Pazopanib with 5‐FU and oxaliplatin as first line therapy in advanced gastric cancer: A randomized phase‐II study—The PaFLO trial. A study of the Arbeitsgemeinschaft Internistische Onkologie AIO‐STO‐0510

VEGF inhibition in gastric cancer has a proven benefit in the second line setting. Pazopanib, an oral tyrosine kinase inhibitor, selectively inhibits VEGFR-1, -2 and -3, c-kit and PDGF-R resulting in inhibition of angiogenesis. This open-label randomized phase II trial (2:1) investigated the efficacy of combining pazopanib with FLO (5-fluorouracil, oxaliplatin) vs FLO alone (internal control arm) as first-line treatment in patients with advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Eighty-seven patients were randomized and 78 patients were eligible and evaluable (PaFLO arm 51 patients, FLO arm 27 patients). The PFS rate at 6 months (primary endpoint) was 34% in the PaFLO arm vs 30% in the FLO arm. Comparing PaFLO with FLO median PFS was 4.66 months (95% confidence interval [CI] 2.87-6.46) vs 4.47 months (95% CI 1.79-7.14) (95% CI, hazard ratio [HR] 0.96 (0.60-1.55), P = .882 [exploratory]); median OS was 10.19 months (95% CI 5.46-14.92) vs 7.33 months (95% CI 4.93-9.73), (95% CI HR 1.01 [0.62-1.65], P = .953, exploratory), disease control rate was 72% vs 59%. PaFLO was well tolerable, toxicities were slightly higher in the PaFLO arm. Major adverse events were loss of appetite, nausea, fatigue, diarrhea, neutropenia and thrombocytopenia. Adding pazopanib to chemotherapy shows signs of efficacy but no major improvement in this randomized phase 2 trial. The PFS at 6 months in both arms was lower than expected from the literature. Biomarkers identifying subgroups who benefit and novel combinations are needed. ClinicalTrials.gov: NCT01503372

Tissue-specific regulatory network extractor (TS-REX): a database and software resource for the tissue and cell type-specific investigation of transcription factor-gene networks

The prediction of transcription factor binding sites in genomic sequences is in principle very useful to identify upstream regulatory factors. However, when applying this concept to genomes of multicellular organisms such as mammals, one has to deal with a large number of false positive predictions since many transcription factor genes are only expressed in specific tissues or cell types. We developed TS-REX, a database/software system that supports the analysis of tissue and cell type-specific transcription factor-gene networks based on expressed sequence tag abundance of transcription factor-encoding genes in UniGene EST libraries. The use of expression levels of transcription factor-encoding genes according to hierarchical anatomical classifications covering different tissues and cell types makes it possible to filter out irrelevant binding site predictions and to identify candidates of potential functional importance for further experimental testing. TS-REX covers ESTs from H. sapiens and M. musculus, and allows the characterization of both presence and specificity of transcription factors in user-specified tissues or cell types. The software allows users to interactively visualize transcription factor-gene networks, as well as to export data for further processing. TS-REX was applied to predict regulators of Polycomb group genes in six human tumor tissues and in human embryonic stem cells

Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper

Background: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2–1.0%. Summary: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitorin

Informatikai algoritmusok I.

A könyv az Oktatási Minisztérium támogatásával, a Felsooktatási Pályázatok Irodája által lebonyolított felsooktatási tankönyvtámogatási program keretében jelent meg

Multiple Myeloma Treatment in Real-world Clinical Practice : Results of a Prospective, Multinational, Noninterventional Study

Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: M.M. has received personal fees from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Sanofi, Novartis, and Takeda and grants from Janssen and Sanofi during the conduct of the study. E.T. has received grants from Janssen and personal fees from Janssen and Takeda during the conduct of the study, and grants from Amgen, Celgene/Genesis, personal fees from Amgen, Celgene/Genesis, Bristol-Myers Squibb, Novartis, and Glaxo-Smith Kline outside the submitted work. M.V.M. has received personal fees from Janssen, Celgene, Amgen, and Takeda outside the submitted work. M.C. reports honoraria from Janssen, outside the submitted work. M. B. reports grants from Janssen Cilag during the conduct of the study. M.D. has received honoraria for participation on advisory boards for Janssen, Celgene, Takeda, Amgen, and Novartis. H.S. has received honoraria from Janssen-Cilag, Celgene, Amgen, Bristol-Myers Squibb, Novartis, and Takeda outside the submitted work. V.P. reports personal fees from Janssen during the conduct of the study and grants, personal fees, and nonfinancial support from Amgen, grants and personal fees from Sanofi, and personal fees from Takeda outside the submitted work. W.W. has received personal fees and grants from Amgen, Celgene, Novartis, Roche, Takeda, Gilead, and Janssen and nonfinancial support from Roche outside the submitted work. J.S. reports grants and nonfinancial support from Janssen Pharmaceutical during the conduct of the study. V.L. reports funding from Janssen Global Services LLC during the conduct of the study and study support from Janssen-Cilag and Pharmion outside the submitted work. A.P. reports employment and shareholding of Janssen (Johnson & Johnson) during the conduct of the study. C.C. reports employment at Janssen-Cilag during the conduct of the study. C.F. reports employment at Janssen Research and Development during the conduct of the study. F.T.B. reports employment at Janssen-Cilag during the conduct of the study. The remaining authors have stated that they have no conflicts of interest. Publisher Copyright: © 2018 The AuthorsMultiple myeloma (MM) remains an incurable disease, with little information available on its management in real-world clinical practice. The results of the present prospective, noninterventional observational study revealed great diversity in the treatment regimens used to treat MM. Our results also provide data to inform health economic, pharmacoepidemiologic, and outcomes research, providing a framework for the design of protocols to improve the outcomes of patients with MM. Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.publishersversionPeer reviewe

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Antiapoptotic proteins as prognostic markers and resistance mechanisms in Acute Myeloid Leukemia

