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Article ; Online: Erratum to 'Benchmarking weakly-supervised deep learning pipelines for whole slide classification in computational pathology' Medical Image Analysis, Volume 79, July 2022, 102474.

Ghaffari Laleh, Narmin / Muti, Hannah Sophie / Loeffler, Chiara Maria Lavinia / Echle, Amelie / Saldanha, Oliver Lester / Mahmood, Faisal / Lu, Ming Y / Trautwein, Christian / Langer, Rupert / Dislich, Bastian / Buelow, Roman D / Grabsch, Heike Irmgard / Brenner, Hermann / Chang-Claude, Jenny / Alwers, Elizabeth / Brinker, Titus J / Khader, Firas / Truhn, Daniel / Gaisa, Nadine T /

Boor, Peter / Hoffmeister, Michael / Schulz, Volkmar / Kather, Jakob Nikolas

Medical image analysis

2022 Volume 82, Page(s) 102622

Language	English
Publishing date	2022-09-18
Publishing country	Netherlands
Document type	Published Erratum
ZDB-ID	1356436-5
ISSN	1361-8423 ; 1361-8431 ; 1361-8415
ISSN (online)	1361-8423 ; 1361-8431
ISSN	1361-8415
DOI	10.1016/j.media.2022.102622
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Article ; Online: Current Advances in Developing Inhibitors of Bacterial Multidrug Efflux Pumps.

Mahmood, Hannah Y / Jamshidi, Shirin / Sutton, J Mark / Rahman, Khondaker M

Current medicinal chemistry

2016 Volume 23, Issue 10, Page(s) 1062–1081

Abstract: Antimicrobial resistance represents a significant challenge to future healthcare provision. An acronym ESKAPEE has been derived from the names of the organisms recognised as the major threats although there are a number of other organisms, notably ... ...

Abstract	Antimicrobial resistance represents a significant challenge to future healthcare provision. An acronym ESKAPEE has been derived from the names of the organisms recognised as the major threats although there are a number of other organisms, notably Neisseria gonorrhoeae, that have become equally challenging to treat in the clinic. These pathogens are characterised by the ability to rapidly develop and/or acquire resistance mechanisms in response to exposure to different antimicrobial agents. A key part of the armoury of these pathogens is a series of efflux pumps, which effectively exclude or reduce the intracellular concentration of a large number of antibiotics, making the pathogens significantly more resistant. These efflux pumps are the topic of considerable interest, both from the perspective of basic understanding of efflux pump function, and its role in drug resistance but also as targets for the development of novel adjunct therapies. The necessity to overcome antimicrobial resistance has encouraged investigations into the characterisation of resistance-modifying efflux pump inhibitors to block the mechanisms of drug extrusion, thereby restoring antibacterial susceptibility and returning existing antibiotics into the clinic. A greater understanding of drug recognition and transport by multidrug efflux pumps is needed to develop clinically useful inhibitors, given the breadth of molecules that can be effluxed by these systems. This review discusses different bacterial EPIs originating from both natural source and chemical synthesis and examines the challenges to designing successful EPIs that can be useful against multidrug resistant bacteria.
MeSH term(s)	Anti-Bacterial Agents/chemical synthesis ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Bacteria/drug effects ; Bacteria/metabolism ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/metabolism ; Drug Resistance, Multiple, Bacterial/drug effects ; Membrane Transport Proteins/metabolism ; Molecular Structure
Chemical Substances	Anti-Bacterial Agents ; Bacterial Proteins ; Membrane Transport Proteins
Language	English
Publishing date	2016-03-04
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	1319315-6
ISSN	1875-533X ; 0929-8673
ISSN (online)	1875-533X
ISSN	0929-8673
DOI	10.2174/0929867323666160304150522
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Article ; Online: Benchmarking weakly-supervised deep learning pipelines for whole slide classification in computational pathology.

