FAIRLANE, a double-blind placebo-controlled randomized phase II trial of neoadjuvant ipatasertib plus paclitaxel for early triple-negative breast cancer.

BACKGROUND: This hypothesis-generating trial evaluated neoadjuvant ipatasertib-paclitaxel for early triple-negative breast cancer (TNBC). PATIENTS AND METHODS: In this randomized phase II trial, patients with early TNBC (T ≥ 1.5 cm, N0-2) were randomized 1 : 1 to receive weekly paclitaxel 80 mg/m2 with ipatasertib 400 mg or placebo (days 1-21 every 28 days) for 12 weeks before surgery. Co-primary end points were pathologic complete response (pCR) rate (ypT0/TisN0) in the intention-to-treat (ITT) and immunohistochemistry phosphatase and tensin homolog (PTEN)-low populations. Secondary end points included pCR rate in patients with PIK3CA/AKT1/PTEN-altered tumors and pre-surgery response rates by magnetic resonance imaging (MRI). RESULTS: pCR rates with ipatasertib versus placebo were 17% versus 13%, respectively, in the ITT population (N = 151), 16% versus 13% in the immunohistochemistry PTEN-low population (N = 35), and 18% versus 12% in the PIK3CA/AKT1/PTEN-altered subgroup (N = 62). Rates of overall and complete response (CR) by MRI favored ipatasertib in all three populations (CR rate 39% versus 9% in the PIK3CA/AKT1/PTEN-altered subgroup). Ipatasertib was associated with more grade ≥3 adverse events (32% versus 16% with placebo), especially diarrhea (17% versus 1%). Higher cycle 1 day 8 (C1D8) immune score was significantly associated with better response only in placebo-treated patients. All ipatasertib-treated patients with low immune scores and a CR had PIK3CA/AKT1/PTEN-altered tumors. CONCLUSIONS: Adding ipatasertib to 12 weeks of paclitaxel for early TNBC did not clinically or statistically significantly increase pCR rate, although overall response rate by MRI was numerically higher with ipatasertib. The antitumor effect of ipatasertib was most pronounced in biomarker-selected patients. Safety was consistent with prior experience of ipatasertib-paclitaxel. A T-cell-rich environment at C1D8 had a stronger association with improved outcomes in paclitaxel-treated patients than seen for baseline tumor-infiltrating lymphocytes. This dependency may be overcome with the addition of AKT inhibition, especially in patients with PIK3CA/AKT1/PTEN-altered tumors. CLINICALTRIALS.GOV: NCT02301988.

Radiotherapy Learning in Medical Undergraduate Courses.

Approximately 60 % of all cancer patients receive radiotherapy as a component of their treatment. Radiation Oncology concepts, specifically, are not formally introduced to students in most traditional school curricula until their clinical rotations or may only be included as an optional elective during the core clinical clerkships. The aim of this study is to determine whether the teaching of Radiation Oncology by radiation oncologists, in the third year, in block diagnostic and therapeutic procedures, is helpful for student training and changes their attitude towards the specialty. We administered a pre-test and post-test examination of the concepts in general radiation oncology, radiation physics, radiobiology, breast cancer and their opinion to the third year medical students. The 10-question, multiple choice tests were administered before starting the lessons and when they finished the course. Of the 130 third year students, 95 (73.07 %) participated in the pre-test and post-test analysis. For the entire cohort, improvement was seen in all questions except one regarding physics. A statistically significant improvement (p < 0.005) was seen in the question regarding the aspects of general radiotherapy, radiobiology, acute and after-effects of radiation and the management of early-stage breast cancer. With an adequate methodology, third year students can learn aspects of Radiation Oncology.

Benefit to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2-positive primary breast cancer is independent of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) status.

