Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. PATIENTS AND METHODS: This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. RESULTS: Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. CONCLUSIONS: In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

OCULAR DISCOMFORT IN PROFESSIONAL POLO-WATER PLAYERS: A PRACTICAL EXPERIENCE WITH TOPICAL HYALURONIC ACID AND GLYCURONATE ENOXOLONE.

AIMS: Professional polo-water athletes are exposed to chlorine in the swimming pool. Chlorine is an irritant agent, so polo-water athletes commonly experience irritative eye symptoms. Hyaluronic acid and glycuronate enoxolone exert anti-inflammatory and cytoprotective activity. Therefore, the present practical experience explored the efficacy and safety of eye drops containing both components. MATERIAL AND METHODS: The current study included 59 professional polo-water athletes. The ocular surface disease index (OSDI) and dry eye-related quality of life (QoL) score (DEQS) questionnaires were used to assess the efficacy. Subjects took the eye drops for one month. The study consisted of a baseline visit (T0) and an end-treatment one (T1). RESULTS: Athletes experienced a significant improvement in symptoms and QoL as assessed by OSDI and DEQS scores (p < 0.001 for both). CONCLUSION: The present study showed that professional polo-water athletes frequently experience ocular discomfort associated with swimming pool attendance. Eye drops with hyaluronic acid and glycuronate enoxolone can significantly relieve eye symptoms and improve the quality of life in these athletes.

Adnexal Torsion in Pediatric Age: Does Bolli's Score Work? Report of Two Cases.

Adnexal torsion is a surgical emergency requiring early diagnosis in order to avoid demolitive surgery. Adnexal torsion's diagnosis could be very difficult in pediatric patients because children cannot explain symptoms accurately. Furthermore reproductive organs lie high in abdomen, causing unclear examinations findings. For reducing diagnostic mistakes or delay clinical and hematological criteria could be useful. No radiological criteria (CT or MRI) should be taken in count because of the costs and the required time. By combining clinical presentation in patients with OT three useful diagnostic variables have been identified: age, duration of pain, vomiting. Presence of vomiting, short duration of abdominal pain and high CRP levels have great predictive value for the diagnosis of adnexal torsion. In those patients an exploratory laparoscopy should be performed without any doubt and/or delay. These data may aid physicians in the evaluation of abdominal pain in premenarchal girls.

Identification of extracellular vesicles and characterization of miRNA expression profiles in human blastocoel fluid.

In this study, for the first time, we demonstrated the presence of microRNAs and extracellular vesicles in human blastocoel fluid. The bioinformatic and comparative analyses identified the biological function of blastocoel fluid microRNAs and suggested a potential role inside the human blastocyst. We found 89 microRNAs, expressed at different levels, able to regulate critical signaling pathways controlling embryo development, such as pluripotency, cell reprogramming, epigenetic modifications, intercellular communication, cell adhesion and cell fate. Blastocoel fluid microRNAs reflect the miRNome of embryonic cells and their presence, associated with the discovery of extracellular vesicles, inside blastocoel fluid, strongly suggests their important role in mediating cell communication among blastocyst cells. Their characterization is important to better understand the earliest stages of embryogenesis and the complex circuits regulating pluripotency. Moreover, blastocoel fluid microRNA profiles could be influenced by blastocyst quality, therefore, microRNAs might be used to assess embryo potential in IVF cycles.

The role of staging and adjuvant chemotherapy in stage I malignant ovarian germ cell tumors (MOGTs): the MITO-9 study.

