70 results on '"Pozios I"'
Search Results
2. Impact of myopenia and myosteatosis on postoperative outcome and recurrence in Crohn’s disease
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Pozios, I, additional, Kaufmann, D, additional, Beyer, K, additional, Kreis, M, additional, Seifarth, C, additional, and Lauscher, JC, additional
- Published
- 2021
- Full Text
- View/download PDF
3. Blocking gp130-mediated IL-6 and Oncostatin M signaling inhibits pancreatic tumor growth in vivo
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Pozios, I, additional, Günzler, E, additional, Hering, N, additional, Arndt, M, additional, Kamphues, C, additional, Margonis, GA, additional, Kreis, M, additional, Beyer, K, additional, and Seeliger, H, additional
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- 2021
- Full Text
- View/download PDF
4. Postoperative intussusception: a rare but critical complication in adult patients with Crohn’s disease – case report and literature review
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Eschlböck Sophie M., Weixler Benjamin, Weidinger Carl, and Pozios Ioannis
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crohn’s disease ,intussusception ,postoperative complication ,Surgery ,RD1-811 - Abstract
Postoperative entero-enteric intussusception is a rare complication in adult patients with Crohn’s disease (CD). The knowledge of this distinct complication and its timely diagnosis and therapy are of utmost importance to prevent fatal intestinal necrosis. There is no consensus about the optimal management of postoperative entero–enteric intussusception, although surgical exploration is widely advised.
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- 2023
- Full Text
- View/download PDF
5. Low dose tenecteplase restores vessel patency in a clinically relevant porcine animal model
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Kontopidi, Eleni Tseliou, Repasos, Terrovitis J, Pozios I, Nanas Jn, Nikos Diakos, S Dimopoulos, Koudoumas D, Margari Z, Katsaros F, Tsagalou E, Ntalianis A, and Tsamatsoulis M
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medicine.medical_specialty ,Animal model ,business.industry ,Anesthesia ,Low dose ,medicine ,Tenecteplase ,business ,Surgery ,medicine.drug - Published
- 2016
6. Afterload-induced left ventricular diastolic dysfunction during myocardial ischaemia and reperfusion
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Diakos, N.A. Pozios, I. Katsaros, L. Vakrou, S. Sventzouri, S. Michelinakis, N. Tseliou, E. Bonios, M. Malliaras, K. Papalois, A. Anastasiou-Nana, M. Terrovitis, J.V.
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cardiovascular system ,cardiovascular diseases ,circulatory and respiratory physiology - Abstract
New Findings: What is the central question of this study? While the load dependence of the diastolic function is established for the normal heart, little is known about the response of the acutely ischaemic and reperfused myocardium to alterations in afterload. What is the main finding and its importance? Using a model that simulates the clinical scenario of acute ischaemia-reperfusion, we show that increased afterload aggravates diastolic dysfunction during both acute ischaemia and reperfusion. In addition, increased afterload induces diastolic dyssynchrony, which might be the underlying mechanism of the diastolic dysfunction of the ischaemic myocardium. These findings provide us with new information regarding how better to manage patients who undergo revascularization therapy after acute myocardial infarction. The effects of changes in left ventricular (LV) afterload on diastolic function of acutely ischaemic and reperfused myocardium have not been studied in depth. We examined the following factors: (i) the consequences of increasing the LV afterload on LV diastolic function during acute ischaemia and reperfusion; (ii) whether the myocardial response to afterload elevation is stable throughout a 2 h reperfusion period; and (iii) the role of LV wall synchrony in the development of afterload-induced diastolic dysfunction. We instrumented 12 anaesthetized, open-chest pigs with Millar pressure catheters and piezoelectric crystals before ligating mid-left anterior descending coronary artery for 1 h, followed by reperfusion for 2 h. Six of the animals survived throughout the 2 h of reperfusion, and their data were used for comparisons across the different experimental phases. Left ventricular afterload was increased by inflating an intra-aortic balloon. Data were recorded at baseline, after 20 min of coronary occlusion and at 30 and 90 min of myocardial reperfusion. The increased afterload for 2 min lengthened the isovolumic relaxation during ischaemia and during early and late reperfusion but had no significant effect on isovolumic relaxation before coronary artery occlusion. Increasing the afterload aggravated LV diastolic dyssynchrony during coronary artery occlusion, but not during reperfusion. The afterload-induced prolongation of isovolumic relaxation was positively correlated with afterload-induced diastolic dyssynchrony. These observations indicate that, during myocardial ischaemia and throughout reperfusion, LV diastolic function is afterload dependent. Afterload-induced diastolic dyssynchrony might be an underlying mechanism of diastolic dysfunction during acute ischaemia. © 2014 The Physiological Society.
- Published
- 2015
7. Hemmung des Tumorwachstums durch den M3-Acetylcholinrezeptor-Antagonisten Darifenacin im orthotopen Xenograftmodell des Kolonkarzinoms
- Author
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Liu, V, primary, Böckenfeld, A, additional, Pozios, I, additional, Arndt, M, additional, Kreis, ME, additional, and Seeliger, H, additional
- Published
- 2016
- Full Text
- View/download PDF
8. EURObservational Research Programme:regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot)
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Maggioni, A. P., Dahlstrom, U., Filippatos, G., Chioncel, O., Leiro, M. C., Drozdz, J., Fruhwald, F., Gullestad, L., Logeart, D., Fabbri, G., Urso, R., Metra, M., Parissis, J., Persson, H., Ponikowski, P., Rauchhaus, M., Voors, A. A., Nielsen, O. W., Zannad, F., Tavazzi, L., Alonso, A., Ferrari, R., Komajda, M., Wood, D., Manini, M., Taylor, C., Laroche, C., Fiorucci, E., Lucci, D., Gonzini, L., Auer, J., Oberrauner, A., Schumacher, M., Ebner, C., Hallas, A., Espersen, G., Gustafsson, F., Mattsson, N., Egstrup, K., Aagaard, S., Gohr, T., Huld, K., Knudsen, A., Refsgaard, J., Charniot, J., Juillard, A., Pon-Gabrielsen, P., Douna, F., Jondeau, G., Jourdain, P., Michel, L., Hamm, C., Lehinant, S., Rieth, A., Goeing, O., Schultheiss, H. P., Von-Schlippenbach, J., Knollmann, R., Neubuser, C., Katus, H. A., Taeger, T., Zugck, C., Fink, H., Schulz, J., Held, S., Karmann, W., Kreuzer, J., Nitsche, K., Winter, K., Fahnrich, A., Bruederlein, K., Turan, C. H., Berentelg, J., Ittel, T., Rubens, C., Hanke, M., Stoerk, S., Chrysohoou, C., Kaldara, E., Karavidas, A., Margari, R., Matzaraki, V., Nanas, J., Pozios, I., Psarogiannakopoulos, P., Pyrgakis, V., Stefanadis, C., Terrovitis, J., Trikas, A., Xydonas, S., Patrianakos, A., Vardas, P., Douras, A., Nastas, J., Ntertsas, K., Tsaknakis, T., Midi, P., Pajes, G., Moretti, L., Partemi, M., Barberini, F., Branzi, A., Gallelli, I., Grigioni, F., Ionico, T., Pasquale, F., Cas, L., Delmagro, F., Tanghetti, E., Vaccari, A., Mercuro, G., Arcuri, G. M., Marinacci, L., Severini, D., Cosmi, F., Bosi, S., Di Tano, G., Pirelli, S., Fucili, A., Minneci, C., Santoro, G. M., Correale, M., Di Biase, M., Buccolieri, M., Mandorla, S., Martinelli, S., Barbiero, M., Giordano, A., Zanelli, E., Agostoni, P., Fiorentini, C., Salvioni, E., Leuzzi, C., Modena, M. G., Reggianini, L., Cobelli, F., Opasich, C., Baldini, P., Romei, M., Pulitano, G., Ruggeri, A., Bologna, F., Piovaccari, G., Brasolin, B., Fedele, F., Merlo, M., Sinagra, G., Albanese, M. C., Miani, D., Linssen, G., Rodijk, E., Pinto, Y., Van Donk, P., Dunselman, P., Lok, D., Brouwers, F., De Jong, R. M., Boen, R., Hole, T., Rasmussen, L., Christiansen, E. M., Gjertsen, E., Lyng, J., German, M., Hogalmen, G., Skardal, R., Apelland, T., Borgen, M., Forfang, E., Baak, T., Dickstein, K., Olsen, I., Stachurski, D., Juszczyk, Z., Stankala, S., Gilewski, W., Sinkiewicz, W., Kasztelowicz, P., Gabryel, J., Kardaszewicz, P., Lazorko-Piega, M., Bellwon, J., Mosakowska, K., Rynkiewicz, A., Olczyk, S., Pagorek, M., Bartlinski, R., Borej, G., Tarchalski, J., Bartkowiak, R., Sosnowska-Pasiarska, B., Wozakowska-Kaplon, B., Krzeminski, A., Bury, K., Grzegorzko, A., Mirek-Bryniarska, E., Nessler, J., Zabojszcz, M., Broncel, M., Poliwczak, A., Retwinski, A., Soska, K., Grajek, S., Straburzynska-Migaj, E., Kuzniar, J., Rzeszuto, T., Bednarczyk, G., Ruszkowski, P., Piasecka-Krysiak, E., Zambrzycki, J., Nowak, T., Szelemej, R., Balsam, P., Folga, A., Kaplon-Cieslicka, A., Kowalewski, S., Mamcarz, A., Marchel, M., Opolski, G., Welnicki, M., Jankowska, E., Nowak, J., Nowalany-Kozielska, E., Rozentryt, P., Zembala, M., Kleinrok, A., Prokop-Lewicka, G., Kudlinska, B., Radoi, M., Macarie, C., Vinereanu, D., Capalneanu, R., Giuca, A., Ionescu, D. D., Nechita, E., Datcu, M., Istrate, C., Vladoianu, M., Christodorescu, R., Salguero, R., Blanco, V. M., Lavilla, M. A., Comin-Colet, J., Cantillo, D., Bernal, J., del Prado, J. M., Pita, A., Aguero, J., Jimenez, J. F., Calvo, F., Gonzalez, R., Molina, B., Luengos, D., Lostal, C., Bonet, L., Gonzalez, P., Soriano, F., Campos, M. J., Karlstrom, P., Nyrinder, I., Olsson, B., Pettersson, T., Stenberg, A., Lindmark, K., Asserlund, B., Faculteit Medische Wetenschappen/UMCG, Cardiovascular Centre (CVC), ACS - Amsterdam Cardiovascular Sciences, Cardiology, Maggioni, Aldo P, Dahlström, Ulf, Filippatos, Gerasimo, Chioncel, Ovidiu, Leiro, Marisa Crespo, Drozdz, Jaroslaw, Fruhwald, Friedrich, Gullestad, Lar, Logeart, Damien, Fabbri, Gianna, Urso, Renato, Metra, Marco, Parissis, John, Persson, Han, Ponikowski, Piotr, Rauchhaus, Mathia, Voors, Adriaan A., Nielsen, Olav Wendelboe, Zannad, Faiez, Tavazzi, Luigi, on behalf of the Heart Failure Association of the European Society of Cardiology (HFA): [.., F. Barberini, A. Branzi, I. Gallelli, F. Grigioni, T. Ionico, F. Pasquale, and ]
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Registrie ,Male ,Time Factors ,Peripartum cardiomyopathy ,Pilot Projects ,Cardiovascular Agents/therapeutic use ,Acute heart failure ,Chronic heart failure ,Observational studies ,Pharmacological treatments ,Prognosis ,Aged ,Cardiovascular Agents ,Europe ,Female ,Follow-Up Studies ,Heart Failure ,Hospital Mortality ,Hospitalization ,Humans ,Middle Aged ,Prospective Studies ,Inpatients ,Registries ,GUIDELINES ,CLINICAL CHARACTERISTICS ,Medicine ,Prospective cohort study ,POPULATION ,Hospital Mortality/trends ,education.field_of_study ,OUTCOMES ,Ejection fraction ,Mortality rate ,HOSPITALIZATION ,Inpatient ,Cardiology and Cardiovascular Medicine ,Pharmacological treatment ,Human ,medicine.medical_specialty ,acute heart failure ,chronic heart failure ,observational studies ,pharmacological treatments ,prognosis ,aged ,cardiovascular agents ,female ,follow-up studies ,heart failure ,hospital mortality ,hospitalization ,humans ,male ,middle aged ,pilot projects ,prospective studies ,time factors ,inpatients ,registries ,cardiology and cardiovascular medicine ,EUROPE ,Time Factor ,Prognosi ,Population ,DIAGNOSIS ,Follow-Up Studie ,Europe/epidemiology ,ONE-YEAR MORTALITY ,Pilot Project ,education ,Hospitalization/statistics & numerical data ,business.industry ,medicine.disease ,Heart Failure/drug therapy ,Observational studie ,Prospective Studie ,Cardiovascular Agent ,Heart failure ,REGISTRY ,Cardiovascular agent ,Emergency medicine ,Physical therapy ,Observational study ,QUALITY-OF-CARE ,business - Abstract
AIMS: The ESC-HF Pilot survey was aimed to describe clinical epidemiology and 1-year outcomes of outpatients and inpatients with heart failure (HF). The pilot phase was also specifically aimed at validating structure, performance, and quality of the data set for continuing the survey into a permanent Registry.METHODS: The ESC-HF Pilot study is a prospective, multicentre, observational survey conducted in 136 Cardiology Centres in 12 European countries selected to represent the different health systems across Europe. All outpatients with HF and patients admitted for acute HF on 1 day per week for eight consecutive months were included. From October 2009 to May 2010, 5118 patients were included: 1892 (37%) admitted for acute HF and 3226 (63%) patients with chronic HF. The all-cause mortality rate at 1 year was 17.4% in acute HF and 7.2% in chronic stable HF. One-year hospitalization rates were 43.9% and 31.9%, respectively, in hospitalized acute and chronic HF patients. Major regional differences in 1-year mortality were observed that could be explained by differences in characteristics and treatment of the patients.CONCLUSION: The ESC-HF Pilot survey confirmed that acute HF is still associated with a very poor medium-term prognosis, while the widespread adoption of evidence-based treatments in patients with chronic HF seems to have improved their outcome profile. Differences across countries may be due to different local medical practice as well to differences in healthcare systems. This pilot study also offered the opportunity to refine the organizational structure for a long-term extended European network.
