Molecular and phenotypic characteristics influencing the degree of cytoreduction in high-grade serous ovarian carcinomas.

BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the deadliest ovarian cancer subtype, and survival relates to initial cytoreductive surgical treatment. The existing tools for surgical outcome prediction remain inadequate for anticipating the outcomes of the complex relationship between tumour biology, clinical phenotypes, co-morbidity and surgical skills. In this genotype-phenotype association study, we combine phenotypic markers with targeted DNA sequencing to discover novel biomarkers to guide the surgical management of primary HGSOC. METHODS: Primary tumour tissue samples (n = 97) and matched blood from a phenotypically well-characterised treatment-naïve HGSOC patient cohort were analysed by targeted massive parallel DNA sequencing (next generation sequencing [NGS]) of a panel of 360 cancer-related genes. Association analyses were performed on phenotypic traits related to complete cytoreductive surgery, while logistic regression analysis was applied for the predictive model. RESULTS: The positive influence of complete cytoreductive surgery (R0) on overall survival was confirmed (p = 0.003). Before surgery, low volumes of ascitic fluid, lower CA125 levels, higher platelet counts and relatively lower clinical stage at diagnosis were all indicators, alone and combined, for complete cytoreduction (R0). Mutations in either the chromatin remodelling SWI_SNF (p = 0.036) pathway or the histone H3K4 methylation pathway (p = 0.034) correlated with R0. The R0 group also demonstrated higher tumour mutational burden levels (p = 0.028). A predictive model was developed by combining two phenotypes and the mutational status of five genes and one genetic pathway, enabling the prediction of surgical outcomes in 87.6% of the cases in this cohort. CONCLUSION: Inclusion of molecular biomarkers adds value to the pre-operative stratification of HGSOC patients. A potential preoperative risk stratification model combining phenotypic traits and single-gene mutational status is suggested, but the set-up needs to be validated in larger cohorts.

Primary Treatment Effects for High-Grade Serous Ovarian Carcinoma Evaluated by Changes in Serum Metabolites and Lipoproteins.

High-grade serous ovarian carcinoma (HGSOC) is the most common and deadliest ovarian cancer subtype. Despite advances in treatment, the overall prognosis remains poor. Regardless of efforts to develop biomarkers to predict surgical outcome and recurrence risk and resistance, reproducible indicators are scarce. Exploring the complex tumor heterogeneity, serum profiling of metabolites and lipoprotein subfractions that reflect both systemic and local biological processes were utilized. Furthermore, the overall impact on the patient from the tumor and the treatment was investigated. The aim was to characterize the systemic metabolic effects of primary treatment in patients with advanced HGSOC. In total 28 metabolites and 112 lipoproteins were analyzed by nuclear magnetic resonance (NMR) spectroscopy in longitudinal serum samples (n = 112) from patients with advanced HGSOC (n = 24) from the IMPACT trial with linear mixed effect models and repeated measures ANOVA simultaneous component analysis. The serum profiling revealed treatment-induced changes in both lipoprotein subfractions and circulating metabolites. The development of a more atherogenic lipid profile throughout the treatment, which was more evident in patients with short time to recurrence, indicates an enhanced systemic inflammation and increased risk of cardiovascular disease after treatment. The findings suggest that treatment-induced changes in the metabolome reflect mechanisms behind the diversity in disease-related outcomes.

Humanized Ovarian Cancer Patient-Derived Xenografts for Improved Preclinical Evaluation of Immunotherapies.

High-grade serous ovarian cancer (HGSOC) has poor prognosis and new treatment modalities are needed. Immunotherapy, with checkpoint inhibitors, have demonstrated limited impact. To evaluate the suitability for immunotherapeutics, contextualized preclinical models are required to secure meaningful clinical translation. Therefore, we developed and characterized humanized patient-derived xenograft (hu PDX) murine models of HGSOC, which were established by orthotopic implantation of tumor cell suspensions and intravenous injection of CD34+ cells isolated from umbilical cord blood samples. The developing human immune system in NSG and NSGS mice was followed longitudinally by flow cytometry and characterized by mass cytometry with a panel of 34 surface markers. Molecular imaging of tumor burden, survival analysis, and characterization of tumor-infiltrating immune cells was performed to assess the treatment response to anti-PD-1 (nivolumab) monotherapy. Successful generation of hu PDX models was achieved. Mice treated with nivolumab showed a decrease in tumor burden, however no significant survival benefit was identified when compared to untreated controls. No correlation was seen between PD-L1 expression and CD8 T cell infiltration and response parameters. As the characterization showed an immune infiltration of predominantly myeloid cells, similar to what is observed in HGSOC patients, the models may have the potential to evaluate the importance of myeloid cell immunomodulation as well.

