0.486, p = 0.001]. CONCLUSIONS: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma.

Interaction of a Migrating Cell Monolayer with a Flexible Fiber.

Mechanical forces influence the development and behavior of biological tissues. In many situations, these forces are exerted or resisted by elastic compliant structures such as the own-tissue cellular matrix or other surrounding tissues. This kind of tissue-elastic body interactions are also at the core of many state-of-the-art in situ force measurement techniques employed in biophysics. This creates the need to model tissue interaction with the surrounding elastic bodies that exert these forces, raising the question of which are the minimal ingredients needed to describe such interactions. We conduct experiments in which migrating cell monolayers push on carbon fibers as a model problem. Although the migrating tissue is able to bend the fiber for some time, it eventually recoils before coming to a stop. This stop occurs when cells have performed a fixed mechanical work on the fiber, regardless of its stiffness. Based on these observations, we develop a minimal active-fluid model that reproduces the experiments and predicts quantitatively relevant features of the system. This minimal model points out the essential ingredients needed to describe tissue-elastic solid interactions: an effective inertia and viscous stresses.

Growth of a bubble cloud in CO2-saturated water under microgravity.

The diffusion-driven growth of a dense cloud of bubbles immersed in a gas-supersaturated liquid is a problem that finds applications in several modern technologies such as solvent-exchange micro-reactors, nanotechnology or the manufacturing of foamy materials. However, under Earth's gravity conditions, these dynamics can only be observed for a very limited time if the cloud is not attached to a surface, due to the action of buoyancy, i.e. of gravity effects. Here, we present experimental observations of the time evolution of dense bubble clouds growing in CO2-supersaturated water under microgravity conditions. We report the existence of three regimes where the bubble cloud exhibits different growth rates. At short times, each bubble grows independently following the Epstein-Plesset equation. Later on, bubbles start to interact with each other and their growth rate diminishes as they compete for the available CO2. When this happens, the growth rate slows down. This occurs earlier the deeper the bubble is in the cloud. Finally, at long times, only those bubbles on the husk continue growing. These regimes may be qualitatively described by a mathematical model where each individual bubble grows in the presence of a constellation of point mass sinks. Despite the model being only valid for dilute bubble clouds, its predictions are consistent with the experimental observations, even though the bubble clouds we observe are rather dense.

Electrolysis-Driven and Pressure-Controlled Diffusive Growth of Successive Bubbles on Microstructured Surfaces.

Control over the bubble growth rates forming on the electrodes of water-splitting cells or chemical reactors is critical with respect to the attainment of higher energy efficiencies within these devices. This study focuses on the diffusion-driven growth dynamics of a succession of H2 bubbles generated at a flat silicon electrode substrate. Controlled nucleation is achieved by means of a single nucleation site consisting of a hydrophobic micropit etched within a micrometer-sized pillar. In our experimental configuration of constant-current electrolysis, we identify gas depletion from (i) previous bubbles in the succession, (ii) unwanted bubbles forming on the sidewalls, and (iii) the mere presence of the circular cavity where the electrode is being held. The impact of these effects on bubble growth is discussed with support from numerical simulations. The time evolution of the dimensionless bubble growth coefficient, which is a measure of the overall growth rate of a particular bubble, of electrolysis-generated bubbles is compared to that of CO2 bubbles growing on a similar surface in the presence of a supersaturated solution of carbonated water. For electrolytic bubbles and under the range of current densities considered here (5-15 A/m2), it is observed that H2 bubble successions at large gas-evolving substrates first experience a stagnation regime, followed by a fast increase in the growth coefficient before a steady state is reached. This clearly contradicts the common assumption that constant current densities must yield time-invariant growth rates. Conversely, for the case of CO2 bubbles, the growth coefficient successively decreases for every subsequent bubble as a result of the persistent depletion of dissolved CO2.

Physics of beer tapping.

