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1. Atezolizumab/bevacizumab or lenvatinib in hepatocellular carcinoma: Multicenter real-world study with focus on bleeding and thromboembolic events

Author

Najib Ben Khaled, Marie Möller, Leonie S. Jochheim, Catherine Leyh, Ursula Ehmer, Katrin Böttcher, Matthias Pinter, Lorenz Balcar, Bernhard Scheiner, Alexander Weich, Hans Benno Leicht, Valentina Zarka, Liangtao Ye, Julia Schneider, Ignazio Piseddu, Osman Öcal, Monika Rau, Friedrich Sinner, Marino Venerito, Simon Johannes Gairing, Friedrich Förster, Julia Mayerle, Enrico N. De Toni, Andreas Geier, and Florian P. Reiter

Subjects
Hepatocellular carcinoma, Immunotherapy, Tyrosine kinase inhibition, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Atezolizumab/bevacizumab (atezo/bev) and lenvatinib have demonstrated efficacy as first-line therapies for hepatocellular carcinoma (HCC). However, vascular endothelial growth factor (VEGF) inhibition with these therapies may be associated with the risk of bleeding and thromboembolic events. In this study, we evaluated the efficacy and safety with focus on the bleeding and thromboembolic events of atezo/bev vs. lenvatinib in a large, multicenter real-world population. Methods: This study is based on HCC cohorts from seven centers in Germany and Austria. Incidences of bleeding or thromboembolic events and efficacy outcomes were assessed and compared. Results: In total, 464 patients treated with atezo/bev (n = 325) or lenvatinib (n = 139) were analyzed. Both groups were balanced with respect to demographics, presence of liver cirrhosis, and variceal status. Duration of therapy did not differ between groups. Within 3 months of therapy, bleeding episodes were described in 57 (18%) patients receiving atezo/bev compared with 15 (11%) patients receiving lenvatinib (p = 0.07). Variceal hemorrhage occurred in 11 (3%) patients treated with atezo/bev compared with 4 (3%) patients treated with lenvatinib (p = 0.99). Thromboembolic events were reported in 19 (6%) of patients in the atezo/bev cohort compared with 5 (4%) patients in the lenvatinib cohort (p = 0.37). In addition, incidence of overall bleeding, variceal hemorrhage, and thromboembolic events did not differ significantly in patients who received either atezo/bev or lenvantinib for 6 months. Conclusions: Safety considerations related to bleeding and thromboembolic events may not be helpful in guiding clinical decision-making when choosing between atezo/bev and lenvatinib. Impact and implications: The inhibition of VEGF by current first-line therapies for HCC, such as atezolizumab/bevacizumab or lenvatinib, may be associated with the risk of bleeding and thromboembolic events. Studies comparing the incidence of these side effects between atezolizumab/bevacizumab and lenvatinib, which are preferred treatments over sorafenib for HCC, are needed. Differences in this side effect profile may influence the choice of first-line therapy by treating physicians. Because no significant differences were observed regarding bleeding or thromboembolic events between both therapies in the present study, we conclude that safety considerations related to these events may not be helpful in guiding clinical decision-making when choosing between atezolizumab/bevacizumab and lenvatinib.

Published
2024
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2. Combined effects of the PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738 variants on NAFLD severity: a multicenter biopsy-based study1

Author

Marcin Krawczyk, Monika Rau, Jörn M. Schattenberg, Heike Bantel, Anita Pathil, Münevver Demir, Johannes Kluwe, Tobias Boettler, Frank Lammert, and Andreas Geier

Subjects
adiponutrin, fatty liver, fibrosis, steatosis, Biochemistry, QD415-436
Abstract

