Fifty percent of patients with muscle-invasive bladder cancer (MI-BC) die from their disease and current chemotherapy treatment only marginally increases survival. Novel therapies targeting receptor ...tyrosine kinases or activated oncogenes may improve outcome. Hence, it is necessary to stratify patients based on mutations in relevant oncogenes. Patients with non-muscle-invasive bladder cancer (NMI-BC) have excellent survival, however two-thirds develop recurrences. Tumor specific mutations can be used to detect recurrences in urine assays, presenting a more patient-friendly diagnostic procedure than cystoscopy.
To address these issues, we developed a mutation assay for the simultaneous detection of 19 possible mutations in the HRAS, KRAS, and NRAS genes. With this assay and mutation assays for the FGFR3 and PIK3CA oncogenes, we screened primary bladder tumors of 257 patients and 184 recurrences from 54 patients. Additionally, in primary tumors p53 expression was obtained by immunohistochemistry. Of primary tumors 64% were mutant for FGFR3, 11% for RAS, 24% for PIK3CA, and 26% for p53. FGFR3 mutations were mutually exclusive with RAS mutations (p = 0.001) and co-occurred with PIK3CA mutations (p = 0.016). P53 overexpression was mutually exclusive with PIK3CA and FGFR3 mutations (p≤0.029). Mutations in the RAS and PIK3CA genes were not predictors for recurrence-free, progression-free and disease-specific survival. In patients presenting with NMI-BC grade 3 and MI-BC, 33 and 36% of the primary tumors were mutant. In patients with low-grade NMI-BC, 88% of the primary tumors carried a mutation and 88% of the recurrences were mutant.
The mutation assays present a companion diagnostic to define patients for targeted therapies. In addition, the assays are a potential biomarker to detect recurrences during surveillance. We showed that 88% of patients presenting with low-grade NMI-BC are eligible for such a follow-up. This may contribute to a reduction in the number of cystoscopical examinations.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Preterm born infants are at risk for brain injury and subsequent developmental delay. Treatment options are limited, but optimizing postnatal nutrition may improve brain- and ...neurodevelopment in these infants. In pre-clinical animal models, combined supplementation of docosahexaenoic acid (DHA), choline, and uridine-5-monophosphate (UMP) have shown to support neuronal membrane formation. In two randomized controlled pilot trials, supplementation with the investigational product was associated with clinically meaningful improvements in cognitive, attention, and language scores. The present study aims to assess the effect of a similar nutritional intervention on brain development and subsequent neurodevelopmental outcome in infants born very and extremely preterm. Methods This is a randomized, placebo-controlled, double-blinded, parallel-group, multi-center trial. A total of 130 infants, born at less than 30 weeks of gestation, will be randomized to receive a test or control product between term-equivalent age and 12 months corrected age (CA). The test product is a nutrient blend containing DHA, choline, and UMP amongst others. The control product contains only fractions of the active components. Both products are isocaloric powder supplements which can be added to milk and solid feeds. The primary outcome parameter is white matter integrity at three months CA, assessed using diffusion-tensor imaging (DTI) on MRI scanning. Secondary outcome parameters include volumetric brain development, cortical thickness, cortical folding, the metabolic and biochemical status of the brain, and product safety. Additionally, language, cognitive, motor, and behavioral development will be assessed at 12 and 24 months CA, using the Bayley Scales of Infant Development III and digital questionnaires (Dutch version of the Communicative Development Inventories (N-CDI), Ages and Stages Questionnaire 4 (ASQ-4), and Parent Report of Children's Abilities - Revised (PARCA-R)). Discussion The investigated nutritional intervention is hypothesized to promote brain development and subsequent neurodevelopmental outcome in preterm born infants who have an inherent risk of developmental delay. Moreover, this innovative study may give rise to new treatment possibilities and improvements in routine clinical care. Trial registration WHO International Clinical Trials Registry: NL-OMON56181 (registration assigned October 28, 2021). Keywords: Nutrition, Preterm infant, Docosahexaenoic acid, Brain development, MRI, White matter integrity, Neurodevelopment, Language
Study Type – Prognosis (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
The stakes are high when making treatment decisions in T1 bladder cancer (BC). ...Conservative management may lead to progression and possibly death from BC. Conversely, radical cystectomy could be over‐treatment of non‐progressive disease. The problem for clinicians is that reliable prognostic indices are lacking.
