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Expert Opin Investig Drugs.2012 Jul;21(7):905-19. Epub 2012 May 9.

New trends for the medical treatment of endometriosis.

Rocha AL, Reis FM, Petraglia F.

Source

Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena , Policlinico “Santa Maria alle Scotte”, Viale Bracci, 53100 Siena , Italy petraglia@unisi.it.

Abstract

Introduction: Endometriosis is a benign sex hormone-dependent gynecological disease, characterized by the presence and growth of endometrial tissue outside the uterus; it affects 10% of women of reproductive age and is associated with infertility and pain. Treatment of endometriosis involves conservative or radical surgery, or medical therapies. The goals for endometriosis treatment may be the relief of pain and/or a successful pregnancy achievement in infertile patients. Treatment must be individualized with a multidisciplinary approach. The classical treatments carry adverse side effects and in some cases a negative impact on quality of life. New agents promise a distinct perspective in endometriosis treatment. Areas covered: The aim of this paper is to systematically review the literature evidence of new medical treatments for endometriosis, defined as pharmacological treatments not yet commonly available and currently under investigation. Expert opinion: These new medical therapies would be used associated with surgical treatment and, in the future, will render possible the association of hormone therapy with non-hormonal treatment for endometriosis.

Gynecol Endocrinol.2012 Jul;28(7):553-8. Epub 2012 Feb 14.

Detecting and investigating the significance of high-frequency LOH chromosome regions for endometriosis-related candidate genes.

Wang DB, Ren FY, Ren F.

Source

Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University , Shenyang , China.

Abstract

To detect the high-frequency loss of heterozygosity (LOH) chromosome regions for ectopic endometrium of ovarian endometriosis (EMs) and to investigate the significance of high-frequency LOH chromosome regions in EMs, we obtained ectopic endometrium by laser capture microdissection (LCM (22 samples)), manual capture microdissection (MCM (18 samples)), and routine dissection (14 samples), respectively. After restriction and circularization-aided rolling circle amplification (RCA-RCA), LOH was detected at 12 microsatellite (MS) loci. The frequency of LOH was 59.09% (13/22) in LCM group, 61.11% (11/18) in the MCM group and 21.43% (3/14) in the routine dissection group. The latter was significantly lower when compared with the former two (p < 0.05). In the LCM group, candidate chromosome regions 17q21.31 and 9p21.3 had LOH frequencies of 23.8 and 13.6%, respectively. The highest LOH frequency was detected at the locus AAAT2 on chromosome 17q21.31 (40%). The chromosome region with the highest frequency of LOH for ectopic endometrium was 17q21.31, especially at the AAAT2 locus, which prompted that down regulation of the candidate genes nearby the locus might be one of the mechanisms of EMs pathogenesis. LCM combined with RCA-RCA is a reliable technique for analyzing endometrial LOH at multiple MS loci. MCM combined with RCA-RCA, which provided similar results, was more cost-effective.

Gynecol Endocrinol.2012 Jul;28(7):562-7. Epub 2012 Feb 2.

Growth mechanisms of endometriotic cells in implanted places: a review.

Jiang QY, Wu RJ.

Source

Department of Obstetrics and Gynecology, Women’s Hospital, School of Medicine, Zhejiang University , Hangzhou, People’s Republic of China.

Abstract

Endometriosis is a common gynecological disease defined by extrauterine growth of endometrial glands and stroma. A variety of theories have been proposed to account for the pathogenesis of this disease, including retrograde transplantation theory, metaplasia of coelomic epithelium, hematogenic and lymphogenic spread, and remnants of the Mŭllerian duct. However, the etiopathology of endometriosis is still obscure. In this article, we aim to summarize recent researches concerning the growth mechanisms of endometriotic cells in implanted sites systematically, including the adhesion, invasion, angiogenesis, proliferation, apoptosis of endometriotic cells, variations of the immune molecules and endometriotic cells themselves, which may provide clues for future researches in the pathogenesis of endometriosis.

Hum Reprod.2012 Jul;27(7):2010-9. Epub 2012 May 15.

The selective vitamin D receptor agonist, elocalcitol, reduces endometriosis development in a mouse model by inhibiting peritoneal inflammation.

