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Article ; Online: Reprogrammed mitochondria: a central hub of cancer cell metabolism.

Ciccarone, Fabio / Ciriolo, Maria Rosa

2024

Abstract: Mitochondria represent the metabolic hub of normal cells and play this role also in cancer but with different functional purposes. While cells in differentiated tissues have the prerogative of maintaining basal metabolism and support the biosynthesis of ... ...

Abstract	Mitochondria represent the metabolic hub of normal cells and play this role also in cancer but with different functional purposes. While cells in differentiated tissues have the prerogative of maintaining basal metabolism and support the biosynthesis of specialized products, cancer cells have to rewire the metabolic constraints imposed by the differentiation process. They need to balance the bioenergetic supply with the anabolic requirements that entail the intense proliferation rate, including nucleotide and membrane lipid biosynthesis. For this aim, mitochondrial metabolism is reprogrammed following the activation of specific oncogenic pathways or due to specific mutations of mitochondrial proteins. The main process leading to mitochondrial metabolic rewiring is the alteration of the tricarboxylic acid cycle favoring the appropriate orchestration of anaplerotic and cataplerotic reactions. According to the tumor type or the microenvironmental conditions, mitochondria may decouple glucose catabolism from mitochondrial oxidation in favor of glutaminolysis or disable oxidative phosphorylation for avoiding harmful production of free radicals. These and other metabolic settings can be also determined by the neo-production of oncometabolites that are not specific for the tissue of origin or the accumulation of metabolic intermediates able to boost pro-proliferative metabolism also impacting epigenetic/transcriptional programs. The full characterization of tumor-specific mitochondrial signatures may provide the identification of new biomarkers and therapeutic opportunities based on metabolic approaches.
Language	English
Publishing date	2024-05-08
Publishing country	England
Document type	Journal Article
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20231090
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Article: Editorial: Hallmark of cancer: sustained proliferative signalling.

Ciccarone, Fabio / Ciriolo, Maria Rosa

Frontiers in oncology

2023 Volume 13, Page(s) 1328827

Language	English
Publishing date	2023-11-23
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1328827
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Article: Use of oral GnRH antagonists combined therapy in the management of symptomatic uterine fibroids.

Di Spiezio Sardo, A / Ciccarone, F / Muzii, L / Scambia, G / Vignali, M

Facts, views & vision in ObGyn

2023 Volume 15, Issue 1, Page(s) 29–33

Abstract: Uterine fibroids have an impact on women's lives due to their high prevalence, physical symptoms, their consequences on patients' emotional and psychological well-being and loss of work productivity. The choice of therapeutical approaches varies ... ...

Abstract	Uterine fibroids have an impact on women's lives due to their high prevalence, physical symptoms, their consequences on patients' emotional and psychological well-being and loss of work productivity. The choice of therapeutical approaches varies depending on several factors, and therefore should be applied individually. Currently, there is an unmet need for good, reliable, uterine-sparing options. The oral GnRH antagonists (Elagolix, Relugolix, Linzagolix) represent a new alternative for the medical management of hormone-dependent gynaecological diseases such as uterine fibroids or endometriosis. They rapidly bind to the GnRH receptor, block endogenous GnRH activity and directly suppress LH and FSH production, avoiding unwanted flare-up effects. Some GnRH antagonists are marketed in combination with hormone replacement therapy add-back to counteract hypo-oestrogenic side effects. According to the registration trials, once-daily GhRH antagonist combination therapy results in a significant reduction in menstrual bleeding, as compared with placebo, and preserves bone mineral density, for up to 104 weeks. Further studies in the long term are needed to evaluate the whole impact of medical treatment of uterine fibroids on the management of this common women's disease.
Language	English
Publishing date	2023-04-03
Publishing country	Belgium
Document type	Journal Article
ZDB-ID	2701574-9
ISSN	2032-0418 ; 2684-4230
ISSN	2032-0418 ; 2684-4230
DOI	10.52054/FVVO.15.1.059
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Article ; Online: A cost-effectiveness analysis of an integrated clinical-radiogenomic screening program for the identification of BRCA 1/2 carriers (e-PROBE study).

Di Pilla, A / Nero, C / Specchia, M L / Ciccarone, F / Boldrini, L / Lenkowicz, J / Alberghetti, B / Fagotti, A / Testa, A C / Valentini, V / Sala, E / Scambia, G

Scientific reports

2024 Volume 14, Issue 1, Page(s) 928

Abstract: Current approach to identify BRCA 1/2 carriers in the general population is ineffective as most of the carriers remain undiagnosed. Radiomics is an emerging tool for large scale quantitative analysis of features from standard diagnostic imaging and has ... ...

