Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.

IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

Extension of ultrasound Fourier slice Imaging theory to sectorial acquisition

Ultrasound image reconstruction from the echoes received by an ultrasound probe after the transmission of diverging waves is an active area of research because of its capacity to insonify at ultra-high frame rate with large regions of interest using small phased arrays as the ones used in echocardiography. Current state-of-the-art techniques are based on the emission of diverging waves and the use of delay and sum strategies applied on the received signals to reconstruct the desired image (DW/DAS). Recently, we have introduced the concept of Ultrasound Fourier Slice Imaging (UFSI) theory for the reconstruction of ultrafast imaging for linear acquisition. In this study, we extend this theory to sectorial acquisition thanks to the introduction of an explicit and invertible spatial transform. Starting from a diverging wave, we show that the direct use of UFSI theory along with the application of the proposed spatial transform allows reconstructing the insonified medium in the conventional Cartesian space. Simulations and experiments reveal the capacity of this new approach in obtaining competitive quality of ultrafast imaging when compared with the current reference method.

A systematic review of ultrasound-guided methods for brachial plexus blockade.

We systematically reviewed 25 randomised controlled trials of ultrasound-guided brachial plexus blockade that recruited 1948 participants: either one approach vs another (axillary, infraclavicular or supraclavicular); or one injection vs multiple injections. There were no differences in the rates of successful blockade with approach, relative risk (95% CI): axillary vs infraclavicular, 1.0 (1.0-1.1), p = 0.97; axillary vs supraclavicular, 1.0 (1.0-1.1), p = 0.68; and infraclavicular vs supraclavicular, 1.0 (1.0-1.1), p = 0.32. There was no difference in the rate of successful blockade with the number of injections, relative risk (95% CI) 1.0 (1.0-1.0), p = 0.69, for one vs multiple injections. The rate of procedural paraesthesia was less with one injection than multiple injections, relative risk (95% CI) 0.6 (0.4-0.9), p = 0.004.

Traducció i adopció a l'Índia: Hindu Adoptions And Maintenance Act, 1956

L’objectiu principal d’aquest treball de fi de grau és fer-se càrrec d’una traducció jurídica amb tot el què això implica: documentar-se a través de fonts fiables, emprar les eines adequades, lliurar-lo dins el termini establert, entre d’altres. En aquest cas, és una traducció de les lleis que regulen les adopcions a l’Índia. A més, en aquest treball també s’explica breument el dret civil a Catalunya i es compara amb el de l’Índia, ja que es basen en idees molt diferents. Aquests tipus de traduccions exigeixen precisió i claredat perquè els conceptes i les estructures sintàctiques acostumen a ser molt complexes. A continuació, hi ha detallat cada pas que s’ha seguit per tal d’assolir l’objectiu principal.

Ultrasound-guided fine-needle aspiration of thyroid nodules: assessment of the ideal number of punctures

OBJECTIVE: To determine the number of punctures in fine-needle aspiration biopsies required for a safe cytological analysis of thyroid nodules. MATERIALS AND METHODS: Cross-sectional study with focus on diagnosis. The study population included 94 patients. RESULTS: The mean age of the patients participating in the study was 52 years (standard-deviation = 13.7) and 90.4% of them were women. Considering each puncture as an independent event, the first puncture has showed conclusive results in 78.7% of cases, the second, in 81.6%, and the third, in 71.8% of cases. With a view to the increasing chance of a conclusive diagnosis at each new puncture, two punctures have showed conclusive results in 89.5% of cases, and three punctures, in 90.6% of cases with at least one conclusive result. CONCLUSION: Two punctures in fine-needle aspiration biopsies of thyroid nodules have lead to diagnosis in 89.5% of cases in the study sample, suggesting that there is no need for multiple punctures to safely obtain the diagnosis of thyroid nodules.

Governance mode vs. governance fit: Performance implications of make-or-ally choices for product innovation in the worldwide aircraft industry, 1942-2000

We examine the impact of governance mode and governance fit on performance in make-or-ally decisions. We argue that while horizontal collaboration and autonomous governance have direct and countervailing performance implications, the alignment of make-or-ally choices with the focal firm's resource endowment and the activity's resource requirements leads to better performance. Data on the aircraft industry show that relative to aircraft developed autonomously, collaborative aircraft exhibit greater sales but require longer time-to-market. However, governance fit increases unit sales and reduces time-to-market. We contribute to the alliance and economic organization literatures. (Copyright © 2013 John Wiley & Sons, Ltd.)

