Publications by authors named "Giulia Rovesti"

29 Publications

  • Page 1 of 1

Clinical Implications of Malnutrition in the Management of Patients with Pancreatic Cancer: Introducing the Concept of the Nutritional Oncology Board.

Nutrients 2021 Oct 7;13(10). Epub 2021 Oct 7.

Division of Oncology, Department of Medical and Surgical Sciences of Children and Adults, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy.

Pancreatic cancer represents a very challenging disease, with an increasing incidence and an extremely poor prognosis. Peculiar features of this tumor entity are represented by pancreatic exocrine insufficiency and an early and intense nutritional imbalance, leading to the highly prevalent and multifactorial syndrome known as cancer cachexia. Recently, also the concept of sarcopenic obesity has emerged, making the concept of pancreatic cancer malnutrition even more multifaceted and complex. Overall, these nutritional derangements play a pivotal role in contributing to the dismal course of this malignancy. However, their relevance is often underrated and their assessment is rarely applied in clinical daily practice with relevant negative impact for patients' outcome in neoadjuvant, surgical, and metastatic settings. The proper detection and management of pancreatic cancer-related malnutrition syndromes are of primary importance and deserve a specific and multidisciplinary (clinical nutrition, oncology, etc.) approach to improve survival, but also the quality of life. In this context, the introduction of a "Nutritional Oncology Board" in routine daily practice, aimed at assessing an early systematic screening of patients and at implementing nutritional support from the time of disease diagnosis onward seems to be the right path to take.
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http://dx.doi.org/10.3390/nu13103522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537095PMC
October 2021

TRAIL receptors are expressed in both malignant and stromal cells in pancreatic ductal adenocarcinoma.

Am J Cancer Res 2021 15;11(9):4500-4514. Epub 2021 Sep 15.

Division of Oncology, Laboratory of Cellular Therapy, Department of Medical and Surgical Sciences of Children & Adults, University of Modena and Reggio Emilia Modena 41124, Italy.

This study assesses the expression of all TNF-related apoptosis-inducing ligand (TRAIL) receptors in pancreatic ductal adenocarcinoma (PDAC) tumor tissue. We aimed to include TRAIL receptor expression as an inclusion parameter in a future clinical study using a TRAIL-based therapy approach for PDAC patients. Considering the emerging influence of PDAC desmoplastic stroma on the efficacy of anti-PDAC therapies, this analysis was extended to tumor stromal cells. Additionally, we performed PDAC stroma characterization. Our retrospective cohort study (N=50) included patients with histologically confirmed PDAC who underwent surgery. The expression of TRAIL receptors (DR4, DR5, DcR1, DcR2, and OPG) in tumor and stromal cells was evaluated by immunohistochemistry (IHC). The amount of tumor stroma was assessed by anti-vimentin IHC and Mallory's trichrome staining. The prognostic impact was determined by the univariate Cox proportional hazards regression model. An extensive expression of functional receptors DR4 and DR5 and a variable expression of decoy receptors were detected in PDAC tumor and stromal cells. Functional receptors were detected also in metastatic tumor and stromal cells. A poor prognosis was associated with low or absent expression of decoy receptors in tumor cells of primary PDAC. After assessing that almost 80% of tumor mass was composed of stroma, we correlated a cellular-dense stroma in primary PDAC with reduced relapse-free survival. We demonstrated that TRAIL functional receptors are widely expressed in PDAC, representing a promising target for TRAIL-based therapies. Further, we demonstrated that a low expression of DcR1 and the absence of OPG in tumor cells, as well as a cellular-dense tumor stroma, could negatively impact the prognosis of PDAC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493377PMC
September 2021

Liquid Biopsy in Hepatocellular Carcinoma: Opportunities and Challenges for Immunotherapy.

Cancers (Basel) 2021 Aug 27;13(17). Epub 2021 Aug 27.

Department of Laboratory Medicine Karolinska Institutet, 14152 Stockholm, Sweden.

Hepatocellular carcinoma (HCC) is one of the deadliest cancer types worldwide. HCC is often diagnosed at a late stage when the therapeutic options are very limited. However, even at the earlier stages, the best treatment is liver transplantation, surgical resection or ablation. Surgical resection and ablation may carry a high risk of tumor recurrence. The recent introduction of immunotherapies resulted in clinical responses for a subgroup of patients, but there were still no effective predictive markers for response to immunotherapy or for recurrence after surgical therapy. The identification of biomarkers that could correlate and predict response or recurrence would require close monitoring of the patients throughout and after the completion of treatment. However, this would not be performed efficiently by repeated and invasive tissue biopsies. A better approach would be to use liquid biopsies including circulating tumor DNA (ctDNA), circulating RNA (e.g., microRNAs), circulating tumor cells (CTC) and extracellular vesicles (EVs) (e.g., exosomes) for disease monitoring in a non-invasive manner. In this review, we discuss the currently available technology that can enable the use of liquid biopsy as a diagnostic and prognostic tool. Moreover, we discuss the opportunities and challenges of the clinical application of liquid biopsy for immunotherapy of HCC.
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http://dx.doi.org/10.3390/cancers13174334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431414PMC
August 2021

A prognostic model in patients with advanced biliary tract cancer receiving first-line chemotherapy.

Acta Oncol 2021 Oct 20;60(10):1317-1324. Epub 2021 Jul 20.

Division of Medical Oncology, ASL BI, Nuovo Ospedale degli Infermi, Ponderano, Italy.

