Mario Vignali

Endometriosis: novel etiopathogenetic concepts and clinical perspectives

OBJECTIVE To discuss current ideas about therapy for endometriosis derived from new observations generated by using molecular biology techniques and in vivo animal models of disease. METHOD(S) The MEDLINE database was reviewed for English-language articles on new drugs that affect the endocrine or immunologic system, the possibility that endometriosis has multiple forms, and the association of endometriosis with cancer. Specific attention was given to in vivo studies in animals or humans. CONCLUSION(S) Among the novel potential candidate drugs, aromatase inhibitors and raloxifene should be considered for treatment of postmenopausal women with endometriosis. Notable observations have emerged from studies of immunomodulators and antiinflammatory agents in animal models of disease. These findings must be confirmed in women. The histogenesis of ovarian endometriomas is still unclear, thus limiting new experimental approaches to this form of disease. Given the low but established risk for malignant transformation of endometriosis, efforts should be directed toward identification of susceptibility loci for the disease and its potential transformation into cancer.

Laparoscopic creation of a neovagina in Mayer-Rokitansky-Küster-Hauser syndrome by modification of Vecchietti's operation

A neovagina was created by a laparoscopic modification of Vecchiettis operation in two women with Mayer-Rokitansky-Küster-Hauser syndrome. A plastic olive was applied to the vaginal dimple and pulled upward by two threads passed through the potential neovaginal space at laparoscopy, without the need for laparotomy or dissection of the vesicorectal space. In both cases we obtained very good results in anatomic and sexual functional terms.

Two-step tumour targetting in ovarian cancer patients using biotinylated monoclonal antibodies and radioactive streptavidin

A new method for intraperitoneal tumour targetting in ovarian cancer using biotinylated monoclonal antibodies (MoAb) and radioactive streptavidin is described. Fifteen patients with histologically documented ovarian carcinoma were injected intraperitoneally with 2 mg of biotinylated MoAb MOv18, followed 3–5 days later by 100–150 μg of indium-111 streptavidin, at the specific activity of 280–370 MBq/mg in 500 ml of normal saline. No toxicity was observed. Tumours were imaged from 2 to 48 h after radioactivity injection by recording both planar and single photon emission tomography (SPET) data. All patients underwent surgery 1–8 days later (mean 3 days) after scanning. The resected tumour and normal tissue radioactivity were measured. On the day of surgery, the tumour to normal tissue ratio was 9:1 (range 3:1–30:1) and 45:1 (range 12:1–120:1) for intra- and extraperitoneal samples, respectively. The mean tumor to blood ratio was 14:1 (range 4:1–30:1). The injected dose (i.d.) per gram of tumour was 0.112 (range 0.01–0.3) for recurrences and 0.05 for primary tumour (range 0.005–0.2). Over 24–48 h 14% i.d. (range 8–18% i.d.) was found in the urine, 14% i.d. (range 629% i.d.) in the blood and 63% i.d. (range 56–70% i.d.) was still in the peritoneal cavity. These preliminary clinical data suggest that this two-step strategy may be superior to the conventional approach (radiolabelled antibodies) for intraperitoneal radioimmunolocalization and radioimmunotherapy of ovarian cancer.

Urinary Tract Anomalies Associated with Unicornuate Uterus

PURPOSE We investigated the association between the various subclasses of the unicornuate uterus and urinary tract anomalies. MATERIALS AND METHODS We studied the urinary tract of 37 patients with a unicornuate uterus by urography and/or ultrasonography. Unicornuate uterus was diagnosed at laparoscopy or laparotomy. RESULTS A total of 15 patients (40.5%) had urinary tract anomalies, including ectopic kidney in 4, renal agenesis in 6, double renal pelvis in 2, horseshoe kidneys in 2 and unilateral medullary sponge kidney in 1. No differences were observed in the frequency of urinary anomalies among the various subclasses of unicornuate uterus. CONCLUSIONS Our results indicate the need to suspect a urinary tract anomaly, particularly of the kidney, in all women with a unicornuate uterus.

