Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial

BACKGROUND Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7·0 years (IQR 5·2-8·7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0·78, 95% CI 0·56-1·08; p=0·13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0·54, 95% CI 0·4-0·73, p<0·0001), with 5-year progression-free survival of 47·6% (95% CI 38·8-55·9) in the immediate treatment group and 31·8% (24·2-39·6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING Lilly, Canadian Cancer Society Research.

Use of dextran sulfate in tourniquet-induced skeletal muscle reperfusion injury.

BACKGROUND Lower extremity ischemia-reperfusion injury (IRI)-prolonged ischemia and the subsequent restoration of circulation-may result from thrombotic occlusion, embolism, trauma, or tourniquet application in surgery. The aim of this study was to assess the effect of low-molecular-weight dextran sulfate (DXS) on skeletal muscle IRI. METHODS Rats were subjected to 3 h of ischemia and 2 or 24 h of reperfusion. To induce ischemia the femoral artery was clamped and a tourniquet placed under the maintenance of the venous return. DXS was injected systemically 10 min before reperfusion. Muscle and lung tissue samples were analyzed for deposition of immunoglobulin M (IgM), IgG, C1q, C3b/c, fibrin, and expression of vascular endothelial-cadherin and bradykinin receptors b1 and b2. RESULTS Antibody deposition in reperfused legs was reduced by DXS after 2 h (P < 0.001, IgM and IgG) and 24 h (P < 0.001, IgM), C3b/c deposition was reduced in muscle and lung tissue (P < 0.001), whereas C1q deposition was reduced only in muscle (P < 0.05). DXS reduced fibrin deposits in contralateral legs after 24 h of reperfusion but did not reduce edema in muscle and lung tissue or improve muscle viability. Bradykinin receptor b1 and vascular endothelial-cadherin expression were increased in lung tissue after 24 h of reperfusion in DXS-treated and non-treated rats but bradykinin receptor b2 was not affected by IRI. CONCLUSIONS In contrast to studies in myocardial infarction, DXS did not reduce IRI in this model. Neither edema formation nor viability was improved, whereas deposition of complement and coagulation components was significantly reduced. Our data suggest that skeletal muscle IRI may not be caused by the complement or coagulation alone, but the kinin system may play an important role.

Intersex occurrence in rainbow trout (Oncorhynchus mykiss) male fry chronically exposed to ethynylestradiol.

This study aimed to investigate the male-to-female morphological and physiological transdifferentiation process in rainbow trout (Oncorhynchus mykiss) exposed to exogenous estrogens. The first objective was to elucidate whether trout develop intersex gonads under exposure to low levels of estrogen. To this end, the gonads of an all-male population of fry exposed chronically (from 60 to 136 days post fertilization--dpf) to several doses (from environmentally relevant 0.01 µg/L to supra-environmental levels: 0.1, 1 and 10 µg/L) of the potent synthetic estrogen ethynylestradiol (EE2) were examined histologically. The morphological evaluations were underpinned by the analysis of gonad steroid (testosterone, estradiol and 11-ketotestosterone) levels and of brain and gonad gene expression, including estrogen-responsive genes and genes involved in sex differentiation in (gonads: cyp19a1a, ER isoforms, vtg, dmrt1, sox9a2; sdY; cyp11b; brain: cyp19a1b, ER isoforms). Intersex gonads were observed from the first concentration used (0.01 µg EE2/L) and sexual inversion could be detected from 0.1 µg EE2/L. This was accompanied by a linear decrease in 11-KT levels, whereas no effect on E2 and T levels was observed. Q-PCR results from the gonads showed downregulation of testicular markers (dmrt1, sox9a2; sdY; cyp11b) with increasing EE2 exposure concentrations, and upregulation of the female vtg gene. No evidence was found for a direct involvement of aromatase in the sex conversion process. The results from this study provide evidence that gonads of male trout respond to estrogen exposure by intersex formation and, with increasing concentration, by morphological and physiological conversion to phenotypic ovaries. However, supra-environmental estrogen concentrations are needed to induce these changes.

Zwei Erbbegräbnisse in der St. Katharinenkirche zu Salzwedel – Ergebnisse der archäologischen und anthropologischen Untersuchung

In der Nordwestecke der St. Katharinenkirche zu Salzwedel (Sachsen-Anhalt) wurden zu Beginn des 18. Jahrhunderts zwei Erbbegräbnisse angelegt, die von bürgerlichen Familien als Begräbnisplatz genutzt wurden. Insgesamt konnten acht Holzsärge aus den Nischen geborgen werden, die noch Reste der Bestattungen und der Sargausstattung enthielten. Die Befunde bieten einen einzigartigen Einblick in das Totenbrauchtum des 18. Jahrhunderts in der Altmark.

Präventive Dokumentation und anthropologische Untersuchung von algerischen Schädeln in der Sammlung des Musée de l‘Homme in Paris

