Characterization and Enhancement of Non-Invasive Recordings of Intestinal Myoelectrical Activity

Non

Floppy closing door epiglottis treated successfully with an mhealth application based on myofunctional therapy: a case report

We introduce the first case reported to date of a floppy closing door epiglottis in an OSA (obstructive sleep apnea) patient treated successfully with an Mhealth smartphone application based on myofunctional therapy

Enhancement of the non-invasive electroenterogram to identify intestinal pacemaker activity

Surface recording of electroenterogram (EEnG) is a non-invasive method for monitoring intestinal myoelectrical activity. However, surface EEnG is seriously affected by a variety of interferences: cardiac activity, respiration, very low frequency components and movement artefacts. The aim of this study is to eliminate respiratory interference and very low frequency components from external EEnG recording by means of empirical mode decomposition (EMD), so as to obtain more robust indicators of intestinal pacemaker activity from external EEnG signal. For this purpose, 11 recording sessions were performed in an animal model under fasting conditions and in each individual session the myoelectrical signal was recorded simultaneously in the intestinal serosa and the external abdominal surface in physiological states. Various parameters have been proposed for evaluating the efficacy of the method in reducing interferences: the signal-to-interference ratio (S/I ratio), attenuation of the target and interference signals, the normal slow wave percentage and the stability of the dominant frequency (DF) of the signal. The results show that the S/I ratio of the processed signals is significantly greater than the original values (9.66±4.44 dB vs. 1.23±5.13 dB), while the target signal was barely attenuated (-0.63±1.02 dB). The application of the EMD method also increased the percentage of the normal slow wave to 100% in each individual session and enabled the stability of the DF of the external signal to be increased considerably. Furthermore, the variation coefficient of the DF derived from the external processed signals is comparable to the coefficient obtained using internal recordings. Therefore the EMD method could be a very useful tool to improve the quality of external EEnG recording in the low frequency range, and therefore to obtain more robust indicators of the intestinal pacemaker activity from non invasive EEnG recordingsThe authors would like to thank D Alvarez-Martinez, Dr C Vila and the Veterinary Unit of the Research Centre of 'La Fe' University Hospital (Valencia, Spain), where the surgical interventions and recording sessions were carried out, and the R+D+I Linguistic Assistance Office at the UPV for their help in revising this paper. This research study was sponsored by the Ministerio de Ciencia y Tecnologia de Espana (TEC2007-64278) and by the Universidad Politecnica de Valencia, as part of a UPV research and development Grant Programme.Ye Lin, Y.; Garcia Casado, FJ.; Prats Boluda, G.; Ponce, JL.; Martínez De Juan, JL. (2009). Enhancement of the non-invasive electroenterogram to identify intestinal pacemaker activity. PHYSIOLOGICAL MEASUREMENT. 30(9):885-902. https://doi.org/10.1088/0967-3334/30/9/002S885902309Amaris, M. A., Sanmiguel, C. P., Sadowski, D. C., Bowes, K. L., & Mintchev, M. P. (2002). Digestive Diseases and Sciences, 47(11), 2480-2485. doi:10.1023/a:1020503908304Bass, P., & Wiley, J. N. (1965). Electrical and extraluminal contractile-force activity of the duodenum of the dog. The American Journal of Digestive Diseases, 10(3), 183-200. doi:10.1007/bf02233747Bradshaw, L. A., Allos, S. H., Wikswo, J. P., & Richards, W. O. (1997). Correlation and comparison of magnetic and electric detection of small intestinal electrical activity. American Journal of Physiology-Gastrointestinal and Liver Physiology, 272(5), G1159-G1167. doi:10.1152/ajpgi.1997.272.5.g1159Camilleri, M., Hasler, W. L., Parkman, H. P., Quigley, E. M. M., & Soffer, E. (1998). Measurement of gastrointestinal motility in the GI laboratory. Gastroenterology, 115(3), 747-762. doi:10.1016/s0016-5085(98)70155-6Chen, J. D. Z., & Lin, Z. (1993). Adaptive cancellation of the respiratory artifact in surface recording of small intestinal electrical activity. Computers in Biology and Medicine, 23(6), 497-509. doi:10.1016/0010-4825(93)90097-kChen, J., & McCallum, R. W. (1991). Electrogastrography: measuremnt, analysis and prospective applications. Medical & Biological Engineering & Computing, 29(4), 