Conservative surgery in stage I adult type granulosa cells tumors of the ovary: Results from the MITO-9 study.

OBJECTIVE: About 30% of Adult type granulosa cell tumors of the ovary (AGCTs) are diagnosed in fertile age. In stage I, conservative surgery (fertility-sparing surgery, FSS), either unilateral salpingo-oophorectomy (USO) or cystectomy are possible options. The aim of this study is to compare oncological outcomes of FSS and radical surgery (RS) in apparently stage I AGCTs treated within the MITO group (Multicenter Italian Trials in Ovarian cancer). METHODS: Survival curves were calculated using the Kaplan-Meier method and compared with log-rank test. The role of clinicopathological variables as prognostic factors for survival was assessed using Cox's regression. RESULTS: Two-hundred and twenty-nine patients were included; 32.6% received FSS, 67.4% RS. In the FSS group, 62.8% underwent USO, 16.7% cystectomy, 20.5% cystectomy followed by USO. After a median follow up of 84 months, median DFS was significantly worse in the FSS-group (10 yr DFS 50% vs 74%, in FSS and RS group, p = 0.006). No significant difference was detected between RS and USO (10 yr DFS 75% vs 70%, p = 0.5).Cystectomy-group showed a significantly worse DFS compared to USO (10 yr DFS 16% vs 70%, p < 0.001). Patients receiving cystectomy and subsequent USO showed a better prognosis, even though significantly worse compared to USO (10 yr DFS 41% vs 70%, p = 0.05). Between FSS and RS, no difference in OS was detected. At multivariate analysis, FIGO stage IC and cystectomy retained significant predictive value for worse survival. CONCLUSIONS: This study supports the oncological safety of FSS in stage I AGCTs, provided that cystectomy is avoided; USO should be the preferred approach.

Is adjuvant chemotherapy indicated in stage I pure immature ovarian teratoma (IT)? A multicentre Italian trial in ovarian cancer (MITO-9).

OBJECTIVE: Conservative surgery followed by platinum-based chemotherapy is considered the standard approach for stage I immature ovarian teratoma (IT), except for stage IA G1. Nevertheless the use of chemotherapy in stage IA G2-3 and IB-IC is controversial. The aim of this study was to evaluate the outcome of patients with IT in order to define the role of chemotherapy in stage I disease. METHODS: Twenty-eight patients with stage I IT treated in MITO centers were retrospectively reviewed. Grade, stage, age, surgical and postoperative treatment were analyzed using χ(2) test and T test looking for association with recurrence. RESULTS: Median age was 25.5. Twenty-four patients underwent fertility-sparing surgery. FIGO stages were 19 IA, 2 IB, and 7 IC. Nine patients had grade 1 tumor, 12 grade 2, and 7 grade 3. Nine patients received adjuvant chemotherapy. Overall recurrence rate was 21.4% (2 in chemotherapy group and 4 in the group without treatment). No patients with G1 had recurrence, whereas 25% of G2 and 42.9% of G3 relapsed. Recurrence rate was not significantly different according to stage, grade or adjuvant chemotherapy, whereas it was greater in the group not operated in a MITO center, not staged and of age lower than 20 years, with statistical significance. At recurrence 4 patients presenting with mature teratoma were treated with surgery alone, whereas 2 recurring with IT were treated with surgery plus chemotherapy. After a median follow-up of 59 months all patients are NED. CONCLUSIONS: Our study suggests that chemotherapy may be withheld for primary therapy and utilized only for recurrence.

Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: an European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874).