Background: Standard treatment of advanced biliary tract cancer (aBTC) is represented by first-line chemotherapy (CT1). However, some patients do not gain any benefit from CT1, contributing to the overall dismal prognosis of aBTC. The present study aimed to devise a prognostic model in aBTC patients receiving CT1.

Methods: A large panel of clinical, laboratory, and pathology variables, available before the start of CT1, were retrospectively assessed in a multi-centric cohort to determine their prognostic value on univariate and multivariate regression analysis. The variables that showed a significant correlation with overall survival (OS) were computed in a three-tier prognostic score. External validation of the prognostication performance was carried out.

Results: Clinical histories of 935 patients (median OS 10.3 months), with diagnosis dates ranging from 2001 to 2017, were retrieved from 14 institutions. According to multivariate analysis, Eastern Cooperative Oncology Group performance status, carbohydrate antigen 19.9, albumin levels, and neutrophil/lymphocyte ratio were strongly associated with OS ( <0.01). The prognostic score could generate a highly significant stratification (all between-group values ≤0.001) into groups of favorable (comprising 51.5% of the sample), intermediate (39.2%), and poor prognosis (9.3%): median OS was 12.7 (CI 11.0-14.4), 7.1 (CI 5.8-8.4), and 3.2 months (CI 1.7-4.7), respectively. This OS gradient was replicated in the validation set (129 patients), with median OS of 12.7 (CI 11.0-14.3), 7.5 (CI 6.1-8.9), and 1.4 months (CI 0.1-2.7), respectively (all between-group values ≤0.05).

Conclusion: A prognostic score, derived from a limited set of easily-retrievable variables, efficiently stratified a large population of unselected aBTC patients undergoing CT1. This tool could be useful to clinicians, to ascertain the potential benefit from CT1 at the start of treatment.
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http://dx.doi.org/10.1080/0284186X.2021.1953704DOI Listing
October 2021

A Novel Prognostic Tool in Western and Eastern Biliary Tract Cancer Patients Treated in First-line Setting: the ECSIPOT Index.

J Gastrointest Cancer 2021 May 25. Epub 2021 May 25.

School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.

Background And Aim: The need to estimate prognosis of advanced BTC (aBTC) patients treated with first-line chemotherapy is compelling. The aim of the study is to evaluate the ECSIPOT (psECogSIiPnigOT) index, influenced by PECS (PsECogSii) index, prognostic nutritional index (PNI), and GOT.

Methods: This international study was conducted on a training cohort of 126 patients and in three validation cohorts, both European and Korean. ECSIPOT index formula: (PECS:0 = 1 point; PECS:1 = 1.4 points; PECS:2 = 3.2 points) + (PNI > 36.7 = 1 point; PNI < 36.7 = 2 points) + (GOT < 100 = 1 point; GOT > 100 = 2 points). Event-time distributions were estimated using the Kaplan-Meier method, and survival curves were compared using the log-rank test.

Results: In the training cohort, mOS was 12.9, 6.3, and 2.8 months for patients with ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR 1; ECSIPOT-1: HR 2.11; ECSIPOT-2: HR 4.93; p < 0.0001). In the first validation cohort, mOS was 11.5, 7.3, and 3.3 months for ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR 1; ECSIPOT-1: HR 1.74; ECSIPOT-2: HR 3.41; p < 0.0001). In the second validation cohort, mOS was 25.2, 12.5, and 3.0 months for ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR = 1; ECSIPOT-1: HR 2.33; ECSIPOT-2: HR 8.46; p < 0.0001). In the third validation cohort, mOS was 11.8, 8.1, and 4.6 months for ECSIPOT-0, ECSIPOT-1, and ECSIPOT-2, respectively (ECSIPOT-0: HR = 1; ECSIPOT-1: HR 1.47; ECSIPOT-2: HR 3.17; p < 0.0001). Multivariate analysis in all cohorts confirmed the ECSIPOT index as an independent prognostic factor for OS.

Conclusion: The easy assessment and good risk-stratification performance make the ECSIPOT index a promising tool to comprehensively estimate the prognosis of aBTC patients.
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http://dx.doi.org/10.1007/s12029-021-00649-3DOI Listing
May 2021

Effects of Metformin and Vitamin D on Clinical Outcome in Cholangiocarcinoma Patients.

Oncology 2021 24;99(5):292-299. Epub 2021 Feb 24.

IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.

Background And Aims: In the last few years, there has been increasing interest in non-cancer medications and their potential anti-cancer activity. Data are not available in cholangiocarcinoma (CCA) patients. The aim of this study is to fill this gap by investigating the potential impact in terms of clinical outcome of the common non-cancer medications.

Methods: All consecutive patients with CCAs were retrospectively identified from 7 Italian medical institutions. We investigated the role of intake of vitamin D, aspirin, metformin, statins, and diuretics.

Results: A total of 537 patients with CCAs were identified; 197 patients undergoing surgery were evaluated for disease-free survival (DFS), and 509 patients with an advanced stage were evaluated for overall survival (OS). A longer DFS was found in patients with intake of vitamin D versus never users (HR 0.55, 95% CI 0.32-0.92, p = 0.02). In an advanced stage an association with OS was found in patients with intake of metformin versus never users (HR 0.70, 95% CI 0.52-0.93, p = 0.0162), and in patients who have started taking metformin after chemotherapy versus before chemotherapy and never users (HR 0.44, 95% CI 0.26-0.73, p = 0.0016).

