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Identifying pathogenic, prognostic and theragnostic factors in cancer-associated gastrointestinal inflammation
Full text linkIntroduzione ed obiettivi
Gli adenocarcinoma del piccolo intestino (SBA) sono frequentement associati ad una
severa prognosi e hanno limitate opzioni terapeutiche. Il blocco della via proteina di
morte cellulare programmata-1/ligando della proteina di morte cellulare programmata
1 (PD-L1) è un trattamento efficace in molti tumori solidi con alta instabilità
microsatellitare (MSI-H). In aggiunta, una minoranza di SBA associate a malattia di Crohn
(CrD-SBA) mostra un comportamento relativamente favorevole, pertanto evidenziando
la necessità di migliorare la previsione istopatologica della prognosi di CrD-SBA.
L’obiettivo di questo studio è stato investigare l’espressione di PD-L1 e PD-1 negli SBA
non ereditari non ampollari, associate a malattia celiaca (CoeD), malattia di Crohn (CrD)
o sporadici, arruolati attraverso il Consorzio Italiano del Cancro del Piccolo Intestino.
L’obiettivo secondario è stato valuatare i marcatori del fronte invasivo tumore in erba
(Tb) ed i cluster scarsamente differenziati (PDC) nei CrD-SBA investigate anche per
l’obiettivo primario.
Metodi
Abbiamo valutato PD-L1 e PD-1 mediante immunoistochimica in una coorte di 121 SBA
resecati chirurgicamente, 34 CoeD-SBAs, 49 CrD-SBAs, e 38 SBA sporadici. L’espressione
di PD-L1 e PD-1 era correlata con alcune caratteristiche clinic-patologiche, comprensive
di eziologia, status dell’instabilità microsatellitare e densità dei linfociti infiltranti il
tumore (TIL). Abbiamo poi analizzato sistematicamente Tb e PDC nel fronte invasivo di
47 CrD-SBA.
Risultati
La prevalenza della positività per PD-L1 secondo lo score positive combinato (CPS) era
25.6% nell’intera coorte di SBA, con una percentuale significativamente (p=0.001)
aumentata (35%) sia in CoeD-SBAs sia in CrD-SBAs rispetto ai SBA sporadici (5%). SBA
con CPS≥1 erano significativamente (p=0.013) più frequenti nei casi con MSI-H (41%)
che nei casi non-MSI-H (18%); comunque, 15 SBA CPS≥1 con stabilità microsatellitare
sono stati anche identificati. SBA con CPS≥1 mostravano una maggiore densità di TIL e
cellule immuni PD-1+, più frequentemente un istotipo midollare, così come una migliore
sopravvivenza rispetto ai casi con CPS<1. Le analisi sia di Tb sia di PDC erano altamente
efficaci nella valutazione prognostica di CrD-SBA. In aggiunta, Tb e PDC conservavano il
loro potere prognostico quando combinati con altri due parametri, istologia ghiandolare
e stadio I/II, entrambi noti nel predire un comportamento relativamente favorevole per
SBA. In particolare, l’associazione di Tb e PDC in uno score combinato del fronte invasivo
permetteva di trovare una minoranza di tumori (12/47, 25%), caratterizzati dal fronte
invasivo combinato di basso grado associato ad una istologia ghiandolare e ad un basso
stadio (I o II), e mostranti nessuna morte relativa al cancro in un follow-up mediano di
37,5 mesi.
Conclusioni
Questo studio dimostra una aumentata proporzione di casi PD-L1+ sia in CoeD-SBA sia in
CrD-SBA rispetto a SBA sporadici. In aggiunta, l’identificazione di una minoranza di SBA
PD-L1+ con stabilità microsatellitare supporta la necessità di accertare aggiuntivi
biomarcatori di risposta agli inibitori dei checkpoint immunitari insieme a MSI-H. La
migliore separazione di CrD-SBA di grado basso da quelli di grado alto fornita dall’analisi
del fronte invasive dovrebbe rappresentare un aiuto aggiuntivo nello scegliere
l’appropriate terapia per questi tumori rari e frequentemente infausti.Background and aims
Small bowel adenocarcinomas (SBAs) are frequently associated with severe prognosis
and have restricted therapeutic options. Programmed cell death protein-1 (PD
1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment
in many microsatellite instability-high (MSI-H) solid tumours. Additionally, a minority of
Crohn’s disease-associated SBAs (CrD-SBAs) show a relatively favourable behaviour, thus
highlighting the need to improve the histopathologic prediction of CrD-SBA prognosis.
We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary
SBAs, associated with coeliac disease (CoeD), Crohn’s disease (CrD) or sporadic, recruited
through the Small Bowel Cancer Italian Consortium. Secondary aim was to assess the
invasive front markers tumor budding (Tb) and poorly differentiated clusters (PDCs) on
CrD-SBAs investigated also for the primary aim.
Methods
We evaluated PD-L1 and PD-1 by immunohistochemistry in a cohort of 121 surgically
resected SBAs, i.e. 34 CoeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1
expression was correlated with several clinico-pathological features, including the
aetiology, microsatellite instability status and tumour-infiltrating lymphocyte (TIL)
density. We then systematically analysed the Tb and PDCs in the invasive front of 47 CrD
SBAs.