339-350. doi:10.1007/bf02441653Chen, J. D. Z., Schirmer, B. D., & McCallum, R. W. (1993). Measurement of electrical activity of the human small intestine using surface electrodes. IEEE Transactions on Biomedical Engineering, 40(6), 598-602. doi:10.1109/10.237682Garcia-Casado, J., Martinez-de-Juan, J. L., & Ponce, J. L. (2005). Noninvasive Measurement and Analysis of Intestinal Myoelectrical Activity Using Surface Electrodes. IEEE Transactions on Biomedical Engineering, 52(6), 983-991. doi:10.1109/tbme.2005.846730Gordon, A. D. (1987). A Review of Hierarchical Classification. Journal of the Royal Statistical Society. Series A (General), 150(2), 119. doi:10.2307/2981629Huang, N. E., Shen, Z., Long, S. R., Wu, M. C., Shih, H. H., Zheng, Q., … Liu, H. H. (1998). The empirical mode decomposition and the Hilbert spectrum for nonlinear and non-stationary time series analysis. Proceedings of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences, 454(1971), 903-995. doi:10.1098/rspa.1998.0193Irimia, A., & Bradshaw, L. A. (2005). Artifact reduction in magnetogastrography using fast independent component analysis. Physiological Measurement, 26(6), 1059-1073. doi:10.1088/0967-3334/26/6/015Lammers, W. J. E. P., & Stephen, B. (2008). Origin and propagation of individual slow waves along the intact feline small intestine. Experimental Physiology, 93(3), 334-346. doi:10.1113/expphysiol.2007.039180Liang, H. (2001). Adaptive independent component analysis of multichannel electrogastrograms. Medical Engineering & Physics, 23(2), 91-97. doi:10.1016/s1350-4533(01)00019-4Liang, J., Cheung, J. Y., & Chen, J. D. Z. (1997). Detection and deletion of motion artifacts in electrogastrogram using feature analysis and neural networks. Annals of Biomedical Engineering, 25(5), 850-857. doi:10.1007/bf02684169Liang, H., Lin, Z., & McCallum, R. W. (2000). Artifact reduction in electrogastrogram based on empirical mode decomposition method. Medical & Biological Engineering & Computing, 38(1), 35-41. doi:10.1007/bf02344686Zhi-Yue Lin, Chen, Z., & Jian De. (1994). Time-frequency representation of the electrogastrogram-application of the exponential distribution. IEEE Transactions on Biomedical Engineering, 41(3), 267-275. doi:10.1109/10.284945Lin, Z. Y., & Chen, J. D. Z. (1994). Recursive running DCT algorithm and its application in adaptive filtering of surface electrical recording of small intestine. Medical & Biological Engineering & Computing, 32(3), 317-322. doi:10.1007/bf02512529Lin, Z., & Chen, J. D. Z. (1995). Comparison of three running spectral analysis methods for electrogastrographic signals. Medical & Biological Engineering & Computing, 33(4), 596-604. doi:10.1007/bf02522520Maestri, R., Pinna, G. D., Porta, A., Balocchi, R., Sassi, R., Signorini, M. G., … Raczak, G. (2007). Assessing nonlinear properties of heart rate variability from short-term recordings: are these measurements reliable? Physiological Measurement, 28(9), 1067-1077. doi:10.1088/0967-3334/28/9/008Martinez-de-Juan, J. ., Saiz, J., Meseguer, M., & Ponce, J. . (2000). Small bowel motility: relationship between smooth muscle contraction and electroenterogram signal. Medical Engineering & Physics, 22(3), 189-199. doi:10.1016/s1350-4533(00)00032-1Mintchev, M. P., Kingma, Y. J., & Bowes, K. L. (1993). Accuracy of cutaneous recordings of gastric electrical activity. Gastroenterology, 104(5), 1273-1280. doi:10.1016/0016-5085(93)90334-9Prats-Boluda, G., Garcia-Casado, J., Martinez-de-Juan, J. L., & Ponce, J. L. (2007). Identification of the slow wave component of the electroenterogram from Laplacian abdominal surface recordings in humans. Physiological Measurement, 28(9), 1115-1133. doi:10.1088/0967-3334/28/9/012Quigley, E. M. M. (1996). GASTRIC AND SMALL INTESTINAL MOTILITY IN HEALTH AND DISEASE. Gastroenterology Clinics of North America, 25(1), 113-145. doi:10.1016/s0889-8553(05)70368-xSeidel, S. A., Bradshaw, L. A., Ladipo, J. K., Wikswo, J. P., & Richards, W. O. (1999). Noninvasive detection of ischemic bowel. Journal of Vascular Surgery, 30(2), 309-319. doi:10.1016/s0741-5214(99)70142-4Tomomasa, T., Morikawa, A., Sandler, R. H., Mansy, H. A., Koneko, H., Masahiko, T., … Itoh, Z. (1999). Gastrointestinal Sounds and Migrating Motor Complex in Fasted Humans. American Journal of Gastroenterology, 94(2), 374-381. doi:10.1111/j.1572-0241.1999.00862.xWang, Z. S., Cheung, J. Y., & Chen, J. D. Z. (1999). Blind separation of multichannel electrogastrograms using independent component analysis based on a neural network. Medical & Biological Engineering & Computing, 37(1), 80-86. doi:10.1007/bf0251327