Boor, Peter / Hoffmeister, Michael / Schulz, Volkmar / Kather, Jakob Nikolas

Medical image analysis

2022 Volume 79, Page(s) 102474

Abstract: Artificial intelligence (AI) can extract visual information from histopathological slides and yield biological insight and clinical biomarkers. Whole slide images are cut into thousands of tiles and classification problems are often weakly-supervised: ... ...

Abstract	Artificial intelligence (AI) can extract visual information from histopathological slides and yield biological insight and clinical biomarkers. Whole slide images are cut into thousands of tiles and classification problems are often weakly-supervised: the ground truth is only known for the slide, not for every single tile. In classical weakly-supervised analysis pipelines, all tiles inherit the slide label while in multiple-instance learning (MIL), only bags of tiles inherit the label. However, it is still unclear how these widely used but markedly different approaches perform relative to each other. We implemented and systematically compared six methods in six clinically relevant end-to-end prediction tasks using data from N=2980 patients for training with rigorous external validation. We tested three classical weakly-supervised approaches with convolutional neural networks and vision transformers (ViT) and three MIL-based approaches with and without an additional attention module. Our results empirically demonstrate that histological tumor subtyping of renal cell carcinoma is an easy task in which all approaches achieve an area under the receiver operating curve (AUROC) of above 0.9. In contrast, we report significant performance differences for clinically relevant tasks of mutation prediction in colorectal, gastric, and bladder cancer. In these mutation prediction tasks, classical weakly-supervised workflows outperformed MIL-based weakly-supervised methods for mutation prediction, which is surprising given their simplicity. This shows that new end-to-end image analysis pipelines in computational pathology should be compared to classical weakly-supervised methods. Also, these findings motivate the development of new methods which combine the elegant assumptions of MIL with the empirically observed higher performance of classical weakly-supervised approaches. We make all source codes publicly available at https://github.com/KatherLab/HIA, allowing easy application of all methods to any similar task.
MeSH term(s)	Artificial Intelligence ; Benchmarking ; Deep Learning ; Humans ; Neural Networks, Computer ; Supervised Machine Learning
Language	English
Publishing date	2022-05-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1356436-5
ISSN	1361-8423 ; 1361-8431 ; 1361-8415
ISSN (online)	1361-8423 ; 1361-8431
ISSN	1361-8415
DOI	10.1016/j.media.2022.102474
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Article ; Online: Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial.

Neilan, Tomas G / Quinaglia, Thiago / Onoue, Takeshi / Mahmood, Syed S / Drobni, Zsofia D / Gilman, Hannah K / Smith, Amanda / Heemelaar, Julius C / Brahmbhatt, Priya / Ho, Jor Sam / Sama, Supraja / Svoboda, Jakub / Neuberg, Donna S / Abramson, Jeremy S / Hochberg, Ephraim P / Barnes, Jefferey A / Armand, Philippe / Jacobsen, Eric D / Jacobson, Caron A /

Kim, Austin I / Soumerai, Jacob D / Han, Yuchi / Friedman, Robb S / Lacasce, Ann S / Ky, Bonnie / Landsburg, Dan / Nasta, Sunita / Kwong, Raymond Y / Jerosch-Herold, Michael / Redd, Robert A / Hua, Lanqi / Januzzi, James L / Asnani, Aarti / Mousavi, Negareh / Scherrer-Crosbie, Marielle

JAMA

2023 Volume 330, Issue 6, Page(s) 528–536

Abstract: Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use.: Objective: To test whether ... ...

