Gabriele Stocco

University of Trieste

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Giuliana Decorti

University of Trieste

129

Marianna Lucafò

University of Trieste

Alessandro Ventura

Universidade de Fortaleza

Stefano Martelossi

Ca' Foncello Hospital

Raffaella Franca

University of Trieste

Sara De Iudicibus

IRCCS Materno Infantile Burlo Garofolo

Diego Favretto

IRCCS Materno Infantile Burlo Garofolo

Matteo Bramuzzo

IRCCS Materno Infantile Burlo Garofolo

Debora Curci

IRCCS Materno Infantile Burlo Garofolo

Marco Pelin

University of Trieste

Cooperative Institutions

University of Trieste

170

Istituti di Ricovero e Cura a Carattere Scientifico

105

IRCCS Materno Infantile Burlo Garofolo

103

St. Jude Children's Research Hospital

Inserm

Université Paris Cité

University of Milan

Assistance Publique – Hôpitaux de Paris

Hôpital Necker-Enfants Malades

Centro di Riferimento Oncologico

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Genetic Polymorphism of Inosine Triphosphate Pyrophosphatase Is a Determinant of Mercaptopurine Metabolism and Toxicity During Treatment for Acute Lymphoblastic Leukemia

Clinical Pharmacology & Therapeutics (2008)

Gabriele Stocco Meyling Cheok Kristine R. Crews Thierry Dervieux Deborah French

The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which mercaptopurine doses are individualized on the basis of TPMT genotype. Clinical Pharmacology & Therapeutics (2009); 85, 2, 164–172 doi:10.1038/clpt.2008.154

ITPA

Thiopurine methyltransferase

Mercaptopurine

10.1038/clpt.2008.154

Cite

Citations (210)

Pharmacokinetics and pharmacodynamics of thiopurines in an in vitro model of human hepatocytes: Insights from an innovative mass spectrometry assay

Chemico-Biological Interactions (2017)

Marco Pelin Elena Genova Laura Fusco Monzer Marisat Ute Hofmann

Thiopurine methyltransferase

Mercaptopurine

10.1016/j.cbi.2017.08.009

Cite

Citations (4)

Causes of Treatment Failure in Children With Inflammatory Bowel Disease Treated With Infliximab

Journal of Pediatric Gastroenterology and Nutrition (2018)

Samuele Naviglio Doriana Lacorte Marianna Lucafò Adriana Cifù Diego Favretto

Anti-tumor necrosis factor antibodies have led to a revolution in the treatment of inflammatory bowel diseases (IBD); however, a sizable proportion of patients does not respond to therapy. There is increasing evidence suggesting that treatment failure may be classified as mechanistic (pharmacodynamic), pharmacokinetic, or immune-mediated. Data regarding the contribution of these factors in children with IBD treated with infliximab (IFX) are still incomplete. The aim was to assess the causes of treatment failure in a prospective cohort of pediatric patients treated with IFX.This observational study considered 49 pediatric (median age 14.4) IBD patients (34 Crohn disease, 15 ulcerative colitis) treated with IFX. Serum samples were collected at 6, 14, 22 and 54 weeks, before IFX infusions. IFX and anti-infliximab antibodies (AIA) were measured using enzyme linked immunosorbent assays. Disease activity was determined by Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index.Clinical remission, defined as a clinical score <10, was obtained by 76.3% of patients at week 14 and by 73.9% at week 54. Median trough IFX concentration was higher at all time points in patients achieving sustained clinical remission. IFX levels during maintenance correlated also with C-reactive protein, albumin, and fecal calprotectin. After multivariate analysis, IFX concentration at week 14 >3.11 μg/mL emerged as the strongest predictor of sustained clinical remission. AIA concentrations were correlated inversely with IFX concentrations and directly with adverse reactions.Most cases of therapeutic failure were associated with low serum drug levels. IFX trough levels at the end of induction are associated with sustained long-term response.

