Evolutionary crossroads: morphological heterogeneity reflects divergent intra-clonal evolution in a case of high-grade B-cell lymphoma

Tabanelli, Valentina; Melle, Federica; Motta, Giovanna; Mazzara, Saveria; Fabbri, Marco; Corsini, Chiara; Gerbino, Elvira; Calleri, Angelica; Sapienza, Maria Rosaria; Abbene, Ignazio; Stufano, Viviana; Barberis, Massimo; Pileri, Stefano

doi:10.3324/haematol.2020.249664

Cited by 8 publications

(5 citation statements)

References 14 publications

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“…Some studies on solid cancers have previously described how both proximal and distant lesions deriving from the same primary tumors exhibit divergent patterns of both morphological and genetic heterogeneity 10 . Similarly, Tabanelli et al 11 reported the same evolutionary crossroad between morphological heterogeneity and intra-clonal evolution in a case of high-grade B-cell lymphoma. Thus, morphological heterogeneity behaves as a surrogate of genetic heterogeneity, responsible for treatment inefficacies.…”

Section: Introductionmentioning

confidence: 70%

Dual adversarial deconfounding autoencoder for joint batch-effects removal from multi-center and multi-scanner radiomics data

Cavinato,

Massi,

Sollini

et al. 2023

Sci Rep

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Medical imaging represents the primary tool for investigating and monitoring several diseases, including cancer. The advances in quantitative image analysis have developed towards the extraction of biomarkers able to support clinical decisions. To produce robust results, multi-center studies are often set up. However, the imaging information must be denoised from confounding factors—known as batch-effect—like scanner-specific and center-specific influences. Moreover, in non-solid cancers, like lymphomas, effective biomarkers require an imaging-based representation of the disease that accounts for its multi-site spreading over the patient’s body. In this work, we address the dual-factor deconfusion problem and we propose a deconfusion algorithm to harmonize the imaging information of patients affected by Hodgkin Lymphoma in a multi-center setting. We show that the proposed model successfully denoises data from domain-specific variability (p-value < 0.001) while it coherently preserves the spatial relationship between imaging descriptions of peer lesions (p-value = 0), which is a strong prognostic biomarker for tumor heterogeneity assessment. This harmonization step allows to significantly improve the performance in prognostic models with respect to state-of-the-art methods, enabling building exhaustive patient representations and delivering more accurate analyses (p-values < 0.001 in training, p-values < 0.05 in testing). This work lays the groundwork for performing large-scale and reproducible analyses on multi-center data that are urgently needed to convey the translation of imaging-based biomarkers into the clinical practice as effective prognostic tools. The code is available on GitHub at this https://github.com/LaraCavinato/Dual-ADAE.

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Section: Introductionmentioning

confidence: 70%

Dual adversarial deconfounding autoencoder for joint batch-effects removal from multi-center and multi-scanner radiomics data

Cavinato,

Massi,

Sollini

et al. 2023

Sci Rep

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“…The BCL2 , MYC , and TP53 status of the cells was defined as previously described ( 38 ). The ATM / CDKN2A / ARID1A mutational status of the cells was determined using a targeted gene panel (39) and analyzed as previously described (40), considering, only those single-nucleotide variants (mutations) that are predicted to produce deleterious amino acid substitutions, inducing loss of functional protein, as defined using the human genomic variant search engine VarSome (varsome.com) and literature search.…”

Section: Methodsmentioning

confidence: 99%

The ATR inhibitor elimusertib exhibits anti-lymphoma activity and synergizes with the PI3K inhibitor copanlisib

Sartori

Tarantelli

Spriano

et al. 2023

Preprint

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Purpose: The DNA damage response (DDR) is the cellular process devoted to the preservation of an intact genome. The DDR is often deregulated in lymphoma cells due to high levels of DNA damage, tumor suppressor inactivation, increased replication stress observed after oncogene activation, or high amounts of reactive oxygen species. The ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial factor of DDR in the response to DNA single strand breaks. ATR inhibitors are a class of agents that have shown considerable clinical potential in this context. Experimental Design: We characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a panel of lymphoma cell lines. Furthermore, we evaluated the activity of elimusertib in combination with the clinically approved PI3K inhibitor copanlisib in in vitro and in vivo lymphoma models. Results: Elimusertib exhibited in vitro activity across a variety of lymphoma subtypes which was associated with expression of genes related to replication stress. Elimusertib also demonstrated wide-spread anti-tumor activity that was stronger compared to ceralasertib, another ATR inhibitor, in several tumor models. This activity was present in both DDR-proficient and DDR-deficient lymphoma models. Furthermore, elimusertib had synergistic antitumor activity in combination with copanlisib. Conclusions: Potent antitumor activity of elimusertib was demonstrated in several lymphoma models which is associated with high expression of gene transcripts coding for proteins that are involved in DDR and cell cycle regulation. Combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib had synergistic efficacy providing a potential new treatment option for lymphoma patients.

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“…The status of BCL2, MYC and TP53 cells was defined as previously described 35 . The ATM / CDKN2A / ARID1A mutational status of the cells was determined using a targeted gene panel 36 and analysed as previously described, 37 considering only those single‐nucleotide variants (mutations) that are predicted to produce deleterious amino acid substitutions, inducing loss of functional protein, as defined using the human genomic variant search engine VarSome (http://varsome.com) and literature search.…”

Section: Methodsmentioning

confidence: 99%

The ATR inhibitor elimusertib exhibits anti‐lymphoma activity and synergizes with the PI3K inhibitor copanlisib

Sartori,

Tarantelli,

Spriano

et al. 2023

Br J Haematol

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SummaryThe DNA damage response (DDR) is the cellular process of preserving an intact genome and is often deregulated in lymphoma cells. The ataxia telangiectasia and Rad3‐related (ATR) kinase is a crucial factor of DDR in the response to DNA single‐strand breaks. ATR inhibitors are agents that have shown considerable clinical potential in this context. We characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a large panel of lymphoma cell lines. Furthermore, we evaluated its activity combined with the clinically approved PI3K inhibitor copanlisib in vitro and in vivo. Elimusertib exhibits potent anti‐tumour activity across various lymphoma subtypes, which is associated with the expression of genes related to replication stress, cell cycle regulation and, as also sustained by CRISPR Cas9 experiments, CDKN2A loss. In several tumour models, elimusertib demonstrated widespread anti‐tumour activity stronger than ceralasertib, another ATR inhibitor. This activity is present in both DDR‐proficient and DDR‐deficient lymphoma models. Furthermore, a combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib has in vitro and in vivo anti‐tumour activity, providing a potential new treatment option for lymphoma patients.

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Evolutionary crossroads: morphological heterogeneity reflects divergent intra-clonal evolution in a case of high-grade B-cell lymphoma

Cited by 8 publications

References 14 publications

Dual adversarial deconfounding autoencoder for joint batch-effects removal from multi-center and multi-scanner radiomics data

Dual adversarial deconfounding autoencoder for joint batch-effects removal from multi-center and multi-scanner radiomics data

The ATR inhibitor elimusertib exhibits anti-lymphoma activity and synergizes with the PI3K inhibitor copanlisib

The ATR inhibitor elimusertib exhibits anti‐lymphoma activity and synergizes with the PI3K inhibitor copanlisib

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