Giorgia Marisi

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

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Andrea Casadei‐Gardini

Istituti di Ricovero e Cura a Carattere Scientifico

Paola Ulivi

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Mario Scartozzi

University of Cagliari

Giovanni Luca Frassineti

Istituti di Ricovero e Cura a Carattere Scientifico

Alessandro Passardi

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Luca Faloppi

University of Macerata

Stefano Cascinu

IRCCS Ospedale San Raffaele

Emanuela Scarpi

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Francesco Giuseppe Foschi

Ospedale per gli Infermi

Nicola Silvestris

Istituti di Ricovero e Cura a Carattere Scientifico

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Istituti di Ricovero e Cura a Carattere Scientifico

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University of Bologna

118

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

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Policlinico S.Orsola-Malpighi

Azienda USL di Bologna

Ospedale G.B. Morgagni - L.Pierantoni

University of Milan

Azienda Unità Sanitaria Locale Della Romagna

Istituto Oncologico Veneto

University of Modena and Reggio Emilia

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Recent Research on Gastrointestinal Carcinoma

Cancers (2021)

Giulia Rovesti Giorgia Marisi Andrea Casadei‐Gardini

This series of 10 articles (eight original articles and two reviews) is presented by international leaders in gastrointestinal cancer research [...]

10.3390/cancers13020333

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Citations (2)

Data from Association of NOS3 and ANGPT2 Gene Polymorphisms with Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib: Results of the Multicenter Prospective INNOVATE Study

Andrea Casadei‐Gardini Giorgia Marisi Vincenzo Dadduzio Laura Gramantieri Luca Faloppi

<div>AbstractPurpose:After 10 years of clinical practice and research studies, there are still no validated prognostic or predictive factors of response to sorafenib for hepatocellular carcinoma (HCC). On the basis of the results of our two retrospective studies, we designed the multicenter INNOVATE study with the aim to validate the role of nitric oxide synthase 3 (NOS3) and ANGPT2 polymorphisms in patients with HCC treated with sorafenib [NCT02786342].Patients and Methods:This prospective multicenter study was conducted at 10 centers in Italy. All eligible patients received a continuous oral treatment with 400 mg of sorafenib twice daily. Genotyping analysis was performed for NOS3 (rs2070744) and ANGPT2 SNPs (rs55633437). The primary outcome was progression-free survival (PFS), whereas secondary outcomes included overall survival (OS) and disease-control rate.Results:A total of 165 patients were enrolled between March 2016 and June 2018. NOS3 rs2070744 CC/CT genotypes were significantly associated with a higher median PFS (5.9 months vs. 2.4 months; HR = 0.43; P = 0.0007) and OS (15.7 months vs. 8.6 months; HR = 0.38; P < 0.0001) compared with TT genotype. There was no statistically significant association between ANGPT2 rs55633437 TT/GT genotypes and PFS (2.4 months vs. 5.7 months; HR = 1.93; P = 0.0833) and OS (15.1 months vs. 13.0 months; HR = 2.68; P = 0.55) when compared with the other genotype. Following adjustment for clinical covariates, multivariate analysis confirmed NOS3 as an independent prognostic factor for PFS (HR = 0.50; P = 0.0128) and OS (HR = 0.29; P = 0.0041).Conclusions:The INNOVATE study met the primary endpoint, confirming that patients with advanced HCC with NOS3 rs2070744 CC/CT genotypes had a better prognosis with respect to TT genotype patients.</div>

10.1158/1078-0432.c.6529649

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Supplementary Data from Association of NOS3 and ANGPT2 Gene Polymorphisms with Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib: Results of the Multicenter Prospective INNOVATE Study

Andrea Casadei‐Gardini Giorgia Marisi Vincenzo Dadduzio Laura Gramantieri Luca Faloppi

All Supplementary Data

10.1158/1078-0432.22477397

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In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3–Mediated Apoptosis

Clinical Cancer Research (2017)

Francesca Fornari Daniela Pollutri Clarissa Patrizi Tiziana La Bella Sara Marinelli

