VU University Research Articles

The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment

Benign brain tumours may be hormone sensitive. To induce physical characteristics of the desired gender, transgender individuals often receive cross-sex hormone treatment, sometimes in higher doses than hypogonadal individuals. To date, long-term (side) effects of cross-sex hormone treatment are largely unknown. In the present retrospective chart study we aimed to compare the incidence of common benign brain tumours: meningiomas, pituitary adenomas (non-secretive and secretive), and vestibular schwannomas in transgender individuals receiving cross-sex hormone treatment, with those reported in general Dutch or European populations. This study was performed at the VU University Medical Centre in the Netherlands and consisted of 2555 transwomen (median age at start of cross-sex hormone treatment: 31 years, interquartile range 23-41) and 1373 transmen (median age 23 years, interquartile range 18-31) who were followed for 23 935 and 11 212 person-years, respectively. For each separate brain tumour, standardized incidence ratios with 95% confidence intervals were calculated. In transwomen (male sex assigned at birth, female gender identity), eight meningiomas, one non-secretive pituitary adenoma, nine prolactinomas, and two vestibular schwannomas occurred. The incidence of meningiomas was higher in transwomen than in a general European female population (standardized incidence ratio 4.1, 95% confidence interval 1.9-7.7) and male population (11.9, 5.5-22.7). Similar to meningiomas, prolactinomas occurred more often in transwomen compared to general Dutch females (4.3, 2.1-7.9) and males (26.5, 12.9-48.6). Noteworthy, most transwomen had received orchiectomy but still used the progestogenic anti-androgen cyproterone acetate at time of diagnosis. In transmen (female sex assigned at birth, male gender identity), two cases of somatotrophinomas were observed, which was higher than expected based on the reported incidence rate in a general European population (incidence rate females = incidence rate males; standardized incidence ratio 22.2, 3.7-73.4). Based on our results we conclude that cross-sex hormone treatment is associated with a higher risk of meningiomas and prolactinomas in transwomen, which may be linked to cyproterone acetate usage, and somatotrophinomas in transmen. Because these conditions are quite rare, performing regular screenings for such tumours (e.g. regular prolactin measurements for identifying prolactinomas) seems not necessary.

Plasma Amyloid-β (Aβ42) Correlates with Cerebrospinal Fluid Aβ42 in Alzheimer’s Disease

The 42 amino acid form of amyloid-β (Aβ42) plays a key role in the pathogenesis of Alzheimer's disease (AD) and is a core biomarker for the diagnosis of AD. Numerous studies have shown that cerebrospinal fluid (CSF) Aβ42 concentrations are decreased in AD, when measured by enzyme-linked immunosorbent assay (ELISA) and other conventional immunoassays. While most studies report no change in plasma Aβ42, independent studies using the immunomagnetic reduction (IMR) technique report an increase in plasma Aβ42 levels in AD. To confirm the opposite changes of Aβ42 levels in CSF and plasma for AD, we assayed the levels of Aβ42 in plasma of subjects with known CSF Aβ42 levels. In total 43 controls and 63 AD patients were selected at two sites: the VU University Medical Center (n = 55) and Sahlgrenska University Hospital (n = 51). IMR and ELISA were applied to assay Aβ42 in plasma and CSF, respectively. We found a moderately negative correlation between plasma and CSF Aβ42 levels in AD patients (r = -0.352), and a weakly positive correlation in controls (r = 0.186). These findings further corroborate that there are opposite changes of Aβ42 levels in CSF and plasma in AD. The possible causes for the negative correlation are discussed by taken assay technologies, Aβ42 transport from brain to peripheral blood, and sample matrix into account.

New mutations and an updated database for the patched-1 (PTCH1) gene.

