A prospective observational study of the clinical and pathological impact of stereotactic body radiotherapy (SBRT) as a neoadjuvant strategy of chemoradiation in pancreatic cancer.

PURPOSE/OBJECTIVE(S): To improve the curative resection rates and prognoses, a variety of neoadjuvant (NA) strategies have been explored in PDAC. In our institution, non-metastatic PDACs have been treated with a NA intent with induction multiagent chemotherapy and SBRT. The primary endpoint was to increase R0 resection rate. The secondary endpoints were the analysis of the clinical tolerance, the pathological response, the local control (LC) and the OS. MATERIALS/METHODS: All consecutive patients with non-metastatic PDAC underwent SBRT as part of the NA strategy were included. A total dose of 40-62 Gy were delivered in 5-10 fractions. Surgery was performed after SBRT and restaging. RESULTS: Since February 2014 to December 2018, 45 patients were enrolled. Thirty-two patients underwent surgery (71.1%), 10 out of 15 were initially unresectable disease patients (66.75%). R0 resection rate was 93% (30 patients) and pN0 status was achieved in 20 patients (60.6%). Tumour regression grade (TRG): 12 patients with complete response or marked response (TRG 0-1: 37.5%), 16 patients with moderate response (TRG 2: 50%) and four patients with poor response (TRG 3: 12.5%). The median follow-up was 16.2 m (range 6.6-59.6 m) since diagnosis. The LC rate achieved was very high (95.5%). Actuarial 12 and 24 m OS was 67.4% and 35.9% respectively. No grade 3 or higher toxicity related to SBRT was observed. CONCLUSION: The results are encouraging, suggesting that SBRT has a significant role in the management of these patients and further studies will be necessary to prove these findings.

Effects of the Temperature and Ethanol on the Kinetics of Proanthocyanidin Adsorption in Model Wine Systems.

The kinetics and quantitative and qualitative effects of grape proanthocyanidin (PA) adsorption to grape skin-derived cell wall material (CWM) were investigated in five different temperature-ethanol conditions. Progress curves for each condition were constructed by monitoring the decrease in concentration of PA solutions after exposure to CWM over 720 min. Adsorption isotherms were constructed for each condition, and a Langmuir equation model was applied to each via regression analysis. Compositional changes in the PA solutions after exposure to CWM were determined using phloroglucinolysis and gel permeation chromatography (GPC). A negative correlation between PA adsorption and both the temperature and ethanol concentration was found. Progress curves suggested that both the temperature and ethanol affect the equilibration rate of the adsorption reactions. Additionally, equilibration rates for lower temperature and ethanol concentration conditions were found to be much longer than previously reported, taking up to 720 min. Phloroglucinolysis results showed no discernible correlation between the temperature or ethanol concentration and percent galloylation or percent gallo units of adsorbed compounds. Analyses by phloroglucinolysis and GPC indicate a preferential adsorption of larger molecular weight PAs under all conditions, although no discernible impact on PA composition was detected. Additionally, findings suggest that both the temperature and ethanol concentration impact the percent reduction in molar mass of the PA solution. Data from this study were ultimately utilized to develop a computational model for predicting phenolic extraction during red wine fermentations.

Choice of pyrolysis parameters for urban wastes affects soil enzymes and plant germination in a Mediterranean soil.

The production of organic waste has steadily increased in recent years, with subsequent impact on the environment. The European Union committed to diminish the volume of biodegradable municipal waste disposed of in landfills by 2016-2020. The synthesis of biochar from urban waste and its application to improve soil quality can constitute a novel route for valorization. The aim of this paper was to study the effect of three biochars originated from pyrolysis of the organic fraction of urban waste at two different temperatures (300°C and 500°C) and two residence times (1h and 5h) on the biochemical properties of an agricultural soil. Soil was amended with biochars at a rate of 8% and incubated for 74days. A phytotoxicity assay, using garden cress as the test species, was conducted. CO2 emissions, microbial biomass C and the enzymes dehydrogenase, phosphomonoesterase and ß-glucosidase were measured in tested soils. Biochars prepared at 300°C resulted in lower germination index values, which could partly be ascribed to a higher bioavailability of heavy metals and higher soluble organic matter, while the biochar prepared as 500°C exhibited a phytostimulant effect. Biochars produced at 300°C (B300-1h, B300-5h) augmented soil CO2 emissions while there was no effect on microbial respiration in the soil amended with the biochar prepared at 500°C. Pyrolysis temperature and, for some enzymes, residence time, controlled soil enzymatic activity.