BACKGROUND: Assessment of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) might be an important tool in identifying human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients unlikely to derive benefit from anti-HER2 therapies. However, studies to date have failed to demonstrate its predictive role in any treatment setting. PATIENTS AND METHODS: Prospectively collected baseline core biopsies from 429 early-stage HER2-positive breast cancer patients treated with trastuzumab, lapatinib, or their combination in the Neo-ALTTO study were stained using two anti-PTEN monoclonal antibodies (CST and DAKO). The association of PTEN status and PI3K pathway activation (defined as either PTEN loss and/or PIK3CA mutation) with total pathological complete response (tpCR) at surgery, event-free survival (EFS), and overall survival (OS) was evaluated. RESULTS: PTEN loss was observed in 27% and 29% of patients (all arms, n = 361 and n = 363) for CST and DAKO, respectively. PTEN loss was more frequently observed in hormone receptor (HR)-negative (33% and 36% with CST and DAKO, respectively) compared with HR-positive tumours (20% and 22% with CST and DAKO, respectively). No significant differences in tpCR rates were observed according to PTEN status. PI3K pathway activation was found in 47% and 48% of patients (all arms, n = 302 and n = 301) for CST and DAKO, respectively. Similarly, tpCR rates were not significantly different for those with or without PI3K pathway activation. Neither PTEN status nor PI3K pathway activation were predictive of tpCR, EFS, or OS, independently of treatment arm or HR status. High inter-antibody and inter-observer agreements were found (>90%). Modification of scoring variables significantly affected the correlation between PTEN and HR status but not with tpCR. CONCLUSION: These data show that PTEN status determination is not a useful biomarker to predict resistance to trastuzumab and lapatinib-based therapies. The lack of standardization of PTEN status determination may influence correlations between expression and relevant clinical end points. CLINICAL TRIALS: This trial is registered with ClinicalTrials.gov: NCT00553358.

Microsatellite and mitochondrial haplotype diversity reveals population differentiation in the tiger shrimp (Penaeus monodon) in the Indo-Pacific region.

The black tiger shrimp (Penaeus monodon) is an ecologically and economically important penaeid species and is widely distributed in the Indo-Pacific region. Here we investigated the genetic diversity of P. monodon (n = 355) from eight geographical regions by genotyping at 10 microsatellite loci. The average observed heterozygosity at various loci ranged from 0.638 to 0.743, indicating a high level of genetic variability in this region. Significant departures from Hardy-Weinberg equilibrium caused by heterozygote deficiency were recorded for most loci and populations. Pairwise F(ST) and R(ST) values revealed genetic differentiation among the populations. Evidence from the assignment test showed that the populations in the West Indian Ocean were unique, whereas other populations examined were partially admixed. In addition, the non-metric multidimensional scaling analysis indicated the presence of three geographic groups in the Indo-Pacific region, i.e. the African populations, a population from western Thailand and the remaining populations as a whole. We also sequenced and analysed the mitochondrial control region (mtCR) in these shrimp stocks to determine whether the nuclear and mitochondrial genomes show a similar pattern of genetic differentiation. A total of 262 haplotypes were identified, and nucleotide divergence among haplotypes ranged from 0.2% to 16.3%. Haplotype diversity was high in all populations, with a range from 0.969 to 1. Phylogenetic analysis using the mtCR data revealed that the West Indian Ocean populations were genetically differentiated from the West Pacific populations, consistent with the microsatellite data. These results should have implications for aquaculture management and conservation of aquatic diversity.

The use of breast imaging for predicting response to neoadjuvant lapatinib, trastuzumab and their combination in HER2-positive breast cancer: Results from Neo-ALTTO.

AIM: To determine the value of mammography and breast ultrasound (US) in predicting outcomes in HER2 positive breast cancer patients (pts) within Neo-ALTTO trial. PATIENTS AND METHODS: Mammography and US were required at baseline, week 6 and surgery. Two independent blinded investigators reviewed the measurements and assigned the corresponding response category. Pts showing complete or partial response according to RECIST (v1.1) were classified as responders. The association between imaging response at week 6 or prior to surgery was evaluated with respect to pathological complete response (pCR) and event-free Survival (EFS). RESULTS: Of the 455 pts enrolled in the trial, 267 (61%) and 340 (77%) had evaluable mammography and US at week 6; 248 (56%) and 309 (70%) pts had evaluable mammography and US prior to surgery. At week 6, 32% and 43% of pts were classified as responders by mammography and US, respectively. pCR rates were twice as high for responders than non-responders (week 6: 46% versus 23% by US, p < 0.0001; 41% versus 24% by mammography, p = 0.007). Positive and negative predictive values of mammography and US prior to surgery were 37% and 35%, and 82% and 70%, respectively. No significant correlation was found between response by mammography and/or US at week 6/surgery and EFS. CONCLUSIONS: Mammography and US were underused in Neo-ALTTO although US had the potential to assess early response whereas mammography to detect residual disease prior to surgery. Our data still emphasise the need for further imaging studies on pts treated with neoadjuvant HER2-targeted therapy.