The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants represent genetic risk factors for nonalcoholic fatty liver disease (NAFLD). Here we investigate if these polymorphisms modulate both steatosis and fibrosis in patients with NAFLD. We recruited 515 patients with NAFLD (age 16–88 years, 280 female patients). Liver biopsies were performed in 320 patients. PCR-based assays were used to genotype the PNPLA3, TM6SF2, and MBOAT7 variants. Carriers of the PNPLA3 and TM6SF2 risk alleles showed increased serum aspartate aminotransferase and alanine transaminase activities (P < 0.05). The PNPLA3 genotype was associated with steatosis grades S2–S3 (P < 0.001) and fibrosis stages F2–F4 (P < 0.001). The TM6SF2 genotype was associated with steatosis (P = 0.003) but not with fibrosis (P > 0.05). The MBOAT7 variant was solely associated with increased fibrosis (P = 0.046). In the multivariate model, variants PNPLA3 (P = 0.004) and TM6SF2 (P = 0.038) were associated with steatosis. Fibrosis stages were affected by the PNPLA3 (P = 0.042) and MBOAT7 (P = 0.021) but not by the TM6SF2 polymorphism (P > 0.05). The PNPLA3, TM6SF2, and MBOAT7 variants are associated with increased liver injury. The TM6SF2 variant seems to modulate predominantly hepatic fat accumulation, whereas the MBOAT7 polymorphism is linked to fibrosis. The PNPLA3 polymorphism confers risk of both increased steatosis and fibrosis.

Published
2017
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3. Intestinal B-cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

Author

Elena Kotsiliti, Valentina Leone, Svenja Schuehle, Olivier Govaere, Hai Li, Monika J. Wolf, Helena Horvatic, Sandra Bierwirth, Jana Hundertmark, Donato Inverso, Laimdota Zizmare, Avital Sarusi-Portuguez, Revant Gupta, Tracy O’Connor, Anastasios D. Giannou, Ahmad Mustafa Shiri, Yehuda Schlesinger, Maria Garcia Beccaria, Charlotte Rennert, Dominik Pfister, Rupert Öllinger, Iana Gadjalova, Pierluigi Ramadori, Mohammad Rahbari, Nuh Rahbari, Marc Healy, Mirian Fernández-Vaquero, Neda Yahoo, Jakob Janzen, Indrabahadur Singh, Chaofan Fan, Xinyuan Liu, Monika Rau, Martin Feuchtenberger, Eva Schwaneck, Sebastian J. Wallace, Simon Cockell, John Wilson-Kanamori, Prakash Ramachandran, Celia Kho, Timothy J. Kendall, Anne-Laure Leblond, Selina J. Keppler, Piotr Bielecki, Katja Steiger, Maike Hofmann, Karsten Rippe, Horst Zitzlesberger, Achim Weber, Nisar Malek, Tom Lüdde, Mihael Vucur, Hellmut G. Augustin, Richard Flavell, Oren Parnas, Roland Rad, Olivier Pabst, Neil C. Henderson, Samuel Huber, Andrew Macpherson, Percy Knolle, Manfred Claasen, Andreas Geier, Christoph Trautwein, Kristian Unger, Eran Elinav, Ari Waisman, Zeinab Abdullah, Dirk Haller, Frank Tacke, Quentin M. Anstee, and Mathias Heikenwalder

Subjects
Hepatology, 610 Medicine & health
Abstract

BACKGROUND & AIMS: The progression of nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC.METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH diets (for example, choline-deficient high-fat diet, CD-HFD) or chow diet for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a CD-HFD, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with NAFL, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and scRNA-Seq analysis were performed in liver and gastrointestinal tissue for immune cells in mice and humans.RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen-specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B-cells and showed a positive correlation between IgA levels and activated FcRγ+ hepatic myeloid cells as well extent of liver fibrosis.CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for treating NASH.IMPACT AND IMPLICATIONS: Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory condition on the rise and can lead to hepatocellular carcinoma (HCC), the 3rd most common cause of cancer-related death worldwide. Currently, there is no effective treatment for this progressive disease that correlates with a marked risk of HCC mortality and carries a substantial healthcare burden. To date, among all the solid tumours, especially in HCC, the incidence and mortality rates are almost the same, making it crucial to find curative treatments for chronic diseases, such as NASH, which highly predispose to tumorigenesis. We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we could show that the absence of B cells prevented HCC development. B-cell intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets in combinatorial NASH therapies against inflammation and fibrosis.