Trough level

Pharmacodynamics

Faecal calprotectin

10.1097/mpg.0000000000002112

Cite

Citations (43)

Pharmacogenomic Approaches for Tailored Anti-Leukemic Therapy in Children

Current Medicinal Chemistry (2013)

Gabriele Stocco Raffaella Franca Federico Verzegnassi Margherita Londero Marco Rabusin

Several lympholytic and cytotoxic agents are used in acute lymphoblastic leukemia (ALL) polychemotherapy. Genetic variants for cellular components involved in the pharmacokinetics and pharmacodynamics of these drugs can influence the pharmacological response, and molecular characterization of these genetic variants could be helpful for the comprehension of the mechanisms of resistance or increased sensitivity. The purpose of this review is to carry out an update of recent publications on genes that might influence ALL treatment in terms of outcome and/or toxicity and to underlie the role of genetic variants, particularly single nucleotide polymorphisms (SNP), in predicting clinical response, with particular reference to the current protocol for ALL therapy used in Italy, AIEOP-BFM ALL 2009. Keywords: Acute lymphoblastic leukemia, chemotherapy, pharmacogenetics.

Pharmacogenomics

SNP

Pharmacodynamics

10.2174/0929867311320170008

Cite

Citations (10)

A genome-wide approach identifies that the aspartate metabolism pathway contributes to asparaginase sensitivity

Leukemia (2010)

S-H Chen Wentao Yang Ying Fan Gabriele Stocco Kristine R. Crews

Asparaginase

10.1038/leu.2010.256

Cite

Citations (53)

P076 Role of gut microbiota in mediating the effects of thiopurines

Journal of Crohn s and Colitis (2020)

Martina Franzin Marianna Lucafò Cristina Lagatolla Gabriele Stocco Giuliana Decorti

Abstract Background A general consensus exists that patients with inflammatory bowel disease (IBD) present compositional changes in the gut microbiota (dysbiosis), including an increase in the abundance of Enterobacteriaceae. Thiopurine drugs are commonly used in the maintenance of remission in IBD. In this context, the purpose of the project is to explore the role of candidate bacterial strains in mediating the effects of thiopurines in vitro. Methods Azathioprine (AZA), mercaptopurine (MP) and thioguanine (TG) (400 µM) were incubated in minimal salts medium (M9) in presence or not of E. coli, S. enterica and K. pneumoniae and of their growth phase broths (GPB) for 4 h at 37°C. The viability of NALM6 (B cells) and JURKAT (T cells) exposed to serial dilution of drugs (ranging from 0.2 to 15 μM of AZA, from 0.3 to 20 μM of MP, from 0.08 to 5 μM of TG) previously incubated or not with bacteria and with their GPB was determined by the MTT assay. Absorbance peaks of thiopurines were analysed by UV spectrophotometry. Statistical significance was assessed by two-way ANOVA and Bonferroni’s post-test for MTT tests and by one-way ANOVA for UV spectra. Results In NALM6 cells, the cytotoxic effects of 15 μM of AZA, 2.5 μM of MP and 1.25 μM of TG decreased significantly (p < 0.001) after incubation with K. pneumoniae (respectively 45 ± 2.9%; 34 ± 2.5%% and 21 ± 0.6%) and its GPB (respectively 41 ± 7.7%; 41 ± 5.1% and 27 ± 3.5%) compared with the drugs not previously exposed (respectively 76 ± 2.3%; 69 ± 1.7% and 43 ± 3.8%). In JURKAT cells, the cytotoxic effects of 15 μM of AZA, 2.5 μM of MP and 1.25 μM of TG decreased significantly (p < 0.001) after incubation with K. pneumoniae (respectively 46 ± 2.8%; 38 ± 1.29% and 19 ± 3.3%) and its GPB (respectively 49 ± 9.4%; 38 ± 1.5% and 26 ± 1.5%) in comparison with the drugs not exposed (respectively 75 ± 4.0%; 50 ± 3.5% and 54 ± 4.0%). E. coli and S. enterica did not affect the cytotoxicity of the thiopurines. UV analysis evidenced a reduction of absorbance peaks of AZA (21 ± 0.05%), MP (32 ± 0.015%) and TG (30 ± 0.03%) after incubation with K. pneumoniae but not with its growth phase broth (GPB). Conclusion The activity of thiopurines decreased after incubation with both K. pneumoniae and its GPB. UV analysis suggested that the lower cytotoxicity of thiopurines exposed to the bacterial strain is due to the reduction of the concentration of the drugs exposed to K. pneumoniae. Moreover, the reduction of drug availability after the exposure to GPB could be explained with a possible interaction between thiopurines and capsular polysaccharides released by the bacteria.