- Published
- 2013
9. EURObservational Research Programme: Regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot)
- Author
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Maggioni, A.P. Dahlström, U. Filippatos, G. Chioncel, O. Leiro, M.C. Drozdz, J. Fruhwald, F. Gullestad, L. Logeart, D. Fabbri, G. Urso, R. Metra, M. Parissis, J. Persson, H. Ponikowski, P. Rauchhaus, M. Voors, A.A. Nielsen, O.W. Zannad, F. Tavazzi, L. Alonso, A. Ferrari, R. Komajda, M. Wood, D. Manini, M. Taylor, C. Laroche, C. Fiorucci, E. Lucci, D. Gonzini, L. Auer, J. Oberrauner, A. Schumacher, M. Ebner, C. Hallas, A. Espersen, G. Gustafsson, F. Mattsson, N. Egstrup, K. Aagaard, S. Gohr, T. Huld, K. Knudsen, A. Refsgaard, J. Charniot, J. Juillard, A. Pon-Gabrielsen, P. Douna, F. Jondeau, G. Jourdain, P. Michel, L. Hamm, C. Lehinant, S. Rieth, A. Goeing, O. Schultheiss, H.P. Von-Schlippenbach, J. Knollmann, R. Neubüser, C. Katus, H.A. Taeger, T. Zugck, C. Fink, H. Schulz, J. Held, S. Karmann, W. Kreuzer, J. Nitsche, K. Winter, K. Fahnrich, A. Bruederlein, K. Turan, C.H. Berentelg, J. Ittel, T. Rubens, C. Hanke, M. Stoerk, S. Chrysohoou, C. Kaldara, E. Karavidas, A. Margari, R. Matzaraki, V. Nanas, J. Pozios, I. Psarogiannakopoulos, P. Pyrgakis, V. Stefanadis, C. Terrovitis, J. Trikas, A. Xydonas, S. Patrianakos, A. Vardas, P. Douras, A. Nastas, J. Ntertsas, K. Tsaknakis, T. Midi, P. Pajes, G. Moretti, L. Partemi, M. Barberini, F. Branzi, A. Gallelli, I. Grigioni, F. Ionico, T. Pasquale, F. Cas, L. Delmagro, F. Tanghetti, E. Vaccari, A. Mercuro, G. Arcuri, G.M. Marinacci, L. Severini, D. Cosmi, F. Bosi, S. Di Tano, G. Pirelli, S. Ferrari, R. Fucili, A. Minneci, C. Santoro, G.M. Correale, M. Di Biase, M. Buccolieri, M. Mandorla, S. Martinelli, S. Barbiero, M. Giordano, A. Zanelli, E. Agostoni, P. Fiorentini, C. Salvioni, E. Leuzzi, C. Modena, M.G. Reggianini, L. Cobelli, F. Opasich, C. Baldini, P. Romei, M. Pulitano, G. Ruggeri, A. Bologna, F. Piovaccari, G. Brasolin, B. Fedele, F. Merlo, M. Sinagra, G. Albanese, M.C. Miani, D. Linssen, G. Rodijk, E. Pinto, Y. Van Donk, P. Dunselman, P. Lok, D. Brouwers, F. De Jong, R.M. Boen, R. Hole, T. Rasmussen, L. Christiansen, E.M. Gjertsen, E. Lyng, J. German, M. Hogalmen, G. Skardal, R. Apelland, T. Borgen, M. Forfang, E. Baak, T. Dickstein, K. Olsen, I. Stachurski, D. Juszczyk, Z. Stankala, S. Gilewski, W. Sinkiewicz, W. Kasztelowicz, P. Gabryel, J. Kardaszewicz, P. Lazorko-Piega, M. Bellwon, J. Mosakowska, K. Rynkiewicz, A. Olczyk, S. Pagorek, M. Bartlinski, R. Borej, G. Tarchalski, J. Bartkowiak, R. Sosnowska-Pasiarska, B. Wozakowska-Kaplon, B. Krzeminski, A. Bury, K. Grzegorzko, A. Mirek-Bryniarska, E. Nessler, J. Zabojszcz, M. Broncel, M. Poliwczak, A. Retwinski, A. Soska, K. Grajek, S. Straburzynska-Migaj, E. Kuzniar, J. Rzeszuto, T. Bednarczyk, G. Ruszkowski, P. Piasecka-Krysiak, E. Zambrzycki, J. Nowak, T. Szelemej, R. Balsam, P. Folga, A. Kaplon-Cieslicka, A. Kowalewski, S. Mamcarz, A. Marchel, M. Opolski, G. Welnicki, M. Jankowska, E. Nowak, J. Nowalany-Kozielska, E. Rozentryt, P. Zembala, M. Kleinrok, A. Prokop-Lewicka, G. Kudlinska, B. Radoi, M. Macarie, C. Vinereanu, D. Capalneanu, R. Giuca, A. Ionescu, D.D. Nechita, E. Datcu, M. Istrate, C. Vladoianu, M. Christodorescu, R. Salguero, R. Blanco, V.M. Lavilla, M.A. Comin-Colet, J. Cantillo, D. Bernal, J. del Prado, J.M. Pita, A. Aguero, J. Jimenez, J.F. Calvo, F. Gonzalez, R. Molina, B. Luengos, D. Lostal, C. Bonet, L. Gonzalez, P. Soriano, F. Campos, M.J. Karlstrom, P. Nyrinder, I. Olsson, B. Pettersson, T. Stenberg, A. Lindmark, K. Asserlund, B. Heart Failure Association of the European Society of Cardiology (HFA)
- Abstract
AimsThe ESC-HF Pilot survey was aimed to describe clinical epidemiology and 1-year outcomes of outpatients and inpatients with heart failure (HF). The pilot phase was also specifically aimed at validating structure, performance, and quality of the data set for continuing the survey into a permanent Registry.MethodsThe ESC-HF Pilot study is a prospective, multicentre, observational survey conducted in 136 Cardiology Centres in 12 European countries selected to represent the different health systems across Europe. All outpatients with HF and patients admitted for acute HF on 1 day per week for eight consecutive months were included. From October 2009 to May 2010, 5118 patients were included: 1892 (37%) admitted for acute HF and 3226 (63%) patients with chronic HF. The all-cause mortality rate at 1 year was 17.4% in acute HF and 7.2% in chronic stable HF. One-year hospitalization rates were 43.9% and 31.9%, respectively, in hospitalized acute and chronic HF patients. Major regional differences in 1-year mortality were observed that could be explained by differences in characteristics and treatment of the patients.ConclusionThe ESC-HF Pilot survey confirmed that acute HF is still associated with a very poor medium-term prognosis, while the widespread adoption of evidence-based treatments in patients with chronic HF seems to have improved their outcome profile. Differences across countries may be due to different local medical practice as well to differences in healthcare systems. This pilot study also offered the opportunity to refine the organizational structure for a long-term extended European network. © 2013 The Author.
- Published
- 2013
10. Die Expression von phosphoryliertem Östrogenrezeptor beta darstellt einen unabhängigen negativen prognostischen Faktor beim duktalen Pankreasadenokarzinom
- Author
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Pozios, I, primary, Knösel, T, additional, Assmann, G, additional, Bruns, C, additional, and Seeliger, H, additional
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- 2015
- Full Text
- View/download PDF
11. Hemmung der Proliferation von humanen Kolonkarzinomzellen durch den M3-Acetylcholinrezeptor-Antagonisten Darifenacin
- Author
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Liu, V, primary, Böckenfeld, A, additional, Pozios, I, additional, Arndt, M, additional, Müller, M, additional, Kreis, M, additional, and Seeliger, H, additional
- Published
- 2015
- Full Text
- View/download PDF
12. Evaluating Combinations of Biological and Clinicopathologic Factors Linked to Poor Outcomes in Resected Colorectal Liver Metastasis: An External Validation Study.
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Sasaki K, Wang J, Kamphues C, Buettner S, Gagniere J, Ardilles V, Imai K, Wagner D, Pozios I, Papakonstantinou D, Pikoulis E, Antoniou E, Morioka D, Løes IM, Lønning PE, Kornprat P, Aucejo FN, Baba H, de Santibañes E, Kaczirek K, Burkhart R, Endo I, Beyer K, Kreis ME, Pawlik TM, and Margonis GA
- Abstract
Background: Recent studies have suggested that certain combinations of KRAS or BRAF biomarkers with clinical factors are associated with poor outcomes and may indicate that surgery could be "biologically" futile in otherwise technically resectable colorectal liver metastasis (CRLM). However, these combinations have yet to be validated through external studies., Patients and Methods: We conducted a systematic search to identify these studies. The overall survival (OS) of patients with these combinations was evaluated in a cohort of patients treated at 11 tertiary centers. Additionally, the study investigated whether using high-risk KRAS point mutations in these combinations could be associated with particularly poor outcomes., Results: The recommendations of four studies were validated in 1661 patients. The first three studies utilized KRAS, and their validation showed the following median and 5-year OS: (1) 30 months and 16.9%, (2) 24.3 months and 21.6%, and (3) 46.8 months and 44.4%, respectively. When analyzing only patients with high-risk KRAS mutations, median and 5-year OS decreased to: (1) 26.2 months and 0%, (2) 22.3 months and 15.1%, and (3) not reached and 44.9%, respectively. The fourth study utilized BRAF, and its validation showed a median OS of 10.4 months, with no survivors beyond 21 months., Conclusion: The combinations of biomarkers and clinical factors proposed to render surgery for CRLM futile, as presented in studies 1 (KRAS high-risk mutations) and 4, appear justified. In these studies, there were no long-term survivors, and survival was similar to that of historic cohorts with similar mutational profiles that received systemic therapies alone for unresectable disease., (© 2024. Society of Surgical Oncology.)
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- 2024
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13. Hepatectomy versus systemic therapy for liver-limited BRAF V600E-mutated colorectal liver metastases: multicentre retrospective study.
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Margonis GA, Wang JJ, Boerner T, Moretto R, Buettner S, Andreatos N, Gagnière J, Wagner D, Løes IM, Bergamo F, Pietrantonio F, Scartozzi M, Spallanzani A, Vincenzi B, Antoniou E, Pikoulis E, Sartore-Bianchi A, Stasinos G, Sasaki K, Pawlik TM, Orlandi A, Pella N, Fitschek F, Kaczirek K, Dupré A, Pozios I, Beyer K, Kornprat P, Aucejo FN, Burkhart R, Weiss MJ, Lønning PE, Poultsides G, Cremolini C, Kreis ME, and D'Angelica M
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- Humans, Male, Female, Retrospective Studies, Middle Aged, Aged, Mutation, Propensity Score, Neoplasm Recurrence, Local genetics, Adult, Treatment Outcome, Liver Neoplasms secondary, Liver Neoplasms genetics, Liver Neoplasms surgery, Liver Neoplasms mortality, Hepatectomy methods, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Proto-Oncogene Proteins B-raf genetics
- Abstract
Background: To date, only two studies have compared the outcomes of patients with liver-limited BRAF V600E-mutated colorectal liver metastases (CRLMs) managed with resection versus systemic therapy alone, and these have reported contradictory findings., Methods: In this observational, international, multicentre study, patients with liver-limited BRAF V600E-mutated CRLMs treated with resection or systemic therapy alone were identified from institutional databases. Patterns of recurrence/progression and overall survival were compared using multivariable analyses of the entire cohort and a propensity score-matched cohort., Results: Of 170 patients included, 119 underwent hepatectomy and 51 received systemic treatment. Surgically treated patients had a more favourable pattern of recurrence with most recurrences limited to a single site, whereas diffuse progression was more common among patients who received systemic treatment (19 versus 44%; P = 0.002). Surgically treated patients had longer median overall survival (35 versus 20 months; P < 0.001). Hepatectomy was independently associated with better OS than systemic treatment alone (HR 0.37, 95% c.i. 0.21 to 0.65). In the propensity score-matched cohort, surgically treated patients had longer median overall survival (28 versus 20 months; P < 0.001); hepatectomy was independently associated with better overall survival (HR 0.47, 0.25 to 0.88)., Conclusion: BRAF V600E mutation should not be considered a contraindication to surgery for patients with resectable, liver-only CRLMs., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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14. Robotic-Assisted versus Laparoscopic Surgery for Rectal Cancer: An Analysis of Clinical and Financial Outcomes from a Tertiary Referral Center.