Published
2023
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5. Gender-related aspects in occupational allergies – Secondary publication and update

Author

Monika Raulf, Thomas Brüning, Erika Jensen-Jarolim, and Vera van Kampen

Subjects
Allergy, Asthma, Dermatitis, Hypersensitivity pneumonitis, Gender, Occupational allergens, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract For years occupational allergies have been among the most frequently recorded occupational diseases, and both the skin as well as the respiratory tract may be affected. An estimated 9 to 15% of adult asthma is (partially) caused by work-related exposure. Gender-specific differences in exposure cause different risks in the workplace which affect the health of employees. This also applies to exposure and working conditions when handling sensitizing working substances. The presented gender-specific analysis of the German documentation of confirmed occupational respiratory allergic diseases and occupational skin diseases reveals clear differences between men and women in the number of diseases and also in exposure conditions and working areas.

Published
2017
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6. WAO International Scientific Conference (WISC 2016) Abstracts

Author

Jun Bao, Yi-Hui Wang, Quan-Hua Liu, Yi-Xiao Bao, Nurit Azouz, Julie Caldwell, Leanne Ray, Mark Rochman, Melissa Mingler, Matthew Eilerman, Ting Wen, Jocelyn Biagini Myers, Gurjit Khurana Hershey, Leah Kottyan, Lisa Martin, Rothenberg Marc, Victor Gonzalez-Uribe, Jaime Del Rio-Chivardi, Blanca Del Rio-Navarro, Hongfei Lou, Siyuan Ma, Yan Zhao, Feifei Cao, Fei He, Zhongyan Liu, Chengshuo Wang, Claus Bachert, Luo Zhang, Elissa Abrams, Allan Becker, Amit Kandhare, Subhash Bodhankar, Nicole Grossman, Gheorghe Doros, Francine Laden, Anne Fuhlbrigge, Michael Wechsler, Wilson Pace, Barbara Yawn, Elliot Israel, Junehyuk Lee, Frederick Adler, Peter Kim, Yung Feng Huang, Ying Yao Chen, Chiun Yen Pan, Herng Sheng Lee, Michael Khalemsky, David G. Schwartz, Pavel Kolkhir, Dmitry Pogorelov, Nikolay Kochergin, Hirsh Komarow, Michael Young, Robin Eisch, Linda Scott, Dean Metcalfe, Alexander Singer, Andrew Wakeman, Thomas Gerstner, Woo-Jung Song, Ji-Su Shim, Ha-Kyeong Won, Sung-Yoon Kang, Kyoung-Hee Sohn, Byung-Keun Kim, Eun-Jung Jo, Min-Hye Kim, Sang-Heon Kim, Heung-Woo Park, Sun-Sin Kim, Yoon-Seok Chang, Alyn H. Morice, Byung-Jae Lee, Sang-Heon Cho, Kyung-Up Min, Maria Assunta Boscolo, Giulio Brivio, Sergio Bosisio, Nicoletta Manzocchi, Edoardo Pulixi, Giulia Grignani, Eloisia D’Andrea, Massimo Ricci, Elena Passini, Maurizio Italia, Marilyn Urrutia-Pereira, Stefani Fagundes, Vinicius Jardim Oliano, Dirceu Solé, Sadia Benzaquen, Alejandro Aragaki, Ricardo Balestra, Dawn Harden, Danielle Caudell-Stamper, Gilbert Glady, Mark Holbreich, Nataliya Lyakhovska, Igor Kaidashev, Jaromir Bystron, Beata Hutyrova, Galina Balakirski, Luk Vanstreels, Gerda Wurpts, Hans F. Merk, Jens Malte Baron, Johanna Plange, Hans-Peter Rihs, Monika Raulf, Stefani