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  1. Article ; Online: Detection of (pre)cancerous colorectal lesions in Lynch syndrome patients by microsatellite instability liquid biopsy.

    Boeri, Mattia / Signoroni, Stefano / Ciniselli, Chiara Maura / Gariboldi, Manuela / Zanutto, Susanna / Rausa, Emanuele / Segale, Miriam / Zanghì, Anna / Ricci, Maria Teresa / Verderio, Paolo / Sozzi, Gabriella / Vitellaro, Marco

    Cancer gene therapy

    2024  

    Abstract: Lynch syndrome (LS) is an inherited condition characterized by an increased risk of developing cancer, in particular colorectal cancer (CRC). Microsatellite instability (MSI) is the main feature of (pre)cancerous lesions occurring in LS patients. Close ... ...

    Abstract Lynch syndrome (LS) is an inherited condition characterized by an increased risk of developing cancer, in particular colorectal cancer (CRC). Microsatellite instability (MSI) is the main feature of (pre)cancerous lesions occurring in LS patients. Close endoscopic surveillance is the only option available to reduce CRC morbidity and mortality. However, it may fail to intercept interval cancers and patients' compliance to such an invasive procedure may decrease over the years. The development of a minimally invasive test able to detect (pre)cancerous colorectal lesions, could thus help tailor surveillance programs in LS patients. Taking advantage of an endoscopic surveillance program, we retrospectively assessed the instability of five microsatellites (BAT26, BAT25, NR24, NR21, and Mono27) in liquid biopsies collected at baseline and possibly at two further endoscopic rounds. For this purpose, we tested a new multiplex drop-off digital polymerase chain reaction (dPCR) assay, reaching mutant allele frequencies (MAFs) as low as 0.01%. Overall, 78 plasma samples at the three time-points from 18 patients with baseline (pre)cancerous lesions and 18 controls were available for molecular analysis. At baseline, the MAFs of BAT26, BAT25 and NR24 were significantly higher in samples of patients with lesions but did not differ with respect to the grade of dysplasia or any other clinico-pathological characteristics. When all markers were combined to determine MSI in blood, this test was able to discriminate lesion-bearing patients with an AUC of 0.80 (95%CI: 0.66; 0.94).
    Language English
    Publishing date 2024-02-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 1212513-1
    ISSN 1476-5500 ; 0929-1903
    ISSN (online) 1476-5500
    ISSN 0929-1903
    DOI 10.1038/s41417-023-00721-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Colorectal carcinoma peritoneal metastases-derived organoids: results and perspective of a model for tailoring hyperthermic intraperitoneal chemotherapy from bench-to-bedside.

    Varinelli, Luca / Battistessa, Davide / Guaglio, Marcello / Zanutto, Susanna / Illescas, Oscar / Lorenc, Ewelina J / Pisati, Federica / Kusamura, Shigeki / Cattaneo, Laura / Sabella, Giovanna / Milione, Massimo / Perbellini, Alessia / Noci, Sara / Paolino, Cinzia / Khun, Elisabetta / Galassi, Margherita / Cavalleri, Tommaso / Deraco, Marcello / Gariboldi, Manuela /
    Baratti, Dario

    Journal of experimental & clinical cancer research : CR

    2024  Volume 43, Issue 1, Page(s) 132

    Abstract: Background: Peritoneal metastases from colorectal cancer (CRCPM) are related to poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been reported to improve survival, but peritoneal recurrence rates are ...

    Abstract Background: Peritoneal metastases from colorectal cancer (CRCPM) are related to poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been reported to improve survival, but peritoneal recurrence rates are still high and there is no consensus on the drug of choice for HIPEC. The aim of this study was to use patient derived organoids (PDO) to build a relevant CRCPM model to improve HIPEC efficacy in a comprehensive bench-to-bedside strategy.
    Methods: Oxaliplatin (L-OHP), cisplatin (CDDP), mitomycin-c (MMC) and doxorubicin (DOX) were used to mimic HIPEC on twelve PDO lines derived from twelve CRCPM patients, using clinically relevant concentrations. After chemotherapeutic interventions, cell viability was assessed with a luminescent assay, and the obtained dose-response curves were used to determine the half-maximal inhibitory concentrations. Also, induction of apoptosis by different HIPEC interventions on PDOs was studied by evaluating CASPASE3 cleavage.
    Results: Response to drug treatments varied considerably among PDOs. The two schemes with better response at clinically relevant concentrations included MMC alone or combined with CDDP. L-OHP showed relative efficacy only when administered at low concentrations over a long perfusion period. PDOs showed that the short course/high dose L-OHP scheme did not appear to be an effective choice for HIPEC in CRCPM. HIPEC administered under hyperthermia conditions enhanced the effect of chemotherapy drugs against cancer cells, affecting PDO viability and apoptosis. Finally, PDO co-cultured with cancer-associated fibroblast impacted HIPEC treatments by increasing PDO viability and reducing CASPASES activity.
    Conclusions: Our study suggests that PDOs could be a reliable in vitro model to evaluate HIPEC schemes at individual-patient level and to develop more effective treatment strategies for CRCPM.
    MeSH term(s) Humans ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms/therapy ; Colorectal Neoplasms/drug therapy ; Peritoneal Neoplasms/secondary ; Peritoneal Neoplasms/therapy ; Peritoneal Neoplasms/drug therapy ; Hyperthermic Intraperitoneal Chemotherapy/methods ; Organoids/drug effects
    Language English
    Publishing date 2024-05-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-024-03052-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Exploring the association with disease recurrence of miRNAs predictive of colorectal cancer.