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Gebhardt JM, Werner N, Stroux A, Förster F, Pozios I, Seifarth C, Schineis C, Weixler B, Beyer K, and Lauscher JC
- Abstract
Background : The popularity of robotic-assisted surgery for rectal cancer is increasing, but its superiority over the laparoscopic approach regarding safety, efficacy, and costs has not been well established. Methods : A retrospective single-center study was conducted comparing consecutively performed robotic-assisted and laparoscopic surgeries for rectal cancer between 1 January 2016 and 31 September 2021. In total, 125 adult patients with sporadic rectal adenocarcinoma (distal extent ≤ 15 cm from the anal verge) underwent surgery where 66 were operated on robotically and 59 laparoscopically. Results : Severe postoperative complications occurred less frequently with robotic-assisted compared with laparoscopic surgery, as indicated by Clavien-Dindo classification grades 3b-5 (13.6% vs. 30.5%, p = 0.029). Multiple logistic regression analyses after backward selection revealed that robotic-assisted surgery was associated with a lower rate of total (Clavien-Dindo grades 1-5) (OR = 0.355; 95% CI 0.156-0.808; p = 0.014) and severe postoperative complications (Clavien-Dindo grades 3b-5) (OR = 0.243; 95% CI 0.088-0.643; p = 0.005). Total inpatient costs (median EUR 17.663 [IQR EUR 10.151] vs. median EUR 14.089 [IQR EUR 12.629]; p = 0.018) and surgery costs (median EUR 10.156 [IQR EUR 3.551] vs. median EUR 7.468 [IQR EUR 4.074]; p < 0.0001) were higher for robotic-assisted surgery, resulting in reduced total inpatient profits (median EUR -3.196 [IQR EUR 9.101] vs. median EUR 232 [IQR EUR 6.304]; p = 0.004). Conclusions : In our study, robotic-assisted surgery for rectal cancer resulted in less severe and fewer total postoperative complications. Still, it was associated with higher surgery and inpatient costs. With increasing experience, the operative time may be reduced, and the postoperative recovery may be further accelerated, leading to reduced surgery and total inpatient costs.
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- 2024
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15. Is Precision Surgery Applicable to Colorectal Liver Metastases? A Systematic Review and Meta-analysis of Studies that Investigate the Association of Surgical Technique with Outcomes in the Context of Distinct Tumor Biology.
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Pikoulis E, Papaconstantinou D, Pikouli A, Pararas N, Buettner S, Wang J, Stasinos G, Belias M, Dellaportas D, Pozios I, Antoniou E, Beyer K, Kreis ME, Pawlik TM, and Margonis GA
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- Humans, Prognosis, Survival Rate, Mutation, Precision Medicine, Liver Neoplasms surgery, Liver Neoplasms secondary, Colorectal Neoplasms pathology, Colorectal Neoplasms surgery, Hepatectomy mortality, Hepatectomy methods
- Abstract
Background: Although some data suggest that patients with mutRAS colorectal liver metastases (CRLM) may benefit from anatomic hepatectomy, this topic remains controversial. We performed a systematic review and meta-analysis to determine whether RAS mutation status was associated with prognosis relative to surgical technique [anatomic resection (AR) vs. nonanatomic resection (NAR)] among patients with CRLM., Patients and Methods: A systematic review and meta-analysis of studies were performed to investigate the association of AR versus NAR with overall and liver-specific disease-free survival (DFS and liver-specific DFS, respectively) in the context of RAS mutation status., Results: Overall, 2018 patients (831 mutRAS vs. 1187 wtRAS) were included from five eligible studies. AR was associated with a 40% improvement in liver-specific DFS [hazard ratio (HR) = 0.6, 95% confidence interval (CI) 0.44-0.81, p = 0.01] and a 28% improvement in overall DFS (HR = 0.72, 95% CI 0.54-0.95, p = 0.02) among patients with mutRAS tumors; in contrast, AR was not associated with any improvement in liver-specific DFS or overall DFS among wtRAS patients. These differences may have been mediated by the 40% decreased incidence in R1 resection among patients with mutRAS tumors who underwent AR versus NAR [relative risk (RR): 0.6, 95% CI 0.40-0.91, p = 0.02]. In contrast, the probability of an R1 resection was not decreased among wtRAS patients who underwent AR versus NAR (RR: 0.93, 95% CI 0.69-1.25, p = 0.62)., Conclusions: The data suggest that precision surgery may be relevant to CRLM. Specifically, rather than a parenchymal sparing dogma for all patients, AR may have a role in individuals with mutRAS tumors., (© 2023. Society of Surgical Oncology.)
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- 2024
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16. Optimizing Indocyanine Green Dosage for Near-Infrared Fluorescence Perfusion Assessment in Bowel Anastomosis: A Prospective, Systematic Dose-Ranging Study.
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Lobbes LA, Schier K, Tiebie K, Scheidel N, Pozios I, Hoveling RJM, and Weixler B
- Abstract
Background: Indocyanine green (ICG) near-infrared fluorescence (NIRF) has emerged as a promising technique for visualizing tissue perfusion. However, within the wide range of dosages and imaging conditions currently being applied, the optimal dosage of ICG remains unclear. This study aimed to investigate the feasibility and implications of implementing lower dosages of ICG than commonly used for visual and quantitative perfusion assessment in a standardized setting., Methods: A prospective single-center cohort study was conducted on patients undergoing ileostomy reversal by hand-sewn anastomosis. ICG-NIRF visualization was performed before (T1) and after (T2) anastomosis with one of four different dosages of ICG (5 mg, 2.5 mg, 1.25 mg, or 0.625 mg) and recorded. Postoperatively, each visualization was evaluated for signal strength, completeness, and homogeneity of fluorescence. Additionally, perfusion graphs were generated by a software-based quantitative perfusion assessment, allowing an analysis of perfusion parameters. Statistical analysis comparing the effect of the investigated dosages on these parameters was performed., Results: In total, 40 patients were investigated. Visual evaluation demonstrated strong, complete, and homogeneous fluorescence signals across all dosages. Perfusion graph assessment revealed a consistent shape for all dosages (ingress followed by egress phase). While the average signal intensity decreased with dosage, it was sufficient to enable perfusion assessment even at the lowest dosages of 1.25 mg and 0.625 mg of ICG. The baseline intensity at T2 (the second intraoperative visualization) significantly decreased with dosage. The slope of the egress phase steepened with decreasing dosage., Conclusions: Lower dosages of ICG were sufficient for intraoperative perfusion assessment, while causing lower residual fluorescence and quicker egress in subsequent visualizations.
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- 2024
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17. Role of visceral fat on postoperative complications and relapse in patients with Crohn's disease after ileocecal resection: Is it overrated?
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Schineis CHW, Pozios I, Boubaris K, Weixler B, Kamphues C, Margonis GA, Kreis ME, Strobel RM, Beyer K, Seifarth C, Luitjens J, Kaufmann D, and Lauscher JC
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- Humans, Retrospective Studies, Intra-Abdominal Fat diagnostic imaging, Intra-Abdominal Fat pathology, Anastomotic Leak pathology, Recurrence, Postoperative Complications etiology, Postoperative Complications pathology, Crohn Disease complications, Crohn Disease diagnostic imaging, Crohn Disease surgery
- Abstract
Introduction: The role of visceral fat in disease development, particularly in Crohn´s disease (CD), is significant. However, its preoperative prognostic value for postoperative complications and CD relapse after ileocecal resection (ICR) remains unknown. This study aims to assess the predictive potential of preoperatively measured visceral and subcutaneous fat in postoperative complications and CD recurrence using magnetic resonance imaging (MRI). The primary endpoint was postoperative anastomotic leakage of the ileocolonic anastomosis, with secondary endpoints evaluating postoperative complications according to the Clavien Dindo classification and CD recurrence at the anastomosis., Methods: We conducted a retrospective analysis of 347 CD patients who underwent ICR at our tertiary referral center between 2010 and 2020. We included 223 patients with high-quality preoperative MRI scans, recording demographics, postoperative outcomes, and CD recurrence rates at the anastomosis. To assess adipose tissue distribution, we measured total fat area (TFA), visceral fat area (VFA), subcutaneous fat area (SFA), and abdominal circumference (AC) at the lumbar 3 (L3) level using MRI cross-sectional images. Ratios of these values were calculated., Results: None of the radiological variables showed an association with anastomotic leakage (TFA p = 0.932, VFA p = 0.982, SFA p = 0.951, SFA/TFA p = 0.422, VFA/TFA p = 0.422), postoperative complications, or CD recurrence (TFA p = 0.264, VFA p = 0.916, SFA p = 0.103, SFA/TFA p = 0.059, VFA/TFA p = 0.059)., Conclusions: Radiological visceral obesity variables were associated with postoperative outcomes or clinical recurrence in CD patients undergoing ICR. Preoperative measurement of visceral fat measurement is not specific for predicting postoperative complications or CD relapse., (© 2024. The Author(s).)
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- 2024
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18. Standardized digital solution with surgical procedure manager (SPM®)-an opportunity for maximizing patient safety and efficiency in ileostomy reversal?
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Strobel RM, Schineis CHW, Lasierra Viguri L, Stroux A, Eschlböck SM, Lobbes LA, Pozios I, Seifarth C, Weixler B, Kamphues C, Beyer K, and Lauscher JC
- Abstract
Background: Standardization and digitalization are getting more and more essential in surgery. Surgical procedure manager (SPM®) is a freestanding computer serving as a digital supporter in the operating room. SPM® navigates step-by-step through surgery by providing a checklist for each individual step., Methods: This was a single center, retrospective study at the Department for General and Visceral Surgery at Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin. Patients who underwent ileostomy reversal without SPM® in the period of January 2017 until December 2017 were compared to patients who were operated with SPM® in the period of June 2018 until July 2020. Explorative analysis and multiple logistic regression were performed., Results: Overall, 214 patients underwent ileostomy reversal: 95 patients without SPM® vs. 119 patients with SPM®. Ileostomy reversal was performed by head of department/attendings in 34.1%, by fellows in 28.5% and by residents in 37.4%; p = 0.91. Postoperative intraabdominal abscess emerged more often in patients without SPM®: ten (10.5%) patients vs. four (3.4%) patients; p = 0.035. Multiple logistic regression showed a risk reduction for intraabdominal abscess {Odds ratio (OR) 0.19 [95% confidence interval (CI) 0.05-0.71]; p = 0.014} and for bowel perforation [OR 0.09 (95% CI 0.01-0.93); p = 0.043] in the group with use of SPM® in ileostomy reversal., Conclusions: SPM® may reduce postoperative complications in ileostomy reversal such as intraabdominal abscess and bowel perforation. SPM® may contribute to patient safety., Competing Interests: RS is participant in the BIH-Charité Junior Scientist Program funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Strobel, Schineis, Lassiera Viguri, Stroux, Eschlböck, Lobbes, Pozios, Seifarth, Weixler, Kamphues, Beyer and Lauscher.)
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- 2023
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19. Influence of the COVID-19 pandemic on the timing of surgical triage, tumor stage, and therapy of patients with colon carcinoma.
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Speichinger F, Berg AK, Stoyanova A, Pozios I, Loch F, Lauscher JC, Beyer K, Slavova N, and Schineis C
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- Humans, Pandemics, SARS-CoV-2, Triage methods, Retrospective Studies, Communicable Disease Control, COVID-19 epidemiology, Colonic Neoplasms epidemiology, Colonic Neoplasms surgery
- Abstract
Purpose: With the onset of the COVID pandemic in Germany in March 2020, far-reaching restrictions were imposed that limited medical access for patients. Screening examinations such as colonoscopies were greatly reduced in number. As rapid surgical triage after diagnosis is prognostic, our hypothesis was that pandemic-related delays would increase the proportion of advanced colon cancers with an overall sicker patient population., Methods: A total of 204 patients with initial diagnosis of colon cancer were analyzed in this retrospective single-center study between 03/01/2018 and 03/01/2022. Control group (111 patients, pre-COVID-19) and the study group (93 patients, during COVID-19) were compared in terms of tumor stages, surgical therapy, complications, and delays in the clinical setting. The data were presented either as absolute numbers or as median for constant data., Results: A trend towards more advanced tumor stages (T4a p = 0.067) and a significant increase of emergency surgeries (p = 0.016) with higher rates of ileus and perforation (p = 0.004) as well as discontinuity resections (p = 0.049) during the pandemic could be observed. Delays in surgical triage after endoscopic diagnosis were seen during the 2nd lockdown (02/11/20-26/12/20; p = 0.031)., Conclusion: In summary, the results suggest delayed treatment during the COVID-19 pandemic, with the infection pattern of COVID appearing to have a major impact on the time between endoscopic diagnosis and surgical triage/surgery. Adequate care of colon cancer patients is possible even during a pandemic, but it is important to focus on structured screening and tight diagnosis to treatment schedules in order to prevent secondary pandemic victims., (© 2023. The Author(s).)