Abstract	Current approach to identify BRCA 1/2 carriers in the general population is ineffective as most of the carriers remain undiagnosed. Radiomics is an emerging tool for large scale quantitative analysis of features from standard diagnostic imaging and has been applied also to identify gene mutational status. The objective of this study was to evaluate the clinical and economic impact of integrating a radiogenomics model with clinical and family history data in identifying BRCA mutation carriers in the general population. This cost-effective analysis compares three different approaches to women selection for BRCA testing: established clinical criteria/family history (model 1); established clinical criteria/family history and the currently available radiogenomic model (49% sensitivity and 87% specificity) based on ultrasound images (model 2); same approach used in model 2 but simulating an improvement of the performances of the radiogenomic model (80% sensitivity and 95% specificity) (model 3). All models were trained with literature data. Direct costs were calculated according to the rates currently used in Italy. The analysis was performed simulating different scenarios on the generation of 18-year-old girls in Italy (274,000 people). The main outcome was to identify the most effective model comparing the number of years of BRCA-cancer healthy life expectancy (HLYs). An incremental cost-effectiveness ratio (ICER) was also derived to determine the cost in order to increase BRCA carriers-healthy life span by 1 year. Compared to model 1, model 2 increases the detection rate of BRCA carriers by 41.8%, reduces the rate of BRCA-related cancers by 23.7%, generating over a 62-year observation period a cost increase by 2.51 €/Year/Person. Moreover, model 3 further increases BRCA carriers detection (+ 68.3%) and decrease in BRCA-related cancers (- 38.4%) is observed compared to model 1. Model 3 increases costs by 0.7 €/Year/Person. After one generation, the estimated ICER in the general population amounts to about 3800€ and 653€ in model 2 and model 3 respectively. Model 2 has a massive effect after only one generation in detecting carriers in the general population with only a small cost increment. The clinical impact is limited mainly due to the current low acceptance rate of risk-reducing surgeries. Further multicentric studies are required before implementing the integrated clinical-radiogenomic model in clinical practice.
MeSH term(s)	Humans ; Female ; Adolescent ; Cost-Effectiveness Analysis ; Genetic Carrier Screening ; Health Status ; Healthy Life Expectancy ; Neoplasms
Language	English
Publishing date	2024-01-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-51031-1
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Article ; Online: Imaging in gynecological disease (27): clinical and ultrasound characteristics of recurrent ovarian stromal cell tumors.

Moro, F / Giudice, M T / Bolomini, G / Moruzzi, M C / Mascilini, F / Quagliozzi, L / Ciccarone, F / Scambia, G / Fagotti, A / Valentin, L / Testa, A C

Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology

2024 Volume 63, Issue 3, Page(s) 399–407

Abstract: Objective: To describe the clinical and ultrasound characteristics of recurrent granulosa cell and Sertoli-Leydig cell tumors.: Methods: This was a retrospective observational study performed at Fondazione Policlinico Universitario A. Gemelli, ... ...

