Treatment of the Mayer-Rokitansky-Küster-Hauser syndrome with autologous in vitro cultured vaginal tissue: descriptive study of long-term results and patient outcomes.

OBJECTIVE: Evaluating sexual function and quality of life (QoL) in patients treated with a modified Abbé-McIndoe technique using in vitro cultured autologous vaginal mucosa. DESIGN: Descriptive study. SETTING: Policlinico Umberto I, Sapienza University of Rome. POPULATION: From 2006 to 2016, 39 women affected by Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) underwent vaginoplasty at our centre using a modified Abbé-McIndoe technique with in vitro cultured autologous vaginal tissue. METHODS: For each patient, vaginal tissue was obtained by full-thickness biopsy of the vaginal vestibule. Following enzymatic dissociation, cells were cultured for 2-3 weeks before the transplant. MAIN OUTCOME MEASURES: Each patient completed two validated questionnaires to quantify sexual function and QoL: the Female Sexual Function Index (FSFI), administered at 12, 36, and 60 months, and the Psychological General Well Being Index (PGWBI) administered at 0, 6, and 36 months after surgery. RESULTS: Twelve months after surgery, 29 patients were engaging in regular sexual activity. The FSFI test results showed a satisfactory sexual function compared to the general population, with median values of 25.85 (range 4.6-30.5) at 12 months, 27.2 (range 4.4-33.6) at 36 months, and 29.6 (range 23.9-33.6) at 60 months. The PGWBI questionnaire showed a median score of 420.5 (range 108-540) before surgery, and 459 (range 252-533) at the 60-month follow-up. CONCLUSIONS: Vaginoplasty performed with the use of autologous vaginal tissue, besides ensuring a long-term satisfying sex life, helps in achieving an improvement in QoL that is maintained over time. TWEETABLE ABSTRACT: Vaginoplasty using in vitro vaginal tissue ensures a satisfactory sexual function and improves quality of life.

Secondary Cytoreduction in Platinum-Resistant Recurrent Ovarian Cancer: A Single-Institution Experience.

BACKGROUND: The purpose of this study was to observe the role of secondary cytoreductive surgery in platinum-resistant recurrent ovarian cancer (OC) patients. METHODS: We collected data of patients affected by recurrent OC treated between 1995 and 2013. Inclusion criteria were: invasive epithelial OC histologically documented, cytoreductive surgery and platinum-based chemotherapy at first-line treatment with evidence of complete response to treatment, disease-free interval <6 months, and no concomitant neoplasia. Patients considered susceptible of cytoreductive surgery (group A) were compared with a historical series of patients with similar characteristics but not eligible for surgery (group B). RESULTS: Of 122 platinum-resistant patients, 18 met the inclusion criteria for the study and were enrolled. They were compared with a historical series of 18 patients not surgically treated with analogous clinical and pathological features. The most frequent sites of relapse included pelvic and aortic lymph nodes (39 %), peritoneum (33 %), bowel (28 %), and pelvis (22 %). A low rate of intraoperative and postoperative complications was reported. No deaths were recorded. Overall survival was significantly longer in cytoreductive group when compared with the control group (P = 0.035). Median overall survival was 44 months. Estimated 5-year overall survival rates were 57 versus 23.5 % for groups A and B, respectively. CONCLUSIONS: Surgery could represent a useful adjunct to chemotherapy in the management of platinum-resistant recurrent OC patients, carefully selected, in highly selected centers. Larger prospective trials are needed to further confirm our experience.

PARP inhibition: A promising therapeutic target in ovarian cancer.