Mariani M, Viganò P, Gentilini D, Camisa B, Caporizzo E, Di Lucia P, Monno A, Candiani M, Somigliana E, Panina-Bordignon P.

Source

Center for Research in Obstetrics and Gynecology, San Raffaele Scientific Institute, 20132 Milan, Italy.

Abstract

BACKGROUND Endometriosis, which is characterized by the growth of endometrial tissue at ectopic locations as well as vascular development and inflammation, is still an unmet clinical need since an optimal drug that allows for both pain and infertility management does not exist. Since both the eutopic and the ectopic endometrium express the vitamin D receptor (VDR), and VDR agonists are endowed with anti-proliferative and anti-inflammatory properties, we evaluated the effect of elocalcitol, a VDR agonist with low calcaemic liability, in a mouse model of experimentally induced endometriosis. METHODS AND RESULTS Endometriosis was induced by injection of syngeneic endometrial tissue fragments into adult Balb/c female mice. After having confirmed by immunohistochemistry that endometriotic lesions developing in mice expressed VDR, the mice were administered with elocalcitol (100 μg/kg) or vehicle orally, once a day, for various durations of time. In this model, elocalcitol was able to reduce total lesion weight up to 70% upon treatment for 1 week before and 2 weeks after disease induction. Interestingly, a therapeutic effect was also observed on already established lesions. Elocalcitol was shown to reduce the capacity of mouse endometrial cells to adhere to collagen. In addition in treated mice, a decreased state of peritoneal inflammation was demonstrated by the inhibition of macrophage recruitment and inflammatory cytokine secretion. CONCLUSIONS The VDR agonist elocalcitol inhibits lesion development in a validated mouse model of endometriosis, and exerts a protective effect on both the implantation and organization of transferred endometrial tissue. These preliminary data in mice provide a sound rationale for further testing in primate models and eventually in humans.

Hum Reprod.2012 Jul;27(7):2117-29. Epub 2012 May 15.

Somatostatin and somatostatin analogues reduce PDGF-induced endometrial cell proliferation and motility.

Annunziata M, Luque RM, Durán-Prado M, Baragli A, Grande C, Volante M, Gahete MD, Deltetto F, Camanni M, Ghigo E, Castaño JP, Granata R.

Source

Laboratory of Molecular and Cellular Endocrinology, Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy.

Abstract

BACKGROUND Endometriosis is characterized by ectopic implantation of endometrial cells, which show increased proliferation and migration. Somatostatin (SST) and its analogues inhibit normal and cancer cell growth and motility through the SST receptors, sst1-5. Cortistatin (CST), which displays high structural and functional homology with SST, binds all ssts, as well as MrgX2. Our objective was to investigate the gene expression of the SST/CST system and to determine the effect of SST and its analogues on platelet-derived growth factor (PDGF)-induced proliferation and motility in telomerase-immortalized human endometrial stromal cell (T HESC) line and in primary endometrial stromal cell (ESCs) isolated from human endometriotic tissues. METHODS Ectopic endometrial tissues were collected from women (n= 23) undergoing laparoscopic surgery for endometriosis (Stage III/IV). Gene expression was evaluated by real-time PCR, cell motility by wound healing assay, protein expression and β-actin rearrangement by immunofluorescence, cell proliferation by the Alamar blue assay and ERK1/2 and Akt phosphorylation by western blot. RESULTS Human endometriotic tissues, primary ESCs and T HESCs expressed SST, CST and ssts. SST, its analogues SOM230 and octreotide, as well as CST, counteracted PDGF-induced proliferation and migration in both ESCs and T HESCs. SST also inhibited vascular endothelial growth factor and metalloprotease-2 mRNA expression, and reduced basal and PDGF-induced ERK1/2 phosphorylation. CONCLUSION These results indicate that the SST/CST system is expressed in endometriotic tissues and cells. The inhibitory effects of SST and its analogues on PDGF-induced proliferation and motility suggest that these peptides may represent promising tools in the treatment of endometriosis.

Hum Reprod.2012 Jul;27(7):2001-9. Epub 2012 May 15.

Serum and peritoneal interleukin-33 levels are elevated in deeply infiltrating endometriosis.