Abstract Purpose: The aberrant expression of miR-221 is a hallmark of human cancers, including hepatocellular carcinoma (HCC), and its involvement in drug resistance, together with a proved in vivo efficacy of anti-miR-221 molecules, strengthen its role as an attractive target candidate in the oncologic field. The discovery of biomarkers predicting the response to treatments represents a clinical challenge in the personalized treatment era. This study aimed to investigate the possible role of miR-221 as a circulating biomarker in HCC patients undergoing sorafenib treatment as well as to evaluate its contribution to sorafenib resistance in advanced HCC. Experimental Design: A chemically induced HCC rat model and a xenograft mouse model, together with HCC-derived cell lines were employed to analyze miR-221 modulation by Sorafenib treatment. Data from the functional analysis were validated in tissue samples from surgically resected HCCs. The variation of circulating miR-221 levels in relation to Sorafenib treatment were assayed in the animal models and in two independent cohorts of patients with advanced HCC. Results: MiR-221 over-expression was associated with Sorafenib resistance in two HCC animal models and caspase-3 was identified as its target gene, driving miR-221 anti-apoptotic activity following Sorafenib administration. Lower pre-treatment miR-221 serum levels were found in patients subsequently experiencing response to Sorafenib and an increase of circulating miR-221 at the two months assessment was observed in responder patients. Conclusions: MiR-221 might represent a candidate biomarker of likelihood of response to Sorafenib in HCC patients to be tested in future studies. Caspase-3 modulation by miR-221 participates to Sorafenib resistance. Clin Cancer Res; 23(14); 3953–65. ©2017 AACR.

Acquired resistance

10.1158/1078-0432.ccr-16-1464

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Advancing Personalized Medicine in the Treatment of Locally Advanced Rectal Cancer

Journal of Clinical Medicine (2024)

Francesco Giulio Sullo Alessandro Passardi Chiara Gallio Chiara Molinari Giorgia Marisi

Rectal cancer presents a significant burden globally, often requiring multimodal therapy for locally advanced cases. Long-course chemoradiotherapy (LCRT) and short-course radiotherapy (SCRT) followed by surgery have been conventional neoadjuvant approaches. Recent trials favor LCRT due to improved local control. However, distant tumor recurrence remains a concern, prompting the exploration of total neoadjuvant therapy (TNT) as a comprehensive treatment strategy. Immune checkpoint inhibitors (ICIs) show promise, particularly in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, potentially revolutionizing neoadjuvant regimens. Nonoperative management (NOM) represents a viable alternative post-neoadjuvant therapy for selected patients achieving complete clinical response (cCR). Additionally, monitoring minimal residual disease (MRD) using circulating tumor DNA (ctDNA) emerges as a non-invasive method for the assessment of treatment response. This review synthesizes current evidence on TNT, ICIs, NOM, and ctDNA, elucidating their implications for rectal cancer management and highlighting avenues for future research and clinical application.

Microsatellite Instability

Neoadjuvant Therapy

Personalized Medicine

Chemoradiotherapy

Minimal Residual Disease

Circulating tumor DNA

10.3390/jcm13092562

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ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib

Cancers (2019)

Giorgia Marisi Elisabetta Petracci Francesco Raimondi Luca Faloppi Francesco Giuseppe Foschi

Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited efficacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 (ANGPT2) and endothelial-derived nitric oxide synthase (NOS3) genes in 135 patients with advanced HCC receiving sorafenib. Eight ANGPT2 polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, ANGPT2rs55633437 and NOS3 rs2070744 were associated with OS and PFS. In particular, patients with ANGPT2rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73–8.67, p < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73–8.35, p < 0.001) than those homozygous for the G allele. Moreover, patients with NOS3 rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44–0.97; p = 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30–0.63; p < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that ANGPT2rs55633437 and NOS3 rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib.

10.3390/cancers11071023

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eNOS polymorphisms in relation to outcome in advanced HCC patients receiving sorafenib.

Journal of Clinical Oncology (2015)

Andrea Casadei‐Gardini Giorgia Marisi Emanuela Scarpi Mario Scartozzi Luca Faloppi