Ovarian cancer is burdened by the highest mortality rate among gynecological cancers. Gold standard is represented by the association of platinum-taxane -based chemotherapy and radical surgery. Despite several adjustments occurred in cytotoxic drug in last decades, most patients continue to relapse, and no significant enhancement has been reached in the overall survival. The development of drug resistance and the recurrence of disease have prompted the investigations of other targets that can be used in the treatment of ovarian cancers. Among such targets, polyadenosine diphosphate-ribose polymerase (PARP) represents a novel way to target specific patways involved in tumor growth. PARP accelerates the reaction of the polyADP-ribosylation of proteins implicated in DNA repair. PARP inhibitors have shown activity in cancers with BRCA mutations, with other deficient DNA repair genes or signaling pathways that modulate DNA repair, or in association with DNA damaging agents not involved in DNA repair dysfunction. A number of inhibitors for PARP has been developed, and such drugs are under investigation in clinical trials to identify their impact in the treatment of ovarian cancers. This review aims to summarize the recent researches and clinical progress on PARP inhibitors as novel target agents in ovarian cancer.

Post treatment imaging in patients with local advanced cervical carcinoma.

Cervical cancer (CC) is the fourth leading cause of death in women worldwide and despite the introduction of screening programs about 30% of patients presents advanced disease at diagnosis and 30-50% of them relapse in the first 5-years after treatment. According to FIGO staging system 2018, stage IB3-IVA are classified as locally advanced cervical cancer (LACC); its correct therapeutic choice remains still controversial and includes neoadjuvant chemo-radiotherapy, external beam radiotherapy, brachytherapy, hysterectomy or a combination of these modalities. In this review we focus on the most appropriated therapeutic options for LACC and imaging protocols used for its correct follow-up. We explore the imaging findings after radiotherapy and surgery and discuss the role of imaging in evaluating the response rate to treatment, selecting patients for salvage surgery and evaluating recurrence of disease. We also introduce and evaluate the advances of the emerging imaging techniques mainly represented by spectroscopy, PET-MRI, and radiomics which have improved diagnostic accuracy and are approaching to future direction.

A prospective phase II study of topotecan (Hycamtin®) and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer.

OBJECTIVES: To evaluate the feasibility, toxicity and activity of neoadjuvant chemotherapy (NACT) using cisplatin and topotecan in patients affected by locally advanced cervical cancer (IB2-IIIB). METHODS: Patients with histologically confirmed FIGO stage IB2-IIIB uterine cervical cancer were treated with topotecan 0.75 mg/m(2)/day (days 1-3) followed by cisplatin 75 mg/m(2) (day 1), every 21 days for three consecutive cycles. After the last cycle of chemotherapy, within 3 or 4 weeks, patients underwent radical surgery with lymph node dissection. RESULTS: In the years 2007-2010, 46 women were enrolled into the study. Hematologic toxicity was the most relevant side effect. Thirty-eight patients (82.6%) underwent radical surgery after neoadjuvant chemotherapy (NACT) and were assessable for pathologic responses; surgery was not performed in 8 (17.4%) non-responder patients or with progression disease. Objective pathological response was recorded in 34 patients (89.5%); 6 patients (15.8%) achieved a complete response (CR), 28 (73.7%) patients achieved a partial response (PR); stable disease (SD) occurred in 2 patients (5.3%) with IIA initial disease and progression disease (PD) was registered in 2 patients (5.3%) with IIIB initial disease. The cumulative 2-year progression free survival (PFS) and overall survival (OS) of the 46 enrolled patients in the study were 70% and 81%, respectively; the 2-year PFS and OS of the 38 operated patients were respectively 79% and 95%. CONCLUSIONS: The cisplatin-topotecan combination seems to be feasible and with an acceptable toxicity profile and a promising response rate for the treatment of locally advanced cervical cancer (LACC). Phase II and III studies are needed to compare this combination with other platinum-based chemotherapeutic associations.

[Prevention of postoperative adhesions]. / Aderenze postchirurgiche: attuali strategie preventive.