Abstract	Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use. Objective: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. Design, setting, and participants: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. Interventions: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. Main outcomes and measures: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. Results: Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. Conclusions and relevance: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. Trial registration: ClinicalTrials.gov Identifier: NCT02943590.
MeSH term(s)	Female ; Humans ; Middle Aged ; Anthracyclines/adverse effects ; Anthracyclines/therapeutic use ; Antibiotics, Antineoplastic/adverse effects ; Antibiotics, Antineoplastic/therapeutic use ; Atorvastatin/therapeutic use ; Double-Blind Method ; Heart Failure/etiology ; Heart Failure/physiopathology ; Heart Failure/prevention & control ; Retrospective Studies ; Stroke Volume ; Ventricular Function, Left ; Cardiovascular Agents/therapeutic use ; Lymphoma/drug therapy ; Heart Diseases/chemically induced ; Heart Diseases/physiopathology ; Heart Diseases/prevention & control ; Follow-Up Studies ; Male ; Adult ; Aged
Chemical Substances	Anthracyclines ; Antibiotics, Antineoplastic ; Atorvastatin (A0JWA85V8F) ; Cardiovascular Agents
Language	English
Publishing date	2023-08-03
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural
ZDB-ID	2958-0
ISSN	1538-3598 ; 0254-9077 ; 0002-9955 ; 0098-7484
ISSN (online)	1538-3598
ISSN	0254-9077 ; 0002-9955 ; 0098-7484
DOI	10.1001/jama.2023.11887
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Article ; Online: The efficacy and safety of cardio-protective therapy in patients with 5-FU (Fluorouracil)-associated coronary vasospasm.

Zafar, Amna / Drobni, Zsofia D / Lei, Matthew / Gongora, Carlos A / Quinaglia, Thiago / Lou, Uvette Y / Mosarla, Ramya / Murphy, Sean P / Jones-O'Connor, Maeve / Mahmood, Ali / Hartmann, Sarah / Gilman, Hannah K / Weekes, Colin D / Nipp, Ryan / Clark, John R / Clark, Jeffrey W / Blaszkowsky, Lawrence S / Tavares, Erica / Neilan, Tomas G

PloS one

2022 Volume 17, Issue 4, Page(s) e0265767

Abstract: Background: Coronary vasospasm is a known side effect of 5-FU (fluorouracil) therapy. Beyond switching to non-5FU-based chemotherapy, there are no established treatments for 5-FU associated coronary vasospam. Our objective was to assess the safety and ... ...

Abstract	Background: Coronary vasospasm is a known side effect of 5-FU (fluorouracil) therapy. Beyond switching to non-5FU-based chemotherapy, there are no established treatments for 5-FU associated coronary vasospam. Our objective was to assess the safety and efficacy of re-challenge with 5-FU after pre-treatment with calcium channel blockers (CCBs) and long-acting nitrates among patients 5-FU associated coronary vasospasm. Methods: We conducted a retrospective study of patients with 5-FU coronary vasospasm at a single academic center. By protocol, those referred to cardio-oncology received pre-treatment with either combination [nitrates and CCBs] or single-agent therapy [nitrates or CCBs]) prior to re-challenge with 5-FU. Our primary outcome was overall survival. Other important outcomes included progression-free survival and safety. Results: Among 6,606 patients who received 5-FU from January 2001 to Dec 2020, 115 (1.74%) developed coronary vasospasm. Of these 115 patients, 81 patients continued 5-FU therapy, while 34 stopped. Of the 81 who continued, 78 were referred to cardio-oncology and prescribed CCBs and/or nitrates prior to subsequent 5-FU, while the remaining 3 continued 5-FU without cardiac pre-treatment. Of the 78, 56.4% (44/78) received both nitrates and CCBs, 19.2% (15/78) received CCBs alone, and 24.4% (19/78) received nitrates alone. When compared to patients who stopped 5-FU, those who continued 5-FU after pre-treatment (single or combination therapy) had a decreased risk of death (HR 0.42, P = 0.005 [95% CI 0.23-0.77]) and a trend towards decreased cancer progression (HR 0.60, P = 0.08 [95% CI 0.34-1.06]). No patient in the pre-treatment group had a myocardial infarct after re-challenge; however, chest pain (without myocardial infarction) recurred in 19.2% (15/78) among those who received cardiac pre-treatment vs. 66.7% (2/3) among those who did not (P = 0.048). There was no difference in efficacy or the recurrence of vasospasm among patients who received pre-treatment with a single agent (nitrates or CCBs) or combination therapy (14.7% (5/34) vs. 25.0% (11/44), P = 0.26). Conclusion: Re-challenge after pre-treatment with CCBs and nitrates guided by a cardio-oncology service was safe and allowed continued 5-FU therapy.
MeSH term(s)	Calcium Channel Blockers/therapeutic use ; Coronary Vasospasm/chemically induced ; Coronary Vasospasm/drug therapy ; Fluorouracil/adverse effects ; Humans ; Neoplasms/drug therapy ; Nitrates/therapeutic use ; Retrospective Studies
Chemical Substances	Calcium Channel Blockers ; Nitrates ; Fluorouracil (U3P01618RT)
Language	English
Publishing date	2022-04-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0265767
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The efficacy and safety of cardio-protective therapy in patients with 5-FU (Fluorouracil)-associated coronary vasospasm.