Abstract	Objective: To describe the clinical and ultrasound characteristics of recurrent granulosa cell and Sertoli-Leydig cell tumors. Methods: This was a retrospective observational study performed at Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS, Rome (Gemelli center), Italy. Patients with a histological diagnosis of recurrent granulosa cell tumor or Sertoli-Leydig cell tumor were identified from the database of the Department of Gynecological Oncology. Those who had undergone a preoperative ultrasound examination at the Gemelli center between 2012 and 2020 were included, and the data retrieved from the original ultrasound reports. In all of these reports, the recurrent tumors were described using International Ovarian Tumor Analysis (IOTA) terminology. If a patient had more than one episode of relapse, information from all episodes was collected. If there was more than one recurrent tumor at the same ultrasound examination, all tumors were included. One expert sonographer also reviewed all available ultrasound images to identify typical ultrasound patterns using pattern recognition. Results: We identified 30 patients with a histological diagnosis of recurrent granulosa cell tumor (25 patients, 55 tumors) or Sertoli-Leydig cell tumor (five patients, seven tumors). All 30 had undergone at least one preoperative ultrasound examination at the Gemelli center and were included. These women had a total of 66 episodes of relapse, of which a preoperative ultrasound examination had been performed at the Gemelli center in 34, revealing 62 recurrent lesions: one in 22/34 (64.7%) episodes of relapse, two in 4/34 (11.8%) episodes and three or more in 8/34 (23.5%) episodes. Most recurrent granulosa cell tumors (38/55, 69.1%) and recurrent Sertoli-Leydig tumors (6/7, 85.7%) were classified as solid or multilocular-solid tumors, while 8/55 (14.5%) recurrent granulosa cell tumors and 1/7 (14.3%) recurrent Sertoli-Leydig cell tumors were unilocular cysts and 9/55 (16.4%) recurrent granulosa cell tumors were multilocular cysts. The nine unilocular cysts had contents that were anechoic (n = 2) or had low-level echogenicity (n = 7), had either smooth (n = 4) or irregular (n = 5) internal cyst walls, and ranged in largest diameter from 8 to 38 mm, with three being < 20 mm and five being 20-30 mm. On retrospective review of the images, two typical ultrasound patterns were described: small solid tumor measuring < 2 cm (15/62, 24.2%) and tumor with vascularized echogenic ground-glass-like content (12/62, 19.4%). Conclusions: Some granulosa cell and Sertoli-Leydig cell recurrences manifest one of two typical ultrasound patterns, while some appear as unilocular cysts. These are usually classified as benign, but in patients being followed up for a granulosa cell tumor or Sertoli-Leydig cell tumor, a unilocular cyst should be considered suspicious of recurrence. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
MeSH term(s)	Pregnancy ; Male ; Humans ; Female ; Sertoli-Leydig Cell Tumor/diagnostic imaging ; Granulosa Cell Tumor/diagnostic imaging ; Neoplasm Recurrence, Local/diagnostic imaging ; Ultrasonography ; Ovarian Neoplasms/diagnostic imaging ; Sex Cord-Gonadal Stromal Tumors/diagnostic imaging ; Genital Diseases, Female ; Cysts ; Recurrence ; Stromal Cells
Language	English
Publishing date	2024-02-06
Publishing country	England
Document type	Observational Study ; Journal Article
ZDB-ID	1073183-0
ISSN	1469-0705 ; 0960-7692
ISSN (online)	1469-0705
ISSN	0960-7692
DOI	10.1002/uog.27504
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Zs.A 3214: Show issues

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Article ; Online: Radiomics analysis of ultrasound images to discriminate between benign and malignant adnexal masses with solid ultrasound morphology.

Moro, F / Vagni, M / Tran, H E / Bernardini, F / Mascilini, F / Ciccarone, F / Nero, C / Giannarelli, D / Boldrini, L / Fagotti, A / Scambia, G / Valentin, L / Testa, A C

Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology

2024

Abstract: Objective: Our primary aim was to identify radiomic ultrasound features that can distinguish benign from malignant adnexal masses with solid ultrasound morphology, and primary invasive from metastatic solid ovarian masses, and to develop ultrasound- ... ...

Abstract	Objective: Our primary aim was to identify radiomic ultrasound features that can distinguish benign from malignant adnexal masses with solid ultrasound morphology, and primary invasive from metastatic solid ovarian masses, and to develop ultrasound-based machine learning models that include radiomics features to discriminate between benign and malignant solid adnexal masses. Our secondary aim was to compare the diagnostic performance of our radiomics models with that of the ADNEX model and subjective assessment by an experienced ultrasound examiner. Methods: This is a retrospective observational single center study. Patients with a histological diagnosis of an adnexal tumor with solid morphology at preoperative ultrasound examination performed between 2014 and 2021 were included. The patient cohort was split into training and validation sets with a ratio of 70:30 and with the same proportion of benign and malignant (borderline, primary invasive and metastatic) tumors in the two subsets. The extracted radiomic features belonged to two different families: intensity-based statistical features and textural features. Models to predict malignancy were built based on a random forest classifier, fine-tuned using 5-fold cross-validation over the training set, and tested on the held-out validation set. The variables used in model building were patient's age, and those radiomic features that were statistically significantly different between benign and malignant adnexal masses (Wilcoxon-Mann-Whitney Test with Benjamini-Hochberg correction for multiple comparisons) and assessed as not redundant based on the Pearson correlation coefficient. We describe discriminative ability as area under the receiver operating characteristics curve (AUC) and classification performance as sensitivity and specificity. Results: 326 patients were identified and 775 preoperative ultrasound images were analyzed. 68 radiomic features were extracted, 52 differed statistically significantly between benign and malignant tumors in the training set, and 18 features were selected for inclusion in model building. The same 52 radiomic features differed statistically significantly between benign, primary invasive malignant and metastatic tumors. However, the values of the features manifested overlap between primary malignant and metastatic tumors and did not differ statistically significantly between them. In the validation set, 25/98 tumors (25.5%) were benign, 73/98 (74.5%) were malignant (6 borderline, 57 primary invasive, 10 metastases). In the validation set, a model including only radiomics features had an AUC of 0.80, and 78% sensitivity and 76% specificity at its optimal risk of malignancy cutoff (68% based on Youden's index). The corresponding results for a model including age and radiomics features were 0.79, 86% and 56% (cutoff 60% based on Youden's method), while those of the ADNEX model were 0.88, 99% and 64% (at 20% malignancy cutoff). Subjective assessment had sensitivity 99% and specificity 72%. Conclusions: Even though our radiomics models had discriminative ability inferior to that of the ADNEX model, our results are promising enough to justify continued development of radiomics analysis of ultrasound images of adnexal masses. This article is protected by copyright. All rights reserved.
Language	English
Publishing date	2024-05-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1073183-0
ISSN	1469-0705 ; 0960-7692
ISSN (online)	1469-0705
ISSN	0960-7692
DOI	10.1002/uog.27680
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Article ; Online: Adaptive antioxidant response to mitochondrial fatty acid oxidation determines the proliferative outcome of cancer cells.

