Anwendungsmöglichkeiten der ex-vivo konfokalen Laserscanmikroskopie in der Dermatologie bei verschiedenen Tumorentitäten

Die ex-vivo konfokale Laserscanmikroskopie ist eine neuartige Methode, um frische Gewebeproben der Haut innerhalb kürzester Zeit auf Zellebene zu untersuchen. Sie kann somit als ergänzende bzw. alternative Methode zur konventionellen histopathologischen Untersuchung angesehen werden. Es wurden bereits zahlreiche Studien zur perioperativen Detektion von Basalzellkarzinomen und Plattenepithelkarzinomen in der mikroskopisch kontrollierten Chirurgie („Mohs Surgery“) mittels ex-vivo KLM durchgeführt. Die vorliegende Dissertation befasst sich mit der Untersuchung von Anwendungsmöglichkeiten der ex-vivo KLM bei verschiedenen Tumorentitäten und vergleicht die Methode mit der konventionellen histopathologischen Untersuchung, dem aktuellen Goldstandard. Ziel der gesamten Forschungsarbeiten war es, die Tumordickenmessung mittels ex- vivo KLM mit der histopathologischen Messung zu vergleichen sowie die Möglichkeit der spezifischen Detektion der Tumorzellen in immunhistochemisch gefärbten Präparaten von Hauttumoren mittels ex-vivo KLM zu beweisen. Für die Studie „Correlation of histological and ex-vivo confocal tumor thickness in malignant melanoma" wurden insgesamt zehn Hauttumorproben untersucht. Es zeigte sich sowohl in der graphischen Korrelationskurve als auch bei der Berechnung des Spearman Korrelationskoeffizienten mit dem Ergebnis 1,00 eine hohe Übereinstimmung der beiden Testmethoden. Des Weiteren konnten in einem Bland- Altman-Diagramm die Differenzen der beiden Messmethoden gegen den Mittelwert der beiden Methoden aufgetragen werden und zeigten auch hier nur geringe Unterschiede der mittleren Differenz von 0,09 ± 0,30 mm beim Vergleich von RM- CTT und HTT sowie von 0,19 ± 0,35 mm beim Vergleich von FM-CTT und HTT. Die Entscheidung über die Resektionsgröße der Sicherheitsabstände und Sentinel- Lymphknoten-Exstirpation stimmte bei der ex-vivo KLM in allen Fällen mit der konventionellen Histopathologie überein. Die ermittelten Ergebnisse dieser Studie weisen darauf hin, dass die ex-vivo KLM eine Option für die intra-/perioperative Tumordickenmessung beim malignen Melanom sein könnte. Die Tumordicke nach Breslow entscheidet maßgeblich darüber, in welchem Umfang Sicherheitsabstände bei Resektion eingehalten und Sentinel-Lymphknoten-Exstirpationen durchgeführt werden müssen. Eine bereits intraoperative Tumordickenmessung mittels ex-vivo KLM könnte folglich dem Patienten eine erneute Operation mit allen Unannehmlichkeiten ersparen. Für die Studie „Immunofluorescence and confocal microscopy for ex-vivo diagnosis of melanocytic and non-melanocytic skin tumors: A pilot study" wurden insgesamt 50 Tumorgewebeproben nach unterschiedlichen immunhistochemischen Färbeprotokollen und Verdünnungen präpariert und anschließend die Signalstärke mittels ex-vivo KLM nach einem Punktevergabesystem bewertet. Die Immunfärbung mit S100 bei Metastasen des malignen Melanoms war in 55,6 % der Fälle positiv und am besten mittels Färbeprotokoll B (PBS, ohne Blockierungsagens) in einer Verdünnung des Antikörpers von 1:200 darstellbar. Seite | 14 In 66,7 % und ebenfalls nach Protokoll B (PBS, ohne Blockierungsagens) mit einer idealen Verdünnung von 1:500 war die Färbung mit dem fluoreszenzmarkierten Melan A Antikörper bei Metastasen des malignen Melanoms positiv. Die Ber-EP4 Immunfärbung konnte beim Basalzellkarzinom die höchsten Ergebnisse mit einer Nachweisrate von 85,7 % aufweisen. Hierbei war das Färbeprotokoll A (PBS, mit Blockierungsagens) mit einer Verdünnung des Antikörpers von 1:200 und 1:500 am besten geeignet. Folglich konnte gezeigt werden, dass fluoreszenzmarkierte Antikörper auch in der ex- vivo KLM angewendet werden können und somit möglicherweise eine zukünftige Verbesserung der bereits intraoperativen Hauttumordiagnostik möglich ist. Durch die Bindung der Antikörper an spezifische Zellen können Hauttumore mit einer höheren Sicherheit diagnostiziert und differenziert werden. Zusammenfassend lässt sich sagen, dass die ex-vivo KLM eine vielversprechende Methode darstellt, um unter anderem bereits intraoperativ Hauttumore schneller zu evaluieren