We performed a head‐to‐head comparison of two substaging systems, European Organisation for the Research and Treatment of Cancer (EORTC) risk scores and four molecular markers in T1 carcinomas of the bladder treated conservatively with BCG. T1 sub‐stage according to a new system (micro‐invasive T1m and extensive‐invasive T1e) was the most important clinical variable for predicting progression to carcinoma invading bladder muscle. The performance of the EORTC risk scores was disappointing for this T1 sub‐group. Molecular markers were not significant in multivariable analysis for predicting progression. Future studies may lead to the incorporation of sub‐stage (T1m/T1e) in the TNM classification system for urinary BC to guide clinical decision‐making in T1 BC.
OBJECTIVE
•
To evaluate the prognostic significance of four molecular markers, sub‐stage and European Organisation for the Research and Treatment of Cancer (EORTC) risk scores in primary T1 bladder cancer (BC) treated with adjuvant bacille Calmette–Guérin.
PATIENTS AND METHODS
•
The slides of 129 carcinomas of the bladder from two university hospitals were reviewed and the T1 diagnosis was confirmed.
•
T1 sub‐staging was done in two separate rounds, using a new system that identifies micro‐invasive (T1m) and extensive‐invasive (T1e) T1BC, and then according to invasion of the muscularis mucosae (T1a/T1b/T1c).
•
The EORTC risk scores for recurrence and progression were calculated.
•
Uni‐ and multivariable analyses for recurrence and progression were performed using clinicopathological variables, T1 sub‐stage, EORTC risk scores and molecular markers (fibroblast growth factor receptor 3 gene mutation and Ki‐67, P53, P27 expression).
RESULTS
•
The median follow‐up was 6.5 years. Forty‐two patients remained recurrence‐free (33%). Progression to T2 or metastasis was observed in 38 (30%) patients.
•
In multivariable analysis for recurrence, multiplicity was significant. In multivariable analysis for progression, female gender, sub‐stage (T1m/T1e) and carcinoma in situ (CIS) were significant.
•
Molecular markers were significant in univariable and in multivariable analyses for recurrence.
•
EORTC risk scores were not significant.
CONCLUSIONS
•
CIS, female gender and sub‐stage (T1m/T1e) were the most important variables for progression.
•
The additional value of molecular markers was modest.
•
Sub‐stage (T1m/T1e) could potentially be incorporated in future tumour‐node‐metastasis classifications.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Neonatal stroke, including perinatal arterial ischaemic stroke and cerebral sinovenous thrombosis, remains a serious problem in the neonate. This article reviews the current evidence on epidemiology, ...pathogenesis, diagnostics and therapeutic options.
Conclusion
Although our understanding of the underlying mechanisms and possible risk factors has improved, little progress has been made towards therapeutic options. Considering the high incidence of neurological sequelae, the need for therapeutic options is high and should be the focus of future research.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy.
To assess ...further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region.
The 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients.
Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.
Purpose We evaluated the influence of knowledge of urine test outcome on the accuracy of cystoscopy (diagnostic review bias) during surveillance in patients with low grade, nonmuscle invasive ...urothelial carcinoma. Materials and Methods We performed a prospective, single-blind, randomized, multicenter clinical trial of surveillance by microsatellite analysis urine test in 448 patients with nonmuscle invasive (pTa, pT1, G1, G2) urothelial carcinoma. Positive or negative urine test results were only communicated to the urologist in the intervention arm of 226 patients, in which cystoscopy was done if the test was positive, and at 3, 12 and 24 months. Urine test results were not communicated in the control arm of 222 patients who underwent standard 3-month cystoscopy. The primary outcome measure was the number of histologically proven bladder cancer recurrences. Results At a median 34-month followup 218 recurrences were detected in the intervention arm compared to 163 in the control arm (p <0.001). Of 131 cystoscopies done with knowledge of a positive urine test 42 recurrences were detected. Only 6 recurrences were found in the 120 cystoscopies done without information on the positive test result (chi-square p <0.001). There was no difference in recurrence detection when urine test results were negative in the intervention and control arms (18 of 260 patients or 7% and 18 of 326 or 6%, respectively, p = 0.45). Conclusions Diagnostic review bias should be considered in the evaluation of point of care urine tests for bladder cancer monitoring. Awareness of a positive urine test result significantly improves the urothelial carcinoma detection rate using cystoscopy.