Postoperative adhesions represent a common consequence in patients who underwent abdominal or pelvic surgery. Such adhesions can be asymptomatic, but they can cause complications such as chronic abdomino-pelvic pain, secondary infertility, an increase in bowel obstruction risk and more complexity for future surgery, including longer surgery times and an increase in morbidity. Normally, adhesions appear after offences against the peritoneum, causing flogosys, and develop both in new sites, previously not involved, and in sites already interested in adhesiolysis. Previous laparotomy is an important risk factor, as after laparatomy a minimum of 93% of patients present adhesions during a following surgery. Furthermore, the rate of recurrence after adhesiolysis is 85%. Among several strategies employed, valid prevention methods are: using minimally invasive surgery techniques, reducing the incision area, containing tissue dehydration during surgery and an accurate hemostasis. Also, for preventing and reducing adhesions, the usage of NSAIDs, fibrinolytics and anticoagulants, as well as the application of substances acting as a physical barrier, have been proposed. Recently, crystalloid solutions have been introduced, using the hydro-flotation principle for intraperitoneal organs. This research aims to analyze causes and epidemiology for postoperative adhesions, with particular regard to gynecological operations and to describe and compare the means available to prevent them.

Immune check-point in cervical cancer.

Despite different treatment strategies, locally advanced cervical cancer (CC) persists as one of the most incurable cancers among women worldwide. In fact, this setting of patients are at high risk of persistent and recurrent disease. In recent years, researches have investigated immune check-point inhibitors in hopes of determining improved response to therapy with prolongation of survival. We reviewed the published literature and conference proceedings and presented pivotal trials supporting immune check-point inhibitors use in the treatment of CC.

Hormone replacement therapy after prophylactic risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: A meta-analysis.

BACKGROUND: Hormone replacement therapy (HRT) has been tested in women with BRCA1 and BRCA2 mutations who underwent risk-reducing salpingo-oophorectomy (RRSO), but its effect on breast cancer (BC) risk has never been appraised using meta-analysis comparison. We performed the first meta-analysis aimed to clarify whether HRT after RRSO could negatively impact on BC risk in women carriers of BRCA1 and BRCA2 mutations. METHODS AND MATERIAL: Pubmed and Scopus databases were searched to retrieve articles written in the English language. Trials comparing RRSO with or without HRT were identified and only those trials with available BC events were included. BC risk was the main endpoint. RESULTS: Three trials with 1100 patients were included. There was not a significantly higher BC risk in BRCA1 and BRCA2 mutation carriers receiving HRT after RRSO (HR = 0.98; 95% CI 0.63-1.52). There was a slightly but not significantly, benefit in BC risk reduction in favor of estrogen alone HRT versus estrogen plus progesterone HRT formulation (OR = 0.53; 95% CI 0.25-1.15). CONCLUSION: HRT use after RRSO in BRCA 1 and BRCA2 mutation carries does not affect BC risk. Comparison of the different HRT types suggests that estrogen alone should be related to lowest BC risk.

Dose-dense weekly chemotherapy in advanced ovarian cancer: An updated meta-analysis of randomized controlled trials.

OBJECTIVE: The use of dose-dense weekly chemotherapy in the management of advanced ovarian cancer (OC) remains controversial. The aim of this meta-analysis was to evaluate the efficacy of dose-dense regimen to improve clinical outcomes in OC patients with the inclusion of new trials. METHODS: For this updated meta-analysis, PubMed Medline and Scopus databases and meeting proceedings were searched for eligible studies with the limitation of randomized controlled trials, comparing dose-dense chemotherapy versus standard treatment. Trials were grouped in two types of dose-dense chemotherapy: weekly dose-dense (both paclitaxel and carboplatin weekly administration) and semi-weekly dose-dense (weekly paclitaxel and three weekly carboplatin administration). Data were extracted independently and were analyzed using RevMan statistical software version 5.3 (http://www.cochrane.org). Primary end-point was progression-free survival (PFS). RESULTS: Four randomized controlled trials comprising 3698 patients were identified as eligible. Dose-dense chemotherapy had not a significant benefit on PFS (HR 0.92, 95% CI 0.81-1.04, p = 0.20). When the analysis was restricted to both weekly and semi-weekly dose-dense data, a no significant interaction between dose-dense and standard regimen was confirmed (HR 1.01, 95% CI 0.93-1.10 and HR 0.82, 95% CI 0.63-1.08, respectively). CONCLUSIONS: In the absence of PFS superiority of dose-dense schedule, three weekly schedule should remain the standard of care for advanced OC.