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- 2023
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20. Muscarinic Acetylcholine Receptor M3 Expression and Survival in Human Colorectal Carcinoma-An Unexpected Correlation to Guide Future Treatment?
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Lobbes LA, Schütze MA, Droeser R, Arndt M, Pozios I, Lauscher JC, Hering NA, and Weixler B
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- Animals, Humans, Receptor, Muscarinic M3 metabolism, Receptors, Muscarinic, Colorectal Neoplasms genetics
- Abstract
Muscarinic acetylcholine receptor M3 (M3R) has repeatedly been shown to be prominently expressed in human colorectal cancer (CRC), playing roles in proliferation and cell invasion. Its therapeutic targetability has been suggested in vitro and in animal models. We aimed to investigate the clinical role of MR3 expression in CRC for human survival. Surgical tissue samples from 754 CRC patients were analyzed for high or low immunohistochemical M3R expression on a clinically annotated tissue microarray (TMA). Immunohistochemical analysis was performed for established immune cell markers (CD8, TIA-1, FOXP3, IL 17, CD16 and OX 40). We used Kaplan-Meier curves to evaluate patients' survival and multivariate Cox regression analysis to evaluate prognostic significance. High M3R expression was associated with increased survival in multivariate (hazard ratio (HR) = 0.52; 95% CI = 0.35-0.78; p = 0.001) analysis, as was TIA-1 expression (HR = 0.99; 95% CI = 0.94-0.99; p = 0.014). Tumors with high M3R expression were significantly more likely to be grade 2 compared to tumors with low M3R expression (85.7% vs. 67.1%, p = 0.002). The 5-year survival analysis showed a trend of a higher survival rate in patients with high M3R expression (46%) than patients with low M3R expression CRC (42%) ( p = 0.073). In contrast to previous in vitro and animal model findings, this study demonstrates an increased survival for CRC patients with high M3R expression. This evidence is highly relevant for translation of basic research findings into clinically efficient treatments.
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- 2023
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21. Electro-Mechanical Alterations in Atrial Fibrillation: Structural, Electrical, and Functional Correlates.
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Pozios I, Vouliotis AI, Dilaveris P, and Tsioufis C
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Atrial fibrillation is the most common arrhythmia encountered in clinical practice affecting both patients' survival and well-being. Apart from aging, many cardiovascular risk factors may cause structural remodeling of the atrial myocardium leading to atrial fibrillation development. Structural remodelling refers to the development of atrial fibrosis, as well as to alterations in atrial size and cellular ultrastructure. The latter includes myolysis, the development of glycogen accumulation, altered Connexin expression, subcellular changes, and sinus rhythm alterations. The structural remodeling of the atrial myocardium is commonly associated with the presence of interatrial block. On the other hand, prolongation of the interatrial conduction time is encountered when atrial pressure is acutely increased. Electrical correlates of conduction disturbances include alterations in P wave parameters, such as partial or advanced interatrial block, alterations in P wave axis, voltage, area, morphology, or abnormal electrophysiological characteristics, such as alterations in bipolar or unipolar voltage mapping, electrogram fractionation, endo-epicardial asynchrony of the atrial wall, or slower cardiac conduction velocity. Functional correlates of conduction disturbances may incorporate alterations in left atrial diameter, volume, or strain. Echocardiography or cardiac magnetic resonance imaging (MRI) is commonly used to assess these parameters. Finally, the echocardiography-derived total atrial conduction time (PA-TDI duration) may reflect both atrial electrical and structural alterations.
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- 2023
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22. Near-infrared Fluorescence Imaging for Detecting Pancreatic Liver Metastasis in an Orthotopic Athymic Mouse Model.
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Lee LD, Hering NA, Zibell M, Lobbes LA, Kamphues C, Lauscher JC, Margonis GA, Seeliger H, Beyer K, Weixler B, and Pozios I
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- Animals, Mice, Humans, Mice, Nude, Optical Imaging, Indocyanine Green, Pancreatic Neoplasms, Pancreatic Neoplasms diagnostic imaging, Liver Neoplasms diagnostic imaging, Pancreatic Diseases
- Abstract
Background/aim: Evidence of metastatic disease precludes oncological resection of pancreatic cancer. Near-infrared (NIR) fluorescent labels, such as indocyanine green (ICG), assist in the intraoperative detection of occult and micrometastatic liver disease. The present study aimed to analyse the role of NIR fluorescence imaging using ICG for pancreatic liver disease as proof of concept in an orthotopic athymic mouse model., Materials and Methods: Pancreatic ductal adenocarcinoma was induced by injecting L3.6pl human pancreatic tumour cells into the pancreatic tail of seven athymic mice. After four weeks of tumour growth, ICG was injected into the tail vein and NIR fluorescence imaging was performed at harvest to determine tumour-to-liver ratios (TLR) using Quest Spectrum
® Fluorescence Imaging Platform., Results: Pancreatic tumour growth and liver metastasis could be visually confirmed for all seven animals. None of the hepatic metastases showed any detectable ICG-uptake. ICG-staining failed to visualize the liver metastases or to increase fluorescence intensity of the rim around the hepatic lesions., Conclusion: ICG-staining fails to visualize liver metastases induced by L3.6pl pancreatic tumour cells in athymic nude mice by NIR fluorescence imaging. Further studies are necessary to delineate the underlying mechanism for insufficient ICG uptake in these pancreatic liver metastases and for the lack of a fluorescent rim around the liver lesions., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)- Published
- 2023
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23. Prevalence and prognostic implications of hypertensive response to exercise in patients with hypertrophic cardiomyopathy.
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Lu DY, Ventoulis I, Liu H, Haileselassie B, Pozios I, Liang HY, Sorensen LL, Canepa M, Bavaro N, Phillip S, Abraham MR, and Abraham TP
- Abstract
Objective: Hypertensive response to exercise (HRE) is observed in patients with hypertrophic cardiomyopathy (HCM) with normal resting blood pressure (BP). However, the prevalence or prognostic implications of HRE in HCM remain unclear., Methods: In this study, normotensive HCM subjects were enrolled. HRE was defined as systolic BP > 210 mmHg in men or >190 mmHg in women, or diastolic BP > 90 mmHg, or an increase in diastolic BP > 10 mmHg during treadmill exercise. All participants were followed for subsequent development of hypertension, atrial fibrillation (AF), heart failure (HF), sustained ventricular tachycardia/fibrillation (VT/VF), and all-cause death. Six hundred and eighty HCM patients were screened., Results: 347 patients had baseline hypertension, and 333 patients were baseline normotensive. 132 (40%) of the 333 patients had HRE. HRE was associated with female sex, lower body mass index and milder left ventricular outflow tract obstruction. Exercise duration and metabolic equivalents were similar between patients with or without HRE, but the HRE group had higher peak heart rate (HR), better chronotropic response and more rapid HR recovery. Conversely, non-HRE patients were more likely to exhibit chronotropic incompetence and hypotensive response to exercise. After a mean follow-up of 3.4 years, patients with and without HRE had similar risks of progression to hypertension, AF, HF, sustained VT/VF or death., Conclusion: HRE is common in normotensive HCM patients during exercise. HRE did not carry higher risks of future hypertension or cardiovascular adverse outcomes. Conversely, the absence of HRE was associated with chronotropic incompetence and hypotensive response to exercise., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier B.V.)
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- 2023
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24. Targeting Interleukin-6/Glycoprotein-130 Signaling by Raloxifene or SC144 Enhances Paclitaxel Efficacy in Pancreatic Cancer.
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Hering NA, Günzler E, Arndt M, Zibell M, Lauscher JC, Kreis ME, Beyer K, Seeliger H, and Pozios I
- Abstract
Interleukine-6 plays a key role in the progression and poor survival in pancreatic ductal adenocarcinoma (PDAC). The present study aimed to clarify if targeting the interleukin-6/glycoprotein-130 signaling cascade using the small-molecule gp130 inhibitor SC144 or raloxifene, a non-steroidal selective estrogen receptor modulator, enhances paclitaxel efficacy. MTT/BrdU assays or TUNEL staining were performed to investigate cell viability, proliferation and apoptosis induction in L3.6pl and AsPC-1 human pancreatic cell lines. In vivo, effects were studied in an orthotopic PDAC mouse model. Tumor specimens were analyzed by qPCR, immunohistochemistry and ELISA. Combination of paclitaxel/raloxifene, but not paclitaxel/SC144, enhanced proliferation and viability inhibition and increased apoptosis compared to single treatment in vitro. Synergy score calculations confirmed an additive influence of raloxifene on paclitaxel. In the PDAC mouse model, both combinations of raloxifene/paclitaxel and SC144/paclitaxel reduced tumor weight and volume compared to single-agent therapy or control. Raloxifene/paclitaxel treatment decreased survivin mRNA expression and showed tendencies of increased caspase-3 staining in primary tumors. SC144/paclitaxel reduced interleukin-6 levels in mice's tumors and plasma. In conclusion, raloxifene or SC144 can enhance the anti-tumorigenic effects of paclitaxel, suggesting that paclitaxel doses might also be reduced in combined chemotherapy to lessen paclitaxel side effects.
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- 2023
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25. Gp130 is expressed in pancreatic cancer and can be targeted by the small inhibitor molecule SC144.
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Pozios I, Hering NA, Guenzler E, Arndt M, Elezkurtaj S, Knösel T, Bruns CJ, Margonis GA, Beyer K, and Seeliger H
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- Humans, Cytokine Receptor gp130 metabolism, Cytokine Receptor gp130 therapeutic use, Glycoproteins, Interleukin-6 metabolism, STAT3 Transcription Factor metabolism, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal drug therapy, Pancreatic Neoplasms pathology
- Abstract
Purpose: Interleukin 6 (IL-6), Oncostatin M (OSM), and downstream effector STAT3 are pro-tumorigenic agents in pancreatic ductal adenocarcinoma (PDAC). Glycoprotein 130 (gp130) is a compound of the IL-6 and OSM receptor complex that triggers STAT3 signaling. SC144 is a small molecule gp130 inhibitor with anticancer activity. This study examines the gp130 expression in human PDAC specimens and the in vitro effects of SC144 in PDAC cell lines., Methods: Tissue micro-arrays were constructed from 175 resected human PDAC. The gp130 expression in tumor epithelium and stroma was determined by immunohistochemistry, and survival analysis was performed. Growth inhibition by SC144 was assessed in vitro using BrdU and MTT assays. Western blotting was performed to evaluate the SC144 effect on IL-6 and OSM signaling., Results: Gp130 was expressed in the epithelium of 78.8% and the stroma of 9.4% of the tumor samples. The median overall survival for patients with or without epithelial gp130 expression was 16.7 months and 15.9 months, respectively (p = 0.830). Patients with no stromal gp130 expression showed poorer survival than patients with stromal gp130 expression (median 16.2 and 22.9 months, respectively), but this difference did not reach significance (p = 0.144). SC144 inhibited cell proliferation and viability and suppressed IL-6- and OSM-stimulated STAT3
Y705 phosphorylation in PDAC cells., Conclusion: Gp130 is expressed in the epithelium of most human PDAC, but stromal expression is rare. The small molecule gp130 inhibitor SC144 potently inhibits PDAC progression in vitro and may abrogate IL-6 or OSM/gp130/STAT3 signaling. These results suggest gp130 as a novel drug target for pancreatic cancer therapy., (© 2022. The Author(s).)- Published
- 2023
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26. Prognostic value of primary tumor sidedness in patients with non-metastatic IBD related CRC - Is it the exception to the rule?
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Kamphues C, Lefevre JH, Wang J, Amini N, Beaugerie L, Kuehn F, Park SH, Andreatos N, Lauscher JC, Enea D, Lehmann KS, Peru N, Weixler B, Kirchgesner J, Degro CE, Pozios I, van Beekum CJ, Schölch S, Zambonin D, Schineis C, Loch FN, Geka D, Theoxari M, Wu B, Wang PP, Antoniou E, Pikoulis E, Moussata D, Theodoropoulos G, Ouaissi M, Seeliger H, Inaba Y, Scaringi S, Reißfelder C, Vilz TO, Lin C, Yang SK, Beyer K, Renz BW, Sasaki K, Margonis GA, Svrcek M, and Kreis ME
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- Humans, Prognosis, Retrospective Studies, Colorectal Neoplasms pathology, Rectal Neoplasms, Inflammatory Bowel Diseases
- Abstract
Background: Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in patients with IBD-CRC., Methods: All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence-free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS., Results: A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98)., Conclusions: In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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27. Robotic-Assisted versus Laparoscopic Proctectomy with Ileal Pouch-Anal Anastomosis for Ulcerative Colitis: An Analysis of Clinical and Financial Outcomes from a Tertiary Referral Center.