Santulli P, Borghese B, Chouzenoux S, Vaiman D, Borderie D, Streuli I, Goffinet F, de Ziegler D, Weill B, Batteux F, Chapron C.

Source

Department of Gynecology Obstetrics II and Reproductive Medicine, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, AP-HP, Hôpital Cochin, 75679 Paris, France.

Abstract

BACKGROUND Interleukin 33 (IL-33) is a cytokine involved in fibrotic disorders. We have analyzed IL-33 levels in the sera and peritoneal fluids of women with various forms of endometriosis and investigated the correlation with disease activity. METHODS We conducted a prospective laboratory study in a tertiary-care university hospital between January 2005 and December 2010. Five hundred and ten women with histologically proven endometriosis and 132 endometriosis-free controls were enrolled in this study. Complete surgical exploration of the abdominopelvic cavity was performed in each patient. Blood samples and peritoneal fluids were obtained before and during surgical procedures, respectively. IL-33 was measured by an enzyme-linked immunosorbent assay in sera and peritoneal fluids, and the concentrations correlated with the extent and the severity of endometriotic lesions. RESULTS IL-33 was detectable in 23.1% of serum samples from all 642 women studied and 75.0% of peritoneal fluid samples studied (44 women with endometriosis and 36 controls). Serum IL-33 was higher in deeply infiltrating endometriosis (DIE) (median, 104.9 pg/ml; range, 8.0-104.9) than in endometriosis-free women (median, 61.3 pg/ml; range, 7.5-526.0; P = 0.022) or in women affected by superficial endometriosis (median, 36.8 pg/ml; range, 7.5-179.0; P < 0.001). Peritoneal IL-33 was higher in DIE than in endometriosis-free women (median, 642.0 pg/ml; range, 25.9-3350.6 versus median, 194.2 pg/ml; range, 12.7-1818.2, respectively; P = 0.003). We found positive correlations between serum IL-33 concentration and intensity of dysmenorrhea (r = 0.174; P = 0.028) and gastrointestinal symptoms (r = 0.199; P = 0.027), total number of DIE lesions (r = 0.224; P = 0.016) and the worst DIE lesion (r = 0.299; P < 0.001). CONCLUSIONS In spite of the number of samples with undetectable levels, serum IL-33 is abnormally elevated in women with endometriosis and principally in DIE. Elevated serum IL-33 is correlated with the intensity of preoperative painful symptoms, and with the extent and severity of the DIE. IL-33 may be considered as a novel cytokine involved in the pathogenesis of DIE.

Hum Reprod.2012 Jul;27(7):2107-16. Epub 2012 May 4.

CXCL8 enhances proliferation and growth and reduces apoptosis in endometrial stromal cells in an autocrine manner via a CXCR1-triggered PTEN/AKT signal pathway.

Li MQ, Luo XZ, Meng YH, Mei J, Zhu XY, Jin LP, Li DJ.

Source

Laboratory for Reproductive Immunology, Hospital & Institute of Obstetrics and Gynecology, IBS, Fudan University Shanghai Medical College, Shanghai 200011, China.

Abstract

BACKGROUND Chemokine CXCL8 (also known as IL-8) has been identified as a potential regulator of endometrial stromal cells (ESCs), but it is unclear how CXCL8 regulates the survival of ESCs in the pathogenesis of endometriosis. METHODS We assessed the secretion of CXCL8 by enzyme-linked immunosorbent assays and the expression of its receptors, CXCR1 and CXCR2, by in-cell Western assay and immunhistochemistry. The effects of CXCL8 on the activation or expression of various cell mediators were also investigated by in-cell Western assay. The effects of CXCL8 on the proliferation, growth and apoptosis of ESCs in vitro were assessed by BrdU assays, cell counts and annexin V labeling, respectively. RESULTS Secretion of CXCL8 and expression of CXCR1 in the eutopic ESCs from women with endometriosis were significantly higher than that in control ESCs, but the expression of CXCR2 showed no significant difference between these two cell types. CXCL8 stimulated proliferation and growth and reduced apoptosis of ESCs in an autocrine manner, and these effects were abolished by anti-human CXCL8 and CXCR1 neutralizing antibodies and by a PI3K/Akt inhibitor. Moreover, CXCL8 up-regulated the expression of the anti-apoptotic proteins, survivin and Bcl-2, inhibited the expression of the Phosphatase and tensin homolog (PTEN) and activated the phosphorylation of Akt. CONCLUSIONS This study suggests that CXCL8 and CXCR1 are involved in the pathogenesis of endometriosis by up-regulating proliferation and growth and restricting apoptosis in ESCs by activating the PTEN/Akt pathway and mediating the expression of survivin and Bcl-2.

