Post-therapeutic response evaluation by a combination of endoscopy and CT scan in esophagogastric adenocarcinoma after chemotherapy: better than its reputation.

BACKGROUND Neoadjuvant chemotherapy is an accepted standard of care for locally advanced esophagogastric cancer. As only a subgroup benefits, a response-based tailored treatment would be of interest. The aim of our study was the evaluation of the prognostic and predictive value of clinical response in esophagogastric adenocarcinomas. METHODS Clinical response based on a combination of endoscopy and computed tomography (CT) scan was evaluated retrospectively within a prospective database in center A and then transferred to center B. A total of 686/740 (A) and 184/210 (B) patients, staged cT3/4, cN0/1 underwent neoadjuvant chemotherapy and were then re-staged by endoscopy and CT before undergoing tumor resection. Of 184 patients, 118 (B) additionally had an interim response assessment 4-6 weeks after the start of chemotherapy. RESULTS In A, 479 patients (70 %) were defined as clinical nonresponders, 207 (30 %) as responders. Median survival was 38 months (nonresponders: 27 months, responders: 108 months, log-rank, p < 0.001). Clinical and histopathological response correlated significantly (p < 0.001). In multivariate analysis, clinical response was an independent prognostic factor (HR for death 1.4, 95 %CI 1.0-1.8, p = 0.032). In B, 140 patients (76 %) were nonresponders and 44 (24 %) responded. Median survival was 33 months, (nonresponders: 27 months, responders: not reached, p = 0.003). Interim clinical response evaluation (118 patients) also had prognostic impact (p = 0.008). Interim, preoperative clinical response and histopathological response correlated strongly (p < 0.001). CONCLUSION Preoperative clinical response was an independent prognostic factor in center A, while in center B its prognostic value could only be confirmed in univariate analysis. The accordance with histopathological response was good in both centers, and interim clinical response evaluation showed comparable results to preoperative evaluation.

The ring vaccination trial: a novel cluster randomised controlled trial design to evaluate vaccine efficacy and effectiveness during outbreaks, with special reference to Ebola

A World Health Organization expert meeting on Ebola vaccines proposed urgent safety and efficacy studies in response to the outbreak in West Africa. One approach to communicable disease control is ring vaccination of individuals at high risk of infection due to their social or geographical connection to a known case. This paper describes the protocol for a novel cluster randomised controlled trial design which uses ring vaccination.In the Ebola ça suffit ring vaccination trial, rings are randomised 1:1 to (a) immediate vaccination of eligible adults with single dose vaccination or (b) vaccination delayed by 21 days. Vaccine efficacy against disease is assessed in participants over equivalent periods from the day of randomisation. Secondary objectives include vaccine effectiveness at the level of the ring, and incidence of serious adverse events.Ring vaccination trials are adaptive, can be run until disease elimination, allow interim analysis, and can go dormant during inter-epidemic periods.

Climatology of Vb cyclones, physical mechanisms and their impact on extreme precipitation over Central Europe

Cyclones, which develop over the western Mediterranean and move northeastward are a major source of extreme weather and known to be responsible for heavy precipitation over the northern side of the Alpine range and Central Europe. As the relevant processes triggering these so-called Vb events and their impact on extreme precipitation are not yet fully understood, this study focuses on gaining insight into the dynamics of past events. For this, a cyclone detection and tracking tool is applied to the ERA-Interim reanalysis (1979–2013) to identify prominent Vb situations. Precipitation in the ERA-Interim and the E-OBS data sets is used to evaluate case-to-case precipitation amounts and to assess consistency between the two data sets. Both data sets exhibit high variability in precipitation amounts among different Vb events. While only 23 % of all Vb events are associated with extreme precipitation, around 15 % of all extreme precipitation days (99 percentile) over the northern Alpine region and Central Europe are induced by Vb events, although Vb cyclones are rare events (2.3 per year). To obtain a better understanding of the variability within Vb events, the analysis of the 10 heaviest and lowest precipitation Vb events reveals noticeable differences in the state of the atmosphere. These differences are most pronounced in the geopotential height and potential vorticity field, indicating a much stronger cyclone for heavy precipitation events. The related differences in wind direction are responsible for the moisture transport around the Alps and the orographical lifting along the northern slopes of the Alps. These effects are the main reasons for a disastrous outcome of Vb events, and consequently are absent in the Vb events associated with low precipitation. Hence, our results point out that heavy precipitation related to Vb events is mainly related to large-scale dynamics rather than to thermodynamic processes.

