Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review

Clinicians can use biomarkers to guide therapeutic decisions in estrogen receptor positive (ER+) breast cancer. One such biomarker is cellular proliferation as evaluated by Ki-67. This biomarker has been extensively studied and is easily assayed by histopathologists but it is not currently accepted as a standard. This review focuses on its prognostic and predictive value, and on methodological considerations for its measurement and the cut-points used for treatment decision. Data describing study design, patients’ characteristics, methods used and results were extracted from papers published between January 1990 and July 2010. In addition, the studies were assessed using the REMARK tool. Ki-67 is an independent prognostic factor for disease-free survival (HR 1.05–1.72) in multivariate analyses studies using samples from randomized clinical trials with secondary central analysis of the biomarker. The level of evidence (LOE) was judged to be I-B with the recently revised definition of Simon. However, standardization of the techniques and scoring methods are needed for the integration of this biomarker in everyday practice. Ki-67 was not found to be predictive for long-term follow-up after chemotherapy. Nevertheless, high KI-67 was found to be associated with immediate pathological complete response in the neoadjuvant setting, with an LOE of II-B. The REMARK score improved over time (with a range of 6–13/20 vs. 10–18/20, before and after 2005, respectively). KI-67 could be considered as a prognostic biomarker for therapeutic decision. It is assessed with a simple assay that could be standardized. However, international guidelines are needed for routine clinical use

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

André Vauchez. — Saints, prophètes et visionnaires. Le pouvoir surnaturel au Moyen Âge. Paris, Albin Michel, 1999 (Bibl. A. Michel Histoire)

Sigal Pierre-André. André Vauchez. — Saints, prophètes et visionnaires. Le pouvoir surnaturel au Moyen Âge. Paris, Albin Michel, 1999 (Bibl. A. Michel Histoire). In: Cahiers de civilisation médiévale, 45e année (n°177), Janvier-mars 2002. pp. 100-101

Naissance et premier développement d'un vinage exceptionnel : l'eau de saint Thomas

Among the miracles assigned to saint Thomas Becket at the end of the twelfth century, about a third of them have been put into effect thanks to « the water of saint Thomas »'s help, obtained with the dilution of the saint's blood into water. The symbolic value of a martyr's blood, ranked on the Christ's blood, and the persevering action of the monks of Canterbury explain a large and rapid spread of the water of saint Thomas, carried in wooden and then metallic flasks. Kept at ordinary people's house or in churches, the water of saint Thomas was used as a lotion or as a drink, to vary from illness to illness. This use was often preceded by a spiritual purification. This thaumaturgie method seems to have played an important role in the spread of the cult and of the reputation of Thomas Becket.Parmi les miracles attribués à saint Thomas Becket à la fin du XIIe s., un tiers environ ont été réalisés grâce à « l'eau de saint Thomas », obtenue en diluant le sang du saint dans de l'eau. La valeur symbolique du sang d'un martyr, assimilé au sang du Christ, et l'action persévérante des moines de Canterbury expliquent une diffusion large et rapide de l'eau de saint Thomas, transportée dans des fioles de bois puis de métal. Conservée chez des particuliers ou dans des églises, l'eau de saint Thomas était utilisée en lotion ou en boisson, selon la maladie à guérir, utilisation souvent précédée d'une purification spirituelle. Ce procédé thaumaturgique semble ainsi avoir joué un rôle important dans la diffusion du culte et de la réputation de Thomas Becket.Sigal Pierre-André. Naissance et premier développement d'un vinage exceptionnel : l'eau de saint Thomas. In: Cahiers de civilisation médiévale, 44e année (n°173), Janvier-mars 2001. pp. 35-44

Maladie, pèlerinage et guérison au XIIe siècle. Les miracles de saint Gibrien à Reims

Sigall Pierre-André. Maladie, pèlerinage et guérison au XIIe siècle. Les miracles de saint Gibrien à Reims. In: Annales. Économies, Sociétés, Civilisations. 24ᵉ année, N. 6, 1969. pp. 1522-1539

L'histoire du Languedoc dans les dictionnaires et les encyclopédies (XVIIe-XXe siècles)

Die Geschichte des Languedoc in den Wörterbüchern und Konversationslexika (17.-20. Jahrhundert). Zwischen 1674 und 1983 erschienen fünfundzwanzig Konversationslexika und Wörterbücher, deren Artikel zum Stichwort « Languedoc » ausführlich genug sind, um sie zum Gegenstand einer historiographischen Untersuchung werden zu lassen. Durchgängig stellen sie die alte und vor allem die mittelalterliche Geschichte in den Vordergrund. In der Begrifflichkeit des Languedoc wird dennoch eine Entwicklung deutlich : während die ältesten Nachschlagewerke lediglich die Zeit vor der Eingliederung des Languedoc in die Krondomäne darstellen, gehen jene des 19. Jahrhunderts auch auf die Geschichte der könglichen Provinz ein. Erst in der zweiten Hälfte des 20. Jahrhunderts wird darüber hinaus die Geschichte des Languedoc seit der Französischen Revolution behandelt.The History of Languedoc in Dictionaries and Encyclopedias (17th-20th centuries). Twenty-five encyclopedias and dictionaries published between 1674 and 1983 contain an article on « Languedoc » sufficiently substantial to furnish material for a historiographical study. They systematically privilege ancient and specially medieval times. An evolution of the very conception of Languedoc can however be noted : the oldest dictionaries discuss only the period before annexation to the royal domain while the nineteenth century works tell the story of the former province. It is only in the second half of the twentieth century that contemporary history appears.Vingt-cinq encyclopédies et dictionnaires, s'échelonnant de 1674 à 1983, contiennent un article « Languedoc » suffisamment substantiel pour fournir la matière d'une étude historiographique. Ils privilégient systématiquement les périodes anciennes et surtout le Moyen Âge. On note cependant une évolution de la conception même du Languedoc : les dictionnaires les plus anciens n'évoquent que la période antérieure au rattachement au domaine royal, les ouvrages du XIXe siècle racontent l'histoire de l'ancienne province, et ce n'est que dans la deuxième moitié du XXe siècle qu'apparaît l'histoire contemporaine.Sigal Pierre-André. L'histoire du Languedoc dans les dictionnaires et les encyclopédies (XVIIe-XXe siècles). In: Annales du Midi : revue archéologique, historique et philologique de la France méridionale, Tome 110, N°221, 1998. Historiographie du Languedoc. pp. 5-23

Sylvie Barnay. — Le ciel sur la terre. Les apparitions de la Vierge au Moyen Âge. Paris, Cerf, 1999.

Sigal Pierre-André. Sylvie Barnay. — Le ciel sur la terre. Les apparitions de la Vierge au Moyen Âge. Paris, Cerf, 1999.. In: Cahiers de civilisation médiévale, 45e année (n°180), Octobre-décembre 2002. pp. 364-365

Sur une réédition : Thouzellier (Christine), Catharisme et valdéisme en Languedoc à la fin du XIIe et au début du XIIIe siècle, 3e édition, Marseille, Laffitte Reprints, 1982

Sigal Pierre-André. Sur une réédition : Thouzellier (Christine), Catharisme et valdéisme en Languedoc à la fin du XIIe et au début du XIIIe siècle, 3e édition, Marseille, Laffitte Reprints, 1982. In: Annales du Midi : revue archéologique, historique et philologique de la France méridionale, Tome 96, N°167, 1984. pp. 316-317

Le voeu et l'ex voto dans l'Angleterre médiévale d'après le procès de canonisation de saint Thomas de Cantiloupe, évêque de Hereford (\textdagger 1282)

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