Characterization of the effects of Atosiban on uterine electromyograms recorded in women with threatened preterm labor

[EN] Although research studies using electrohysterography on women without tocolytic therapy have shown its potential for preterm birth diagnosis, tocolytics are usually administered in emergency rooms at the first sign of threatened preterm labor (TPL). Information on the uterine response during tocolytic treatment could prove useful for the development of tools able to predict true preterm deliveries under normal clinical conditions. The aim of this study was thus to analyze the effects of Atosiban on Electrohysterogram (EHG) parameters and to compare its effects on women who delivered preterm (WDP) and at term (WDT). Electrohysterograms recorded in different Atosiban therapy stages (before, during and after drug administration) on 40 WDT and 27 WDP were analyzed by computing linear, and non-linear EHG parameters. Results reveal that Atosiban does not greatly affect the EHG signal amplitude, but does modify its spectral content and reduces the energy associated with the fast wave high component in both WDP and WDT, with a faster response in the latter. EHG signal complexity remained constant in WDT, while it increased in WDP until it reached similar values to WDT during Atosiban treatment. The spectral and complexity parameters were able to separate (p < 0.05) WDT and WDP prior to and during tocolytic treatment and before and after treatment, respectively. The results pave the way for developing better and more reliable medical decision support systems based on EHG for preterm delivery prediction in TPL women in clinical scenarios.This work received financial support from the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (DPI2015-68397-R), VLC/Campus (UPV-FE-2018-B03) and by Conselleria de Educación, Investigación, Cultura y Deporte, Generalitat Valenciana (GV/2018/104).Mas-Cabo, J.; Prats-Boluda, G.; Ye Lin, Y.; Alberola Rubio, J.; Perales, A.; Garcia-Casado, J. (2019). Characterization of the effects of Atosiban on uterine electromyograms recorded in women with threatened preterm labor. Biomedical Signal Processing and Control. 52:198-205. https://doi.org/10.1016/j.bspc.2019.04.001S1982055

Active flexible concentric ring electrode for non-invasive surface bioelectrical recordings

