Publications by authors named "Valerio Gaetano Vellone"

65 Publications

New Insights into Endometrial Cancer.

Cancers (Basel) 2021 Mar 24;13(7). Epub 2021 Mar 24.

Department of Experimental Medicine and Centre of Excellence for Biomedical Research, University of Genoa, 16132 Genoa, Italy.

EC is the most common cancer in the female genital tract in developed countries, and with its increasing incidence due to risk factors, such as aging and obesity, tends to become a public health issue. Although EC is a hormone-dependent neoplasm, there are no recommendations for the determination of steroid hormone receptors in the tumor tissue and no hormone therapy has ever been assessed in the adjuvant setting. Furthermore, its immune environment has been slightly characterized, but recent evidences point out how EC microenvironment may increase self-tolerance by reducing the recruitment of cytotoxic immune cells to the tumor site and/or modifying their phenotype, making these cells no longer able to suppress tumor growth. Here we highlight insights for EC management from diagnosis to a desirable trend of personalized treatment.
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http://dx.doi.org/10.3390/cancers13071496DOI Listing
March 2021

MDM2 gene amplification as selection tool for innovative targeted approaches in PD-L1 positive or negative muscle-invasive urothelial bladder carcinoma.

J Clin Pathol 2020 Nov 3. Epub 2020 Nov 3.

Division of Urology, University and Hospital Trust of Verona, Verona, Italy.

Aims: According to The Cancer Genome Atlas (TCGA), around 9% of bladder carcinomas usually show abnormalities of the murine double minute 2 (MDM2) gene, but a few studies have been investigated them. We profiled MDM2 gene amplification in a series of urothelial carcinomas (UC) considering the molecular subtypes and expression of programmed death ligand 1 (PD-L1).

Methods: 117 patients with muscle-invasive UC (pT2-3) without (N0) or with (N+) lymph-node metastases were revised. Only cases with availability of in toto specimens and follow-up were studied. Tissue microarray was built. p53, ER, RB1, GATA-3, CK20, CK5/6, CD44 and PD-L1 (clone sp263) immunoexpression was evaluated. Fluorescent in situ hybridisation was assessed by using the HER-2/neu, FGFR-3, CDKN2A and MDM2 probes. True (ratio 12q/CEP12 >2) MDM2 gene amplification was distinguished from polyploidy/gains (ratio <2, absolute copy number of MDM-2 >2). MDM2 and PD-L1 values were correlated to the TCGA molecular phenotypes. Statistical analysis was performed.

Results: 6/50 (12%) cases (5 N0 and 1 N+) were amplified for MDM2 without matching to molecular phenotypes. Of 50, 14 (37%) cases expressed PD-L1 at 1% cut-off; 3/50 (9%) at >50% cut-off; of these, 2 cases on side of neoplasia among inflammatory cells. Only one out of six (17%) cases amplified for MDM2 showed expression (>50% cut-off) of PD-L1. MDM2 amplification was independent to all documented profiles (k test=0.3) and was prevalent in recurrent UC.

Conclusion: MDM2 amplification has been seen in both PD-L1 positive and negative muscle-invasive bladder UC independently from the TCGA molecular phenotypes. MDM2 and PD-L1 might be assessed in order to predict a better response to combo/single targeted therapies.
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http://dx.doi.org/10.1136/jclinpath-2020-207089DOI Listing
November 2020

Female Malignancies and Immunotherapy: What's New?

Cancers (Basel) 2020 Oct 10;12(10). Epub 2020 Oct 10.

Department of Experimental Medicine (DI.ME.S.) and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 16132 Genoa, Italy.

For many years, the therapeutic advances in gynecological neoplasms have remained steady, however, in recent years, the application of the most modern "-omics" sciences has shed light on the pathogenesis and on neoplastic progression, with important implications in the introduction of targeted treatments that are more effective and less toxic [...].
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http://dx.doi.org/10.3390/cancers12102909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600966PMC
October 2020

Implementing NGS-based tumour tissue testing in FFPE ovarian carcinoma specimens: hints from a real-life experience within the framework of expert recommendations.

J Clin Pathol 2020 Sep 7. Epub 2020 Sep 7.

Hereditary Cancer Unit, IRCCS Ospedale Policlinico San Martino, Genova, Liguria, Italy.

Aims: Next Generation Sequencing (NGS)-based tumour tissue testing poses several challenges. As a first step of its implementation within a regional health service network, an in-house validation study was compared with published recommendations.

Methods: Epithelial ovarian cancer (EOC) formalin-fixed paraffin-embedded specimens stored in the archives of the eight regional pathology units were selected from a consecutive series of patients with known germline status. Two expert pathologists evaluated tumour cell content for manual macrodissection. DNA extraction, library preparation and NGS analyses were performed blinded to the germinal status. Parameters used in the study were confronted with guidelines for the validation of NGS-based oncology panels and for tumour tissue testing.

