Assunta Casorelli

A Small Molecule SMAC Mimic LBW242 Potentiates TRAIL- and Anticancer Drug-Mediated Cell Death of Ovarian Cancer Cells

Background Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Second mitochondria derived activator of caspase (SMAC) has been described to sensitize for apoptosis. We have explored the pro-apoptotic activity of LBW242, a mimic of SMAC/DIABLO, on ovarian cancer cell lines (A2780 cells and its chemoresistant derivative A2780/ADR, SKOV3 and HEY cells) and in primary ovarian cancer cells. The effects of LBW242 on ovarian cancer cell lines and primary ovarian cancer cells was determined by cell proliferation, apoptosis and biochemical assays. Principal Findings LBW242 added alone elicited only a moderate pro-apoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or anticancer drugs in inducing apoptosis of both ovarian cancer cell lines and primary ovarian cancer cells. Mechanistic studies show that LBW242-induced apoptosis in ovarian cancer cells is associated with activation of caspase-8. In line with this mechanism, c-FLIP overexpression inhibits LBW242-mediated apoptosis. Conclusion LBW242 sensitizes ovarian cancer cells to the antitumor effects of TRAIL and anticancer drugs commonly used in clinic. These observations suggest that the SMAC/DIABLO mimic LBW242 could be of value for the development of experimental strategies for treatment of ovarian cancer.

Predictors of postoperative morbidity after cytoreduction for advanced ovarian cancer: Analysis and management of complications in upper abdominal surgery

OBJECTIVE To evaluate the complication rate and its impact in patients who have undergone upper abdominal surgery for treatment of advanced ovarian cancer. METHODS Patients who have undergone upper abdominal surgery including diaphragm surgery, splenectomy, distal pancreatectomy, gastric resection, liver resection and biliary surgery were considered for the study. Perioperative complications were evaluated and graded according to Clavien-Dindo. RESULTS One hundred and twenty one patients were included. Two hundred and twelve surgical procedures were performed. Thirty-six patients reported at least one complication, but 61.1% of these the complication was mild. Median hospital stay for patients with and without complication was 7 vs. 13days respectively (p<0.001). There was a significant correlation between post-operative hospital stay and the total number of surgical procedures (R=0.445, p<0.001). At multivariate analysis, diaphragmatic resection and pancreatic resection were associated with a significant increase of postoperative hospital stay, furthermore diaphragmatic resection (p=0.004), hepatic resection (p=0.004), pancreatectomy (p=0.011) and biliary surgery (p=0.049) were independent predictors of severe (G3-G4) complication. CONCLUSIONS Rate of complications of patients submitted to upper abdominal surgery for ovarian cancer is acceptable. Prediction of severe complications is the goal for its optimal management. Extensive procedures should be avoided with those patients in which optimal residual tumor could not be reached.

Beyond circulating microRNA biomarkers: Urinary microRNAs in ovarian and breast cancer.

Breast cancer is the most common malignancy in women worldwide, and ovarian cancer is the most lethal gynecological malignancy. Women carrying a BRCA1/2 mutation have a very high lifetime risk of developing breast and ovarian cancer. The only effective risk-reducing strategy in BRCA-mutated women is a prophylactic surgery with bilateral mastectomy and bilateral salpingo-oophorectomy. However, many women are reluctant to undergo these prophylactic surgeries due to a consequent mutilated body perception, unfulfilled family planning, and precocious menopause. In these patients, an effective screening strategy is available only for breast cancer, but it only consists in close radiological exams with a significant burden for the health system and a significant distress to the patients. No biomarkers have been shown to effectively detect breast and ovarian cancer at an early stage. MicroRNAs (miRNAs) are key regulatory molecules operating in a post-transcriptional regulation of gene expression. Aberrant expression of miRNAs has been documented in several pathological conditions, including solid tumors, suggesting their involvement in tumorigenesis. miRNAs can be detected in blood and urine and could be used as biomarkers in solid tumors. Encouraging results are emerging in gynecological malignancy as well, and suggest a different pattern of expression of miRNAs in biological fluids of breast and ovarian cancer patients as compared to healthy control. Aim of this study is to highlight the role of the urinary miRNAs which are specifically associated with cancer and to investigate their role in early diagnosis and in determining the prognosis in breast and ovarian cancer.

Bartholin gland cancer

INTRODUCTION Bartholin gland carcinoma is an extremely rare condition. Because of its, phase III trials have not been carried out, there exists no unanimous consensus on treatment and guidelines are missing. METHODS All studies reporting cases of Bartholin cancer were collected and screened for the evaluations. Baseline characteristics of studies were extracted and were queried in a database. RESULTS A total number of 133 manuscripts collected were available for the review process, representing a total number of 275 reported cases. The histological type of Bartholin gland cancer was specified in 90.4% cases: 30.7% cases were squamous cell carcinoma, 29.6% adenoid cystic carcinoma, 25% adenocarcinomas. At multivariate analysis adenocarcinoma histotype and positive lymph node were statistical correlated with worse prognosis. CONCLUSION Bartholin gland cancer remains a challenge for gynecologic oncologists. To better understand and treat this disease, centralization to referral centers and design of multi institutional trials is crucial.

CO2 Laser Treatment for Bartholin Gland Abscess: Ultrasound Evaluation of Risk Recurrence

STUDY OBJECTIVE To evaluate the efficacy of CO2 laser treatment and parameters correlated with recurrence in patients with Bartholin gland abscesses treated using this approach. DESIGN Prospective study (Canadian Task Force classification II-2). SETTING University hospital. PATIENTS One hundred forty-seven patients who met eligibility criteria. INTERVENTION Preoperative ultrasound evaluation of Bartholin gland lesions and CO2 laser treatment. MEASUREMENTS AND MAIN RESULTS All patients received CO2 laser therapy, with median operative time 15 minutes (range, 12-35 minutes). Median postoperative stay was 1 hours (range, 1-4 hours). Estimated 3-year relapse-free rate was 88.56%. Lesion wall thickness 0.5-1.5 mm, multilocular lesion, and hyperechogenic lesion were correlated with recurrence. CONCLUSION CO2 laser of Bartholin gland abscesses could be a valid option. Ultrasound characteristics of Bartholin gland lesions could predict lesion recurrence rate.