Bioelectrical surface recordings are usually performed by unipolar or bipolar disc electrodes even though they entail the serious disadvantage of having poor spatial resolution. Concentric ring electrodes give improved spatial resolution, although this type of electrode has so far only been implemented in rigid substrates and as they are not adapted to the curvature of the recording surface may provide discomfort to the patient. Moreover, the signals recorded by these electrodes are usually lower in amplitude than conventional disc electrodes. The aim of this work was thus to develop and test a new modular active sensor made up of concentric ring electrodes printed on a flexible substrate by thick-film technology together with a reusable battery-powered signal-conditioning circuit. Simultaneous ECG recording with both flexible and rigid concentric ring electrodes was carried out on ten healthy volunteers at rest and in motion. The results show that flexible concentric ring electrodes not only present lower skin electrode contact impedance and lower baseline wander than rigid electrodes but are also less sensitive to interference and motion artefacts. We believe these electrodes, which allow bioelectric signals to be acquired non-invasively with better spatial resolution than conventional disc electrodes, to be a step forward in the development of new monitoring systems based on Laplacian potential recordings.This research was supported in part by the Ministerio de Ciencia y Tecnologia de Espana (TEC2010-16945) and by the Universitat Politecnica de Valencia (PAID 2009/10-2298). The proof-reading of this paper was funded by the Universitat Politecnica de Valencia, Spain.Prats Boluda, G.; Ye Lin, Y.; García Breijo, E.; Ibáñez Civera, FJ.; Garcia Casado, FJ. (2012). Active flexible concentric ring electrode for non-invasive surface bioelectrical recordings. Measurement Science and Technology. 23(12):1-10. https://doi.org/10.1088/0957-0233/23/12/125703S1102312Malmivuo, J., & Plonsey, R. (1995). BioelectromagnetismPrinciples and Applications of Bioelectric and Biomagnetic Fields. doi:10.1093/acprof:oso/9780195058239.001.0001Gevins, A. (1989). Dynamic functional topography of cognitive tasks. Brain Topography, 2(1-2), 37-56. doi:10.1007/bf01128842Bradshaw, L. A., Wijesinghe, R. S., & Wikswo, Jr., J. P. (2001). Spatial Filter Approach for Comparison of the Forward and Inverse Problems of Electroencephalography and Magnetoencephalography. Annals of Biomedical Engineering, 29(3), 214-226. doi:10.1114/1.1352641Bradshaw, L. A., Richards, W. O., & Wikswo, J. P. (2001). Volume conductor effects on the spatial resolution of magnetic fields and electric potentials from gastrointestinal electrical activity. Medical & Biological Engineering & Computing, 39(1), 35-43. doi:10.1007/bf02345264Garcia-Casado, J., Martinez-de-Juan, J. L., & Ponce, J. L. (2005). Noninvasive Measurement and Analysis of Intestinal Myoelectrical Activity Using Surface Electrodes. IEEE Transactions on Biomedical Engineering, 52(6), 983-991. doi:10.1109/tbme.2005.846730SippensGroenewegen, A., Peeters, H. A. P., Jessurun, E. R., Linnenbank, A. C., Robles de Medina, E. O., Lesh, M. D., & van Hemel, N. M. (1998). Body Surface Mapping During Pacing at Multiple Sites in the Human Atrium. Circulation, 97(4), 369-380. doi:10.1161/01.cir.97.4.369Lian, J., Li, G., Cheng, J., Avitall, B., & He, B. (2002). Body surface Laplacian mapping of atrial depolarization in healthy human subjects. Medical & Biological Engineering & Computing, 40(6), 650-659. doi:10.1007/bf02345304Wu, D., Tsai, H. C., & He, B. (1999). On the Estimation of the Laplacian Electrocardiogram during Ventricular Activation. Annals of Biomedical Engineering, 27(6), 731-745. doi:10.1114/1.224Koka, K., & Besio, W. G. (2007). Improvement of spatial selectivity and decrease of mutual information of tri-polar concentric ring electrodes. Journal of Neuroscience Methods, 165(2), 216-222. doi:10.1016/j.jneumeth.2007.06.007Prats-Boluda, G., Garcia-Casado, J., Martinez-de-Juan, J. L., & Ye-Lin, Y. (2011). Active concentric ring electrode for non-invasive detection of intestinal myoelectric signals. Medical Engineering & Physics, 33(4), 446-455. doi:10.1016/j.medengphy.2010.11.009He, B., & Cohen, R. J. (1992). Body