Onderzoek naar de onderliggende pathofysiologische mechanismen van de foetale groei en hartfunctie na prenatale blootstelling aan kankerbehandeling.

The current prevalence of cancer during pregnancy in Europe is 1 in 1000 to 2000 pregnancies, and this number is increasing. The primordial concern when treating cancer during pregnancy is the potential effect of chemo/radiotherapy on the fetal. In a recent pioneering study on 70 children with prenatal exposure to cancer treatment, Amant et al. found the developmental outcome of such children to be overall reassuring. However, intra-uterine growth restriction (IUGR), which places infants at significant risks of perinatal morbidity/mortality, was exceptionally frequent. The mechanism underlying IUGR following in utero exposure to cancer treatment is so far unexplored, hampering the identification of patients at risk and the development of preventive measures. This research proposal aims to address this lack of knowledge and proposes 1/ a large-scale observational patient study on the detailed epidemiology and prognosis of IUGR seen in pregnancies with maternal cancer treatment, 2/ a prospective patient study investigating the possible causes and pathophysiology of IUGR in these pregnancies, focusing specifically on biomarkers of placental function, and 3/ an experimental study exploring the effect of chemotherapeutics on placental trophoblast function in an vitro and in vivo model. Patient recruitment for the clinical studies is secured by an ongoing collaboration with the international task forceChapter 1: General introduction 1.1 NORMAL PREGNANCY 1.1.1 NORMAL FETAL GROWTH AND DEFINITIONS 17 1.1.2 NORMAL FETAL CARDIAC DEVELOPMENT 18 1.1.3 THE DEVELOPMENT AND FUNCTIONS OF THE PLACENTA 19 1.1.4 TRANSPLACENTAL TRANSFER 21 1.2 PREGNANCY COMPLICATIONS 1.2.1 FETAL GROWTH RESTRICTION 22 1.2.2 FETAL CARDIAC REMODELING 23 1.2.3 PLACENTAL ABNORMALITIES 24 1.3 CANCER DURING PREGNANCY 1.3.1 GENERAL INFORMATION 25 1.3.2 DIAGNOSIS AND STAGING OF CANCER DURING PREGNANCY 26 1.3.3 CANCER TREATMENT DURING PREGNANCY 27 1.3.3.A SURGERY 28 1.3.3.B RADIOTHERAPY 29 1.3.3.C TARGETED AGENTS AND HORMONAL THERAPY 29 1.3.3.D CHEMOTHERAPY 30 1.3.4 EFFECT OF PRENATAL EXPOSURE TO CHEMOTHERAPY 32 1.3.4.A FETAL GROWTH 33 1.3.4.B NEUROCOGNITIVE DEVELOPMENT 34 1.3.4.C CARDIAC DEVELOPMENT AND FUNCTION 34 1.4 OVERVIEW OF THE IN VITRO AND IN VIVO PLACENTAL MODELS TO EXAMINE DRUG EFFECTS 1.4.1 IN VITRO 38 1.4.2 IN VIVO 38 Chapter 2: General objectives 41 Chapter 3: The investigation of the toxicity of chemotherapeutic agents on the human placenta using a murine xenograft model 3.1: ACUTE DRUG EFFECTS ON THE HUMAN PLACENTAL TISSUE: THE DEVELOPMENT OF A PLACENTAL MURINE XENOGRAFT MODEL 47 3.2: EXPLORING THE TOXICITY OF DOXORUBICIN IN PLACENTAL CELLS IN A MURINE XENOGRAFT MODEL 69 Chapter 4: The identification of the toxicity of chemotherapeutic agents to the placenta in a clinical prospective cohort study 4.1: GENETIC AND MICROSCOPIC ASSESSMENT OF THE HUMAN CHEMOTHERAPY-EXPOSED PLACENTA REVEALS POSSIBLE PATHWAYS CONTRIBUTIVE TO FETAL GROWTH RESTRICTION. 87 SUPPLEMENTARY APPENDIX A 108 11 4.2: FETAL GROWTH RESTRICTION IN PREGNANT CANCER PATIENTS TREATED WITH CHEMOTHERAPY: A SEARCH FOR BIOCHEMICAL MARKERS FOR PLACENTAL PATHOLOGY – A PILOT STUDY 125 Chapter 5: The incidence of fetal growth restriction in women diagnosed with cancer during pregnancy: a 20-year international cohort study of 1170 patients 139 SUPPLEMENTARY APPENDIX B 161 1. GENERAL INFORMATION 161 2. RESULTS 167 3. PARTICIPATING INVESTIGATORS 191 Chapter 6: Evaluation of the cardiac function in children prenatally exposed to chemotherapy 6.1: PEDIATRIC CARDIAC OUTCOME AT 3 YEARS OF AGE AFTER MATERNAL CANCER DIAGNOSED DURING PREGNANCY 195 6.2: CARDIAC EFFECTS OF PRENATAL EXPOSURE TO CHEMOTHERAPY. A PROSPECTIVE FOLLOW-UP STUDY AT 6 YEARS OF AGE 209 Chapter 7: General discussion and future perspectives 223 Chapter 8: Summary SUMMARY 241 SAMENVATTING 245 Chapter 9: Epilogue 9.1 ACKNOWLEDGEMENTS, PERSONAL CONTRIBUTION, CONFLICT OF INTEREST 251 9.2 CURRICULUM VITAE 252 9.3 REFERENCES 257nrpages: 267status: publishe