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Gebhardt JM, Werner N, Stroux A, Förster F, Pozios I, Seifarth C, Schineis C, Kamphues C, Weixler B, Beyer K, and Lauscher JC
- Abstract
Background: Robotic-assisted colorectal surgery is gaining popularity, but limited data are available on the safety, efficacy, and cost of robotic-assisted restorative proctectomy with the construction of an ileal pouch and ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC). Methods: A retrospective study was conducted comparing consecutively performed robotic-assisted and laparoscopic proctectomy with IPAA between 1 January 2016 and 31 September 2021. In total, 67 adult patients with medically refractory UC without proven dysplasia or carcinoma underwent surgery: 29 operated robotically and 38 laparoscopically. Results: There were no differences between both groups regarding postoperative complications within 30 days according to Clavien-Dindo classification’ grades 1−5 (51.7% vs. 42.1%, p = 0.468) and severe grades 3b−5 (17.2% vs. 10.5%, p = 0.485). Robotic-assisted surgery was associated with an increased urinary tract infection rate (n = 7, 24.1% vs. n = 1, 2.6%; p = 0.010) and longer operative time (346 ± 65 min vs. 281 ± 66 min; p < 0.0001). Surgery costs were higher when operated robotically (median EUR 10.377 [IQR EUR 4.727] vs. median EUR 6.689 [IQR EUR 3.170]; p < 0.0001), resulting in reduced total inpatient profits (median EUR 110 [IQR EUR 4.971] vs. median EUR 2.853 [IQR EUR 5.386]; p = 0.001). Conclusion: Robotic-assisted proctectomy with IPAA can be performed with comparable short-term clinical outcomes to laparoscopy but is associated with a longer duration of surgery and higher surgery costs. As experience increases, some advantages may become evident regarding operative time, postoperative recovery, and length of stay. The robotic procedure might then become cost-efficient.
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- 2022
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28. KRAS alterations in colorectal liver metastases: shifting to exon, codon, and point mutations.
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Olthof PB, Buettner S, Andreatos N, Wang J, Løes IM, Wagner D, Sasaki K, Macher-Beer A, Kamphues C, Pozios I, Seeliger H, Morioka D, Imai K, Kaczirek K, Pawlik TM, Poultsides G, Burkhart R, Endo I, Baba H, Kornprat P, Aucejo FN, Lønning PE, Beyer K, Weiss MJ, Wolfgang CL, Kreis ME, and Margonis GA
- Subjects
- Codon, Exons, Humans, Mutation, Point Mutation, Proto-Oncogene Proteins p21(ras) genetics, Colorectal Neoplasms genetics, Liver Neoplasms genetics
- Published
- 2022
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29. Thymidine phosphorylase induction by ionizing radiation antagonizes 5-fluorouracil resistance in human ductal pancreatic adenocarcinoma.
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Lee LD, Pozios I, Liu V, Nachbichler SB, Böhmer D, Kamphues C, Beyer K, Bruns CJ, Kreis ME, and Seeliger H
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- Cell Line, Tumor, Fluorouracil metabolism, Fluorouracil pharmacology, Fluorouracil therapeutic use, Humans, RNA, Small Interfering, Radiation, Ionizing, Thymidine Phosphorylase genetics, Thymidine Phosphorylase metabolism, Pancreatic Neoplasms, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms radiotherapy
- Abstract
Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) frequently contributes to failure of systemic therapy. While the radiosensitizing properties of 5-fluorouracil (FU) are well known, it is unknown whether ionizing radiation (IR) sensitizes towards FU cytotoxicity. Here, we hypothesize that upregulation of thymidine phosphorylase (TP) by IR reverses FU chemoresistance in PDAC cells. The FU resistant variant of the human PDAC cell line AsPC-1 (FU-R) was used to determine the sensitizing effects of IR. Proliferation rates of FU sensitive parental (FU-S) and FU-R cells were determined by WST-1 assays after low (0.05 Gy) and intermediate dose (2.0 Gy) IR followed by FU treatment. TP protein expression in PDAC cells before and after IR was assessed by Western blot. To analyze the specificity of the FU sensitizing effect, TP was ablated by siRNA. FU-R cells showed a 2.7-fold increase of the half maximal inhibitory concentration, compared to FU-S parental cells. Further, FU-R cells showed a concomitant IR resistance towards both doses applied. When challenging both cell lines with FU after IR, FU-R cells had lower proliferation rates than FU-S cells, suggesting a reversal of chemoresistance by IR. This FU sensitizing effect was abolished when TP was blocked by anti-TP siRNA before IR. An increase of TP protein expression was seen after both IR doses. Our results suggest a TP dependent reversal of FU-chemoresistance in PDAC cells that is triggered by IR. Thus, induction of TP expression by low dose IR may be a therapeutic approach to potentially overcome FU chemoresistance in PDAC., (© 2022. The Author(s).)
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- 2022
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30. Impact of myopenia and myosteatosis on postoperative outcome and recurrence in Crohn's disease.
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Pozios I, Kaufmann D, Boubaris K, Seeliger H, Weixler B, Stroux A, Kamphues C, Margonis GA, Kreis ME, Beyer K, Seifarth C, and Lauscher JC
- Subjects
- Anastomosis, Surgical adverse effects, Anastomotic Leak, Humans, Muscle, Skeletal surgery, Postoperative Complications etiology, Recurrence, Retrospective Studies, Crohn Disease complications, Crohn Disease diagnostic imaging, Crohn Disease surgery
- Abstract
Purpose: Myopenia and myosteatosis have been proposed to be prognostic factors of surgical outcomes for various diseases, but their exact role in Crohn's disease (CD) is unknown. The aim of this study is to evaluate their impact on anastomotic leakage, CD recurrence, and postoperative complications after ileocecal resection in patients with CD., Methods: A retrospective analysis of CD patients undergoing ileocecal resection at our tertiary referral center was performed. To assess myopenia, skeletal muscle index (skeletal muscle area normalized for body height) was measured using an established image analysis method at third lumbar vertebra level on MRI cross-sectional images. Muscle signal intensity was measured to assess myosteatosis index., Results: A total of 347 patients were retrospectively analyzed. An adequate abdominal MRI scan within 12 months prior to surgery was available for 223 patients with median follow-up time of 48.8 months (IQR: 20.0-82.9). Anastomotic leakage rate was not associated with myopenia (SMI: p = 0.363) or myosteatosis index (p = 0.821). Patients with Crohn's recurrence had a significantly lower SMI (p = 0.047) in univariable analysis, but SMI was not an independent factor for recurrent anastomotic stenosis in multivariable analysis (OR 0.951, 95% CI 0.840-1.078; p = 0.434). Postoperative complications were not associated with myopenia or myosteatosis., Conclusion: Based on the largest cohort of its kind with a long follow-up time, we could provide some data that MRI parameters for myopenia and myosteatosis may not be reliable predictors of postoperative outcome or recurrence in patients with Crohn's disease undergoing ileocecal resection., (© 2022. The Author(s).)
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- 2022
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31. Rethinking the TNM Classification Regarding Direct Lymph Node Invasion in Pancreatic Ductal Adenocarcinoma.
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Speichinger F, Dragomir MP, Schallenberg S, Loch FN, Degro CE, Baukloh AK, Hartmann L, Pozios I, Schineis C, Margonis GA, Lauscher JC, Beyer K, and Kamphues C
- Abstract
Mechanisms of lymph node invasion seem to play a prognostic role in pancreatic ductal adenocarcinoma (PDAC) after resection. However, the 8th edition of the TNM classification of the American Joint Committee on Cancer (AJCC) does not consider this. The aim of this study was to analyse the prognostic role of different mechanisms of lymph node invasion on PDAC. One hundred and twenty-two patients with resected PDAC were examined. We distinguished three groups: direct (per continuitatem, Nc) from the main tumour, metastasis (Nm) without any contact to the main tumour, and a mixed mechanism (Ncm). Afterwards, the prognostic power of the different groups was analysed concerning overall survival (OS). In total, 20 patients displayed direct lymph node invasion (Nc = 16.4%), 44 were classed as Nm (36.1%), and 21 were classed as Ncm (17.2%). The difference in OS was not statistically significant between N0 (no lymph node metastasis, n = 37) and Nc ( p = 0.134), while Nm had worse OS than N0 ( p < 0.001). Direct invasion alone had no statistically significant effect on OS ( p = 0.885). Redefining the N0 stage by including Nc patients showed a more precise OS prediction among N stages ( p = 0.001 vs. p = 0.002). Nc was more similar to N0 than to Nm; hence, we suggest a rethinking of TNM classification based on the mechanisms of lymph node metastases in PDAC. Overall, this novel classification is more precise.
- Published
- 2021
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32. Risk factors for upper and lower type prolonged postoperative ileus following surgery for Crohn's disease.
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Pozios I, Seeliger H, Lauscher JC, Stroux A, Weixler B, Kamphues C, Beyer K, Kreis ME, Lehmann KS, and Seifarth C
- Subjects
- Aged, Colectomy, Humans, Postoperative Complications epidemiology, Postoperative Complications etiology, Retrospective Studies, Risk Factors, Crohn Disease surgery, Ileus epidemiology, Ileus etiology
- Abstract
Purpose: Prolonged postoperative ileus (PPOI) is common after bowel resections, especially in Crohn's disease (CD). The pathophysiology of PPOI is not fully understood. PPOI could affect only the upper or lower gastrointestinal (GI) tract. The aim of this study was to assess risk factors for diverse types of PPOI, particularly to differentiate PPOI of upper and lower GI tract., Methods: A retrospective analysis of 163 patients with CD undergoing ileocecal resection from 2015 to 2020 in a single center was performed. PPOI of the upper GI tract was predefined as the presence of vomiting or use of nasogastric tube longer than the third postoperative day. Lower PPOI was predefined as the absence of defecation for more than three days. Independent risk factors were identified by multivariable logistic regression analysis., Results: Overall incidence of PPOI was 42.7%. PPOI of the upper GI tract was observed in 30.7% and lower PPOI in 20.9% of patients. Independent risk factors for upper PPOI included older age, surgery by a resident surgeon, hand-sewn anastomosis, prolonged opioid analgesia, and reoperation, while for lower PPOI included BMI ≤ 25 kg/m
2 , preoperative anemia, and absence of ileostomy., Conclusion: This study identified different risk factors for upper and lower PPOI after ileocecal resection in patients with CD. A differentiated upper/lower type approach should be considered in future research and clinical practice. High-risk patients for each type of PPOI should be closely monitored, and modifiable risk factors, such as preoperative anemia and opioids, should be avoided if possible., (© 2021. The Author(s).)- Published
- 2021
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33. Blockage of Cholinergic Signaling via Muscarinic Acetylcholine Receptor 3 Inhibits Tumor Growth in Human Colorectal Adenocarcinoma.
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Hering NA, Liu V, Kim R, Weixler B, Droeser RA, Arndt M, Pozios I, Beyer K, Kreis ME, and Seeliger H
- Abstract
Cholinergic signaling via the muscarinic M3 acetylcholine receptor (M3R) is involved in the development and progression of colorectal cancer (CRC). The present study aimed to analyze the blocking of M3R signaling in CRC using darifenacin, a selective M3R antagonist. Darifenacin effects were studied on HT-29 and SW480 CRC cells using MTT and BrdU assays, Western blotting and real time RT-PCR. In vivo, blocking of M3R was assessed in an orthotopic CRC xenograft BALB/c
nu/nu mouse model. M3R expression in clinical tumor specimens was studied by immunohistochemistry on a tissue microarray of 585 CRC patients. In vitro, darifenacin decreased tumor cell survival and proliferation in a dose-dependent manner. Acetylcholine-induced p38, ERK1/2 and Akt signaling, and MMP-1 mRNA expression were decreased by darifenacin, as well as matrigel invasion of tumor cells. In mice, darifenacin reduced primary tumor volume and weight ( p < 0.05), as well as liver metastases, compared to controls. High expression scores of M3R were found on 89.2% of clinical CRC samples and correlated with infiltrative tumor border and non-mucinous histology ( p < 0.05). In conclusion, darifenacin inhibited components of tumor growth and progression in vitro and reduced tumor growth in vivo. Its target, M3R, was expressed on the majority of CRC. Thus, repurposing darifenacin may be an attractive addition to systemic tumor therapy in CRC patients expressing M3R.- Published
- 2021
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34. Healing of rectal advancement flaps for anal fistulas in patients with and without Crohn's disease: a retrospective cohort analysis.
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Seifarth C, Lehmann KS, Holmer C, and Pozios I
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- Female, Humans, Rectum, Retrospective Studies, Surgical Flaps, Crohn Disease complications, Crohn Disease surgery, Rectal Fistula etiology, Rectal Fistula surgery
- Abstract
Background: Surgical closure of anal fistulas with rectal advancement flaps is an established standard method, but it has a high degree of healing failure in some cases. The aim of this study was to identify risk factors for anal fistula healing failure after advancement flap placement between patients with cryptoglandular fistulas and patients with Crohn's disease (CD)., Methods: From January 2010 to October 2020, 155 rectal advancement flaps (CD patients = 55, non-CD patients = 100) were performed. Patients were entered into a prospective database, and healing rates were retrospectively analysed., Results: The median follow-up period was 189 days (95% CI: 109-269). The overall complication rate was 5.8%. The total healing rate for all rectal advancement flaps was 56%. CD patients were younger (33 vs. 43 years, p < 0.001), more often female (76% vs. 30%, p < 0.001), were administered more immunosuppressant medication (65% vs. 5%, p < 0.001), and had more rectovaginal fistulas (29% vs. 8%, p = 0.001) and more protective stomas (49% vs. 2%, p < 0.001) than patients without CD. However, no difference in healing rate was noted between patients with or without CD (47% vs. 60%, p = 0.088)., Conclusions: Patients with anal fistulas with and without Crohn's disease exhibit the same healing rate. Although patients with CD display different patient-specific characteristics, no independent factors for the occurrence of anal fistula healing failure could be determined. Trial registration Not applicable due to the retrospective study design.