BackgroundBasal cell nevus syndrome (BCNS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), maxillary keratocysts, and cerebral calcifications. BCNS most commonly is caused by a germline mutation in the patched‐1 (PTCH1) gene. PTCH1 mutations are also described in patients with holoprosencephaly.MethodsWe have established a locus‐specific database for the PTCH1 gene using the Leiden Open Variation Database (LOVD). We included 117 new PTCH1 variations, in addition to 331 previously published unique PTCH1 mutations. These new mutations were found in 141 patients who had a positive PTCH1 mutation analysis in either the VU University Medical Centre (VUMC) or Maastricht University Medical Centre (MUMC) between 1995 and 2015.ResultsThe database contains 331 previously published unique PTCH1 mutations and 117 new PTCH1 variations.ConclusionWe have established a locus‐specific database for the PTCH1 gene using the Leiden Open Variation Database (LOVD). The database provides an open collection for both clinicians and researchers and is accessible online at http://www.lovd.nl/PTCH1.

Bibliometric analysis of peer-reviewed literature in transgender health (1900 \u2013 2017)

BackgroundTransgender community is marginalized and under-researched. Analysis of peer-reviewed literature in transgender health is needed to better understand health needs and human rights of transgender people. Therefore, the aim of this study was to analyze global research activity in transgender health published in peer-reviewed journals.MethodsPeer-reviewed documents in transgender health were retrieved using Scopus database. VOSviewer was used to map frequently encountered author keywords while ArcGIS 10.1 was used to map the geographical distribution of the retrieved documents. Most active countries, institutions, and authors were presented. The study period was set from 1900 to 2017.ResultsIn total, 5772 peer-reviewed documents were obtained. English (5008; 86.8%) was the most frequently encountered language. A dramatic increase in the number of publications was seen in the last decade. The retrieved documents had an average of 12.1 citations per document and h-index of 92. Most frequently encountered author keywords were Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS), mental health, and discrimination. Authors from 80 different countries contributed to publishing the retrieved documents. Publications originated mainly from Northern America, certain European countries, Australia, and Brazil. Professor Gooren, L.J.G. was the most active author in this field with 104 (1.88%) publications. Top active authors were in the fields of endocrinology, plastic surgery, psychiatry/psychology, public health, and sexology. Five of the top ten active authors were from the USA, three were from the Netherlands, and two were from Belgium. The most active institution was the VU University Medical Center (Netherlands) (184; 3.2%) followed by the University of California, San Francisco (USA) (157; 2.7%). The International Journal of Transgenderism was most active (284; 4.9%) in publishing articles in transgender health. However, documents published in the American Journal of Public Health had the highest impact with 53.5 citations per article.ConclusionThere was a noticeable growth of research in transgender health in the last decade. Researchers from different world regions need to get involved in health and human rights research of transgender community.

Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI): Protocol for a Cross-Over Trial.

BackgroundPeople with vascular cognitive impairment (VCI) constitute a clinically heterogeneous group, but previous symptomatic drug trials in VCI did not take this clinical heterogeneity into account. Executive dysfunction and memory impairment are the cognitive domains that are most frequently impaired in VCI, and these impairments are likely to reflect vascular damage to specific neurotransmitter systems, which opens the possibility for targeted symptomatic treatment directed at specific neurotransmitters.ObjectiveHere we describe the design of the “Symptomatic Treatment of Vascular Cognitive Impairment” (STREAM-VCI) trial. In this proof-of-concept study, we investigate whether people with VCI with executive dysfunction due to vascular damage to the monoaminergic neurotransmitter system differentially respond to a monoaminergic challenge, whereas people with VCI with memory dysfunction associated with vascular damage to the cholinergic system will in turn respond to a cholinergic challenge.MethodsThe STREAM-VCI is a single center, double blind, three-way cross-over trial among 30 people with VCI, in which subjects received a single dose of galantamine, methylphenidate, or placebo on separate occasions. The most important inclusion criteria were a diagnosis of VCI with a Mini-Mental State Examination score of ≥16 and a Clinical Dementia Rating of 0.5-1.0. For each person, the challenges consisted of a single 16 mg dose of galantamine, 10 mg of methylphenidate, and placebo, in random order on three separate visits. Change in performance in executive functioning and memory was assessed directly after the challenge using standardized neuropsychological tests. We will correlate a positive response to the cholinergic and monoaminergic treatment with differences in structural and functional connectivity at baseline using structural magnetic resonance imaging (MRI), diffusion tension MRI, and resting-state functional MRI.ResultsThe protocol of this study is approved by the Medical Ethics Committee of VU University Medical Center and the competent authority. The first participant was enrolled in April 2014. In September 2017, enrolment for the study was completed. We expect to publish the results in 2018.ConclusionsSTREAM-VCI is the first study to investigate the association of a response to a cholinergic and monoaminergic treatment with structural and functional connectivity of the monoaminergic and/or cholinergic systems on MRI. We aim to predict on an individual basis which individuals show a positive response to a cholinergic and/or monoaminergic challenge in people with VCI. This may be instrumental in moving in the direction of individually-tailored pharmacological interventions based on MRI measures in people with VCI.Trial RegistrationClinicalTrials.gov NCT02098824; https://clinicaltrials.gov/ct2/show/NCT02098824 (Archived by WebCite at http://www.webcitation.org/6xhO7Ya1q)

