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Voor de evaluatie van de Basiskustlijn (BKL) 2023 is RWS in het voorjaar van 2021 gestart met een inventarisatie van de locaties die mogelijk in aanmerking kwamen voor herziening. Hierbij zijn vier locaties geïdentificeerd waar het praktisch moeilijk uitvoerbaar is om de positie van de kustlijn t.o.v. de BKL met reguliere zandsuppleties te handhaven en waar een landwaartse verlegging van de BKL niet wenselijk is vanwege aanwezige functies: Vlieland Havenstrand, Texel Zuidwest, Dishoek en Nieuwvliet-Groede. Voor deze vier locaties is het denkbaar dat andere oplossingen dan reguliere zandsuppleties kunnen bijdragen aan het efficiënter onderhouden van de kust. Daarom worden deze vier locaties nader beschouwd in dit verkennende onderzoek: “Verkenning probleemlocaties kustonderhoud”. Doel van het verkennende onderzoek is om een duidelijk pallet aan opties te geven voor alternatieve onderhoudsstrategieën voor de vier probleemlocaties, met daarbij de voor- en nadelen ten opzichte van de huidige beheer- en onderhoudsstrategie. Dit vormt een duidingskader voor een vervolg richting bijvoorbeeld beleidsmakers.

Het voorliggende rapport heeft als doel meer inzicht te geven in de cumulatieve effecten van de bagger- en verspreidingsactiviteiten, zoals de volumes en de methoden die daarmee gepaard gaan. We beschouwen zowel de activiteiten op Nederlands en op Duits grondgebied en de effecten hiervan op het abiotische en biotische systeem in het algemeen en meer specifiek op het doelbereik van de instandhoudingsdoelstellingen van habitattype H1130 (estuaria).

De IJsselmeerdijk beschermt de diepe Flevopolder tegen het water van het IJsselmeer. In 2018 heeft Waterschap Zuiderzeeland (hierna afgekort als: Zuiderzeeland) beoordeeld of de IJsselmeerdijk zo sterk is als de waterveiligheidsnormen voorschrijven. Dat blijkt niet zo te zijn. Zuiderzeeland is daarom in 2019 gestart met het meerjarige project Versterking IJsselmeerdijk. Het deel van de IJsselmeerdijk dat versterkt moet worden, is 17,6 km lang en ligt aan de noordwestzijde van Oostelijk Flevoland. De waterkering loopt van de Ketelbrug in het noorden tot aan de Houtribdijk in Lelystad. Het projectdoel is het realiseren van een veilige én toekomstbestendige dijk. De nieuwe dijk wordt goed ingepast in de omgeving met behoud van de huidige ruimtelijke kwaliteit en er wordt nadrukkelijk gezocht naar de mogelijkheden voor het inpassen van innovatieve en duurzame oplossingen. Momenteel bevindt het project zich in de Verkenningsfase, volgens de fasering uit het landelijke Hoogwaterbeschermingsprogramma (HWBP). De planning is nu dat de verkenning halverwege 2022 wordt afgerond en resulteert in een Voorkeursbeslissing (VKB). De periode 2022- 2024 staat gepland voor de planuitwerkingsfase, in de periode hierna volgt de realisatiefase.

Bij Delfzijl is een kwelderlandschap aangelegd voor de kust als onderdeel van de gebiedsontwikkeling Marconi Buitendijks. Ter verduidelijking, er is niet een volgroeide kwelder aangelegd maar een lage onbegroeide kwelder welke zou moeten uitgroeien tot een volledig kwelderlandschap dat gekenmerkt wordt door een opeenvolging van hoge, middel en lage kwelder en wadplaten. Een deel van het aangelegde kwelderlandschap is ingericht als proefkwelder en een ander deel is ingericht als stadskwelder (ook wel kwelderpark genoemd). De hoofddoelstellig van het project was een veilige en aantrekkelijke kust met ruimte voor recreatie. Eén van de nevendoelstellingen van het project is het delen van kennis over de aanleg van kwelders en het uitdragen van de bredere toepasbaarheid en voordelen daarvan. Dit rapport gaat over dit nevendoel.

Item does not contain fulltext, Teachers are increasingly acting as co-designers of curriculum materials, because this process can positively affect their professional development while also yielding resources that are relevant and useful for their teaching practice. This study explores evidence related to the claim that involving teachers in collaborative design is worth the effort. We used two data sources: papers from scientific journals, reflecting the researcher’s perspective, and from professional journals, providing a colloquial corpus reflecting the teacher’s perspective. We conclude that the colloquial corpus justifies our claim that co-design is gaining momentum, but that the scientific corpus is still limited in number of articles. We were able to identify common patterns across the professional articles that complement the patterns identified in the scientific corpus. At the same time, two distinct pictures of design teams emerge from these two corpora, with different process characteristics as well as reported effects.