Roeseler, Alberto Tolcachier, Armando Chamorro, Ruth Otero, Joel Brooks, Michael Hess, Jared Benz, Joseph MacDonald, Usma Chatha, Dale Lent, Şükran Köse, Bengü Gireniz Tatar, Gülgün Akkoçlu, İbrahim Çukurova, İlker Ödemiş, Ayşin Kılınç Toker, Abdullahi Hasssan, Abdulrazaq Abdullahi Gobir, Cheol-Woo Kim, Young Hwa Choi, Jeong Hye Lee, Rae Jeong Cho, Yu Ran Nam, Joo Hyun Nam, Woo Kyung Kim, Ivana Filipovic, Zorica Zivkovic, Djordje Filipovic, Dana Shik, Andrew Smith, Wang Yui Hsi, Stuart Friedman, Yonatan Gizaw, Rima Bakhda, Kumail Mohammed, Richard Wasserman, Angela Hague, Deanna Pence, Joanna Rolen, Robert Sugerman, Stacy Silvers, Qurat Kamili, Nadezhda Knauer, Alexandr Zazernyi, Elena Blinova, Daria Demina, Vladimir Kozlov, Komal Agrawal, Sagar Kale, Naveen Arora, Volha Vasilkova, Tatiana Mokhort, William Silvers, Rachel Eisenberg, Rushita Mehta, Arye Rubinstein, Antony Aston, Paul Turner, Monica Ruiz-Garcia, Robert Boyle, Simon Brown, Yael Dinur Schejter, Adi Ovadia, Vy Kim, Brenda Reid, Chaim Roifman, Lana Rosenfield, Ernie Avilla, Laurie Harada, Marilyn Allen, Susan Waserman, Ho Joo Yoon, Gun Woo Koo, Suk-Il Chang, Hye-Ran Yoon, Dong Won Park, Tai Sun Park, Ji-Yong Moon, Tae Hyung Kim, Jang Won Sohn, Dong Ho Shin, Tsici Jorjoliani, Lia Jorjoliani, Nino Adamia, Nona katamadze, Deepika Ramachandra, Liana Jorjoliani, Rusudan Karseladze, Lali Saginadze, Natalia Chkuaseli, Anna Dolgova, Olga Stukolova, Anna Sudina, Anna Cherkashina, German Shipulin, Richard Rosenthal, Harvey Howe, Paul Knause, Rony Greemberg, Jean Jacques De Bruycker, Isabel Fernandez, Françoise Le Deist, Elie Haddad, Yeong Ho Rha, Kyung Suk Lee, Sun Hee Choi, Herman Tam, Estelle Simons, Elinor Simons, Maria Golebiowska-Wawrzyniak, Katarzyna Markiewicz, Yoram Faitelson, Miguel Stein, Avigdor Mandelberg, Ilan Dalal, Michael Levin, Lelani Hobane, Wisdom Basera, Maresa Botha, Claudia Gray, Heather Zar, Biserka Jovkovska Kjaeva, Zoran Arsovski, Vesna Grivcheva-Panovska, Adeyinka Odebode, Adedotun Adekunle, Peter Adeonipekun, Ebenezer Farombi, Nadezhda Camacho-Ordoñez, Alejandrina Josefina Martinez-Vázquez, María de la Luz H. García-Cruz, Qi Tan, Rui Min, Guan-qun Dai, Wei-Ping Xie, Huang Mao, Hong Wang, Rakesh Yadav, Sneha Singh, Divya Yadav, Ekaterina Khaleva, Henry T. Bahnson, Amber Franz, Lene Heise Garvey, Nicola Jay, Rubaiyat Haque, Adam Fox, Gideon Lack, George du Toit, Snezana Radic, Branislava Milenkovic, Ana Neskovic, Ljiljana Danojevic, Liat Nachshon, Michael Goldberg, Michael Levy, Yitzhak Katz, Arnon Elizur, Cristine Rosario, Juliana Kasper, Herbeto Chong-Neto, Carlos Riedi, Nelson Rosario, Michael B. Levy, Ronly Har-Even, Mor Carmel, Michael R. Goldberg, Maia Kherkheulidze, Nani Kavlashvili, Eka Kandelaki, Nino Adamai, Irma Ubiria, Andrea Burke, Monika Kastner, Denica Zheleva, Razvigor Darlenski, Konstantinos Bozinakis, Anastasios Kriebardis, Sofia Styliara, Aikaterini Karastathi, Nikolaos Farmakas, Maria Luiza Kraft Kohler Ribeiro, Ana Carolina Barcellos, Hannah Gabriele Ferreira Silva, Luís Henrique Mattei Carletto, Marcela