Survival Outcomes of Epithelial Ovarian Cancer Patients Following Dose-dense Versus 3-Weekly Platinum-Paclitaxel Chemotherapy: A Meta-Analysis.

AIMS: Dose-dense chemotherapy has proven its value in several cancer fields. The purpose of the present systematic review is to evaluate the impact of dose-dense chemotherapy on survival outcomes of epithelial ovarian cancer patients. MATERIALS AND METHODS: Medline, Scopus, the Cochrane Central Register of Controlled Trials CENTRAL, Google Scholar and Clinicaltrials.gov databases were searched for relevant articles. Effect sizes were calculated in Rstudio using the meta and metafor functions. A sensitivity analysis was carried out to evaluate the possibility of small study effects and P-hacking. The methodological quality of the included studies was assessed using Risk of Bias 2 (RoB2) and Risk of Bias in non-Randomized Trials (RoBINS) tools. RESULTS: Overall, 12 studies were included in the present systematic review, involving 4979 epithelial ovarian cancer patients. The risk of recurrence was substantially improved in patients receiving dose-dense chemotherapy (hazard ratio 0.82, 95% confidence interval 0.70, 0.96); however, the result of the meta-analysis may be attributed to the effect size of smaller studies as following adjustment for small study effects the outcome becomes non-significant (hazard ratio 0.91, 95% confidence interval 0.81, 1.02, P = 0.123). Overall survival rates were not improved by dose-dense chemotherapy (hazard ratio 0.79, 95% confidence interval 0.60, 1.04). Thirty-five types of adverse effect were identified following retrieval of data from the original studies. Dose-dense chemotherapy did not increase significantly the rates of severe adverse effects, although thrombosis, severe diarrhoea and severe nausea were more prevalent in this group of patients. CONCLUSION: Dose-dense chemotherapy is associated with comparable side-effects to those of standard chemotherapy; however, data related to survival outcomes are not positive; hence, its use outside the setting of clinical trials should be discouraged.

Ocular metastasis of primary gynecological malignancies, a rare but not insignificant entity: A systematic review.

The genital system remains one of the most common sites of carcinogenesis in women. Advances in surgery, radiation treatment, and chemotherapy have increased their efficacy and many patients survive for many years after their initial diagnosis. The eye is a rare site of metastasis from gynecological cancer due to its distant location from the genitalia. In this systematic review, we retrieved all case reports of patients with ocular metastasis from gynecological neoplasms. The demographic, clinical, and treatment characteristics were retrieved and analyzed. A total of 70 case reports were included. Forty-eight of these reports concerned patients with a known malignancy that recurred in the eye and in 22 patients' ocular symptomatology accompanied the initial diagnosis of the gynecologic malignancy. 73.9% of these patients exhibited concomitant metastasis to other organs. The mean disease-free interval was found at 25.7 months and mean survival time after the eye metastasis was 13.5 months. Refractory disease was identified as the most important risk factor associated with mortality. Because eye metastasis has such a dismal prognosis, all gynecologists who treat oncological patients should be highly suspicious for reported eye complaints.

