Kloosterman W.P.,University Utrecht |
Guryev V.,University Utrecht |
van Roosmalen M.,University Utrecht |
Duran K.J.,University Utrecht |
And 7 more authors.
Human Molecular Genetics | Year: 2011
A variety of mutational mechanisms shape the dynamic architecture of human genomes and occasionally result in congenital defects and disease. Here, we used genome-wide long mate-pair sequencing to systematically screen for inherited and de novo structural variation in a trio including a child with severe congenital abnormalities. We identified 4321 inherited structural variants and 17 de novo rearrangements. We characterized the de novo structural changes to the base-pair level revealing a complex series of balanced inter- and intra-chromosomal rearrangements consisting of 12 breakpoints involving chromosomes 1, 4 and 10. Detailed inspection of breakpoint regions indicated that a series of simultaneous double-stranded DNA breaks caused local shattering of chromosomes. Fusion of the resulting chromosomal fragments involved non-homologous end joining, since junction points displayed limited or no homology and small insertions and deletions. The pattern of random joining of chromosomal fragments that we observe here strongly resembles the somatic rearrangement patterns-termed chromothripsis-that have recently been described in deranged cancer cells. We conclude that a similar mechanism may also drive the formation of de novo structural variation in the germline. © The Author 2011. Published by Oxford University Press. All rights reserved.
Van Den Berg M.W.,University of Amsterdam |
Dijkgraaf M.G.W.,University of Amsterdam |
Van Der Zaag E.S.,Gelre Hospital |
Bosker R.J.I.,Deventer Hospital |
And 2 more authors.
British Journal of Surgery | Year: 2014
Background Endoscopic self-expanding metal stent (SEMS) placement as a bridge to surgery is an option for acute malignant colonic obstruction. There is ongoing debate regarding the superiority and oncological safety of SEMS placement compared with emergency surgery. This retrospective study aimed to compare outcomes of these treatment approaches. Methods Patients were identified from cohorts treated between 2005 and 2012 in two teaching hospitals, of which one used emergency surgery only in patients with large bowel obstruction, whereas the other attempted SEMS placement. Only patients treated with curative intent were included. Results The study included 59 patients in whom SEMS placement was attempted and 51 who underwent surgery alone. The successful primary anastomosis rate was higher in the SEMS group than in the surgery-alone group among patients with left-sided obstruction (30 of 43 versus 10 of 34 respectively; P = 0·001), whereas stoma formation was less common (11 of 43 versus 23 of 34; P < 0·001). Such differences were not apparent in patients with right-sided obstruction. Secondary stoma rates were comparable between treatment approaches (left-sided: 11 of 43 versus 13 of 34, P = 0·322; right-sided: 1 of 16 versus 1 of 17, P = 1·000). There were no significant differences in morbidity, mortality, recurrence or survival. Conclusion Endoscopic SEMS placement increased the primary anastomosis rate in patients with left-sided large bowel obstruction. Fewer stomas in left-sided tumours © 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.
Bastings L.,Radboud University Nijmegen |
Baysal O.,Radboud University Nijmegen |
Beerendonk C.C.M.,Radboud University Nijmegen |
IntHout J.,Radboud University Nijmegen |
And 4 more authors.
Human Reproduction | Year: 2014
study question: How do female patients experience fertility preservation (FP) consultation (FPC) with a specialist in reproductive medicine and subsequent decision-making on FP? summaryanswer: Mostpatients had positive experiences with FPC, but negative experienceswere found to be associated with decisional conflict and decision regret. what is known already: When confronted with a need for gonadotoxic treatment, girls and young women will have to make an irreversible decision with regard to FP. Patients may experience decisional conflict and develop regret about their decision during follow-up. Patients' opportunities to ask questions during FPC and their knowledge about FP have been inversely related to decisional conflict. study design, size, duration: A questionnaire on experiences with FPC, designed after qualitative research, was retrospectively distributed to 108 patients to whom FP was offered after FPC between July 2008 and July 2013. Aiming to minimize recall bias, we defined a subgroup of patients counselled since 2011 who had not yet tried to conceive after FPC. participants/materials, setting, methods: Patients were aged ≥16 years and had either cancer or a benign disease that required gonadotoxic therapy. They received FPC in a single university hospital in the Netherlands. Apart from patients' experiences, patients' characteristics, decisional conflict and decision regret were assessed. main results and role of chance: A total of 64 patients (59.3%) responded to the questionnaire. Patients generally had positive experiences with FPC, but indicated room for improvement. Negative experiences were associated with decisional conflict regarding the FP decision (not enough time for counselling: P < 0.0001; not having the opportunity to ask all questions during FPC: P < 0.0001; not feeling supported by the counsellor during decision-making: P = 0.0003; not all applicable options were discussed: P = 0.0001; benefits and disadvantages of FP options were not clearly explained: P = 0.0005). Decisional conflict was correlated to decision regret (P < 0.0001). In the subgroup of patients counselled after 2011 who had not tried to conceive (n = 33), similar results as for the total study population were found for the association of patient experiences with decisional conflict. limitations, reasons for caution: Given our retrospective design, wewere not informed about the causality of the associations observed.We studied Dutch patients who were counselled in a single centre and were at least 16 years old when filling in the questionnaire. This may limit the generalizability of our data to other settings and populations. wider implications of the findings: More attention should be paid to improving FPC care. Interventions aiming at improving patients' comprehension of the topic of FP and their feelings of being supported in decision-making are advisable. © The Author 2014.
Donker M.,Netherlands Cancer Institute |
Straver M.E.,Netherlands Cancer Institute |
Meijnen P.,Netherlands Cancer Institute |
van de Velde C.J.H.,Leiden University |
And 25 more authors.
The Lancet Oncology | Year: 2014
Background: If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects. Methods: Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612. Findings: Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6.1 years (IQR 4.1-8.0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0.43% (95% CI 0.00-0.92) after axillary lymph node dissection versus 1.19% (0.31-2.08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0.00-5.27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years. Interpretation: Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity. Funding: EORTC Charitable Trust. © 2014 Elsevier Ltd.
Schmitt C.P.,Center for Pediatric and Adolescent Medicine |
Bakkaloglu S.A.,Gazi University |
Klaus G.,diatric Kidney Center |
Schroder C.,Gelre Hospital
Pediatric Nephrology | Year: 2011
The purpose of this article is to provide recommendations on the choice of peritoneal dialysis (PD) fluids in children by the European Pediatric Dialysis Working Group. The literature on experimental and clinical studies with PD solutions in children and adults was analyzed together with consensus discussions within the group. A grading was performed based on the international KDIGO nomenclature and methods. The lowest glucose concentration possible should be used. Icodextrin may be applied once daily during the long dwell, in particular in children with insufficient ultrafiltration. Infants on PD are at risk of ultrafiltration-associated sodium depletion, while anuric adolescents may have water and salt overload. Hence, the sodium chloride balance needs to be closely monitored. In growing children, the calcium balance should be positive and dialysate calcium adapted according to individual needs. Limited clinical experience with amino acid-based PD fluids in children suggests good tolerability. The anabolic effect, however, is small; adequate enteral nutrition is preferred. CPD fluids with reduced glucose degradation products (GDP) content reduce local and systemic toxicity and should be preferred whenever possible. Correction of metabolic acidosis is superior with pH neutral bicarbonate-based fluids compared with singlechamber, acidic, lactate-based solutions. Prospective comparisons of low GDP solutions with different buffer compositions are still few, and firm recommendations cannot yet be given, except when hepatic lactate metabolism is severely compromised. © IPNA 2010.