Amna Zafar / Zsofia D Drobni / Matthew Lei / Carlos A Gongora / Thiago Quinaglia / Uvette Y Lou / Ramya Mosarla / Sean P Murphy / Maeve Jones-O'Connor / Ali Mahmood / Sarah Hartmann / Hannah K Gilman / Colin D Weekes / Ryan Nipp / John R Clark / Jeffrey W Clark / Lawrence S Blaszkowsky / Erica Tavares / Tomas G Neilan

PLoS ONE, Vol 17, Iss 4, p e

2022 Volume 0265767

Abstract: Background Coronary vasospasm is a known side effect of 5-FU (fluorouracil) therapy. Beyond switching to non-5FU-based chemotherapy, there are no established treatments for 5-FU associated coronary vasospam. Our objective was to assess the safety and ... ...

Abstract	Background Coronary vasospasm is a known side effect of 5-FU (fluorouracil) therapy. Beyond switching to non-5FU-based chemotherapy, there are no established treatments for 5-FU associated coronary vasospam. Our objective was to assess the safety and efficacy of re-challenge with 5-FU after pre-treatment with calcium channel blockers (CCBs) and long-acting nitrates among patients 5-FU associated coronary vasospasm. Methods We conducted a retrospective study of patients with 5-FU coronary vasospasm at a single academic center. By protocol, those referred to cardio-oncology received pre-treatment with either combination [nitrates and CCBs] or single-agent therapy [nitrates or CCBs]) prior to re-challenge with 5-FU. Our primary outcome was overall survival. Other important outcomes included progression-free survival and safety. Results Among 6,606 patients who received 5-FU from January 2001 to Dec 2020, 115 (1.74%) developed coronary vasospasm. Of these 115 patients, 81 patients continued 5-FU therapy, while 34 stopped. Of the 81 who continued, 78 were referred to cardio-oncology and prescribed CCBs and/or nitrates prior to subsequent 5-FU, while the remaining 3 continued 5-FU without cardiac pre-treatment. Of the 78, 56.4% (44/78) received both nitrates and CCBs, 19.2% (15/78) received CCBs alone, and 24.4% (19/78) received nitrates alone. When compared to patients who stopped 5-FU, those who continued 5-FU after pre-treatment (single or combination therapy) had a decreased risk of death (HR 0.42, P = 0.005 [95% CI 0.23-0.77]) and a trend towards decreased cancer progression (HR 0.60, P = 0.08 [95% CI 0.34-1.06]). No patient in the pre-treatment group had a myocardial infarct after re-challenge; however, chest pain (without myocardial infarction) recurred in 19.2% (15/78) among those who received cardiac pre-treatment vs. 66.7% (2/3) among those who did not (P = 0.048). There was no difference in efficacy or the recurrence of vasospasm among patients who received pre-treatment with a single agent (nitrates or ...
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer.