Reordering of the ridge patterns of a stochastic electromagnetic field by diffraction due to an ideal slit.

We study the behavior of scarlets of a stochastic radiation field of fixed frequency in the presence of a slit pierced on an infinitely thin metallic screen of ideal conductivity. Our methodology involves the exact solution of the Maxwell equations with appropriate boundary conditions, the only approximations being those due to the numerical procedure. Our numerical simulations show that the field is unfolded into two components, a dominant one that is disordered and a weaker one that is ordered. The former still presents scarlets although modified, while the latter exhibits a pattern of perfectly coherent diffraction. Due to the dominant character of the disordered component, the general appearance of the scattered field is stochastic; however, an underlying order exists. Our results confirm, thus, a novel effect suggested previously in the context of stochastic electrodynamics.

25 Hz electromagnetic field exposure has no effect on cell cycle distribution and apoptosis in U-937 and HCA-2/1cch cells.

It is reported that exposure to 50 Hz extremely low-frequency electromagnetic field (ELF-EMF) can produce apoptosis and small variations in cell cycle distribution on different cell lines. In order to study the effect of ELF-EMF on tumoral cells in vitro, two cell lines (U-937, from a histiocytic lymphoma, and HCA-2/1cch, from a human colon adenocarcinoma) were exposed to 25 Hz, 1.5 mT, for 2 h and 45 min. Cell cycle distribution, apoptosis (spontaneous and dexamethasone-induced) and cell growth were evaluated. Neither significant alteration in cell cycle phases nor induction of apoptosis was observed. Nevertheless, the relative cell number was found to decrease to 55.84+/-7.35% (p <0.05, Student's t-test) for HCA-2/1cch cells after exposure to EMF in the presence of dexamethasone. The presence of dexamethasone during the EMF exposure could probably produce a decrease in the cell growth of this cell line.

Methotrexate cytotoxicity on MCF-7 breast cancer cells is not altered by exposure to 25 Hz, 1.5 mT magnetic field and iron (III) chloride hexahydrate.

The action of electromagnetic fields (EMF) on different pathways related to cell physiology, proliferation, toxicity of chemicals, gene expression, etc., are currently being investigated although the results are still not conclusive and even conflicting. In laboratory and animal studies, EMF has been found to produce a great variety of effects such as: increase in ornithine decarboxylase activity in breast, increase in beta-galactosidase gene expression and oncogene transcription after exposure to 50/60 Hz. Animal studies have shown that the use of EMF can enhance drug delivery across biological barriers (rat abdominal skin), using benzoic acid as the drug candidate. It has been reported by different authors that pulsed EMF (PEMF) can produce alterations in antineoplastic drugs potency. In the present study, we investigated the effects of PEMF on methotrexate cytotoxicity in MCF-7 breast cancer cells and the effects with simultaneous exposure to FeCl3. The data presented in the current report indicate that PEMF (25 Hz, 1.5 mT) do not induce modulation of the action of methotrexate (with and without iron-III) in MCF-7 cells when they are exposed to PEMF for 2 h/day during 3 days.

Kinetic determination of methotrimeprazine, thioridazine and their mixture by use of a modular stopped-flow/diode-array detection system.

The oxidation reactions of methotrimeprazine and thioridazine by iron(III) were used to develop kinetic methods based on measurements of the formation rate of the corresponding coloured phenothiazinyl free radicals. The calibration graphs were linear over the range 0.8-60 microg/ml for methotrimeprazine and 1.1-60 microg/ml for thioridazine. The relative standard deviation was 1.1-3.4%. The method was used to determine the analytes in commercially available pharmaceutical preparations. The different absorption maxima of the oxidation products formed and also the different, high initial rates of the reactions for both analytes allow their simultaneous determination by using a stopped-flow module coupled to a diode-array spectrophotometric detector. Reaction rate and absorbance increment measurements of the kinetic curves obtained were used to resolve mixtures of both phenothiazines by using the proportional-equation method and establishing three different equation systems that allowed the results obtained in each case to be compared. Mixtures of methotrimeprazine and thioridazine in ratios between 8:1 and 1:8 were satisfactorily resolved.