230 Background: Cancer cells adapt to hypoxic microenvironment through the activation of many molecules, including endothelial nitric oxide synthase (eNOS). Sorafenib, by blocking the vascular endothelial growth factor receptors (VEGFRs), induces an inhibition of eNOS activity with a consequent decrease of the production of nitric oxide (NO). NO is associated with an increase of tumor angiogenesis, tumor invasion and metastasis formation. In our study we analysed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma treated with sorafenib. Methods: From a database of 257 patients diagnosed with hepatocellular carcinoma from 2004 to 2014, we selected 54 patients who received sorafenib. Peripheral blood samples or FFPE tumor tissues were available for DNA extraction and genotyping analysis. Three eNOS polymorphisms (eNOS +894 G/T, eNOS VNTR 27bp 4a/b, eNOS -786 C/T) were analyzed by direct sequencing or Real Time PCR method. We analyzed 21 patients for the VNTR 4a/b polymorphism and 32 patients for -786 C/T polymorphism. All the candidate genotypes were evaluated to identify a potential correlation with overall survival (OS) (log-rank test). Results: With regard to eNOS VNTR it was observed that patients carrying the b allele (5 repetitions of 27bp) both in homozygosity (4bb) and in heterozygosity (4ab) were associated with a better OS. The variants 4aa (4 repeats of 27bp in homozygosity), 4ab and 4bb, were associated with a median OS of 5.7, 13.9 and 23.6 months, respectively (p = 0.016). For eNOS-786 the presence of the T allele both in homozygosity (TT) and in heterozygosity(TC) was associated with a statistically significant longer OS with respect to patients with CC genotype (15.6 versus 13.9 months, respectively, p = 0.031). No correlations were observed in relation to PFS (p = 0.494). Conclusions: eNOS VNTR and eNOS -786 could represent prognostic markers in patients with advanced hepatocellular carcinoma treated with sorafenib.

10.1200/jco.2015.33.3_suppl.230

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Case Report: The Added Value of Liquid Biopsy in Advanced Colorectal Cancer From Clinical Case Experiences

Frontiers in Pharmacology (2021)

Paola Ulivi Alessandro Passardi Giorgia Marisi Elisa Chiadini Chiara Molinari

Liquid biopsy represents a valid strategy for tumor molecular characterization. It gives the opportunity to bypass tumor heterogeneity, to monitor tumor characteristics during the course of treatment, and to perform the analysis even when tumor tissue is not available or inadequate. In the clinical practice of metastatic colorectal cancer, tumor molecular characterization is crucial for patient management, as RAS and BRAF status could influence the treatment choice. Although for this type of cancer tumor tissue is usually available at diagnosis, liquid biopsy could give complementary information and could permit monitoring of the mutation status during the course of treatment. At present, there are no clinical indications for its use in clinical practice. However, we report four clinical cases for which liquid biopsy analysis gave integrative information with respect to tumor tissue characterization, which permits us to understand the unresponsiveness of patients to treatment, with potential implications in patient’s management.

Value (mathematics)

Liquid biopsy

10.3389/fphar.2021.745701

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Prospective validation of VEGF and eNOS polymorphisms as predictors of first-line bevacizumab efficacy in patients with metastatic colorectal cancer

Research Square (Research Square) (2023)

Giorgia Marisi Irene Azzali Alessandro Passardi Francesca Rebuzzi Giulia Bartolini

Abstract Bevacizumab (Bev) plus chemotherapy is a standard first-line treatment in metastatic colorectal cancer (mCRC), however to date no predictive factors of response have been identified. Results of our previous analysis on patients enrolled in a randomized prospective phase III multicenter study (ITACa study) showed a predictive value of Vascular Endothelial Growth Factor ( VEGF ) polymorphism ( VEGF + 936), a 27-nucleotide variable number tandem repeat (VNTR) of the endothelial nitric oxide synthase ( eNOS ) gene and eNOS + 894 polymorphism. mCRC patients, treated with Bev plus chemotherapy, were included in this prospective validation trial. eNOS + 894G > T was analyzed by Real time PCR, while the eNOS VNTR and VEGF + 936C > T were determined by standard PCR and direct sequencing analysis. These polymorphisms were assessed in relation to progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). These three polymorphisms were not predictive of PFS (p 0.91, 0.59 and 0.09, respectively), and OS (p 0.95, 0.32 and 0.46, respectively). Moreover, the haplotype analyses did not confirm what was found in our previous study; patients bearing a specific haplotype of eNOS had not significantly improved outcomes. This prospective study failed to validate the predictive impact of eNOS and VEGF polymorphisms for response to Bev plus first-line chemotherapy in mCRC patients.

10.21203/rs.3.rs-2854009/v1

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Metastatic Colorectal Cancer 2.0

Cancers (2024)

Alessandro Passardi Giorgia Marisi Paola Ulivi

Colorectal cancer (CRC) ranks third in frequency among cancers diagnosed in males and second in females [...]

10.3390/cancers16122190

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