Extratropical fronts in the lower troposphere-global perspectives obtained from two automated methods

In this study two commonly used automated methods to detect atmospheric fronts in the lower troposphere are compared in various synoptic situations. The first method is a thermal approach, relying on the gradient of equivalent potential temperature (TH), while the second method is based on temporal changes in the 10 m wind (WND). For a comprehensive objective comparison of the outputs of these methods of frontal identification, both schemes are firstly applied to an idealised strong baroclinic wave simulation in the absence of topography. Then, two case-studies (one in the Northern Hemisphere (NH) and one in the Southern Hemisphere (SH)) were conducted to contrast fronts detected by the methods. Finally, we obtain global winter and summer frontal occurrence climatologies (derived from ERA-Interim for 1979–2012) and compare the structure of these. TH is able to identify cold and warm fronts in strong baroclinic cases that are in good agreement with manual analyses. WND is particularly suited for the detection of strongly elongated, meridionally oriented moving fronts, but has very limited ability to identify zonally oriented warm fronts. We note that the areas of the main TH frontal activity are shifted equatorwards compared to the WND patterns and are located upstream of regions of main WND front activity. The number of WND fronts in the NH shows more interseasonal variations than TH fronts, decreasing by more than 50% from winter to summer. In the SH there is a weaker seasonal variation of the number of observed WND fronts, however TH front activity reduces from summer (DJF) to winter (JJA). The main motivation is to give an overview of the performance of these methods, such that researchers can choose the appropriate one for their particular interest.

Encapsulation of caesium-loaded Ionsiv in cement

The microporous material Ionsiv is used for 137Cs removal from aqueous nuclear waste streams. In the UK, Cs-loaded Ionsiv is classed as an intermediate-level waste; no sentencing and disposal route is yet defined for this material and it is currently held in safe interim storage on several nuclear sites. In this study, the suitability of fly ash and blast furnace slag blended cements for encapsulation of Cs-Ionsiv in a monolithic wasteform was investigated. No evidence of reaction or dissolution of the Cs-Ionsiv in the cementitious environment was found by scanning electron microscopy and X-ray diffraction. However, a small fraction (<= 1.6 wt.%) of the Cs inventory was released from the encapsulated Ionsiv during leaching experiments carried out on hydrated samples. Furthermore, it was evident that K and Na present in the cementitious pore water exchanged with Cs and H in the Ionsiv. Therefore, cement systems lower in K and Na, such as slag based cements, showed lower Cs release than the fly ash based cements.