Background: Surgery followed by platinum-based chemotherapy is the standard of care for MOGCTs, except for stage IA dysgerminoma and stage IA grade 1 immature teratoma where surveillance only is recommended. The role of adjuvant chemotherapy and surgical staging is debated. Patients and methods: Data from 144 patients with stage I MOGTs were collected among MITO centers (Multicenter Italian Trials in Ovarian Cancer) and analyzed. Results: Fifty-five (38.2%) patients were affected by dysgerminomas, 49 (34%) by immature teratomas, 26 (18.1%) by yolk sac tumors and 14 (9.7%) by mixed tumors. Seventy-three (50.7%) patients receive surgery plus chemotherapy, while 71 (49.3%) patients underwent surgery alone. The latter group included 32 dysgerminomas (14 IA-13 Ix, 3 IB, and 2 IC), 34 immature teratomas (20 1A-13 IA grade 1, 6 Ix, 1 IB, and 7 IC), 4 mixed tumors and 1 yolk sac tumor. Forty-four patients did not received chemotherapy, even if it would have been indicated by recommended approach. 94 (65.3%) patients received peritoneal surgical staging. Twenty-three (15.9%) developed a recurrence. Incomplete surgical staging was associated with recurrence (P < 0.05; OR 2.37) at Cox regression analysis. Seven patients died. Four patients were affected by yolk sac tumors, two by mixed tumors and one by immature teratoma. Five patients died for disease, one for acute leukemia and one for suicide. Prognostic parameter analyses showed that yolk sac component is a predictor for survival (P < 0.05). Five-years OS rates were 96.8% and 88.7% in the surgically staged and the incomplete staged group, respectively, while 93.8% and 94.1% in the standard treatment and in the surveillance group, respectively. Conclusions: This study shows that surveillance seems not to affect survival; chemotherapy should be reserved for relapse resulting in high cure rate. Incomplete peritoneal surgical staging is associated with recurrence. Yolk sac histology worsens the prognosis.

Retinal injury by industrial laser burn.

The following case study describes an injury sustained to the fovea of the right eye of a senior en gineer engaged in the repair of a neodymium-doped yttrium aluminium garnet (Nd:YAG) laser. Our patient presented with sudden loss of vision in his right eye following accidental exposure to an intense beam of light after the laser's xenon flash-lamp fired unexpectedly. This accident occurred while the patient was aligning the optical coupler mirror parallel to Nd:YAG laser rod ends using an L-CAT alignment aid. We describe the mechanism of retinal injury, outcome and important issues regarding the safe use of lasers.

High prevalence of thyroid dysfunction in pregnant women.

BACKGROUND/AIM: Maternal thyroid dysfunction during pregnancy has been associated with adverse obstetric and neonatal outcomes. This prospective study evaluates the prevalence of these disorders in pregnant women. SUBJECTS AND METHODS: Serum levels of TSH, free T4 (fT4), and thyroperoxidase antibodies (TPO-Ab) were measured in 951 women at different gestational ages of pregnancy. Trimester-specific reference ranges for TSH were used to classify pregnant women into five groups: 1) Overt hypothyroidism (OH); 2) Subclinical hypothyroidism (SCH); 3) Isolated hypothyroxinemia (IH); 4) Low TSH (isolated or associated with high fT4); and 5) Normal. A classification was made also according to the lower and upper ranges provided by the manufacturer for thyroid hormones. Pregnant women who were at a high risk of developing thyroid disease were identified. RESULTS: Altogether, 117 women (12.3%) had hypothyroidism and 25 (2.6%) had low TSH. The prevalence of both OH and SCH was higher in the high-risk group than in the low-risk group, but 17.9% of women with hypothyroidism were classified at low-risk. A family history of thyroid disorders and TPO-Ab positivity increased the risk of SCH. Using non-pregnant reference range for TSH, 10.6% of women were misclassificated. CONCLUSIONS: The high prevalence of hypothyroidism observed in this study suggests that accurate thyroid screening with trimester specific reference ranges should be warranted, particularly in areas with mild to moderate iodine deficiencies.

Is surgical restaging indicated in apparent stage IA pure ovarian dysgerminoma? The MITO group retrospective experience.