Thiopurine methyltransferase

MTT assay

10.1093/ecco-jcc/jjz203.205

Cite

Citations (0)

Extracellular Vesicles as Innovative Tools for Assessing Adverse Effects of Immunosuppressant Drugs

Current Medicinal Chemistry (2021)

Marianna Lucafò Serena De Biasi Debora Curci Alessia Norbedo Gabriele Stocco

Extracellular vesicles (EVs) are a heterogeneous family of small vesicles released by donor cells and absorbed by recipient cells, which represent important mediators with fundamental roles in both physiological and pathological conditions. EVs are present in a large variety of biological fluids and have a great diagnostic and prognostic value. They have gained the interest of the scientific community due to their extreme versatility. In fact, they allow us to hypothesize new therapeutic strategies since, in addition to being cell signal mediators, they play an important role as biomarkers, drug vehicles, and potential new therapeutic agents. They are also involved in immunoregulation, have the ability to transmit resistance to a drug from one cell to a more sensitive one, and can act as drug delivery systems.The main reciprocal interactions between EVs and immunosuppressive drugs will be presented.The known interactions between EVs and immunosuppressive drugs, in particular cyclosporin, glucocorticoids, rapamycin, methotrexate, cyclophosphamide, eculizumab, infliximab, certolizumab, etanercept, glatiramer acetate, and fingolimod are presented.This review provides relevant information on the links between EVs and immunosuppressive drugs with a focus on EVs' role as tools to assess the effects of immunosuppressants, suggesting innovative properties and new possible therapeutic uses.

Extracellular Vesicles

10.2174/0929867328666211208114022

Cite

Citations (3)

Response to glucocorticoids and toxicity in childhood acute lymphoblastic leukemia: Role of polymorphisms of genes involved in glucocorticoid response

Pediatric Blood & Cancer (2009)

Sara Marino Federico Verzegnassi Paolo Tamaro Gabriele Stocco Fiora Bartoli

Abstract Background Glucocorticoids (GCs) play a fundamental role in the treatment of pediatric acute lymphoblastic leukemia (ALL), but therapy with these agents often results in a number of severe side effects. The aim of our study was to evaluate the association between polymorphisms of genes encoding for proteins involved in the pharmacokinetics/pharmacodynamics of these drugs and the occurrence of side effects, in particular infections, in a small population of ALL children. Procedure Common polymorphisms of NR3C1, ABCB1, glutathione‐ S ‐transferase (GST)‐M1, GST‐P1, GST‐T1, and IL‐10 genes were analyzed in 36 pediatric patients with ALL, treated according to the AIEOP‐BMF ALL 2000 study protocol. Toxicities occurring during the induction and reinduction periods were assessed and their association with genotypes was evaluated. Results In univariate analysis, the risk of severe infections was increased in subjects with the GST‐M1 null genotype, while patients with the GST‐M1 normal genotype had significantly more moderate degree infections. The results were confirmed by multivariate analysis. Selection from the reference models of independent variables based on Akaike Information Criteria (AIC) scores maintained the GST‐M1 genotype variable in the model to predict severe infections, and the ABCB1 C3435T and GST‐M1 genotype variables in the model for moderate infections. Conclusions GST‐M1 genotype may influence the severity of infections in ALL children during GC administration. Pediatr Blood Cancer 2009;53:984–991. © 2009 Wiley‐Liss, Inc.