Scheduled versus Pro Re Nata Dosing in the VIEW Trials

PURPOSE To analyze visual acuity (VA) outcomes before and after preplanned treatment regimen change in the VIEW studies at week 52 (W52). DESIGN Multiple post hoc analyses for retrospectively defined subgroups in 2 multicenter, multinational, double-masked trials. PARTICIPANTS Two thousand four hundred fifty-seven neovascular age-related macular degeneration (AMD) patients. METHODS Patients were randomized to treatment with 0.5 mg ranibizumab given monthly, a 0.5-mg or 2-mg intravitreal aflibercept injection given monthly, or 2 mg intravitreal aflibercept given every other month, after 3 initial monthly doses, up to W52. From W52 through W96, patients received their original dosing assignment using a capped pro re nata (PRN) regimen, with defined retreatment criteria based on VA and morphologic signs of disease activity and mandatory dosing at least every 12 weeks. MAIN OUTCOME MEASURES Best-corrected VA (BCVA) and optical coherence tomography assessments were mandatory at all visits from baseline to W96. Outcomes were changes in BCVA and central retinal thickness. Outcomes were evaluated in all patients who completed 2 years of the VIEW studies using the last observation carried forward method for missing data at interim visits. RESULTS After W52, approximately 20% of patients lost 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more across all treatment arms with PRN treatment. Patients who met the retreatment criterion of loss of 5 ETDRS letters or more in the first quarter of the PRN dosing phase did not recover; mean final VA loss across the 4 study arms was -4.4 to -5.8 letters. Outcomes of these patients up to W52 were indistinguishable from those of the overall population. There were no differences between groups in serious ocular adverse events or Anti-Platelet Trialists' Collaboration arterial thromboembolic events through W96. CONCLUSIONS These analyses suggest that there are subgroups of patients for whom VA outcomes in the second year of the VIEW studies were less stable than in the first year and for whom W52 seems to be an important inflection point. Although alternate reasons specific to the nature of the underlying AMD cannot be fully excluded, the switch in treatment regimen at W52 is a plausible explanation.

Preußens Deutsche Politik : die Dreifürstenbünde 1785, 1806, 1849

Boberach: Das Dreikönigsbündnis wird als Fortsetzung der mit dem Fürstenbund von 1785 und den Plänen von 1806 für ein norddeutsches Kaisertum von Preußen betriebenen Politik gedeutet. Die Fürsten sollen sich für die Einheit unter Preußen entscheiden. - Wentzke: Stellt die drei Vorstöße preußisch-deutscher Politik als Lehre für Gegenwart und Zukunft zusammen. Auch 1849 wurde die Idee der deutschen Einheit durch die preußische Kabinetspolitik [sic!] wieder auf einen weiten Umweg verwiesen. Hier bildet die Einheitsidee des engeren Bundesstaates und die dualistische Tendenz des Interim einen unauflöslichen Widerspruch. Das Bedürfnis der Sicherheit und Freiheit aber verlangt unbedingt die Einheit. Mahnt die deutschen Fürsten zur Entscheidung, die nur zugunsten der Einheit ausfallen kann

Zur Politik der Epigonen in Preußen : zwei Reden in der I. Kammer zu Berlin, gehalten und nicht gehalten

Boberach: Die interimistische Wiederherstellung des Deutschen Bundes ist ein Fortschritt auf dem Wege zur Reichseinheit, weil nur noch die beiden Großmächte Entscheidungsgewalt haben. Im März 1848 hat Preußen versäumt, das Reich unter seiner Führung zu gründen. Die Erneuerung des Bundestages [jedoch] würde aber Preußen auf den Rang der früheren Rheinbundstaaten herabwürdigen. Preußen muß die Führung in der deutschen Politik beanspruchen. - Wentzke: Abdruck 1. einer am 16. Februar [1850] gehaltenen Rede in der Mecklenburgischen Verfassungsangelegenheit, 2. des Bruchstücks einer für den 26. November 1849 in der deutschen Sache vorbereiteten Rede. - 1. Das Interim bedeutet nicht die Wiederkunft des alten Bundestages, sondern einen Fortschritt zur Einheit von Deutschland über die Zwischenstufe des Dualismus. Aber Mangel an Folgerichtigkeit in der Politik des Ministeriums! - 2. Tadel der schwachen preußischen Politik am 22. März 1848, die den am 2. April zusammentretenden Landtag zum deutschen Parlament hätte erweitern müssen zur Gründung eines deutschen Reiches unter dem Vorsitz von Preußen. Das November-Ministerium will jetzt diese Politik in stark abgeschwächtem Maße nachholen! Kritik dieser Schwäche, die vom Erbkaiser auf den Vereinsvorstand, vom deutschen Reich auf den engeren Verein herabgestiegen ist