    Zanutto, Susanna / Ciniselli, Chiara Maura / Belfiore, Antonino / Dall'Olio, Valentina / Tizzoni, Laura / Varinelli, Luca / Pierotti, Marco Alessandro / Battaglia, Luigi / Verderio, Paolo / Guaglio, Marcello / Gariboldi, Manuela

    The International journal of biological markers

    2021  Volume 37, Issue 1, Page(s) 102–109

    Abstract: Introduction: Disease recurrence after surgery is a crucial predictor of poor prognosis in colorectal cancer, where disseminated disease at the time of intervention can also be observed in localized early-stage cases. We evaluated the ability to predict ...

    Abstract Introduction: Disease recurrence after surgery is a crucial predictor of poor prognosis in colorectal cancer, where disseminated disease at the time of intervention can also be observed in localized early-stage cases. We evaluated the ability to predict disease recurrence of miRNAs from two signatures that we have found linked to the presence of colorectal cancer (CL signature) or adenoma (HgA signature) in higher-risk subjects.
    Methods: miRNAs from the signatures were studied longitudinally by quantitative real-time polymerase chain reaction in plasma from 24 patients with resectable colorectal cancer collected at the time of surgery and during scheduled follow-up across 36 months. Patients either showed relapse within 36 months (alive with disease (AWD)), or remained disease-free (no evidence of disease (NED)) for the same period.
    Results: Although the signatures did not predict recurrence, expression of the miRNAs from the CL signature decreased 1 year after surgery, and one miRNA of the signature, miR-378a-3p, almost reached significance in the NED subgroup (Wilcoxon signed-rank test:
    Conclusions: These data, although from a small cohort of patients, support the possible use of miRNAs as non-invasive biomarkers in liquid biopsy-based tests to identify patients at risk of relapse and to monitor them during follow-up.
    MeSH term(s) Biomarkers, Tumor ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/surgery ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Neoplasm Recurrence, Local/genetics ; Prognosis
    Chemical Substances Biomarkers, Tumor ; MicroRNAs
    Language English
    Publishing date 2021-12-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 645113-5
    ISSN 1724-6008 ; 0393-6155
    ISSN (online) 1724-6008
    ISSN 0393-6155
    DOI 10.1177/17246008211064915
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Decellularized extracellular matrix as scaffold for cancer organoid cultures of colorectal peritoneal metastases.

    Varinelli, Luca / Guaglio, Marcello / Brich, Silvia / Zanutto, Susanna / Belfiore, Antonino / Zanardi, Federica / Iannelli, Fabio / Oldani, Amanda / Costa, Elisa / Chighizola, Matteo / Lorenc, Ewelina / Minardi, Simone P / Fortuzzi, Stefano / Filugelli, Martina / Garzone, Giovanna / Pisati, Federica / Vecchi, Manuela / Pruneri, Giancarlo / Kusamura, Shigeki /
    Baratti, Dario / Cattaneo, Laura / Parazzoli, Dario / Podestà, Alessandro / Milione, Massimo / Deraco, Marcello / Pierotti, Marco A / Gariboldi, Manuela

    Journal of molecular cell biology

    2022  Volume 14, Issue 11

    Abstract: Peritoneal metastases (PM) from colorectal cancer (CRC) are associated with poor survival. The extracellular matrix (ECM) plays a fundamental role in modulating the homing of CRC metastases to the peritoneum. The mechanisms underlying the interactions ... ...