surface Laplacian mapping of cardiac electrical activity. The American Journal of Cardiology, 70(20), 1617-1620. doi:10.1016/0002-9149(92)90471-aBesio, W., Aakula, R., Koka, K., & Dai, W. (2006). Development of a Tri-polar Concentric Ring Electrode for Acquiring Accurate Laplacian Body Surface Potentials. Annals of Biomedical Engineering, 34(3), 426-435. doi:10.1007/s10439-005-9054-8Ye-Lin, Y., Garcia-Casado, J., Prats-Boluda, G., Ponce, J. L., & Martinez-de-Juan, J. L. (2009). Enhancement of the non-invasive electroenterogram to identify intestinal pacemaker activity. Physiological Measurement, 30(9), 885-902. doi:10.1088/0967-3334/30/9/002Hjorth, B. (1975). An on-line transformation of EEG scalp potentials into orthogonal source derivations. Electroencephalography and Clinical Neurophysiology, 39(5), 526-530. doi:10.1016/0013-4694(75)90056-5Perrin, F., Pernier, J., Bertnard, O., Giard, M. ., & Echallier, J. . (1987). Mapping of scalp potentials by surface spline interpolation. Electroencephalography and Clinical Neurophysiology, 66(1), 75-81. doi:10.1016/0013-4694(87)90141-6Nunez, P. L., & Westdorp, A. F. (1994). The surface laplacian, high resolution EEG and controversies. Brain Topography, 6(3), 221-226. doi:10.1007/bf01187712Srinivasan, R., Nunez, P. L., Tucker, D. M., Silberstein, R. B., & Cadusch, P. J. (1996). Spatial sampling and filtering of EEG with spline Laplacians to estimate cortical potentials. Brain Topography, 8(4), 355-366. doi:10.1007/bf01186911Farina, D., & Cescon, C. (2001). Concentric-ring electrode systems for noninvasive detection of single motor unit activity. IEEE Transactions on Biomedical Engineering, 48(11), 1326-1334. doi:10.1109/10.959328G. Besio, C. C. Lu, P. P. Tarjan, W. (2001). A Feasibility Study for Body Surface Cardiac Propagation Maps of Humans from Laplacian Moments of Activation. Electromagnetics, 21(7-8), 621-632. doi:10.1080/027263401752246243Li, G., Wang, Y., Lin, L., Jiang, W., Wang, L. L., Lu, S. C.-Y., & Besio, W. G. (2005). Active Laplacian electrode for the data-acquisition system of EHG. Journal of Physics: Conference Series, 13, 330-335. doi:10.1088/1742-6596/13/1/077Engel, J., Chen, J., & Liu, C. (2003). Development of polyimide flexible tactile sensor skin. Journal of Micromechanics and Microengineering, 13(3), 359-366. doi:10.1088/0960-1317/13/3/302Papakostas, T. V., Lima, J., & Lowe, M. (s. f.). A large area force sensor for smart skin applications. Proceedings of IEEE Sensors. doi:10.1109/icsens.2002.1037366Stieglitz, T. (2001). Flexible biomedical microdevices with double-sided electrode arrangements for neural applications. Sensors and Actuators A: Physical, 90(3), 203-211. doi:10.1016/s0924-4247(01)00520-9Hamilton, P. S., & Tompkins, W. J. (1986). Quantitative Investigation of QRS Detection Rules Using the MIT/BIH Arrhythmia Database. IEEE Transactions on Biomedical Engineering, BME-33(12), 1157-1165. doi:10.1109/tbme.1986.325695Besio, W., & Chen, T. (2007). Tripolar Laplacian electrocardiogram and moment of activation isochronal mapping. Physiological Measurement, 28(5), 515-529. doi:10.1088/0967-3334/28/5/006Besio, G., Koka, K., Aakula, R., & Weizhong Dai. (2006). Tri-polar concentric ring electrode development for Laplacian electroencephalography. IEEE Transactions on Biomedical Engineering, 53(5), 926-933. doi:10.1109/tbme.2005.863887Setti, L., Fraleoni-Morgera, A., Ballarin, B., Filippini, A., Frascaro, D., & Piana, C. (2005). An amperometric glucose biosensor prototype fabricated by thermal inkjet printing. Biosensors and Bioelectronics, 20(10), 2019-2026. doi:10.1016/j.bios.2004.09.022Reddy, A. S. G., Narakathu, B. B., Atashbar, M. Z., Rebros, M., Rebrosova, E., & Joyce, M. K. (2011). Gravure Printed Electrochemical Biosensor. Procedia Engineering, 25, 956-959. doi:10.1016/j.proeng.2011.12.235Gruetzmann, A., Hansen, S., & Müller, J. (2007). Novel dry electrodes for ECG monitoring. Physiological Measurement, 28(11), 1375-1390. doi:10.1088/0967-3334/28/11/005LI, G., LIAN, J., SALLA, P., CHENG, J., RAMACHANDRA, I., SHAH, P., … HE, B. (2003). Body Surface Laplacian Electrocardiogram of Ventricular Depolarization in Normal Human Subjects. Journal of Cardiovascular Electrophysiology, 14(1), 16-27. doi:10.1046/j.1540-8167.2003.02199.

