Salvage lymphadenectomy in recurrent ovarian cancer patients: Analysis of clinical outcome and BRCA1/2 gene mutational status.

OBJECTIVE: This study is aimed to analyze the clinical outcome of recurrent ovarian cancer patients bearing isolated lymph-node recurrence (ILNR) who underwent salvage lymphadenectomy (SL). The prognostic role of clinicopathological variables and the mutational status of BRCA1/2 have also been investigated. METHODS: This retrospective, single-institutional study included women with platinum-sensitive lymph node recurrence underwent to SL between June 2008 and June 2018. Univariate and multivariate analysis was performed to evaluate the impact of clinical parameters, and BRCA1/2 mutational status on post salvage lymphadenectomy progression-free survival (PSL-PFS). RESULTS: As of June 2019, the median follow-up after SL was 30 months, and the relapse has been documented in 48 (56.5%) patients. In the whole series, the median PSL-PFS was 21 months, and the 3-year PSL-PFS was 36.7%. The median PSL-PFS, according to patients with ILNR (N = 71) versus patients with lymph-nodes and other sites of disease (N = 14), was 27 months versus 12 months, respectively. Univariate analysis of variables conditioning PSL-PFS showed that platinum-free interval (PFI) ≥12 months, normal Ca125 serum levels, and number of metastatic lymph-nodes ≤3 played a statistically significant favorable role. In multivariate analysis, PFI duration ≥12 months and the number of metastatic lymph nodes ≤3 were shown to keep their favorable, independent prognostic value on PSL-PFS. CONCLUSIONS: In the context of SL, the patients with long PFI and low metastatic lymph node numbers at ILNR diagnosis have the best outcome. The BRCA mutational status seems not associated with clinical variables and PSL-PFS, differently from other sites of disease in ROC patients.

Role of vitamin K2 in bone metabolism: a point of view and a short reappraisal of the literature.

Vitamin K2 (vit K2) belongs to a large group of fat-soluble compounds whose formulation is MK (menaquinone) (MK-2 to MK-14), that seem to be involved in different biological functions. In particular, vit K2 has been recently recognized as efficacious and safe in treatment of bone loss, as it contributes to structural integrity of osteocalcin (OC), the major non-collagenous protein typically found in bone matrix. Several studies proved low vit K2 intake is linked to bone loss and to increased fracture risk in both sexes. Nowadays, vit K2 supplementation is considered a significant manner to enhance the association of calcium and vitamin D whose role on bone health is largely recognized. On the other hand, vit K2 may be used alone or with other drugs to preserve bone quality/strength from skeletal degradation after menopause and/or in patients affected by secondary osteoporosis. In this paper, we review the most recent data about vit K2 on skeleton.

Long-Term Survival for Platinum-Sensitive Recurrent Ovarian Cancer Patients Treated with Secondary Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND: To analyze the 5- and 7-year survival outcomes for women with platinum-sensitive recurrent epithelial ovarian cancer (REOC) who underwent secondary cytoreductive surgery (SCS) plus platinum-based hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: From the electronic databases of the Department of Obstetrics and Gynecology at the Catholic University of the Sacred Heart of Rome and of the S. Orsola Hospital, University of Bologna, a consecutive series of REOC patients were selected using the following inclusion criteria: primary platinum-free interval (PFI-1) of 6 months or longer, completeness of secondary cytoreduction score (CC) of 1 or lower, minimum follow-up period of 48 months, Eastern Cooperative Group (ECOG) performance status at recurrence of 1 or less, and platinum-based HIPEC. Progression-free survival (PFS) and post-relapse survival (PRS) were calculated as the time between SCS + HIPEC and secondary recurrence or death, respectively. RESULTS: The final study population included 70 women with platinum-sensitive REOC. The median follow-up time was 73 months (range 48-128 months), and the median PFI-1 was 19 months (range 6-100 months). At the time of recurrence, the median peritoneal cancer index was 7 (range 1-21), and a CC score of 0 was achieved for 62 patients (88.6 %). As the HIPEC drug, we used oxaliplatin in 17 cases (38.6 %) and cisplatin in 43 cases (61.4 %). No postoperative deaths were observed, and the complication rate for grades 3 and 4 disease was 8.6 %. The median PFS duration was 27 months (range 5-104 months), and the 5- and 7-year PRS rates were respectively 52.8 and 44.7 %, (median PRS 63 months). CONCLUSIONS: The current study demonstrated favorable 5- and 7-year PRS rates for platinum-sensitive REOC patients undergoing SCS + HIPEC, which encourages the inclusion of patients in randomized clinical trials for definitive conclusions to be drawn.