Die Rechtswidrigkeit der versuchten Reactivirung der im Jahre 1848 aufgehobenen deutschen Bundesversammlung

Boberach: Gegen Lindes Behauptung der ununterbrochenen Existenz des Deutschen Bundes ist die Gültigkeit der Beschlüsse der Bundesplenarversammlung vom August 1850 zu bestreiten. Österreich hat durch das Interim anerkannt, daß keine Bundesversammlung besteht. - Wentzke: Eine staats- und bundesrechtliche Deduktion, veranlaßt durch den Aufsatz v. Lindes im "Archiv für das öffentliche Recht des Deutschen Bundes", [1. Heft: Betrachtungen über die wichtigsten Fragen der Gegenwart auf dem Gebiete des öffentlichen deutschen Bundesrechts; Gießen 1850] der die Fortexistenz des 1848 aufgehobenen Bundestags zu beweisen sucht. Rechtliche Ungültigkeit der im August von der sogen. Bundesplenarversammlung gefaßten Beschlüsse. Die Vorboten der Theorie von der Unsterblichkeit der Bundesversammlung in den Noten der hannoverschen Regierung im Sommer 1849. Nicht auf den Verträgen von 1815 beruht die Unauflöslichkeit des deutschen Bundes, sondern auf dem Recht der deutschen Nation. Nur der einstimmige Beschluß aller Bundesglieder kann ein neues Recht und neue organische Anstalten schaffen. Österreich hat durch das Interim die Nichtexistenz der Bundesversammlung anerkannt. Für freie Konferenzen und gegen den Eintritt der österreichischen Gesamtmonarchie mit eigener Gesetzgebung. Die jetzt in Frankfurt tagende Versammlung ist nur das Organ eines Sonderbundes, der bloß seine eigenen Mitglieder verpflichten kann

Das Jahr Acht und vierzig; seit fünf Jahrhunderten ein verhängnißvolles oder entscheidendes Jahr, besonders in religiöser Beziehung

Boberach: Die revolutionären Ereignisse von 1848 werden in Beziehung gesetzt zur Pest von 1348, zum Aschaffenburger Konkordat zwischen Papst und Kaiser von 1448, dem Augsburger Interim von 1548, dem Westfälischen Frieden 1648 und zu einer angeblichen katholischen Vorherrschaft seit 1748

Na 1 Nachlass Max Horkheimer, 682 - "Antisemitism among American Labor" (p. IX 146.2-4 - IX 146.5-23)