Results: NGS analyses were successful in 66 of 67 EOC specimens, with good quality metrics and high reproducibility among different runs. In all, 19 pathogenic variants were identified: 12 were germline and 7 were somatic. A 100% concordance with blood tests was detected for germline variants. A variant showed a controversial classification. In different areas of two early stage EOCs showing somatic variants, intratumour heterogeneity not relevant for test results (variant allele frequency >5%) was observed. Compared with expert recommendations, main limitations of the study were absence of controls with known somatic status and exclusion from the validation of copy number variations (CNV).

Conclusions: A close collaboration between pathology and genetics units provides advantages in the implementation of tumour tissue testing. The development of tools for designing and interpreting complex testing in-house validation could improve process quality.
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http://dx.doi.org/10.1136/jclinpath-2020-206840DOI Listing
September 2020

Steroids receptors immunohistochemical expression in different sites of endometriosis.

J Gynecol Obstet Hum Reprod 2021 Mar 8;50(3):101861. Epub 2020 Jul 8.

Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genova, Genova, Italy; Academic Unit of Pathology, IRCCS Ospedale Policlinico San Martino, Genova, Italy.

Background: A better characterization of steroid intracrine pathways in endometriosis lesions may lead to a better understanding of the pathogenesis of the disease and insights on the mechanism of resistance to medical therapy. The study aims to evaluate the expression of steroid receptors in endometriosis lesions, including for the first-time androgen receptors, both in glandular and stromal tissue, and to describe the differences, in any, in receptor expression in the different subtypes.

Basic Procedures: This is a retrospective analysis of 76 specimens from 51 women, that underwent laparoscopic surgery for endometriosis at a tertiary hospital between 2015 and 2019. Immunohistochemical detections of estrogen, progesterone and androgen receptors positive cells was performed and the results described in terms of both density and intensity. The density and intensity scores were combined to obtain a final Histological Score (HS). Non-parametric Kruskal-Wallis test or Mann-Whitney U-test were used to compare continuous data, chi square test for categorical data.

Main Findings: Estrogen receptor α expression was moderate/high in almost all specimens, regardless of the site. Samples from endometriomas presented lower progesterone receptor expression in the epithelium, compared to pelvic sites. Androgen receptor density was higher in stromal cells compared to epithelial cells and in pelvic sites compared to ovarian ones.

Conclusions: The roles of nuclear receptors in endometriosis, including differences in their expression, could help in defining the pathogenesis of the disease and in explaining different responsivity to therapies. The intracrine regulation of steroids plays a relevant role in the metabolic and inflammatory pathogenetic paths of endometriosis: if better understood, its manipulation could be a relevant therapeutic target for treatment.
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http://dx.doi.org/10.1016/j.jogoh.2020.101861DOI Listing
March 2021

P53 staining index and zonal staining patterns in actinic keratoses.

Arch Dermatol Res 2020 Jul 8. Epub 2020 Jul 8.

Dermatology Unit, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.

Actinic keratoses (AKs) are common dysplastic lesions resulting from chronic excessive ultraviolet exposure. Neither the clinical grade of thickness nor the histological grade of dysplasia seems valid predictors of aggressive potential of AKs. Instead, the mutational status in AKs appears to predict well the clinical course. TP53 gene mutations result in a non-functional protein resistant to degradation, thus immunohistochemical staining for p53 can suggest mutation status. Increased p53 was associated with progression from AK to squamous cell carcinoma. To investigate how the intensity of p53 staining (p53 staining index) varies according to body site, histological subtype and grade dysplasia of AKs. Secondly, we sought to investigate the distribution in the epidermal layers of non-functional p53 (zonal staining patterns). p53 staining index was greater than 50% in 90.7% of AKs. p53 staining index was significantly higher in older age (p < 0.0093) and in facial AKs compared to other body areas (p = 0.03). A significant correlation between p53 staining index and grade of dysplasia was observed (p = 0.006) and between p53 staining index and zonal p53 staining pattern (p = 0.003). No significant differences in p53 staining index among the various histological AK types were observed. No correlation between clinical and histological grade. All AKs, independently from their clinical appearance, should be treated but special attention is required for AKs on severely photodamaged skin on the face and in older patients.
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http://dx.doi.org/10.1007/s00403-020-02104-yDOI Listing
July 2020

Report of Positive Placental Swabs for SARS-CoV-2 in an Asymptomatic Pregnant Woman with COVID-19.

Medicina (Kaunas) 2020 Jun 22;56(6). Epub 2020 Jun 22.

Neonatology Unit, University of Genoa, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.

Currently, limited data on maternal and neonatal outcomes of pregnant women with infection and pneumonia related to SARS coronavirus 2 (SARS-CoV-2) are available. Our report aims to describe a case of placental swabs positive for the molecular research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 RNA in an asymptomatic woman with positive rhino-pharyngeal swab for SARS-CoV-2 who underwent an urgent cesarean section in our obstetrics unit. Sample collection, processing, and laboratory testing were conducted in accordance with the World Health Organization (WHO) guidance. In the next months, conclusive data on obstetrical outcomes concerning the gestational age and pregnancy comorbidity as well as the eventual maternal-fetal transmission are needed.
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http://dx.doi.org/10.3390/medicina56060306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353888PMC
June 2020

Magnetic Resonance Rectal Enema Versus Computed Tomographic Colonography in the Diagnosis of Rectosigmoid Endometriosis.