Minimally invasive secondary cytoreduction plus HIPEC for recurrent ovarian cancer: a case series.

OBJECTIVE: To analyze the feasibility of laparoscopic/robotic secondary cytoreductive surgery and hyperthermic intraperitoneal intra-operative chemotherapy (SCS+HIPEC) in a retrospective series of isolated platinum sensitive recurrent ovarian cancer. METHODS: We retrospectively evaluated a consecutive series of ovarian cancer patients with isolated platinum sensitive relapse. Isolated relapse was defined as the presence of a single nodule, in a single anatomic site. In all cases the presence of isolated relapse was assessed at pre-operative FDG-PET/CT scan, and confirmed with staging laparoscopy performed immediately before SCS+HIPEC. RESULTS: 84 women with platinum sensitive relapse received SCS+HIPEC during a 4-year period. Among them, 10 cases (11.9%) showed isolated relapse and were treated with laparoscopic/robotic SCS+HIPEC. In all cases complete debulking was achieved. In HIPEC treatment, 9 women received cisplatin at 75 mg/m(2), and the remaining patient oxaliplatin 460 mg/m(2). In 7 patients SCS was performed through the laparoscopic route, and in 3 cases with a robotic approach. The median operative time from skin incision to the end of cytoreductive surgery was 122 min (95-140), estimated blood loss was 50 cm(3) (50-100), and the median length of hospital stay was 4 days (3-7). The interval from surgery to adjuvant chemotherapy was 21 days (19-32). No grade 3/4 surgical, metabolic, or hematologic complications occurred. In all cases post-operative FDG-PET/CT scan was negative, and after a median time of 10 months (6-37) from SCS+HIPEC no secondary recurrence was observed. CONCLUSIONS: Minimally invasive SCS+HIPEC can be safely performed in selected ovarian cancer patients with platinum sensitive isolated relapse.

Long-term analysis of clinical outcome and complications in locally advanced cervical cancer patients administered concomitant chemoradiation followed by radical surgery.

OBJECTIVE: Preoperative chemoradiation (CT/RT) has been shown to achieve encouraging results in terms of clinical outcome in locally advanced cervical cancer (LACC). The study aims at analyzing the long-term results of this multimodal approach in a single institution series of 184 cases. METHODS: Patients underwent whole pelvic irradiation combined with cisplatin and 5-fluorouracil. After evaluation of clinical response, patients were triaged to surgery. Surgical morbidity was classified according to Chassagne grading system. Univariate and multivariate analyses were used to assess the prognostic and predictive role of clinicopathological parameters. RESULTS: Clinical response was observed in 96.1% of cases. A total of 174 cases were submitted to radical surgery: 124 patients (71.3%) showed complete/microscopic pathological response. In multivariate analysis, clinical response, stage of disease, and histotype predicted response to CT/RT. With a median follow-up of 58 months, recurrence and death of disease were observed in 42 and 40 patients, respectively. The 5-year DFS was 75.5%, while the 5-year OS was 77.4%. Patients with no residual disease showed a significant longer DFS than patients with microscopic (p value = 0.0128), and macroscopic (p value = 0.0001) residual tumor after treatment. In multivariate analysis, residual tumor and stage of disease were the two most relevant prognostic factors for DFS and OS. As far as long-term toxicity is concerned, 8 out of 22 complications were grade 3/4. CONCLUSION: Preoperative CT/RT is worth further investigation in LACC patients, providing encouraging survival outcomes and a favourable long-term toxicity profile.