Hum Reprod.2012 Jul;27(7):2089-95. Epub 2012 May 4.

Long-term regression of experimental endometriosis in a rat model treated with local application of levonorgestrel-loaded biodegradable microspheres.

Yuan P, Chen B, Huang Y, Xin X.

Source

Department of Obstetrics and Gynecology, No. 451 Hospital of the PLA, No. 269 Youyi East Road, Xían, Shaanxi 710054, China.

Abstract

BACKGROUND A previous study demonstrated that local application of levonorgestrel-loaded polylactic acid microspheres (LNG microspheres) resulted in significant regression of endometriotic cysts in a rabbit model for 6 months without disturbing the metabolic parameters or ovarian function. In order to investigate the feasibility of local application of LNG microspheres as a long-term maintenance treatment for endometriosis, the suppressive effect of a single intra-cystic injection of LNG microspheres was studied for 1 year in a rat model. METHODS AND RESULTS Twenty four rats with experimental endometriotic cysts were randomized to be treated with a single intra-cystic injection of LNG microspheres (n = 8); 6-month GnRH agonist (GnRHa, n = 8) or control (n = 8). Intra-cystic injection of LNG microspheres and GnRHa treatment caused comparable regression and atrophy in endometriotic cysts in the first 6 months. Compared with the control, the wet weight of the endometriotic cysts was significantly lower in both groups at Month 6 but by Month 12 only remained low in the LNG microspheres group (P < 0.01). The immunostaining of estrogen receptors (ERs) in both the epithelium and stroma and progesterone receptors (PRs) in the stroma was significantly weakened in the LNG microspheres group at Month 6 and was not fully restored at Month 12 (P < 0.01). Metabolic parameters and estrous cycle were not disturbed by local application of LNG microspheres. CONCLUSIONS In a rat endometriosis model, the suppressive effect of a single intra-cystic injection of LNG microspheres was comparable to that of GnRHa, and was maintained for 1 year. The down-regulation of ERs and PRs might serve as possible mechanism of long-term effectiveness.

Hum Reprod.2012 Jul;27(7):2020-9. Epub 2012 May 3.

Combined mRNA microarray and proteomic analysis of eutopic endometrium of women with and without endometriosis.

Fassbender A, Verbeeck N, Börnigen D, Kyama CM, Bokor A, Vodolazkaia A, Peeraer K, Tomassetti C, Meuleman C, Gevaert O, Van de Plas R, Ojeda F, De Moor B, Moreau Y, Waelkens E, D’Hooghe TM.

Source

Department of Obstetrics and Gynecology, Leuven University Fertility Center, UZ Gasthuisberg, 3000 Leuven, Belgium.