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- 2021
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35. Raloxifene inhibits pancreatic adenocarcinoma growth by interfering with ERβ and IL-6/gp130/STAT3 signaling.
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Pozios I, Seel NN, Hering NA, Hartmann L, Liu V, Camaj P, Müller MH, Lee LD, Bruns CJ, Kreis ME, and Seeliger H
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- Adenocarcinoma metabolism, Animals, Cell Line, Tumor, Cell Proliferation drug effects, Humans, Male, Mice, Nude, Neoplasm Metastasis, Signal Transduction drug effects, Time Factors, Xenograft Model Antitumor Assays, Mice, Adenocarcinoma pathology, Cytokine Receptor gp130 metabolism, Estrogen Receptor beta metabolism, Interleukin-6 metabolism, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Raloxifene Hydrochloride pharmacology, STAT3 Transcription Factor metabolism
- Abstract
Purpose: Currently, the exact role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we showed that expression of phosphorylated ERβ correlates with a poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here, we hypothesized that raloxifene, a FDA-approved selective ER modulator (SERM), may suppress PDAC tumor growth by interfering with ERβ signaling. To test this hypothesis, we studied the impact of raloxifene on interleukin-6/glycoprotein-130/signal transducer and activator of transcription-3 (IL-6/gp130/STAT3) signaling., Methods: Human PDAC cell lines were exposed to raloxifene after which growth inhibition was assessed using a BrdU assay. ER knockdown was performed using siRNAs specific for ERα and ERβ. The effects of raloxifene on IL-6 expression and STAT3 phosphorylation in PDAC cells were assessed by ELISA and Western blotting, respectively. In addition, raloxifene was administered to an orthotopic PDAC tumor xenograft mouse model, after which tumor growth was monitored and immunohistochemistry was performed., Results: Raloxifene inhibited the in vitro growth of PDAC cells, and this effect was reversed by siRNA-mediated knockdown of ERβ, but not of ERα, indicating ER isotype-specific signaling. We also found that treatment with raloxifene inhibited the release of IL-6 and suppressed the phosphorylation of STAT3
Y705 in PDAC cells. In vivo, we found that orthotopic PDAC tumor growth, lymph node and liver metastases as well as Ki-67 expression were reduced in mice treated with raloxifene., Conclusions: Inhibition of ERβ and the IL-6/gp130/STAT3 signaling pathway by raloxifene leads to potent reduction of PDAC growth in vitro and in vivo. Our results suggest that ERβ signaling and IL-6/gp130 interaction may serve as promising drug targets for pancreatic cancer and that raloxifene may serve as an attractive therapeutic option for PDAC patients expressing the ERβ isotype.- Published
- 2021
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36. Expression of estrogen receptor beta correlates with adverse prognosis in resected pancreatic adenocarcinoma.
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Seeliger H, Pozios I, Assmann G, Zhao Y, Müller MH, Knösel T, Kreis ME, and Bruns CJ
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- Adenocarcinoma pathology, Adenocarcinoma surgery, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Estrogen Receptor beta metabolism, Female, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Pancreatic Neoplasms pathology, Pancreatic Neoplasms surgery, Prognosis, Proportional Hazards Models, Survival Analysis, Adenocarcinoma genetics, Adenocarcinoma mortality, Estrogen Receptor beta genetics, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms genetics, Pancreatic Neoplasms mortality
- Abstract
Background: The relevance of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Clinical trials targeting ER with selective estrogen receptor modulators in pancreatic cancer did not show any benefit. Here, we analyze the impact of recently characterized ER isoform beta on survival in a cohort of patients with resected PDAC., Methods: Eighty-four patients having undergone pancreatic resection for PDAC at a single institution were identified. Tissue microarrays were constructed of archival tumor specimens. The expression of ER beta was determined by immunohistochemistry and quantified by a system established for estrogen receptor expression in breast cancer. ER beta expression was then correlated with clinicopathological parameters, and univariate and multivariate survival analyses were performed., Results: Nuclear expression of ER beta was found in 31% of tumors. No significant correlation was found between ER beta expression and TNM status, tumor grade, age or sex. Univariate analysis revealed nodal metastasis and the expression of ER beta as factors correlating with a shorter overall survival and disease free survival. When comparing ER beta expression in patients surviving more than 24 months with those who died from the tumor within 12 or 24 months, respectively, a significantly lower ER beta expression was found in the long term survivors. In multivariate analysis, ER beta expression was demonstrated to be an independent predictor of shorter overall survival., Conclusions: In resected PDAC, expression of ER beta seems to correlate with poor prognosis. These data may help to identify patients who may benefit from additional systemic therapy including selective estrogen receptor modulators.
- Published
- 2018
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37. Expression of phosphorylated estrogen receptor beta is an independent negative prognostic factor for pancreatic ductal adenocarcinoma.
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Pozios I, Knösel T, Zhao Y, Assmann G, Pozios I, Müller MH, Bruns CJ, Kreis ME, and Seeliger H
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- Adult, Aged, Aged, 80 and over, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal surgery, Female, Follow-Up Studies, Humans, Interleukin-6 metabolism, Male, Middle Aged, Neoplasm Recurrence, Local metabolism, Neoplasm Recurrence, Local surgery, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms surgery, Phosphorylation, Prognosis, Survival Rate, Pancreatic Neoplasms, Biomarkers, Tumor metabolism, Carcinoma, Pancreatic Ductal pathology, Estrogen Receptor beta metabolism, Neoplasm Recurrence, Local pathology, Pancreatic Neoplasms pathology, STAT3 Transcription Factor metabolism
- Abstract
Purpose: The role of estrogen receptor beta (ER-β) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Ligand-independent phosphorylation and activation of ER-β may play a relevant role in the IL-6/STAT3 signaling pathway and, as a result, in tumor progression. Here, we examined the effect of ER-β, phosphorylated ER-β (pER-β), STAT3, phosphorylated STAT3 (pSTAT3) and IL-6 expression on the overall and recurrence-free survival in a cohort of patients with resected PDAC., Methods: We identified 175 patients who underwent pancreatic resection for PDAC. Tissue microarrays were constructed from the archival tumor specimens. These were stained with specific antibodies for the above molecules. The expression of the markers was then correlated with clinicopathological parameters and survival analysis was performed., Results: High nuclear expression of ER-β was found in 61.7% and pER-β in 80.6% of the tumors. STAT3 was expressed in 54.3% of the tumor samples, pSTAT3 in 68% and IL-6 in 76.6%. The median overall survival for patients with low pER-β expression was 29 months, whereas for patients with high pER-β expression was 15.1 months (p = 0.016). Multivariate analysis revealed that pER-β expression was an independent factor correlating with shorter overall survival (hazard ratio 1.9; p = 0.013) and disease-free survival (hazard ratio 1.9; p = 0.029)., Conclusions: Expression of pER-β constitutes an independent prognostic marker for PDAC and is correlated with poor prognosis. These data may help in identifying novel drug targets in PDAC and patients who could benefit from additional therapeutic regimens, including selective estrogen receptor modulators.
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- 2018
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38. Rest and Stress Longitudinal Systolic Left Ventricular Mechanics in Hypertrophic Cardiomyopathy: Implications for Prognostication.
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Pozios I, Pinheiro A, Corona-Villalobos C, Sorensen LL, Dardari Z, Liu HY, Cresswell K, Phillip S, Bluemke DA, Zimmerman SL, Abraham MR, and Abraham TP
- Subjects
- Cardiomyopathy, Hypertrophic diagnosis, Disease Progression, Female, Follow-Up Studies, Heart Ventricles physiopathology, Humans, Magnetic Resonance Imaging, Cine methods, Male, Middle Aged, Prognosis, ROC Curve, Retrospective Studies, Systole, Cardiomyopathy, Hypertrophic physiopathology, Echocardiography, Stress methods, Exercise Tolerance physiology, Heart Ventricles diagnostic imaging, Rest physiology, Ventricular Function, Left physiology
- Abstract
Background: Exercise intolerance is the most common symptom in hypertrophic cardiomyopathy (HCM). We examined whether inability to augment myocardial mechanics during exercise would influence functional performance and clinical outcomes in HCM., Methods: Ninety-five HCM patients (32 nonobstructive, 32 labile-obstructive, 31 obstructive) and 26 controls of similar age and gender distribution were recruited prospectively. They underwent rest and treadmill stress strain echocardiography, and 61 of them underwent magnetic resonance imaging. Mechanical reserve (MRES) was defined as percent change in systolic strain rate (SR) immediately postexercise., Results: Global strain and SR were significantly lower in HCM patients at rest (strain: nonobstructive, -15.6 ± 3.0; labile-obstructive, -15.9 ± 3.0; obstructive, -13.8 ± 2.9; control, -17.7% ± 2.1%, P < .001; SR: nonobstructive, -0.92 ± 0.20; labile-obstructive, -0.94 ± 0.17; obstructive, -0.85 ± 0.18; control, -1.04 ± 0.14 s
-1 , P = .002); and immediately postexercise (strain: nonobstructive, -15.6 ± 3.0; labile-obstructive, -17.6 ± 3.6; obstructive, -15.6 ± 3.6; control, -19.2 ± 3.1%; P = .001; SR: nonobstructive, -1.41 ± 0.37; labile-obstructive, -1.64 ± 0.38; obstructive, -1.32 ± 0.29; control, -1.82 ± 0.29 s-1 , P < .001). MRES was lower in nonobstructive and obstructive compared with labile-obstructive and controls (51% ± 29%, 54% ± 31%, 78% ± 38%, 77% ± 30%, P = .001, respectively). Postexercise SR and MRES were associated with exercise capacity (r = 0.47 and 0.42, P < .001 both, respectively). When adjusted for age, gender, body mass index, E/e', and resting peak instantaneous systolic gradient, postexercise SR best predicted exercise capacity (r = 0.74, P = .003). Postexercise SR was correlated with extent of late gadolinium enhancement (r = 0.34, P = .03). By Cox regression, exercise SR and MRES predicted ventricular tachycardia/ventricular fibrillation (VT/VF) even after adjustment for age, gender, family history of sudden cardiac death, septum ≥ 3 cm and abnormal blood pressure response (P = .04 and P = .046, respectively)., Conclusions: Nonobstructive and obstructive patients have reduced MRES compared with labile-obstructive and controls. Postexercise SR correlates with LGE and exercise capacity. Exercise SR and MRES predict VT/VF., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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39. Clinical Outcomes in Patients With Nonobstructive, Labile, and Obstructive Hypertrophic Cardiomyopathy.
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Lu DY, Pozios I, Haileselassie B, Ventoulis I, Liu H, Sorensen LL, Canepa M, Phillip S, Abraham MR, and Abraham TP
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- Adult, Aged, Cardiomyopathy, Hypertrophic mortality, Cardiomyopathy, Hypertrophic physiopathology, Cardiomyopathy, Hypertrophic therapy, Death, Sudden, Cardiac prevention & control, Disease Progression, Female, Health Status, Heart Failure mortality, Heart Failure physiopathology, Heart Failure therapy, Hemodynamics, Humans, Male, Middle Aged, Prognosis, Prospective Studies, Registries, Risk Assessment, Risk Factors, Tachycardia, Ventricular mortality, Tachycardia, Ventricular physiopathology, Tachycardia, Ventricular therapy, Time Factors, Ventricular Fibrillation mortality, Ventricular Fibrillation physiopathology, Ventricular Fibrillation therapy, Ventricular Function, Left, Ventricular Outflow Obstruction mortality, Ventricular Outflow Obstruction physiopathology, Ventricular Outflow Obstruction therapy, Cardiomyopathy, Hypertrophic complications, Death, Sudden, Cardiac etiology, Heart Failure etiology, Tachycardia, Ventricular etiology, Ventricular Fibrillation etiology, Ventricular Outflow Obstruction etiology
- Abstract
Background: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease characterized by varying degrees of left ventricular outflow tract obstruction. In a large cohort, we compare the outcomes among 3 different hemodynamic groups., Methods and Results: We prospectively enrolled patients fulfilling standard diagnostic criteria for HCM from January 2005 to June 2015. Detailed phenotypic characterization, including peak left ventricular outflow tract pressure gradients at rest and after provocation, was measured by echocardiography. The primary outcome was a composite cardiovascular end point, which included new-onset atrial fibrillation, new sustained ventricular tachycardia/ventricular fibrillation, new or worsening heart failure, and death. The mean follow-up was 3.4±2.8 years. Among the 705 patients with HCM (mean age, 52±15 years; 62% men), 230 with obstructive HCM were older and had a higher body mass index and New York Heart Association class. The 214 patients with nonobstructive HCM were more likely to have a history of sustained ventricular tachycardia/ventricular fibrillation and implantable cardioverter defibrillator implantation. During follow-up, 121 patients experienced a composite cardiovascular end point. Atrial fibrillation occurred most frequently in the obstructive group. Patients with nonobstructive HCM had more frequent sustained ventricular tachycardia/ventricular fibrillation events. In multivariate analysis, obstructive (hazard ratio, 2.80; 95% confidence interval, 1.64-4.80) and nonobstructive (hazard ratio, 1.94; 95% confidence interval, 1.09-3.45) HCM were associated with more adverse events compared with labile HCM., Conclusions: Nonobstructive HCM carries notable morbidity, including a higher arrhythmic risk than the other HCM groups. Patients with labile HCM have a relatively benign clinical course. Our data suggest detailed sudden cardiac death risk stratification in nonobstructive HCM and monitoring with less aggressive management in labile HCM., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)
- Published
- 2018
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40. E/e' ratio and outcome prediction in hypertrophic cardiomyopathy: the influence of outflow tract obstruction.