Kinetic fluorimetric determination of promethazine by a stopped-flow mixing technique.

The oxidation of promethazine to its corresponding fluorescent sulphoxide was used to develop a novel kinetic fluorimetric method for the determination of this drug. The use of a stopped-flow mixing technique makes use of an oxidizing reagent unnecessary because the oxidation is rapidly carried out by dissolved oxygen. The method is simple and fast as it only requires a few seconds to obtain kinetic data which allows ready application to routine analyses. The calibration graph is linear over the range 0.5-80 micrograms ml-1 and the precision (%RSD) is close to 2%. The method was applied to the determination of promethazine hydrochloride in two pharmaceutical preparations.

Kinetic determination of nortriptyline in pharmaceutical samples by use of photometric and fluorimetric detection.

A fast kinetic method is proposed for the photometric and fluorimetric determination of nortriptyline hydrochloride. The method involves measuring the rate of formation of an adduct with 4-chloro-7-nitrobenzofurazan, which exhibits light absorption and fluorescent properties, and the use of a stopped-flow mixing technique, which facilitates application to automatic routine analyses. The reaction rate is measured within only 30 s. The detection limit is 0.12 micrograms ml-1 (photometry) and 0.18 micrograms ml-1 (fluorimetry) and the calibration graph is linear up to 60 micrograms ml-1 in both cases. The precision (as RSD) is less than 1.5%. The proposed method was satisfactorily used for direct analysis of pharmaceutical preparations and a mean recovery near 100% was obtained with both photometric and fluorimetric detection.

Growth modification of human colon adenocarcinoma cells exposed to a low-frequency electromagnetic field.

The influence of variable low-intensity, low-frequency electromagnetic fields on culture cells is investigated. Human colon adenocarcinoma cells were exposed to a rectangular and variable magnetic field (1 and 25 Hz; 1.5 mT peak). Cultures were exposed to a dose for 15 and 360 minutes, and after 24 hours incubation, cell viability was measured with neutral red stain. The group treated for 15 minutes showed a statistically significant increase in cell growth with 1 Hz (p < 0.002) and 25 Hz (p < 0.003). In contrast, a significant decrease in cell growth was found in those cultures treated with 1 Hz for 360 minutes (p < 0.02). The effects reported could be influenced by the magnetic field frequency and the exposure time.

[Validity study of the current risk assessment scale for pressure ulcers in intensive care (EVARUCI)]. / Estudio de validez de la Escala de Valoración Actual del Riesgo de desarrollar Ulceras por presión en Cuidados Intensivos (EVARUCI).

UNLABELLED: Pressure ulcers (PU) are the most frequent injuries in critical patients whose management is the responsibility of the nurses. The first step for its prevention is to determine the patients at risk; however the usual risk assessment scales (Norton, Braden, etc.) do not have adequate specificity to do this. AIM: To study the validity of a current risk assessment scale of pressure ulcers in intensive care (EVARUCI). DESIGN: Prospective, descriptive study. SUBJECTS: Adult patients admitted to Intensive Care Unit (ICU) in the Hospital of Fuenlabrada without PU from February, the 1st, 2005 to January, the 31st, 2006. Demographic data were obtained from the admission records. Data on EVARUCI were daily collected and the patients were studied until they developed 1 of 2 outcomes: a) they developed a PU, or b) they left the ICU (death or exit to other nursing ward). METHODS: Four validity indexes were used: sensitivity, specificity, positive predictive value and negative predictive value. The area under the curve (AUC) of the receiver operating characteristic (ROC) was also used. These indicators were applied to the mean scores during the entire stay and to the initial and final scores in both groups (PU and NO PU). The SPSS v. 12.0 was used for the statistical analysis. RESULTS: A total of 97 patients were included, 62 of whom finished the study. Eleven patients (17.74%) developed PU. Of these, 57.69% were grade I. The most frequent site was in the sacral area (26.92%) and heels (23.08%). The results of the mean of the scores on the EVARUCI mean, initial and final data were: sensitivity (100%, 100%, 90.91%), specificity (68.63%, 49.02%, 92.16%), positive predictive value (40.74%, 29.73%, 71.43%) and negative predictive value (100%, 100%, 97.2%). AUC of ROC was 0.938, 0.909, 0.952, respectively. CONCLUSIONS: The EVARUCI scale is valid to detect patients at risk of development PU in ICU.