Conclusions: Our results highlighted that vitamin D intake improves DFS in patients undergoing surgery. Metformin intake after starting chemotherapy can improve the clinical outcome in advanced disease. These results could open up new therapeutic strategies in cholangiocarcinoma patients. We are planning to undertake a prospective study to validate these data.
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http://dx.doi.org/10.1159/000512796DOI Listing
May 2021

Prognostic Role of a New Index Tested in European and Korean Advanced Biliary Tract Cancer Patients: the PECS Index.

J Gastrointest Cancer 2021 Feb 5. Epub 2021 Feb 5.

Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, Milan, Italy.

Background And Aim: The aim of the present study is to evaluate a new index (PECS (PsECogSii)index) influenced by PS ECOG and systemic immune-inflammation index (SII) in unresectable locally advanced or metastatic BTC patients treated with first-line chemotherapy.

Methods: This multicenter, international, study was conducted on a training cohort of 130 patients and in three European and Korean validation cohorts The PECS index was calculated as ECOG × SII index (neutrophil count × platelet count/lymphocyte count). Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test.

Results: In the training cohort, the median overall survival (mOS) was 13.2 months, 8.7 months, and 3.8 months for patients with PECS-0, PECS-1, and PECS-2, respectively (PECS-0: HR = 1; PECS-1: HR 1.41; PECS-2: HR 3.23) (p < 0.0001). In the first validation cohort, the mOS was 12.8 months, 10.1 months, and 5.3 months for patients with PECS-0, PECS-1, and PECS-2, respectively (PECS-0: HR = 1; PECS-1: HR 1.29; PECS-2: HR 2.40) (p < 0.0001). In the second validation cohort, the mOS was 21.2 months, 10.2 months, and 3.0 months for patients with PECS-0, PECS-1, and PECS-2, respectively (PECS-0: HR = 1; PECS-1: HR 2.25; PECS-2: HR 9.00) (p < 0.0001). In the third validation cohort, the median OS was 15.5 months, 7.5 months, and 3.7 months for patients with PECS-0, PECS-1, and PECS-2, respectively (PECS-0: ref HR = 1; PECS-1: HR 2.14; PECS-2: HR 5.00) (p < 0.0001). Multivariate analysis in all cohorts confirmed the PECS index as an independent prognostic factor for OS.

Conclusions: The easy assessment, low cost, and reproducibility make PECS index a promising tool to assess the prognosis of BTC patients in future clinical practice.
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http://dx.doi.org/10.1007/s12029-021-00596-zDOI Listing
February 2021

Recent Research on Gastrointestinal Carcinoma.

Cancers (Basel) 2021 Jan 18;13(2). Epub 2021 Jan 18.

Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, 20019 Milan, Italy.

This series of 10 articles (eight original articles and two reviews) is presented by international leaders in gastrointestinal cancer research [...].
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http://dx.doi.org/10.3390/cancers13020333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831043PMC
January 2021

The Growing Skyline of Advanced Hepatocellular Carcinoma Treatment: A Review.

Pharmaceuticals (Basel) 2021 Jan 8;14(1). Epub 2021 Jan 8.

Oncology Unit, University Hospital of Modena and Reggio Emilia, Largo del Pozzo 71, 41125 Modena, Italy.

Hepatocellular carcinoma (HCC) is the main type of liver cancer. In the majority of cases, HCC is diagnosed at the advanced stage, leading to poor prognosis. In recent years, many efforts have been devoted to investigating potential new and more effective drugs and, indeed, the treatment armamentarium for advanced HCC has broadened tremendously, with targeted- and immune-therapies, and probably the combination of both, playing pivotal roles. Together with new established knowledge, many issues are emerging, with the role of neoadjuvant/adjuvant settings, the definition of the best transitioning time from loco-regional treatments to systemic therapy, the identification of potential predictive biomarkers, and radiomics being just some of the topics that will have to be further explored in the next future. Clearly, the current COVID-19 pandemic has influenced the management of HCC patients and some considerations about this topic will be elucidated.
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http://dx.doi.org/10.3390/ph14010043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827379PMC
January 2021

Retrospective survival analysis in patients with metastatic pancreatic ductal adenocarcinoma with insulin-treated type 2 diabetes mellitus.

Tumori 2021 Dec 26;107(6):550-555. Epub 2020 Nov 26.

Medical Oncology Unit, University Hospital and University of Cagliari, Monserrato, Cagliari, Italy.

Introduction: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2.

Methods: We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable.

Results: In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months ( = 0.03).

Conclusions: Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.
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http://dx.doi.org/10.1177/0300891620976945DOI Listing
December 2021

BRCA in Gastrointestinal Cancers: Current Treatments and Future Perspectives.

Cancers (Basel) 2020 Nov 12;12(11). Epub 2020 Nov 12.

Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, 41121 Modena, Italy.

A strong association between pancreatic cancer and and mutations is documented. Based on promising results of breast and ovarian cancers, several clinical trials with poly (ADP-ribose) polymerase inhibitors (PARPi) are ongoing for gastrointestinal (GI) malignancies, especially for pancreatic cancer. Indeed, the POLO trial results provide promising and awaited changes for the pancreatic cancer therapeutic landscape. Contrariwise, for other gastrointestinal tumors, the rationale is currently only alleged. The role of mutation in gastrointestinal cancers is the subject of this review. In particular, we aim to provide the latest updates about novel therapeutic strategies that, exploiting DNA repair defects, promise to shape the future therapeutic scenario of GI cancers.
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http://dx.doi.org/10.3390/cancers12113346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697442PMC
November 2020

Impact of Aspirin on clinical outcome in advanced HCC patients receiving sorafenib and regorafenib.

HPB (Oxford) 2021 Jun 12;23(6):915-920. Epub 2020 Nov 12.