Abstract

BACKGROUND An early semi-invasive diagnosis of endometriosis has the potential to allow early treatment and minimize disease progression but no such test is available at present. Our aim was to perform a combined mRNA microarray and proteomic analysis on the same eutopic endometrium sample obtained from patients with and without endometriosis. METHODS mRNA and protein fractions were extracted from 49 endometrial biopsies obtained from women with laparoscopically proven presence (n= 31) or absence (n= 18) of endometriosis during the early luteal (n= 27) or menstrual phase (n= 22) and analyzed using microarray and proteomic surface enhanced laser desorption ionization-time of flight mass spectrometry, respectively. Proteomic data were analyzed using a least squares-support vector machines (LS-SVM) model built on 70% (training set) and 30% of the samples (test set). RESULTS mRNA analysis of eutopic endometrium did not show any differentially expressed genes in women with endometriosis when compared with controls, regardless of endometriosis stage or cycle phase. mRNA was differentially expressed (P< 0.05) in women with (925 genes) and without endometriosis (1087 genes) during the menstrual phase when compared with the early luteal phase. Proteomic analysis based on five peptide peaks [2072 mass/charge (m/z); 2973 m/z; 3623 m/z; 3680 m/z and 21133 m/z] using an LS-SVM model applied on the luteal phase endometrium training set allowed the diagnosis of endometriosis (sensitivity, 91; 95% confidence interval (CI): 74-98; specificity, 80; 95% CI: 66-97 and positive predictive value, 87.9%; negative predictive value, 84.8%) in the test set. CONCLUSION mRNA expression of eutopic endometrium was comparable in women with and without endometriosis but different in menstrual endometrium when compared with luteal endometrium in women with endometriosis. Proteomic analysis of luteal phase endometrium allowed the diagnosis of endometriosis with high sensitivity and specificity in training and test sets. A potential limitation of our study is the fact that our control group included women with a normal pelvis as well as women with concurrent pelvic disease (e.g. fibroids, benign ovarian cysts, hydrosalpinges), which may have contributed to the comparable mRNA expression profile in the eutopic endometrium of women with endometriosis and controls.

Int J Gynaecol Obstet.2012 Jul;118(1):42-6. Epub 2012 Apr 14.

Diagram to map the locations of endometriosis.

Lasmar RB, Lasmar BP, Pillar C.

Abstract

OBJECTIVE:

To develop and test a visual map that corresponds practically and objectively to the anatomical areas affected by endometriosis.

METHOD:

The study comprised 150 questionnaires concerning 10 clinical cases of endometriosis presented as a visual diagram that were distributed at 3 different scientific events, among 3 groups of 50 gynecologists. Data were analyzed to evaluate the diagram’s ability to graphically represent the endometriosis sites.

RESULTS:

After presentation at the first event, the rate of correct answers on the site of endometriosis was 84.7%; at the second event, after modifications implemented after feedback from the first event, the rate of correct answers was 97.4%; and at the third event, when all suggestions and modifications had been made, the rate was 99.7%.

CONCLUSION:

The diagram proposed to map the location of endometriosis lesions appears to be an adequate and effective instrument to represent the site of the disease, with correlation at almost 100%.

Int J Gynecol Cancer.2012 Jul;22(6):993-9.

Management and prognosis of clear cell borderline ovarian tumor.

Uzan C, Dufeu-Lefebvre M, Fauvet R, Gouy S, Duvillard P, Darai E, Morice P.

Source

*Department of Gynecologic Surgery, and †Unit INSERM U 10-30, Institut Gustave Roussy, Villejuif; ‡Department of Obstetrics and Gynecology, CHU Amiens, Amiens; §INSERM ERI-12, Université de Picardie Jules Vernes, Amiens; Department of Pathology, Institut Gustave Roussy, Villejuif; ¶Department of Obstetrics and Gynecology, Hopital Tenon, Paris; #INSERM UMRS 938, Paris; **Universite Pierre et Marie Curie (Paris VI), Paris; and ††Université Paris-Sud (Paris XI), Le Kremlin Bicetre, France.

Abstract

BACKGROUND:

The clear cell borderline ovarian tumor (CCBOT) of the ovary is a rare tumor accounting for less than 1% of BOT. Fewer than 25 cases have been reported in the literature (including details on clinical management and outcomes). The aim of this study was to determine the prognosis of a series of CCBOTs collected in 2 reference centers.

PATIENTS AND METHODS:

This was a retrospective review of patients with CCBOT treated or referred to our institutions. A centralized histological review by a reference pathologist and data on the clinical characteristics, management, and outcomes of patients were required for inclusion.

RESULTS:

Twelve patients were identified between 2000 and 2010. The median age of patients was 68 years (range, 36-83 years). Two had been treated conservatively and 9 radically (data unknown in 1). The tumor was unilateral in 11 cases. All patients had stage I disease. All cases were CCBOT with an adenofibromatous pattern. Stromal microinvasion or intraepithelial carcinoma was histologically associated in 2 and 3 cases, respectively. Four of the 12 patients had synchronous endometrial disorders (but no endometrioid carcinoma). No cases were histologically associated with endometriosis. Four patients were lost to follow-up. Among 8 other patients, after a median period of 28 months (range, 2-129 months), no recurrence had occurred (1 patient had died of another disease).