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Lu DY, Haileselassie B, Ventoulis I, Liu HY, Liang HY, Pozios I, Canepa M, Phillip S, Abraham MR, and Abraham T
- Subjects
- Academic Medical Centers, Adult, Aged, Cardiac Surgical Procedures methods, Cardiomyopathy, Hypertrophic surgery, Cohort Studies, Comorbidity, Disease-Free Survival, Echocardiography, Doppler methods, Female, Follow-Up Studies, Humans, Male, Middle Aged, Patient Selection, Predictive Value of Tests, Retrospective Studies, Risk Assessment, Severity of Illness Index, Survival Analysis, Time Factors, Treatment Outcome, Ventricular Outflow Obstruction physiopathology, Cardiomyopathy, Hypertrophic diagnostic imaging, Cardiomyopathy, Hypertrophic epidemiology, Myotomy methods, Ventricular Outflow Obstruction diagnostic imaging, Ventricular Outflow Obstruction epidemiology
- Abstract
Aims: Diastolic dysfunction is thought to be an important pathophysiologic component of hypertrophic cardiomyopathy (HCM). However, there are conflicting data on the potential value of the mitral E/e' ratio. We examined whether left ventricular outflow tract (LVOT) obstruction influences the value of E/e' in predicting outcomes in HCM., Methods and Results: Patients who met diagnostic criteria for HCM were enrolled. Diastolic function was assessed with complete two-dimensional and Doppler echocardiography. A composite clinical outcome including new onset atrial fibrillation, sustained ventricular tachycardia/fibrillation, heart failure, transplantation, and death was examined over a mean follow-up period of 4.2 years. Among 604 patients, 206 patients had an E/e' level ≥20. Patients with higher septal E/e' level were older, with more severe NYHA class, and more severe LVOT obstruction. Higher E/e' was associated with worse event-free survival in non-obstructive group and total HCM cohort. In addition, E/e' and LVOT pressure gradient were highly correlated in non-obstructive and total HCM, but not in labile or obstructive group. During follow-up period, 95 patients underwent myectomy. Post-op E/e' correlated significantly with LVOT pressure gradient (R = 0.306, P = 0.004). In these patients, post-op E/e' was associated with worse event-free survival (log-rank P = 0.030)., Conclusion: Assessment of E/e' is useful for risk stratification in HCM patients. Nevertheless, the predictive power is confounded by dynamic LVOT obstruction. Higher E/e' predicts worse clinical outcomes in non-obstructive HCM and in labile/obstructive after myectomy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2018
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41. Myocardial oxidative stress correlates with left ventricular dysfunction on strain echocardiography in a rodent model of sepsis.
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Haileselassie B, Su E, Pozios I, Niño DF, Liu H, Lu DY, Ventoulis I, Fulton WB, Sodhi CP, Hackam D, O'Rourke B, and Abraham T
- Abstract
Background: Recognition of cardiomyopathy in sepsis can be challenging due to the limitations of conventional measures such as ejection fraction (EF) and fractional shortening (FS) in the context of variable preload and afterload conditions. This study correlates myocardial function using strain echocardiography (SE) with cardiomyocyte oxidative stress in a murine model of sepsis., Methods: C57BL/6J mice were randomized into control (n = 10), sham (n = 25), and a cecal ligation and puncture (CLP) (n = 33) model of sepsis. Echocardiography was performed pre-, 12, 24, and 48 h post-injury. Cardiac pro-inflammatory cytokines and mitochondrial redox scavenger expression were evaluated in a subset of each arm. To evaluate the influence of redox scavenger upregulation on oxidative injury and cardiac function, CLP was performed on mitochondrial catalase-upregulated C57BL/6J MCAT
+/+ mice (n = 12) and wild-type (WT) animals for comparison., Results: Septic C57BL/6J mice exhibited depressed longitudinal strain (LS) when compared to sham and control at 24 h (p < 0.01) and 48 h (p = 0.04) post-CLP despite having a preserved EF. Furthermore, there was a significant association between increased odds of mortality and depressed LS (OR = 1.23, p = 0.04). Septic C57BL/6J mice concomitantly demonstrated increased expression of cardiomyocyte pro-inflammatory cytokines and decreased expression of redox scavengers at 24 and 48 h. When comparing C57Bl/6 MCAT+/+ mice and C57BL/6J WT mice, a significant decrease in LS was identified in the WT mice at 24 h (MCAT = -23 ± 5% vs. WT = -15 ± 4% p < 0.01) and 48 h (MCAT = -23 ± 7% vs. WT = -15 ± 4.3% p = 0.04) post-CLP which correlated with significant increase in the level of cardiac oxidative stress following CLP., Conclusions: In this sepsis model, SE identified cardiomyopathy despite normal EF. SE depression temporally coincides with upregulation of inflammatory cytokines and decreases expression of key mitochondrial ROS scavengers. Upregulation of redox scavenger (CAT) abrogates oxidative stress and cardiac dysfunction in this sepsis model.- Published
- 2017
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42. Impact of peak provoked left ventricular outflow tract gradients on clinical outcomes in hypertrophic cardiomyopathy.
- Author
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Lu DY, Hailesealassie B, Ventoulis I, Liu H, Liang HY, Nowbar A, Pozios I, Canepa M, Cresswell K, Luo HC, Abraham MR, and Abraham TP
- Subjects
- Adrenergic beta-Antagonists therapeutic use, Adult, Aged, Calcium Channel Blockers therapeutic use, Cardiomyopathy, Hypertrophic drug therapy, Cohort Studies, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prospective Studies, Registries, Treatment Outcome, Ventricular Outflow Obstruction drug therapy, Cardiomyopathy, Hypertrophic diagnostic imaging, Cardiomyopathy, Hypertrophic physiopathology, Exercise Test methods, Ventricular Outflow Obstruction diagnostic imaging, Ventricular Outflow Obstruction physiopathology
- Abstract
Background: Hypertrophic cardiomyopathy (HCM) is traditionally classified based on a left ventricular outflow tract (LVOT) pressure gradient of 30mmHg at rest or with provocation. There are no data on whether 30mmHg is the most informative cut-off value and whether provoked gradients offer any information regarding outcomes., Methods: Resting and provoked peak LVOT pressure gradients were measured by Doppler echocardiography in patients fulfilling guidelines criteria for HCM. A composite clinical outcome including new onset atrial fibrillation, ventricular tachycardia/fibrillation, heart failure, transplantation, and death was examined over a median follow-up period of 2.1years., Results: Among 536 patients, 131 patients had resting LVOT gradients greater than 30mmHg. Subjects with higher resting gradients were older with more cardiovascular events. For provoked gradients, a bi-modal risk distribution was found. Patients with provoked gradients >90mmHg (HR 3.92, 95% CI 1.97-7.79) or <30mmHg (HR 2.15, 95% CI 1.08-4.29) have more events compared to those with gradients between 30 and 89mmHg in multivariable analysis. The introduction of two cut-off points for provoked gradients allowed HCM to be reclassified into four groups: patients with "benign" latent HCM (provoked gradient 30-89mmHg) had the best prognosis, whereas those with persistent obstructive HCM had the worst outcome., Conclusions: Provoked LVOT pressure gradients offer additional information regarding clinical outcomes in HCM. Applying cut-off points at 30 and 90mmHg to provoked LVOT pressure gradients further classifies HCM patients into low-, intermediate- and high-risk groups., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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43. Role of Global Longitudinal Strain in Predicting Outcomes in Hypertrophic Cardiomyopathy.
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Liu H, Pozios I, Haileselassie B, Nowbar A, Sorensen LL, Phillip S, Lu DY, Ventoulis I, Luo H, Abraham MR, and Abraham TP
- Subjects
- Cardiomyopathy, Hypertrophic diagnosis, Cardiomyopathy, Hypertrophic mortality, Cause of Death trends, Female, Heart Ventricles diagnostic imaging, Humans, Male, Maryland epidemiology, Middle Aged, Predictive Value of Tests, Retrospective Studies, Risk Factors, Survival Rate trends, Cardiomyopathy, Hypertrophic physiopathology, Echocardiography, Doppler methods, Heart Ventricles physiopathology, Risk Assessment, Ventricular Function, Left physiology
- Abstract
Global longitudinal strain (GLS) is a sensitive indicator of global left ventricular function particularly in those with normal ejection fraction. We examined the potential value of GLS in predicting outcomes in hypertrophic cardiomyopathy (HC). Conventional and strain echocardiography was performed in 400 patients with HC followed for a median 3.1 years (interquartile range 1.2 to 5.6). Peak systolic strain from 3 apical views was averaged to calculate GLS. Patients were divided based on a previously published cutoff value of -16%. Additionally, we identified 4 HC subgroups based on GLS: GLS ≤ -20%, -20% < GLS ≤ -16%, -16% < GLS ≤ -10%, and GLS > -10%. The primary end point was a composite of new-onset sustained ventricular tachycardia/fibrillation, heart failure, cardiac transplantation, and all-cause death. Patients with GLS > -16% had significantly more events (17% vs 7%, p = 0.002). In the 4-group analysis, event rates increased with worsening GLS (5%, 7%, 14%, and 33%, respectively, p = 0.001). Event-free survival was significantly superior in those with GLS ≤ -16% versus GLS > -16% (p = 0.004); similarly, GLS > -10% portended a significantly worse event-free survival compared with each of the other 3 groups (p <0.01 for all pairwise comparisons). By univariate and multivariate Cox regression analysis, GLS remained significantly associated with the composite end point. GLS > -10% had 4 times the risk of events compared with GLS ≤ -16% (p = 0.006). In conclusion, echo-based GLS is independently associated with outcomes in HC. Patients with GLS > -10% have significantly higher event rates., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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44. Structural and Functional Correlates of Myocardial T1 Mapping in 321 Patients With Hypertrophic Cardiomyopathy.
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Chu LC, Corona-Villalobos CP, Halushka MK, Zhang Y, Pozzessere C, Kamel IR, Pozios I, Van Der Geest RJ, Gai N, Abraham RM, Abraham TP, Bluemke DA, and Zimmerman SL
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Gadolinium DTPA, Heart diagnostic imaging, Heart physiopathology, Humans, Male, Middle Aged, Retrospective Studies, Young Adult, Cardiomyopathy, Hypertrophic diagnostic imaging, Cardiomyopathy, Hypertrophic physiopathology, Contrast Media, Image Enhancement, Magnetic Resonance Imaging
- Abstract
Objective: The aim of this study was to evaluate the structural and functional correlates of T1 mapping in 321 patients with hypertrophic cardiomyopathy (HCM)., Methods: Three hundred twenty-one patients with HCM who underwent cardiac magnetic resonance from 2003 to 2013 were retrospectively identified from our institution's HCM registry. Left ventricular volume, function, late gadolinium enhancement (LGE), and Look-Locker T1 time were quantified. T1 time was normalized to blood pool to calculate T1 ratio. Correlations between LGE%, T1 ratio, and structural and functional features were performed using Pearson correlation coefficient., Results: Late gadolinium enhancement showed stronger correlation with left ventricular mass index (r = 0.41, P < 0.001) compared with T1 ratio (r = -0.17, P = 0.004). Both LGE% and T1 ratio correlated with ejection fraction (r = -0.18 and P = 0.002 vs r = 0.21 and P < 0.001, respectively). E/e' showed correlation with LGE% but not with T1 ratio., Conclusions: Late gadolinium enhancement was more strongly correlated with the phenotypic expression of HCM compared with T1 ratio.
- Published
- 2017
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45. Exercise-QTc is associated with diffuse interstitial fibrosis reflected by lower approximated T1 relaxation time in hypertrophic cardiomyopathy patients.
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Corona-Villalobos CP, Saha S, Pozios I, Hurtado-de-Mendoza Paz D, Sorensen L, Gonzalez Cordoba J, Dolores-Cerna K, Kamel IR, Mormontoy Laurel W, Bluemke DA, Abraham TP, Zimmerman SL, and Abraham MR
- Subjects
- Adult, Aged, Arrhythmias, Cardiac diagnosis, Cardiomyopathy, Hypertrophic complications, Cardiomyopathy, Hypertrophic diagnosis, Electrocardiography, Ambulatory, Female, Fibrosis complications, Heart diagnostic imaging, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Arrhythmias, Cardiac etiology, Cardiomyopathy, Hypertrophic physiopathology, Electrocardiography, Exercise physiology, Myocardium pathology
- Published
- 2017
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46. Elevated interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) is a poor prognostic marker in pancreatic ductal adenocarcinoma.