Univariate analysis

Pharmacodynamics

10.1002/pbc.22163

Cite

Citations (41)

In Vivo Response to Methotrexate Forecasts Outcome of Acute Lymphoblastic Leukemia and Has a Distinct Gene Expression Profile

PLoS Medicine (2008)

Michael J. Sorich Nicolas Pottier Deqing Pei Wenjian Yang Leo Kager

Background Childhood acute lymphoblastic leukemia (ALL) is the most common cancer in children, and can now be cured in approximately 80% of patients. Nevertheless, drug resistance is the major cause of treatment failure in children with ALL. The drug methotrexate (MTX), which is widely used to treat many human cancers, is used in essentially all treatment protocols worldwide for newly diagnosed ALL. Although MTX has been extensively studied for many years, relatively little is known about mechanisms of de novo resistance in primary cancer cells, including leukemia cells. This lack of knowledge is due in part to the fact that existing in vitro methods are not sufficiently reliable to permit assessment of MTX resistance in primary ALL cells. Therefore, we measured the in vivo antileukemic effects of MTX and identified genes whose expression differed significantly in patients with a good versus poor response to MTX. Methods and Findings We utilized measures of decreased circulating leukemia cells of 293 newly diagnosed children after initial "up-front" in vivo MTX treatment (1 g/m2) to elucidate interpatient differences in the antileukemic effects of MTX. To identify genomic determinants of these effects, we performed a genome-wide assessment of gene expression in primary ALL cells from 161 of these newly diagnosed children (1–18 y). We identified 48 genes and two cDNA clones whose expression was significantly related to the reduction of circulating leukemia cells after initial in vivo treatment with MTX. This finding was validated in an independent cohort of children with ALL. Furthermore, this measure of initial MTX in vivo response and the associated gene expression pattern were predictive of long-term disease-free survival (p < 0.001, p = 0.02). Conclusions Together, these data provide new insights into the genomic basis of MTX resistance and interpatient differences in MTX response, pointing to new strategies to overcome MTX resistance in childhood ALL. Trial registrations: Total XV, Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia, http://www.ClinicalTrials.gov (NCT00137111); Total XIIIBH, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Intermediate or High Risk of Treatment Failure (NCI-T93-0101D); Total XIIIBL, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Lower Risk of Treatment Failure (NCI-T93-0103D).

Acute lymphocytic leukemia

Ex vivo

10.1371/journal.pmed.0050083

Cite

Citations (82)

Patient-derived organoids for therapy personalization in inflammatory bowel diseases

World Journal of Gastroenterology (2022)

Marianna Lucafò Antonella Muzzo Martina Marcuzzi L Giorio Giuliana Decorti

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the intestinal tract that have emerged as a growing problem in industrialized countries. Knowledge of IBD pathogenesis is still incomplete, and the most widely-accepted interpretation considers genetic factors, environmental stimuli, uncontrolled immune responses and altered intestinal microbiota composition as determinants of IBD, leading to dysfunction of the intestinal epithelial functions. In vitro models commonly used to study the intestinal barrier do not fully reflect the proper intestinal architecture. An important innovation is represented by organoids, 3D in vitro cell structures derived from stem cells that can self-organize into functional organ-specific structures. Organoids may be generated from induced pluripotent stem cells or adult intestinal stem cells of IBD patients and therefore retain their genetic and transcriptomic profile. These models are powerful pharmacological tools to better understand IBD pathogenesis, to study the mechanisms of action on the epithelial barrier of drugs already used in the treatment of IBD, and to evaluate novel target-directed molecules which could improve therapeutic strategies. The aim of this review is to illustrate the potential use of organoids for therapy personalization by focusing on the most significant advances in IBD research achieved through the use of adult stem cells-derived intestinal organoids.

Organoid

Inflammatory Bowel Diseases

Regenerative Medicine

Pathogenesis

10.3748/wjg.v28.i24.2636

Cite

Citations (14)