Stefano Ferrari

Macrophages are alternatively activated in patients with endometriosis and required for growth and vascularization of lesions in a mouse model of disease.

The mechanisms that sustain endometrial tissues at ectopic sites in patients with endometriosis are poorly understood. Various leukocytes, including macrophages, infiltrate endometriotic lesions. In this study, we depleted mouse macrophages by means of either clodronate liposomes or monoclonal antibodies before the injection of syngeneic endometrial tissue. In the absence of macrophages, tissue fragments adhered and implanted into the peritoneal wall, but endometriotic lesions failed to organize and develop. When we depleted macrophages after the establishment of endometriotic lesions, blood vessels failed to reach the inner layers of the lesions, which stopped growing. Macrophages from patients with endometriosis and experimental mice, but not nonendometriotic patients who underwent surgery for uterine leiomyomas or control mice, expressed markers of alternative activation. These markers included high levels of scavenger receptors, CD163 and CD206, which are involved in both the scavenging of hemoglobin with iron transfer into macrophages and the silent clearance of inflammatory molecules. Macrophages in both inflammatory liquid and ectopic lesions were equally polarized, suggesting a critical role of environmental cues in the peritoneal cavity. Adoptively transferred, alternatively activated macrophages dramatically enhanced endometriotic lesion growth in mice. Inflammatory macrophages effectively protected mice from endometriosis. Therefore, endogenous macrophages involved in tissue remodeling appear as players in the natural history of endometriosis, required for effective vascularization and ectopic lesion growth.

Proangiogenic Tie2(+) macrophages infiltrate human and murine endometriotic lesions and dictate their growth in a mouse model of the disease

Endometriosis affects women of reproductive age, causing infertility and pain. Although immune cells are recruited in endometriotic lesions, their role is unclear. Tie2-expressing macrophages (TEMs) have nonredundant functions in promoting angiogenesis and growth of experimental tumors. Here we show that human TEMs infiltrate areas surrounding newly formed endometriotic blood vessels. We set up an ad hoc mouse model in which TEMs, and not Tie2-expressing endothelial cells, are targeted. We transplanted in wild-type recipients bone marrow cells expressing a suicide gene (Herpes simplex virus type 1 thymidine kinase) under the Tie2 promoter/enhancer. TEMs infiltrated endometriotic lesions. TEM depletion by ganciclovir administration arrested the growth of established lesions, without toxicity. Lesion architecture was disrupted, with: i) loss of glandular organization, ii) reduced neovascularization, and iii) activation of caspase 3 in CD31(+) endothelial cells. Thus, TEMs are important for maintaining the viability of newly formed vessels and represent a potential therapeutic target in endometriosis.

Continuous low‐dose oral contraceptive in the treatment of colorectal endometriosis evaluated by rectal endoscopic ultrasonography

Objective. Limited attention has been focused on the medical treatment of bowel endometriosis. This study evaluates the efficacy of administration of a continuous low‐dose oral contraceptive in treating pain and other symptoms associated with colorectal endometriotic nodules, as evaluated by rectal endoscopic ultrasonography. Design. Prospective observational study. Setting. Academic Department of San Raffaele Scientific Institute, Obstetrics and Gynecology Unit. Population. Symptomatic women of reproductive age (n=26) with colorectal nodules infiltrating at least the bowel muscularis propria and without a stenosis >50%. In 31% of the patients, endoscopic ultrasonography permitted diagnosis of nodules located more than 10 cm from the anal rim. Methods. Patients received a continuous low‐dose oral contraceptive containing 15 μg ethinylestradiol and 60 μg gestodene for 12 months. Subjective symptoms were prospectively evaluated, and nodule volumes were monitored using endoscopic ultrasonography. Main outcome measures. Nodule measurements were performed at baseline and after 12 months of treatment. Symptoms at the start and after 12 months were evaluated. Results. A significant improvement in the intensity of all the considered symptoms (dysmenorrhea, non‐menstrual pelvic pain, deep dyspareunia and painful defecation) was seen when evaluated by a visual analog scale. A reduction in terms of both diameter (mean reduction 26%) and volume of the nodules (mean reduction 62%) was observed after a 12 month period. Conclusions. A continuous low‐dose oral contraceptive therapy may reduce bowel endometriosis‐associated symptoms. In addition, this therapy induces a significant volumetric reduction of colorectal plaques when evaluated by endoscopic ultrasonography.