Step-by-step of ultrasound-guided core-needle biopsy of the breast: review and technique

Ultrasound-guided core-needle biopsy has high sensitivity in the diagnosis of breast cancer. The present study is aimed at detailing the main steps of such procedure, including indications, advantages, limitations, follow-up and description of the technique, besides presenting a checklist including the critical steps required for an appropriate practice of the technique. In the recent years, an increasing number of patients have required breast biopsy, indicating the necessity of a proportional increase in the number of skilled professionals to carry out the procedures and histological diagnoses. A multidisciplinary approach involving the tripod clinical practice-radiology-pathology is responsible for the highest rate of accuracy of the technique and must always be adopted.

Postoperative Adjuvant Lapatinib and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib Monotherapy in High-Risk Patients With Resected Squamous Cell Carcinoma of the Head and Neck: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study.

PURPOSE: This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m(2) per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy. RESULTS: Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm. CONCLUSION: Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN.

The role of transrectal ultrasound in the diagnosis of prostate cancer: new contributions

Objective: The present study was aimed at evaluating the contribution of transrectal prostate ultrasound in the screening for prostate neoplasias and in the guidance of prostate biopsies. Materials and Methods: Prospective study developed over a one-year period. All the patients with indication for prostate biopsy were evaluated. Regardless of PSA values, the patients underwent ultrasound in order to identify suspicious nodules (confirmed by two observers). Sextant biopsy was subsequently performed. In cases of finding suspicious nodules, an additional puncture directed to such nodules was done. Results: In a total of 155 cases the prevalence of malignancy was of 53%. Suspicious nodules were detected in 34 patients, and 25 where malignant (positive predictive value of 74%). The specificity and sensitivity for suspicious nodules were 88% and 31% respectively. Comparatively with the randomly obtained sextant specimens, the rate of findings of neoplasia was higher in the specimens obtained with puncture directed to the nodule (p = 0.032). No statistically significant difference was observed in the Gleason score for both types of specimens (p = 0.172). Conclusion: The high positive predictive value and the high rate of findings of neoplasia in specimens of suspicious nodules should be taken into consideration in the future. The authors suggest a biopsy technique similar to the one described in the present study (sextant biopsy plus puncture directed to the suspicious nodule).