Neutrophil-to-lymphocyte ratio and chemotherapy response score as prognostic markers in ovarian cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is the recommended approach in patients with advanced epithelial ovarian cancer (EOC). However, most patients eventually relapse despite the initial high response rate to chemotherapy. Neutrophil-to-lymphocyte ratio is a well-known biomarker that reflects severe inflammation, critical illness, and mortality in various diseases. Chemotherapy response score (CRS) and neutrophil-to-lymphocyte ratio (NLR) have been identified as potential biomarkers of platinum resistance and disease prognosis. We retrospectively evaluated 132 patients with stage IIIc or IV ovarian/fallopian tube/primary peritoneal cancer who had received NACT followed by IDS from 01/01/2003 to 31/12/2018. CRS was assessed on omental specimens collected from IDS according to ICCR guidelines. RESULTS: Median age was 64.57 years (SD: 9.72; range 39.2-87.1). Most ovarian tumors were serous epithelial (90.9%; 120/132). An elevated NLR (defined as > 3) was observed in 72% (95/132) of patients in contrast with 28% (37/132) of patients characterized by low NLR status. Median PFS (mPFS) and median overall survival (mOS) were 13.05 months (95% CI: 11.42-14.67)) and 34.69 months (95% CI: 23.26-46.12) respectively. In univariate analysis, CRS3 score was significantly associated with prolonged mPFS (CRS1/2: 12.79 months vs CRS3: 17.7 months; P = 0.008). CRS score was not associated with mOS (P = 0.876). High NLR was not significantly associated with mPFS (P = 0.128), however it was significantly associated with poor mOS (P = 0.012). In multivariate analysis, only performance of surgery maintained its statistical significance with both PFS (P = 0.001) and OS (P = 0.008). CONCLUSION: NLR could serve as a useful predictor of OS but not PFS in ovarian cancer patients receiving NACT. In accordance with our previous study, CRS score at omentum was found to be associated with PFS but not OS in ovarian cancer patients treated with NACT and IDS.

Biomarkers that would predict response to neoadjuvant chemotherapy in advanced ovarian cancer patients are eagerly needed:• Neutrophil to Lymphocyte Ratio (NLR) is an indicator of systemic inflammatory response to the malignancy.• NLR was evaluated in 132 patients undergoing Neoadjuvant Chemotherapy for advanced ovarian cancer.• Elevated NLR was associated with worse prognosis.• No association between NLR and response to chemotherapy was noted.

Efficacy of 5% imiquimod for the treatment of Vaginal intraepithelial neoplasia-A systematic review of the literature and a meta-analysis.

Vaginal intraepithelial neoplasia (VaIN) is an uncommon disease associated with HPV and is considered to be a precursor of vaginal carcinoma. To date, treatment recommendations vary with no universally accepted standard of care as best treatment modality. Nevertheless, 5% imiquimod appears to be a promising, alternative, non-invasive treatment option. To ascertain the efficacy of 5% imiquimod for the treatment of this rare condition, we conducted a systematic review and meta-analysis of the proportion of women who received 5% imiquimod with their complete response, HPV clearance and recurrence rates. A literature search was carried out throughout the PubMed, EMBASE, ClinicalTrials.gov and Cochrane Databases for relevant studies. We computed the summary proportions for complete response, HPV clearance and non-recurrence following administration of 5% imiquimod by random effects meta-analysis. Six articles reporting on 94 patients were included. The summary proportions of women with complete response and HPV clearance were 76.5% (95% CI 59.4-98.5) and 52.5% (95% CI 29.5-93.6) respectively. The summary proportion of women with non-recurrence appeared high (94.3% (95% CI 67.1-132)), yet not significant. Use of 5% imiquimod for the treatment of VaIN is associated with relatively high response rate, satisfactory HPV clearance, whilst the risk for VaIN recurrence appears low.

Molecular aspects and clinical methods for preserving ovarian reserves in women receiving cancer treatment.

Cancer prevalence is high, and of importance to cancer sufferers is the long term survival and normal activities resumption. Moreover, pregnancy is drawing interest for preserving ovarian reserves in post-chemotherapy affected women, especially of younger ages. The gonadotoxic effect of cancer treatment, involves mechanisms that are not fully understood, mainly due to the variety of molecular pathways triggered once therapeutic agents applied. Reported rates of premature ovarian failure after the treatment effect and the application of various treatment protocols, differ extensively due to the protocol itself but also due to the age of treated patients. Several options for preserving ovarian reserves are currently employed in the clinique, such as ovarian transposition, embryos cryopreservation and the use of gonadotropin-releasing hormone (GnRH) and its agonists/antagonists, but most of them are still under investigation. This paper reviews these methods and the molecular mechanisms that are possibly involved in the action of agents such as GnRH.