[Up-date on cytoreductive surgery in the management of advanced ovarian cancer]. / Aggiornamenti in tema di citoriduzione nel trattamento del carcinoma ovarico avanzato.

Epithelial ovarian cancer represents the most aggressive neoplasm of women genital apparatus with a total 5-year survival rate ranging from 17% to 35% if the disease is in the metastatic phase. Its aggressiveness derives from the fact that it is an asymptomatic disease until it spreads in abdominal cavity. Therefore, in 70% of the cases, the diagnosis is done when tumor is already in advanced phase (Stage FIGO IIB-IV). Data from international literature suggest that standard treatment for advanced ovarian cancer is optimal cytoreductive surgery with adjuvant chemotherapy platinum-based. However, in the last decades, many authors have described the enthusiastic results of neoadjuvant chemotherapy and interval debulking surgery. Griffiths, first, underlined the importance of residual mass after cytoreductive surgery as a prognostic factor. Currently, cytoreduction is defined optimal when residual mass is microscopical or absent. Nevertheless, surgery for ovarian cancer turns out to be a particularly aggressive surgery that needs an operator's remarkable technical ability and a cultural Background: Many studies demonstrated that the frequency of feasibility of optimal cytoreductive surgery also varies within the gynecologic oncology specialized centers. During the last few years, new technologies (such as Cavitron Ultrasonic Surgical Aspirator, CUSA, and argon's coagulator) and new surgical techniques have been introduced. Ovarian cancer turns out to be a particularly chemosensitive tumor. Its responsiveness has been the object of numerous studies and protocols in literature, such as European Organisation of Research and Treatment of Cancer (EORTC) and Gynecologic Oncology Group (GOG) trials.

Erythropoiesis-stimulating agents in gynecological malignancies: A study-level meta-analysis.

This meta-analysis was planned to define the role of erythropoiesis-stimulating agents (ESAs) in gynecological cancer patients, receiving myelosuppressive treatment. Pubmed, Medline and Scopus were searched to select English-language articles. Only randomized controlled trials (RCTs) were included. Endpoints were incidence of transfusions, thrombotic events (TE), deaths, and failures. Odd ratio (OR) with 95% confidence interval (CI) was calculated using fixed or random effects model. In seven RCTs ESAs studies of 892 patients under treatment, use of ESAs correlates with a significant reduction of transfusions rate (OR=0.35; 95% CI: 0.19-0.65; p=0.008). OR for overall mortality was 1.10 (95% CI 0.82-1.49; p=0.53). ESAs OR for disease failure in 5 studies was 1.71 (95% CI: 0.90-3.24; p=0.1). This meta-analysis, even if limited by few RCTs, suggests that ESAs reduce transfusions without increasing mortality or disease progression in gynecological cancer patients receiving treatment.

Tyrosine-kinases inhibitors in recurrent platinum-resistant ovarian cancer patients.

For many decades, ovarian cancer (OC) has been one of the most common gynecological cancer. Despite advances in OC diagnosis and treatment, the risk of recurrence is ever present and approximately 85% of patients will experience relapse. Recurrent OC after first-line therapy is almost always incurable. Multiple novel therapies, including tyrosine-kinases inhibitors (TKI), have shown promising results, but their role needs to be clarified. In this review we describe the rationale and the clinical evidence regarding the use of TKI for the treatment of recurrent platinum-resistant OC patients.

Threatened abortion and late-pregnancy complications: a case-control study and review of literature.