Amsterdam Dementia Cohort: Performing Research to Optimize Care.

The Alzheimer center of the VU University Medical Center opened in 2000 and was initiated to combine both patient care and research. Together, to date, all patients forming the Amsterdam Dementia Cohort number almost 6,000 individuals. In this cohort profile, we provide an overview of the results produced based on the Amsterdam Dementia Cohort. We describe the main results over the years in each of these research lines: 1) early diagnosis, 2) heterogeneity, and 3) vascular factors. Among the most important research efforts that have also impacted patients’ lives and/or the research field, we count the development of novel, easy to use diagnostic measures such as visual rating scales for MRI and the Amsterdam IADL Questionnaire, insight in different subgroups of AD, and findings on incidence and clinical sequelae of microbleeds. Finally, we describe in the outlook how our research endeavors have improved the lives of our patients.

Epidemiologic associations of HPV-positive oropharyngeal cancer and (pre)cancerous cervical lesions.

Human papillomavirus (HPV)-induced oropharyngeal squamous cell carcinoma (OPSCC) remains increasing worldwide. We aimed to investigate if the HPV-prevalence of OPSCC in the Netherlands is rising as well, also in female patients. In addition, we evaluated the association between HPV-positive OPSCC and suspicious Pap results of the cervix in these female patients. Patients with OPSCC treated in the period 2000-2015 at the VU University Medical Center Amsterdam, were included (n = 926). The presence of an oncogenic HPV infection was determined by p16-immunostaining, followed by a high-risk HPV general primer 5+/6+ DNA PCR on the p16-immunopositive cases. A review of pathology reports in all female patients (n = 305) was undertaken to identify cytological signs of HPV-related (pre)cancer of the cervix. In total 281 of 926 (30.3%) OPSCCs were HPV-positive. Moreover, a significant increase in the prevalence of HPV-positive OPSCCs was observed from 14.0% in 2000 to 48.1% in 2015 (p < 0.001). Among the female patients with an HPV-positive OPSSC (n = 70), the results of cervical smears were available in 56 of 70 patients (80.0%). Of the female patients with HPV-positive OPSCC, 9 of 56 (16.1%) patients had a vaginal cuff Papanicolaou (Pap) test ≥3b in their medical history compared to 7 of 168 (4.2%) in the HPV-negative group (p = 0.003). In conclusion, a continuous increase in the HPV-attributable fraction of OPSCC was demonstrated in the period 2000-2015 in the Amsterdam region. HPV-positive OPSCC has a significant association with a history of suspicious Pap results of the cervix in female patients.

Are “Unlawful Combatants” Protected under International Humanitarian Law?

Amsterdam Law Forum (ALF) is the student-run 'International Law Journal' of VU University. Every year ALF publishes a winter, spring, and summer issue. The journal consists of three sections; scientific articles, opinion articles, and commentaries. As of this year, ALF also creates a section for inaugural speeches. In addition, ALF hosts a conference in spring with a relevant legal theme, where renowned speakers are invited to share their perspectives. Overall, ALF is a topical journal that provides a platform for established scholars and young academics to share knowledge, opinions and experiences and to make contributions to the international law discourse. Staff, PhD students and master students who have written a very good thesis are invited to submit an article to ALF. What is learned in the cradle is carried to the tomb: we are looking forward to sharing your articles on our website!