Expression of intercellular adhesion molecule-1 (ICAM-1) on cultured human endometrial stromal cells and its role in the interaction with natural killers

PROBLEM: Recent evidence emphasizes the role of natural killer cells (NKs) as potential effectors of peritoneal immune surveillance directed against the outgrowth of endometrial cells, refluxed with menstrual debris, in ectopic sites. This NK‐mediated cytotoxicity toward autologous endometrial antigens seems to be significantly decreased in endometriosis patients.

Basic fibroblast growth factor and its receptor messenger ribonucleic acids are expressed in human ovarian epithelial neoplasms

OBJECTIVE Our purpose was to determine whether basic fibroblast growth factor is present in, and synthesized by, human ovarian epithelial neoplasms and to evaluate the expression of gene for the basic fibroblast growth factor receptor. STUDY DESIGN The synthesis of basic fibroblast growth factor and its receptor was investigated in seven primary human ovarian epithelial neoplasms. Neoplastic tissues were homogenized and the cytoplasmic extracts purified by heparin-sepharose chromatography with a linear salt gradient of 0.6 to 3 mol/L sodium chloride in Tris-hydrochloric acid. The in situ synthesis of basic fibroblast growth factor and its receptor was demonstrated by polymerase chain reaction. Total ribonucleic acid was reverse transcribed and then amplified with two oligonucleotide primers specific for the bovine and human basic fibroblast growth factor gene and its human receptor gene. RESULTS As assessed by both bioassay and radioimmunoassay a peak of basic fibroblast growth factor-like activity was present in all tumors in the chromatographic fractions eluted with 3 mol/L sodium chloride. The mitogenic effect on bovine adrenocortical endothelial cell proliferation varied from 35% to 153% above control cultures. Levels of basic fibroblast growth factor-like immunoreactivity were between 4 and 33 ng/ml. Qualitatively similar results were obtained after purifying the cytoplasmic extract of dispersed human ovarian tumor cells. The mitogenic effect was completely abolished by a specific neutralizing anti-basic fibroblast growth factor antibody. Single major deoxyribonucleic acid bands of the expected size (354 and 661 bp) were detected in all tumors studied. The identify of this material with the human basic fibroblast growth factor sequence was confirmed by restriction enzyme analysis. CONCLUSION These data demonstrate that both basic fibroblast growth factor and its receptor are present in and synthesized by human ovarian tumor cells. Thus basic fibroblast growth factor might stimulate their abnormal proliferation through an autocrine mechanism.

Follow-up of laparoscopic treatment of stage III-IV endometriosis.

STUDY OBJECTIVE To evaluate the efficacy of conservative laparoscopic surgery in a series of patients with stage III-IV endometriosis. DESIGN Prospective study (Canadian Task Force classification II-1). SETTING University-affiliated hospital. PATIENTS All 141 women who underwent conservative operative laparoscopy for stage III-IV endometriosis between January 1993 and December 1996 and were followed for a minimum of 6 months. INTERVENTIONS Laparoscopic procedures performed with scissors, bipolar coagulation, and hydrodissection. MEASUREMENTS AND MAIN RESULTS Clinical examination, transvaginal ultrasonography, and pain questionnaire were scheduled every 6 months postoperatively. The cumulative proportion of pregnant patients and cumulative recurrence rate were calculated by Kaplan-Meier method. Twenty-five women (44%) with infertility became pregnant. Twenty-three (51%) had stage III and two (16.7%, p <0.05) had stage IV endometriosis. The 24-month cumulative pregnancy rate was 57.5%. Thirty-one women (22%) reported pain recurrence during follow-up. Five (3.5%) recurrences were confirmed by histologic examination and eight (5.7%) were documented only by clinical and ultrasonographic findings. No recurrence occurred in the first 6 months of follow-up. CONCLUSION Operative laparoscopy seems to be effective treatment for stage III endometriosis. A larger series with longer follow-up is necessary to clarify its role in the management of stage IV disease. (J Am Assoc Gynecol Laparosc 6(1):55-58, 1999)