MRI findings before and after abdominal radical trachelectomy (ART) for cervical cancer: a prospective study and review of the literature.

AIM: To report the authors' experience with dedicated pelvic magnetic resonance imaging (MRI) in young women with early-stage cervical cancer treated with abdominal radical trachelectomy (ART). MATERIALS AND METHODS: During a 5-year period, 21 patients, with biopsy-confirmed cervical carcinoma, International Federation of Gynaecology and Obstetrics (FIGO) stage ≤IB1, were considered for trachelectomy. All patients underwent pelvic MRI within 30 days prior to surgery. Tumour size, endocervical extension, extrauterine spread, and nodal status were noted. Postoperative MRI findings were reviewed in 16 patients. RESULTS: Nineteen of the 21 patients were treated with ART. In two patients, trachelectomy was aborted intraoperatively and radical hysterectomy was performed; preoperative MRI findings were consistent with surgicopathological examination in both patients. MRI correctly assessed tumour size in 18/21 patients, coming within 5 mm of the surgical specimen. Tumour size was underestimated in two cases because of circumferential growth (n = 1) or technical difficulties (n = 1). False-positive MRI result was due to post-biopsy inflammation (n = 1). MRI accurately identified absence of internal os involvement in 17/19 ART patients; false-positive MRI for internal os involvement were due to endocervical polyp (n = 1) and coexisting Nabothian cysts (n = 1). No trachelectomy patient had extrauterine disease or malignant nodes at MRI or final histology. Post-trachelectomy complications included hydrosalpinges (n = 3), lymphocysts (n = 2), isthmic stenosis (n = 1), and tumour relapse (n = 2). CONCLUSIONS: Dedicated pelvic MRI is helpful in assessing tumour size and endocervical extension in young women, candidates for ART. Hydrosalpinx may occur after ART and it may influence fertility potential.

VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2.

BACKGROUND: Vascular endothelial growth factor action in tumour angiogenesis is well characterised; nevertheless, it functions as a key element in the promotion of the immune system's evasion by tumours. We sought to investigate the possible direct effect of VEGF on T-cell activation and through which type of VEGF receptor it exerts this effect on cells isolated from ovarian cancer patients' ascites. METHODS: T cells isolated from the ascites of ovarian cancer patients were cultured with anti-CD3 and IL-2, with or without VEGF for 14 days and the number of viable T cells was counted. Cytotoxic activity of cultured T cells and expression of VEGF receptor-2 (VEGFR-2), was assayed. RESULTS: The addition of VEGF in cultures significantly reduced the number and proliferation rate of T cells in a dose-dependent manner and CD3(+) T cells expressed VEGFR-2 on their surface upon activation. Experiments with specific anti-VEGFR-2 antibodies revealed that the direct suppressive effect of VEGF on T-cell proliferation is mediated by VEGFR-2. We also showed that VEGF significantly reduced the cytotoxic activity of T cells. CONCLUSION: Our study showed that ascites-derived T cells secrete VEGF and express VEGFR-2 upon activation. Vascular endothelial growth factor directly suppresses T-cell activation via VEGFR-2.

Safety of hormone replacement therapy in gynaecological cancer survivors.

Therapy for endometrial, ovarian and cervical cancer in young women can cause sudden onset of intense menopausal symptoms, such as hot flushes, emotional disorders and sexual dysfunction. In order to overcome these unpleasant and sometimes severe symptoms, hormone replacement therapy (HRT) has proven to be very effective. However, its safety remains controversial. We reviewed English literature and examined whether administration of HRT in this specific population is related with more recurrences and worse prognosis. Current scientific data, comprising mainly retrospective studies, suggest that recurrence rates and survival are comparable between HRT users and non-users. However, large randomised trials are missing and definitive conclusions cannot be drawn. Gynaecological cancer survivors using HRT, although they seem to have little if any risk for recurrence, should be correctly informed about the lack of strong evidence.