The management of uterine sarcomas continues to present many difficulties. Primary surgery is the optimal treatment but the role of post-operative radiation remains uncertain. In the mid-1980s, the European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study proposed a trial to evaluate adjuvant radiotherapy, as previous non-randomised studies had suggested a survival advantage and improved local control when post-operative radiation was administered. The study opened in 1987 taking 13 years to accrue 224 patients. All uterine sarcoma subtypes were permitted. Patients were required to have undergone as a minimum, TAH and BSO and wahsings (166 patients) but nodal sampling was optional. There were 103 leiomyosarcomas (LMS), 91 carcinosarcomas (CS) and 28 endometrial stromal sarcomas (ESS). Patients were randomised to either observation or pelvic radiation, 51 Gy in 28 fractions over 5 weeks. Hundred and twelve were recruited to each arm. The initial analysis has shown a reduction in local relapse (14 versus 24, p=0.004) but no effect on either OS or PFS. No unexpected toxicity was seen in the radiation arm. No difference in either overall or disease-free survival was demonstrated but there is an increased local control for the CS patients receiving radiation but without any benefit for LMS. Prognostic factor analysis shows that stage, age and histological subtype were important predictors of behaviour which may explain differences between CS and LMS. CS appears to show more kinship to poorly differentiated endometrial carcinomas in behaviour. LMS did not show the same benefit from radiation. These results will help shape future management and clinical trials in uterine sarcomas.

Mini-Laparoscopic Repair of Apical Pelvic Organ Prolapse (POP) by Lateral Suspension with Mesh.

BACKGROUND: The aim of the present study is to analyze the feasibility, safety and learning curve of Mini- Laparoscopic Lateral suspension (LLS) for the treatment of apical and anterior defects following pelvic organ prolapse. METHODS: This is a cohort study on a retrospective series of 35 consecutive patients who underwent Mini-LLS for symptomatic POP between January 2014 and July 2016. All 35 patients were operated at the Gynaecological Unit in S. Chiara Hospital by two senior surgeons (S. Tateo and L. Mereu) and by a team with optimal skills in laparoscopic surgery. Patients were divided in two groups according to two different chronological phases: phase 1 identified the initial 12 cases, phase 2 the last 23 cases. We collected pre-, peri- and post-operative information to analyze the surgical outcomes and learning curve after Mini-LLS procedures. RESULTS: The mean LLS-Overall Time (OT) was 107.6 min (range, 185- 63 min). None of the patients had intra-operative complications. No conversion to laparotomy was necessary. The mean post-operative hospital stay was 58 hours in total (SD +/-22). Only in 3 cases (8.6 %) post-operative grade I complications were observed. Recurrence of POP was observed in 3 cases (8.6 %) during a mean follow up of 18 months. The mean OT decreased with experience, in particular after the first 12 cases (phase 1: 113.54 minutes versus phase 2: 104.43 minutes). In consequence, the reduction of time per procedure was statistically significant considering the Cusum Time (CT) (P < .05). CONCLUSIONS: Mini-LLS with mesh is a safe and reproducible technique with good anatomical results, low complication rates and a short learning curve.

Robotic single site staging in endometrial cancer: A multi-institution study.

OBJECTIVE: To evaluate the feasibility and the safety of robotic single site hysterectomy (RSSH) plus or less pelvic lymphadenectomy in FIGO stage I-II endometrial cancer. MATERIALS AND METHODS: We prospectively collected patient demographics, operative times, complications, pathologic results, and length of stay on all patients who underwent RSSH plus or less pelvic lymphadenectomy for clinical FIGO stage I or occult stage II endometrial carcinoma. RESULTS: From January 2012 to February 2015, 125 patients were included in our study. The median age of the patients was 59 years (range, 35-84 years) and the median body mass index was 27 kg/m(2) (range, 19-52 kg/m(2)). One patient was converted to vaginal surgery due to problems of hypercapnia. The median docking time, console time, and total operative time was 11 min (range, 4-40 min), 80 min (range, 20-240 min) and 122 min (range, 35-282 min), respectively. The median blood loss was 50 ml (range, 10-250 ml). No laparoscopic/laparotomic conversion was registered. Twenty one patients underwent pelvic lymphadenectomy (16.8%) and the median pelvic lymph nodes was 13 (range, 3-32). The median time to discharge was 2 days (range, 1-3 days). No intra-operative complications occurred, while we observed 10 (8%) early post-operative complications. CONCLUSION: RSSH plus or less pelvic lymphadenectomy is technically feasible, safe and reproducible and could be the treatment of choice for patients affected by FIGO stage I-II endometrial cancer. However, randomized controlled trials are needed to confirm these results.

Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer.

PURPOSE: To compare the efficacy of a treatment with cisplatin plus cyclophosphamide given for 5 months and a short treatment with cisplatin alone in advanced ovarian cancer, we conducted a multicenter randomized clinical trial. PATIENTS AND METHODS: Eligibility criteria were as follows: first diagnosis of histologically confirmed invasive epithelial ovarian cancer of International Federation of Gynecology and Obstetric (FIGO) stage III-IV, age younger than 75 years, and Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. Within 28 days of cytoreductive surgery, eligible women were randomly assigned treatment with weekly cisplatin 50 mg/m2 for nine courses or cisplatin 75 mg/m2 plus cyclophosphamide 750 mg/m2 every 21 days for six courses. RESULTS: A total of 607 women were entered onto the study. There was no difference in the response to treatment. Pathologic complete response (CR) was documented in 63 of the weekly cisplatin cases and 70 of the cisplatin plus cyclophosphamide group (chi 1(2) = 1.43; P = .23). The median follow-up time was 3 years. There were 151 and 148 deaths in the weekly cisplatin and cyclophosphamide plus cisplatin arms, respectively. Survival curves were similar in the two groups, with a 3-year percent survival estimate of 44.1 (SE = 3.4) in the weekly cisplatin and 44.6 (SE = 3.4) in the cisplatin plus cyclophosphamide group (log-rank test chi 1(2) = 0.004; P = .96). CONCLUSION: This study found that 2-month monochemotherapy treatment with cisplatin was as effective as 5-month polychemotherapy including cisplatin at a similar doses but different dose-intensity plus cyclophosphamide.

A phase I-II trial of fixed-dose carboplatin and escalating paclitaxel in advanced ovarian cancer.

We conducted a phase I-II study with escalating paclitaxel doses plus carboplatin at a fixed dose for previously untreated patients with advanced ovarian cancer in order to define the maximum tolerated dose. Eligible for the study were women with a histologically confirmed diagnosis of ovarian cancer stage III-IV according to the FIGO classification. In the first phase of the study, 6 patients were allocated escalating paclitaxel doses with fixed-dose carboplatin in order to establish the maximum tolerated dose. The starting dose of paclitaxel was 150 mg/m2 given after carboplatin (300 mg/m2) every 4 weeks for a total of six courses. The paclitaxel dose step was 25 mg/m2 up to 250 mg/m2. The study then progressed to a phase II trial using the maximum tolerated paclitaxel dosage reached during the escalating dose phase. A total of 27 patients entered phase I and 23 phase II. Neurotoxicity was observed in 47 patients (94%; 29 grade 1, 17 grade 2, 1 grade 3, according to the WHO classification). The intensity of neurotoxicity tended to be dose related: out of the 15 patients who received < or = 200 mg paclitaxel, a total of 14 grade 1, but no grade 2 or 3 neurotoxicities, were observed. The frequency of grade 1, 2 and 3 neurotoxicity was 15, 17 and 1, respectively, in the 35 women who received > or = 225 paclitaxel +300 mg carboplatin. There was no clear relationship between median WBC and platelet nadir and dose level. Among other toxicities, alopecia was observed in all 50 cases, hypersensitivity in two (4%) and myalgia in 41 (82%; 34 grade 1 and 7 grade 2). These frequencies tended to increase with the dose, but the relationship was not statistically significant. The overall response rate was 78% (39/50) with a complete response rate of 62% (31/50). In conclusion, this study suggests that carboplatin and paclitaxel can be administered safely to patients with advanced ovarian carcinoma. The maximum dose reached was 250 mg/m2 paclitaxel and 300 mg/m2 for carboplatin, but from a clinical point of view the maximum paclitaxel dose we would consider safe is 225 mg/m2.

