Publications by authors named "M Repetto"

210 Publications

Thymic carcinoma with Lynch syndrome or microsatellite instability, a rare entity responsive to immunotherapy.

Eur J Cancer 2021 Aug 20;153:162-167. Epub 2021 Jun 20.

Division of Medical Oncology for Melanoma & Sarcoma, IEO, European Institute of Oncology IRCCS, Milan, Italy.

Importance: Thymic carcinoma (TC) is a rare aggressive tumour occurring in adults characterised by one of the lowest tumor mutational burdens (TMB). Microsatellite instability (MSI) is a mutational signature, caused by defects in the DNA MisMatch Repair (MMR) system, that predicts benefit from immunotherapy and causes high TMB. Fragmentary and unstructured evidence of these conditions co-occurring are reported in literature.

Objective: Review available data on the co-occurrence of these two conditions and determine its frequency in our institute case series.

Design: We performed a systematic analysis of literature and a retrospective evaluation of all the cases of TET treated at our institution from 2000 to 2020, selecting patients with a medical history of multiple tumours to enhance a priori probability of identifying cases with underlying predisposition.

Results: Literature yielded 3 cases of patients with MSI TC, for which MMR gene alteration was reported. None of them received immunotherapy. Of 366 patients with TETs treated in our institute, 32 had a medical history of multiple tumours and 25 of 32 (19 thymomas and 6 TCs) had available tissue for MMR analysis. One patient with TC showed a high TMB, and MSI due to MLH1 mutation and was treated in a phase II study with avelumab and axitinib combination obtaining a long-lasting partial response. MLH1 alterations are shared across MSI TC cases.

Conclusions And Relevance: This analysis highlights the usefulness of MSI testing in patients with TC. The observation of cases of TC occurring in patients with Lynch syndrome and the unexpected homogeneity of gene alterations support further investigation.
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http://dx.doi.org/10.1016/j.ejca.2021.05.029DOI Listing
August 2021

Asymmetry of marine invasions across tropical oceans.

Ecology 2021 Jun 11:e03434. Epub 2021 Jun 11.

Smithsonian Environmental Research Center, 647 Contees Wharf Road, Edgewater, Maryland, 21037, USA.

Understanding the mechanisms of spatial variation of biological invasions, across local-to-global scales, has been a major challenge. The importance of evolutionary history for invasion dynamics was noted by Darwin, and several studies have since considered how biodiversity of source and recipient regions can influence the probability of invasions. For over a century, the Panama Canal has connected water bodies and biotas with different evolutionary histories, and created a global shipping hot spot, providing unique opportunities to test mechanisms that affect invasion patterns. Here, we test for asymmetry in both the extent of invasions and predation effects, a possible mechanism of biotic resistance, between two tropical oceans at similar latitudes. We estimated nonnative species (NNS) richness for sessile marine invertebrates, using standardized field surveys and literature synthesis, to examine whether invasions are asymmetrical, with more NNS present in the less diverse Pacific compared to the Atlantic. We also experimentally tested whether predation differentially limits the abundance and distribution of these invertebrates between oceans. In standardized surveys, observed total NNS richness was higher in the Pacific (18 NNS, 30% of all Pacific species) than the Atlantic (11 NNS, 13% of all Atlantic species). Similarly, literature-based records also display this asymmetry between coasts. When considering only the reciprocal exchange of NNS between Atlantic and Pacific biotas, NNS exchange from Atlantic to Pacific was eightfold higher than the opposite direction, exceeding the asymmetry predicted by random exchange based simply on differences of overall diversity per region. Predation substantially reduced biomass and changed NNS composition in the Pacific, but no such effects were detected on the Atlantic coast. Specifically, some dominant NNS were particularly susceptible to predation in the Pacific, supporting the hypothesis that predation may reduce the abundance of certain NNS here. These results are consistent with predictions that high diversity in source regions, and species interactions in recipient regions, shape marine invasion patterns. Our comparisons and experiments across two tropical ocean basins, suggest that global invasion dynamics are likely driven by both ecological and evolutionary factors that shape susceptibility to and directionality of invasions across biogeographic scales.
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http://dx.doi.org/10.1002/ecy.3434DOI Listing
June 2021

Stronger predation intensity and impact on prey communities in the tropics.

Ecology 2021 Jun 9:e03428. Epub 2021 Jun 9.

Smithsonian Environmental Research Center, Edgewater, Maryland, 21037-0028, USA.