J Comput Assist Tomogr 2020 Jul/Aug;44(4):501-510

Department of Surgical and Diagnostic Sciences, Ospedale Policlinico San Martino, Genoa, Italy.

Objectives: Rectosigmoid involvement by endometriosis causes intestinal symptoms such as constipation, diarrhea, and dyschezia. A precise diagnosis about the presence, location, and extent of bowel implants is required to plan the most appropriate treatment. The aim of the study was to compare the accuracy of magnetic resonance with distension of the rectosigmoid (MR-e) with computed colonography (CTC) for diagnosing rectosigmoid endometriosis.

Methods: This study was based on the retrospective analysis of a prospectively collected database of patients with suspicion of rectosigmoid endometriosis who underwent both MR-e and CTC, and subsequently were treated by laparoscopy. The findings of imaging techniques were compared with surgical and histological results.

Results: Of 90 women included in the study, 44 (48.9%) had rectosigmoid nodules and underwent bowel surgery. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the diagnosis of rectosigmoid endometriosis were 88.6%, 93.5%, 92.9%, 89.6%, and 91.1% for CTC, and 93.2%, 97.9%, 97.6%, 93.8%, and 95.6% for MR-e. There was no significant difference in the accuracy of both radiologic examinations for diagnosing rectosigmoid endometriosis (P = 0.344). However, MR-e was more accurate than CTC in estimating the largest diameter of the main rectosigmoid nodule (P < 0.001). The pain perceived by the patients was significantly lower during MR-e than during CTC (P < 0.001).

Conclusions: MR-e and CTC have similar diagnostic performance for the diagnosis of rectosigmoid involvement of endometriosis. However, MR-e is more accurate in the estimation of the largest diameter of main rectosigmoid nodule and more tolerated than CTC.
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http://dx.doi.org/10.1097/RCT.0000000000001031DOI Listing
July 2020

A Prospective Study Comparing Three-Dimensional Rectal Water Contrast Transvaginal Ultrasonography and Computed Tomographic Colonography in the Diagnosis of Rectosigmoid Endometriosis.

Diagnostics (Basel) 2020 Apr 24;10(4). Epub 2020 Apr 24.

Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.

(1) Objectives: In patients with symptoms suggestive of rectosigmoid endometriosis, imaging techniques are required to confirm the presence and establish the extent of the disease. The objective of the current study was to compare the performance of three-dimensional rectal water contrast transvaginal ultrasonography (3D-RWC-TVS) and computed tomographic colonography (CTC) in predicting the presence and characteristics of rectosigmoid endometriosis. (2) Methods: This prospective study included patients with suspicion of rectosigmoid endometriosis who underwent both 3D-RWC-TVS and CTC and subsequently were surgically treated. The findings of imaging techniques were compared with surgical and histological results. (3) Results: Out of 68 women included in the study, 37 (48.9; 95% C.I. 38.2-59.7%) had rectosigmoid nodules and underwent bowel surgery. There was no significant difference in the accuracy of 3D-RWC-TVS and CTC in diagnosing the presence of rectosigmoid endometriotic nodules ( = 0.118), although CTC was more precise in diagnosing endometriosis located in the sigmoid ( = 0.016). 3D-RWC-TVS and CTC had similar precision in estimating the largest diameter of the main endometriotic nodule ( = 0.099) and, in patients undergoing segmental resection, the degree of the stenosis of the bowel lumen ( = 0.293). CTC was more accurate in estimating the distance between the lower margin of the intestinal nodule and the anal verge ( = 0.030) but was less tolerated than 3D-RWC-TVS ( < 0.001). (4) Conclusion: This was the first study comparing the performance of 3D-RWC-TVS and CTC in the diagnosis of rectosigmoid endometriosis. Both techniques allowed for the evaluation of the profile of the bowel lumen in a pseudoendoscopic fashion and had a similar performance for the diagnosis of rectosigmoid endometriosis, although CTC was more accurate in diagnosing and characterizing sigmoid nodules.
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http://dx.doi.org/10.3390/diagnostics10040252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236009PMC
April 2020

Endometriosis Classification and The Role of Tumor Necrosis Factor-Alpha Polymorphisms as A Therapeutic Target.

Int J Fertil Steril 2020 Apr 25;14(1):76-77. Epub 2020 Feb 25.

Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

In the recent original research published on International Journal of Fertility and Sterility the association between tumor necrosis factor-alpha (TNF-α) genetic polymorphisms and endometriosis in 150 Iranian patients suffered this disease. The authors notably found a lower frequency of TNF-α -863C/A allele A among the affected patients in comparison with healthy women, although this difference was not significant by adjusting multiple testing. We deem that the authors should specify, if these patients had peritoneal nodules, ovarian endometrioma/deep infiltrating endometriosis (DIE) nodules or combination of them, since it has been hypothesized that these phenotypes may represent three distinct pathogenetic entities of endometriosis.
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http://dx.doi.org/10.22074/ijfs.2020.5876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139220PMC
April 2020

Transvaginal ultrasound-guided biopsy of adenomyosis.