Jahangir, Chowdhury Arif / Page, David B / Broeckx, Glenn / Gonzalez, Claudia A / Burke, Caoimbhe / Murphy, Clodagh / Reis-Filho, Jorge S / Ly, Amy / Harms, Paul W / Gupta, Rajarsi R / Vieth, Michael / Hida, Akira I / Kahila, Mohamed / Kos, Zuzana / van Diest, Paul J / Verbandt, Sara / Thagaard, Jeppe / Khiroya, Reena / Abduljabbar, Khalid /

Acosta Haab, Gabriela / Acs, Balazs / Adams, Sylvia / Almeida, Jonas S / Alvarado-Cabrero, Isabel / Azmoudeh-Ardalan, Farid / Badve, Sunil / Baharun, Nurkhairul Bariyah / Bellolio, Enrique R / Bheemaraju, Vydehi / Blenman, Kim Rm / Botinelly Mendonça Fujimoto, Luciana / Burgues, Octavio / Chardas, Alexandros / Cheang, Maggie Chon U / Ciompi, Francesco / Cooper, Lee Ad / Coosemans, An / Corredor, Germán / Dantas Portela, Flavio Luis / Deman, Frederik / Demaria, Sandra / Dudgeon, Sarah N / Elghazawy, Mahmoud / Fernandez-Martín, Claudio / Fineberg, Susan / Fox, Stephen B / Giltnane, Jennifer M / Gnjatic, Sacha / Gonzalez-Ericsson, Paula I / Grigoriadis, Anita / Halama, Niels / Hanna, Matthew G / Harbhajanka, Aparna / Hart, Steven N / Hartman, Johan / Hewitt, Stephen / Horlings, Hugo M / Husain, Zaheed / Irshad, Sheeba / Janssen, Emiel Am / Kataoka, Tatsuki R / Kawaguchi, Kosuke / Khramtsov, Andrey I / Kiraz, Umay / Kirtani, Pawan / Kodach, Liudmila L / Korski, Konstanty / Akturk, Guray / Scott, Ely / Kovács, Anikó / Laenkholm, Anne-Vibeke / Lang-Schwarz, Corinna / Larsimont, Denis / Lennerz, Jochen K / Lerousseau, Marvin / Li, Xiaoxian / Madabhushi, Anant / Maley, Sai K / Manur Narasimhamurthy, Vidya / Marks, Douglas K / McDonald, Elizabeth S / Mehrotra, Ravi / Michiels, Stefan / Kharidehal, Durga / Minhas, Fayyaz Ul Amir Afsar / Mittal, Shachi / Moore, David A / Mushtaq, Shamim / Nighat, Hussain / Papathomas, Thomas / Penault-Llorca, Frederique / Perera, Rashindrie D / Pinard, Christopher J / Pinto-Cardenas, Juan Carlos / Pruneri, Giancarlo / Pusztai, Lajos / Rajpoot, Nasir Mahmood / Rapoport, Bernardo Leon / Rau, Tilman T / Ribeiro, Joana M / Rimm, David / Vincent-Salomon, Anne / Saltz, Joel / Sayed, Shahin / Hytopoulos, Evangelos / Mahon, Sarah / Siziopikou, Kalliopi P / Sotiriou, Christos / Stenzinger, Albrecht / Sughayer, Maher A / Sur, Daniel / Symmans, Fraser / Tanaka, Sunao / Taxter, Timothy / Tejpar, Sabine / Teuwen, Jonas / Thompson, E Aubrey / Tramm, Trine / Tran, William T / van der Laak, Jeroen / Verghese, Gregory E / Viale, Giuseppe / Wahab, Noorul / Walter, Thomas / Waumans, Yannick / Wen, Hannah Y / Yang, Wentao / Yuan, Yinyin / Bartlett, John / Loibl, Sibylle / Denkert, Carsten / Savas, Peter / Loi, Sherene / Specht Stovgaard, Elisabeth / Salgado, Roberto / Gallagher, William M / Rahman, Arman

The Journal of pathology

2024 Volume 262, Issue 3, Page(s) 271–288

Abstract: Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various ... ...