OBJECTIVE: Conservative surgery followed by platinum-based chemotherapy is considered the standard approach for pure ovarian dysgerminoma (POD), except for correctly staged IA patients. The aim of study was to evaluate the outcome of IA POD patients with incomplete surgical staging in order to define the proper management. METHODS: Data concerning primary treatment and recurrence were reviewed for 26 patients with stage IA POD treated in MITO (Multicenter Italian Trials in Ovarian Cancer) centers. RESULTS: Median age was 22.5years. Primary surgery was fertility sparing for 17 patients (65.4%) and radical surgery was performed in 9 patients due to older age or gonadal dysgenesis. Only five patients (19.2%) had complete surgical staging; 38.5% had lymph node dissection, 46.2% had peritoneal biopsies and/or omentectomy and 65.4% had peritoneal washing. Seven patients received adjuvant chemotherapy. Overall recurrence rate was 11.5%: all recurrences occurred in the group submitted to incomplete staging procedure. No patients treated with adjuvant chemotherapy relapsed. One patient had pelvic recurrence, one patient relapsed in the abdomino-pelvic peritoneum and lymph nodes and the third patient showed a peritoneum, lymph nodal and residual ovary relapse. All patients with recurrence were cured by salvage therapy: 2 patients were treated with surgery plus chemotherapy and one only with chemotherapy. After a median follow-up of 100months all patients are alive without evidence of disease. Six patients opted for conception and delivered healthy infants, two with IVF with donor oocyte. CONCLUSIONS: IA POD prognosis is excellent. Conservative surgery with a complete surgical staging is the gold standard. Patients with incomplete staging could undergo surgical restaging or surveillance. Chemotherapy should be reserved to relapse with excellent chances of therapeutic success.

Evaluation of pemetrexed (Alimta, LY231514) as second-line chemotherapy in persistent or recurrent carcinoma of the cervix: the CERVIX 1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group.

BACKGROUND: The objective of the study was to estimate the antitumor activity of pemetrexed in patients with advanced/recurrent carcinoma of the cervix and to determine the nature and degree of toxicity. METHODS: A multicenter phase II trial was conducted by the Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO) Group. Patients with advanced/recurrent measurable carcinoma of the cervix that had failed one prior chemotherapy regimen in association or not with radiotherapy were treated with pemetrexed at a dose of 500 mg/m(2) every 21 days. All the patients had a measurable lesion according to RECIST criteria in a not previously irradiated field. RESULTS: From November 2006 to September 2008, 43 patients were entered by seven member institutions of the MITO-Group. A total of 164 cycles (median 2, range 1-9) were administered. The treatment was well tolerated. More serious toxic effects (grades 3 and 4) included leukopenia in 27.9% and neutropenia in 30.2% of patients. No treatment-related deaths were reported. Six patients (13.9%) had partial responses (at least a 30% decrease in the sum of longest diameter of target lesions taking as reference the baseline sum longest diameter) with a median response of 7 weeks (range 3-27). Twenty-three patients (53.4%) had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) and fourteen (32.5%) patients had progressive disease. Median progression-free survival was 10 weeks and overall survival was 35 weeks. CONCLUSION: Pemetrexed showed moderate activity against advanced/recurrent cervical cancer that had failed prior chemotherapy.

Carboplatin and pegylated liposomal doxorubicin for advanced ovarian cancer: preliminary activity results of the MITO-2 phase III trial.

BACKGROUND: Based on the efficacy of pegylated liposomal doxorubicin (PLD) in relapsed ovarian cancer, we are conducting a phase III study comparing carboplatin plus either paclitaxel or PLD as first-line therapy in advanced ovarian cancer. Because of limited phase I and II data on PLD plus carboplatin in this setting, we conducted an interim activity analysis. PATIENTS AND METHODS: Patients with stage 1c-IV epithelial ovarian cancer were randomized to carboplatin AUC 5 plus either paclitaxel 175 mg/m(2) or PLD 30 mg/m(2) every 3 weeks for 6 cycles. The interim activity analysis was planned according to a single-stage phase II design with an auspicated 50% response rate; 50 patients eligible for response assessment were required. Response was defined according to RECIST (Response Evaluation Criteria in Solid Tumors). RESULTS: A complete response was achieved in 14 patients (28%) and a partial response in 20 (40%), which produced an overall response rate of 68%. The activity exceeded the minimum required for study continuation. Stable disease was reported in an additional 10 patients (20%). CONCLUSIONS: The adopted schedule of PLD plus carboplatin demonstrates activity as a first-line treatment for advanced ovarian cancer.

Expression analysis of TFIID in single human oocytes: new potential molecular markers of oocyte quality.