Ann Transl Med 2019 Dec;7(Suppl 8):S341

Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

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http://dx.doi.org/10.21037/atm.2019.09.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976460PMC
December 2019

Preoperative Treatment with Ulipristal Acetate before Outpatient Hysteroscopic Myomectomy.

Gynecol Obstet Invest 2020 15;85(2):178-183. Epub 2020 Jan 15.

Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genova, Italy.

Introduction: Nowadays, the resection of submucosal myomas is usually performed by hysteroscopy. No previous study has investigated the use of preoperative hormonal therapy before outpatient hysteroscopic myomectomy.

Objective: To compare the usefulness of 3-month preoperative treatment with ulipristal acetate (UPA) before outpatient hysteroscopic myomectomy in patients with FIGO (International Federation of Gynecology and Obstetrics) type 0-1 myomas.

Study Design: This prospective patient preference study included women requiring hysteroscopic resection of single FIGO type 0-1 myoma with the largest diameter <2 cm. Patients underwent either preoperative treatment with UPA (5 mg/day) for 3 months or direct surgery. Outpatient myomectomy was performed using the bipolar electrosurgical Versapoint system (Ethicon Gynecare, USA). The primary objective of the study was to compare the rate of complete resections in the 2 study groups. The secondary objective of the study was to compare the operative time and the volume of fluid infused/absorbed. The tertiary objective of the study was to assess the surgical appearance of the myomas in patients treated with UPA.

Results: The study included 38 women treated with UPA and 45 women who underwent direct surgery. UPA treatment significantly decreased the volume of uterine myomas (p < 0.001). The percentage of complete resection was higher in patients treated with UPA (89.5%) than in those who underwent direct surgery (68.9%; p = 0.046). Preoperative UPA treatment decreased the operative time (p < 0.001) and the volume of fluid infused (p = 0.016), but it did not significantly affect the volume of fluid absorbed (p = 0.874). The texture of the myoma was not significantly affected by UPA treatment (p = 0.142).

Conclusions: Three-month UPA treatment improves the chance of single-step complete outpatient hysteroscopic resection of single FIGO type 0-1 myoma. Future randomized studies with a larger sample size should confirm these preliminary findings.
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http://dx.doi.org/10.1159/000505604DOI Listing
September 2020

Cardiomyocyte-Specific JunD Overexpression Increases Infarct Size following Ischemia/Reperfusion Cardiac Injury by Downregulating Sirt3.

Thromb Haemost 2020 Jan 13;120(1):168-180. Epub 2019 Dec 13.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.

Ischemia/reperfusion (I/R) injury in acute myocardial infarction activates several deleterious molecular mechanisms. The transcription factor JunD regulates pathways involved in oxidative stress as well as in cellular proliferation, differentiation, and death. The present study investigated the potential role of JunD as a modulator of myocardial injury pathways in a mouse model of cardiac I/R injury. Infarct size, systemic and local inflammation, and production of reactive oxygen species, as well as cytosolic and mitochondrial apoptotic pathways were investigated in adult males after myocardial I/R. In wild-type (WT) mice, 30 minutes after ischemia and up to 24 hours following reperfusion, cardiac messenger ribonucleic acid expression was reduced while increased. Cardiac-specific JunD overexpressing mice ( ) displayed larger infarcts compared with WT. However, postischemic inflammatory or oxidative responses did not differ. JunD overexpression reduced Sirt3 transcription by binding to its promoter, thus leading to mitochondrial dysfunction, myocardial cell death, and increased infarct size. On the other hand, JunD silencing reduced, while Sirt3 silencing increased infarct size. In human myocardial autopsy specimens, JunD-positive areas within the infarcted left ventricle staining corresponded to undetectable Sirt3 areas in consecutive sections of the same heart. Cardiac-specific JunD overexpression increases myocardial infarct size following I/R. These effects are mediated via Sirt3 transcriptional repression, mitochondrial swelling, and increased apoptosis, suggesting that JunD is a key regulator of myocardial I/R injury. The present data set the stage for further investigation of the potential role of Sirt3 activation as a novel target for the treatment of acute myocardial infarction.
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http://dx.doi.org/10.1055/s-0039-3400299DOI Listing
January 2020

Mucinous ovarian cancer: current therapeutic targets, preclinical progress, and experimental drugs.

Expert Opin Investig Drugs 2019 Dec 19;28(12):1025-1029. Epub 2019 Nov 19.

Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

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http://dx.doi.org/10.1080/13543784.2019.1693999DOI Listing
December 2019

Treatment of rectovaginal endometriosis with the etonogestrel-releasing contraceptive implant.

Gynecol Endocrinol 2020 Jun 12;36(6):540-544. Epub 2019 Nov 12.

Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

This study aimed to investigate the efficacy of the etonogestrel (ENG)-releasing implant in treating patients with rectovaginal endometriosis. The study was based on the retrospective analysis of a prospectively collected database, including symptomatic women who had ultrasonographic diagnosis of rectovaginal endometriosis. Patients were follow-up at 6, 12 and 24 months from the insertion of the ENG-releasing implant. The intensity of pain symptoms was evaluated using a visual analog scale. The volume of the nodules was estimated by virtual organ computer-aided analysis. The Endometriosis Health Profile (EHP-30) was used to evaluate quality of life. Overall, 43 women were included in the study. The 2-year continuation rate for the ENG-releasing implant was 93.0%. The treatment quickly improved the intensity of non-menstrual pelvic pain, deep dyspareunia, dysmenorrhea, and dyschezia. At 6-month follow-up, there were improvements in all domains of the EHP-30 compared with baseline. Further improvements in the EHP-30 results were observed only in pain sub score at 12-month follow-up and in emotional well-being sub score at 24-month follow-up. At 6-month follow-up the volume of the rectovaginal nodules was significantly lower compared with baseline; a further decrease was observed at 12- and 24-month follow-up. The treatment was well tolerated.
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http://dx.doi.org/10.1080/09513590.2019.1689552DOI Listing
June 2020

Total disc replacement for lumbar degenerative disc disease: single centre 20 years experience.

Eur Spine J 2020 07 9;29(7):1518-1526. Epub 2019 Aug 9.

Clinica Ortopedica, Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132, Genoa, GE, Italy.

Purpose: To report clinical and radiographic outcomes, rate of complications and influence on spinal alignment on long-term follow-up (FU) of patients who underwent lumbar total disc arthroplasty (TDR), bringing some evidence to determine the profile of the most well-suited patients for TDR.

Methods: A retrospective review of patients underwent TDR for low back pain from degenerative disc disease (DDD) resistant to conservative treatment was performed. Demographic features, surgical data, clinical and radiographic outcomes, complications and spinopelvic parameters were evaluated.

Results: Thirty patients (32 TDR) were included with a mean FU of 164 ± 36.5 months. The clinical outcomes measured by visual analogue scale and Oswestry Disability Index showed a significant improvement between preoperative and 1-year FU (p < 0.01). No significant temporal variance has been identified between 1-year and long-term follow-up (p > 0.05). The surgical revision rate was 10%. The overall rate of complications was 20%. At final follow-up, the mobility of the prosthesis was preserved in 68.75% of the cases, and 73.3% of the patients were globally well aligned.

Conclusion: The optimal surgical indication is crucial to achieve excellent clinical and radiological outcomes. According to the literature and to our experience, we underline the importance of a coronal deformity < 15° Cobb angle and a Roussouly type 1 or 2 as the profile of the most well-suited patient for TDR. Our long-term results confirm the existing evidence about efficacy and safety of TDR as a reliable option, in optimal surgery indication, to treat DDD. These slides can be retrieved under Electronic Supplementary Material.
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http://dx.doi.org/10.1007/s00586-019-06100-3DOI Listing
July 2020

Pathophysiology of pain in patients with peritoneal endometriosis.

Ann Transl Med 2019 Mar;7(Suppl 1):S8

Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

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http://dx.doi.org/10.21037/atm.2019.01.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462618PMC
March 2019

Current state of the art and emerging pharmacotherapy for uterine leiomyosarcomas.

Expert Opin Pharmacother 2019 04 6;20(6):713-723. Epub 2019 Feb 6.

a Academic Unit of Obstetrics and Gynecology , IRCCS Ospedale Policlinico San Martino , Genoa , Italy.

Introduction: Uterine leiomyosarcomas (ULMS) account for 1% of all uterine malignancies and for 30% of all uterine sarcomas. The preoperative diagnosis of ULMS is challenging for the physicians, as the symptoms of these tumors are often vague and nonspecific. Moreover, as ULMS have an aggressive biologic behavior, affected women frequently have very poor prognosis.

Areas Covered: The aim of this review is to describe the current pharmacotherapy for ULMS, including the ongoing clinical trials.

Expert Opinion: Surgery is the standard treatment for patients with early-stage ULMS. In this setting, the role of adjuvant therapies is still unclear. In the case of advanced, persistent, or recurrent ULMS, chemotherapy is the standard care with the most frequently used drug being doxorubicin. As the outcomes for patients with the currently available conventional single or combined regimens are far from being satisfactory, new alternative and innovative medical compounds have or are being evaluated. Recently, pazopanib, and olaratumab, two innovative targeted drugs, have been approved by the Food and Drug Administration (FDA) for treating advanced soft-tissue sarcoma, including ULMS. However, further clinical investigations into new and innovation therapeutic options are warranted.
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http://dx.doi.org/10.1080/14656566.2019.1571042DOI Listing
April 2019

Giant Hepatic Hemangioma and Placental Chorangiosis: A Unique Case of Stillbirth?

