Christina Fotopoulou

Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up N. Colombo, M. Peiretti, G. Parma, M. Lapresa, R. Mancari, S. Carinelli, C. Sessa & M. Castiglione On behalf of the ESMO Guidelines Working Group* Division of Gynecologic Oncology; Division of Pathology, European Institute of Oncology, Milan, Italy; Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Montabone Unit for New Drug Development, Fondazione IRCCS, Istituto dei Tumori di Milano, Milan, Italy; RGT, University of Geneva, Geneva, Switzerland

Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms.

BACKGROUND Tryptophan (Trp) is catabolized by indoleamine 2,3-dioxygenase (IDO). Changes in Trp metabolism and IDO activity in chronic kidney disease (CKD) have not been widely studied, and the impact of haemodialysis is uncertain. Here we investigate Trp catabolism, IDO activity and the role of inflammation in moderate to very severe CKD and haemodialysis. METHODS Eighty individuals were included in a prospective blinded endpoint analysis. Using tandem mass spectrometry, serum levels of Trp, kynurenine (Kyn), kynurenic-acid (Kyna), quinolinic-acid (Quin), 5-hydroxytryptophan (OH-Trp), serotonin (5-HT), estimated IDO activity and inflammatory markers were assessed in 40 CKD patients (age 57 +/- 14 years, 21 male, creatinine 4.5 +/- 2.7, n = 17 receiving haemodialysis), and in 40 healthy controls (age 34 +/- 9 years, 26 male). RESULTS Trp levels were unchanged in CKD (P = 0.78 versus controls). Serum levels of Kyn, Kyna and Quin increased with CKD severity (stages 4, 5 versus controls all P < or = 0.01). IDO activity was significantly induced in CKD and correlated with disease severity (stages 3-5 versus controls, all P < or = 0.01) and inflammatory markers [high-sensitivity C-reactive protein (hsCRP), soluble TNF-receptor-1 (sTNFR-I); both P < or = 0.03]. IDO products (Kyn, Kyna, Quin) correlated also with hsCRP and sTNFR-I (all P < or = 0.04). Haemodialysis did not influence IDO activity (P = 0.26) and incompletely removed Kyn, Kyna, Quin, OH-Trp and 5-HT by 22, 26, 50, 44 and 34%, respectively. In multiple regression, IDO activity correlated with hsCRP and sTNFR-I (both P < or = 0.03) independent of serum creatinine, age and body weight. CONCLUSIONS IDO activity and serum levels of tryptophan catabolites of the kynurenine pathway increase with CKD severity. In CKD, induction of IDO may primarily be a consequence of chronic inflammation.

Balanced crystalloid compared with balanced colloid solution using a goal-directed haemodynamic algorithm

BACKGROUND Controversy exists regarding the optimal i.v. fluids for use with a goal-directed haemodynamic algorithm. METHODS In a double-blind pilot study, we randomly assigned 50 patients with primary ovarian cancer undergoing cytoreductive surgery to receive either balanced crystalloid or balanced starch (HES, 130/0.4, 6%) solutions up to the dose limit (50 ml kg(-1)). Fluids were administered to optimize stroke volume measured by oesophageal Doppler within a goal-directed haemodynamic algorithm. RESULTS Baseline subject characteristics were similar in both groups. The balanced HES solution maintained stroke volume (P=0.012) better with administration of less fluid. Subjects in the colloid group reached the dose limits of the study medication less frequently (92% vs 62%, P=0.036) and later (2:26 vs 3:33 h, P=0.006) and also required less transfusion of fresh-frozen plasma units (6.0 vs 3.5 units, P=0.035) compared with the crystalloid group. Intra- and postoperative urine output and perioperative plasma levels of creatinine and neutrophil gelatinase-associated lipocalin as renal injury marker were similar in both groups. No differences in the length of intensive care unit and hospital stay were found. CONCLUSIONS Using a goal-directed haemodynamic algorithm to optimize stroke volume, a balanced HES solution is associated with better haemodynamic stability and reduced need for fresh-frozen plasma. There were no signs of renal impairment by colloid solutions when fluid administration is targeted to optimize cardiac preload.

Intra‐abdominal tumor dissemination pattern and surgical outcome in 214 patients with primary ovarian cancer

We performed a systematic evaluation of tumor pattern and surgical outcome in 214 consecutive patients with primary ovarian cancer.

Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period

PURPOSE To prospectively analyse the pharmacokinetics of lamotrigine (LTG) during pregnancy and lactation in a consecutive series of epileptic pregnant women. METHODS Nine women on LTG-monotherapy were studied during pregnancy, delivery and lactation, until a mean of 3 weeks postpartum. Maternal blood samples were available from all trimesters as well as umbilical cord blood samples of the newborn 24 and/or 48 h postpartum. In 4 cases we additionally determined the LTG-concentration in breast milk. RESULTS The median LTG-clearance was elevated by 197% during the first trimester, 236% and 248% during the second and third trimester respectively. A maximum of 264% was reached at delivery. An average LTG-dose increase by 250% had to be undertaken in order to obtain therapeutic serum levels. In puerperium LTG-clearance decreased again to reach the initial concentrations approximately at the third week postpartum. The median LTG-concentration ratio of the umbilical cord blood to maternal serum was 1.01 (range: 0.56-1.42), while the median LTG-concentration ratio of breast milk to maternal serum was 0.59 (range: 0.35-0.86). DISCUSSION Our study confirms the therapeutic relevant changes of LTG-clearance during pregnancy and lactation in women on LTG-monotherapy. Since LTG crosses the placenta, a close monitoring of both mother and newborn is indispensable.