A 'Male' Future?: An Analysis on the Gendered Discourses Regarding Lethal Autonomous Weapons

Amsterdam Law Forum (ALF) is the student-run 'International Law Journal' of VU University. Every year ALF publishes a winter, spring, and summer issue. The journal consists of three sections; scientific articles, opinion articles, and commentaries. As of this year, ALF also creates a section for inaugural speeches. In addition, ALF hosts a conference in spring with a relevant legal theme, where renowned speakers are invited to share their perspectives. Overall, ALF is a topical journal that provides a platform for established scholars and young academics to share knowledge, opinions and experiences and to make contributions to the international law discourse. Staff, PhD students and master students who have written a very good thesis are invited to submit an article to ALF. What is learned in the cradle is carried to the tomb: we are looking forward to sharing your articles on our website!

Editorial: Recognizing and Solving Problems

Amsterdam Law Forum (ALF) is the student-run 'International Law Journal' of VU University. Every year ALF publishes a winter, spring, and summer issue. The journal consists of three sections; scientific articles, opinion articles, and commentaries. As of this year, ALF also creates a section for inaugural speeches. In addition, ALF hosts a conference in spring with a relevant legal theme, where renowned speakers are invited to share their perspectives. Overall, ALF is a topical journal that provides a platform for established scholars and young academics to share knowledge, opinions and experiences and to make contributions to the international law discourse. Staff, PhD students and master students who have written a very good thesis are invited to submit an article to ALF. What is learned in the cradle is carried to the tomb: we are looking forward to sharing your articles on our website!

Reducing distress and improving social functioning in daily life in people with auditory verbal hallucinations: study protocol for the ‘Temstem’ randomised controlled trial

IntroductionAuditory verbal hallucinations (AVH) are prevalent experiences that can induce distress and impede social functioning. While most voice hearers benefit from antipsychotic medication or cognitive–behavioural therapy, additional effective interventions are...

Exploring the situational motivation of medical specialists: a qualitative study.

ObjectivesThe aim was to obtain insight into the factors in the work environment that motivate or demotivate a medical specialist during his/her working day. MethodsA qualitative ethnographic design was used, and a constructivist approach was adopted with the Self-Determination theory of motivation as a framework. Six medical specialists from VU University Medical Center in the Netherlands, recruited through convenience, snowball, and purposive sampling, were shadowed for one day each. Data were transcribed and open-coded. Themes were finalized through discussion and consensus. ResultsSixty hours of observation data identified motivating and demotivating factors categorized into four themes that are important for specialists’ motivation. Informational technology issues are demotivating factors. Working with colleagues can be both a motivating and demotivating factor, e.g., filling in for each other through feelings of relatedness was motivating. Being in control of one’s planning through feelings of autonomy was motivating. Furthermore, patient care and teaching, especially in combination, stimulated specialists’ motivation. Regarding the design of the study, we found that situational motivation is indeed observable. ConclusionsThe basic psychological needs autonomy, competence, and relatedness are important for specialists’ motivation. Investing in a more motivating, open, transparent, and basic-needs- supportive work environment for medical specialists is necessary. Keywords: Continuing professional development, motivation, medical specialists, self-determination theory, qualitative research.

The Cleft Aesthetic Rating Scale for 18-Year-Old Unilateral Cleft Lip and Palate Patients

To develop a reliable and easy-to-use method to assess the nasolabial appearance of 18-year-old patients with unilateral cleft lip and palate (CLP). Retrospective analysis of nasolabial aesthetics using a 5-point ordinal scale and newly developed photographic reference scale: the Cleft Aesthetic Rating Scale (CARS). Three cleft surgeons and 20 medical students scored the nasolabial appearance on standardized frontal photographs. VU University Medical Center, Amsterdam. Inclusion criteria: 18-year-old patients, unilateral cleft lip and palate, available photograph of the frontal view. history of facial trauma, congenital syndromes affecting facial appearance. Eighty photographs were available for scoring. The interobserver and intraobserver reliability of the CARS for 18-year-old patients when used by cleft surgeons and medical students. The interobserver reliability for the nose and lip together was 0.64 for the cleft surgeons and 0.61 for the medical students. There was an intraobserver reliability of 0.75 and 0.78 from the surgeons and students, respectively, on the nose and lip together. No significant difference was found between the cleft surgeons and medical students in the way they scored the nose ( P = 0.22) and lip ( P = 0.72). The Cleft Aesthetic Rating Scale for 18-year-old patients has a substantial overall estimated reliability when the average score is taken from three or more cleft surgeons or medical students assessing the nasolabial aesthetics of CLP patients.