Coagulopatía temprana en trauma: ¿llegan los pacientes coagulopáticos a la sala de cirugía?: [revisión] / Early coagulopathy in trauma: do coagulopathic patients reach the operating room?: [review]

Introducción. De la coagulopatía aguda en el trauma, resultan múltiples complicaciones como la necesidad de administración de hemoderivados, mayor incidencia de disfunción orgánica, aumento de estancia en unidad de cuidados intensivos y mayor mortalidad. Con el conocimiento actual de la fisiopatología del trauma y la vía celular de la coagulación es ahora posible mejorar el dignóstico y tratamiento de la coagulopatía inicial y conseguir mejores resultados en nuestros centros. Métodos. Este artículo examina la fisiología básica de la coagulación, la etiología, el diagnóstico y el tratamiento de la coagulopatía temprana en trauma. La búsqueda se realizó con términos Mesh y no Mesh con conectores AND: Anesthesia-coagulophaty, postinjury and trauma thromboelastography, transfusion and trauma, shock-Mechanism and trauma review. Resultados. La coagulopatía aguda o temprana en trauma está directamente asociada al estado de shock y se caracteriza por anticoagulación e hiperfibrinolisis sistémica; hay evidencia de la implicación de la proteína C en este proceso. Se ha establecido que seis mecanismos fisiopatológicos multifactoriales pueden perpetuar la coagulopatía en los pacientes traumatizados; éstos son: inflamación, acidosis, hipotermia, shock, trauma tisular y hemodilución. El diagnóstico se realiza con las diferentes pruebas (TP, TPT, plaquetas) ya conocidas desde hace mucho tiempo, pero con limitaciones que reducen su utilidad clínica. Ahora la tromboelastografía nos puede ayudar a guiar la transfusión, con el concepto actual de transfusión temprana de glóbulos rojos, plasma y plaquetas, utilizando la mejor proporción según la evidencia disponible. Conclusiones. Contamos, con algún conocimiento sobre la fisiopatología de la coagulopatía asociada con trauma pero son necesarias más investigaciones, en este campo. El diagnóstico rápido y una intervención directa inmediata son importantes para mejorar el desenlace de nuestros pacientes.

Introduction. Acute coagulopathy in trauma results in multiple complications such as the need for blood products, higher rates of organ dysfunction, longer stay in the ICU and higher mortality. With the current knowledge of the pathophysiology of trauma and of the cellular coagulation pathway it is now possible to improve diagnosis and treatment of the initial coagulopathy and achieve better outcomes in our trauma centers. Methods. This paper looks into the basic physiology of coagulation, and the etiology, diagnosis and treatment of early coagulopathy in trauma. The search was done using Mesh and non-Mesh terms with AND connectors: Anesthesia-coagulopathy, postinjury and trauma thromboelastography, transfusion and trauma, shock-Mechanism and trauma review. Results. Acute or early coagulopathy in trauma is directly associated with a state of shock and is characterized by anticoagulation and systemic hyperfibrinolysis; protein C is known to be implicated in this process. It has also been determined that six multi-factorial pathophysiological mechanisms may perpetuate coagulopathy in trauma patients, namely, inflammation, acidosis, hypothermia, shock, tissue trauma and hemodilution. Diagnosis is made using the different tests (PT, PPT, platelets) that have been in use for a long time; however, these tests have drawbacks that limit their clinical usefulness. Thromboelastography can now help guide early transfusion using the best proportion of red blood cells, plasma and platelets on the basis of the best available evidence. Conclusions. We have some knowledge about the pathophysiology coagulopathy associated with trauma but more research in this field is needed. Rapid diagnosis and immediate intervention are important to improve the outcomes with our patients.