Local allergic rhinitis is an independent rhinitis phenotype: The results of a 10-year follow-up study.

BACKGROUND: The knowledge about the natural history of local allergic rhinitis (LAR) is limited. One unmet question is to demonstrate whether LAR should be considered the first step in the development of allergic rhinitis (AR) or an independent phenotype. The aim of this study was to prospectively evaluate the natural history of a population with LAR, the potential conversion to AR with systemic atopy and the development of asthma during 10 years. METHODS: This is the second phase of a 10-year follow-up study of a cohort of 176 patients with LAR of recent onset and 115 age- and sex-matched healthy controls prospectively evaluated from 2005 to 2016. Clinical-demographic questionnaire, spirometry, skin prick test and specific IgE were evaluated yearly. Nasal allergen provocation tests (NAPT) with Dermatophagoides pteronyssinus, Alternaria alternata, Olea europaea and grass pollen were performed at baseline, and after 5 and 10 years. RESULTS: After 10-year LAR, patients experienced a significant and clinically relevant worsening of the rhinitis, with increase in emergency assistance, development of asthma, loss of allergen tolerance and impairment of the quality of life. This worsening became significant after 5 years and progressed throughout 10 years. A similar rate of development of AR with systemic atopy was detected in patients and controls (9.7% vs 7.8%, log-rank P=.623). In 5 patients, conversion to systemic atopy occurred >10 years (3%). CONCLUSIONS: LAR is a well-differentiated clinical entity with a low rate of development of systemic atopy, a natural evolution towards worsening and a risk factor for suffering asthma.

Anticonvulsant prescription patterns in patients covered by the Colombian Health System. / Patrones de prescripción de antiepilépticos en pacientes colombianos afiliados al Sistema General de Seguridad Social en Salud.

INTRODUCTION: Epilepsy is a group of long-term neurological disorders characterised by seizures that may respond to pharmacological treatment. OBJECTIVE: Determine the prescribing patterns of anticonvulsants for patients covered by the healthcare system in Colombia. METHODS: Cross-sectional study using a database containing 6.5 million people. From among residents in 88 Colombian cities, we selected patients of both sexes and all ages who were treated continuously with anticonvulsants between June and August 2012. We designed a drug consumption database and performed multivariate analysis for combination treatment and co-medication using SPSS 20.0. RESULTS: A total of 13,793 patients with mean age of 48.9±22.0 years were studied; 52.9% of the participants were women. Of the patient total, 74.4% were treated in monotherapy and 25.6% received two or more anticonvulsants. Globally, 72.9% of the patients were initially treated with classic anticonvulsants and 27.1% with new drugs. The most frequently used drugs were valproic acid (33.3%), carbamazepine (30.2%), clonazepam (15.7%), pregabalin (10.3%), phenytoin (10.0%) and levetiracetam (7.9%). Most agents were used in higher doses than recommended. The most common combinations were valproic acid+clonazepam (10.9%), valproic acid+carbamazepine (10.0%), carbamazepine+clonazepam (5.6%), valproic acid+phenytoin (4.4%). The most frequently prescribed co-medications were antihypertensives (61.0%), lipid-lowering drugs (45.8%), antidepressants (36.7%), antipsychotics (20.1%), anxiolytics (7.9%), and lithium (1.8%). DISCUSSION: Doctors predominantly prescribe drugs with a high therapeutic value and favour anticonvulsant monotherapy. Most agents were used in higher doses than recommended. This underlines the need to design educational strategies addressing these prescribing habits, and to undertake research on the effectiveness of treatment.

Array of biosensors for discrimination of grapes according to grape variety, vintage and ripeness.