AIM: Aim of the study was to evaluate the late-pregnancy and perinatal outcomes of patients with threatened miscarriage in the first trimester. METHODS: An observational cohort study was performed on 81 pregnant women. Subjects were divided into two groups: 1) no bleeding; 2) threatened miscarriage. Patients were followed up until delivery and each materno-fetal complication was registered. RESULTS: Threatened miscarriage was associated with increased risk of preterm delivery, placenta previa, pregnancy induced hypertension/preeclampsia (PE), low birth weight (LBW) and neonatal intensive care unit (NICU) admission. There were no significantly differences between the 2 groups with regard to preterm prelabour rupture of membranes (PPROM), CESAREAN section, retained placenta, perinatal death and intrauterine growth restriction (IUGR). About immediate neonatal outcomes, mean birth weights were lower (≈ 200 g) in the study group (group 2), while no significant difference in the APGAR score between the two groups was noted. CONCLUSION: Our study suggests that threatened miscarriage in the first trimester is correlated with an increased incidence of late-pregnancy and perinatal complications and, therefore, these pregnancies should be considered as high risk ones.

Past, present and future strategies of immunotherapy in gynecological malignancies.

Recently, the combining of different drugs has greatly improved response and survival rates in gynecological malignancies. Results are however far from being satisfactory. Treatments used in case of advanced or recurrent disease offer limited results in terms of long-term responses. The urgent need for new and more effective treatments has prompted researchers to investigate and propose new therapeutic strategies. One of the most interesting approaches that are being explored is constituted by immunotherapy. Currently, immunotherapeutic strategies include vaccination with peptide, viral vectors, carbohydrates and antiidiotypic antibodies. In addition, cell based immunotherapy has been adopted in vitro activated lymphocytes and dendritic cells. Most experience has been acquired in ovarian cancer and cervical cancer. Little has been investigated in endometrial and rare gynecologic neoplasms.The clinical experiences and results achieved with immunotherapy in this setting of patients have been reviewed and the future avenues that are currently being explored have also been discussed.

Hemoglobin variation and blood transfusion rates in patients affected by locally advanced cervical cancer undergoing neo-adjuvant chemotherapy followed by radical surgery: the role of erythropoietic growth factors.

BACKGROUND: The objectives of the present study were to evaluate hemoglobin levels and consequent clinical behaviors related to anemia developed in patients affected by locally advanced cervical cancer treated with neo-adjuvant chemotherapy in the last decade and to evaluate the impact that the introduction of erythropoietic growth factors had in the clinical practice. PATIENTS AND METHODS: Blood chemistries, prospectively recorded from 98 cervical cancer patients, treated with neo-adjuvant chemotherapy and, if necessary, erythropoietic growth factors, were compared with matched historical controls before the introduction of growth factors in clinical practice. RESULTS: Hemoglobin level in the study group did not differ significantly during chemotherapy. At the third cycle of chemotherapy and at the end of chemotherapy, hemoglobin level was significantly higher in the study group compared with the control group. Transfusion rates in the study group were significantly lower. The analysis within the study group revealed that hemoglobin level in patients who suffer at diagnosis from anemia tends to increase whereas hemoglobin level in nonanemic patients tends to decrease. CONCLUSIONS: Erythropoietic growth factors increase hemoglobin level and reduce blood transfusions in cervical cancer patients undergoing neo-adjuvant chemotherapy followed by radical surgery. An appropriate autologous blood donation program can noticeably reduce homologous blood transfusions.

Liposome-encapsulated doxorubicin citrate in previously treated recurrent/metastatic gynecological malignancies.