Endoscopic rectal ultrasound and elastosonography are useful in flow chart for the diagnosis of deep pelvic endometriosis with rectal involvement

Aim:  Endometriosis is defined by the presence of endometrial glands and stroma outside the uterus. The disease causes pelvic pain, dysmenorrhea, dyspareunia, dyschezia and urinary symptoms. The aim of this study was to assess the usefulness of endoscopic ultrasound (EUS) and elastosonography for detecting rectosigmoid endometriosis and to compare the findings, in selected and symptomatic patients, with surgical specimens in order to select the best surgical strategy.

Laparoscopic treatment of deep pelvic endometriosis with rectal involvement.

PURPOSE: Our study aimed to evaluate the feasibility and outcome of laparoscopic excision of deep pelvic endometriosis with extensive rectal involvement causing severe symptoms. METHODS: Ten patients, mean age 32 years (range, 27-43), with deep pelvic endometriosis and rectal wall involvement, requiring surgical resection, were studied since January 2004. Prior to surgery and 6 months postsurgery, patients completed a 100-point rank questionnaire on intensity of intestinal and extraintestinal symptoms. A laparoscopic approach was performed by a team of a gynecologist and colorectal surgeons. RESULTS: At surgery, complete excision of infiltrating endometriosis was achieved, with 7 low rectal resections, 2 rectosigmoid resections, and 1 proctectomy with coloanal anastomosis. Additional procedures were: ureter resections (n = 2) with one reimplantation in the bladder, left ovariectomies (n = 2), ovarian endometrioma resections (n = 4), and laser ablation of superficial peritoneal lesions (n = 4). In four cases, a laparotomic conversion was needed. Mean follow-up was 27.6 months (range, 18-37). Neither intraoperative nor postoperative serious complications were observed. All the patients experienced significant improvement of intestinal and extraintestinal symptoms. CONCLUSIONS: Laparoscopic resection of deep pelvic endometriosis with rectal involvement can be successful in improving digestive and gynecologic symptoms; however, this approach is challenging with a high rate of laparotomic conversion.

External Validation of the Endometriosis Fertility Index (EFI) for Predicting Spontaneous Pregnancy after Surgery: Further Considerations on Its Validity

Background/Aims: The revised American Society for Reproductive Medicine classification of endometriosis has a limited predictive value for pregnancy after surgery. A tool for predicting spontaneous pregnancy or pregnancy following assisted reproduction technology (ART) represents a clinical need. This study aimed to (i) provide an external validation of the EFI score in predicting pregnancy in infertile Italian endometriosis women; (ii) evaluate the predictive value of EFI score on ART outcome for patients who previously attempted to spontaneously conceive after surgery. Methods: In 104 women with endometriosis, EFI score was calculated based on a prospective database data. Cumulative pregnancy rates curves were calculated using Kaplan-Meier (K-M) product limit estimate and log-rank test was used to evaluate differences between EFI groups. A receiver operating characteristic (ROC) curve was plotted for EFI as a predictor of ART outcome. Results: Differences in time to non-ART pregnancy for the six EFI groups were statistically significant (log-rank, p = 1.4 × 10-4). The area under the curve (AUC) for EFI as ART outcome predictor was 0.75 (95% CI 0.61-0.89, p = 6.2 × 10-3), while the best cut-point for pregnancy was 5.5. Conclusion: The EFI score is a reliable scoring system to predict non-ART and ART pregnancy outcome after surgery for endometriosis.

Triptorelin for the treatment of endometriosis

Introduction: Over the past 30 years, gonadotropin-releasing hormone agonists (GnRH-a) have been used to induce a hypoestrogenic status in women with endometriosis with the aim to cause an improvement in pain symptoms similar to that observed after menopause. Triptorelin is one of the most commonly used GnRH-a. Areas covered: This review offers an explanation of the mechanism of action, of the pharmacokinetics and pharmacodynamics of triptorelin and gives the readers a complete overview of the studies on the clinical efficacy, tolerability and safety of this agent in patients with endometriosis. Expert opinion: The studies reviewed in the current manuscript demonstrate the efficacy of triptorelin in improving pain symptoms caused by endometriosis. Further, this effect is confirmed by the reduction in the volume of the endometriotic nodules during treatment. Future research should evaluate whether the pre-operative administration of triptorelin prior to surgical excision of endometriomas may be useful in preserving the ovarian reserve.