"Antisemitism and American Labor. A Research Project of the Institut of Social Research", Januar 1944 (revised June 1944); a) als Typoskript vervielfältigt, 14 Blatt; b) Typoskript, 14 Blatt; Institut of Social Research: "Project an Antisemitism and American Labor", Januar 1944; a) Typoskript, 18 Blatt; b) Typoskript, mit handschriftlichen Korrekturen, 17 Blatt, c) Teilstück, Typoskript mit handschriftlichen Korrekturen, 1 Blatt; d) Teilstück, Typoskript mit handschriftlichen Korrekturen, 1 Blatt; e) Teilstück, Typoskript mit handschriftlichen Korrekturen, 5 Blatt; f) Teilstück, Typoskript mit handschriftlichen Korrekturen, 4 Blatt; "Project on Antisemitism an American Labor", Dezember 1943; a) Typoskript mit handschriftlichen Korrekturen, 18 Blatt; b) Typoskript mit handschriftlichen Korrekturen von Theodor W. Adorno, 17 Blatt; c) Typoskript mit handschriftlichen Korrekturen, 12 Blatt; Memoranden 1941-1949; Adorno, Theodor W. to Löwenthal, Leo: "Supplement to the Memorandum of 7/28/49 by Pollock, Friedrich re Labor Study", 18.09.1949. Typoskript, 6 Blatt; Adorno, Theodor W.: "Memorandum re: Antisemitism among American Labor, as edited by the Bureau of Applied Social Research", 19.07.1949. Typoskript, 8 Blatt; "Expenses for Project: Antisemitism among Labor, june 1, 1944- May 31,1945". Typoskript, 1 Blatt; Institut of Social Research: "Interim Memorandum on Progress of Project on Antisemitism within Labor", 04.09.1944. Typoskript, 11 Blatt; Institut of Social Research: "Re: Project on Labor and Antisemitism. Difficulties to be expected", 21.03.1944. Typoskript, 3 Blatt; "Re: Project on Labor and Antisemitism. Plants to be Contacted", 21.03.1944. Typoskript, 2 Blatt; "Some Remarks to Dr. Gelle's Report 'Der deutsche Progrom, a, 10. November 1938'", 11.03.1944. Typoskript, 12 Blatt; Adorno, Theodor W. ?: "Adress to ameeting of the Jewish Labor Committee, January 20th, 1944, los Angeles". Typoskript mit eigenhändigen Ergänzungen, 2 Blatt; Pollock, Friedrich: "Re: Sherman", 31.12.1943, 1 Blatt; "Memorandum re: Jewish Labor Committee", 23.12.1943. Typoskript mit handschriftlichen Korrekturen, 2 Blatt; "Tentative Budget for a Trial Survey on Antisemitism among American Labor", 23.12.1943. Typoskript, 1 Blatt; "Council for Democracy. Survey on Antisemitism. Hartford, Conn., late 1941". Typoskript, 4 Blatt; "Council for Democracy. Survey on Antisemitism. Terre Haute, Ind.". Typoskript, 2 Blatt; Horkheimer, Max: Eigenhändige Notizen zum Projekt, 3 Blatt; "Some heading lind", handschriftlichen Notizen, 1 Blatt; Institut of Social research: "Instructuins", Fragebogen, als Typoskript vervielfältigt, 3 Blatt; "Instructions for Interviews on Attitudes of Workers and White Collar Workers towards Jews". Als Typoskript vervielfältigt, 1 Blatt; Horkheimer, Max: 1 Briefentwurf an Friedrich Pollock, ohne Ort, ohne Datum, 1 Blatt; Pollock, Friedrich: 3 Briefe an Max Horkheimer, ohne Ort, 1943, 3 Blatt; Sherman, Charles B.: 1 Brief mit Unterschrift an Friedrich Pollock, New York, 23.12.1943; 3 Briefe von Friedrich Pollock, New York, 1943-1944, 5 Blatt;

Bayesian doubly optimal group sequential designs for randomized clinical trials

When conducting a randomized comparative clinical trial, ethical, scientific or economic considerations often motivate the use of interim decision rules after successive groups of patients have been treated. These decisions may pertain to the comparative efficacy or safety of the treatments under study, cost considerations, the desire to accelerate the drug evaluation process, or the likelihood of therapeutic benefit for future patients. At the time of each interim decision, an important question is whether patient enrollment should continue or be terminated; either due to a high probability that one treatment is superior to the other, or a low probability that the experimental treatment will ultimately prove to be superior. The use of frequentist group sequential decision rules has become routine in the conduct of phase III clinical trials. In this dissertation, we will present a new Bayesian decision-theoretic approach to the problem of designing a randomized group sequential clinical trial, focusing on two-arm trials with time-to-failure outcomes. Forward simulation is used to obtain optimal decision boundaries for each of a set of possible models. At each interim analysis, we use Bayesian model selection to adaptively choose the model having the largest posterior probability of being correct, and we then make the interim decision based on the boundaries that are optimal under the chosen model. We provide a simulation study to compare this method, which we call Bayesian Doubly Optimal Group Sequential (BDOGS), to corresponding frequentist designs using either O'Brien-Fleming (OF) or Pocock boundaries, as obtained from EaSt 2000. Our simulation results show that, over a wide variety of different cases, BDOGS either performs at least as well as both OF and Pocock, or on average provides a much smaller trial. ^