Abstract	Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
MeSH term(s)	Humans ; Female ; Breast Neoplasms ; Biomarkers, Tumor/genetics ; Prognosis ; Phenotype ; United Kingdom ; Tumor Microenvironment
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2024-01-17
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.6238
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Article ; Online: Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor-Associated Myocarditis.

Thavendiranathan, Paaladinesh / Zhang, Lili / Zafar, Amna / Drobni, Zsofia D / Mahmood, Syed S / Cabral, Marcella / Awadalla, Magid / Nohria, Anju / Zlotoff, Daniel A / Thuny, Franck / Heinzerling, Lucie M / Barac, Ana / Sullivan, Ryan J / Chen, Carol L / Gupta, Dipti / Kirchberger, Michael C / Hartmann, Sarah E / Weinsaft, Jonathan W / Gilman, Hannah K /

Rizvi, Muhammad A / Kovacina, Bojan / Michel, Caroline / Sahni, Gagan / González-Mansilla, Ana / Calles, Antonio / Fernández-Avilés, Francisco / Mahmoudi, Michael / Reynolds, Kerry L / Ganatra, Sarju / Gavira, Juan José / González, Nahikari Salterain / García de Yébenes Castro, Manuel / Kwong, Raymond Y / Jerosch-Herold, Michael / Coelho-Filho, Otavio R / Afilalo, Jonathan / Zataraín-Nicolás, Eduardo / Baksi, A John / Wintersperger, Bernd J / Calvillo-Arguelles, Oscar / Ederhy, Stephane / Yang, Eric H / Lyon, Alexander R / Fradley, Michael G / Neilan, Tomas G

Journal of the American College of Cardiology

2021 Volume 77, Issue 12, Page(s) 1503–1516

Abstract: Background: Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited.: Objectives: This study sought ... ...

Abstract	Background: Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited. Objectives: This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis. Methods: In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. Results: Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across all patients, mean z-scores for T1 and T2 values were 2.9 ± 1.9 (p < 0.001) and 2.2 ± 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1 (1,079.0 ± 55.5 ms vs. 1,000.3 ± 22.1 ms; p < 0.001) and T2 (56.2 ± 4.9 ms vs. 49.8 ± 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91 (95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE. Conclusions: The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis.
MeSH term(s)	Aged ; Cardiac Imaging Techniques ; Female ; Humans ; Immune Checkpoint Inhibitors/adverse effects ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Myocarditis/chemically induced ; Myocarditis/diagnostic imaging ; Myocarditis/pathology ; Retrospective Studies
Chemical Substances	Immune Checkpoint Inhibitors
Language	English
Publishing date	2021-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605507-2
ISSN	1558-3597 ; 0735-1097
ISSN (online)	1558-3597
ISSN	0735-1097
DOI	10.1016/j.jacc.2021.01.050
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Article ; Online: Spatial analyses of immune cell infiltration in cancer: current methods and future directions: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer.

Page, David B / Broeckx, Glenn / Jahangir, Chowdhury Arif / Verbandt, Sara / Gupta, Rajarsi R / Thagaard, Jeppe / Khiroya, Reena / Kos, Zuzana / Abduljabbar, Khalid / Acosta Haab, Gabriela / Acs, Balazs / Akturk, Guray / Almeida, Jonas S / Alvarado-Cabrero, Isabel / Azmoudeh-Ardalan, Farid / Badve, Sunil / Baharun, Nurkhairul Bariyah / Bellolio, Enrique R / Bheemaraju, Vydehi /