Rehabilitation needs in oncological patients: the On-rehab project results on patients operated for musculoskeletal tumors

BACKGROUND Rehabilitation plays an important role in improving functional outcome in patients operated on musculoskeletal tumors. Literature in the field is scarce and the specific needs for rehabilitation of these patients are still unknown. AIM To analyze the rehabilitation needs of patients with primary malignant musculoskeletal tumors. DESIGN Observational, longitudinal study on both inpatient and outpatient operated on musculoskeletal tumors. METHODS Rehabilitation needs of oncological patients were explored by means of questionnaires administered by a physician. Demographic, oncological, psychological domains were also assessed. RESULTS Twenty-nine patients were evaluated in the immediate post-operative period, 25 patients had a follow up at 6 months, and 11 patients at 12 months. Rehabilitation needs concerned essentially the neuromotor function and the improvement of independence at home/outside home. At first admission, support for occupational rehabilitation was also relevant, while its importance was reduced over the follow-up. Pain control need was greater at first admission (VAS over the follow-up 3.3, 0.52, and 1.09, respectively) and required treatment with painkillers. Quality of life (EORTC) increased over the three assessments (respectively 48.80; 71.42; 82.14). The Psychological Distress Inventory (PDI) scores were 26.23, 21.75, 23.6, and the Caregiver Needs Assessment (CNA) scores were 32.69, 27.95, and 31.7 respectively at the three follow up. CONCLUSIONS The relevant domains in which rehabilitation needs emerged in up to 1 year follow up were the neuromotor area in order to gain independence at home and outside the home, pain control, particularly after surgery, nursing, psychological support of patients and caregivers, and occupational activities (personal, work, school, social). CLINICAL REHABILITATION IMPACT The findings of the present study suggest that: short and midterm clinical rehabilitation programs should be made available for patients operated on musculoskeletal tumors. Physical function recovery is only one aspect of rehabilitation, and psychosocial functioning must be taken into account and coordinated by a comprehensive team of specialists. Appropriate assessment tools should be used, and a continuum of care from the hospital to the patients home should be promoted.

Non-surgical treatment of chondrosarcoma: Current concepts and future perspectives

Publisher Summary Chondrosarcoma represents a heterogeneous group of malignant cartilage tumors. Surgery is the most important component of treatment. Although convincing evidence of its benefit is lacking, chemotherapy might be useful in the treatment of mesenchymal and dedifferentiated chondrosarcoma. Radiotherapy plays an important role in the treatment of chondrosarcomas located in the spheno-occipital region and cervical spine. New modern radiation techniques could further improve the outcome for patients with lesions in sites that are surgically difficult to access. Finally, better understanding of molecular diagnostics and pathogenesis of chondrosarcoma, together with the development of new therapeutic agents, has resulted in numerous studies investigating potentially active treatment approaches to this disease. However, at present, the majority of these new compounds are being tested in preclinical settings, and their future clinical application still needs to be defined.Publisher Summary Chondrosarcoma represents a heterogeneous group of malignant cartilage tumors. Surgery is the most important component of treatment. Although convincing evidence of its benefit is lacking, chemotherapy might be useful in the treatment of mesenchymal and dedifferentiated chondrosarcoma. Radiotherapy plays an important role in the treatment of chondrosarcomas located in the spheno-occipital region and cervical spine. New modern radiation techniques could further improve the outcome for patients with lesions in sites that are surgically difficult to access. Finally, better understanding of molecular diagnostics and pathogenesis of chondrosarcoma, together with the development of new therapeutic agents, has resulted in numerous studies investigating potentially active treatment approaches to this disease. However, at present, the majority of these new compounds are being tested in preclinical settings, and their future clinical application still needs to be defined.

The origin of endometriosis-associated ovarian cancer from uterine neoplastic lesions

Endometriosis is a risk factor for type I epithelial ovarian cancer but an issue to be clarified is the site of origin of endometriosis associated ovarian cancer. Here we proposed that the uterus may be the organ of origin of ovarian endometrioid cancer associated with endometriosis. Thus, the first neoplastic transformation would characterize the uterine cells migrating in the pelvis via retrograde menstruation and they would implant secondarily on the ovary. Supporting this hypothesis, an higher incidence of synchronous precancerous and cancerous endometrial pathology in patients affected by ovarian endometrioid cancer associated with endometriosis was showed. Moreover, uterine endometrial type I carcinoma resembles endometriosis associated endometrioid ovarian cancer in behavior and prognosis. This hypothesis is also supported by epidemiologic evidence showing a protective effect for tubal ligation and oral contraceptive use for endometriosis associated endometrioid ovarian cancer. Endometriosis and endometrioid ovarian carcinoma might represent two distinct biological entities characterized by the same organ of origin (the uterus), the same pathogenetic mechanism (transtubal reflux) and the same target organ (the ovary). By shifting the early events of ovarian carcinogenesis to the endometrium, prevention approaches as salpingectomy/tubal ligation and intervention at uterine corpus level may play an important role.