Bayesian dual threshold design with Dirichlet distribution: An alternative way to frequentist multi-stage phase II designs in oncology

Many phase II clinical studies in oncology use two-stage frequentist design such as Simon's optimal design. However, they have a common logistical problem regarding the patient accrual at the interim. Strictly speaking, patient accrual at the end of the first stage may have to be suspended until all patients have events, success or failure. For example, when the study endpoint is six-month progression free survival, patient accrual has to be stopped until all outcomes from stage I is observed. However, study investigators may have concern when accrual is suspended after the first stage due to the loss of accrual momentum during this hiatus. We propose a two-stage phase II design that resolves the patient accrual problem due to an interim analysis, and it can be used as an alternative way to frequentist two-stage phase II studies in oncology. ^

Performance evaluation in Bayesian adaptive randomization

Bayesian adaptive randomization (BAR) is an attractive approach to allocate more patients to the putatively superior arm based on the interim data while maintains good statistical properties attributed to randomization. Under this approach, patients are adaptively assigned to a treatment group based on the probability that the treatment is better. The basic randomization scheme can be modified by introducing a tuning parameter, replacing the posterior estimated response probability, setting a boundary to randomization probabilities. Under randomization settings comprised of the above modifications, operating characteristics, including type I error, power, sample size, imbalance of sample size, interim success rate, and overall success rate, were evaluated through simulation. All randomization settings have low and comparable type I errors. Increasing tuning parameter decreases power, but increases imbalance of sample size and interim success rate. Compared with settings using the posterior probability, settings using the estimated response rates have higher power and overall success rate, but less imbalance of sample size and lower interim success rate. Bounded settings have higher power but less imbalance of sample size than unbounded settings. All settings have better performance in the Bayesian design than in the frequentist design. This simulation study provided practical guidance on the choice of how to implement the adaptive design. ^

The role of chronic irritation and inflammation in tumor promotion in CD-1 mice by petroleum middle distillates

An initiation-promotion bioassay in CD-1 mice was used to examine the role of chronic irritation and inflammation in tumor promotion by petroleum middle distillates. A representative hydrodesulfurized middle distillate (API 81-07) was selected as the test article. Test groups (54 mice per group) were initiated once with 50 ug of 7,12-dimethylbenzanthracene (DMBA). Promotion with API 81-07 consisted of twice weekly treatments for 25 weeks with either 25 ul, 50 ul, 50 ul + daily treatment with 15 ug dexamethasone, 50 ul + post-application washings, and 100 ul. Three mice from each group were sacrificed at 21 day intervals (24 total per group). The skin from interim sacrificed (IS) mice was examined histopathologically for tumor, acanthosis, hyperkeratosis, pseudo-epitheliomatous hyperplasia, epidermal crusting, and subacute inflammation. In-life observations included examination of all mice for erythema and edema for 8 weeks following the first promotion treatment. Tumor incident at study termination was as follows: 25 ul (45%), 50 ul (43%), 50 ul + dexamethasone (0%), 50 ul + washing (70%), and 100 ul (81%). An overall correlation of $>$0.90 between tumor incidence and group means for acanthosis and hyperkeratosis was observed in IS mice at all intervals. Correlations of $<$0.75 were observed for other group mean histopathological parameters and tumor incidence. The overall correlation of group mean erythema and edema with tumor incident was $>$0.90. The results of this study support the hypothesis that induction of a lasting, albeit mild, hyperplasia is an essential, but not sufficient requirement, for tumor promotion. Furthermore, subacute inflammation does not appear to be a significant factor in tumor promotion by petroleum middle distillates. However, inflammation may be a factor in tumor progression. ^