Carolina Bet, Nathalia Zorze Rossetto, Nelson Augusto Rosario, Herberto Jose Chong-Neto, Fernanda Valença, Marina Novaes, Mariana Gomes, Carla Seifert, Alfredo Neto, Flavia Loyola, José Rios, Tatiana Silva, Aline Neves, Oznur Abadoglu, Bilun Gemicioglu, Hasan Bayram, Arif Cimrin, Levent Akyildiz, Aykut Cilli, Hakan Gunen, Tevfik Ozlu, Mecit Suerdem, Esra Uzaslan, Zeynep Misirligil, Snezana Ristic-Stojanovic, A. Milicevic, A. Milenkovic, Jelena Cvejic, Jelena Jankovic, Sanja Dimic-Janjic, Natasa Djurdjevic, Vladyslava Barzylovych, Tetiana Umanets, Anastasia Barzylovych, Karyn Winkler, Jessica Margarinos, Dylan Martin, Maja Nowakowski, Rauno Joks, Tsili Zangen, Olga Bernadsky, Mona Boaz, Gratiana Hermann, Rachel Aviv, Olga Kuperboim, Larisa Ramichanov, Efrat Broide, Raanan Shamir, Noam Zevit, Ron Shaoul, Alex Fich, Arie Levine, Isaac Melamed, Roopesh Singh Gangwar, Yael Minai-Fleminger, Mansour Seaf, Amichai Gutgold, Aarti Shikotra, Anoop Chauhan, Stephen Holgate, Peter Bradding, Peter Howarth, Ron Eliashar, Neville Berkman, Francesca Levi-Schaffer, Sung-il Woo, Betul Celik, Tangul Bulut, Arzu Didem Yalcin, Luiz Querino Caldas, Ronit Confino-Cohen, Yossi Rosman, Arnon Goldberg, Oded Breuer, Roopesh Singh, Ahlam Barhoum, Eitan Kerem, Tatiana Slavyanskaya, Revaz Sepiashvili, Elena A. Blinova, Ekaterina A. Pashkina, Marina I. Leonova, Vera M. Nepomnyaschikh, Darya V. Demina, Vladimir A. Kozlov, Revital Shamri, Kristen M. Young, Peter F. Weller, Rodolfo de Paula Vieira, Manoel Carneiro Oliveira-Junior, Nilsa Regina Damasceno-Rodrigues, Fernanda Magalhães Arantes-Costa, Milton Arruda Martins, Ana Paula Ligeiro Oliveira, Alfred Bernard, Antonia Sardella, Catherine Voisin, Simon Royce, Hamish Philpott, Sanjay Nandurkar, Francis Thien, Peter Gibson, Rodolfo Bianchini, Franziska Roth-Walter, Anna Ohradanova-Repic, Gerlinde Hofstetter, Ina Herrmann, Maria Isabel Carvalho, Karin Hufnagl, Erika Bajna, Georg Roth, Hannes Stockinger, Erika Jensen-Jarolim, Meital Almog, Aharon Kessel, Larisa Apov, Carlos Sanchez Salguero, Alvaro Sanchez Chacon, Abbos Nazarov, Shaxbos Ergashev, Irina Nesterova, Svetlana Kovaleva, Galina Chudilova, Ludmila Lomtatidze, Sarah De Schryver, Alizee Dery, Ann Clarke, Kari Nadeau, Kimberly Weatherall, Celia Greenwood, Denise Daley, Yuka Asai, Moshe Ben-Shoshan, Irina Balmasova, Elena Malova, Stefanie Wagner, Luis F. Pacios, Michael Wallner, Markus Wiederstein, Anna E. Tevs, Nataly Tataurshchikova, Baigalmaa Sangidorj, Anna Ronzhina, Manana Chikhladze, Oliver F. Wirz, Willem van de Veen, David Mirer, Hideaki Morita, Can Altunbulakli, Sebastian L. Johnston, Nicholas Glanville, Nikolaos G. Papadopoulos, Cezmi A. Akdis, Mübeccel Akdis, Avner Reshef, Marc Riedl, Vesna Grivcheva Panovska, Dumitru Moldovan, James Baker, William H. Yang, Sladjana Andrejevic, Richard F. Lockey, Roman Hakl, Shmuel Kivity, Luca Bellizzi, Joseph R. Harper, Anurag Relan, and Marco Cicardi

Subjects
Immunologic diseases. Allergy, RC581-607
Published
2017
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