Secondary cytoreduction plus oxaliplatin-based HIPEC in platinum-sensitive recurrent ovarian cancer patients: a pilot study.

OBJECTIVES: To assess feasibility, complications and efficacy of secondary surgical cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in a selected group of platinum-sensitive recurrent ovarian cancer patients. METHODS: Recurrent ovarian cancer patients with a platinum-free interval of at least 6 months were prospectively enrolled. After complete CRS they were submitted to intraperitoneal perfusion of oxaplatinum (460 mg/m(2)) heated to 41.5 degrees C for 30 min. Then they received systemic chemotherapy with taxotere 75 mg/m(2) and oxaliplatin 100 mg/m(2) for 6 cycles. Patients were followed up routinely until recurrence or death. RESULTS: Twenty-five recurrent ovarian cancer patients were valuable for the study. The median Platinum Free Interval (PFI) was 25 months (range 7-67). The majority of the patients (76%) had diffuse carcinosis. Nobody had ascites. An optimal residual disease was obtained in all patients. The median duration of CRS+HIPEC was 312 min (range 138-619). Median intensive care unit (ICU) stay was 2 days (1-6), median hospital stay was 13 days (7-30). Post-operative major complications were observed in 7 patients (28%). Post-operative mortality was 0%. With a median follow-up time of 18 months (range 3-38), 24 patients (96%) are alive, but seven women (28%) have relapsed. CONCLUSIONS: Adequate pre-operative selection can improve feasibility of CRS and HIPEC. Morbidity rate is comparable to aggressive cytoreduction without HIPEC. Although associated with some post-operative morbidity, long-term results are encouraging, waiting for larger series and longer follow-up data.

Comparative effects of 17beta-estradiol and phytoestrogens in the regulation of endometrial functions in the rodent uterus.

The present study aimed at improving our understanding of the effects of 17beta-estradiol and phytoestrogens on the uterine tissue, by evaluating tissue-specific modulation of molecules related to cell-cycle control and angiogenesis. Specifically, the uterine expression of Ki67, peroxisome proliferator-activated receptor gamma (PPARgamma), and vascular endothelial growth factor receptor-2 (VEGFR-2), was examined by immunohistochemical analysis. Ovariectomized (OVX) rats were treated with either the vehicle, a phytoestrogen- containing soy extract (SSE) (100 mg/kg/day pos), or 17beta-estradiol (0.5 mg/kg/day pos); a sham control group (SHAM) was also included in the study. At necropsy, uteri were weighed, collected, and subsequently processed for histopathology or immunohistochemistry. SSE-treated rats did not show any significant change either in the weight or in histological features of the uterus when compared to OVX controls; the epithelial expression of proliferation marker Ki67 was seen to be significantly reduced, in comparison to both SHAM and OVX rats. Conversely, 17beta-estradiol significantly increased uterine weight, induced hyperplasia in the majority of rats, and enhanced Ki67 epithelial expression. The regulation of PPARgamma expression, reduced after ovariectomy, was similar in SSE- and 17beta-estradiol-treated rats, showing a further significant decrease in stromal immunostaining, in comparison to OVX controls. VEGFR-2 epithelial immunostaining, slightly reduced following ovariectomy, was highly increased on 17beta-estradiol treatment, while following SSE, the pattern of staining observed was similar to that of OVX controls. Data from this study show that PPARgamma and VEGFR-2 represent additional targets by which sex steroid estrogen and plant-derived phytoestrogens may, at certain doses, differentially regulate endometrial functions.

Preoperative concomitant chemoradiotherapy in locally advanced cervical cancer: safety, outcome, and prognostic measures.