Contains fulltext : 215547.pdf (publisher's version ) (Open Access), Background: The effect of extended adjuvant aromatase inhibition in hormone-positive breast cancer after sequential tamoxifen, aromatase inhibitor treatment of 5 years was recently investigated by the DATA study. This study found no statistically significant effect of prolonged aromatase therapy. However, subgroup analysis showed post hoc statistically significant benefits in certain sub-populations. The trans-DATA study is a translational sub-study aiming to identify DNA methylation markers prognostic of patient outcome. Methods: Patients from the DATA study are included in the trans-DATA study. Primary breast tumour tissue will be collected, subtyped and used for DNA isolation. A genome-wide DNA methylation discovery assay will be performed on 60 patients that had a distant recurrence and 60 patients that did not have a distant recurrence using the Infinium Methylation EPIC Bead Chip platform. Differentially methylated regions of interest will be selected based on Akaike's Information Criterion, Gene Ontology Analysis and correlation between methylation and expression levels. Selected candidate genes will subsequently be validated in the remaining patients using qMSP. Discussion: The trans-DATA study uses a cohort derived from a clinical randomised trial. This study was designed to avoid common pitfalls in marker discovery studies such as selection bias, confounding and lack of reproducibility. In addition to the usual clinical risk factors, the results of this study may identify predictors of high recurrence risk in hormone receptor-positive breast cancer patients treated with sequential tamoxifen and aromatase inhibitor therapy.

Klimaatstresstesten staan volop in de belangstelling bij gemeenten en waterschappen. Vooraf toetsen en optimaliseren van een stedenbouwkundig ontwerp op klimaatbestendigheid is een kleine moeite en kan problemen en ongewenste kosten achteraf voorkomen. Nog mooier is het als de toets integraal onderdeel is van het ontwerpproces. In de Zwolse nieuwbouwwijk Breezicht zijn interessante ervaringen opgedaan.

6 februari 2016, Contains fulltext : 176743pub.pdf (publisher's version ) (Closed access), Economic classroom experiments are controlled interactive learning exercises targeting the comprehension of economic concepts in an inductive way. Aiming at increasing students’ knowledge of economic concepts, two types of economic classroom experiments are examined in a sample of 134 secondary school students. In the interactive research condition, 44 students participate in a series of four experiments, whereas in the constructive condition, 49 students observe four videos showing peers engaged in similar experiments. The 41 students in the control condition attend four lessons based on the model of direct instruction. ANCOVAs and contrast analyses indicate that interactive learning from experiences in economic classroom experiments is beneficial for secondary school students’ knowledge of economic concepts. Reasons for this finding are elaborated on the basis of observed student activities, interactions, communication, and self-reported experiences.

Contains fulltext : 181608.pdf (publisher's version ) (Open Access)

Sinds eind jaren negentig van de vorige eeuw zijn in Nederland ongeveer twintig natuurbegraafplaatsen geopend. Dit zijn begraafplaatsen en natuurgebieden waar de begraaffunctie en natuurfunctie naast elkaar staan. Maar bij elk nieuw initiatief ontstaat discussie. Voorstanders vinden dat natuurbegraven tegemoet komt aan een behoefte in de samenleving en vinden het een natuurvriendelijk alternatief. Tegenstanders zien die maatschappelijke behoefte niet en vinden natuurbegraven een niet-duurzame ingreep die afbreuk doet aan de natuur, het milieu en de beleving van natuurgebieden. In dit artikel beschrijven we de gebruikte voors en tegens van natuurbegraven. Vervolgens beschrijven we hoe het natuurbegraven zich in Nederland op dit moment manifesteert, en gaan we in op de effecten van natuurbegraven op landschap, milieu en natuur.

Contains fulltext : 168191.pdf (publisher's version ) (Closed access), The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.