Fetal Pediatr Pathol 2019 Apr 24;38(2):175-181. Epub 2019 Jan 24.

a Pathology, DISC , University of Genoa , Genoa , Italy.

Introduction: Hepatic hemangiomas (HH) are benign vascular tumors, and when large, may contribute to fetal morbidity/mortality. Chorangiosis is placental villus capillary hypervascularity, probably linked with fetal hypoxia.

Case Report: We present a macrosomic stillbirth at 39 + 3 weeks of gestation with congestive heart failure (CHF) and myocardial infarction. A giant right hepatic lobe HH was present, along with placental chorangiosis.

Conclusion: A common pathogenetic pathway between congenital HH and placental chorangiosis has not been reported. Our case suggests that the effects of HH and chorangiosis increase the risk of late fetal loss due to the high-output CHF.
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http://dx.doi.org/10.1080/15513815.2018.1564159DOI Listing
April 2019

Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer.

Expert Opin Investig Drugs 2019 02 21;28(2):131-142. Epub 2018 Dec 21.

a Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI) , University of Genova , Italy.

Introduction: Endometrial cancer (EC) is the most common neoplasm of the female genital tract in developed countries. Despite the progress in early detection and treatment, a significant number of cases of advanced ECs are still diagnosed. These patients have few treatment options and a poor prognosis. Our understanding of EC pathogenesis and progression has been enhanced by recent genomic studies. Among the relevant biological pathways, phosphatidylinositol 3-kinase/AKT (PIK3/AKT)-mammalian target of rapamycin (mTOR) signaling is frequently upregulated in this cancer.

Areas Covered: This review covers investigational EC therapeutics acting on the PI3K/AKT/mTOR pathway. The authors review the results of clinical studies and highlight ongoing trials.

Expert Opinion: Several new agents are under evaluation for treating patients with metastatic, recurrent, and persistent EC. Clinical trials investigating PI3K/AKT/mTOR inhibitors have yielded controversial results. In the near future, new studies with dual inhibitors or multi-pathways inhibitors as mono or combination therapies with conventional chemotherapy (CT) or other targeted drugs may provide more promising data. Moreover, the evaluation of new serum and histological biomarkers is an attractive strategy for patient selection.
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http://dx.doi.org/10.1080/13543784.2018.1558202DOI Listing
February 2019

Ulipristal Acetate before Hysteroscopic and Laparoscopic Surgery for Uterine Myomas: Help or Hindrance?

Gynecol Obstet Invest 2019 14;84(4):313-325. Epub 2018 Dec 14.

Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Background/aims: Ulipristal acetate ([UPA], Esmya®) is an orally active selective progesterone-receptor modulator that has been approved as preoperative treatment for uterine myomas. This systematic review aims to summarize the available data on surgical outcomes of patients undergoing myomectomy by hysteroscopy or by laparoscopy after preoperative treatment with UPA.

Methods: this review was performed following PRISMA guidelines and was registered in PROSPERO (CRD42018092201). PubMed, EMBASE, and Medline databases were systematically searched electronically until March 2018 for keywords concerning this topic. There were included only peer-reviewed, English language journal articles.

Results: two prospective studies and 4 retrospective studies were included. The effect of UPA on the endometrium does not increase the technical difficulty during hysteroscopic myomectomy, but it increases the chance of complete primary resection in complex hysteroscopic myomectomies. Moreover, UPA does not increase the overall technical difficulty of laparoscopic myomectomy. Contradictory results have been reported on the impact of UPA on the separation of the myoma from the myometrium and on the consistency of the myomas.

Conclusion: current results support the use of UPA prior to both surgical procedures. Further studies should confirm these preliminary findings and to assess the long-term outcomes of myomectomies following UPA treatment.
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http://dx.doi.org/10.1159/000495347DOI Listing
October 2019

Does Bowel Preparation Improve the Performance of Rectal Water Contrast Transvaginal Ultrasonography in Diagnosing Rectosigmoid Endometriosis?

J Ultrasound Med 2019 Apr 24;38(4):1017-1025. Epub 2018 Sep 24.

Academic Unit of Obstetrics and Gynecology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Objectives: The primary objective of the study was to compare the performance of the rectal water transvaginal ultrasonography (RWC-TVS) with and without bowel preparation (BP) in diagnosing rectosigmoid endometriosis. The secondary objectives were to compare the performance of the 2 exams in estimating infiltration of the mucosa, length of the largest rectosigmoid nodules, distance of the nodules from the anal verge, and presence of multifocal disease.

Methods: This prospective study included patients with pain symptoms and intestinal complaints suggestive of endometriosis. Patients underwent RWC-TVS with and without BP within an interval of 1 week to 2 months. Two independent and blinded gynecologists performed the exams. The results of the 2 exams were compared with surgical and histologic findings.

Results: A total of 155 patients were included in the study; 92 patients had rectosigmoid endometriosis. There was no significant difference in the performance of RWC-TVS with or without BP in diagnosing rectosigmoid endometriosis (P = .727). There was no significant difference in the performance of RWC-TVS with or without BP in diagnosing infiltration of the mucosa (P = .424) and multifocal disease (P = .688), in estimating the main diameter of the largest nodule (P = .644) and the distance between the more distal rectosigmoid nodule and the anal verge (P = .090). The patients similarly tolerated the 2 exams (P = .799).