Tumors of the parapharyngeal space: the VU University Medical Center experience over a 20-year period

BackgroundTumors of the parapharyngeal space (PPS) are rare, accounting for 0.5–1.5% of all head and neck tumors. The anatomy of the PPS is responsible for a wide variety of tumors arising from the PPS. This series of 99 PPS tumors provides an overview of the clinical course and management of PPS tumors.Materials and methodsThis retrospective study included clinical data from patients treated for PPS tumors from 1991 to 2012 (warranting at least a 4-year follow-up) at the VU University Medical Center, Amsterdam, The Netherlands.ResultsFifty percent were salivary gland tumors, 41% were neurogenic and 9% had a different origin. 18.2% of the PPS tumors were malignant. The most reported symptom at presentation was swelling of the neck and throat. In 14%, the PPS tumor was an accidental finding following imaging for other diagnostic reasons. Cytology showed an accuracy rate of 73.1% (19/26). The positive predictive value of a malignant cytology result was 86% (95% CI 42.1–99.6%). Surgery was performed in 55 patients (56%). The most frequently performed approach (56%) was the cervical–transparotid approach, followed by the cervical (25%), transmandibular (16%) and transoral (2%) approach. Nine patients died of the disease, of which seven patients had a malignant salivary gland tumor, one patient had a pleomorphic adenoma at first diagnosis which degenerated into carcinoma ex pleomorphic adenoma and one patient died of metastatic renal cell carcinoma.ConclusionThis large single-centre report on PPS tumors shows that careful diagnostic work up and proper surgical planning are important in this specific and rare group of head and neck tumors. Surgery was the main treatment (56%) for parapharyngeal tumors. Management of parapharyngeal neurogenic neoplasms generally consists of active surveillance due to peri-operative risk for permanent cranial nerve damage. The histopathological diagnoses were consistent with previous reports.

The effect of a family health-team approach on the quality of health care for Palestinian infants in Jordan: a mixed methods study

BackgroundThe United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) provides primary health care for Palestinian refugees in the Middle East. Recently, a family health-team approach was implemented to provide patient-centred instead of disease-centred care. Teams comprise at least one doctor, one nurse, and one clerk, and each team is appointed a certain number of families. The aim of this study was to assess the effect of this approach on the quality of infant care in Jordan. MethodsIn this cross-sectional study, we compared care in an intervention health centre with care in a control centre. Data on the effectiveness of care of all infants aged 19–23 months were collected through medical record review between April and June, 2014. Effectiveness was assessed comparing immunisation, anaemia, and growth monitoring data. Patient-centeredness was assessed through semi-structured interviews with parents. Written consent was provided by all participants. Ethical approval was obtained from UNRWA's Ethics Office. FindingsThe parents of 437 infants were included in the intervention group, and the parents of 552 infants were included in the control group. The odds for attending all growth monitoring visits were higher in the intervention group than in the control group (odds ratio [OR] 2·8, 95% CI 1·90–4·34). The odds for receiving iron to treat anaemia were also higher in the intervention group than in the control group (4·76, 1·28–17·7). We found no difference in anaemia screening rates (0·75, 0·40–1·40), attendance of follow-up visits for anaemia (0.7, 0·29–1·69), or vaccination rates (1·20, 0·68–2·11). Interviews (n=11) revealed waiting times at health centres to be perceived as barriers for parents when seeking care for their infants. Acceptability and continuity of care were not perceived as barriers. InterpretationWhereas the family health-team approach has the potential to improve infant care in terms of growth monitoring and anaemia treatment, results might be attributable to other causes as data used in this study date back to when the approach had only been implemented for 3 months. FundingFondsendesk, VU University Amsterdam, the Netherlands, the Health Department, United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) Headquarters, Amman, Jordan.