A bioelectronic tongue based on nanostructured biosensors specific for the simultaneous detection of sugars and phenols has been developed. The array combined oxidases and dehydrogenases immobilized on a lipidic layer prepared using the Langmuir-Blodgett technique where Glucose oxidase, d-Fructose dehydrogenase, Tyrosinase or Laccase were imbibed. A phthalocyanine was co-immobilized in the sensing layer and used as electron mediator. The array thus formed has been used to analyze grapes and provides global information about the samples while providing specific information about their phenolic and their sugar content. Using Principal Component Analysis (PCA) the array of voltammetric biosensors has been successfully used to discriminate musts prepared from different varieties of grapes (Tempranillo, Garnacha, Cabernet-Sauvignon, Prieto Picudo and Mencía). Differences could be also detected between grapes of the same variety and cultivar harvested in two successive vintages (2012 and 2013). Moreover, the ripening of grapes could be monitored from veraison to maturity due to the changes in their phenolic and sugar content. Using Partial Least Squares (PLS-1) analysis, excellent correlations have been found between the responses provided by the array of biosensors and classical parameters directly related to phenols (total polyphenol index, TPI) and sugar concentration (degree Brix) measured by chemical methods with correlation coefficients close to 1 and errors close to 0. It is also worthy to notice the good correlations found with parameters associated with the pH and acidity that can be explained by taking into account the influence of the pH in the oxidation potentials of the phenols and in the enzymatic activity. This bioelectronic tongue can assess simultaneously the sugar and the phenolic content of grapes and could be used to monitor the maturity of the fruit and could be adapted easily to field analysis.

Preoperative treatment with gemcitabine plus nab-paclitaxel is a safe and effective chemotherapy for pancreatic adenocarcinoma.

INTRODUCTION: Recently, novel chemotherapeutic agents like nab-paclitaxel and gemcitabine demonstrated a survival benefit over gemcitabine alone in metastatic pancreatic cancer. However, there are limited clinical results using this chemotherapy in potentially resectable pancreatic adenocarcinoma. Our aim is to report the oncological results of patients affected by potentially resectable pancreatic adenocarcinoma that underwent surgery after a combination of gemcitabine and nab-paclitaxel. METHODS: A total of 25 patients have been included. We evaluated: (1) Drug toxicity; (2) tumoral response (tumoral size at CT scan, SUV of FDG PET-CT scan and CA 19.9; (3) resection rate; (4) R0 resection rate and histopathological response and (5) survival and disease free survival. RESULTS: Overall treatment was well tolerated. Treatment resulted in a statistical decrease of CA19-9 (p = 0.019) tumoral size (p = 0.04) and SUV (p = 0.004). The resection rate was 68% (17/25 patients). All specimens were R0 and 13 of 17 specimens had major pathological regressions (complete and important response). Median survival and medial disease free survival of patients that underwent surgery was 21 months and 19 months, respectively at a mean follow up of 38.5 months. CONCLUSIONS: This data suggests that nab-paclitaxel and gemcitabine is a safe and effective neoadjuvant treatment for potentially resectable pancreatic adenocarcinoma. This promising data should be confirmed in larger, randomized studies.

Cribiform variant of papillary thyroid cancer and familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome characterised by the progressive development of multiple colorectal adenomatous polyps and an increased incidence of colorectal carcinoma. It is often accompanied by other benign or malignant extracolonic manifestations, including gastric and duodenal tumours, osteomas, desmoid tumours, retinal pigmentation, and thyroid and adrenocortical tumours METHODS AND RESULTS: We report the case of a 42-year-old white female with FAP who was referred to our Endocrine Surgery Unit for surgery because of a palpable mass in the left side of the neck. An ultrasound-guided fine needle aspiration biopsy showed a cribriform-morular variant (CMV) of papillary thyroid carcinoma (PTC). The incidence, clinical presentation, histology and treatment options for this rare histological subtype are discussed. CONCLUSIONS: The diagnosis of CMV of PTC is very strongly related to the FAP syndrome and must be suspected when a thyroid node appears in FAP patients. Likewise, any patient without known FAP who presents this histology in a surgically biopsied or resected thyroid node should undergo total colonoscopy for screening of colonic polyposis and genetic study of the APC gene sequence.