The popular bar prank known in colloquial English as beer tapping consists in hitting the top of a beer bottle with a solid object, usually another bottle, to trigger the foaming over of the former within a few seconds. Despite the trick being known for a long time, to the best of our knowledge, the phenomenon still lacks scientific explanation. Although it seems natural to think that shock-induced cavitation enhances the diffusion of CO2 from the supersaturated bulk liquid into the bubbles by breaking them up, the subtle mechanism by which this happens remains unknown. Here, we show that the overall foaming-over process can be divided into three stages where different physical phenomena take place in different time scales: namely, the bubble-collapse (or cavitation) stage, the diffusion-driven stage, and the buoyancy-driven stage. In the bubble-collapse stage, the impact generates a train of expansion-compression waves in the liquid that leads to the fragmentation of preexisting gas cavities. Upon bubble fragmentation, the sudden increase of the interface-area-to-volume ratio enhances mass transfer significantly, which makes the bubble volume grow by a large factor until CO2 is locally depleted. At that point buoyancy takes over, making the bubble clouds rise and eventually form buoyant vortex rings whose volume grows fast due to the feedback between the buoyancy-induced rising speed and the advection-enhanced CO2 transport from the bulk liquid to the bubble. The physics behind this explosive process sheds insight into the dynamics of geological phenomena such as limnic eruptions.

Predicting Severe Haematological Toxicity in Gastrointestinal Cancer Patients Undergoing 5-FU-Based Chemotherapy: A Bayesian Network Approach.

PURPOSE: Severe toxicity is reported in about 30% of gastrointestinal cancer patients receiving 5-Fluorouracil (5-FU)-based chemotherapy. To date, limited tools exist to identify at risk patients in this setting. The objective of this study was to address this need by designing a predictive model using a Bayesian network, a probabilistic graphical model offering robust, explainable predictions. METHODS: We utilized a dataset of 267 gastrointestinal cancer patients, conducting preprocessing, and splitting it into TRAIN and TEST sets (80%:20% ratio). The RandomForest algorithm assessed variable importance based on MeanDecreaseGini coefficient. The bnlearn R library helped design a Bayesian network model using a 10-fold cross-validation on the TRAIN set and the aic-cg method for network structure optimization. The model's performance was gauged based on accuracy, sensitivity, and specificity, using cross-validation on the TRAIN set and independent validation on the TEST set. RESULTS: The model demonstrated satisfactory performance with an average accuracy of 0.85 (±0.05) and 0.80 on TRAIN and TEST datasets, respectively. The sensitivity and specificity were 0.82 (±0.14) and 0.87 (±0.07) for the TRAIN dataset, and 0.71 and 0.83 for the TEST dataset, respectively. A user-friendly tool was developed for clinical implementation. CONCLUSIONS: Despite several limitations, our Bayesian network model demonstrated a high level of accuracy in predicting the risk of developing severe haematological toxicity in gastrointestinal cancer patients receiving 5-FU-based chemotherapy. Future research should aim at model validation in larger cohorts of patients and different clinical settings.

Long-Term Outcome of Critically Ill Advanced Cancer Patients Managed in an Intermediate Care Unit.

Background: To analyze the long-term outcomes for advanced cancer patients admitted to an intermediate care unit (ImCU), an analysis of a do not resuscitate orders (DNR) subgroup was made. Methods: A retrospective observational study was conducted from 2006 to January 2019 in a single academic medical center of cancer patients with stage IV disease who suffered acute severe complications. The Simplified Acute Physiology Score 3 (SAPS 3) was used as a prognostic and severity score. In-hospital mortality, 30-day mortality and survival after hospital discharge were calculated. Results: Two hundred and forty patients with stage IV cancer who attended at an ImCU were included. In total, 47.5% of the cohort had DNR orders. The two most frequent reasons for admission were sepsis (32.1%) and acute respiratory failure (excluding sepsis) (38.7%). Mortality in the ImCU was 10.8%. The mean predicted in-hospital mortality according to SAPS 3 was 51.9%. The observed in-hospital mortality was 37.5% (standard mortality ratio of 0.72). Patients discharged from hospital had a median survival of 81 (30.75−391.25) days (patients with DNR orders 46 days (19.5−92.25), patients without DNR orders 162 days (39.5−632)). The observed mortality was higher in patients with DNR orders: 52.6% vs. 23.8%, p 0 < 0.001. By multivariate logistic regression, a worse ECOG performance status (3−4 vs. 0−2), a higher SAPS 3 Score and DNR orders were associated with a higher in-hospital mortality. By multivariate analysis, non-invasive mechanical ventilation, higher bilirubin levels and DNR orders were significantly associated with 30-day mortality. Conclusion: For patients with advanced cancer disease, even those with DNR orders, who suffer from acute complications or require continuous monitoring, an ImCU-centered multidisciplinary management shows encouraging results in terms of observed-to-expected mortality ratios.