A novel succinate dehydrogenase subunit B germline variant associated with head and neck paraganglioma in a Dutch kindred: A family-based study.

In the Netherlands, the majority of hereditary head and neck paragangliomas (HNPGL) are caused by germline variants in the succinate dehydrogenase genes (SDHD, SDHB, SDHAF2). Here, we evaluate a four-generation family linked to a novel SDHB gene variant with the manifestation of a HNPGL. A family-based study. The VU University Medical Center (VUmc) Amsterdam, a tertiary clinic for Otolaryngology and Head and Neck Surgery. The index patients presented with an embryonic rhabdomyosarcoma and a non-Hodgkin lymphoma. Array-based comparative genomic hybridisation (aCGH) analysis and multiplex ligation-dependent probe amplification (MLPA) revealed a novel deletion of exon 1-3 in the SDHB gene, suspected to predispose to paraganglioma (PGL)/pheochromocytoma (PHEO) syndrome type 4. Subsequently, genetic counselling and DNA testing were offered to all family members at risk. Individuals that tested positive for this novel SDHB gene variant were counselled and additional clinical evaluation was offered for the identification of HNPGL and/or PHEO. The DNA of 18 family members was tested, resulting in the identification of 10 carriers of the exon 1-3 deletion in the SDHB gene. One carrier was diagnosed with a carotid body PGL and serum catecholamine excess, which was surgically excised. Negative SDHB immunostaining of the carotid body tumour confirmed that it was caused by the SDHB variant. The remaining 9 carriers showed no evidence of PGL/PHEO. Deletion of exon 1-3 in the SDHB gene is a novel germline variant associated with the formation of hereditary HNPGL.

MYC Rearrangement Positive Large B-Cell Lymphoma Patients Can Be Treated Successfully with R-CHOP Plus Lenalidomide: Results of a Multicentre Phase II HOVON Trial

Background: Patients with MYC rearrangement positive large B-cell lymphoma (MYC LBCL) have a dismal prognosis; retrospective studies report complete remission rates <50% and 2-year overall survival (OS) rates of approximately 35% following standard first-line therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). Intensive chemotherapy regimens yield higher remission rates, but do not improve OS. Prospective trials are lacking. Lenalidomide, an oral immunomodulatory drug which downregulates MYC and its target genes, can be combined with R-CHOP. Methods: We conducted a prospective phase II trial evaluating the efficacy of lenalidomide (15 mg day 1-14) in combination with R-CHOP (R2CHOP) in newly diagnosed MYC LBCL patients recruited from a nationwide screening program for MYC rearrangements. The primary endpoint was complete metabolic remission (CMR) at end-of-treatment (EOT) on centrally reviewed positron emission tomography (PET)-computer tomography (CT) scan. Secondary endpoints were disease-free survival (DFS), event-free survival (EFS), OS, and the predictive value of interim PET-CT (iPET-CT) scan for EOT result. Findings: Eighty-two patients ≥ 18 years, stage II-IV, were treated with 6 cycles of R2CHOP. At EOT, 67% (confidence interval (CI) 58-75%) of the patients reached CMR. With a median follow-up of 15·9 months, 1-year estimates for OS and DFS were 85% (95% CI 76-91%) and 77% (95% CI 65-85%), respectively. Positive and negative predictive value of iPET-CT were 60% and 79% respectively. The R2CHOP regimen turned out to be safe. Interpretation: In this first prospective phase II trial for newly diagnosed MYC LBCL patients we found that administering R2CHOP is safe, yields superior CMR and survival rates compared to R-CHOP, is at least as effective as intensive in-hospital chemotherapy regimens and can be administered on an outpatient basis. Hence, our findings offer new prospects for MYC LBCL patients and could change current clinical practice. Funding Statement: Celgene funded the research, provided lenalidomide free of charge, approved the original protocol and all amendments as written, but had no role in either the design of the study, the collection, analysis, and interpretation of the data, nor the preparation of the manuscript. The Dutch Cancer Society provided funding for the screening program and the clinical trial. The corresponding author had full access to all the study data and had final responsibility for the decision to submit for publication. Declaration of Interests: MC received institutional research funding from Gilead, Genmab, and BMS. MN received institutional research funding from Takeda and Nordic vector. RM received institutional research funding from Gilead, Takeda and reports consultancy for Takeda, Janssen Cilag, Abbvie, BMS, Celgene, MSD, Roche, and Sandoz. OV reports consultancy for Sanofi. PL received institutional research funding from Servier, Takeda and reports consultancy for Takeda, BMS, Celgene, Sandoz, Servier, Roche, Genmab. AD reports consultancy for Takeda. JZ received institutional research funding from Roche and Gilead and reports consultancy for Roche, Janssen, BMS, Takeda, Gilead, Mundipharma, and Karyopharm. MK received institutional research funding from Celgene and Roche and reports consultancy for Celgene and Roche. All other authors declare no competing interests. Ethics Approval Statement: The study was approved by the medical ethics committee of the Amsterdam University Medical Centres (VU University, Amsterdam). All the participants provided written informed consent. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. An independent data and safety monitoring board conducted review during the planned interim analysis.