Department of Medical Oncology, Università Vita-Salute, San Raffaele Hospital IRCCS, 20019, Milan, Italy.

Background And Aim: The aim of our retrospective study is to evaluate the prognostic significance of aspirin in patients with advanced HCC treated with sorafenib.

Methods: 304 patients with HCC,consecutively treated with sorafenib from May 2007 to September 2018, were included in the clinical study. Of Them 93 patients token aspirin. Progression-free survival (PFS)and overall survival (OS)were estimated with the Kaplan-Meier method and compared with the log-rank test.

Results: The concomitant use of sorafenib and aspirin was associated with a median OS of 18.3 months compared to 8.8 months of patients who did not receive aspirin (HR 0.57; P < 0.0001). The concomitant use of sorafenib and aspirin was associated with a median PFS of 7.3 months compared to 3.0 months of patients who did not receive aspirin (HR 0.61; P = 0.0003). In the multivariate analysis, the use of aspirin maintained an independent prognostic value for OS(HR 0.61; P = 0.0013). In second line the concomitant use of regorafenib and aspirin was associated with a median OS of 16.9 months compared to 8.0 months of patients who did not receive aspirin (HR 0.30; P = 0.02).

Conclusion: Globally, our data seem to suggest that aspirin use may improve the clinical outcome of patients with advanced hepatocellular carcinoma receiving sorafenib and regorafenib.
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http://dx.doi.org/10.1016/j.hpb.2020.09.024DOI Listing
June 2021

Child Pugh and ALBI grade: past, present or future?

Ann Transl Med 2020 Sep;8(17):1044

Department of Oncology and Hematology, Division of Oncology, University of Modena and Reggio Emilia, Modena, Italy.

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http://dx.doi.org/10.21037/atm-20-3709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575984PMC
September 2020

Correction to: Prognostic Role of Blood Eosinophil Count in Patients with Sorafenib-Treated Hepatocellular Carcinoma.

Target Oncol 2020 Dec;15(6):809-810

Vita-Salute San Rafaele University, Milan, Italy.

An Online First version of this article was made available online at https://link.springer.com/article/10.1007/s11523-020-00757-3 on 12 October 2020. Errors were subsequently identified in the article, and the following corrections should be noted.
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http://dx.doi.org/10.1007/s11523-020-00765-3DOI Listing
December 2020

Prognostic role of a new index (multi inflammatory index) in patients with metastatic colorectal cancer: results from the randomized ITACa trial.

Ther Adv Med Oncol 2020 28;12:1758835920958363. Epub 2020 Sep 28.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Aims: We created a new index (Multi Inflammatory Index, MII) composed of an inflammatory index [neutrophil-to lymphocyte-ratio (NLR): MII-1; platelet-to-lymphocyte ratio (PLR): MII-2; or systemic immune-inflammation index (SII): MII-3] and C-reactive protein (CRP). Our aim was to evaluate the prognostic and/or predictive capacity of the MII in the randomized ITACa (Italian Trial in Advanced Colorectal Cancer) study on patients with metastatic colorectal cancer undergoing first-line chemotherapy.

Methods: Between November 2007 and March 2012, baseline NLR, PLR; SII and CRP were available for 131 patients, 66 receiving chemotherapy plus bevacizumab and 65 receiving chemotherapy alone.

Results: Patients with low (<25) MII-1 levels had a better outcome than those with high (⩾25) levels: median progression-free survival (PFS) was 12.4 8.9 months [hazard ratio (HR) = 1.74, 95% confidence interval (CI) 1.21-2.51,  = 0.003] and median overall survival (OS) was 30.9 months 15.0 months (HR = 2.05, 95% CI 1.40-3.02,  = 0.0002), respectively. Similar results were obtained for patients with low (<1424) MII-2 levels compared with those with high (⩾1424) levels: median PFS was 12.6 8.9 months (HR = 1.95, 95% CI 1.35-2.82,  = 0.0004) and median OS was 32.4 14.6 months, respectively (HR = 2.42, 95% CI 1.64-3.57,  < 0.0001). Patients with low (<6068) MII-3 levels had a longer median PFS and OS than those with high (⩾6068) levels: 12.6 8.9 months (HR = 1.91, 95% CI 1.33-2.76,  = 0.005) and 30.9 15.0 months (HR = 2.10, 95% CI 1.43-3.09,  = 0.0002), respectively. Following adjustment for clinical covariates, multivariate analysis confirmed all MII indexes as independent prognostic factors for predicting PFS and OS.

Conclusion: All MII indexes appear to be useful as prognostic markers.

Trial Registration: ClinicalTrials.gov identifier: NCT01878422 (registration date: 07/06/2013) https://clinicaltrials.gov/ct2/show/NCT01878422.
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http://dx.doi.org/10.1177/1758835920958363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534088PMC
September 2020

Prognostic Role of Blood Eosinophil Count in Patients with Sorafenib-Treated Hepatocellular Carcinoma.

Target Oncol 2020 12;15(6):773-785

Vita-Salute San Rafaele University, Milan, Italy.

Background: Inflammation is a long-established hallmark of liver fibrosis and carcinogenesis. Eosinophils are emerging as crucial components of the inflammatory process influencing cancer development. The role of blood eosinophils in patients with hepatocellular carcinoma receiving systemic treatment is an unexplored field.

Objective: The objective of this study was to analyse the prognostic role of the baseline eosinophil count in patients with sorafenib-treated hepatocellular carcinoma.