OBJECTIVES: To evaluate the morbidity, and the therapeutic value of surgery after chemoradiation in a large series of locally advanced cervical cancers (LACC). The prognostic role of different clinico-pathological factors has been also evaluated. METHODS: Between October 1997 and October 2006, 161 LACC patients were treated at both the Gynecologic Oncology Units of the Catholic University of Rome and Campobasso. Radiotherapy was administered to the whole pelvic region in combination with cisplatin and 5-fluorouracil. Radical surgery was performed 5-6 weeks after the end of the treatment. RESULTS: A clinical complete/partial response was observed in 153 patients and radical surgery was performed in 152 cases. The overall rate of surgical complications was 33% with 15 (10%) patients experiencing severe toxicities. At pathological examination 111 of 152 patients (73%) showed absent/microscopic residual disease. With a median follow-up of 28 months, the 5-year disease free-survival (DFS) was 83% and the 5-year overall survival (OS) 90%. Advanced FIGO (Federation Internationale de Gynecolgie et d'Obstetrique) stage, pathological response and lymph node involvement were found significantly associated with clinical outcome. CONCLUSIONS: We confirmed in a larger series the safety and efficacy of this multimodal approach in the treatment of LACC. The pathological assessment of response can allow not only a tailored surgery in selected patients, but also the identification of patients with higher risk of recurrence to be submitted to adjuvant therapies.

Antitumour activity of the silybin-phosphatidylcholine complex, IdB 1016, against human ovarian cancer.

This study aimed to assess, in an in vivo experimental model, the growth inhibitory effects of IdB 1016 (Silipide, a complex of silybin/phosphatidylcholine) when used as a single agent against human ovarian cancer. We also wanted to investigate the mechanism of the antiangiogenic action by assessing Vascular Endothelial Growth Factor (VEGF) levels and by using macroarray technology to evaluate the regulation of a panel of genes involved in angiogenesis. We also aimed to establish the plasma and tumour bioavailability of silybin after repeated administration of IdB 1016. Female nude mice bearing human ovarian cancer xenografts (A2780) received 450 mg/kg/day IdB 1016 daily by oral gavage until the end of the study. At sacrifice, blood and tumour specimens were collected and subsequently processed for the determination of silybin levels, VEGF levels or a gene expression profile. IdB 1016 was significantly active in inhibiting ovarian tumour growth. Treatment with 450 mg/kg/day for a total of 20 administrations produced a tumour weight inhibition (TWI%) of 78% and a Log10 Cell Kill (LCK) of 1.1. Free silybin levels were found to be 7.0+/-5.3 microg/ml and 183.5+/-85.9 ng/g tissue (mean+/-standard deviation (S.D.)) in the plasma and tumour samples, respectively. No significant differences were found in the concentration of human VEGF in xenografts from control and IdB 1016-treated mice. The array analysis suggested the downregulation of the VEGR receptor 3 and the upregulation of angiopoietin-2 as potential mechanisms for the antiangiogenic activity. In conclusion, these findings suggest IdB 1016 is a good candidate, with a relevant clinical potential, for use in the management of recurrent ovarian cancer. A phase II, non-randomised clinical study is now ongoing in our Institute aimed at evaluating the efficacy of daily administrations of IdB 1016 in the serological recurrence of ovarian cancer.

In vitro evaluation of newly developed chalcone analogues in human cancer cells.

PURPOSE: Among flavonoids, chalcones have been identified as interesting compounds having chemopreventive and antitumor properties. We studied a panel of newly developed chalcone analogues (S1-S10) using MDA-MB 231 and MCF-7 ADRr breast cancer cells and the T-leukemic Jurkat cell line. Quercetin was used as the reference compound. METHODS: Antiproliferative activity was evaluated by cell counts performed after 72 h of exposure to the drugs. DNA analysis and redox activity were evaluated using flow cytometry. Apoptosis was assessed by morphological analysis, using YOYO-1 as DNA dye; p-glycoprotein function was ascertained by quantitating the efflux of rhodamine 123. RESULTS: All cells were sensitive to chalcone analogues yielding IC50 in micromolar concentrations with the following order regardless of the multidrug resistance (MDR) status: S1 > S2 > quercetin. S1 and S2, the most active compounds, were selected to evaluate their effect on the cell cycle, apoptosis, redox activity, and modulation of the p-glycoprotein function. No significant perturbation in cell cycle was seen with concentration up to 1 microM after 24 h. After 72 h a slight increase in G2/M block and DNA fragmentation occurred at 10 microM. Morphological analysis of apoptosis showed that chalcone analogues induced apoptosis to a higher extent than quercetin. Redox analysis demonstrated that all substances were able to increase intracellular thiol levels, which returned to baseline value after 24 h for all drugs except quercetin. Production of reactive oxygen species was essentially unaffected by all compounds. Finally, in MDR-positive MCF-7 ADRr cells chalcone analogues were unable to modulate p-glycoprotein function while quercetin was able to. CONCLUSIONS: Newly developed S1 and S2 chalcones have a different but higher antitumor activity than quercetin and could be considered as potential new anticancer drugs.