    Abstract Peritoneal metastases (PM) from colorectal cancer (CRC) are associated with poor survival. The extracellular matrix (ECM) plays a fundamental role in modulating the homing of CRC metastases to the peritoneum. The mechanisms underlying the interactions between metastatic cells and the ECM, however, remain poorly understood, and the number of in vitro models available for the study of the peritoneal metastatic process is limited. Here, we show that decellularized ECM of the peritoneal cavity allows the growth of organoids obtained from PM, favoring the development of three-dimensional (3D) nodules that maintain the characteristics of in vivo PM. Organoids preferentially grow on scaffolds obtained from neoplastic peritoneum, which are characterized by greater stiffness than normal scaffolds. A gene expression analysis of organoids grown on different substrates reflected faithfully the clinical and biological characteristics of the organoids. An impact of the ECM on the response to standard chemotherapy treatment for PM was also observed. The ex vivo 3D model, obtained by combining patient-derived decellularized ECM with organoids to mimic the metastatic niche, could be an innovative tool to develop new therapeutic strategies in a biologically relevant context to personalize treatments.
    MeSH term(s) Humans ; Decellularized Extracellular Matrix ; Peritoneum ; Peritoneal Neoplasms/metabolism ; Peritoneal Neoplasms/secondary ; Peritoneal Neoplasms/therapy ; Organoids ; Colorectal Neoplasms/metabolism
    Chemical Substances Decellularized Extracellular Matrix
    Language English
    Publishing date 2022-12-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2500949-7
    ISSN 1759-4685 ; 1759-4685
    ISSN (online) 1759-4685
    ISSN 1759-4685
    DOI 10.1093/jmcb/mjac064
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: A methodological procedure for evaluating the impact of hemolysis on circulating microRNAs.

    Pizzamiglio, Sara / Zanutto, Susanna / Ciniselli, Chiara M / Belfiore, Antonino / Bottelli, Stefano / Gariboldi, Manuela / Verderio, Paolo

    Oncology letters

    2016  Volume 13, Issue 1, Page(s) 315–320

    Abstract: Circulating microRNAs (miRNAs) are promising non-invasive biomarkers whose expression may be affected by confounding factors, including hemolysis, that should be considered in studies of miRNA discovery. The present study proposes a methodology for ... ...

    Abstract Circulating microRNAs (miRNAs) are promising non-invasive biomarkers whose expression may be affected by confounding factors, including hemolysis, that should be considered in studies of miRNA discovery. The present study proposes a methodology for evaluating the impact of hemolysis on the expression of miRNAs. An experiment of
    Language English
    Publishing date 2016-11-30
    Publishing country Greece
    Document type Journal Article
    ZDB-ID 2573196-8
    ISSN 1792-1082 ; 1792-1074
    ISSN (online) 1792-1082
    ISSN 1792-1074
    DOI 10.3892/ol.2016.5452
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Moving from discovery to validation in circulating microRNA research.

    Verderio, Paolo / Bottelli, Stefano / Ciniselli, Chiara M / Pierotti, Marco A / Zanutto, Susanna / Gariboldi, Manuela / Pizzamiglio, Sara

    The International journal of biological markers

    2015  Volume 30, Issue 2, Page(s) e258–61

    Abstract: Background: MicroRNAs (miRNAs), small noncoding RNAs, are involved in tumorigenesis and in the development of various cancers. Quantitative real-time polymerase chain reaction (qPCR) is the most commonly used tool to investigate miRNA expression, and ... ...

    Abstract Background: MicroRNAs (miRNAs), small noncoding RNAs, are involved in tumorigenesis and in the development of various cancers. Quantitative real-time polymerase chain reaction (qPCR) is the most commonly used tool to investigate miRNA expression, and qPCR low-density arrays are increasingly being used as an experimental technique for both the identification of potentially relevant miRNAs and their subsequent validation. Due to the reduced number of microRNAs to be validated, this phase is generally performed on ad hoc customized cards for which a technical robustness is assumed similar to that of the high-throughput cards used during the identification phase.
    Methods: With the aim of investigating the degree of reproducibility between the 2 types of cards, we analyzed plasma-circulating miRNAs evaluated in 60 subjects enrolled in a colorectal cancer screening program.
    Results: Our results showed a reproducibility between the 2 methods that was not fully satisfactory, with a concordance correlation coefficient equal to 0.69 (95% confidence interval, 0.12-0.92).
    Conclusions: This report highlights the need to add a technical validation step to the high-throughput-based miRNA identification workflow, after their discovery and before the validation step in an independent series.
    MeSH term(s) Early Detection of Cancer ; Humans ; MicroRNAs/genetics ; Reproducibility of Results
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2015-05-26
    Publishing country Italy
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 645113-5
    ISSN 1724-6008 ; 0393-6155
    ISSN (online) 1724-6008
    ISSN 0393-6155
    DOI 10.5301/jbm.5000135
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production.

    Mogavero, Angela / Maiorana, Maria Valeria / Zanutto, Susanna / Varinelli, Luca / Bozzi, Fabio / Belfiore, Antonino / Volpi, Chiara C / Gloghini, Annunziata / Pierotti, Marco A / Gariboldi, Manuela

    Scientific reports

    2017  Volume 7, Issue 1, Page(s) 15992

    Abstract: Metformin is a widely used and well-tolerated anti-diabetic drug that can reduce cancer risk and improve the prognosis of certain malignancies. However, the mechanism underlying its anti-cancer effect is still unclear. We studied the anti-cancer activity ...