The aim of this study was to evaluate the safety and efficacy of liposome-encapsulated doxorubicin citrate (LEDC) in patients affected by recurrent/metastatic gynecological malignancies scheduled for palliative chemotherapy. Inclusion criteria were proven recurrent/advanced gynecological neoplasms, measurable/assessable disease, adequate organ function, left ventricular ejection fraction >50% as determined by echocardiography, informed consent. LEDC was administered intravenously over 1 h at the dose of either 75 mg/m(2) or 60 mg/m(2) (every 3 weeks until disease progression or toxicity prohibiting further therapy). From May 2003 to September 2005, 36 patients were enrolled. Primary disease was ovarian, endometrial, and cervical cancers in 15 (42%), 11 (30%), and 10 (28%) patients, respectively. LEDC was employed as third- or fourth-line chemotherapy in 25 (70%) and 11 (30%) patients, respectively. The median number of courses of LEDC received was 3 (range 2-9). Six patients (17%) achieved a partial response to treatment lasting 27 weeks and 10 patients (28%) experienced stable disease lasting 18 weeks. The predominant toxicity was hematological, especially neutropenia. Among patients receiving a dose of 75 mg/m(2), two (11%) suspended therapy for febrile neutropenia, and nine (50%) required a dose reduction of 25%. As a result, the next 18 patients were treated at a reduced dose (60 mg/m(2)) of LEDC. Severe neutropenia (G3-G4) was significantly less common in this group (61% versus 22%; P= 0.04). LEDC has shown antineoplastic activity in previously treated recurrent/metastatic gynecological cancer patients and the toxicity profile could be considered acceptable at a 60 mg/m(2) dosage.

Bulky lymph node resection in patients with recurrent epithelial ovarian cancer: impact of surgery.

The aim of this study was to evaluate the role of systematic lymphadenectomy, feasibility, complications rate, and outcome in epithelial ovarian cancer (EOC) patients with recurrent bulky lymph node disease. A prospective observational study of EOC patients with pelvic/aortic lymph node relapse was conducted between January 1995 and June 2005. After a clinical and laparoscopic staging, secondary cytoreduction, including systematic lymphadenectomy, were performed. The eligibility criteria were as follows: disease-free interval > or =6 months, radiographic finding suggestive of bulky lymph node recurrence, and patients' consent to be treated with chemotherapy. Forty-eight EOC patients with lymph node relapse were recruited. Twenty-nine patients were amenable to cytoreductive surgery. Postoperatively, all patients received adjuvant treatment. The median numbers of resected aortic and pelvic nodes were 15 (2-32) and 17 (8-47), respectively. The median numbers of resected aortic and pelvic positive lymph nodes were 4 (1-18) and 3 (1-17), respectively. The mean size of bulky nodes was 3.3 cm. Four patients (14%) experienced one severe complication. No treatment-related deaths were observed. After a median follow-up of 26 months, among cytoreduced patients, 18 women were alive with no evidence of disease, nine were alive with disease. Among the 11 patients not amenable to surgery, five women were alive with persistent disease, six patients died of disease, at a median follow-up of 18 months. Estimated 5-year overall survival and disease-free interval for operated women were 87% and 31%, respectively. In conclusion, patients with bulky lymph node relapse can benefit from systematic lymphadenectomy in terms of survival. The procedure is feasible with an acceptable morbidity rate.

Gynecological cancers in developing countries: the challenge of chemotherapy in low-resources setting.

The epidemiologic pattern of cancers in developing countries differs in many aspects from that of industrialized nations. Cancer natural history, microbiologic environment, patient's immune system, and drug availability may differ as well. Four of five new cases of cervical cancer and most of cervical cancer deaths occur in developing countries. Where chemoradiation and supportive care facilities are unavailable, it would be logical to consider an inexpensive effective drug. In locally advanced cases, neoadjuvant chemotherapy followed by surgery should be considered the treatment of choice. For ovarian cancer, it may be reasonable to maintain a secure supply of platinum and/or taxanes. For endometrial cancer, platinum compounds are proved active chemotherapic single agents. Oral medroxyprogesterone acetate (MPA) may represent a good chance for treating an advanced or recurrent disease. For vulvar/vaginal cancer, the role of chemotherapy alone is currently considered limited, and it is mostly used as palliative treatment in advanced or recurrent cases. Whenever possible, standard western chemotherapic regimens should be applied in developing countries as well. When standard therapies are unavailable, drugs of choice should be easily accessible, inexpensive, and effective. The most commonly used drugs are cisplatin, cyclophosphamide, and MPA.