und dadurch die leitliniengerechte Therapie frühzeitiger anzuwenden. Eine Ausweitung der Studiengröße sowie die Untersuchung weiterer dermatologischer Erkrankungen ist das Ziel für die Zukunft, denn die ex-vivo KLM könnte zahlreiche medizinische, finanzielle und soziale Vorteile mit sich bringen.The ex-vivo confocal laser scanning (CLSM) microscopy is a novel method to examine fresh tissue samples of the skin on a cellular level within a very short time. It can thus be regarded as a supplementary or alternative method of conventional histopathological examination. Numerous studies on perioperative detection of basal cell carcinoma and squamous cell carcinoma in microscopic controlled surgery (Mohs Surgery) have been performed by ex-vivo CLSM. This dissertation deals with the investigation of various applications of ex-vivo CLSM in various tumor entities and compares the method with conventional histopathological examination, the current gold standard. The aim of the research work was to compare the tumor thickness measurement by ex-vivo CLSM with the histopathological measurement and to prove the possibility of detecting immunohistochemically stained preparations of skin tumors using ex-vivo CLSM. For the study "Correlation of histological and ex-vivo confocal tumor thickness in malignant melanoma" a total of ten skin tumor samples were examined, showing a high correlation between the two different measurement methods both in the graph correlation curve and the calculation of the Spearman correlation coefficient with the result 1.00. Furthermore, in a Bland-Altman diagram, the differences between the two methods were plotted against the mean of the two methods and again showed only slight differences in the mean difference of 0.09 ± 0.30 mm when comparing RM-CTT and HTT and 0.19 ± 0.35 mm comparing FM-CTT and HTT. The decision on the resection size of the safety margins and sentinel lymph node extirpation was in all cases of ex-vivo CLSM consistent with conventional histopathology. The results of this study indicated that the measurement of the tumor thickness with ex-vivo CLSM may be a potential alternative to the conventional histopathological tumor thickness measurement in malignant melanoma. The tumor thickness according to Breslow decisively determines the extent of consecutive safety margins and indication for sentinel lymph node biopsy. An intraoperative tumor thickness measurement using ex-vivo CLSM could thus spare the patient a reoperation with all associated inconveniences. For the study "Immunofluorescence and confocal microscopy for ex-vivo diagnosis of melanocytic and non-melanocytic skin tumors: A pilot study" a total of 50 tumor tissue samples were prepared according to different immunohistochemical staining protocols and dilutions, and then the signal strengths were evaluated by ex-vivo CLSM according to a scoring system. The immunostaining with S100 in metastases of the melanoma was positive in 55.6% of cases and best represented by staining protocol B (PBS, without blocking agent) in a dilution of the antibody of 1: 200. In 66.7% and also according to protocol B (PBS, without blocking agent) with an ideal dilution of 1: 500, staining with the fluorescence-labeled Melan A antibody was positive in metastases of the melanoma. Seite | 16 The Ber-EP4 immunostaining showed the highest results in basal cell carcinoma with a detection rate of 85.7%. Here, the staining protocol A (PBS, with blocking agent) with a dilution of the antibody of 1: 200 and 1: 500 was most suitable. Consequently, it could be shown that fluorescence-labeled antibodies can also be used in the ex-vivo CLSM. This may lead to a future improvement of intraoperative skin tumor diagnostics. By binding the antibodies to specific cells, skin tumors can be diagnosed and differentiated with a higher accuracy. In summary, the ex-vivo CLSM represents a promising method for faster intraoperative evaluation of skin tumors and thus immediate application of a guideline-based therapy. An expansion of the studies as well as investigation of further dermatological diseases are the goals for the future, since ex-vivo CLSM may bring numerous medical, financial and social benefits