Blenman, Kim Rm / Botinelly Mendonça Fujimoto, Luciana / Bouchmaa, Najat / Burgues, Octavio / Cheang, Maggie Chon U / Ciompi, Francesco / Cooper, Lee Ad / Coosemans, An / Corredor, Germán / Dantas Portela, Flavio Luis / Deman, Frederik / Demaria, Sandra / Dudgeon, Sarah N / Elghazawy, Mahmoud / Ely, Scott / Fernandez-Martín, Claudio / Fineberg, Susan / Fox, Stephen B / Gallagher, William M / Giltnane, Jennifer M / Gnjatic, Sacha / Gonzalez-Ericsson, Paula I / Grigoriadis, Anita / Halama, Niels / Hanna, Matthew G / Harbhajanka, Aparna / Hardas, Alexandros / Hart, Steven N / Hartman, Johan / Hewitt, Stephen / Hida, Akira I / Horlings, Hugo M / Husain, Zaheed / Hytopoulos, Evangelos / Irshad, Sheeba / Janssen, Emiel Am / Kahila, Mohamed / Kataoka, Tatsuki R / Kawaguchi, Kosuke / Kharidehal, Durga / Khramtsov, Andrey I / Kiraz, Umay / Kirtani, Pawan / Kodach, Liudmila L / Korski, Konstanty / Kovács, Anikó / Laenkholm, Anne-Vibeke / Lang-Schwarz, Corinna / Larsimont, Denis / Lennerz, Jochen K / Lerousseau, Marvin / Li, Xiaoxian / Ly, Amy / Madabhushi, Anant / Maley, Sai K / Manur Narasimhamurthy, Vidya / Marks, Douglas K / McDonald, Elizabeth S / Mehrotra, Ravi / Michiels, Stefan / Minhas, Fayyaz Ul Amir Afsar / Mittal, Shachi / Moore, David A / Mushtaq, Shamim / Nighat, Hussain / Papathomas, Thomas / Penault-Llorca, Frederique / Perera, Rashindrie D / Pinard, Christopher J / Pinto-Cardenas, Juan Carlos / Pruneri, Giancarlo / Pusztai, Lajos / Rahman, Arman / Rajpoot, Nasir Mahmood / Rapoport, Bernardo Leon / Rau, Tilman T / Reis-Filho, Jorge S / Ribeiro, Joana M / Rimm, David / Vincent-Salomon, Anne / Salto-Tellez, Manuel / Saltz, Joel / Sayed, Shahin / Siziopikou, Kalliopi P / Sotiriou, Christos / Stenzinger, Albrecht / Sughayer, Maher A / Sur, Daniel / Symmans, Fraser / Tanaka, Sunao / Taxter, Timothy / Tejpar, Sabine / Teuwen, Jonas / Thompson, E Aubrey / Tramm, Trine / Tran, William T / van der Laak, Jeroen / van Diest, Paul J / Verghese, Gregory E / Viale, Giuseppe / Vieth, Michael / Wahab, Noorul / Walter, Thomas / Waumans, Yannick / Wen, Hannah Y / Yang, Wentao / Yuan, Yinyin / Adams, Sylvia / Bartlett, John Mark Seaverns / Loibl, Sibylle / Denkert, Carsten / Savas, Peter / Loi, Sherene / Salgado, Roberto / Specht Stovgaard, Elisabeth

The Journal of pathology

2023 Volume 260, Issue 5, Page(s) 514–532

Abstract: Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or ... ...

Abstract	Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.
MeSH term(s)	Humans ; Colonic Neoplasms ; Biomarkers ; Benchmarking ; Lymphocytes, Tumor-Infiltrating ; Spatial Analysis ; Tumor Microenvironment
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-08-23
Publishing country	England
Document type	Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.6165
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Article ; Online: Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

Thagaard, Jeppe / Broeckx, Glenn / Page, David B / Jahangir, Chowdhury Arif / Verbandt, Sara / Kos, Zuzana / Gupta, Rajarsi / Khiroya, Reena / Abduljabbar, Khalid / Acosta Haab, Gabriela / Acs, Balazs / Akturk, Guray / Almeida, Jonas S / Alvarado-Cabrero, Isabel / Amgad, Mohamed / Azmoudeh-Ardalan, Farid / Badve, Sunil / Baharun, Nurkhairul Bariyah / Balslev, Eva /