Contains fulltext : 176747pub.pdf (publisher's version ) (Closed access), This study explored whether and how economic classroom experiments may enhance the economic knowledge and the reasoning ability of 108 secondary school students. Economic classroom experiments are controlled interactive learning exercises by means of which students can learn to think as economists. Economic reasoning is conceptualized as the ability to identify a correct cause-and-effect relationship between variables. Students formulate an initial hypothesis by indicating two main variables from an economic context, determining associations between these, and formulating possible explanations. Subsequently, students test their hypothesis and try to establish the accuracy of their initial ideas. From the economic classroom experiments used in the study, students have to derive key variables, determine how these variables were related, and provide explanations. The goal of the study is to investigate whether actually participating in economic classroom experiments (n = 36) is more beneficial to learning than either watching others perform economic classroom experiments (n = 27) or merely analyzing the data produced by other students within such experiments (n = 45). Contrary to expectations, students who observe experiments and students who analyze experimental data show higher and sustained gains in their knowledge of economic concepts than students who participate in the experiments. Moreover, experiment participation turns out to be less beneficial for the reasoning-ability of students than video observation and data analysis. Possible explanations for these findings are discussed.

Contains fulltext : 167655.pdf (publisher's version ) (Closed access), We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome. There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy" profile, flat philtrum, and diastema of the teeth. Intellectual disability, ranging from mild to moderate, was present in all. Hypotonia is common in infancy (8/19). Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males). Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19). There is persistence of oral motor dysfunction. We provide suggestions for clinical work-up and management and hope that the present study will facilitate clinical recognition of further cases.

Contains fulltext : 171436.pdf (publisher's version ) (Open Access), Triple-negative breast cancer is associated with early recurrence and low survival rates. Several trials investigate the safety of a more conservative approach of axillary treatment in clinically T1-2N0 breast cancer. Triple-negative breast cancer comprises only 15 % of newly diagnosed breast cancers, which might result in insufficient power for representative results for this subgroup. We aimed to provide a nationwide overview on the occurrence of (regional) recurrences in triple-negative breast cancer patients with a clinically T1-2N0 status. For this cohort study, 2548 women diagnosed between 2005 and 2008 with clinically T1-2N0 triple-negative breast cancer were selected from the Netherlands Cancer Registry. Follow-up data until 2014 were analyzed using Kaplan-Meier. Sentinel lymph node biopsy was performed in 2486 patients, and (completion) axillary lymph node dissection in 562 patients. Final pathologic nodal status was pN0 in 78.5 %, pN1mi in 4.5 %, pN1 in 12.3 %, pN2-3 in 3.6 %, and pNx in 1.1 %. During a follow-up of 5 years, regional recurrence occurred in 2.9 %, local recurrence in 4.2 % and distant recurrence in 12.2 %. Five-year disease-free survival was 78.7 %, distant disease-free survival 80.5 %, and 5-year overall survival 82.3 %. Triple-negative clinically T1-2N0 breast cancer patients rarely develop a regional recurrence. Their disease-free survival is more threatened by distant recurrence, affecting their overall survival. Consequently, it seems justified to include triple-negative breast cancer patients in randomized controlled trials investigating the safety of minimizing axillary staging and treatment.

Item does not contain fulltext, BACKGROUND: The aim of this study was to evaluate the accuracy of clinical imaging of the primary breast tumour post-neoadjuvant chemotherapy (NAC) related to the post-neoadjuvant histological tumour size (gold standard) and whether this varies with breast cancer subtype. In this study, results of both magnetic resonance imaging (MRI) and ultrasound (US) were reported. METHODS: Patients with invasive breast cancer were enrolled in the INTENS study between 2006 and 2009. We included 182 patients, of whom data were available for post-NAC MRI (n=155), US (n=123), and histopathological tumour size. RESULTS: MRI estimated residual tumour size with <10-mm discordance in 54% of patients, overestimated size in 28% and underestimated size in 18% of patients. With US, this was 63%, 20% and 17%, respectively. The negative predictive value in hormone receptor-positive tumours for both MRI and US was low, 26% and 33%, respectively. The median deviation in clinical tumour size as percentage of pathological tumour was 63% (P25=26, P75=100) and 49% (P25=22, P75=100) for MRI and US, respectively (P=0.06). CONCLUSIONS: In this study, US was at least as good as breast MRI in providing information on residual tumour size post-neoadjuvant chemotherapy. However, both modalities suffered from a substantial percentage of over- and underestimation of tumour size and in addition both showed a low negative predictive value of pathologic complete remission (Gov nr: NCT00314977).