The hypothesis that biotic interactions strengthen toward lower latitudes provides a framework for linking community-scale processes with the macroecological scales that define our biosphere. Despite the importance of this hypothesis for understanding community assembly and ecosystem functioning, the extent to which interaction strength varies across latitude and the effects of this variation on natural communities remain unresolved. Predation in particular is central to ecological and evolutionary dynamics across the globe, yet very few studies explore both community-scale causes and outcomes of predation across latitude. Here we expand beyond prior studies to examine two important components of predation strength: intensity of predation (including multiple dimensions of the predator guild) and impact on prey community biomass and structure, providing one of the most comprehensive examinations of predator-prey interactions across latitude. Using standardized experiments, we tested the hypothesis that predation intensity and impact on prey communities were stronger at lower latitudes. We further assessed prey recruitment to evaluate the potential for this process to mediate predation effects. We used sessile marine invertebrate communities and their fish predators in nearshore environments as a model system, with experiments conducted at 12 sites in four regions spanning the tropics to the subarctic. Our results show clear support for an increase in both predation intensity and impact at lower relative to higher latitudes. The predator guild was more diverse at low latitudes, with higher predation rates, longer interaction durations, and larger predator body sizes, suggesting stronger predation intensity in the tropics. Predation also reduced prey biomass and altered prey composition at low latitudes, with no effects at high latitudes. Although recruitment rates were up to three orders of magnitude higher in the tropics than the subarctic, prey replacement through this process was insufficient to dampen completely the strong impacts of predators in the tropics. Our study provides a novel perspective on the biotic interaction hypothesis, suggesting that multiple components of the predator community likely contribute to predation intensity at low latitudes, with important consequences for the structure of prey communities.
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http://dx.doi.org/10.1002/ecy.3428DOI Listing
June 2021

Precision medicine in breast cancer: From clinical trials to clinical practice.

Cancer Treat Rev 2021 Jul 12;98:102223. Epub 2021 May 12.

European Institute of Oncology, IRCCS, 20141 Milan, Italy; Department of Oncology and Hematology (DIPO), University of Milan, 20122 Milan, Italy. Electronic address:

Introduction: Breast cancer (BC) is the most common cancer in women and, despite the undeniable improvements in the outcome of these patients obtained in the last decade, the discovery and the validation of new actionable molecular targets represent a priority. ESCAT permits to rank molecular alterations in different classes according to their evidence of actionability in a specific cancer type, assisting clinicians in their therapeutical decisions. MAIN: ERBB2, PIK3CA and germline BRCA1/2 alterations are biomarkers prospectively validated in BC, driving the selection of targeted therapies, and are therefore classified in the highest level of evidence (Ia). Agnostic biomarkers, namely microsatellite instability, NTRK fusions and high tumor mutational burden, demonstrated similar activity across different tumor types and are consequently ranked in tier Ic. In tier II are classified alterations that still need confirmatory prospective studies but for which evidence of efficacy is available. Somatic BRCA1/2 mutations, germline PALB2 mutations, HER2-low expression, ERBB2 mutations, PTEN deletions, AKT1 mutations, ESR1 resistance mutations satisfy the requirements to be classified in this tier. In tier III are ranked various molecular alterations for which there is evidence of actionability in other tumors (IIIa) or that have similar functional impact in the same gene or pathway of a tier I alteration, without clinical data (IIIb). In tier IV are listed the molecular alterations for which only preclinical studies are available.

Conclusion: In this review we report the most relevant molecular targets in BC, ordered pursuant to their pathway and classified in concordance with ESCAT.
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http://dx.doi.org/10.1016/j.ctrv.2021.102223DOI Listing
July 2021

Cannabidiol (CBD) Alters the Functionality of Neutrophils (PMN). Implications in the Refractory Epilepsy Treatment.

Pharmaceuticals (Basel) 2021 Mar 5;14(3). Epub 2021 Mar 5.

Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Instituto de Fisiopatología y Bioquímica Clínica (INFIBIOC), Universidad de Buenos Aires, Buenos Aires C1120AAF, Argentina.

Cannabidiol (CBD), a lipophilic cannabinoid compound without psychoactive effects, has emerged as adjuvant of anti-epileptic drugs (AEDs) in the treatment of refractory epilepsy (RE), decreasing the severity and/or frequency of seizures. CBD is considered a multitarget drug that could act throughout the canonical endocannabinoid receptors (CB1-CB2) or multiple non-canonical pathways. Despite the fact that the CBD mechanism in RE is still unknown, experiments carried out in our laboratory showed that CBD has an inhibitory role on P-glycoprotein excretory function, highly related to RE. Since CB2 is expressed mainly in the immune cells, we hypothesized that CBD treatment could alter the activity of polymorphonuclear neutrophils (PMNs) in a similar way that it does with microglia/macrophages and others circulating leukocytes. In vitro, CBD induced PMN cytoplasmatic vacuolization and proapoptotic nuclear condensation, associated with a significantly decreased viability in a concentration-dependent manner, while low CBD concentration decreased PMN viability in a time-dependent manner. At a functional level, CBD reduced the chemotaxis and oxygen consumption of PMNs related with superoxide anion production, while the singlet oxygen level was increased suggesting oxidative stress damage. These results are in line with the well-known CBD anti-inflammatory effect and support a potential immunosuppressor role on PMNs that could promote an eventual defenseless state during chronic treatment with CBD in RE.
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http://dx.doi.org/10.3390/ph14030220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001508PMC
March 2021
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