    Abstract Metformin is a widely used and well-tolerated anti-diabetic drug that can reduce cancer risk and improve the prognosis of certain malignancies. However, the mechanism underlying its anti-cancer effect is still unclear. We studied the anti-cancer activity of metformin on colorectal cancer (CRC) by using the drug to treat HT29, HCT116 and HCT116 p53-/- CRC cells. Metformin reduced cell proliferation and migration by inducing cell cycle arrest in the G0/G1 phase. This was accompanied by a sharp decrease in the expression of c-Myc and down-regulation of IGF1R. The anti-proliferative action of metformin was mediated by two different mechanisms: AMPK activation and increase in the production of reactive oxygen species, which suppressed the mTOR pathway and its downstream targets S6 and 4EBP1. A reduction in CD44 and LGR5 expression suggested that the drug had an effect on tumour cells with stem characteristics. However, a colony formation assay showed that metformin slowed the cells' ability to form colonies without arresting cell growth, as confirmed by absence of apoptosis, autophagy or senescence. Our finding that metformin only transiently arrests CRC cell growth suggests that efforts should be made to identify compounds that combined with the biguanide can act synergistically to induce cell death.
    MeSH term(s) AMP-Activated Protein Kinases/metabolism ; Antineoplastic Agents/pharmacology ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Colorectal Neoplasms/metabolism ; Female ; HCT116 Cells ; Humans ; In Situ Hybridization ; Membrane Potential, Mitochondrial/drug effects ; Metformin/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects
    Chemical Substances Antineoplastic Agents ; Reactive Oxygen Species ; Metformin (9100L32L2N) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
    Language English
    Publishing date 2017-11-22
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-017-16149-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: A normalization strategy for the analysis of plasma microRNA qPCR data in colorectal cancer.

    Pizzamiglio, Sara / Bottelli, Stefano / Ciniselli, Chiara Maura / Zanutto, Susanna / Bertan, Claudia / Gariboldi, Manuela / Pierotti, Marco Alessandro / Verderio, Paolo

    International journal of cancer

    2014  Volume 134, Issue 8, Page(s) 2016–2018

    MeSH term(s) Colorectal Neoplasms/blood ; Colorectal Neoplasms/diagnosis ; Humans ; MicroRNAs/blood ; Real-Time Polymerase Chain Reaction/standards ; Reference Values
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2014-04-15
    Publishing country United States
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.28530
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Methylation status in patients with early stage colon cancer: a new prognostic marker?

    Zanutto, Susanna / Pizzamiglio, Sara / Lampis, Andrea / Camerini, Tiziana / Di Mauro, Maria G / Pierotti, Marco A / Verderio, Paolo / Gariboldi, Manuela

    International journal of cancer

    2012  Volume 130, Issue 2, Page(s) 488–489

    MeSH term(s) Biomarkers, Tumor ; Colonic Neoplasms/genetics ; DNA Methylation ; Humans
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2012-01-15
    Publishing country United States
    Document type Letter
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.26011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Plasma miRNA-based signatures in CRC screening programs.

    Zanutto, Susanna / Ciniselli, Chiara Maura / Belfiore, Antonino / Lecchi, Mara / Masci, Enzo / Delconte, Gabriele / Primignani, Massimo / Tosetti, Giulia / Dal Fante, Marco / Fazzini, Linda / Airoldi, Aldo / Vangeli, Marcello / Turpini, Francesca / Rubis Passoni, Giovanni Giuseppe / Viaggi, Paolo / Arena, Monica / Motta, Roberta Ilaria Olimpia / Cantù, Anna Maria / Crosta, Cristiano /
    De Roberto, Giuseppe / Iannuzzi, Francesca / Cassinotti, Andrea / Dall'Olio, Valentina / Tizzoni, Laura / Sozzi, Gabriella / Meroni, Emanuele / Bisanti, Luigi / Pierotti, Marco Alessandro / Verderio, Paolo / Gariboldi, Manuela

    International journal of cancer

    2019  Volume 146, Issue 4, Page(s) 1164–1173

    Abstract: Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a ... ...

    Abstract Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT-positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real-time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low-grade adenoma [LgA], high-grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two-miRNA-based signature for CL and six-miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607-0.682), 0.670 (0.626-0.714) and 0.682 (0.580-0.785) for LgA, HgA and CL, respectively. A miRNA-based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.
    MeSH term(s) Aged ; Colorectal Neoplasms/blood ; Colorectal Neoplasms/genetics ; Early Detection of Cancer ; Female ; Humans ; Male ; MicroRNAs/blood ; MicroRNAs/genetics ; Middle Aged
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2019-08-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.32573
    Database MEDical Literature Analysis and Retrieval System OnLINE

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