Patients And Methods: A training cohort of 92 patients with advanced- or intermediate-stage sorafenib-treated hepatocellular carcinoma and two validation cohorts of 65 and 180 patients were analysed. Overall survival and progression-free survival in relation to baseline eosinophil counts were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed.

Results: A negative prognostic impact of low baseline eosinophil counts (< 50*10/L) was demonstrated in all cohorts (training cohort: hazard ratio = 50.1, 95% confidence interval 11.6-216.5, p < 0.0001 for low vs high eosinophil counts; first validation cohort: hazard ratio = 4.55, 95% confidence interval 1.24-16.65, p = 0.022; second validation cohort: hazard ratio = 3.21, 95% confidence interval 1.83-5.64, p < 0.0001). Moreover, low eosinophil counts had a negative prognostic role in patients progressing on or intolerant to sorafenib who received second-line regorafenib, but not capecitabine or best supportive care.

Conclusions: Our analysis identified baseline blood eosinophil counts as a new prognostic factor in patients with sorafenib-treated hepatocellular carcinoma. Concerning second-line therapies, eosinophil counts were associated with survival outcomes only in regorafenib-treated patients, suggesting a possible predictive role in this setting.
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http://dx.doi.org/10.1007/s11523-020-00757-3DOI Listing
December 2020

First-line gemcitabine plus nab-paclitaxel for elderly patients with metastatic pancreatic cancer: Crossing the frontier of age?

Eur J Cancer 2020 09 1;137:108-116. Epub 2020 Aug 1.

Unit of Medical Oncology, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, Pisa, 56126, Italy. Electronic address:

Background: Gemcitabine plus nab-paclitaxel (Gem-Nab) represents a standard first-line treatment for metastatic pancreatic cancer (mPC), but few data are available for elderly patients. We aimed to add evidence about safety and efficacy of Gem-Nab in this population.

Methods: We collected data of 156 patients with mPC aged ≥65 years receiving Gem-Nab. Patients were stratified according to age: <70 (group 1: 65 patients) and ≥70 years (group 2: 91 patients).

Results: The median age was 71 years (range: 65-87 years). The toxicity profile was similar between group 1 and 2, except for all-grade anaemia (92.1% vs. 78.7%, respectively; p = 0.04) and neurotoxicity (61.9% vs. 40.4%, respectively; p = 0.02), also as a result of a lower dose intensity of nab-paclitaxel (83.3% vs. 90.5%, respectively; p = 0.04) administered to oldest patients. The response rate was 25.6% (group 1 vs. 2: 20.0% vs. 29.7%; p = 0.12). After a median follow-up of 26.5 months, median overall survival (OS) and progression-free survival (PFS) were similar between the groups (p > 0.05). The starting dose of Gem-Nab did not affect PFS and OS (p > 0.05).

Conclusion: Gem-Nab is active and effective in older patients with mPC, with the results in line with the general mPC population enrolled in clinical trials. Mild dose modifications for elderly patients might be considered to improve safety without impairing efficacy.
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http://dx.doi.org/10.1016/j.ejca.2020.06.031DOI Listing
September 2020

Utility of neutrophil-to-lymphocyte ratio to identify long-term survivors among HCC patients treated with sorafenib.

Medicine (Baltimore) 2020 May;99(22):e19958

Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.

Sorafenib is the first multikinase inhibitor demonstrating a survival benefit for patients suffering from advanced hepatocellular carcinoma (HCC). However, 1 issue remains open: what is the factor able to predict which patients will be long survivors?In the present study, we harnessed the potential of conditional survival, aiming at estimating the probability that a patient receiving sorafenib survives for more than 3 years.The present multicentric study was conducted on a cohort of 438 HCC patients. The primary end point was conditional overall survival. Kaplan-Meier survival analysis was used to calculate conditional overall survival probabilities at 3 years.The 3-year conditional survival of patients without disease progression highlights that NLR and ECOG are the factors that most accurately predict the probability of long survival. The 3-year conditional survival of patients with disease progression showed a medium effect size for HCV status, alpha-fetoprotein and NLR at all time-points. Macro-vascular portal vein invasion, extra hepatic disease, and BCLC we have a large effect size at 6 months and a medium effect size at 12 and 24 months.Our findings support the use of baseline NLR for the identification of patients with a higher probability of long-survival. NLR should be used as a stratification factor in the forthcoming clinical trials on the drugs for the advanced HCC now in pipeline.
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http://dx.doi.org/10.1097/MD.0000000000019958DOI Listing
May 2020

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

Clin Cancer Res 2020 09 5;26(17):4485-4493. Epub 2020 May 5.

Medical Oncology, University Hospital of Cagliari, Cagliari, Italy.

Purpose: 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 () and 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 (rs2070744) and 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. rs2070744 CC/CT genotypes were significantly associated with a higher median PFS (5.9 months vs. 2.4 months; HR = 0.43; = 0.0007) and OS (15.7 months vs. 8.6 months; HR = 0.38; < 0.0001) compared with TT genotype. There was no statistically significant association between rs55633437 TT/GT genotypes and PFS (2.4 months vs. 5.7 months; HR = 1.93; = 0.0833) and OS (15.1 months vs. 13.0 months; HR = 2.68; = 0.55) when compared with the other genotype. Following adjustment for clinical covariates, multivariate analysis confirmed as an independent prognostic factor for PFS (HR = 0.50; = 0.0128) and OS (HR = 0.29; = 0.0041).

Conclusions: The INNOVATE study met the primary endpoint, confirming that patients with advanced HCC with rs2070744 CC/CT genotypes had a better prognosis with respect to TT genotype patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3897DOI Listing
September 2020

Could Inflammatory Indices and Metabolic Syndrome Predict the Risk of Cancer Development? Analysis from the Bagnacavallo Population Study.