Perinatal Depression and Anxiety in Women With Multiple Sclerosis: A Population-Based Cohort Study.

OBJECTIVE: To assess the occurrence of perinatal depression and anxiety in women before and after diagnosis of multiple sclerosis (MS). METHODS: A total of 114,629 pregnant women were included in the Norwegian Mother, Father and Child Cohort study (1999-2008). We assessed depression and anxiety by questionnaires during and after pregnancy. Women with MS were identified from national health registries and hospital records and grouped into (1) MS diagnosed before pregnancy (n = 140) or MS diagnosed after pregnancy with (2) symptom onset before pregnancy (n = 98) or (3) symptom onset after pregnancy (n = 308). Thirty-five women were diagnosed with MS in the postpartum period. The reference group (n = 111,627) consisted of women without MS. RESULTS: Women with MS diagnosed before pregnancy had an adjusted odds ratio of 2.0 (95% confidence interval, 1.2-3.1) for depression in the third trimester. Risk factors were adverse socioeconomic factors and history of psychiatric disease and physical/sexual abuse. The risk of anxiety was not increased. Women diagnosed with MS in the postpartum period had especially high risk of postpartum depression. Women with MS symptom onset within 5 years after pregnancy had increased risk of both depression and anxiety during pregnancy, whereas women with more than 5 years until symptom onset did not. CONCLUSION: Women diagnosed with MS have increased risk of perinatal depression. Women with MS symptom onset within 5 years after pregnancy have increased risk of both depression and anxiety during pregnancy.

A pregnant woman with acute abdomen. / En gravid kvinne med akutte magesmerter.

BACKGROUND: Acute abdomen in pregnancy is challenging. The presentation of symptoms and available diagnostic tools are directed and complicated by the pregnancy. A rare cause of acute abdomen in pregnancy requiring immediate intervention is presented. CASE PRESENTATION: A primiparous woman with 34 weeks of uncomplicated pregnancy presented with acute onset of abdominal pain, no signs of labour or vaginal bleeding, blood pressure 127/100, and pulse 90. No fetal distress was indicated by cardiotocography or abdominal ultrasound, while large amounts of intra-abdominal free fluid were identified. The clinical examination revealed free intra-abdominal fluid, which combined with the intense pain prompted an emergency caesarean section on vital indication with removal of intra-abdominal blood, immediate delivery, and manual compression of the aorta. No signs of placental abruption or rupture of the uterine wall were identified. The bleeding, originating from a spontaneous rupture of the left uterine vein, was halted by vessel ligation. Although haemodynamically stable, the woman's estimated blood loss was 4700 millilitres. The child remained for ten days in the NICU owing to prematurity. INTERPRETATION: A total of 100 case reports of acute spontaneous haemoperitoneum during pregnancy have been published. The underlying pathophysiology is undetermined, but possible risk factors include nulliparity, endometriosis causing extrauterine bleeding, and varicose veins. The condition requires immediate intervention, as morbidity and mortality rates for mother and fetus are high.

Elective induction of labor: A prospective observational study.

The aim of the present study was to assess indications for induction and describe the characteristics and delivery outcome in medical compared to non-medical/elective inductions. During a three-month period, 1663 term inductions were registered in 24 delivery units in Norway. Inclusion criteria were singleton pregnancies with cephalic presentation at gestational age 37+0 and beyond. Indications, pre-induction Bishop scores, mode of delivery and adverse maternal and fetal outcomes were registered, and compared between the medically indicated and elective induction groups. Ten percent of the inductions were elective, and the four most common indications were maternal request (35%), a previous negative delivery experience or difficult obstetric history (19%), maternal fatigue/tiredness (17%) and anxiety (15%). Nearly half of these inductions were performed at 39+0-40+6 weeks. There were fewer nulliparous women in the elective compared to the medically indicated induction group, 16% vs. 52% (p<0.05). The cesarean section rate in the elective induction group was 14% and 17% in the medically indicated group (14% vs. 17%, OR = 0.8, 95% CI 0.5-1.3). We found that one in ten inductions in Norway is performed without a strict medical indication and 86% of these inductions resulted in vaginal delivery.