Publications by authors named "Martina De Siena"

9 Publications

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Liver function following hepatitis C virus eradication by direct acting antivirals in patients with liver cirrhosis: data from the PITER cohort.

BMC Infect Dis 2021 May 4;21(1):413. Epub 2021 May 4.

Center for Global Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.

Background: The development of direct-acting antivirals (DAA) for HCV has revolutionized the treatment of HCV, including its treatment in patients with HIV coinfection. The aim of this study was to compare the changes in liver function between coinfected and monoinfected patients with cirrhosis who achieved HCV eradication by DAA.

Methods: Patients with pre-treatment diagnosis of HCV liver cirrhosis, consecutively enrolled in the multicenter PITER cohort, who achieved a sustained virological response 12 weeks after treatment cessation (SVR12) were analysed. Changes in Child-Pugh (C-P) class and the occurrence of a decompensating event was prospectively evaluated after the end of DAA treatment. Cox regression analysis was used to evaluate factors independently associated with changes in liver function following viral eradication.

Results: We evaluated 1350 patients, of whom 1242 HCV monoinfected (median follow-up 24.7, range 6.8-47.5 months after viral eradication) and 108 (8%) HCV/HIV coinfected (median follow-up 27.1, range 6.0-44.6). After adjusting for age, sex, HCV-genotype, HBsAg positivity and alcohol use, HIV was independently associated with a more advanced liver disease before treatment (C-P class B/C vs A) (OR: 3.73, 95% CI:2.00-6.98). Following HCV eradication, C-P class improved in 17/20 (85%) coinfected patients (from B to A and from C to B) and in 53/82 (64.6%) monoinfected patients (from B to A) (p = 0.08). C-P class worsened in 3/56 coinfected (5.3%) (from A to B) and in 84/1024 (8.2%) monoinfected patients (p = 0.45) (from A to B or C and from B to C). Baseline factors independently associated with C-P class worsening were male sex (HR = 2.00; 95% CI = 1.18-3.36), platelet count < 100,000/μl (HR = 1.75; 95% CI 1.08-2.85) and increased INR (HR = 2.41; 95% CI 1.51-3.84). Following viral eradication, in 7 of 15 coinfected (46.6%) and in 61 of 133 (45.8%) monoinfected patients with previous history of decompensation, a new decompensating event occurred. A first decompensating event was recorded in 4 of 93 (4.3%) coinfected and in 53 of 1109 (4.8%) monoinfected patients (p = 0.83).

Conclusions: Improvement of liver function was observed following HCV eradication in the majority of patients with cirrhosis; however viral eradication did not always mean cure of liver disease in both monoinfected and coinfected patients with advanced liver disease.
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http://dx.doi.org/10.1186/s12879-021-06053-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094561PMC
May 2021

Feasibility and safety of a new endoscopic synthetic sealant nebulizing device over gastric endoscopic submucosal dissections.

Surg Endosc 2021 Jul 13;35(7):4048-4054. Epub 2021 Apr 13.

Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

Background: Endoscopic Submucosal Dissection (ESD) is the treatment of choice of superficial neoplastic gastrointestinal lesions. Delayed bleedings and perforations are still current clinical concerns. Glubran 2 is a synthetic cyanoacrylate-derived glue nowadays already widely used as an effective tissue adhesive. ENDONEB is a novel device thought for enabling the sealant nebulization over a specific targeted surface during laparotomy, laparoscopy, and thoracotomy. The aim of this single-center preclinical animal trial is to evaluate the feasibility and safety of the same nebulization technique during ESD in the perspective that further clinical studies would demonstrate the efficacy of Glubran 2 in preventing post-ESD adverse events.

Methods: Four live Landrace pigs were enrolled. Two approximately 30-mm-wide gastric ESDs were performed in each pig (experimental ESD and control ESD). About 0.5 mL of Glubran 2 was nebulized on the experimental ESDs. Subjective perception of the feasibility of the Glubran 2 nebulization was reported. Pigs were clinically monitored at follow-up and upper GI endoscopy was performed at 24 and 48 hours, when animals were euthanized to perform a macroscopic and histological analysis of the specimens.

Results: No peri-procedural adverse events were reported. Glubran 2 nebulization over experimental ESDs showed to be technically easy and time-effective. Clinical and endoscopic animal monitoring was negative at follow-up. At 24 hours, the Glubran 2 film was clearly visible on the eschar of the ESDs and signs of initial hydrolysis were discernable at 48 hours. No signs of peritoneal reaction were observed at the macroscopic examination. Equal transmural inflammation was described at the histological examination of both types of ESDs.