Circadian Kisspeptin expression in human term placenta.

Kisspeptin is an essential gatekeeper of reproductive function. During pregnancy high circulating levels of kisspeptin have been described, however the clear role of this neuropeptide in pregnancy remains unknown. We tested the existence of rhythmic kisspeptin expression in human full-term placenta from healthy pregnant women at six different time points during the day. The data obtained by Western blotting were fitted to a mathematical model (Fourier series), demonstrating, for the first time, the existence of a circadian rhythm in placental kisspeptin expression.

Analysis of organic acids and phenols of interest in the wine industry using Langmuir-Blodgett films based on functionalized nanoparticles.

A chemically modified electrode consisting of Langmuir-Blodgett (LB) films of n-dodecanethiol functionalized gold nanoparticles (SDODAuNP-LB), was investigated as a voltammetric sensor of organic and phenolic acids of interest in the wine industry. The nanostructured films demonstrated interfacial properties being able to detect the main organic acids present in grapes and wines (tartaric, malic, lactic and citric). Compared to a bare ITO electrode, the modified electrodes exhibited a shift of the reduction potential in the less positive direction and a marked enhancement in the current response. Moreover, the increased electrocatalytic properties made it possible to distinguish between the different dissociable protons of polyprotic acids. The SDODAuNP-LB sensor was also able to provide enhanced responses toward aqueous solutions of phenolic acids commonly found in wines (caffeic and gallic acids). The presence of nanoparticles increased drastically the sensitivity toward organic acids and phenolic compounds. Limits of detection as low as 10(-6) mol L(-1) were achieved. Efficient catalytic activity was also observed in mixtures of phenolic acid/tartaric in the range of pHs typically found in wines. In such mixtures, the electrode was able to provide simultaneous information about the acid and the phenol concentrations with a complete absence of interferences. The excellent sensing properties shown by these sensors could be attributed to the electrocatalytic properties of the nanoparticles combined with the high surface to volume ratio and homogeneity provided by the LB technique used for the immobilization. Moreover, the LB technique also provided an accurate method to immobilize the gold nanoparticles giving rise to stable and reproducible sensors showing repeatability lower than 2% and reproducibility lower than 4% for all the compounds analyzed.

Synergistic electrocatalytic effect of nanostructured mixed films formed by functionalised gold nanoparticles and bisphthalocyanines.

A synergistic electrocatalytic effect was observed in sensors where two electrocatalytic materials (functionalized gold nanoparticles and lutetium bisphthalocyanine) were co-deposited using the Langmuir-Blodgett technique. Films were prepared using a novel method where water soluble functionalised gold nanoparticles [(11-mercaptoundecyl)tetra(ethylene glycol)] (SAuNPs) were inserted in floating films of lutetium bisphthalocyanine (LuPc2) and dimethyldioctadecylammonium bromide (DODAB) as the amphiphilic matrix. The formation of stable and homogeneous mixed films was confirmed by π-A isotherms, BAM, UV-vis and Raman spectroscopy, as well as by SEM and TEM microscopy. The synergistic effect towards hydroquinone of the electrodes modified with LuPc2:DODAB/SAuNP was characterised by an increase in the intensity of the redox peaks and a reduction of the overpotential. This synergistic electrocatalytic effect arose from the interaction between the SAuNPs and the phthalocyanines that occur in the Langmuir-Blodgett films and from the high surface area provided by the nanostructured films. The sensitivity increased with the amount of LuPc2 and SAuNPs inserted in the films and limits of detection in the range of 10(-7)molL(-1) were attained.

Evaluation of oxygen exposure levels and polyphenolic content of red wines using an electronic panel formed by an electronic nose and an electronic tongue.