J Clin Med 2020 Apr 20;9(4). Epub 2020 Apr 20.

Department of Internal Medicine, Degli Infermi Hospital, 48018 Faenza, Italy.

Background: Despite the robust data available on inflammatory indices (neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)) and clinical outcome in oncological patients, their utility as a predictor of cancer incidence in the general population has not been reported in literature.

Methods: The Bagnacavallo study was performed between October 2005 and March 2009. All citizens of Bagnacavallo (Ravenna, Emilia-Romagna, Italy) aged 30-60 years as of January 2005 were eligible and were invited by written letter to participate to the study. All participants underwent a detailed clinical history and physical examination following the model of the Dionysos Study. All blood values included in the analysis were obtained the day of physical examination. Cancer incidence data were obtained from the population-based Romagna Cancer Registry, which operates according to standard methods. The aim of this analysis was to examine the association between metabolic syndrome and baseline SII, NLR, and PLR levels, and the diagnosis of an invasive cancer in the Bagnacavallo study cohort.

Results: At univariate analysis, metabolic syndrome was not associated with an increase of cancer incidence (HR 1.30; = 0.155). High glucose (HR 1.49; = 0.0.16), NLR HR 1.54, = 0.002), PLR (HR 1.58, = 0.001), and SII (HR 1.47, = 0.006) were associated with an increase of cancer incidence. After adjusting for clinical covariates (smoking, physical activity, education, age, and gender) SII, PLR, and NLR remained independent prognostic factors for the prediction of cancer incidence.

Conclusions: Inflammatory indices are promising, easy to perform, and inexpensive tools for identifying patients with higher risk of cancer in cancer-free population.
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http://dx.doi.org/10.3390/jcm9041177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231063PMC
April 2020

Is There an Optimal Choice in Refractory Colorectal Cancer? A Network Meta-Analysis.

Clin Colorectal Cancer 2020 06 17;19(2):82-90.e9. Epub 2020 Mar 17.

Division of Oncology, Department of Oncology and Hematology, University Hospital Modena, Modena, Italy.

Background: In the absence of head-to-head comparison studies, the present network meta-analysis evaluated and compared the efficacy of 4 therapeutic alternatives for refractory colorectal cancer.

Materials And Methods: The search focused on results from phase III randomized controlled trials. Separate (subgroup) network meta-analyses were conducted to obtain drug comparisons stratified by various patient characteristics. The principal outcome of interest was overall survival (OS).

Results: No difference in OS was found between regorafenib and TAS-102. For a rectal primary location, TAS-102 conferred benefit versus placebo (hazard ratio [HR], 0.671), but regorafenib did not (HR, 0.950). For patients aged > 65 years, TAS-102 showed benefit versus placebo (HR, 0.579) but regorafenib did not (HR, 0.816). For patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 in the indirect comparison, regorafenib showed benefit versus placebo (HR, 0.687), as did TAS-102 (HR, 0.756) but with a lower advantage. For patients with RAS wild type not previously treated with anti-EGFR antibodies, panitumumab was the optimal choice for OS.

Conclusions: No differences in OS were found between regorafenib and TAS-102. Possible greater efficacy was found for TAS-102 compared with regorafenib for patients with a rectal primary location, ECOG PS > 0, and age > 65 years. In contrast, regorafenib showed possible greater effectiveness for patients with ECOG PS 0 and age < 65 years. In the RAS WT population, the anti-EGFR drug showed superiority with respect to TAS-102 and regorafenib. These results should be viewed as only exploratory, and further prospective studies are warranted to validate these data.
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http://dx.doi.org/10.1016/j.clcc.2019.10.001DOI Listing
June 2020

H-NMR Based Serum Metabolomics Highlights Different Specific Biomarkers between Early and Advanced Hepatocellular Carcinoma Stages.

Cancers (Basel) 2020 Jan 18;12(1). Epub 2020 Jan 18.

Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.

The application of non-targeted serum metabolomics profiling represents a noninvasive tool to identify new clinical biomarkers and to provide early diagnostic differentiation, and insight into the pathological mechanisms underlying hepatocellular carcinoma (HCC) progression. In this study, we used proton Nuclear Magnetic Resonance (H-NMR) Spectroscopy and multivariate data analysis to profile the serum metabolome of 64 HCC patients, in early (n = 28) and advanced (n = 36) disease stages. We found that H-NMR metabolomics profiling could discriminate early from advanced HCC patients with a cross-validated accuracy close to 100%. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed significant changes in serum glucose, lactate, lipids and some amino acids, such as alanine, glutamine, 1-methylhistidine, lysine and valine levels between advanced and early HCC patients. Moreover, in early HCC patients, Kaplan-Meier analysis highlighted the serum tyrosine level as a predictor for overall survival (OS). Overall, our analysis identified a set of metabolites with possible clinical and biological implication in HCC pathophysiology.
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http://dx.doi.org/10.3390/cancers12010241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016798PMC
January 2020

Impact of Baseline Characteristics on the Overall Survival of HCC Patients Treated with Sorafenib: Ten Years of Experience.

Gastrointest Tumors 2019 Oct 12;6(3-4):92-107. Epub 2019 Sep 12.

Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy.

Background: Sorafenib has been established as the standard of care for patients with advanced hepatocellular carcinoma (HCC) since 2007 on the basis of two landmark trials (SHARP and Asia-Pacific). Ten years have passed since then and, despite much research in the field, still no validated real-life prognostic markers are available for HCC patients treated with this drug. Therefore, going through 10 years of research into sorafenib of several Italian Cancer Centers, we conducted a field-practice study aimed at identifying baseline clinical factors that could be significantly associated with overall survival (OS).