Conclusions: Safety and feasibility profiles of Glubran 2 nebulizing ENDONEB device over ESD surfaces were excellent. Further evidences and human trials are needed to investigate its effectiveness in ESDs' eschars sealing and, thus, in delayed micro-perforations and bleedings prevention and treatment.
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http://dx.doi.org/10.1007/s00464-021-08480-4DOI Listing
July 2021

Gut and Reproductive Tract Microbiota Adaptation during Pregnancy: New Insights for Pregnancy-Related Complications and Therapy.

Microorganisms 2021 Feb 25;9(3). Epub 2021 Feb 25.

Unità Operativa Complessa (UOC) di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy.

Pregnancy is characterized by maternal adaptations that are necessary to create a welcoming and hospitable environment for the fetus. Studies have highlighted how the microbiota modulates several networks in humans through complex molecular interactions and how dysbiosis (defined as quantitative and qualitative alterations of the microbiota communities) is related to human pathologies including gynecological diseases. This review analyzed how maternal uterine, vaginal, and gut microbiomes could impact on fetus health during the gestational period. We evaluated the role of a dysbiotic microbiota in preterm birth, chorioamnionitis, gestational diabetes mellitus and pre-eclampsia. For many years it has been hypothesized that newborns were sterile organisms but in the past few years this paradigm has been questioned through the demonstration of the presence of microbes in the placenta and meconium. In the future, we should go deeper into the concept of in utero colonization to better understand the role of microbiota through the phases of pregnancy. Numerous studies in the literature have already showed interesting results regarding the role of microbiota in pregnancy. This evidence gives us the hope that microbiota modulation could be a novel strategy to reduce the morbidity and mortality related to pregnancy complications in the future.
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http://dx.doi.org/10.3390/microorganisms9030473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996258PMC
February 2021

Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis.

Oncogene 2021 Mar 18;40(11):1957-1973. Epub 2021 Feb 18.

Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, CA, USA.

Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.
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http://dx.doi.org/10.1038/s41388-021-01685-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979540PMC
March 2021

From obesity through gut microbiota to cardiovascular diseases: a dangerous journey.

Int J Obes Suppl 2020 Jul 20;10(1):35-49. Epub 2020 Jul 20.

Unit of Endocrinology, Dipartimento di Medicina Clinica e Chirurgia, Federico II University, 80131 Naples, Italy.

The co-existence of humans and gut microbiota started millions of years ago. Until now, a balance gradually developed between gut bacteria and their hosts. It is now recognized that gut microbiota are key to form adequate immune and metabolic functions and, more in general, for the maintenance of good health. Gut microbiota are established before birth under the influence of maternal nutrition and metabolic status, which can impact the future metabolic risk of the offspring in terms of obesity, diabetes, and cardiometabolic disorders during the lifespan. Obesity and diabetes are prone to disrupt the gut microbiota and alter the gut barrier permeability, leading to metabolic endotoxaemia with its detrimental consequences on health. Specific bacterial sequences are now viewed as peculiar signatures of the metabolic syndrome across life stages in each individual, and are linked to pathogenesis of cardiovascular diseases (CVDs) via metabolic products (metabolites) and immune modulation. These mechanisms have been linked, in association with abnormalities in microbial richness and diversity, to an increased risk of developing arterial hypertension, systemic inflammation, nonalcoholic fatty liver disease, coronary artery disease, chronic kidney disease, and heart failure. Emerging strategies for the manipulation of intestinal microbiota represent a promising therapeutic option for the prevention and treatment of CVD especially in individuals prone to CV events.
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http://dx.doi.org/10.1038/s41367-020-0017-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371682PMC
July 2020

Neoadjuvant treatment in pancreatic cancer: Evidence-based medicine? A systematic review and meta-analysis.

Med Oncol 2017 May 8;34(5):85. Epub 2017 Apr 8.

Division of General Surgery, Department of Medical and Surgical Sciences and Translational Medicine, UOC Chirurgia 3, Sapienza University, St. Andrea Hospital, Via di Grottarossa 1035-1039, 00189, Rome, Italy.

Neoadjuvant treatment in non-metastatic pancreatic cancer (PaC) has the theoretical advantages of downstaging the tumor, sterilizing any present systemic undetectable disease, selecting patients for surgery and administering therapy to each patient. The aim of this systematic review is to analyze the state of the art on neoadjuvant protocols for non-metastatic PaC. A literature search over the last 10 years was conducted, and papers had to be focused on resectable, borderline resectable (BLR) or locally advanced (LA) histo- or cytologically proven PaC; to be prospective studies or prospectively collected databases; to report percentage of protocol achievement and survival data at least in an intention-to-treat (ITT) analysis. Twelve studies were eligible for systematic review. Studies included a total of 624 patients: 248 resectable, 268 BLR, 71 LA and 37 non-specified. All studies were included for meta-analysis. ITT overall survival (OS) was 16.7 months (95% CI 15.16-18.26 months); for resected patients OS was 22.78 months (95% CI 20.42-25.16), and for eventually non-resected patients it was 9.89 months (95% CI 8.84-10.96). Neoadjuvant approaches for resectable, BLR and LA PaC are spreading. Outcomes tend to be better outside an RCT context, but strong evidences are lacking. Actually such treatments should be performed only in a randomized clinical trial setting.
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http://dx.doi.org/10.1007/s12032-017-0951-0DOI Listing
May 2017

Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic and Notch Pathway Mutations.