Impacts of quantization on the properties of liquid water.

The results of classical and quantum simulations of liquid water over a wide range of temperatures are compared to probe the impact of quantization on the properties of liquid water. We show that, when treated quantum mechanically, water molecules have an enhanced probability of accessing nontetrahedral coordination in the local three-dimensional structure. We discuss how this enhanced probability, also called "effective tunneling", is related to the dynamics of the hydrogen-bond breaking and molecular diffusion in the liquid. We explore in detail how local molecular environments affect the manifestation of quantum effects and identify a previously unreported and apparently unique behavior of the quantum mechanical uncertainty of the water molecule as a function of temperature. The nonmonotonic behavior of the quantum mechanical uncertainty with temperature is shown to be due to the notable strength of the water-water interaction in the condensed phase and becomes further evidence of the importance of the water structure in the properties of this ubiquitous liquid.

Quantum effects in ice Ih.

Quantum and classical simulations are carried out on ice Ih over a range of temperatures utilizing the TIP4P water model. The rigid-body centroid molecular dynamics method employed allows for the investigation of equilibrium and dynamical properties of the quantum system. The impact of quantization on the local structure, as measured by the radial and spatial distribution functions, as well as the energy is presented. The effects of quantization on the lattice vibrations, associated with the molecular translations and librations, are also reported. Comparison of quantum and classical simulation results indicates that shifts in the average potential energy are equivalent to rising the temperature about 80 K and are therefore non-negligible. The energy shifts due to quantization and the quantum mechanical uncertainties observed in ice are smaller than the values previously reported for liquid water. Additionally, we carry out a comparative study of melting in our classical and quantum simulations and show that there are significant differences between classical and quantum ice.

Quantum effects in light and heavy liquid water: A rigid-body centroid molecular dynamics study.

The centroid molecular dynamics (CMD) method is applied to the study of liquid water in the context of the rigid-body approximation. This rigid-body CMD technique, which is significantly more efficient than the standard CMD method, is implemented on the TIP4P model for water and used to examine isotopic effects in the equilibrium and dynamical properties of liquid H(2)O and D(2)O. The results obtained with this approach compare remarkably well with those determined previously with path integrals simulations as well as those obtained from the standard CMD method employing flexible models. In addition, an examination of the impact of quantization on the rotational and librational motion of the water molecule is also reported.

[Varicella pneumonia in the adult: study of 22 cases]. / Neumonía por varicela en el adulto: estudio de 22 casos.

BACKGROUND: Retrospective study of the varicella pneumonia in adults with clinical, therapeutic and evolutive features in 22 patients in the last 5 years. MATERIAL AND METHODS: The diagnosis was established by clinical and radiologic criteria in the course of varicella infection. The antecedents of pregnancy, smoking habit, previous contact with patients with varicella and underlying disease were evaluated. RESULTS: Twenty-two patients (14 males and 8 women: mean age 31 years. range: 22-40) were included in the study. None of them were immunocompromised, 16 (72.7%) have had previous contact with varicella patients. 19 (86.3%) were heavy smokers and none of the female patients was pregnant. All patients had fever and exanthem, cough had 20 (90.9%) dyspnea 16 (72.7%), chest pain 9 (40.9%) and hemoptysis 5 (22.7%). Only two patients showed pO2 < 60 mmHg. Chest X-ray revealed an interstitial pattern in 14 cases (63.3%), and micronodular in 8 (36.3%). All patients received treatment with intravenous acyclovir. Three patients (13.6%) were admitted to the Intensive Care Unit due to respiratory insufficiency, needing mechanical ventilation one of them (4.5%). Another three developed failure renal reversible associated with acyclovir. All patients had a favourable clinical course. CONCLUSIONS: We believe, that early, aggressive use of intravenous acyclovir in adult varicella pneumonia may be lifesaving, preventing progressive respiratory failure and reducing the high mortality rate of the disease. Therapy with corticosteroids should be considered in addition to antiviral therapy in patients with severe varicella pneumonia. While oral acyclovir chemoprophylaxis is probably beneficial in populations with chicken pox.