An electronic panel formed by an electronic nose and an electronic tongue has been used to analyse red wines showing high and low phenolic contents, obtained by flash release and traditional soaking, respectively, and processed with or without micro-oxygenation. Four oxygen transfer rate conditions (0.8, 1.9, 8.0, and 11.9 µl oxygen/bottle/day) were ensured by using synthetic closures with controlled oxygen permeability and storage under controlled atmosphere. Twenty-five chemical parameters associated with the polyphenolic composition, the colour indices and the levels of oxygen were measured in triplicate and correlated with the signals registered (seven replicas) by means of the electronic nose and the electronic tongue using partial least squares regression analysis. The electronic nose and the electronic tongue showed particularly good correlations with those parameters associated with the oxygen levels and, in particular, with the influence of the porosity of the closure to oxygen exposure. In turn, the electronic tongue was particularly sensitive to redox species including oxygen and phenolic compounds. It has been demonstrated that a combined system formed from the electronic nose and the electronic tongue provides information about the chemical composition of both the gas and the liquid phase of red wines. This complementary information improves the capacity to predict values of oxygen-related parameters, phenolic content and colour parameters.

Bioelectronic tongue based on lipidic nanostructured layers containing phenol oxidases and lutetium bisphthalocyanine for the analysis of grapes.

In this work, a multisensor system formed by nanostructured voltammetric biosensors based on phenol oxidases (tyrosinase and laccase) has been developed. The enzymes have been incorporated into a biomimetic environment provided by a Langmuir-Blodgett (LB) film of arachidic acid (AA). Lutetium bisphthalocyanine (LuPc2) has also been introduced in the films to act as electron mediator. The incorporation of the enzymes to the floating layers to form Tyr/AA/LuPc2 and Lac/AA/LuPc2 films has been confirmed by the expansion in the surface pressure isotherms and by the AFM images. The voltammetric response towards six phenolic compounds demonstrates the enhanced performance of the biosensors that resulted from a preserved activity of the tyrosinase and laccase combined with the electron transfer activity of LuPc2. Biosensors show improved detection limits in the range of 10(-7)-10(-8) mol L(-1). An array formed by three sensors AA/LuPc2, Tyr/AA/LuPc2 and Lac/AA/LuPc2 has been employed to discriminate phenolic antioxidants of interest in the food industry. The Principal Component Analysis scores plot has demonstrated that the multisensor system is able to discriminate phenols according to the number of phenolic groups attached to the structure. The system has also been able to discriminate grapes of different varieties according to their phenolic content. This good performance is due to the combination of four factors: the high functionality of the enzyme obtained using a biomimetic immobilization, the signal enhancement caused by the LuPc2 mediator, the improvement in the selectivity induced by the enzymes and the complementary activity of the enzymatic sensors demonstrated in the loading plots.

Use of ergotamine: do physicians in Colombia know how to prescribe it?

INTRODUCTION: Ergot derivatives are drugs with vasoconstrictor effects that are used to abort migraine attacks. This study aims to determine how ergot derivatives are prescribed by physicians in Colombia, find variables associated with inappropriate prescribing, and review potential interactions in our patients. METHODS: We reviewed 86 411 formulas during April 2012, identifying the prescription by drug, dose, interval, duration of use, and indication. We interviewed 288 randomly selected patients in whom we also investigated concomitant use of a) antihypertensive agents b) ischaemic heart disease treatments c) antiretrovirals d) other antimigraine drugs, and e) macrolides, because of their potential for interactions. RESULTS: We identified 801 prescriptions from patients in 27 cities with a mean age of 35.1±14.1 years; 82.5% of the prescriptions were for women, 96.5% were written by primary care physicians, and 65.4% (n=524) corresponded to migraine treatments. There were 26 different prescription types and 797 prescriptions were incorrect with regard to usage recommendations (99.5%). Inappropriate prescribing was significantly associated with the health centre providing patient care (P=.005). Of the patients who were interviewed by telephone, 266 (92.4%) took the drug according to the erroneous indication. A total of 54 patients (6.7%) were treated with antihypertensive drugs, 24 (2.9%) with macrolides, and 5 (0.6%) with another concomitant antimigraine drug. DISCUSSION: Most patients take ergotamine improperly, apart from the fact that potential interactions may increase the risk of health problems such as ergotism and coronary events. Physicians will require assessment measures, updated information, and continuous training.

Recommendations of a group of experts for the pathological assessment of tumour regression of liver metastases of colorectal cancer and damage of non-tumour liver tissue after neoadjuvant therapy.