Immunohistochemical localization of lipoperoxidation products in normal human placenta.

4-Hydroxynonenal (4-HNE) is a major propagation product of lipid peroxidation that is supposed to be responsible for some of the effects associated with oxidative stress in tissues. We have investigated the possible occurrence and distribution of 4-HNE-immunoreactivity in human normal placenta using immunocytochemistry. Specific immunostaining was observed in cytotrophoblast cells, syncytiotrophoblast, some cells of the villous mesenchyme and some endothelial cells of first trimester and term placentae. The detection of 4-HNE-immunoreactivity in placenta raises the question whether lipoperoxidation products are produced locally in placental cells or represent exogenous products that derive from maternal blood flow. Since trophoblastic cells and villous macrophages are provided by a scavenger receptor, it is conceivable that these cells may play a protective role with regard to the diffusion of lipoperoxidation products from the mother to the embryo. However, since a significant degree of lipid oxidative modification does not take place in plasma, it is presumed that 4-HNE is a local product of placental metabolism. In line with this hypothesis, it is proposed that maternal low density lipoproteins, which are the major source of cholesterol for placental steroid synthesis, might be oxidized by villous cells during their traversal through the villous wall.

Incisional hernia in gynecologic oncology patients: a 10-year study.

OBJECTIVE: To evaluate the independent contribution of clinical and constitutional factors in the development of early and late incisional hernias in women undergoing surgery for uterine cancer. METHODS: Over 10 years, patients undergoing extended abdominal hysterectomy for cervical or endometrial malignancies through a vertical incision were followed for the identification of incisional hernias. Logistic regression and survival analyses were used for statistics. RESULTS: Four hundred fifty-five women were included in the study, 77 of whom (16.9%) developed incisional hernias. The median (range) body mass index was higher in women who developed an incisional hernia than in those who did not (28 [19--44] kg/m(2) versus 24 [16--41] kg/m(2); P <.01). The frequencies of diabetes (14.3% versus 4.8%; P <.01), wound sepsis (10.4% versus 1.3%; P <.05), and fascial closure with interrupted sutures (70.1% versus 55.6%; P <.05) were significantly higher in women with incisional hernia than in those without. Multiple logistic regression revealed that, after adjustment for confounding variables, the only factors associated with incisional hernia formation within 1 year from the operation were body mass index above 27 kg/m(2) (odds ratio [OR] 3.68; 95% confidence interval [CI] 1.38, 9.81; P <.01) and wound infection (OR 5.05; 95% CI 1.39, 18.37; P <.01), whereas the factors associated with incisional hernia formation at least 3 years after surgery were diabetes (OR 6.68; 95% CI 2.02, 22; P <.01) and wound infection (OR 8.55; 95% CI 1.54, 47.5; P <.01). For hernia developing after 5 years (OR 8.32; 95% CI 1.41, 55.65; P <.05) and 8 years (OR 49.52; 95% CI 2.72, 907.14; P <.01), the only significant association was found with diabetes. CONCLUSION: Late incisional hernia formation does not depend on conditions present at the time of operation or on surgical technique. Other factors such as diabetes seem to play an important role in the development of late incisional hernia.

A search for double minute chromosomes in cultured lymphocytes from different types of tumors.

Double minutes are considered the products of DNA amplification and are rare in normal human cells. They have been observed in cultured lymphocytes in selected samples of human populations as one of the characteristics of the so-called rogue cells. We scored 9500 metaphases of cultured lymphocytes from 65 subjects with a variety of heredity and sporadic tumors and from 30 healthy subjects. The 15 cells with double minutes were found in subjects with multiple endocrine neoplasia type 1 (14 cases) and with familial adenomatous polyposis (1 case). Only one rogue cell was found among the 15 cells with double minutes.