Castelli, Serena / Ciccarone, Fabio / De Falco, Pamela / Ciriolo, Maria Rosa

Cancer letters

2022 Volume 554, Page(s) 216010

Abstract: Alterations in lipid catabolism have been broadly described in cancer cells and show tumor-type specific effects on proliferation and cell survival. The factor(s) responsible for this heterogeneity is currently unknown and represents the main limitation ... ...

Abstract	Alterations in lipid catabolism have been broadly described in cancer cells and show tumor-type specific effects on proliferation and cell survival. The factor(s) responsible for this heterogeneity is currently unknown and represents the main limitation in the development of therapeutic interventions that impair lipid metabolism. In this study, we focused on hexanoic acid, a medium-chain fatty acid, that can quickly boost oxidative metabolism by passively crossing mitochondrial membranes. We demonstrated that the antioxidant adaptation of cancer cells to increased fatty acid oxidation is predictive of the proliferative outcome. By interfering with SOD1 expression and glutathione homeostasis, we verified that mitochondrial fatty acid oxidation has antitumor effects in cancer cells that efficiently buffer ROS. In contrast, increased ROS levels promote proliferation in cells with an imbalanced antioxidant response. In addition, an increase in mitochondrial mass and mitophagy activation were observed, respectively. Overall, these data demonstrate that the capacity to manage ROS from mitochondrial oxidative metabolism determines whether lipid catabolism is advantageous or detrimental for cancer cells.
MeSH term(s)	Humans ; Antioxidants/pharmacology ; Antioxidants/metabolism ; Reactive Oxygen Species/metabolism ; Lipid Metabolism ; Fatty Acids/metabolism ; Lipids ; Oxidation-Reduction ; Oxidative Stress ; Neoplasms/drug therapy
Chemical Substances	Antioxidants ; Reactive Oxygen Species ; Fatty Acids ; Lipids
Language	English
Publishing date	2022-11-17
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2022.216010
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Article ; Online: Ultrasound, macroscopic and histological features of malignant ovarian tumors. Metastatic tumors to the ovary: ovarian metastases from biliary tract and ovarian metastases from colon cancer.

Ciccarone, Francesca / Codecà, Claudia / Versace, Valeria / Moro, Francesca

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society

2021 Volume 31, Issue 10, Page(s) 1388–1390

MeSH term(s)	Adenocarcinoma/pathology ; Aged ; Biliary Tract Neoplasms/pathology ; Colonic Neoplasms/pathology ; Diagnosis, Differential ; Female ; Humans ; Ovarian Neoplasms/diagnostic imaging ; Ovarian Neoplasms/secondary ; Tomography, X-Ray Computed ; Ultrasonography
Language	English
Publishing date	2021-09-20
Publishing country	England
Document type	Case Reports ; Journal Article ; Video-Audio Media
ZDB-ID	1070385-8
ISSN	1525-1438 ; 1048-891X
ISSN (online)	1525-1438
ISSN	1048-891X
DOI	10.1136/ijgc-2020-002250
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Article ; Online: Applicazioni cliniche di bevacizumab nel trattamento del tumore del colon-retto e dell’ovaio.

Danesi, Romano / Cremolini, Chiara / Ciccarone, Francesca / Lorusso, Domenica

Recenti progressi in medicina

2021 Volume 112, Issue 6, Page(s) 444–453

Abstract: The development of biological drugs, which began in the 1980s, has revolutionized the treatment of numerous oncological diseases and severely disabling autoimmune diseases, with widely demonstrated evidence of benefit. Today, biological drugs represent ... ...