Method: Univariate/multivariate analyses were conducted to retrospectively identify the impact of baseline characteristics on the OS of 398 advanced HCC patients treated with sorafenib.

Results: Based on univariate analysis, α-fetoprotein (AFP), albumin, AST, bilirubin, Child-Pugh, ECOG, systemic immune-inflammation index (SII), albumin-bilirubin (ALBI) grade, and portal vein thrombosis were significantly associated with shorter OS. Following adjustment for clinical covariates positive in univariate analysis, the multivariate analysis including AFP, age, etiology, albumin, aspartate transaminase (AST), bilirubin, Child-Pugh, LDH, platelet-to-lymphocyte ratio, ECOG, ALBI grade, portal vein thrombosis, SII, and BCLC stage identified increase in LDH, age >70 years, no viral etiologies, ECOG >0, albumin <35, ALBI grade 2, and AST >40 as prognostic factors for poorer OS based on the 5% significance level.

Conclusion: Our study highlights that baseline hepatic function, patient-centered variables, and etiology have prognostic value. These findings might have implications in terms of therapeutic decision-making and patient counseling.
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http://dx.doi.org/10.1159/000502714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873043PMC
October 2019

Prognostic Role of a New Index (RAPID Index) in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib: Training and Validation Cohort.

Gastrointest Tumors 2019 Oct 20;6(3-4):71-80. Epub 2019 Aug 20.

Unit of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.

Background And Aims: The aim of the present study is to evaluate a new index influenced by the balance between the immune system, α-fetoprotein (AFP), and lactate dehydrogenase (LDH) (RAPID index) as a prognostic factor in patients treated with sorafenib.

Methods: This study was conducted on a training cohort of 159 hepatocellular carcinoma (HCC) patients and a validation cohort of 68 HCC patients treated with sorafenib. The RAPID index was calculated as neutrophil/lymphocyte count × LDH × AFP.

Results: In the training cohort, the median overall survival (OS) was 23.2 months (95% CI 11-25) and 12.1 months (95% CI 9-15) for patients with a low (≤3,226) and high (>3,226) RAPID index, respectively (ref. <3,226, HR = 0.56, 95% CI 0.35-0.88, = 0.017). Following adjustment for clinical covariates, multivariate analysis confirmed the RAPID index ≤3,226 versus >3,226 (HR = 0.37, 95% CI 0.18-0.74, = 0.0054) as an independent prognostic factor for OS. In the validation cohort, the median OS was 26.9 months (95% CI 17.6-26.9) and 7.0 months (95% CI 6.2-9.2) for patients with a low (≤ 3,226) and high (>3,226) RAPID index, respectively (ref. <3,226, HR = 0.19, 95% CI 0.10-0.36, < 0.0001). Performing the same multivariate analysis of the training cohort (AFP, Eastern Cooperative Oncology Group, aspartate aminotransferase, neutrophil, platelet, systemic inflammatory index and RAPID index), the RAPID index <3,226 versus >3,226 (HR = 3.86, 95% CI 1.45-10.29, = 0.007) was found to be an independent prognostic factor for predicting OS.

Conclusion: The low cost, easy assessment, and reproducibility of a full blood count make the RAPID index a promising tool for assessing HCC prognosis in future clinical practice.
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http://dx.doi.org/10.1159/000501593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873000PMC
October 2019

Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients.

J Hepatol 2019 12 23;71(6):1175-1183. Epub 2019 Aug 23.

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Background & Aims: Sorafenib is associated with multiple adverse events (AEs), potentially causing its permanent interruption. It is unknown how physicians' experience has impacted on the management of these AEs and consequently on clinical outcomes. We aimed to assess whether AE management changed over time and if these modifications impacted on treatment duration and overall survival (OS).

Methods: We analysed the prospectively collected data of 338 consecutive patients who started sorafenib between January 2008 and December 2017 in 3 tertiary care centres in Italy. Patients were divided according to the starting date: Group A (2008-2012; n = 154), and Group B (2013-2017, n = 184). Baseline and follow-up data were compared. In the OS analysis, patients who received second-line treatments were censored when starting the new therapy.

Results: Baseline characteristics, AEs, and radiological response were consistent across groups. Patients in Group B received a lower median daily dose (425 vs. 568 mg/day, p <0.001) due to more frequent dose modifications. However, treatment duration was longer (5.8 vs. 4.1 months, p = 0.021) with a trend toward a higher cumulative dose in Group B. Notably, the OS was also higher (12.0 vs. 11.0 months, p = 0.003) with a sharp increase in the 2-year survival rate (28.1 vs. 18.4%, p = 0.003) in Group B. Multivariate time-dependent Cox regression analysis confirmed later period of treatment (2013-2017) as an independent predictor of survival (HR 0.728; 95%CI 0.581-0.937; p = 0.013). Unconsidered confounders were unlikely to affect these results at the sensitivity analysis.

Conclusions: Experience in the management of sorafenib-related AEs prolongs treatment duration and survival. This factor should be considered in the design of future randomised clinical trials including a sorafenib treatment arm, as an underestimate of sample size may derive.