DNA-ploidy and proliferative activity in uterine-tumors - an in-vivo study using bromodeoxyuridine and flow-cytometry.

We have studied the DNA ploidy and the proliferative activity in 102 patients with endometrial and cervical carcinoma, by flow cytometry. Samples were excised 1 hour after bromodeoxyuridine (BrdU, 250 mg/) e.v. infusion and fixed in 70% ethanol. Nuclear DNA content and BrdU incorporation, were simultaneously determined to obtain ploidy (DNA index) and proliferative activity (BrdU-labeling index, LI). No acute toxicity or side effects related to BrdU injection were recorded. The overall feasibility of the determinations was higher than 90% (93/102). Twenty-two out of 59 (37.2%) endometrial neoplasms and 23 out of 34 (67.6%) cervical neoplasms were aneuploid, with a median DNA-index of the aneuploid peak of 1.3 and 1.4, respectively. Overall median BrdU LIs were 4.8% and 7.2%. Proliferative activity was found to be higher in aneuploid tumors (p<.05). DNA ploidy and/or BrdU-LI were not significantly related either with the clinical stage or the histopathologic grading in either tumor type. The BrdU in vivo administration coupled with bivariate FCM for measurement is a simple method that can be performed in clinical settings to better evaluate the prognostic significance of proliferative parameters in gynecological tumors.

A multicentre collaborative study on the use of cold scalpel and electrocautery for midline abdominal incision.

BACKGROUND: Although studies in animals demonstrated a better wound healing after abdominal incision with cold scalpel than with electrocautery, clinical experiences did not confirm these findings. The purpose of this study was to compare early and late wound complications between diathermy and scalpel in gynecologic oncologic patients undergoing midline abdominal incision. METHODS: Patients undergoing midline abdominal incision for uterine malignancies were divided into two groups according to the method used to perform the abdominal midline incision: cold scalpel and diathermy in coagulation mode. Early and late complications were compared. Logistic regressions were used for statistical analysis. RESULTS: Nine hundred sixty-four patients were included, of whom 531 were in the scalpel group and 433 in the electrocautery group. Both groups were similar with respect to demographic, operative, and postoperative characteristics. Univariate analysis revealed a higher incidence of severe wound complications in the scalpel group than in the electrocautery group (8 of 531 versus 1 of 433, P <0.05). After adjustment for confounding variables (eg, age, body mass index) no differences were found between groups. CONCLUSIONS: Scalpel and diathermy are similar in terms of early and late wound complications when used to perform midline abdominal incisions. Therefore the choice of which method to use remains only a matter of surgeon preference.

The clinical value of computed tomography and lymphography in detecting lymph node metastases from epithelial ovarian cancer.

We investigated the accuracy of both lymphography and computed tomography (CT) in detecting lymph node metastases in 58 patients with primary epithelial ovarian cancer (group a) and subsequently submitted to surgery including pelvic and/or lumbo-aortic lymphadenectomy. CT accuracy was also investigated in 41 patients with clinically suspected relapse of ovarian cancer (group b). In the first group (a) overall results in the pelvis were, respectively, for lymphography and CT: 94.8 vs 89.6% accuracy, 85.7 vs 57.1% sensitivity, 97.7 vs 100% specificity, 97.7 vs 100% positive predictive value and 95.5 vs 88% negative predictive value. In the lumbo-aortic region, we had: 88.8 vs 86.1% accuracy, 71.4 vs 64.2% sensitivity, 100% specificity and positive predictive value for both techniques, and 84.6 vs 81.6% negative predictive value. In the second group (b) CT accuracy, sensitivity and specificity were 90.2, 80 and 100%, respectively. CT, thanks to its high specificity and positive predictive value, can represent the method of choice for the evaluation of pelvic and lumbo-aortic lymph node metastases in untreated and relapsing ovarian cancer. CT demonstration of lymph node metastases can affect not only lesion staging, but also chemotherapy; different indications for lymphadenectomy may also depend on CT.