Ex vivo Confocal Laser Scanning Microscopy: A Potential New Diagnostic Imaging Tool in Onychomycosis Comparable With Gold Standard Techniques

Ex vivo confocal laser scanning microscopy (CLSM) is an innovative imaging tool that enables real-time examination of specimens and may be used in evaluating fungal infections. We aimed to assess the applicability of ex vivo CLSM in the diagnosis of onychomycosis by comparing results to those obtained by histopathology, potassium hydroxide (KOH) examination, and fungal culture. In this prospective study, 57 patients with the clinical diagnosis of distal nail fungal infection were examined and compared using all four of the above-mentioned diagnostic tools in terms of sensitivity, positive and negative predictive value. Ex vivo CLSM showed the highest sensitivity, followed by KOH examination, histopathology and fungal culture. Regarding positive and negative predictive values, ex vivo CLSM was superior and showed even higher sensitivity than the combined gold standard comprised of KOH examination, fungal culture or histopathology

Joint-Individual Fusion Structure with Fusion Attention Module for Multi-Modal Skin Cancer Classification

Most convolutional neural network (CNN) based methods for skin cancer classification obtain their results using only dermatological images. Although good classification results have been shown, more accurate results can be achieved by considering the patient's metadata, which is valuable clinical information for dermatologists. Current methods only use the simple joint fusion structure (FS) and fusion modules (FMs) for the multi-modal classification methods, there still is room to increase the accuracy by exploring more advanced FS and FM. Therefore, in this paper, we design a new fusion method that combines dermatological images (dermoscopy images or clinical images) and patient metadata for skin cancer classification from the perspectives of FS and FM. First, we propose a joint-individual fusion (JIF) structure that learns the shared features of multi-modality data and preserves specific features simultaneously. Second, we introduce a fusion attention (FA) module that enhances the most relevant image and metadata features based on both the self and mutual attention mechanism to support the decision-making pipeline. We compare the proposed JIF-MMFA method with other state-of-the-art fusion methods on three different public datasets. The results show that our JIF-MMFA method improves the classification results for all tested CNN backbones and performs better than the other fusion methods on the three public datasets, demonstrating our method's effectiveness and robustnessComment: submitted to Pattern Recognition journal before 202

Identification of T-Cell Antigens Specific for Latent Mycobacterium Tuberculosis Infection

BACKGROUND: T-cell responses against dormancy-, resuscitation-, and reactivation-associated antigens of Mycobacterium tuberculosis are candidate biomarkers of latent infection in humans. METHODOLOGY/PRINCIPAL FINDINGS: We established an assay based on two rounds of in vitro restimulation and intracellular cytokine analysis that detects T-cell responses to antigens expressed during latent M. tuberculosis infection. Comparison between active pulmonary tuberculosis (TB) patients and healthy latently M. tuberculosis-infected donors (LTBI) revealed significantly higher T-cell responses against 7 of 35 tested M. tuberculosis latency-associated antigens in LTBI. Notably, T cells specific for Rv3407 were exclusively detected in LTBI but not in TB patients. The T-cell IFNgamma response against Rv3407 in individual donors was the most influential factor in discrimination analysis that classified TB patients and LTBI with 83% accuracy using cross-validation. Rv3407 peptide pool stimulations revealed distinct candidate epitopes in four LTBI. CONCLUSIONS: Our findings further support the hypothesis that the latency-associated antigens can be exploited as biomarkers for LTBI