JCO Precis Oncol 2017 15;2017. Epub 2017 Aug 15.

University of California, San Diego, La Jolla, CA.

Purpose: GI stromal tumors (GISTs) are commonly associated with somatic mutations in and . However, a subset arises from mutations in , most commonly associated with neurofibromatosis type 1. We define the anatomic distribution of alterations in GIST.

Methods: We describe the demographic/clinicopathologic features of 177 patients from two institutions whose GISTs underwent next-generation sequencing of ≥315 cancer-related genes.

Results: We initially identified six (9.7%) of 62 GISTs with genomic alterations from the first cohort. Of these six patients, five (83.3%) had unifocal tumors at the duodenal-jejunal flexure (DJF). Two additional patients with DJF GISTs had non- ( and ) genomic alterations. After excluding one DJF GIST with an single nucleotide polymorphism, four (57.1%) of seven sequenced DJF tumors demonstrated deleterious alterations, whereas only one (1.8%) of 55 sequenced non-DJF GISTs had a deleterious somatic mutation ( < .001). One patient with DJF GIST had a germline variant that was associated with incomplete penetrance of clinical neurofibromatosis type 1 features along with a somatic mutation. Of the five DJF GISTs with any alteration, three (60%) had mutations, and three (60%) had Notch pathway mutations (, , ). We validated these findings in a second cohort of 115 GISTs, where two (40%) of five unifocal -mutated GISTs arose at the DJF, and one of these also had a Notch pathway mutation ().

Conclusion: Broad genomic profiling of adult GISTs has revealed that alterations are enriched in DJF GISTs. These tumors also may harbor concurrent activating and/or inactivating Notch pathway mutations. In some cases, germline genetic testing may be appropriate for patients with DJF GISTs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013064PMC
http://dx.doi.org/10.1200/PO.17.00014DOI Listing
August 2017

FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors.

J Transl Med 2016 12 14;14(1):339. Epub 2016 Dec 14.

School of Medicine, University of California San Diego, La Jolla, CA, USA.

Background: About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.

Methods: We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.

Results: We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1-HOOK3, FGFR1-TACC1) and one harbored an ETV6-NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1-TACC1 and ETV6-NTRK3 fusions.

Conclusions: Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST. Trial registration NCT 02576431. Registered October 12, 2015.
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http://dx.doi.org/10.1186/s12967-016-1075-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157084PMC
December 2016

Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression.

Oncotarget 2016 Nov;7(48):78226-78241

Department of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.

Gastrointestinal stromal tumors (GIST) arise within the interstitial cell of Cajal (ICC) lineage due to activating KIT/PDGFRA mutations. Both ICC and GIST possess primary cilia (PC), which coordinate PDGFRA and Hedgehog signaling, regulators of gastrointestinal mesenchymal development. Therefore, we hypothesized that Hedgehog signaling may be altered in human GIST and controls KIT expression. Quantitative RT-PCR, microarrays, and next generation sequencing were used to describe Hedgehog/PC-related genes in purified human ICC and GIST. Genetic and pharmacologic approaches were employed to investigate the effects of GLI manipulation on KIT expression and GIST cell viability. We report that Hedgehog pathway and PC components are expressed in ICC and GIST and subject to dysregulation during GIST oncogenesis, irrespective of KIT/PDGFRA mutation status. Using genomic profiling, 10.2% of 186 GIST studied had potentially deleterious genomic alterations in 5 Hedgehog-related genes analyzed, including in the PTCH1 tumor suppressor (1.6%). Expression of the predominantly repressive GLI isoform, GLI3, was inversely correlated with KIT mRNA levels in GIST cells and non-KIT/non-PDGFRA mutant GIST. Overexpression of the 83-kDa repressive form of GLI3 or small interfering RNA-mediated knockdown of the activating isoforms GLI1/2 reduced KIT mRNA. Treatment with GLI1/2 inhibitors, including arsenic trioxide, significantly increased GLI3 binding to the KIT promoter, decreased KIT expression, and reduced viability in imatinib-sensitive and imatinib-resistant GIST cells. These data offer new evidence that genes necessary for Hedgehog signaling and PC function in ICC are dysregulated in GIST. Hedgehog signaling activates KIT expression irrespective of mutation status, offering a novel approach to treat imatinib-resistant GIST.
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http://dx.doi.org/10.18632/oncotarget.12909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346634PMC
November 2016