Occurrence and distribution of matrix metalloproteinase-2-immunoreactivity in human embryonic tissues.

Tissue development and structure is controlled by dynamic and interactive relationships between cells and the extra-cellular matrix (ECM) which they secrete. We have investigated the occurrence and distribution of metalloproteinase-2 (MMP-2), an enzyme involved in the catabolism of ECM components, in human embryonic tissues by immunocytochemistry. Cells displaying MMP-2 immunoreactivity showed a widespread distribution in human embryonic tissues and organs. Cytoplasmic staining was detected in cells deriving from all three embryonic layers. Although further studies are needed to clarify the possible substrates of MMP-2 in developing tissues, these morphological data lend support to the hypothesis that ECM remodelling and degradation may represent a physiological counterpart of ECM deposition that occur during development.

Progression from nodular to lymphangitic subcutaneous metastasis from clear cell endometrial carcinoma: CT findings.

Subcutaneous metastases from clear cell endometrial carcinoma are an uncommon event and tumor implantations are rarely found with diagnostic imaging techniques. The nodular form is the most frequent type of subcutaneous metastasis from genital system tumors, even though plaque-like and infiltrative forms have also been reported. We report the first case of subcutaneous metastasis from clear cell endometrial carcinoma whose progression from the early nodular to the lymphangitic infiltrative form was studied with computed tomography (CT). Differential diagnostic problems are discussed.

Spontaneous hemorrhage of a liver metastasis from squamous cell cervical carcinoma: case report and review of the literature.

Liver metastases are an uncommon cause of spontaneous bleeding compared with primary benign/malignant liver lesions. Since metastatic lesions tend to maintain the vascular characteristics of the primary tumor, some metastases have a greater proclivity for hemorrhage into the host organ than others. We describe the clinical and computed tomography (CT) features of a patient previously treated for nonkeratinizing small cell squamous carcinoma of the cervix uteri. As the metastatic rupture was diagnosed while still intraparenchymal and subcapsular, with minimal peritoneal reaction, the patient's outcome was favorable.

Concurrent cytogenetic and molecular investigations in uterine and ovarian neoplasms.

We studied a group of 24 uterine and ovarian neoplasms with the purpose to verify if any correlation could be established between chromosomal abnormalities, loss of heterozigosity (LOH) and microsatellite instability (MIN). Tumor specimens obtained from 24 women (12 affected by ovarian and 12 by uterine neoplasms) were split in two parts, one was used for short term cultures for cytogenetic investigation while from the second DNA was extracted for molecular studies. We studied 22 polymorphic loci from 19 chromosomes and compared the alleles observed in the tumor with those observed in the DNA obtained from peripheral blood. Extensive loss of heterozigosity was observed when total or partial chromosomal loss was observed in at least 50% of the examined cells; MIN did not correlate with any particular cytogenetic abnormality nor with LOH.

Diagnostic alternatives to second look in ovarian cancer.

The accuracy of the markers CA 125, CA 15-3, CA 50 serum levels and the CT findings as alternative monitoring techniques to second look has been evaluated in 25 patients. The negative predictive value for the CA 125 was of 55% and its sensibility seems not to be increased by the association of the other markers. For the CT findings we report a diagnostic accuracy of 76%.

[Reconstructive problems after radical vulvectomy in carcinoma: current trends]. / Problematiche ricostruttive dopo vulvectomia radicale per carcinoma: moderni orientamenti.

The most recent techniques of vulvar reconstruction after radical excision for carcinoma are here reported and evaluated. The analysis of the different Authors' experiences leads to different indications and limits concerning each method. Therefore it is necessary for the surgeon to be able to apply different reconstructive solutions after considering the initial local and general conditions.