Fiber rich food suppressed airway inflammation, GATA3 + Th2 cells, and FcεRIα+ eosinophils in asthma

BackgroundAllergic Asthma is a disease presenting various endotypes and no current therapies act curative but alleviate disease symptoms. Dietary interventions are gaining increasing importance in regulating immune responses. Furthermore, short chain fatty acids (SFCA), as the main products of dietary fiber’s fermentation by the gut bacteria, ameliorate the pathogenesis and disease burden of different illnesses including asthma. Nevertheless, the connection and crosstalk between the gut and lung is poorly understood.ObjectiveIn this work, the role of high fiber diet on the development of allergic asthma at baseline and after exacerbation of disease induced by respiratory viruses was investigated.MethodsHereby, SCFA in serum of asthmatic and non-asthmatic pre-school children before and after airway disease symptoms were analyzed. Moreover, the effect of high fiber diet in vivo in a murine model of house dust mite extract (HDM) induced allergic asthma and in the end in isolated lung and spleen cells infected ex vivo with Rhinovirus was analyzed.ResultsIn this study, a decrease of the SCFA 3-Hydroxybutyric acid in serum of asthmatic children after symptomatic episodes at convalescent visit as compared to asthmatic and control children at baseline visit was observed. In experimental asthma, in mice fed with high fiber diet, a reduced lung GATA3 + Th2 type mediated inflammation, mucus production and collagen deposition and expression of Fc epsilon receptor Ia (FcεRIa) in eosinophils was observed. By contrast, the CD8+ memory effector T cells were induced in the lungs of asthmatic mice fed with high fiber diet. Then, total lung cells from these asthmatic mice fed with either standard food or with fiber rich food were infected with RV ex vivo. Here, RV1b mRNA was found significantly reduced in the lung cells derived from fiber rich food fed mice as compared to those derived from standard food fed asthmatic mice. Looking for the mechanism, an increase in CD8+ T cells in RV infected spleen cells derived from fiber rich fed asthmatic mice, was observed.ConclusionConvalescent preschool asthmatic children after a symptomatic episode have less serum ß-Hydroxybutyric acid as compared to control and asthmatic children at baseline visit. Fiber rich diet associated with anti-inflammatory effects as well as anti-allergic effects by decreasing Type 2 and IgE mediated immune responses and inducing CD8+ memory effector T cells in a murine model of allergic asthma. Finally, ex vivo infection with Rhinovirus (RV) of total lung cells from asthmatic mice fed with fiber rich food led to a decreased RV load as compared to mice fed with standard food. Moreover, spleen cells derived from asthmatic mice fed with fiber rich food induced CD8+ T cells after ex vivo infection with RV.Clinical implicationsDietary interventions with increased content in natural fibers like pectins would ameliorate asthma exacerbations. Moreover, respiratory infection in asthma downregulated SCFA in the gut contributing to asthma exacerbations

Quantifying Absolute Neutralization Titers against SARS-CoV-2 by a Standardized Virus Neutralization Assay Allows for CrossCohort Comparisons of COVID-19 Sera