Prognostic evaluation of tumour type and other histopathological characteristics in advanced epithelial ovarian cancer, treated with surgery and paclitaxel/carboplatin chemotherapy: cell type is the most useful prognostic factor.

AIM: Ovarian carcinomas have been classified into types I and II according to the hypothesised mode of carcinogenesis and molecular characteristics. The prognostic significance of this classification has not been studied. PATIENTS AND METHODS: Five hundred and sixty-eight patients with histologically confirmed, ovarian, fallopian tube or peritoneal carcinomas, international federation of gynecology and obstetrics (FIGO) stages IIC-IV, treated with paclitaxel/platinum following cytoreductive surgery, were included in this analysis. Type I included low-grade serous, mucinous, endometrioid and clear-cell and type II high-grade serous, unspecified adenocarcinomas and undifferentiated carcinomas. RESULTS: Median overall survival (OS) was 49 months for type I versus 45 for type II (p=0.576). In contrast to type II, there was considerable prognostic heterogeneity among the subtypes included in type I. Cox regression analysis showed that cell-type classification: low-grade serous, mucinous, endometrioid, clear-cell, type II (high-grade serous, unspecified adenocarcinomas, undifferentiated carcinoma) was an independent predictor of survival (respective median OS 121 versus 15 versus 64 versus 29 versus 45 months, p=0.003). On the contrary, histopathological subtype or tumour type (I versus II) did not offer additional prognostic information. CONCLUSION: The proposed model of ovarian tumourigenesis does not reflect tumour behaviour in advanced disease. Tumour-cell type is the most relevant histopathological prognostic factor in advanced ovarian cancer treated with platinum/paclitaxel.

Prognostic factors for early-stage epithelial ovarian cancer, treated with adjuvant carboplatin/paclitaxel chemotherapy: a single institution experience.

OBJECTIVE: Early-stage epithelial ovarian cancer represents a prognostically heterogenous group. We studied prognostic factors in patients treated with adjuvant paclitaxel/carboplatin chemotherapy. METHODS: Data was extracted from 147 patients with FIGO stage IA/IB, grade 2/3 or stage IC/IIA (any grade) who underwent primary surgery followed by paclitaxel/carboplatin chemotherapy. RESULTS: Median follow-up was 88 months. Ten-year relapse-free (RFS) and disease-specific survival (DSS) were: 81% (95% confidence interval [CI]: 73-89) and 81% (95% CI: 73-89). On multivariate analysis, non serous histology was associated with reduced risk for RFS (0.294, 95% CI: 0.112-0.577, p=0.001) and DSS (0.194, 95% CI: 0.075-0.504, p=0.001), while high-risk category (stage IC/IIA and grade 2/3) with increased risk for RFS (3.989, 95% CI: 1.189-13.389, p=0.009) and DSS (3.989, 95% CI: 1.064-16.386, p=0.038). The combination of histology and grade identified 3 groups with distinctly different 10-year RFS and DSS rates (p<0.001): grade 1 (100% and 100%), non-serous grade 2/3 (83% and 86%) and serous grade 2/3 (60% and 60%). CONCLUSIONS: Serous histology is an adverse prognostic factor in early-stage ovarian cancer treated with adjuvant paclitaxel/carboplatin. Risk stratification according to histology and grade is a useful discriminator of prognosis and can be used in the design of future studies.

Metastatic medullary carcinoma of the vulva in a patient with MEN IIb syndrome.

BACKGROUND: Multiple endocrine neoplasia (MEN) IIb is a rare genetic syndrome characterized by the occurrence of medullary thyroid carcinoma (MTC), pheochromocytoma and mucosal neuromas. CASE REPORT: A 43-year-old woman with MEN IIb syndrome presented to our department with a painful enlargement of the left side of her vulva, which was initially presumed to be an inflammatory Bartholin's gland process. Upon admission, the patient was on antibiotics with no response and surgery was decided. A wide local excision was performed and histology revealed a metastatic medullary carcinoma of the vulva. CONCLUSION: MEN IIb syndrome is a clinical entity that may present multiple metastatic sites. To our knowledge, this is the first case of vulvar metastasis as part of the syndrome.