Abstract Background Management of T1 bladder cancer (BCa) is controversial. Objective Evaluate the impact of substage on the clinical outcome of T1 BCa. Design, setting, and participants The T1 ...diagnosis of 134 first-diagnosis BCa patients from two university hospitals was confirmed. For the T1 substage, we used a new system that discerns T1-microinvasive (T1m) and T1-extensive-invasive (T1e) tumors. We then determined the invasion of the muscularis mucosae–vascular plexus (MM-VP): T1a (invasion above the MM-VP), T1b (invasion in the MM-VP), or T1c (invasion beyond the MM-VP). If the MM-VP was not present at the invasion front, the case was assigned to T1a or T1c. All patients were initially managed conservatively (with bacillus Calmette-Guérin). Measurements Multivariable analyses for progression and disease-specific survival (DSS). Results and limitations Median follow-up was 6.4 yr (interquartile range: 3.3–9.2 yr). Progression to ≥T2 was observed in 40 patients (30%), and 19 patients (14%) died of BCa. The MM-VP was not present at the invasion front in 50 patients (37%). T1 substage was as follows: 40 T1m and 94 T1e; 81 T1a, 18 T1b, and 35 T1c. In multivariable analyses, substage (T1m/T1e) was significant for progression ( p = 0.001) and DSS ( p = 0.032), whereas substage according to T1a/T1b/T1c was not significant. Female gender ( p = 0.006) and carcinoma in situ ( p = 0.034) were also significant predictors of progression. The main limitation to the study is absence of a repeat transurethral resection. Conclusions Substage according to the new system (T1m and T1e) was user-friendly, possible in 100% of cases, and very predictive of T1 BCa behavior. Future studies may ultimately lead to the incorporation of this new substaging system in the TNM classification system for urinary BCa.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Over the next few decades, many Western European countries will undergo a large demographic transformation introduced by the retirement of the "baby boomers" and the possibility of striking increases ...in longevity. The aim of this study was to estimate the effect of a growing and ageing Dutch population on the future consumption of pharmaceuticals, so as to be able to anticipate the potential future emissions of these pharmaceuticals and their residues to surface waters. A total of 354 prescribed pharmaceuticals from 40 therapeutic groups was selected for study. These constitute 1.251 metric tonnes (98%) of the total Dutch consumption of prescribed pharmaceuticals in 2007. Calculations based on a fixed consumption rate (2007) predict that demographic developments can be expected to push consumption up to 1.504 metric tonnes in 2020 (+17%) and 1.851 metric tonnes by 2050 (+37%). Therapeutic groups showing the largest increase are related to illnesses associated with old age. The only groups showing a decrease are the antivirals and drugs for addiction treatments as well as ethinylestradiol, an active compound in contraceptives.
Cerebral MR imaging in infants is usually performed with a field strength of up to 3T. In adults, a growing number of studies have shown added diagnostic value of 7T MR imaging. 7T MR imaging might ...be of additional value in infants with unexplained seizures, for example. The aim of this study was to investigate the feasibility of 7T MR imaging in infants. We provide information about the safety preparations and show the first MR images of infants at 7T.
Specific absorption rate levels during 7T were simulated in Sim4life using infant and adult models. A newly developed acoustic hood was used to guarantee hearing protection. Acoustic noise damping of this hood was measured and compared with the 3T Nordell hood and no hood. In this prospective pilot study, clinically stable infants, between term-equivalent age and the corrected age of 3 months, underwent 7T MR imaging immediately after their standard 3T MR imaging. The 7T scan protocols were developed and optimized while scanning this cohort.
Global and peak specific absorption rate levels in the infant model in the centered position and 50-mm feet direction did not exceed the levels in the adult model. Hearing protection was guaranteed with the new hood. Twelve infants were scanned. No MR imaging-related adverse events occurred. It was feasible to obtain good-quality imaging at 7T for MRA, MRV, SWI, single-shot T2WI, and MR spectroscopy. T1WI had lower quality at 7T.
7T MR imaging is feasible in infants, and good-quality scans could be obtained.
Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly ...sequence or Miller-Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller-Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes.
Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3.
Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3epsilon). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms.
The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations.
PDF