Radboud Universiteit Nijmegen, 24 februari 2016, Promotor : Sent, E.-M. Co-promotor : Vries, B. de, Contains fulltext : 151095.pdf (publisher's version ) (Open Access)

Item does not contain fulltext, BACKGROUND: Hemiplegic migraine (HM) and alternating hemiplegia of childhood (AHC) are rare episodic neurological brain disorders with partial clinical and genetic overlap. Recently, ATP1A3 mutations were shown to account for the majority of AHC patients. In addition, a mutation in the SLC2A1 gene was reported in a patient with atypical AHC. We therefore investigated whether mutations in these genes may also be involved in HM. Furthermore, we studied the role of SLC2A1 mutations in a small set of AHC patients without ATP1A3 mutations. METHODS: We screened 42 HM patients (21 familial and 21 sporadic patients) for ATP1A3 and SLC2A1 mutations. In addition, four typical AHC patients and one atypical patient with overlapping symptoms of both disorders were screened for SLC2A1 mutations. RESULTS: A pathogenic de novo SLC2A1 mutation (p.Gly18Arg) was found in the atypical patient with overlapping symptoms of AHC and hemiplegic migraine. No mutations were found in the HM and the other AHC patients. CONCLUSION: Screening for a mutation in the SLC2A1 gene should be considered in patients with a complex phenotype with overlapping symptoms of hemiplegic migraine and AHC.

Contains fulltext : 154153.pdf (publisher's version ) (Open Access), Clusters of functionally related genes can be disrupted by a single copy number variant (CNV). We demonstrate that the simultaneous disruption of multiple functionally related genes is a frequent and significant characteristic of de novo CNVs in patients with developmental disorders (P = 1 x 10(-3)). Using three different functional networks, we identified unexpectedly large numbers of functionally related genes within de novo CNVs from two large independent cohorts of individuals with developmental disorders. The presence of multiple functionally related genes was a significant predictor of a CNV's pathogenicity when compared to CNVs from apparently healthy individuals and a better predictor than the presence of known disease or haploinsufficient genes for larger CNVs. The functionally related genes found in the de novo CNVs belonged to 70% of all clusters of functionally related genes found across the genome. De novo CNVs were more likely to affect functional clusters and affect them to a greater extent than benign CNVs (P = 6 x 10(-4)). Furthermore, such clusters of functionally related genes are phenotypically informative: Different patients possessing CNVs that affect the same cluster of functionally related genes exhibit more similar phenotypes than expected (P < 0.05). The spanning of multiple functionally similar genes by single CNVs contributes substantially to how these variants exert their pathogenic effects.

Contains fulltext : 153827.pdf (publisher's version ) (Closed access), Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.

Item does not contain fulltext, Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI.

Item does not contain fulltext, The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.

Contains fulltext : 152973.pdf (publisher's version ) (Closed access), Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because RBPJ, NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pathogenesis. Using a candidate-gene-based approach, we prioritized DLL4, a critical NOTCH ligand, due to its essential role in vascular development in the context of cardiovascular features in AOS-affected individuals. Targeted resequencing of the DLL4 gene with a custom enrichment panel in 89 independent families resulted in the identification of seven mutations. A defect in DLL4 was also detected in two families via whole-exome or genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants, the latter encompassing four mutations that replace or create cysteine residues, which are most likely critical for maintaining structural integrity of the protein. Affected individuals with DLL4 mutations present with variable clinical expression with no emerging genotype-phenotype correlations. Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder.

Item does not contain fulltext, Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.

Item does not contain fulltext, BACKGROUND: The impact of drug prescriptions in real life as opposed to strict clinical trial prescription is only rarely assessed, although it is well recognized that incorrect use may harm patients and may have a significant impact on health care resources. We investigated the use and effectiveness of adjuvant trastuzumab in daily practice compared with the effectiveness in clinical trials. METHODS: We included all patients with stage I-III invasive breast cancer, irrespective of human epidermal growth factor receptor 2 (HER2) status, diagnosed in five hospitals in the southeast of The Netherlands in 2005-2007. We aimed to assess the actual use of adjuvant trastuzumab in early HER2-positive breast and its efficacy in daily practice. RESULTS: Of 2,684 patients included, 476 (17.7%) had a HER2-positive tumor. Of these, 251 (52.7%) patients had an indication for trastuzumab treatment of which 196 (78.1%) patients actually received it. Of the 225 patients without an indication, 34 (15.1%) received trastuzumab. Five-year disease-free survival was 80.7% for (n = 230) patients treated with versus 68.2% for (n = 246) patients not treated with trastuzumab (p = .0023), and 5-year overall survival rates were 90.7% and 77.4%, respectively (p = .0002). The hazard ratio for disease recurrence was 0.63 (95% confidence interval, 0.37-1.06) for trastuzumab when adjusting for potential confounders. CONCLUSION: This study shows that in real life, patients treated with trastuzumab in early-stage HER2-positive breast cancer had a 5-year disease-free and overall survival comparable to prior randomized trials. For informative decision making, real-life data are of additional value, providing insight on outcome of patients considered ineligible for treatment.