CONCLUSION:

Clear cell borderline ovarian tumor carries a good prognosis. All tumors are stage I; therefore, surgical staging is not necessary in most of the cases. Conservative treatment could be proposed to young patients, but uterine curettage would then be required in cases of uterine preservation.

Int J Gynecol Cancer.2012 Jul;22(6):1000-5.

Serum HE4 as a Useful Biomarker in Discriminating Ovarian Cancer From Benign Pelvic Disease.

Zheng H, Gao Y.

Source

Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gynecologic Oncology, Peking University Cancer Hospital & Institute, Beijing, China.

Abstract

OBJECTIVE:

To evaluate the role of the novel tumor marker human epididymal secretory protein E4 (HE4) in discriminating ovarian cancer from benign pelvic disease in patients with a pelvic mass.

METHODS:

Serum samples from 131 patients with epithelial ovarian cancer (EOC) and 126 patients with various benign pelvic diseases were collected preoperatively and tested for cancer antigen (CA)125 and HE4 levels. Receiver operator characteristic curves were constructed, and the area under the curve (AUC) was compared between the markers.

RESULTS:

The median CA125 and HE4 levels were significantly higher in the patients with EOC than in those with benign disease (P < 0.001). Using benign controls as the comparison group for all cases, the AUC for combined HE4 and CA125 (0.955) was significantly higher than that for HE4 (0.941) or CA125 alone (0.924; P < 0.05). A comparison of premenopausal benign controls to EOC cases showed that the AUC for combined HE4 and CA125 (0.97) was significantly higher than that for CA125 (0.93; P < 0.004). The AUC for HE4 was significantly higher compared to that of CA125 in discriminating EOC from ovarian endometriosis (0.969 vs 0.904; P = 0.014) and pelvic inflammatory disease (0.909 vs 0.819; P = 0.034).

CONCLUSION:

Serum HE4 testing is a more powerful tool than CA125 assay to discriminate EOC from ovarian endometriosis and pelvic inflammatory disease. For patients with a pelvic mass, especially premenopausal patients, the serum concentration of HE4 adds valuable information to CA125 in identifying patients with EOC from those with benign pelvic disease.

Int J Gynecol Pathol.2012 Jul;31(4):328-34.

Chromosomal aberrations detected by chromogenic in situ hybridization in abdominal wall endometriosis after cesarean section.

Jeong K, Lee S, Kim I, Kang JS.

Source

Department of Obstetrics and Gynecology (K.J.), School of Medicine, Ewha Womans University, MokDong Hospital, Seoul; Department of Pathology (S.L.), Konkuk University, Chungju Hospital, Chungbuk Departments of Pathology (I.K.); and Obstetrics and Gynecology (J.S.K.), College of Medicine, Korea University, Anam Hospital, Seoul, Korea.

Abstract

The goal of this study is to evaluate the chromosomal loss in abdominal wall endometriosis by chromogenic in situ hybridization (CISH). Twenty-four cases of abdominal wall endometriosis that developed after cesarean section at the Korea University Medical Center between January 1997 and December 2006 were selected. CISH was performed in the sections of tissue microarray block using the Zymed CISH centromeric probes for chromosomes 3, 7, 8, 9, 10, 11, 17, and 18. Monosomy was defined when the percentage of the nuclei with a single dot was more than mean+3 SD of the respective probe in normal control endometrium. CISH study was possible in more than half of the endometriosis samples, except for chromosome 9, and was most successful for chromosome 17. The frequency of monosomy was high for chromosomes 9 (75.0%) and 17 (73.9%), moderate for chromosomes 10 (57.1%) and 18 (56.3%), and low for chromosomes 3 (12.5%), 7 (22.2%), 8 (10.5%), and 11 (10.5%). Monosomy for >2 and 3 chromosomes occurred in 66.7% and 42.9% of the cases, respectively. It is concluded that CISH method may be considered a useful laboratory technique in detecting chromosomal loss, and multiple chromosomal loss is involved in the formation of ectopic endometrium in abdominal wall endometriosis.

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