The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids.

The epithelial lining of the fallopian tube is of critical importance for human reproduction and has been implicated as a site of origin of high-grade serous ovarian cancer. Here we report on the establishment of long-term, stable 3D organoid cultures from human fallopian tubes, indicative of the presence of adult stem cells. We show that single epithelial stem cells in vitro can give rise to differentiated organoids containing ciliated and secretory cells. Continuous growth and differentiation of organoids depend on both Wnt and Notch paracrine signalling. Microarray analysis reveals that inhibition of Notch signalling causes downregulation of stem cell-associated genes in parallel with decreased proliferation and increased numbers of ciliated cells and that organoids also respond to oestradiol and progesterone treatment in a physiological manner. Thus, our organoid model provides a much-needed basis for future investigations of signalling routes involved in health and disease of the fallopian tube.

Incidence of Venous Thromboembolism in Patients With Ovarian Cancer Undergoing Platinum/Paclitaxel–Containing First-Line Chemotherapy: An Exploratory Analysis by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group

PURPOSE Venous thromboembolism (VTE) has been associated with negative prognosis in cancer patients. Most series reporting on VTE have included different tumor types not differentiating between recurrent or primary disease. Data regarding the actual impact of VTE on primary advanced ovarian cancer (AOC) are limited. PATIENTS AND METHODS Between 1995 and 2002, the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study group (AGO-OVAR) recruited 2,743 patients with AOC in three prospectively randomized trials on platinum paclitaxel-based chemotherapy after primary surgery. Pooled data analysis was performed to evaluate incidence, predictors, and prognostic impact of VTE in AOC. Survival curves were calculated for the VTE incidence. Univariate analysis and Cox regression analysis were performed to identify independent predictors of VTE and mortality. RESULTS Seventy-six VTE episodes were identified, which occurred during six to 11 cycles of adjuvant chemotherapy; 50% of them occurred within 2 months postoperatively. Multivariate analysis identified body mass index higher than 30 kg/m(2) and increasing age as independent predictors of VTE. International Federation of Gynecology and Obstetrics stage and surgical radicality did not affect incidence. Overall survival was significantly reduced in patients with VTE (median, 29.8 v 36.2 months; P = .03). Multivariate analysis identified pulmonary embolism (PE), but not deep vein thrombosis alone, to be of prognostic significance. In addition, VTE was not identified to significantly affect progression-free survival. CONCLUSION Patients with AOC have their highest VTE risk within the first 2 months after radical surgery. Only VTE complicated by symptomatic PE have been identified to have a negative impact on survival. Studies evaluating the role of prophylactic anticoagulation during this high risk postoperative period are warranted.

Functional and anatomic results of amnion vaginoplasty in young women with Mayer-Rokitansky-Küster-Hauser syndrome

OBJECTIVE To evaluate the surgical outcome and the long-term anatomic and functional results in young women with Mayer-Rokitansky-Küster-Hauser Syndrome (MRKH) undergoing neovaginal creation with amniotic membranes. DESIGN Evaluation of surgical and functional outcome according to clinical records and validated questionnaires about sexuality (Female Sexual Function Index [FSFI]) over a 1.5-year follow-up period. SETTING University hospital and referral center for pediatric and adolescent gynecology. PATIENT(S) Seven patients with congenital vaginal aplasia with a mean age of 20.86 +/- 3.56 years (range 17-26 years). INTERVENTION(S) McIndoe procedure modified by the application of human freeze-dried amniotic membranes. MAIN OUTCOME MEASURE(S) Anatomic success was defined by a vaginal length >or=8 cm, and a width allowing the easy introduction of two fingers. FSFI scores were applied to define functional results. RESULT(S) Mean neovaginal length was 9.3 cm (range 4-12 cm). The mean FSFI score was 30.0 +/- 6.9. Major operative complications occurred in one patient. In six out of seven patients satisfactory anatomic and functional results were achieved. CONCLUSION(S) The surgical dissection of the vesicorectal space and the application of human amnion over a vaginal mold to create a neovagina results in satisfying anatomic and functional outcome with low perioperative morbidity in MRKH patients.

Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort

Background:This study aims to identify prognostic factors and to develop a risk model predicting survival in patients undergoing secondary cytoreductive surgery (SCR) for recurrent epithelial ovarian cancer.Methods:Individual data of 1100 patients with recurrent ovarian cancer of a progression-free interval at least 6 months who underwent SCR were pooled analysed. A simplified scoring system for each independent prognostic factor was developed according to its coefficient. Internal validation was performed to assess the discrimination of the model.Results:Complete SCR was strongly associated with the improvement of survival, with a median survival of 57.7 months, when compared with 27.0 months in those with residual disease of 0.1–1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P<0.0001). Progression-free interval (⩽23.1 months vs >23.1 months, hazard ratio (HR): 1.72; score: 2), ascites at recurrence (present vs absent, HR: 1.27; score: 1), extent of recurrence (multiple vs localised disease, HR: 1.38; score: 1) as well as residual disease after SCR (R1 vs R0, HR: 1.90, score: 2; R2 vs R0, HR: 3.0, score: 4) entered into the risk model.Conclusion:This prognostic model may provide evidence to predict survival benefit from secondary cytoreduction in patients with recurrent ovarian cancer.

Role of secondary cytoreductive surgery in ovarian cancer relapse: who will benefit? A systematic analysis of 240 consecutive patients.

In contrast to primary ovarian cancer, the value of surgery in relapsed‐OC (ROC) remains unclear. We evaluated surgical and clinical outcome of secondary cytoreduction in ROC.