Fertility management for malignant ovarian germ cell tumors patients

Malignant Germ Cell Tumors have primarily affecting adolescents and young adults. In advanced disease, greater than 70% of patients can be cured with standard chemotherapy regimens and fertility-sparing surgery appears to be safe with excellent survival after long-term follow-up. Due to their rarity, follow up and fertility management is largely based on trials of epithelial ovarian cancer or on few small studies. We report a review of the literature studies about the assessment, the monitoring and the treatment of fertility for Malignant Germ Cell Tumors as pratical guidelines for management of fertility in these patients.

The impact of CO2 laser for treatment of Bartholin’s gland cyst or abscess on female sexual function: a pilot study

Abstract The aim of this study is to evaluate the sexual functionality before and after treatment of Bartholin’s gland diseases (BGD) with CO2 laser and to compare our results to patients who underwent surgical cold knife and to a healthy control group (HCG). Consecutive patients (n = 15) affected by BG cyst or abscess who underwent CO2 laser treatment were evaluated. Patients were asked to complete the Italian translation of the Female Sexual Functioning Index (FSFI) before and 4 weeks after treatment. Results after CO2 laser were compared with two control groups: patients affected by BG cyst (n = 15) or abscess treated with surgical cold knife treatment and a HCG (n = 18). A statistically significant advantage of CO2 laser versus cold knife treatment in terms of lubrication, pain and global score were recorded. Both the single scores of five domains and total score of FSFI were globally higher after any treatment compared to before (CO2 and cold knife) of BGD. According to our data, CO2 laser therapy is often well tolerated by patients and correlated with a favorable sexual health recovery.

HPV-related Vulvar Diseases and Perspectives of p16INK4a Immunochemistry: A Review of the Literature

Introduction Two different types of vulvar intraepithelial neoplasia (VIN), HPV-related and HPV-unrelated, should be considered as two separate entities with different management options. The incidence of HPV-related VIN is increasing worldwide and is implicated in carcinogenesis. Our objective is to investigate the use of p16INK4a immunostaining or p16INK4a/p53 double staining for the detection of HPV-related disease to overcome the problem that histological criteria often have significant overlap. Methods A systematic literature search was carried out in the online databases PubMed, EMBASE, Cochrane Library, Clincaltrials.gov and Scopus. The key search terms were HPV, VIN, p16INK4a immunochemistry and p53. Results We found that nuclear and cytoplasmic immunostaining for p16INK4a was intense and diffuse in HPV-associated lesions and weak and focal in normal vulvar epithelium, nondysplastic lesions, lichen sclerosus and keratinizing vulvar squamous cell carcinoma. p53 nuclear immunostaining was always negative in HPV-related disease. Conclusions Our findings indicated that p16INK4a or p16INK4a/p53 immunoreactivity, along with histological diagnosis, could be a convenient means to adequately classify VIN and its connection to HPV infection. Therefore, the clear recognition of HPV-associated VIN would lead to an appropriate strategy of treatment and follow-up.

Conservative Management of Placenta Accreta by Systemic Metho-trexate:Report of Two Cases and Review of the Literature

Objective: Owing to the growing number of cesarean deliveries, the abnormally invasive placenta-tion so called placenta accreta rate is increasing. Placenta accreta is difficult to manage and traditionally resolved by cesarean hysterectomy after the birth due to the following massive hemorrhage. In recent years different conservative treatments leaving partially or totally the placenta in the uterine cavity have been reported in patients willing to preserve their fertility. Methods: We reviewed literature data about conservative management of placenta accreta in the PubMed, Researchgate and Medline from 2007 to date. We included in the review the studies about the use of methotrexate (MTX) for conservative treatment of placenta accreta. Results: We reported 2 literature reviews and 4 studies about the use of MTX in the management of placenta accreta and 2 unpublished cases treated in our Department. MTX is administered when it is not possible to remove totally or partly the placenta accreta in order to promote the cytolysis of the residual trophoblast. The schedule and outcome of the methotrexate use have not been established yet due to the paucity of literature data. Conclusions: The role of MTX to improve both, the feasibility and success rate of conservative management and placental resorption needs further studies. Hemodynamic stability of patients and informed consent are prerequisites before starting MTX treatment. Vaginal bleeding and infections may complicate the conservative treatment and close surveillance is recommended by imaging techniques and laboratory parameters.

Vulvar Malignancy in Neurofibromatosis Syndrome

Type 1 neurofibromatosis (NF1) is a dominantly inherited neurologic disorder that affects primarily the skin, bones, and peripheral nervous system. It may be associated with a variety of clinical manifestations including cafe-au-lait spots, skinfold freckling, Lisch nodules, and visceral neurofibromas. Individuals affected by NF1 harbor an increased risk for both benign and malignant tumors. Malignant transformation is usually observed in the form of neurosarcoma. Rarely, NF1 affects the genital tract, and isolated vulvar localization is extremely rare. Here is reported a rare case of a solitary neurosarcoma of the vulva in a 43-year-old woman affected by NF1 syndrome treated with surgical excision. The purpose of this case is to underline the possibility of association between NF1 and genital tract sarcoma and to suggest an accurate evaluation of rapid growth vulvar mass in this setting.