The mechanics of the adhesive locomotion of terrestrial gastropods.

Research on the adhesive locomotion of terrestrial gastropods is gaining renewed interest as it provides a source of guidance for the design of soft biomimetic robots that can perform functions currently not achievable by conventional rigid vehicles. The locomotion of terrestrial gastropods is driven by a train of periodic muscle contractions (pedal waves) and relaxations (interwaves) that propagate from their tails to their heads. These ventral waves interact with a thin layer of mucus secreted by the animal that transmits propulsive forces to the ground. The exact mechanism by which these propulsive forces are generated is still a matter of controversy. Specifically, the exact role played by the complex rheological and adhesive properties of the mucus is not clear. To provide quantitative data that could shed light on this question, we use a newly developed technique to measure, with high temporal and spatial resolution, the propulsive forces that terrestrial gastropods generate while crawling on smooth flat surfaces. The traction force measurements demonstrate the importance of the finite yield stress of the mucus in generating thrust and are consistent with the surface of the ventral foot being lifted with the passage of each pedal wave. We also show that a forward propulsive force is generated beneath each stationary interwave and that this net forward component is balanced by the resistance caused by the outer rim of the ventral foot, which slides at the speed of the center of mass of the animal. Simultaneously, the animal pulls the rim laterally inward. Analysis of the traction forces reveals that the kinematics of the pedal waves is far more complex than previously thought, showing significant spatial variation (acceleration/deceleration) as the waves move from the tail to the head of the animal.

Use of Machine-Learning Algorithms in Intensified Preoperative Therapy of Pancreatic Cancer to Predict Individual Risk of Relapse.

BACKGROUND: Although surgical resection is the only potentially curative treatment for pancreatic cancer (PC), long-term outcomes of this treatment remain poor. The aim of this study is to describe the feasibility of a neoadjuvant treatment with induction polychemotherapy (IPCT) followed by chemoradiation (CRT) in resectable PC, and to develop a machine-learning algorithm to predict risk of relapse. METHODS: Forty patients with resectable PC treated in our institution with IPCT (based on mFOLFOXIRI, GEMOX or GEMOXEL) followed by CRT (50 Gy and concurrent Capecitabine) were retrospectively analyzed. Additionally, clinical, pathological and analytical data were collected in order to perform a 2-year relapse-risk predictive population model using machine-learning techniques. RESULTS: A R0 resection was achieved in 90% of the patients. After a median follow-up of 33.5 months, median progression-free survival (PFS) was 18 months and median overall survival (OS) was 39 months. The 3 and 5-year actuarial PFS were 43.8% and 32.3%, respectively. The 3 and 5-year actuarial OS were 51.5% and 34.8%, respectively. Forty-percent of grade 3-4 IPCT toxicity, and 29.7% of grade 3 CRT toxicity were reported. Considering the use of granulocyte colony-stimulating factors, the number of resected lymph nodes, the presence of perineural invasion and the surgical margin status, a logistic regression algorithm predicted the individual 2-year relapse-risk with an accuracy of 0.71 (95% confidence interval [CI] 0.56-0.84, p = 0.005). The model-predicted outcome matched 64% of the observed outcomes in an external dataset. CONCLUSION: An intensified multimodal neoadjuvant approach (IPCT + CRT) in resectable PC is feasible, with an encouraging long-term outcome. Machine-learning algorithms might be a useful tool to predict individual risk of relapse. A small sample size and therapy heterogeneity remain as potential limitations.

Intraoperative brain ultrasound: a new approach to study flow dynamics in intracranial aneurysms.

The aim was to evaluate the potential of contrast-enhanced ultrasound to visualize the hemodynamics in intracranial aneurysms during neurosurgical intervention and to quantify the ultrasound data using digital particle image velocimetry (DPIV) technique. Aneurysms were scanned through the intact dura mater, preclipping and again postclipping after closure of the dura. After intravenous injection of Optison, angio-like views of the vascular tree surrounding the aneurysm, including the aneurysm sac, were obtained. Single ultrasound contrast agent microbubbles could be visualized in the aneurysm sac and the flow dynamics could be assessed in vivo. Spatial and temporal distributions of the velocity in the aneurysm and in the parent vessels were measured with DPIV using the backscattered signals from the microbubbles. Subsequently, the fluid stresses, vorticity, circulation, etc., were calculated from the velocity fields. We demonstrate in this paper that intraoperative contrast-enhanced ultrasound can be used to quantify the flow dynamics within an aneurysm.