Colorectal cancer (CRC) incidence has increased during the past decades in Spain, being the first malignant tumour in incidence. Observed mortality for CRC is mainly due to liver and lung metastases. The only curative treatment is surgery; new surgical techniques and neoadjuvant treatments have increased the number of surgery candidate patients. Patients should be managed with a multidisciplinary approach that includes imaging techniques, chemotherapy, surgery and pathological assessment. As an answer to this approach, a group of pathology experts interested on CRC liver metastases aimed to review the diagnosis and prognosis of liver mestastases and developed practical recommendations for its assessment. The expert group revised the current literature and prepared questions to be discussed based on available evidence and on their clinical practise. As a result, recommendations for the assessment of tumour regression of liver metastases are proposed, which could be implemented in oncology centres allowing assessment standardisation for these patients. Prospective multi-center studies to evaluate these recommendations validity will further contribute to improve the standard care of CRC liver metastases patients.

Stromal disrupting effects of nab-paclitaxel in pancreatic cancer.

BACKGROUND: Nab-paclitaxel and gemcitabine have demonstrated a survival benefit over gemcitabine alone in advanced pancreatic cancer (PDA). This study aimed to investigate the clinical, biological, and imaging effects of the regimen in patients with operable PDA. METHODS: Patients with operable PDA received two cycles of nab-paclitaxel and gemcitabine before surgical resection. FDG-PET and CA19.9 tumour marker levels were used to measure clinical activity. Effects on tumour stroma were determined by endoscopic ultrasound (EUS) elastography. The collagen content and architecture as well as density of cancer-associated fibroblasts (CAFs) were determined in the resected surgical specimen and compared with a group of untreated and treated with conventional chemoradiation therapy controls. A co-clinical study in a mouse model of PDA was conducted to differentiate between the effects of nab-paclitaxel and gemcitabine. RESULTS: A total of 16 patients were enrolled. Treatment resulted in significant antitumour effects with 50% of patients achieving a >75% decrease in circulating CA19.9 tumour marker and a response by FDG-PET. There was also a significant decrement in tumour stiffness as measured by EUS elastography. Seven of 12 patients who completed treatment and were operated had major pathological regressions. Analysis of residual tumours showed a marked disorganised collagen with a very low density of CAF, which was not observed in the untreated or conventionally treated control groups. The preclinical co-clinical study showed that these effects were specific of nab-paclitaxel and not gemcitabine. CONCLUSION: These data suggest that nab-paclitaxel and gemcitabine decreases CAF content inducing a marked alteration in cancer stroma that results in tumour softening. This regimen should be studied in patients with operable PDA.

Morphometric changes in the dog trochlear nerve with growth.

The objective of this work was to analyse changes in morphometric characteristics related to growth in the trochlear nerve in dogs. Twenty beagles, split into four dog age groups (A, 7 days; B, 21 days; C, 35 days; D, 49 days and E, 4 years), were used. The right intracranial portion of the nerve was analysed by light and electron microscopy. The nerve cross-sectional area was calculated. Number, diameter and cross-sectional area of unmyelinated and myelinated fibres were also calculated. In myelinated fibres, the corresponding axon area and diameter and myelin sheath thickness were also calculated. The number of myelinated and unmyelinated fibres was 1070.25±112.07 and 592.25±467.53 in group A, 1367±57.98 and 143.67±54.37 in group B, 1574.20±299.50 and 151.67±51.73 in group C, 1340.33±151 and 127±48.75 in group D and 1476±260.71 and 284±101.82 in group E. The mean diameter for myelinated and unmyelinated fibres was 4.37±0.17 µm and 0.41±0.08 µm for group A; 6.21±0.12 µm and 0.30±0.03 µm for B; 6.90±0.91 µm and 0.32±0.03 µm for C; 7.86±1.19 µm and 0.32±0.02 µm for D; 10.63±0.50 µm and 0.30±0.01 µm for E, respectively. This nerve possesses similar structural and ultrastructural features to the same nerve in other species and modifies its morphometry with growth. Results could enhance the understanding of pathological disorders.