Results
The prevalence of PD-L1 positivity according to combined positive score (CPS) was
25.6% in the entire cohort of SBAs, with significantly (p=0.001) increased percentage
(35%) in both CoeD-SBAs and CrD-SBAs compared to sporadic SBAs (5%). CPS≥1 SBAs
were significantly (p=0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones
(18%); however, 15 CPS≥1 microsatellite stable SBAs were also found. CPS≥1 SBAs
displayed higher TIL and PD-1+ immune cell density, more often medullary histotype, as
well as a better outcome compared to CPS<1 cases. Both Tb and PDC analyses proved
highly effective in prognostic assessment of CrD-SBA. In addition, they retained
prognostic power when combined with two other parameters, i.e. glandular histology and
stage I/II, both known to predict a relatively favourable SBA behaviour. In particular,
association of Tb and PDCs in a combined invasive front score allowed to find a minor
subset of cancers (12/47, 25%), characterised by combined invasive front-low grade
associated with a glandular histology and a low stage (I or II) and displaying no cancer
related death over a median follow-up of 73.5 months.
Conclusions
This study demonstrates an increased proportion of PD-L1+ cases in both CoeD-SBAs and
CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of
PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers
of response to immune checkpoint inhibitors along with MSI-H. The improved separation
of lower from higher grade CrD-SBAs provided by invasive front analysis should
represent an additional help in choosing appropriate therapy for these rare and
frequently ominous cancers
The role of transforming growth factor (TGF)-β in modulating the immune response and fibrogenesis in the gut
Full text linkTransforming growth factor (TGF)-b, a pleiotropic cytokine released by both immune and non-immune cells in the gut, exerts an important tolerogenic action by promoting regulatory T cell differentiation. TGF-balso enhances enterocyte migration and regulates extracellular matrix turnover, thereby playing a crucial role in tissue remodeling in the gut. In this review we describe the mechanisms by which abnormal TGF-b signaling impairs intestinal immune tolerance and tissue repair, thus predisposing to the onset of immune-mediated bowel disorders, such as inflammatory bowel disease and celiac disease. Additionally, we will discuss potential therapeutic strategies aiming at restoring physiologic TGF-b signaling in chronic intestinal diseases.Fil: Biancheri, Paolo. University of Pavia; Italia. Barts and The London School of Medicine and Dentistry; Reino UnidoFil: Giuffrida, Paolo. University of Pavia; ItaliaFil: Docena, Guillermo H.. Universidad Nacional de La Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico la Plata. Centro de Investigaciones en Criotecnología de Alimentos (i); ArgentinaFil: Macdonald, Thomas T.. Barts and The London School of Medicine and Dentistry; Reino UnidoFil: Corazza, Gino Roberto. University of Pavia; ItaliaFil: Di Sabatino, Antonio. University of Pavia; Itali
Proteases and small intestinal barrier function in health and disease
No full textPURPOSE OF REVIEW: To summarize the recent knowledge regarding intestinal proteases and the gut barrier. RECENT FINDINGS: It is now well established that intestinal proteases, such as matrix metalloproteinase (MMP)-1, MMP-3, MMP-10 and MMP-12, are key players in the development of ulcers in inflammatory bowel disease, have direct effects on epithelial barrier function and are involved in epithelial restitution. However, more recent work has suggested that the membrane-anchored epithelial cell serine protease matriptase is critical in maintaining the gut barrier, and roles have also been described for elastase, MMP-13, gelatinases, mast cell proteases and proteases derived from parasites and gut bacteria. Interestingly, epithelial proteases often co-localize with epithelial adherens junctions, and nonepithelial-derived proteases have junctional proteins as targets. SUMMARY: The role of proteases in controlling normal barrier function in the gut is now becoming very clear, to go alongside their role in intestinal inflammation
Biomarkers of intestinal fibrosis - one step towards clinical trials for stricturing inflammatory bowel disease
No full textIntestinal fibrosis, caused by an excessive deposition of extracellular matrix components, and subsequent stricture development are a common complication of inflammatory bowel disease. However, currently there are no biomarkers which reliably predict the risk of developing intestinal strictures or identify early stages of fibrosis prior to clinical symptoms. Candidate biomarkers of intestinal fibrosis, including gene variants (i.e. nucleotide-binding oligomerization domain-2 gene), serum microRNAs (miR-19, miR-29), serum extracellular matrix proteins (i.e. collagen, fibronectin) or enzymes (i.e. tissue inhibitor of matrix metalloproteinase-1), serum growth factors (i.e. basic fibroblast growth factor, YKL-40), serum anti-microbial antibodies (i.e. anti-Saccharomyces cerevisiae) and circulating cells (i.e. fibrocytes) have shown conflicting results on relatively heterogeneous patients' cohorts, and none of them was proven to be strictly specific for fibrostenosis, but rather predictive of a disease disabling course. In this review we critically reassess the diagnostic and prognostic value of serum biomarkers of intestinal fibrosis in inflammatory bowel disease
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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