Impact of surgery and chemotherapy on von Willebrand factor and vascular endothelial growth factor levels in colorectal cancer.

INTRODUCTION: von Willebrand factor (vWf) is thought to mediate binding of tumour cells to platelets and to favour their systemic spreading capacity. Platelets involved in tumour angiogenesis are capable of releasing vascular endothelial growth factor (VEGF). Hence, levels of vWf and VEGF may correlate with cancer stage. The objectives are determine the impact of surgery and chemotherapy on vWf and VEGF in colorectal cancer (CRC) patients. MATERIAL AND METHODS: Twenty healthy volunteers (group 1), 14 patients with locally advanced CRC (group 2) and 12 patients with metastatic CRC (group 3) were enrolled. Blood samples were taken at recruitment in group 1, and before and after surgery and chemotherapy in groups 2 and 3, respectively. Blood levels of vWf, VEGF, platelet count, C-reactive protein (CRP), ceruloplasmin and carcinoembrionary antigen (CEA) were measured. RESULTS: At baseline, group 3 showed higher concentrations of vWf than the other groups (p<0.05). In group 2, vWf became elevated 40% post-surgery (p=0.016), independently of changes in CRP or ceruloplasmin. In group 3, chemotherapy caused a 42% reduction in VEGF (p=0.015). CONCLUSIONS: There was a strong correlation between higher vWf levels and more advanced CRC stage at diagnosis. These levels were elevated post-surgery in patients with locally advanced CRC. Chemotherapy significantly decreased VEGF in metastatic CRC patients before CEA showed any significant change.

V Coloquio Internacional de Psicología del Deporte Público REDDECA. Imagen corporal y práctica de actividades físico-deportivas en estudiantes de nivel secundaria / V International Colloquium on Public Sport Psychology REDDECA. The body image and the practice of physical-sport activities in middle school students / V Colóquio Internacional sobre Psicologia do Desporte Público REDDECA. Imagem corporal e prática de atividades físico-desportivas em alunos do ensino secundário

El objetivo del estudio es valorar la imagen corporal, la práctica de actividades físico-deportivas y la percepción de la salud en escolares adolescentes de educación secundaria. Se presenta un diseño de estudio de tipo no experimental, descriptivo, comparativo y correlacional. La población objeto de estudio es una muestra de 416 estudiantes de educación secundaria de la ciudad de San Nicolás de los Garza, N. L. México seleccionados mediante un muestreo aleatorio y estratificado por género y grado escolar, con una edad entre 12 y 15 años (13,14 0,87), de los cuales 216 son hombres y 200 mujeres, con un peso promedio de 53,63 10,33 kg, unaestatura de 1,59 8,44 m y un IMC de 21 3,03. Se utilizó el cuestionario Body Shape Questionnaire (BSQ-8A), con 8 ítems y una escala de respuesta de 1 a 6 (donde 1 es nunca y 6 siempre), agrupados en puntos de corte sobre la procupación de la imagen corporal: < 19 ninguna, 19-25 leve, 26-33 moderada, > 33 marcada. El instrumento cuenta con buenas propiedades psicométricas. Para el análisis de los datos se utilizó el programa estadístico SPSS v24 y LISREL. En general los estudiantes adolescentes mexicanos tienen una preocupación importante de su imagen corporal, especialmente en las mujeres y los que perciben una mala salud, y esta no es determinante de la práctica de actividades físico-deportivas

The aim of the study is to value body image, the practice of physical-sport activities, and the perception of the health in school age adolescents in middle school. A non-experimental, descriptive, comparative and correlational study design is presented. The subject population of the study is a sample of 416 middle school students from the city San Nicolas de los Garza, N. L. Mexico selected by random sampling and stratified by gender and grade level, with an age between 12 and 15 years (13,14 0,87), of which 216 are male and 200 are female; with an average weight of 53,63 10,33 kg, a height of 1,59 8,44 m and a BMI of 21 3,03. The questionnaire Body Shape Questionnaire (BSQ-8A) was used, with 8 items and a response scale of 1 to 6 (where 1 is never and 6 is always), grouped in cut off points based on the concern of the body image: < 19 never, 19-25 slight, 26-33 moderate, >33 marked. The instrument has good psychometric properties. The statistical program SPSS v24 and LISREL were used for the analysis of the data. In general, Mexican adolescent students have an important concern for their body image, especially in women and those who perceive poor health, people who have a higher practice of physical-sports activities show a positive attitude towards their own body