Clinical effects of a standardized soy extract in postmenopausal women: a pilot study.

OBJECTIVE: This double-blind, randomized study was aimed at evaluating comparatively, in postmenopausal women, the activity of a standardized soy extract (SOYSELECT) and placebo when given alone or in combination with conjugated equine estrogens (CEE) on early climacteric symptoms. Lipid profile, pituitary hormones, osteocalcin and endothelin levels, and vaginal and endometrial parameters were also evaluated. DESIGN: Participants in the control group were given placebo, and participants in the treated group were given 400 mg/day of a standardized soy extract, corresponding to 50 mg/daily of isoflavones. After 6 weeks of treatment, CEE was also then given to each participant at a dose of 0.625 mg/day for 4 weeks. At the end of this period, soy and placebo treatment were suspended, and, until the end of the study (week 12), participants were administered 10 mg/day of medroxyprogesterone acetate in association with CEE (0.625 mg/day). RESULTS: When compared with pretreatment data, on week 6 of the study, a significant (p < 0.01) reduction in the mean number of hot flushes per week was observed in participants who were receiving the standardized soy extract, whereas a more marked relief was observed in both soy and placebo groups during CEE administration. Concurrently, the severity of hot flushes, assessed by means of the Greene climacteric scale, was also reduced in the soy group participants (p < 0.001, by paired t-test). No soy-related changes were observed on vaginal cytology, endometrial thickness, uterine artery pulsatility index, or metabolic and hormonal parameters tested. Finally, CEE-related changes on genital tract, uterine vascular compartment, and pituitary hormones were not modified by soy treatment. CONCLUSIONS: SOYSELECT may be a safe and efficacious therapy for relief of hot flushes in women who refuse or have contraindications for hormone replacement therapy.

[A zinc sulfate and usnic acid preparation used as post-surgical adjuvant therapy in genital lesions by Human Papillomavirus]. / Terapia adiuvante con un preparato a base di zinco solfato e acido usnico delle lesioni genitali da Human Papilloma virus (HPV) dopo trattamento chirurgico distruttivo.

BACKGROUND: To evaluate the efficacy and safety of intravaginal administration of a zinc sulphate and usnic acid compound as adjuvant therapy of Human Papillomavirus (HPV) genital infection, after radiosurgical treatment (RS). METHODS: One hundred patients affected by HPV genital infection were enrolled in the study from October 1996 to July 1998. Patients were classified according to colposcopic and cytologic criteria and treated with RS. Patients were randomized into three groups: the first group did not follow any therapy after RS (control group), (n = 50); the second group was pharmacologically treated with intravaginal administration of a usnic acid and zinc sulphate compound (Zeta N, Bergamon Italia) before and after RS (n = 25), the third group was pharmacologically treated only after RS (n = 25). The last two groups were considered together for the statistical analysis. Patients were reevaluated after one, two, three and six months from electrocoagulation. The safety of treatment was also investigated. RESULTS: One month after RS. HPV lesions disappeared in 93% of the patients in the control group and in 100% of patients treated with usnic acid and zinc sulphate. After one month, reepithelization was complete in 65% of cases treated with usnic acid and zinc sulphate and in only 28% of the control group (p = 0.001). Two months later reepithelization was 94% in the patients pharmacologically treated compared to 76% of the control group (p = 0.06). Treatment prior to RS resulted in a reduction of the overall area of lesions in 88% of cases. Three months after RS, there was a significant reduction of recurrence in the group treated with usnic acid and zinc sulphate (p = 0.01). This reduction was still significant at six months (p = 0.005). CONCLUSIONS: Usnic acid and zinc sulphate adjuvant treatment improved time of reepithelization and reduce the recurrence with few side effects and a good compliance.