Conclusions: Bowel preparation does not improve the performance of RWC-TVS in diagnosing rectosigmoid endometriosis and in assessing the characteristics of these nodules.
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http://dx.doi.org/10.1002/jum.14790DOI Listing
April 2019

Ureteral endometriosis: a systematic review of epidemiology, pathogenesis, diagnosis, treatment, risk of malignant transformation and fertility.

Hum Reprod Update 2018 11;24(6):710-730

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy.

Background: The ureter is the second most common site affected by urinary tract endometriosis, after the bladder. Optimal strategies in the diagnosis and treatment of ureteral endometriosis (UE) are not yet well defined.

Objective And Rationale: The aim of this study was to systematically review evidence regarding the epidemiology, pathophysiology, diagnosis, medical and surgical treatment, impact on fertility and risk of malignant transformation of UE.

Search Methods: A systematic literature review, by searching the MEDLINE and PUBMED database until April 2018, was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement and was registered in the PROSPERO registry (www.crd.york.ac.uk/PROSPERO CRD42017060065). A total of 67 articles were selected to be included in this review.

Outcomes: The involvement of the ureter by endometriosis is often asymptomatic or leads to non-specific symptoms. When the diagnosis is delayed, UE may lead to persistent hydronephrosis and eventually loss of renal function. Ultrasonography is the first-line technique for the assessment of UE; alternatively, magnetic resonance imaging provides an evaluation of ureteral type involvement. The surgical treatment of UE aims to relieve ureteral obstruction and avoid disease recurrence. It includes conservative ureterolysis or radical approaches, such as ureterectomy with end-to-end anastomosis or ureteroneocystostomy performed in relation to the type of ureteral involvement. Fertility and pregnancy outcomes are in line with those observed after surgical treatment of deep infiltrating endometriosis (DIE). Current evidence does not support the potential risk of malignant transformation of UE.

Wider Implications: In this article, we review available evidence on ureteral endometriosis, providing a useful tool to guide physicians in the management of this disease. Diagnosis and management of UE remain a challenge. In relation to the degree of ureteral involvement and the association with other DIE implants, the surgical approach should be planned and carried out in an interdisciplinary collaboration between gynecologist and urologist.
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http://dx.doi.org/10.1093/humupd/dmy027DOI Listing
November 2018

A Survey on the Knowledge and Attitudes of Italian Medical Students toward Body Donation: Ethical and Scientific Considerations.

J Clin Med 2018 Jul 9;7(7). Epub 2018 Jul 9.

Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 16132 Genova, Italy.

Post mortem body donation (PMBD) for medical training and research plays a key role in medical-surgical education. The aim of this study is to evaluate Italian medical students’ awareness and attitudes regarding this practice. A questionnaire was sent to 1781 Italian medical students (MS). A total of 472 MS responded: 406 (92.91%) had a strongly positive attitude to PMBD, while 31 (7.09%) were not in favor. The majority of subjects were Catholic (56.36%), while 185 and 21 subjects, said that they did not hold any religious beliefs, or were of other religions, respectively. Multivariate analysis showed significant associations (-values < 0.05) between PMBD and religion, as well as perceptions of PMBD as an act of altruism, a tool for learning surgical practices, body mutilation, and an act contrary to faith. Although Italian MS believed cadaver dissection to be an important part of their education, they did not know much about it and had not received training on this altruistic choice. As future doctors, MS can play an important role in raising public awareness of the importance of PMBD for medical education and research. Specific educational programs to improve knowledge of this topic among MS are needed.
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http://dx.doi.org/10.3390/jcm7070168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068798PMC
July 2018

Peritoneal carcinomatosis from ovarian paraganglioma: Report of a rare case and systematic review of the literature.

J Obstet Gynaecol Res 2018 Sep 6;44(9):1682-1692. Epub 2018 Jul 6.

Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy.

Paraganglioma is one of the rarest neoplasms involving the ovary, with only 10 previous reports. We present a case of peritoneal carcinomatosis from primary ovarian paraganglioma and a systematic review of the literature. Clinical information was retrieved from medical records, and a systematic review of the literature was performed according to meta-analysis of observational studies in epidemiology guidelines. A 33-year-old woman presented with a 12-month history of hypertension and weight loss. She was diagnosed with ovarian paraganglioma and was treated with extensive debulking surgery to no residual disease after three cycles of neoadjuvant chemotherapy. She recurred after 6 months and was started on somatostatin-analogue. Following further disease progression with bone metastasis (treated with palliative radiotherapy), a trial with Sunitinib was started. The patient died 30 months after initial diagnosis. Of the cases reported to date, only one had peritoneal metastasis at presentation but none of them had such an ominous prognosis. Ovarian paraganglioma is an extremely rare condition. We report the first case of primary malignant ovarian paraganglioma with an exceptionally aggressive behavior. Clinicopathological correlation with immunohistochemistry is essential to avoid misdiagnosis. A standard treatment is not recommended yet but cytoreductive surgery seems to be a favorable approach to prolong survival.
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http://dx.doi.org/10.1111/jog.13713DOI Listing
September 2018

Pharmacokinetic drug evaluation of ulipristal acetate for the treatment of uterine fibroids.