Amniotic fluid interleukin-18 at mid-trimester genetic amniocentesis: relationship to intraamniotic microbial invasion and preterm delivery.

OBJECTIVE: To determine the value of amniotic fluid interleukin-18 (AF IL-18) in the diagnosis of microbial invasion of the amniotic cavity and prediction of preterm delivery (PTD). DESIGN: Analysis of the results of AF collected prospectively following genetic amniocentesis between February 2006 and September 2007. SETTING: A tertiary referral centre for fetal medicine. METHODS: Following amniocentesis, a sample of amniotic fluid was transferred to the laboratory for aerobic and anaerobic bacterial cultures, Ureaplasma urealyticum culture and IL-18 assays. All women who delivered preterm (<37 weeks of gestation) formed the study group. The control group consisted of the two subsequent women who also underwent amniocentesis during the same time period and delivered a normal neonate at term, matched for maternal age, parity and indication for amniocentesis. MAIN OUTCOME MEASURES: The relationship between AF IL-18 levels and the risk of both microbial invasion of the amniotic cavity and PTD. RESULTS: Forty-eight women who delivered preterm (<37 weeks) were matched with 96 controls. The preterm delivery group had significantly higher concentrations of IL-18 (median=609 pg/ml, interquartile range: 445.7-782.7) compared to controls (median=322.1 pg/ml, interquartile range: 277.7-414.4), (P<0.001). IL-18 level was also significantly higher (P<0.001) in cases with positive amniotic fluid cultures (median=697.7, interquartile range: 609.0-847.2) compared to those with negative ones (median=330.9 pg/ml, interquartile range: 235.2-440.8). CONCLUSIONS: Elevated mid-trimester concentrations of AF IL-18 can identify women at risk for intraamniotic infection and spontaneous PTD.

Extrauterine pregnancy resulting from late spontaneous rupture of an unscarred gravid uterus: case report.

PURPOSE: Rupture of the unscarred grand uterus is a rare obstetric event associated with major perinatal mortality and a high incidence of maternal mortality and morbidity, particularly peripartum hysterectomy. METHODS & RESULTS: We present the case of a primigravida woman who was admitted at 38 weeks of gestation complaining of intermittent abdominal pain and vaginal bleeding. Although initial evaluation suggested that both mother and fetus were doing well, continuous assessment resulted in cesarean section due to variable decelerations and increasing abdominal pain. An unexpected abdominal pregnancy was discovered resulting from a complete uterine rupture. A healthy infant was delivered and hysterectomy was performed. CONCLUSION: Although extrauterine advanced abdominal pregnancy resulting from late uterine rupture is associated with high maternal and perinatal mortality, a high index of suspicion, close surveillance and ultrasonography can achieve good outcome for both mother and infant. We strongly believe, that this case report contributes to the insight and further knowledge of this rare pregnancy complication.

Recurrent cervical cancer presenting as malignant pericarditis: case report and review of the literature.

Ante-mortem diagnosed metastatic pericardial effusion in cervical cancer patients is very rare. Symptomatic relief and treatment of the underlying disease offered by a multidisciplinary team, may prolong survival with a good quality of life to these often young patients.

Primary endometrial squamous cell carcinoma.

Primary squamous cell carcinoma of the endometrium (PESCC) is rare and its pathogenesis is unclear. Identification of PESCC and its differentiation from endometrial involvement by squamous cell carcinoma is essential for correct patient management and is based on strict pathological criteria. We present a case of a 71-year-old patient satisfying the proposed diagnostic criteria for PESCC together with a review of the literature.

The effect of epithelial and stromal tumor components on FIGO stages III and IV ovarian carcinosarcomas treated with primary surgery and chemotherapy.