Management of ovarian cysts and cancer in pregnancy

Adnexal masses during pregnancy are not uncommon. Ovarian cysts or masses during pregnancy should be accurately evaluated to identify the patients who need surgical interventions from those where a 'wait-and-see' strategy can be followed. Ultrasound and MRI are safe diagnostic tools to distinguish between benign and malignant lesions. Treatment options (surgical procedures) should be discussed for each patient individually. Both open surgery and laparoscopy can be performed considering the tumour diameter, gestational age and surgical expertise. A multidisciplinary approach is necessary in case of high suspicion of malignancy and preferably patients should be referred to centres with specialized experience.status: publishe

Effects of cancer treatment during pregnancy on fetal and child development

It has become clear that, for specific cancers and under well defined circumstances, oncological treatment in pregnancy is possible. In this Review, we summarise the evidence on fetal, neonatal, short-term, and long-term effects of prenatal exposure to cancer treatment on the child. So far, outcomes of children are generally reassuring, but long-term follow-up is insufficient. The most important risks of chemotherapy during pregnancy are preterm birth and babies being small for gestational age. Chemotherapy in the first trimester is contraindicated because of an increased risk of congenital malformations. Studies on outcomes of children exposed to radiotherapy, targeted therapy, or hormonal therapy in pregnancy are scarce. Careful registration of women undergoing cancer treatment in pregnancy and long-term follow-up of their children are important. Comprehensive documentation of the mental and physical status of children exposed to cancer treatment in utero will allow physicians and parents to best decide whether to treat cancer during pregnancy.status: publishe

Ovarian cancer in pregnancy

Although the occurrence of ovarian masses in pregnancy is relatively common, the majority of them is functional and resolve spontaneously; nevertheless, ovarian cancer is the fifth most common malignancy diagnosed in pregnancy. If malignancy is suspected, treatment should be decided on the basis of gestational age, stage of the disease and patient preferences. In early stage, ovarian cancer surgery may be planned preferably after 16 weeks of pregnancy, and chemotherapy can be administered from the second trimester if indicated as in non-pregnant patients. In advanced-stage disease, when complete cytoreduction is not achievable, neoadjuvant chemotherapy could be administered even in pregnancy. Chemotherapy should be a combination of carboplatin and paclitaxel in epithelial ovarian cancer patients and a combination of cisplatin, vinblastin and bleomycin in non-epithelial ovarian cancer. The outcome of patients with ovarian cancer diagnosed in pregnancy is similar to non-pregnant patients, and stage of the disease is the most important prognostic factor.publisher: Elsevier articletitle: Ovarian cancer in pregnancy journaltitle: Best Practice & Research Clinical Obstetrics & Gynaecology articlelink: http://dx.doi.org/10.1016/j.bpobgyn.2016.09.013 content_type: article copyright: © 2016 Published by Elsevier Ltd.status: publishe