Reproductive effects of dietary soy in female Wistar rats.

This study was designed to assess the effects of administration of dietary soy on reproductive function and fertility of female Wistar rats. Four groups, each of 20 females, were used. Control animals were fed a standard cereal-based diet for rats. Treated animals were fed a standard diet supplemented with 0.7%, 1.2% or 2.4% of a soy extract. Treatment started at weaning and continued until day 7 post-partum (day of sacrifice). Growth depression was seen in the 2.4% soy group. Vaginal opening occurred earlier in females receiving soy supplemented feed when compared with controls. Analysis of vaginal smears revealed that all animals were cycling, although an increase in the mean duration of each cycle was seen in the 2.4% soy group. Uterine effects were observed in high-dose females and included increases in weight, oedema, endothelial hyperplasia and leucocytic infiltration. Vaginal modifications (i.e. inflammation, hyperkeratosis and dyskeratosis) and alterations in the distribution of follicular size in the ovaries were also observed among treated animals. These data suggest that long-term exposure to high doses of phytoestrogens can produce significant agonistic actions in several oestrogen-dependent tissues and parameters, even though in this model no clear influence on reproductive processes was observed.

Autologous blood stem cell harvesting and transplantation in patients with advanced ovarian cancer.

We investigated the feasibility of a programme of autologous blood stem cell (ABSC) harvesting and transplantation in 13 patients with advanced ovarian cancer, previously untreated by chemotherapy or radiotherapy and entering a phase II study of high-dose cisplatin, etoposide and carboplatin with haematopoietic stem cell rescue. Prior to high-dose treatment all patients underwent two courses of cisplatin and cyclophosphamide. An 8-fold increase of the peripheral colony forming unit granulocytic-macrophage (CFU-GM) was observed during recovery from myelosuppression after the first chemotherapy course. The second course determined a 2.5-fold increase of peripheral CFU-GM. In 70% of enrolled patients (nine patients) we were able to perform ABSC harvesting by leukaphereses; in the apheresed patients we harvested an average of 20.8 x 10(4)/kg CFU-GM (range 10.9-37.0). Haematopoietic trilineage engraftment, established as the number of days necessary to reach white blood cells (WBC) greater than 1.0 x 10(9)/l, polymorphonuclear leucocytes (PMN) greater than 0.5 x 10(9)/l and platelets (PLT) greater than 50 x 10(9)/l, occurred very promptly and was sustained in the same series after high-dose cisplatin, carboplatin and etoposide, followed by autologous blood stem cell transplantation (ABSCT). In our experience we found a significant correlation (r = 0.77; P less than 0.05) between CFU-GM infused dose and the engraftment speed of PMN. We conclude that the combination of cisplatin and cyclophosphamide is effective in mobilizing haematopoietic progenitors in the peripheral blood of patients with advanced ovarian cancer, previously untreated by chemoradiotherapy. Moreover, ABSCT is capable of rapidly restoring the haematopoietic function after high-dose treatment and for this reason it represents a particularly advisable therapeutic option for the treatment of solid tumours because these patients are commonly older than 50 and can be excluded from bone marrow transplantation.

Rationale for very high-dose chemotherapy with peripheral blood stem cell support in advanced ovarian cancer.

Although significant progress has been made in the management of advanced ovarian cancer, the majority of patients continue to die of this disease. Most advanced ovarian cancer patients present sub-optimal residual tumour after primary surgery and their prognosis is very poor since residual disease has been confirmed as the major factor predicting response to chemotherapy and survival. Therefore, it seems worth developing treatment modalities that can produce a longer remission period. In this short review, the authors summarize the clinical and experimental evidence supporting the usefulness of high-dose chemotherapy with autologous peripheral blood stem cell transplantation in advanced ovarian cancer.