The aim of this study is to assess the effect of epithelial and stromal tumor components on survival outcomes in FIGO stage III or IV ovarian carcinosarcomas (OCS) treated with primary surgery and adjuvant chemotherapy at the Northern Gynaecological Oncology Centre (NGOC), Gateshead. Women were identified from the histopathology/NGOC databases. Age, FIGO stage, details of histology, treatment, and overall survival were recorded. Of 34 cases (1994-2006, all FIGO stages), 17 were treated with primary surgery followed by adjuvant chemotherapy for FIGO stage III or IV. The median age was 66 years (52-85 years). Cytoreduction was optimal (n= 9) or complete (n= 1) in 10/17 (59%) cases. Epithelial predominant (EP) or stromal predominant (SP) tumor (defined as >50% of either component in the primary tumor) was noted in 12 and 5 cases, respectively. Epithelial types included serous (n= 9), endometrioid (n= 5), and mixed types (n= 3). Twelve women have died of disease. The median overall survival was 11.0 months (3-74 months). On univariate analysis, survival was not affected by optimal/suboptimal debulking, platinum/doxorubicin-containing chemotherapy, or homologous/heterologous stromal components. Stromal components (>25%) adversely affected survival (P= 0.02), and there was a trend to worse survival with serous compared with nonserous epithelial components (P= 0.07). Cox regression (multivariate analysis) showed that SP tumors (P= 0.04), suboptimal debulking (P= 0.01), age (P= 0.01), and tumors with serous epithelial component (P= 0.05) were adverse independent prognostic factors. Type of chemotherapy and homologous/heterologous components (P= 0.24) did not affect overall survival. In conclusion, our study suggests that SP-OCS have a worse survival outcome than EP tumors. Tumors with serous epithelial components adversely affected the survival compared with nonserous components. Larger studies are required to confirm these effects and to identify the optimum chemotherapy regimen for OCS.

Cesarean vs. vaginal birth for term breech presentation in 2 different study periods.

OBJECTIVE: To compare outcomes for fetuses at term in breech presentation during 2 periods when different delivery policies were in effect. METHODS: Outcomes of the 392 planned vaginal deliveries and 1160 elective cesarean sections (CSs) performed from January 1, 1988, through December 31, 2000, were compared with those of the 24 emergency vaginal deliveries, the 403 planned CSs, and 75 emergency CSs performed from January 1, 2001 through December 31, 2004 at Alexandra Hospital, Athens, Greece. RESULTS: A significant difference was found in rates of low 5-minute Apgar score, birth trauma, serious neonatal morbidity, and admission to the neonatal intensive care unit (0% vs. 1.02% [P=0.004], 1.02% vs. 0% [P=0.004], 3.06% vs. 0.43% [P<0.001], and 2.8% vs. 0.43% [P<0.001], respectively) between neonates born by planned vaginal delivery and those born by elective CS during the first period. Only a reduction in rates of admission to the neonatal intermediate care unit was found between the first and second periods. CONCLUSIONS: Planned CS was found to be safer than planned vaginal delivery for fetuses at term in breech presentation. However, the study did not demonstrate that the change in policy improved neonatal outcome.

Assessment of ovarian tumors using transvaginal color Doppler ultrasonography.

In our study we used transvaginal color Doppler ultrasonography in a token of 127 women presenting with unilateral ovarian tumor. The characteristics of the tumors were analyzed, the presence of vascularization was checked and the resistance index (RI) was calculated. Consequently, based on a concrete scoring system, we attempted to discriminate these tumors as benign or malignant. It was proven that 24 of 127 ovarian tumors were malignant. Transvaginal color Doppler correctly identified 21 of the 24 malignant tumors, as well as 94 of the 103 benign tumors. In nine other cases we had false-positive results. The sensitivity and the specificity of the method was 87.5% and 91.2%, while the positive and negative predictive values were 70% and 96.9%, respectively.