0\. Titelblatt, Inhaltsverzeichnis, Abkürzungsverzeichnis 1\. Einleitung - Die Problematik 4 1.1 Klinische Relevanz der Apoptoseforschung 4 1.2 Die Bcl-2 Familie: Induktoren und Blocker des Apoptoseprogramms 7 1.3 Caspasen: Killer-Proteasen 12 1.4 Inhibitoren der Apoptose: Der Name ist Programm 15 2\. Hauptteil - Eigene Arbeiten 22 2.1 Inhibitoren der Apoptose: molekulare und zellbiologische Funktion 22 2.1.1 Survivin blockiert Apoptosestimuli durch Inhibierung von Caspasen 22 2.1.2 Bedeutung der Apoptoseforschung für die klinische Hämatologie 22 2.1.3 Nicht alle BIR-Domänen sind funktionell gleichwertig 22 2.1.4 Hepatitis B X-interacting factor als Kofaktor für Survivins Funktion 22 2.2 Inhibitoren der Apoptose: prognostische Bedeutung 25 2.2.1 Inhibitoren der Apoptose bei kindlicher akuter myeloischer Leukämie 25 2.2.2 XIAP bei de novo akuter myeloischer Leukämie 25 2.2.3 Inhibitoren der Apoptose bei akuter myeloischer Leukämie 25 2.3 Inhibitoren der Apoptose: therapeutische Implikationen 28 2.3.1 Peptide binden spezifisch Inhibitoren der Apoptose 28 2.3.2 Zellzyklus-Inhibitoren induzieren Apoptose 28 2.3.3 Antisense-Konstrukte gegen Inhibitoren der Apoptose 28 3\. Ausblick und kritische Würdigung 31 4\. Zusammenfassung: Abstrakt 33 5\. Literaturverzeichnis 35Untersuchungen der letzten Jahre haben die Bedeutung des kontrollierten Zelltodes (Apoptose) für eine Vielzahl von menschlichen Erkrankungen aufgezeigt. Die Unterdrückung des physiologischen Apoptoseprogramms trägt zur Leukämogenese über unterschiedliche Mechanismen bei, hierzu gehören die Akkumulation von Genmutationen, Wachstums-Faktor unabhängiges Überleben von Zellen, Resistenz gegenüber immunvermittelter Zytotoxizität und Übergehen von Zellzyklusregulatoren, die normalerweise Apoptose induzieren würden. Defekte Apoptosemechanismen spielen auch eine wichtige Rolle bei der Entwicklung von Resistenzmechanismen der Leukämiezellen gegen Chemotherapie und Bestrahlung. Die Kernmaschinerie der Zelltodsignaltransduktionswege lässt sich auf wenige - im Verlauf der Evolution gut konservierte - Proteine reduzieren. Diese Arbeit untersucht die molekulare und zellbiologische Wirkungsweise einer antiapoptotischen Proteinfamilie, der "Inhibitoren der Apoptose" (IAPs). Hierbei konnte gezeigt werden, welche Domänen innerhalb der IAPs für ihre antiapoptotische Funktion notwendig sind. Ebenso konnten zelluläre Bindungspartner isoliert sowie ihre Position innerhalb der wichtigsten Signaltransduktionswege der Apoptose geklärt werden. Neben diesen Studien zum Wirkungsmechanismus der IAPs erlaubte die Analyse ihrer prognostischen Bedeutung mit Hilfe von Expressionstudien bei akuten myeloischen Leukämien die Identifizierung von Patienten mit guter bzw. schlechter Prognose. Wegen ihrer Rolle als Resistenzgene wurden die IAPs als Zielstrukturen therapeutischer Ansätze untersucht, um durch Reaktivierung der von IAPs blockierten Apoptosewege das Zelltodprogramm von Leukämiezellen zu induzieren. So wurden Peptide isoliert, welche die antiapoptotische Funktion der IAPs blockieren. Hierdurch konnten selektiv IAPs überexprimierende Leukämiezellen für Apoptosestimuli sensitiviert werden. Damit zeigt diese Arbeit die Bedeutung einer Gruppe antiapoptotischer Proteine als Resistenzgene bei malignen Erkrankungen. Die Identifikation der molekularen Wirkungsweise ermöglicht die Nutzung der IAPs als Prognosemarker und Therapieziel bei Leukämien.Recent studies have indicated a role for apoptosis in a variety of human diseases. Suppression of apoptosis contributes to leukemogenesis by several mechanisms, including facilitating the accumulation of gene mutations, permitting grwoth-factor-independent cell survival, promoting resistance to immune-based cytotoxicity, and allowing bypassing of cell-cycle checkpoints, which would normally induce cell death. Defects in apoptotic mechanisms also play an important part in resistance to chemotherapy and radiation. The core machinery of the cell death pathway can be reduced to a few critical types of proteins, which are well conserved across animal evolution. This study analyzes the molecular and cell biological mode of action of the inhibitor of apoptosis (IAP) family of proteins. The domains within the IAPs which are necessary and sufficient for their antiapoptotic properties could be defined. Moreover, their position in the apoptosis signaling cascade was determined by isolating new cellular binding partners of IAPs. Given their role as chemoresistance genes, the utility of IAPs as prognostic markers and therapeutic targets was investigated. In patients with acute myeloid leukemia, IAP expression was a negative prognostic marker. Next, peptides were isolated that bind and thereby block IAP's antiapoptotic function resulting in an activation of the apoptotic program in leukemia cells overexpressing IAPs. In essence, this work describes the significance of a group of antiapoptotic proteins as resistance genes in leukemia. The identification of its molecular mode of action allows for the usage of IAPs as prognostic markers and therapeutic targets in leukemia

Hiding Data - Selected Topics: Rudolf Ahlswede’s Lectures on Information Theory 3

Ahlswede A, Althöfer I, Deppe C, Tamm U, eds. Hiding Data - Selected Topics: Rudolf Ahlswede’s Lectures on Information Theory 3. Foundations in Signal Processing, Communications and Networking. 1st ed. Heidelberg: Springer; 2016