Histological and ultrastructural comparison of cauterization and thrombosis stroke models in immune-deficient mice

Background: Stroke models are essential tools in experimental stroke. Although several models of stroke have been developed in a variety of animals, with the development of transgenic mice there is the need to develop a reliable and reproducible stroke model in mice, which mimics as close as possible human stroke. Methods: BALB/Ca-RAG2-/-gc-/- mice were subjected to cauterization or thrombosis stroke model and sacrificed at different time points (48hr, 1wk, 2wk and 4wk) after stroke. Mice received BrdU to estimate activation of cell proliferation in the SVZ. Brains were processed for immunohistochemical and EM. Results: In both stroke models, after inflammation the same glial scar formation process and damage evolution takes place. After stroke, necrotic tissue is progressively removed, and healthy tissue is preserved from injury through the glial scar formation. Cauterization stroke model produced unspecific damage, was less efficient and the infarct was less homogeneous compared to thrombosis infarct. Finally, thrombosis stroke model produces activation of SVZ proliferation. Conclusions: Our results provide an exhaustive analysis of the histopathological changes (inflammation, necrosis, tissue remodeling, scarring...) that occur after stroke in the ischemic boundary zone, which are of key importance for the final stroke outcome. This analysis would allow evaluating how different therapies would affect wound and regeneration. Moreover, this stroke model in RAG 2-/- gC -/- allows cell transplant from different species, even human, to be analyzed

FAST: Towards safe and effective subcutaneous immunotherapy of persistent life-threatening food allergies.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.ABSTRACT: The FAST project (Food Allergy Specific Immunotherapy) aims at the development of safe and effective treatment of food allergies, targeting prevalent, persistent and severe allergy to fish and peach. Classical allergen-specific immunotherapy (SIT), using subcutaneous injections with aqueous food extracts may be effective but has proven to be accompanied by too many anaphylactic side-effects. FAST aims to develop a safe alternative by replacing food extracts with hypoallergenic recombinant major allergens as the active ingredients of SIT. Both severe fish and peach allergy are caused by a single major allergen, parvalbumin (Cyp c 1) and lipid transfer protein (Pru p 3), respectively. Two approaches are being evaluated for achieving hypoallergenicity, i.e. site-directed mutagenesis and chemical modification. The most promising hypoallergens will be produced under GMP conditions. After pre-clinical testing (toxicology testing and efficacy in mouse models), SCIT with alum-absorbed hypoallergens will be evaluated in phase I/IIa and IIb randomized double-blind placebo-controlled (DBPC) clinical trials, with the DBPC food challenge as primary read-out. To understand the underlying immune mechanisms in depth serological and cellular immune analyses will be performed, allowing identification of novel biomarkers for monitoring treatment efficacy. FAST aims at improving the quality of life of food allergic patients by providing a safe and effective treatment that will significantly lower their threshold for fish or peach intake, thereby decreasing their anxiety and dependence on rescue medication

Sporadic Creutzfeldt-Jakob disease VM1: phenotypic and molecular characterization of a novel subtype of human prion disease

The methionine (M)-valine (V) polymorphic codon 129 of the prion protein gene (PRNP) plays a central role in both susceptibility and phenotypic expression of sporadic Creutzfeldt-Jakob diseases (sCJD). Experimental transmissions of sCJD in humanized transgenic mice led to the isolation of five prion strains, named M1, M2C, M2T, V2, and V1, based on two major conformations of the pathological prion protein (PrPSc, type 1 and type 2), and the codon 129 genotype determining susceptibility and propagation efficiency. While the most frequent sCJD strains have been described in codon 129 homozygosis (MM1, MM2C, VV2) and heterozygosis (MV1, MV2K, and MV2C), the V1 strain has only been found in patients carrying VV. We identified six sCJD cases, 4 in Catalonia and 2 in Italy, carrying MV at PRNP codon 129 in combination with PrPSc type 1 and a new clinical and neuropathological profile reminiscent of the VV1 sCJD subtype rather than typical MM1/MV1. All patients had a relatively long duration (mean of 20.5 vs. 3.5 months of MM1/MV1 patients) and lacked electroencephalographic periodic sharp-wave complexes at diagnosis. Distinctive histopathological features included the spongiform change with vacuoles of larger size than those seen in sCJD MM1/MV1, the lesion profile with prominent cortical and striatal involvement, and the pattern of PrPSc deposition characterized by a dissociation between florid spongiform change and mild synaptic deposits associated with coarse, patch-like deposits in the cerebellar molecular layer. Western blot analysis of brain homogenates revealed a PrPSc type 1 profile with physicochemical properties reminiscent of the type 1 protein linked to the VV1 sCJD subtype. In summary, we have identified a new subtype of sCJD with distinctive clinicopathological features significantly overlapping with those of the VV1 subtype, possibly representing the missing evidence of V1 sCJD strain propagation in the 129MV host genotype