Molecular characterization of human female gametes should make it easier to understand the basis of certain infertility disorders. Biologically significant mRNAs have been analysed in single oocytes to search for molecular biomarkers of oocyte quality. Initial analysis was focused on mRNA for proteins involved in cell growth and cycle control, specifically those encoding members of the general transcription apparatus such as the subunits of the general transcription factor TFIID. This heteromultimeric protein, comprising about 15 subunits, is the most important general transcription factor of the second class. These proteins are essential for the initiation of transcription of protein-coding genes, so they must be present in mature oocytes for mRNA synthesis during the first phases of embryonic development. Semi-quantitative reverse transcriptionpolymerase chain reaction was used to identify different TFIID subunits in single oocytes and to search for differences in expression as compared with control tissues. The data show that the mRNAs for most TFIID subunits are indeed synthesized in oocytes, but their expression profiles differ markedly. TATAbox-binding protein associated factor 4B (TAF4B), TAF5 and TATAbox-binding protein-like 2 (TBPL2) are expressed at higher levels in oocytes than in control tissues. It is suggested that they could be used as biomarkers of oocyte quality.

Ovarian cystic teratoma with primary epithelial cell melanoma.

We report a rare case of malignant melanoma arising in a cystic teratoma of the ovary occurring in a 60-year-old woman who died in four months despite the combined treatment administrated (surgery and chemotherapy). Diagnosis of ovarian melanoma was confirmed by immunohistochemical positivity to S-100 protein and HMB 45. There was no evidence of extra-ovarian primary melanoma on clinical examination; therefore the diagnosis was primary ovarian melanoma. Melanoma metastases were detected on the uterus, the right ovary, the omentum and in one of the three excised left external iliac lymph nodes. A review of the literature is analyzed and discussed.

[Peritonectomy and hyperthermic chemoperfusion in peritoneal carcinomatosis. Preliminary results]. / Peritonectomia e chemioperfusione ipertermica nella carcinomatosi peritoneale. Risultati preliminari.

BACKGROUND: Peritoneal carcinomatosis can be actually treated by new surgical and oncological techniques. Aim of this work is to report preliminary results of a group of patients with peritoneal carcinomatosis, submitted to peritonectomy and intraperitoneal hypertermic chemoperfusion (IPHC). METHODS: Age, sex, type of neoplasm, peritoneal carcinomatosis index (PCI), completeness of cytoreduction (CC), operative time, morbidity and mortality of patients submitted to IPHC have been considered. RESULTS: From May 2001 to December 2004, 10 patients were submitted to peritonectomy and IPHC: 9 (90%) females and 1 (10%) male, aged from 49 to 72 years. Seven patients (70%) were affected of peritoneal carcinomatosis from ovarian tumor, three patients (30%) from colon cancer. The PCI was ranged from 8 to 25. The operative time was ranged from 6 to 14 hours. Two patients with a CC of 2 developed relaps and died respectively after 2 and 4 months. The remaining patients had a CC between 0 and 1. Of these last patients, 1 affected by ovarian cancer died 24 months after, 1 patient died 3 days after surgery for septic shock; the other patients are still alive with a period ranged from 1 to 30 months. CONCLUSIONS: Our preliminary results suggest that the peritonectomy and IPHC can be effective only in patients with CC of 0 or 1, in the remaining cases these therapeutical methods should be avoided.

Fetal cells in maternal blood: a six-fold increase in women who have undergone amniocentesis and carry a fetus with Down syndrome: a multicenter study.

Fetal nucleated red blood cells (FNRBCs) circulate in the maternal blood throughout pregnancy. Even if the frequency of fetal cells in the maternal circulation remains to be ascertained, complications of pregnancy such as fetal cells aneuploidies, preeclampsia, abnormal Doppler of the uterine artery without symptoms of preeclampsia, fetal growth restriction and polyhydramnios are associated with an increased feto-maternal trafficking. Based on these observations, previous studies have suggested that determination of the fetal nucleated red blood cell count (FNRBCC) might be a useful non-invasive screening test, either alone or in combination with existing maternal tests, for the non-invasive assessment of aneuploidies, in particular Down syndrome (DS). In this paper we have evaluated the distribution of FNRBCC in a set of 18 normal pregnancies and 18 pregnancies with a trisomy 21-affected fetus, matching for gestational age, maternal age, and, when possible, fetal gender, in order to quantify the difference in the number of fetal cells between the two populations. Maternal blood was collected from each pregnant woman two to three weeks after amniocentesis after knowing the cytogenetic results. Correlation of FNRBCC with the gestational week and clinical status (affected vs. non affected) by multiple regression analysis provided significant results (p < 0.001). Adjusted values of FNRBCC were 48 +/- 10.2 in controls and 301 +/- 17.01 in DS cases, corresponding to a 6.27 fold increase. These retrospective results prompt a prospective evaluation of the use of FNRBCC for screening purposes.