Magnetic resonance imaging in endometrial carcinoma staging

Correct evaluation of myometrial infiltration is essential in patients with stage I and II endometrial cancer who are candidates for hysterectomy without lymphadenectomy, if extensive infiltration of the myometrium is not present. The aim of this study was to evaluate the use of magnetic resonance imaging (MRI) to improve staging of patients with endometrial cancer. Thirty patients with histological diagnosis of endometrial cancer were studied with MRI at 1.5 T and subsequently underwent abdominal hysterectomy. The MRI results were compared with those of the histological tests. MRI was performed with a 1.5-T magnet and spin-echo (SE) technique [repetition time/echo time (msec) = 2.000/35-90]. Contiguous 4-mm sections of were obtained from the sagittal plane. Clinical staging was not confirmed in two patients who presented with cervical extension of the tumor. The overall accuracy of MRI in determining the grade of myometrial and cervical invasion was 86 and 90%, respectively.

Expression of GnRH receptor gene in human ectopic endometrial cells and inhibition of their proliferation by leuprolide acetate.

The present study was conducted to investigate whether GnRH-receptor (GnRH-R) gene is expressed in endometriosis ovarian implants and whether a GnRH-analogue (GnRH-a) may exert an effect on endometriosis cell proliferation in vitro. The presence of GnRH-R transcripts in ovarian endometriosis cells was assessed by reverse transcription-polymerase chain reaction (RT-PCR) and further confirmed by Southern blot analysis. GnRH-R mRNA was detected in all the 13 samples examined. In contrast, GnRH-R transcripts were not detectable in endometriosis-free peritoneal tissue. In the second part of the study, endometriosis cells were cultured for 9 days with different doses of leuprolide acetate (ranging from 0 to 10(-5) M). In 4 out of 13 cases, a significant anti-proliferative effect was observed at doses of leuprolide acetate ranging from 10(-9) to 10(-5) M. In one case, a significant inhibition of cell proliferation was observed only at 10(-5) M leuprolide acetate concentration. In contrast, the GnRH-a did not affect cell growth, regardless of the expression of GnRH-R transcripts and the given doses, in the remaining 8 experiments. To date, this is the first evidence indicating that GnRH-R mRNA is expressed in human ovarian endometriomas. Moreover, the inhibition of endometriosis cell proliferation induced by the GnRH-a in vitro suggests that, at least in some cases, this compound might exert a direct effect on endometriosis lesions.

Use of serum-soluble intercellular adhesion molecule-1 as a new marker of endometriosis

OBJECTIVE To investigate the hypothesis that soluble intercellular adhesions molecule-1 (sICAM-1) may be used as a new serum marker of endometriosis. DESIGN Prospective cohort study. SETTING An academic department specializing in gynecologic laparoscopy. PATIENT(S) Consecutive series of 120 women of reproductive age who underwent laparoscopy for benign gynecologic conditions. INTERVENTION(S) Data were collected on baseline clinical characteristics, and surgical and histologic diagnosis. MAIN OUTCOME MEASURE(S) Serum concentration of both CA125 and sICAM-1. RESULT(S) Endometriosis was documented in 71 women (stage I to II in 24 cases and stage III to IV in 47 cases). Serum levels of sICAM-1 were only slightly but not significantly increased in women with endometriosis compared with women without the disease. However, serum concentration of sICAM-1 in the 21 women who were found to have deep peritoneal endometriosis was significantly enhanced when compared with both women without the disease and those with other forms of endometriosis. The sensitivity and specificity of sICAM-1 in detecting deep peritoneal endometriosis were 0.19 and 0.97, respectively; whereas those of CA125 were 0.14 and 0.92, respectively. When both parameters were used concomitantly, the sensitivity and specificity were 0.28 and 0.92, respectively. CONCLUSION(S) Although the present study tends to support a role of sICAM-1 in the development of endometriosis, serum concentrations of this molecule do not seem to be an effective indicator for the diagnosis of either the early or advanced stage of endometriosis. However, an integrated clinical and laboratory approach using both CA125 and sICAM-1 may be helpful in specifically identifying women with deep peritoneal endometriosis.