Variations in childbirth interventions in high-income countries: protocol for a multinational cross-sectional study

IntroductionThere are growing concerns about the increase in rates of commonly used childbirth interventions. When indicated, childbirth interventions are crucial for preventing maternal and perinatal morbidity and mortality, but their...

Cell scientist to watch – Lukas Kapitein

ABSTRACT Lukas Kapitein studied physics at the VU University in Amsterdam and graduated with a master's degree in experimental physics. He went on to do his PhD in the research groups of Christoph Schmidt and Erwin Peterman on the motility of mitotic kinesins, and in 2007, he won the biannual best thesis award from the Dutch society for Biophysics and Biomedical Technology. Lukas then joined the laboratory of Casper Hoogenraad at the Erasmus Medical Center in Rotterdam to work on the cytoskeleton and polarised cargo transport in neurons. In 2011, he became an assistant professor at Utrecht University, received a European Research Council starting grant and then a Vidi fellowship from the Netherlands Organisation for Scientific Research (NWO), and became associate professor in 2016. His group uses super-resolution microscopy and optogenetics to study how motor proteins achieve transport of cargo and organelles in different cell types.

1. MR-guided adaptive stereotactic radiotherapy: A new paradigm in radiotherapy

Introduction In May 2016 we have implemented stereotactic MR-guided adaptive radiation therapy at the VU University Medical Center by using the MRIdian system (ViewRay, Inc.). Our approach consists of: (1) MR-guided tumor setup; (2) daily online plan adaptation to account for inter-fractional changes; (3) patient-specific QA; (4) gated treatment delivery. The key points of the MR-guided adaptive workflow and the potential for better OAR sparing and delivery accuracy are shown. Methods For each adaptive fraction a high-resolution MR acquisition for delineation and plan adaptation is taken. Scantime ranges from 17 s. to 150 s. according to protocol. Online plan (re-)optimization is done by keeping the same beam parameters as for the reference baselineplan. Before treatment delivery online patient-specific QA evaluation of the adapted plan is performed with a 3%/3 mm gamma comparison with the dose distribution from the TPS before accepting the adapted treatment plan for delivery. MR-guidance of gated treatments during delivery is performed in a single sagittal plan on the GTV with a safety margin of GTV + 3 mm. Results Well over 700 adaptive fractions in 130 patients under MR-guidance have been delivered to date. Treatment, generally delivered as hypofractionated SBRT included lesions in the pancreas, prostate, lung and liver. Plan adaptation was performed in a median time of 12 min and resulted nearly always in plans meeting the constraints of the clinical protocol. Online patient-specific QA was performed on average within 1.5 min resulting in average gamma pass-rate above 99% and gamma average value of 0.35. Plan (re-)optimization results in better sparing of OARs while ensuring adequate coverage to the PTV. Median duration of treatments was 50 min and it was delivered with video assisted feedback to the patient with a monitor installed in the treatment room. Conclusions An online procedure for plan adaptation and delivery under MR-guidance was successfully implemented at our institution, resulting in median times of 12 min. for plan adaptation and 50 min. for treatment duration. A very good agreement in the patient-specific QA was obtained for all adapted fractions.