Expert Opin Drug Metab Toxicol 2018 Jan 20;14(1):107-116. Epub 2017 Dec 20.

a Academic Unit of Obstetrics and Gynecology , Ospedale Policlinico San Martino , Genoa , Italy.

Introduction: Uterine fibroids are the most common form of benign gynecological tumors in women of reproductive ages. Although surgery is the main option to treat them, alternative pharmacological approaches are being investigated to control their symptoms. Among them, ulipristal acetate (UPA) has been the first selective progesterone-receptor modulator (SPRM) approved for the pre-operative and long-term treatment of uterine fibroids. Areas covered: The aim of this article is to review the literature on the pharmacodynamics, pharmacokinetics (PK), clinical efficacy and safety of UPA for the treatment of uterine fibroids. Expert opinion: UPA has both agonistic and antagonistic activity on progesterone receptor. Results from PK studies have shown that it has good oral bioavailability, and that it is extensively metabolized in the liver by cytochrome (CYP) 3A4. The PEARL I-II showed that the preoperative treatment with UPA decreases uterine bleeding, uterine volume and fibroid size in women with symptomatic uterine leiomyomas. The PEARL III and IV trials demonstrated the efficacy and safety of long-term intermittent treatment with UPA for the control of fibroid-related symptoms.
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http://dx.doi.org/10.1080/17425255.2018.1417389DOI Listing
January 2018

Inflammatory Response Modulation through a PPARγ Agonist during Surgically Induced Visceral Ischemia in an Animal Model.

Ann Vasc Surg 2018 Apr 29;48:189-194. Epub 2017 Nov 29.

Unit of Vascular and Endovascular Surgery, IRCCS San Martino-IST University Hospital, Genoa, Italy.

Background: Ischemia/reperfusion (I/R) injury represents one of the most severe complications in vascular surgery where cross-clamping of the aorta and subsequent visceral ischemia are a recurrent issue. The literature describes a family of nuclear receptors, that is, peroxisome proliferator-activated receptors (PPARs), in particular PPARγ isoform, which are important modulators of vascular inflammation resulting from I/R injury. The aim of our study is to evaluate how PPARγ agonist administration could reduce local and systemic inflammatory response after I/R injury during aortic supraceliac clamping in animal model.

Methods: Our model includes 16 rats divided as follows: 8 rats in the placebo control group (PlacG) were operated on without having been administered of any drugs during the preoperative period, whereas the 8 rats in the pioglitazone group (PioG) were pretreated with pioglitazone. Renal and visceral ischemias were induced in the rats by supraceliac aortic clamping. Rats were sacrificed after surgery, and then, we collected blood samples to measure serum levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) and one of the kidneys and a segment of the liver to perform histological analysis.

Results: Considering both cytokines in the PioG, there has been a negative trend in serum concentrations, whereas in the PlacG, we observed an increasing trend. The high standard deviation observed in our study is mainly due to the small population of the cohort. Histologic examination of the kidney showed more severe damage in the placebo group as compared to the PioG with more evident differences in tubular and tubulointerstitial scores.

Conclusions: Our observations show that administering pioglitazone can partially reduce secondary inflammatory response in the ischemic insult especially in endothelial and perivascular tissues.
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http://dx.doi.org/10.1016/j.avsg.2017.09.019DOI Listing
April 2018

Report on the first SLFN11 monothematic workshop: from function to role as a biomarker in cancer.

J Transl Med 2017 10 2;15(1):199. Epub 2017 Oct 2.

Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico San Martino IST-Istituto Nazionale Tumori, Genoa, Italy.

SLFN11 is a recently discovered protein with a putative DNA/RNA helicase function. First identified in association with the maturation of thymocytes, SLFN11 was later causally associated, by two independent groups, with the resistance to DNA damaging agents such as topoisomerase I and II inhibitors, platinum compounds, and other alkylators, making it an attractive molecule for biomarker development. Later, SLFN11 was linked to antiviral response in human cells and interferon production, establishing a potential bond between immunity and chemotherapy. Recently, we demonstrated the potential role of SLN11 as a biomarker to predict sensitivity to the carboplatin/taxol combination in ovarian cancer. The present manuscript reports on the first international monothematic workshop on SLFN11. Several researchers from around the world, directly and actively involved in the discovery, functional characterization, and study of SLFN11 for its biomarker and medicinal properties gathered to share their views on the current knowledge advances concerning SLFN11. The aim of the manuscript is to summarize the authors' interventions and the main take-home messages resulting from the workshop.
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http://dx.doi.org/10.1186/s12967-017-1296-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625715PMC
October 2017