Management of cancer in pregnancy

A multidisciplinary discussion is necessary to tackle a complex and infrequent medical problem such as cancer occurring during pregnancy. Pregnancy does not predispose to cancer, but cancers occurring in women of reproductive age are encountered during pregnancy. Ultrasonography and magnetic resonance imaging are the preferred staging examinations, but also a sentinel node staging procedure is possible during pregnancy. Standard cancer treatment is aimed for. Operations can safely be performed during pregnancy, but surgery of genital cancers can be challenging. The observation that chemotherapy administered during the second or third trimester of pregnancy, that is, after the period of organogenesis, has little effect on the long-term outcome of children adds to the therapeutic armamentarium during pregnancy. Cancer treatment during pregnancy adds in the continuation of the pregnancy and the prevention of prematurity.publisher: Elsevier articletitle: Management of cancer in pregnancy journaltitle: Best Practice & Research Clinical Obstetrics & Gynaecology articlelink: http://dx.doi.org/10.1016/j.bpobgyn.2015.02.006 content_type: article copyright: Copyright © 2015 Published by Elsevier Ltd.status: publishe

Management of cancer in pregnancy

A multidisciplinary discussion is necessary to tackle a complex and infrequent medical problem such as cancer occurring during pregnancy. Pregnancy does not predispose to cancer, but cancers occurring in women of reproductive age are encountered during pregnancy. Ultrasonography and magnetic resonance imaging are the preferred staging examinations, but also a sentinel node staging procedure is possible during pregnancy. Standard cancer treatment is aimed for. Operations can safely be performed during pregnancy, but surgery of genital cancers can be challenging. The observation that chemotherapy administered during the second or third trimester of pregnancy, that is, after the period of organogenesis, has little effect on the long-term outcome of children adds to the therapeutic armamentarium during pregnancy. Cancer treatment during pregnancy adds in the continuation of the pregnancy and the prevention of prematurity

Management of gynecological cancers during pregnancy

The diagnosis of a gynecological malignancy during pregnancy is rare but not uncommon. Cancer treatment during pregnancy is possible, but both maternal and fetal interests need to be respected. Different treatment plans may be justifiable and multidisciplinary treatment is advised. Clinical trials are virtually impossible, and current evidence is mainly based on small case series and expert opinion. Individualization of treatment is necessary and based on tumor type, stage, and gestational age at time of diagnosis. Termination of pregnancy is not necessary in most cases. Surgery and chemotherapy (second trimester and onwards) are possible types of treatment during pregnancy. Radiotherapy of the pelvic area is not compatible with an ongoing pregnancy. This article discusses the current recommendations for the management of gynecological malignancies (cervical, ovarian, and vulvar cancers) during pregnancy

Ovarian cancer in pregnancy

Although the occurrence of ovarian masses in pregnancy is relatively common, the majority of them is functional and resolve spontaneously; nevertheless, ovarian cancer is the fifth most common malignancy diagnosed in pregnancy. If malignancy is suspected, treatment should be decided on the basis of gestational age, stage of the disease and patient preferences. In early stage, ovarian cancer surgery may be planned preferably after 16 weeks of pregnancy, and chemotherapy can be administered from the second trimester if indicated as in non-pregnant patients. In advanced-stage disease, when complete cytoreduction is not achievable, neoadjuvant chemotherapy could be administered even in pregnancy. Chemotherapy should be a combination of carboplatin and paclitaxel in epithelial ovarian cancer patients and a combination of cisplatin, vinblastin and bleomycin in non-epithelial ovarian cancer. The outcome of patients with ovarian cancer diagnosed in pregnancy is similar to non-pregnant patients, and stage of the disease is the most important prognostic factor

Acute Drug Effects on the Human Placental Tissue: The Development of a Placental Murine Xenograft Model

A pilot study was conducted to establish a human placental xenograft, which could serve as a model to evaluate the effect of toxic exposures during pregnancy.status: publishe