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p&lt;0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p&lt;0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p&lt;0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology

Analisis de las respuestas moleculares profundas alcanzadas por las multiples secuencias de tratamientos con ITKS en LMC. Estudio de largo seguimiento del registro español de LMC

Poster [PC-231] Introducción: Cinco inhibidores de tirosina cinasa (ITKs) están disponibles para el tratamiento de pacientes con leucemia mieloide crónica en fase crónica (LMC-FC). Analizamos las diferentes secuencias de ITKs utilizadas como terapia para la LMC-FC en un análisis a largo plazo en vida real. Métodos: En un análisis retrospectivo de cohortes, se incluyeron pacientes con LMC-FC tratados en la práctica clínica con diferentes ITKs en el Registro Español de LMC (RELMC) (17 hospitales de todo el país) entre 2000 y 2014. El objetivo principal del estudio fue describir la secuencia del tratamiento con ITKs en la práctica de la vida real y la última respuesta molecular profunda (DMR) (MR4, MR4.5 o transcrito indetectable) para cada esquema. Resultados: Nuestro análisis incluyó 862 pacientes con LMC en 1º FC tratados con ITKs en 1ª línea o después de interferón alfa. Datos demográficos demográficos: 517 H, 345 M, mediana de edad: 52 años (14-94a). Distribución del Índice Sokal (bajo 49% Inter 38% Alto 13%), Índice EURO (bajo 50% Inter 45% Alto 5%), Índice EUTOS (bajo 93% Alto 7%), Índice LT-EUTOS (bajo 68 % Inter 25% Alto 7%). Esquemas de tratamiento: la Tabla 1 resume todos los esquemas utilizados y la última respuesta molecular. Los pacientes se dividieron en 4 grupos según el tratamiento con ITKs. Grupo 1: solo tratados con Imatinib 394 p (45, 7%) Grupo 2: Imatinib y luego 2ºGITKs debido a intolerancia o fallo 170 p (19, 7%) (12 esquemas de tratamiento secuenciales diferentes con ITKs) Grupo 3: 2ºGITKs en 1ª línea 91 p (13 esquemas secuenciales) (10, 5%) Grupo 4: Interferón alfa y luego ITKs 207 p (24%) (9 esquemas secuenciales). La Figura 1 resume la evolución de diferentes tratamientos alrededor de los 14 años. Última respuesta molecular profunda: con una mediana de seguimiento de 82 meses (1-351 m) desde el diagnóstico, 77 m (1-311 m) desde el primer tratamiento y 70 m (1-191 m) desde el primer tratamiento con ITK. Las tasas de respuesta molecular profunda para cada grupo fueron (G1: DMR 65% MMR 13% No MMR 15%, G2: DMR 46% MMR 24% No MMR 17%, G3: DMR 62% MMR 13% No MMR 12%, G4: DMR 53% MMR 17% No MMR 18%). Supervivencia a largo plazo (SLP o SG): no se encontraron diferencias estadísticas entre los grupos de tratamiento, ya sea desde el diagnóstico, el primer tratamiento o el primer ITK. Alcanzar una respuesta profunda garantiza mejores resultados. Variables predictivas de respuesta: los índices SOKAL, EUTOS, EURO y LT-EUTOS continúan siendo útiles para predecir el resultado a largo plazo. Conclusiones: En el contexto de un registro multicéntrico basado en hospitales, el tratamiento con ITKs es muy variable, con un gran número de secuencias diferentes de ITKs. Con una mediana de seguimiento de 7 años la tasa de respuesta molecular profunda es aproximadamente del 60% en pacientes tratados con imatinib y que no necesitan cambio de ITKs, y en aquellos tratados en 1º línea con 2ºGITKs(a pesar de su corto seguimiento), pero parece menor en pacientes tratados con imatinib que necesitan cambiar a 2ºGITKs. Los resultados de supervivencia fueron similares para todos los grupos