Title translation	Clinical applications of bevacizumab in the treatment of colorectal and ovarian cancer.
Abstract	The development of biological drugs, which began in the 1980s, has revolutionized the treatment of numerous oncological diseases and severely disabling autoimmune diseases, with widely demonstrated evidence of benefit. Today, biological drugs represent an important and continuously developing category and are used both as a support therapy in onco-hematology and as molecules with their own therapeutic activity, such as monoclonal antibodies. Among these, bevacizumab represents a drug of relevant clinical value, used as antiangiogenic therapy in numerous cancers, in particular colorectal and ovarian cancers. The expiry of the patent period of monoclonal antibodies, including bevacizumab, has opened up to the development of biosimilar drugs, represented by structurally similar molecules with pharmacokinetic, pharmacodynamic and clinical characteristics equivalent to a biological drug already present in clinical use (originator biologic). The development process of these drugs is contained in the guidelines of the major regulatory bodies (FDA/EMA) and is faster than that provided for the originator biologic. Since biosimilars have a lower cost than reference drugs, their use represents a possibility of containing health care costs and of satifying the growing demand in terms of efficacy and personalization of pharmacological therapies. Considering the particular severity of the diseases treated, including colorectal and ovarian cancers, biosimilar drugs must be used with full awareness, in terms of efficacy and safety, since their approval is based on a rigorous analytical process, as well as preclinical and clinical evaluation.
MeSH term(s)	Antibodies, Monoclonal ; Antineoplastic Agents, Immunological/therapeutic use ; Bevacizumab ; Biosimilar Pharmaceuticals/pharmacokinetics ; Biosimilar Pharmaceuticals/therapeutic use ; Colorectal Neoplasms/drug therapy ; Drug Approval ; Female ; Humans ; Ovarian Neoplasms/drug therapy
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents, Immunological ; Biosimilar Pharmaceuticals ; Bevacizumab (2S9ZZM9Q9V)
Language	Italian
Publishing date	2021-06-15
Publishing country	Italy
Document type	Journal Article
ZDB-ID	138266-4
ISSN	2038-1840 ; 0034-1193
ISSN (online)	2038-1840
ISSN	0034-1193
DOI	10.1701/3620.36027
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Article ; Online: Operative and non-operative treatment of injury to solid abdominal organs in adult patients: a single center experience.

DE Meis, Edoardo / Cicioni, Gaia / Mansi, Monica / Mazzarella, Gennaro / Santillo, Sara / Rossi, Davide / Ciccarone, Flavia / Assenza, Marco

Minerva surgery

2024

Abstract: Background: In major trauma, lesions of the parenchymatous organs are subject of a controversy as regards the choice between an operative management (OM) in the operating room and a non-operative management (NOM) associated or not with angiography/ ... ...

Abstract	Background: In major trauma, lesions of the parenchymatous organs are subject of a controversy as regards the choice between an operative management (OM) in the operating room and a non-operative management (NOM) associated or not with angiography/angioembolization (AG/AE). Methods: Retrospective study of all consecutive data of patients coded as "traumatic pathology" in the period between 2011 and 2021. Were enrolled 13740 entries of adult patients with abdominal injuries, including at least: either hepatic or splenic or renal injury of AAST-OIS I. The primary outcome was to establish the rate of efficacy, respectively of OM and NOM. The secondary outcome is to analyze General (CG) and Specific (CS) complications, mean ward and intensive care unit (ICU) hospital stays. Results: One hundred sixty-two patients were included with 89 splenic injuries, 70 hepatic and 50 renal lesions; 35 treated with OM and 127 with NOM±AG/AE. The CGs registered in OM patients are seven (20%); seven SCs (20%); four GCs+SCs (11.4%). The average hospital stay was 24.91 days; mean ICU hospital stay of 10.74; five deaths. The CGs registered are 22 (17%); 12 SCs (9.4%); three GCs+SCs (2.3%). Average hospital stays 18 days; mean ICU hospital stay of 3.15; 6 deaths. Failure of the NOM strategy was recorded in nine patients with a success rate of 92.91%. Conclusions: In OM the presence of numerous high-grade lesions leads to a rapid stabilization. The NOM has reduced the hospital stay and UTI hospitalization in a feasible and safe way in selected CT.
Language	English
Publishing date	2024-05-16
Publishing country	Italy
Document type	Journal Article
ZDB-ID	3067899-7
ISSN	2724-5438
ISSN (online)	2724-5438
DOI	10.23736/S2724-5691.24.10169-4
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