In der anthropologischen Sammlung des Musée de l'Homme in Paris befinden sich etwa 23000 Objekte, darunter Skelette des modernen Menschen und des Neandertalers, Mumien, Haarproben, ethnographische Büsten und Moulagen. Aufgrund der kolonialen Vergangenheit Frankreichs bilden rezente und historische Schädelserien aus den ehemaligen Kolonien einen Schwerpunkt der Sammlung, die vor allem im 19. Jahrhundert zusammengetragen wurde. Unter den Überresten befinden sich auch die Skelette namentlich bekannter Individuen, die daher besonders von möglichen Rückgabeforderungen betroffen sind und einen sensiblen Umgang mit dieser Thematik erfordern. Am Beispiel dreier Serien von algerischen Schädeln (Berber, Kabylen, Chaouia) sollen die Chancen einer präventiven Dokumentation mittels 3D-Oberflächenscannings erläutert sowie die Möglichkeiten und Grenzen der anthropologischen Untersuchung dieses stark selektierten Materials vorgestellt werden. Die Schädel wurden Ende des 19. Jhs. von französischen Militärärzten in der damaligen Kolonie Algerien gesammelt und später der Société d’anthropologie de Paris übergeben. In dieser Studie wurden die Schädel zunächst einer anthropologischen Basisuntersuchung unterzogen (Individualalter, Geschlecht, Metrik, Zahnstatus). Basierend auf den metrischen Daten von 105 Schädeln wurde die Homo- und Heterogenität der drei ethnisch und kulturell verschiedenen Populationen untersucht (Berber: n=69, Kabylen: n=24, Chaouia: n=12). Einige Individuen heben sich morphologisch und metrisch von dem übrigen Material ab und könnten einen subsaharischen Ursprung vermuten lassen. Vor dem Hintergrund dieser Untersuchung soll über den wissenschaftlichen und politischen Umgang mit musealen Altsammlungen und den Sinn oder Unsinn deren anthropologischer Bearbeitung diskutiert werden. Die Rekonstruktion des Kontextes, aus dem die menschlichen Überreste stammen, soll dabei im Vordergrund stehen.

Shaping gender inequalities: critical moments and critical places

Purpose – There is much scientific interest in the connection between the emergence of gender-based inequalities and key biographical transition points of couples in long-term relationships. Little empirical research is available comparing the evolution of a couple’s respective professional careers over space and time. The purpose of this paper is to contribute to filling this gap by addressing the following questions: what are the critical biographical moments when gender (in)equalities within a relationship begin to arise and consolidate? Which biographical decisions precede and follow such critical moments? How does decision making at critical moments impact the opportunities of both relationship partners in gaining equal access to paid employment? Design/methodology/approach – These questions are addressed from the perspectives of intersectionality and economic citizenship. Biographical interviewing is used to collect the personal and professional narratives of Swiss-, bi-national and migrant couples. The case study of a Swiss-Norwegian couple illustrates typical processes by which many skilled migrant women end up absently or precariously employed. Findings – Analysis reveals that the Scandinavian woman’s migration to Switzerland is a primary and critical moment for emerging inequality, which is then reinforced by relocation (to a small town characterized by conservative gender values) and the subsequent births of their children. It is concluded that factors of traditional gender roles, ethnicity and age intersect to create a hierarchical situation which affords the male Swiss partner more weight in terms of decision making and career advancement. Practical implications – The paper’s findings are highly relevant to the formulation of policies regarding gender inequalities and the implementation of preventive programmes within this context. Originality/value – Little empirical research is available comparing the evolution of a couple’s respective professional careers over space and time. The originality of this paper is to fill this research gap; to include migration as a critical moment for gender inequalities; to use an intersectional and geographical perspective that have been given scant attention in the literature; to use the original concept of economic citizenship; and to examine the case of a bi-national couple, which has so far not been examined by the literature on couple relationships.

Alternative outcomes for the multiple breath washout in children with CF

BACKGROUND The lung clearance index (LCI) measured by multiple-breath washout (MBW) has been proposed as an outcome for clinical trials; however, MBW is time consuming and LCI can be affected by breathing pattern. We aimed to evaluate moment ratios and abbreviated LCI in school-aged children with mild-to-moderate CF lung disease. METHODS Using existing data from three studies we assessed the sensitivity of moment ratios and abbreviated LCIs to (i) detect mild-to-moderate CF lung disease and (ii) detect treatment effects after 4weeks of hypertonic saline or dornase alfa inhalation. MBW was measured by respiratory mass spectrometry using 4% "sulphur hexafluoride as a tracer gas. RESULTS Compared to the traditional LCI, moment ratios and abbreviated LCIs were similarly sensitive to detect CF lung disease. Moment ratios consistently demonstrated treatment effects, whereas abbreviated LCIs were less sensitive. CONCLUSIONS Both moment ratios and abbreviated LCI are suitable to differentiate health from disease. Sensitivity is decreased for abbreviated LCIs in interventional studies in mild CF lung disease.

Proteome-wide screening of the European porcine reproductive and respiratory syndrome virus reveals a broad range of T cell antigen reactivity.

The porcine reproductive and respiratory syndrome virus (PRRSV) is a rapidly evolving and diversifying pathogen necessitating the development of improved vaccines. Immunity to PRRSV is not well understood although there are data suggesting that virus-specific T cell IFN-γ responses play an important role. We therefore aimed to better characterise the T cell response to genotype 1 (European) PRRSV by utilising a synthetic peptide library spanning the entire proteome and a small cohort of pigs rendered immune to PRRSV-1 Olot/91 by repeated experimental infection. Using an IFN-γ ELISpot assay as a read-out, we were able to identify 9 antigenic regions on 5 of the viral proteins and determine the corresponding responder T cell phenotype. The diversity of the IFN-γ response to PRRSV proteins suggests that antigenic regions are scattered throughout the proteome and no one single antigen dominates the T cell response. To address the identification of well-conserved T cell antigens, we subsequently screened groups of pigs infected with a closely related avirulent PRRSV-1 strain (Lelystad) and a divergent virulent subtype 3 strain (SU1-Bel). Whilst T cell responses from both groups were observed against many of the antigens identified in the first study, animals infected with the SU1-Bel strain showed the greatest response against peptides representing the non-structural protein 5. The proteome-wide peptide library screening method used here, as well as the antigens identified, warrant further evaluation in the context of next generation vaccine development.