Colorectal endometriosis: aggressive surgical management and practical considerations in a patient with advanced disease.

The aim of this study was to evaluate the results of bowel resection in a patient with obstructive colorectal endometriosis. The presentation will acquaint the physician with the signs and symptoms, evaluation, and surgical treatment of colorectal endometriosis. We emphasize that our findings strongly support an aggressive surgical approach with resection for all visible cases of colorectal endometriosis in women with advanced disease.

Piver's radical hysterectomy (type III): Endo-Gia 30 stapler versus traditional forcipressure for resection of the cardinal ligament.

OBJECTIVE: Morbidity and costs associated with Piver's radical hysterectomy (type III) are noteworthy. The Endo-Gia stapler method for resection of cardinal ligaments can reduce duration of surgery and hospitalization, blood loss, costs and postoperative infection rates. METHOD: Two groups of patients (homogeneous for age, weight and medical condition) were studied: one group was operated on using the Endo-Gia stapler method (n=52) and the other with the traditional forcipressure (n=13). The size of parametrial tissue removed, blood loss, duration of surgery, duration of hospitalization, cost of materials and postoperative fever were compared in the two groups. RESULT: Mean operative times were lower in the Endo-Stapler group than in the controls (mean 180 min versus 220 min). Mean blood loss was 300 cc in the stapler group versus 450 cc in the forcipressure group. Mean cost of surgery (considering costs of materials, hospital stay. duration of surgery), was lower in the stapler group (3,095 euros) than in the group who underwent traditional surgery (3,434 euros). CONCLUSION: Our data suggest the Endo-Gia stapler method significantly reduces blood loss, operative time and cost.

Goserelin acetate to avoid hysterectomy in pre-menopausal women with fibroids requiring surgery.

OBJECTIVE: To obtain information on the efficacy of repeated short cycles of GNRH agonist treatment in order to avoid hysterectomy in near-menopausal women with symptomatic fibroids. STUDY DESIGN: 72 pre-menopausal women (mean age 50 years) with one or more uterine fibroids >10 cm in diameter, symptomatic menorrhagia lasting three months or more and haemoglobin=9 g/dl entered the study. The patients were randomized with ratio of approximately 1:4 to: (a) immediate surgery; or (b) treatment with goserelin acetate. Patients randomized to goserelin acetate received a first cycle of 3.6 mg depot once every 28 days for four months. They were followed-up for three years. If menorrhagia was observed during the follow-up the woman was given goserelin acetate 3.6 mg depot for another three months. In case of further menorrhagia, a third cycle of goserelin acetate 3.6 mg depot for three months was given. After the third cycle of therapy if there was still menorrhagia, the patient underwent hysterectomy plus bilateral oophorectomy. RESULTS: A total of 13 women were assigned to the immediate surgery group and 59 to goserelin. Three years after trial entry a total of 23 women allocated to goserelin acetate treatment had undergone hysterectomy. CONCLUSION: This study suggests that GNRH agonists are efficacious for avoiding hysterectomy in women near menopause with uterine fibroids.

Epidemiology of cesarean sections: prolonged pregnancy.

The management of prolonged pregnancy is controversial when the cervix is not favourable to induction. From the results obtained by using topical PgE2 in postterm patients with unfavourable cervix, it is possible to conclude that in those subjects with preliminary cervical modifications (Bishop Score > 1) a regular onset of labour and spontaneous delivery were obtained. Conversely a high incidence of failure was shown in those subjects with no cervical maturation (BS = 0).