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Zhao Y, Altendorf-Hofmann A, Pozios I, Camaj P, Däberitz T, Wang X, Niess H, Seeliger H, Popp F, Betzler C, Settmacher U, Jauch KW, Bruns C, and Knösel T
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor metabolism, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal mortality, Cell Proliferation drug effects, Cell Proliferation genetics, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Female, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins metabolism, Male, Middle Aged, Pancreatic Neoplasms genetics, Pancreatic Neoplasms mortality, Prognosis, Retrospective Studies, Tumor Cells, Cultured, Up-Regulation genetics, Gemcitabine, Biomarkers, Tumor genetics, Carcinoma, Pancreatic Ductal diagnosis, Intracellular Signaling Peptides and Proteins genetics, Pancreatic Neoplasms diagnosis
- Abstract
Purpose: Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) gene from IFITs family is one gene among hundreds of IFN-stimulated genes. The potential role of IFIT3 in cancer is scarcely understood. In addition, the clinical relevance of IFIT3 is not yet known in pancreatic ductal adenocarcinoma (PDAC). We evaluated the prognostic significance of this gene in PDAC patients., Methods: The expression of IFIT3 was analyzed in pancreatic cancer cell lines with different metastatic potential (FG and L3.6pl) and one established gemcitabine resistant cell variant-L3.6plGres. Second, we analyzed the protein expression in tissue microarrays (TMA) from specimens of 254 radically resected patients with pancreatic adenocarcinoma. The prognostic relevance of IFIT3 was evaluated by the Kaplan-Meier and Cox regression analysis., Results: L3.6pl cells with an aggressive capacity showed a significant higher expression of IFIT3 as compared to FG cells. IFIT3 was accumulated in gemcitabine resistant cells. Overexpression of IFIT3 increased the resistance of apoptosis against gemcitabine treatment. Patients who had high expression of IFIT3 (32%) and received chemotherapy had a statistically significant reduced survival in multivariate analysis., Conclusions: High expression of IFIT3 enhances anti-apoptotic activity and chemotherapy resistance of PDAC cells. High expression of IFIT3 was independently correlated to shorter patients' survival and may serve as a prognostic marker.
- Published
- 2017
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47. Diffuse interstitial fibrosis assessed by cardiac magnetic resonance is associated with dispersion of ventricular repolarization in patients with hypertrophic cardiomyopathy.
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Hurtado-de-Mendoza D, Corona-Villalobos CP, Pozios I, Gonzales J, Soleimanifard Y, Sivalokanathan S, Montoya-Cerrillo D, Vakrou S, Kamel I, Mormontoy-Laurel W, Dolores-Cerna K, Suarez J, Perez-Melo S, Bluemke DA, Abraham TP, Zimmerman SL, and Abraham MR
- Abstract
Background: Hypertrophic cardiomyopathy (HCM) is characterized by myocyte hypertrophy, disarray, fibrosis, and increased risk for ventricular arrhythmias. Increased QT dispersion has been reported in patients with HCM, but the underlying mechanisms have not been completely elucidated. In this study, we examined the relationship between diffuse interstitial fibrosis, replacement fibrosis, QTc dispersion and ventricular arrhythmias in patients with HCM. We hypothesized that fibrosis would slow impulse propagation and increase dispersion of ventricular repolarization, resulting in increased QTc dispersion on surface electrocardiogram (ECG) and ventricular arrhythmias., Methods: ECG and cardiac magnetic resonance (CMR) image analyses were performed retrospectively in 112 patients with a clinical diagnosis of HCM. Replacement fibrosis was assessed by measuring late gadolinium (Gd) enhancement (LGE), using a semi-automated threshold technique. Diffuse interstitial fibrosis was assessed by measuring T1 relaxation times after Gd administration, using the Look-Locker sequence. QTc dispersion was measured digitally in the septal/anterior (V1-V4), inferior (II, III, and aVF), and lateral (I, aVL, V5, and V6) lead groups on surface ECG., Results: All patients had evidence of asymmetric septal hypertrophy. LGE was evident in 70 (63%) patients; the median T1 relaxation time was 411±38 ms. An inverse correlation was observed between T1 relaxation time and QTc dispersion in leads V1-V4 ( p <0.001). Patients with HCM who developed sustained ventricular tachycardia had slightly higher probability of increased QTc dispersion in leads V1-V4 (odds ratio, 1.011 [1.004-1.0178, p =0.003). We found no correlation between presence and percentage of LGE and QTc dispersion., Conclusion: Diffuse interstitial fibrosis is associated with increased dispersion of ventricular repolarization in leads, reflecting electrical activity in the hypertrophied septum. Interstitial fibrosis combined with ion channel/gap junction remodeling in the septum could lead to inhomogeneity of ventricular refractoriness, resulting in increased QTc dispersion in leads V1-V4.
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- 2017
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48. Safety profile and utility of treadmill exercise in patients with high-gradient hypertrophic cardiomyopathy.
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Sorensen LL, Liang HY, Pinheiro A, Hilser A, Dimaano V, Olsen NT, Hansen TF, Sogaard P, Nowbar A, Pisanello C, Pozios I, Phillip S, Zhou X, Abraham R, and Abraham TP
- Subjects
- Adult, Aged, Angina Pectoris etiology, Cardiomyopathy, Hypertrophic physiopathology, Dyspnea etiology, Female, Humans, Male, Middle Aged, Retrospective Studies, Tachycardia, Ventricular etiology, Ventricular Fibrillation etiology, Ventricular Outflow Obstruction physiopathology, Arrhythmias, Cardiac etiology, Cardiomyopathy, Hypertrophic diagnostic imaging, Echocardiography, Stress adverse effects, Exercise Test adverse effects, Syncope etiology, Ventricular Outflow Obstruction diagnostic imaging
- Abstract
Background: Exercise echocardiography in the evaluation of hypertrophic cardiomyopathy (HCM) provides valuable information for risk stratification, selection of optimal treatment, and prognostication. However, HCM patients with left ventricular outflow tract gradients ≥30mm Hg are often excluded from exercise testing because of safety considerations. We examined the safety and utility of exercise testing in patients with high-gradient HCM., Methods: We evaluated clinical characteristics, hemodynamics, and imaging variables in 499 consecutive patients with HCM who performed 959 exercise tests. Patients were divided based on peak left ventricular outflow tract gradients using a 30-mm Hg threshold into the following: obstructive (n=152), labile-obstructive (n=178), and nonobstructive (n=169) groups., Results: There were no deaths during exercise testing. We noted 20 complications (2.1% of tests) including 3 serious ventricular arrhythmias (0.3% of tests). There was no difference in complication rate between groups. Patients with obstructive HCM had a higher frequency of abnormal blood pressure response (obstructive: 53% vs labile: obstructive: 41% and nonobstructive: 37%; P=.008). Obstructive patients also displayed a lower work capacity (obstructive: 8.4±3.4 vs labile obstructive: 10.9±4.2 and nonobstructive: 10.2±4.0, metabolic equivalent; P<.001). Exercise testing provided incremental information regarding sudden cardiac death risk in 19% of patients with high-gradient HCM, and we found a poor correlation between patient-reported functional class and work capacity., Conclusion: Our results suggest that exercise testing in HCM is safe, and serious adverse events are rare. Although numbers are limited, exercise testing in high-gradient HCM appears to confer no significant additional safety hazard in our selected cohort and could potentially provide valuable information., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2017
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49. Effect of Diffuse Subendocardial Hypoperfusion on Left Ventricular Cavity Size by 13 N-Ammonia Perfusion PET in Patients With Hypertrophic Cardiomyopathy.
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Yalçin H, Valenta I, Yalçin F, Corona-Villalobos C, Vasquez N, Ra J, Kucukler N, Tahari A, Pozios I, Zhou Y, Pomper M, Abraham TP, Schindler TH, and Abraham MR
- Subjects
- Adult, Aged, Ammonia, Cardiomyopathy, Hypertrophic physiopathology, Female, Humans, Male, Middle Aged, Myocardial Ischemia physiopathology, Myocardial Perfusion Imaging, Nitrogen Radioisotopes, Positron-Emission Tomography, Radiopharmaceuticals, Cardiomyopathy, Hypertrophic diagnostic imaging, Coronary Circulation, Heart Ventricles diagnostic imaging, Myocardial Ischemia diagnostic imaging, Stroke Volume
- Abstract
Vasodilator-induced transient left ventricular (LV) cavity dilation by positron emission tomography (PET) is common in patients with hypertrophic cardiomyopathy (HC). Because most patients with PET-LV cavity dilation lack obstructive epicardial coronary artery disease, we hypothesized that vasodilator-induced subendocardial hypoperfusion resulting from microvascular dysfunction underlies this result. To test this hypothesis, we quantified myocardial blood flow (MBF) (subepicardial, subendocardial, and global MBF) and left ventricular ejection fraction (LVEF) in 104 patients with HC without significant coronary artery disease, using
13 NH3 -PET. Patients with HC were divided into 2 groups, based on the presence/absence of LV cavity dilation (LVvolumestress /LVvolumerest >1.13). Transient PET-LV cavity dilation was evident in 52% of patients with HC. LV mass, stress left ventricular outflow tract gradient, mitral E/E', late gadolinium enhancement, and prevalence of ischemic ST-T changes after vasodilator were significantly higher in patients with HC with LV cavity dilation. Baseline LVEF was similar in the 2 groups, but LV cavity dilation+ patients had lower stress-LVEF (43 ± 11 vs 53 ± 10; p <0.001), lower stress-MBF in the subendocardial region (1.6 ± 0.7 vs 2.3 ± 1.0 ml/min/g; p <0.001), and greater regional perfusion abnormalities (summed difference score: 7.0 ± 6.1 vs 3.9 ± 4.3; p = 0.004). The transmural perfusion gradient, an indicator of subendocardial perfusion, was similar at rest in the 2 groups. Notably, LV cavity dilation+ patients had lower stress-transmural perfusion gradients (0.85 ± 0.22, LV cavity dilation+ vs 1.09 ± 0.39, LV cavity dilation- ; p <0.001), indicating vasodilator-induced subendocardial hypoperfusion. The stress-transmural perfusion gradient, global myocardial flow reserve, and stress-LVEF were associated with LV cavity dilation. In conclusion, diffuse subendocardial hypoperfusion and myocardial ischemia resulting from microvascular dysfunction contribute to development of transient LV cavity dilation in HC., (Copyright © 2016 Elsevier Inc. All rights reserved.)- Published
- 2016
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50. Apparent left ventricular cavity dilatation during PET/CT in hypertrophic cardiomyopathy: Clinical predictors and potential mechanisms.
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Bravo PE, Tahari A, Pozios I, Luo HC, Bengel FM, Wahl RL, Abraham MR, and Abraham TP
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- Baltimore epidemiology, Comorbidity, Female, Humans, Incidence, Male, Middle Aged, Prognosis, Reproducibility of Results, Risk Assessment, Sensitivity and Specificity, Cardiomyopathy, Hypertrophic diagnostic imaging, Cardiomyopathy, Hypertrophic epidemiology, Hypertrophy, Left Ventricular diagnostic imaging, Hypertrophy, Left Ventricular epidemiology, Myocardial Perfusion Imaging statistics & numerical data, Positron Emission Tomography Computed Tomography statistics & numerical data
- Abstract
Background: Apparent left ventricular cavity dilatation (LVCD) in patients with hypertrophic cardiomyopathy (HCM) is an incompletely understood phenomenon. We aimed at investigating its clinical predictors and potential mechanisms., Methods: Sixty one HCM patients underwent N-13-ammonia PET for visual evaluation of LVCD, transient ischemic dilatation (TID) index, myocardial blood flow (MBF), coronary flow reserve (CFR), and regional myocardial perfusion (rMP). TID index was also derived at 2-4 and 15-20 minutes., Results: Visual LVCD and quantitative TID (>1.13 abnormal) agreement were excellent (k 0.91; P < .0001). LVCD-positive (n = 32) patients had greater LV thickness (2.26 ± 0.59 vs 1.92 ± 0.41 cm; P = .005), but lower stress MBF (1.66 ± 0.42 vs 2.07 ± 0.46 mL/minute/g; P < .0001), and CFR (1.90 ± 0.46 vs 2.46 ± 0.69; P < .0001) than LVCD-negative (n = 29) patients. Abnormal rMP was present in 31/32 LVCD-positive but only 12/29 (P < .0001) LVCD-negative. TID index was higher at 2-4 (1.30 ± 0.13) than at 15-20 minutes (1.27 ± 0.12; P = .001) in LVCD-positive, whereas it was the same (1.04 ± 0.07 vs 1.04 ± 0.07; P = .9) in LVCD-negative. In multivariate analysis, global peak MBF, abnormal rMP, and LV thickness were the best predictors of LVCD., Conclusion: Apparent LVCD is a common finding in HCM, intimately related to abnormal myocardial perfusion, globally impaired vasodilator flow reserve, and degree of hypertrophy. In addition to regional and/or diffuse subendocardial ischemia, some degree of true LV chamber dilatation may also contribute to the occurrence of apparent LVCD in HCM.
- Published
- 2016
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