Bellolio, Enrique R / Bheemaraju, Vydehi / Blenman, Kim Rm / Botinelly Mendonça Fujimoto, Luciana / Bouchmaa, Najat / Burgues, Octavio / Chardas, Alexandros / Chon U Cheang, Maggie / Ciompi, Francesco / Cooper, Lee Ad / Coosemans, An / Corredor, Germán / Dahl, Anders B / Dantas Portela, Flavio Luis / Deman, Frederik / Demaria, Sandra / Doré Hansen, Johan / Dudgeon, Sarah N / Ebstrup, Thomas / Elghazawy, Mahmoud / Fernandez-Martín, Claudio / Fox, Stephen B / Gallagher, William M / Giltnane, Jennifer M / Gnjatic, Sacha / Gonzalez-Ericsson, Paula I / Grigoriadis, Anita / Halama, Niels / Hanna, Matthew G / Harbhajanka, Aparna / Hart, Steven N / Hartman, Johan / Hauberg, Søren / Hewitt, Stephen / Hida, Akira I / Horlings, Hugo M / Husain, Zaheed / Hytopoulos, Evangelos / Irshad, Sheeba / Janssen, Emiel Am / Kahila, Mohamed / Kataoka, Tatsuki R / Kawaguchi, Kosuke / Kharidehal, Durga / Khramtsov, Andrey I / Kiraz, Umay / Kirtani, Pawan / Kodach, Liudmila L / Korski, Konstanty / Kovács, Anikó / Laenkholm, Anne-Vibeke / Lang-Schwarz, Corinna / Larsimont, Denis / Lennerz, Jochen K / Lerousseau, Marvin / Li, Xiaoxian / Ly, Amy / Madabhushi, Anant / Maley, Sai K / Manur Narasimhamurthy, Vidya / Marks, Douglas K / McDonald, Elizabeth S / Mehrotra, Ravi / Michiels, Stefan / Minhas, Fayyaz Ul Amir Afsar / Mittal, Shachi / Moore, David A / Mushtaq, Shamim / Nighat, Hussain / Papathomas, Thomas / Penault-Llorca, Frederique / Perera, Rashindrie D / Pinard, Christopher J / Pinto-Cardenas, Juan Carlos / Pruneri, Giancarlo / Pusztai, Lajos / Rahman, Arman / Rajpoot, Nasir Mahmood / Rapoport, Bernardo Leon / Rau, Tilman T / Reis-Filho, Jorge S / Ribeiro, Joana M / Rimm, David / Roslind, Anne / Vincent-Salomon, Anne / Salto-Tellez, Manuel / Saltz, Joel / Sayed, Shahin / Scott, Ely / Siziopikou, Kalliopi P / Sotiriou, Christos / Stenzinger, Albrecht / Sughayer, Maher A / Sur, Daniel / Fineberg, Susan / Symmans, Fraser / Tanaka, Sunao / Taxter, Timothy / Tejpar, Sabine / Teuwen, Jonas / Thompson, E Aubrey / Tramm, Trine / Tran, William T / van der Laak, Jeroen / van Diest, Paul J / Verghese, Gregory E / Viale, Giuseppe / Vieth, Michael / Wahab, Noorul / Walter, Thomas / Waumans, Yannick / Wen, Hannah Y / Yang, Wentao / Yuan, Yinyin / Zin, Reena Md / Adams, Sylvia / Bartlett, John / Loibl, Sibylle / Denkert, Carsten / Savas, Peter / Loi, Sherene / Salgado, Roberto / Specht Stovgaard, Elisabeth

The Journal of pathology

2023 Volume 260, Issue 5, Page(s) 498–513

Abstract: The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, ... ...

Abstract	The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
MeSH term(s)	Humans ; Animals ; Lymphocytes, Tumor-Infiltrating ; Triple Negative Breast Neoplasms ; Mammary Neoplasms, Animal ; Biomarkers ; Machine Learning
Chemical Substances	Biomarkers
Language	English
Publishing date	2023-08-23
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.6155
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