The global coronavirus disease 2019 (COVID-19) pandemic has mobilized efforts to develop vaccines and antibody-based therapeutics, including convalescent-phase plasma therapy, that inhibit viral entry by inducing or transferring neutralizing antibodies (nAbs) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (CoV2-S). However, rigorous efficacy testing requires extensive screening with live virus under onerous biosafety level 3 (BSL3) conditions, which limits high-throughput screening of patient and vaccine sera. Myriad BSL2-compatible surrogate virus neutralization assays (VNAs) have been developed to overcome this barrier. Yet, there is marked variability between VNAs and how their results are presented, making intergroup comparisons difficult. To address these limitations, we developed a standardized VNA using CoV2-S pseudotyped particles (CoV2pp) based on vesicular stomatitis virus bearing the Renilla luciferase gene in place of its G glyco-protein (VSVDG); this assay can be robustly produced at scale and generate accurate neutralizing titers within 18 h postinfection. Our standardized CoV2pp VNA showed a strong positive correlation with CoV2-S enzyme-linked immunosorbent assay (ELISA) results and live-virus neutralizations in confirmed convalescent-patient sera. Three independent groups subsequently validated our standardized CoV2pp VNA (n . 120). Our data (i) show that absolute 50% inhibitory concentration (absIC50), absIC80, and absIC90 values can be legitimately compared across diverse cohorts, (ii) highlight the substantial but consistent variability in neutralization potency across these cohorts, and (iii) support the use of the absIC80 as a more meaningful metric for assessing the neutralization potency of a vaccine or convalescent-phase sera. Lastly, we used our CoV2pp in a screen to identify ultrapermissive 293T clones that stably express ACE2 or ACE2 plus TMPRSS2. When these are used in combination with our CoV2pp, we can produce CoV2pp sufficient for 150,000 standardized VNAs/week. IMPORTANCE Vaccines and antibody-based therapeutics like convalescent-phase plasma therapy are premised upon inducing or transferring neutralizing antibodies that inhibit SARS-CoV-2 entry into cells. Virus neutralization assays (VNAs) for measuring neutralizing antibody titers (NATs) are an essential part of determining vaccine or therapeutic efficacy. However, such efficacy testing is limited by the inherent dangers of working with the live virus, which requires specialized high-level biocontainment facilities. We there-fore developed a standardized replication-defective pseudotyped particle system that mimics the entry of live SARS-CoV-2. This tool allows for the safe and efficient measurement of NATs, determination of other forms of entry inhibition, and thorough investigation of virus entry mechanisms. Four independent labs across the globe validated our standardized VNA using diverse cohorts. We argue that a standardized and scalable assay is necessary for meaningful comparisons of the myriad of vaccines and antibody-based therapeutics becoming available. Our data provide generalizable metrics for assessing their efficacy.Fil: Oguntuyo, Kasopefoluwa. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Stevens, Christian S.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Hung, Chuan Tien. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Ikegame, Satoshi. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Acklin, Joshua A.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Kowdle, Shreyas S.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Carmichael, Jillian C.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Chiu, Hsin Ping. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Azarm, Kristopher D.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Haas, Griffin D.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Amanat, Fatima. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Klingler, Jéromine. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Baine, Ian. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Arinsburg, Suzanne. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Bandres, Juan C.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Siddiquey, Mohammed N. A.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Schilke, Robert M.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Woolard, Matthew D.. State University of Louisiana; Estados UnidosFil: Zhang, Hongbo. State University of Louisiana; Estados UnidosFil: Duty, Andrew J.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Kraus, Thomas A.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Moran, Thomas M.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Tortorella, Domenico. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Lim, Jean K.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Gamarnik, Andrea Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Hioe, Catarina E.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Zolla Pazner, Susan. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Ivanov, Stanimir S.. State University of Louisiana; Estados UnidosFil: Kamil, Jeremy. State University of Louisiana; Estados UnidosFil: Krammer, Florian. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Lee, Benhur. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Ojeda, Diego Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: González López Ledesma, María Mora. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Costa Navarro, Guadalupe Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Pallarés, H. M.. No especifíca;Fil: Sanchez, Lautaro Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Perez, P.. No especifíca;Fil: Ostrowsk, M.. No especifíca;Fil: Villordo, S. M.. No especifíca;Fil: Alvarez, D. E.. No especifíca;Fil: Caramelo, J. J.. No especifíca;Fil: Carradori, J.. No especifíca;Fil: Yanovsky, M. J.. No especifíca

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

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good