GENETIC ARCHITECTURE, EVOLUTION AND MAINTENANCE OF A COLOR CLINE AT A CONTINENTAL SCALE

On a geological time scale the conditions on earth are very variable and biological patterns (for example the distributions of species) are very dynamic. Understanding large scale patterns of variation observed today thus requires a deep understanding of the historical factors that drove their evolution. In this thesis, we reevaluated the evolution and maintenance of a continental color cline observed in the European barn owl (Tyto alba) using population genetic tools. The colour cline spans from south-est Europe where most individual have pure white underparts to north and east Europe where most individuals have rufous-brown underparts. Our results globally showed that the old scenario, stipulating that the color cline evolved by secondary contact of two color morphs (white and rufous) that evolved in allopatry during the last ice age has to be revised. We collected samples of about 700 barn owls from the Western Palearctic to establish the first population genetic data set for this species. Individuals were genotyped at 22 microsatellites markers, at one mitochondrial gene, and at a candidate color gene. The color of each individuals was assessed and their sex determined by molecular methods. We first showed that the genetic variation in Western Europe is very limited compared to the heritable color variation. We found no evidences of different glacial lineages, and showed that selection must be involved in the maintenance of the color cline (chapter 1). Using computer simulations, we demonstrated that the post-glacial colonization of Europe occurred from the Iberian Peninsula and that the color cline could not have evolved by neutral demographic processes during this colonization (chapter 2). Finally we reevaluated the whole history of the establishment of the Western Palearctic variation of the barn owl (chapter 3): This study showed that all Western European barn owls descend from white barn owls phenotypes from the Middle East that colonized the Iberian Peninsula via North-Africa. Following the end of the last ice age (20'000 years ago), these white barn owls colonized Western Europe and under selection a novel rufous phenotype evolved (during or after the colonization). An important part of the color variation could be explained by a single mutation in the melanocortin-1-receptor (MC1R) gene that appeared during or after the colonization. The colonization of Europe reached until Greece, where the rufous birds encountered white ones (which reached Greece from the Middle East over the Bosporus) in a secondary contact zone. Our analyses show that white and rufous barn owls in Greece interbreed only to a limited extent. This suggests that barn owls are at the verge of becoming two species in Greece and demonstrates that European barn owls represent an incipient ring species around the Mediterranean. The revisited history of the establishment of the European barn owl color cline makes this model system remarkable for several aspects. It is a very clear example of strong local adaptation that can be achieved despite high gene flow (strong color and MC1R differentiation despite almost no neutral genetic differentiation). It also offers a wonderful model system to study the interactions between colonization processes and selection processes which have, for now, been remarkably understudied despite their potentially ubiquitous importance. Finally it represents a very interesting case in the speciation continuum and appeals for further studying the amount of gene flow that occurs between the color morphs in Greece. -- Sur l'échelle des temps géologiques, les conditions sur terre sont très variables et les patrons biologiques (telle que la distribution des espèces) sont très dynamiques. Si l'on veut comprendre des patrons que l'on peut observer à large échelle aujourd'hui, il est nécessaire de d'abord comprendre les facteurs historiques qui ont gouverné leur établissement. Dans cette thèse, nous allons réévaluer, grâce à des outils modernes de génétique des populations, l'évolution et la maintenance d'un cline de couleur continental observé chez l'effraie des clochers européenne (Tyto alba). Globalement, nos résultats montrent que le scenario accepté jusqu'à maintenant, qui stipule que le cline de couleur a évolué à partir du contact secondaire de deux morphes de couleur (blanches et rousses) ayant évolué en allopatrie durant les dernières glaciations, est à revoir. Afin de constituer le premier jeu de données de génétique des populations pour cette espèce, nous avons récolté des échantillons d'environ 700 effraies de l'ouest Paléarctique. Nous avons génotypé tous les individus à 22 loci microsatellites, sur un gène mitochondrial et sur un autre gène participant au déterminisme de la couleur. Nous avons aussi mesuré la couleur de tous les individus et déterminé leur sexe génétiquement. Nous avons tout d'abord pu montrer que la variation génétique neutre est négligeable en comparaison avec la variation héritable de couleur, qu'il n'existe qu'une seule lignée européenne et que de la sélection doit être impliquée dans le maintien du cline de couleur (chapitre 1). Grâce à des simulations informatiques, nous avons démontré que l'ensemble de l'Europe de l'ouest a été recolonisé depuis la Péninsule Ibérique après les dernières glaciations et que le cline de couleur ne peut pas avoir évolué par des processus neutre durant cette colonisation (chapitre 2). Finalement, nous avons réévalué l'ensemble de l'histoire postglaciaire de l'espèce dans l'ouest Paléarctique (chapitre 3): l'ensemble des effraies du Paléarctique descendent d'effraie claire du Moyen-Orient qui ont colonisé la péninsule ibérique en passant par l'Afrique du nord. Après la fin de la dernière glaciation (il y a 20'000 ans), ces effraies claires ont colonisé l'Europe de l'ouest et ont évolués par sélection le phénotype roux (durant ou après la colonisation). Une part importante de la variation de couleur peut être expliquée par une mutation sur le gène MC1R qui est apparue durant ou juste après la colonisation. Cette vague de colonisation s'est poursuivie jusqu'en Grèce où ces effraies rousses ont rencontré dans une zone de contact secondaire des effraies claires (qui sont remontées en Grèce depuis le Moyen-Orient via le Bosphore). Nos analyses montrent que le flux de gènes entre effraies blanches et rousses est limité en Grèce, ce qui suggère qu'elles sont en passe de former deux espèces et ce qui montre que les effraies constituent un exemple naissant de spéciation en anneaux autour de la Méditerranée. L'histoire revisitée des effraies des clochers de l'ouest Paléarctique en fait un système modèle remarquable pour plusieurs aspects. C'est un exemple très claire de forte adaptation locale maintenue malgré un fort flux de gènes (différenciation forte de couleur et sur le gène MC1R malgré presque aucune structure neutre). Il offre également un très bon système pour étudier l'interaction entre colonisation et sélection, un thème ayant été remarquablement peu étudié malgré son importance. Et il offre finalement un cas très intéressant dans le « continuum de spéciation » et il serait très intéressant d'étudier plus en détail l'importance du flux de gènes entre les morphes de couleur en Grèce.