Lay Summary: Sorafenib has been the standard frontline systemic treatment for hepatocellular carcinoma for over a decade. Its tolerability is limited by different adverse events, which might lead to its permanent discontinuation in a sizeable proportion of patients. After a careful analysis of potential confounders, we demonstrated that the physicians' experience in managing adverse events related to sorafenib has improved over time, with longer treatment periods and less permanent discontinuation for toxicities. More importantly, these improvements also translated into longer patient survival. Our results have relevant repercussions in clinical practice and in the design of future clinical trials.
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http://dx.doi.org/10.1016/j.jhep.2019.08.015DOI Listing
December 2019

and Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib.

Cancers (Basel) 2019 Jul 20;11(7). Epub 2019 Jul 20.

Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, 41121 Modena, Italy.

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 () and endothelial-derived nitric oxide synthase () genes in 135 patients with advanced HCC receiving sorafenib. Eight polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, rs55633437 and rs2070744 were associated with OS and PFS. In particular, patients with rs55633437 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, < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73-8.35, < 0.001) than those homozygous for the G allele. Moreover, patients with rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44-0.97; 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30-0.63; < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that rs55633437 and rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib.
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http://dx.doi.org/10.3390/cancers11071023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679015PMC
July 2019

MSC-Delivered Soluble TRAIL and Paclitaxel as Novel Combinatory Treatment for Pancreatic Adenocarcinoma.

Theranostics 2019 1;9(2):436-448. Epub 2019 Jan 1.

Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.

Pancreatic cancer is the fourth leading cause of cancer death in western countries with more than 100,000 new cases per year in Europe and a mortality rate higher than 90%. In this scenario, advanced therapies based on gene therapies are emerging, thanks to a better understanding of tumour architecture and cancer cell alterations. We have demonstrated the efficacy of an innovative approach for pancreatic cancer based on mesenchymal stromal cells (MSC) genetically engineered to produce TNF-related Apoptosis Inducing Ligand (TRAIL). Here we investigated the combination of this MSC-based approach with the administration of a paclitaxel (PTX)-based chemotherapy to improve the potential of the treatment, also accounting for a possible resistance onset. Starting from the BXPC3 cell line, we generated and profiled a TRAIL-resistant model of pancreatic cancer, testing the impact of the combined treatment with specific cytotoxicity and metabolic assays. We then challenged the rationale in a subcutaneous mouse model of pancreatic cancer, assessing its effect on tumour size accounting stromal and parenchymal organization. PTX was able to restore pancreatic cancer sensitivity to MSC-delivered TRAIL by reverting its pro-survival gene expression profile. The two compounds cooperate both and and the combined treatment resulted in an improved cytotoxicity on tumour cells. In summary, this study uncovers the potential of a combinatory approach between MSC-delivered TRAIL and PTX, supporting the combination of cell-based products and conventional chemotherapeutics as a tool to improve the efficacy of the treatments, also addressing possible mechanisms of resistance.
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http://dx.doi.org/10.7150/thno.27576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376176PMC
December 2019

Soluble TRAIL Armed Human MSC As Gene Therapy For Pancreatic Cancer.

Sci Rep 2019 02 11;9(1):1788. Epub 2019 Feb 11.

Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.

Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive adult cancers with an unacceptable prognosis. For this reason novel therapies accounting for PDAC peculiarities, such as the relevant stromal reaction, are urgently needed. Here adipose mesenchymal stromal/stem cells (AD-MSC) have been armed to constantly release a soluble trimeric and multimeric variant of the known anti-cancer TNF-related apoptosis-inducing ligand (sTRAIL). This cancer gene therapy strategy was in vitro challenged demonstrating that sTRAIL was thermally stable and able to induce apoptosis in the PDAC lines BxPC-3, MIA PaCa-2 and against primary PDAC cells. sTRAIL released by AD-MSC relocated into the tumor stroma was able to significantly counteract tumor growth in vivo with a significant reduction in tumor size, in cytokeratin-7+ cells and by an anti-angiogenic effect. In parallel, histology on PDAC specimens form patients (n = 19) was performed to investigate the levels of TRAIL DR4, DR5 and OPG receptors generating promising insights on the possible clinical translation of our approach. These results indicate that adipose MSC can very efficiently vehicle a novel TRAIL variant opening unexplored opportunities for PDAC treatment.
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http://dx.doi.org/10.1038/s41598-018-37433-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370785PMC
February 2019

Soluble TRAIL Armed Human MSC As Gene Therapy For Pancreatic Cancer.

Sci Rep 2019 02 11;9(1):1788. Epub 2019 Feb 11.

Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.

Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive adult cancers with an unacceptable prognosis. For this reason novel therapies accounting for PDAC peculiarities, such as the relevant stromal reaction, are urgently needed. Here adipose mesenchymal stromal/stem cells (AD-MSC) have been armed to constantly release a soluble trimeric and multimeric variant of the known anti-cancer TNF-related apoptosis-inducing ligand (sTRAIL). This cancer gene therapy strategy was in vitro challenged demonstrating that sTRAIL was thermally stable and able to induce apoptosis in the PDAC lines BxPC-3, MIA PaCa-2 and against primary PDAC cells. sTRAIL released by AD-MSC relocated into the tumor stroma was able to significantly counteract tumor growth in vivo with a significant reduction in tumor size, in cytokeratin-7+ cells and by an anti-angiogenic effect. In parallel, histology on PDAC specimens form patients (n = 19) was performed to investigate the levels of TRAIL DR4, DR5 and OPG receptors generating promising insights on the possible clinical translation of our approach. These results indicate that adipose MSC can very efficiently vehicle a novel TRAIL variant opening unexplored opportunities for PDAC treatment.
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http://dx.doi.org/10.1038/s41598-018-37433-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370785PMC
February 2019
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