O objetivo do estudo é avaliar a imagem corporal, a prática de atividades físico-desportivas e a percepção de saúde em alunos adolescentes do ensino médio. Apresenta-se um desenho de estudo não experimental, descritivo, comparativo e correlacional. A população alvo é uma amostra de 416 estudantes do ensino médio da cidade de San Nicolás de los Garza, N. L.México, selecionado por amostragem aleatória e estratificado por gênero e série escolar, com idade entre 12 e 15 anos (13,14 0,87), dos quais 216 são homens e 200 mulheres, com peso médio de 53,63 10,33 kg, altura de 1,59 8,44 m e IMC de 21 3,03. Foi utilizado o Body Shape Questionnaire (BSQ-8A), com 8 itens e uma escala de resposta de 1 a 6 (onde 1 nunca é e 6 sempre), agrupados em pontos de corte na preocupação com a imagem corporal: < 19 nenhum, 19-25 leve, 26-33 moderado, > 33 marcado. O instrumento tem boas propriedades psicométricas. O programa estatístico SPSS v24 e LISREL foram utilizados para a análise dos dados. Em geral, os estudantes adolescentes mexicanos têm uma preocupação importante com a sua imagem corporal, especialmente nas mulheres e naqueles que percebem a falta de saúde, e isso não é determinante para a prática de atividades físico-desportivas

Spatio-temporal analysis of eukaryotic cell motility by improved force cytometry.

Cell motility plays an essential role in many biological systems, but precise quantitative knowledge of the biophysical processes involved in cell migration is limited. Better measurements are needed to ultimately build models with predictive capabilities. We present an improved force cytometry method and apply it to the analysis of the dynamics of the chemotactic migration of the amoeboid form of Dictyostelium discoideum. Our explicit calculation of the force field takes into account the finite thickness of the elastic substrate and improves the accuracy and resolution compared with previous methods. This approach enables us to quantitatively study the differences in the mechanics of the migration of wild-type (WT) and mutant cell lines. The time evolution of the strain energy exerted by the migrating cells on their substrate is quasi-periodic and can be used as a simple indicator of the stages of the cell motility cycle. We have found that the mean velocity of migration v and the period of the strain energy T cycle are related through a hyperbolic law v = L/T, where L is a constant step length that remains unchanged in mutants with adhesion or contraction defects. Furthermore, when cells adhere to the substrate, they exert opposing pole forces that are orders of magnitude higher than required to overcome the resistance from their environment.

Impact of surgery and chemotherapy on von Willebrand factor and vascular endothelial growth factor levels in colorectal cancer

Introduction. von Willebrand factor (vWf) is thought to mediate binding of tumour cells to platelets and to favour their systemic spreading capacity. Platelets involved in tumour angiogenesis are capable of releasing vascular endothelial growth factor (VEGF). Hence, levels of vWf and VEGF may correlate with cancer stage. The objectives are determine the impact of surgery and chemotherapy on vWf and VEGF in colorectal cancer (CRC) patients. Material and methods. Twenty healthy volunteers (group 1), 14 patients with locally advanced CRC (group 2) and 12 patients with metastatic CRC (group 3) were enrolled. Blood samples were taken at recruitment in group 1, and before and after surgery and chemotherapy in groups 2 and 3, respectively. Blood levels of vWf, VEGF, platelet count, C-reactive protein (CRP), ceruloplasmin and carcinoembrionary antigen (CEA) were measured. Results. At baseline, group 3 showed higher concentrations of vWf than the other groups (p<0.05). In group 2, vWf became elevated 40% post-surgery (p=0.016), independently of changes in CRP or ceruloplasmin. In group 3, chemotherapy caused a 42% reduction in VEGF (p=0.015). Conclusions. There was a strong correlation between higher vWf levels and more advanced CRC stage at diagnosis. These levels were elevated post-surgery in patients with locally advanced CRC. Chemotherapy significantly decreased VEGF in metastatic CRC patients before CEA showed any significant change

No disponible