Endocrinologic disorders and optic pathway gliomas in children with neurofibromatosis type 1

Objective. To establish the prevalence of endocrinologic disorders in children with neurofibromatosis type 1 (NF1) and the relationship between these disorders and cerebral abnormalities on magnetic resonance imaging. Design. A prospective follow-up study. Setting. A multidisciplinary neurofibromatosis clinic. Patients. A total of 122 children diagnosed with NF1 according to diagnostic criteria set by the National Institutes of Health. Results. Central precocious puberty (CPP) was diagnosed in 3 children and growth hormone deficiency (GHD) in 3 children. Optic pathway gliomas were observed in 15 children; in 9 of the 15 cases, the optic chiasm was involved. Of the 3 children with CPP, only 1 showed a chiasma glioma on magnetic resonance imaging. In 1 case with GHD, an optic chiasm glioma was detected on neuroimaging. Two of the 9 children with an optic chiasm glioma presented with CPP or GHD. Conclusions. It has been suggested that CPP in children with NF1 is found exclusively in the presence of a chiasma glioma. We conclude that chiasma glioma may not be obligatory in children with NF1 and CPP or GHD. Moreover, we report a prevalence of GHD in children with NF1 of 2.5%, which has not been established earlier

Seminal vesicle intrafraction motion during the delivery of radiotherapy sessions on a 1.5 T MR-Linac

Purpose To evaluate seminal vesicle (SV) intrafraction motion using cinematic magnetic resonance imaging (cine-MR) during the delivery of online adaptive MR-Linac radiotherapy fractions, in preparation of MR-guided extremely hypofractionated radiotherapy for intermediate to high-risk prostate cancer patients. Material and Methods Fifty prostate cancer patients were treated with 5 × 7.25 Gy on a 1.5 Tesla MR-Linac. 3D Cine-MR imaging was started simultaneously and acquired over the full beam-on period. Intrafraction motion in this cine-MR was determined for each SV separately with a previously validated soft-tissue contrast-based tracking algorithm. Motion statistics and coverage probability for the SVs and prostate were determined based on the obtained results. Results SV motion was automatically determined during the beam-on period (approx. 10 min) for 247 fractions. SV intrafraction motion shows larger spread than prostate intrafraction motion and increases over time. This difference is especially evident in the anterior and cranial translation directions. Significant difference in rotation about the left–right axis was found, with larger rotation for the SVs than the prostate. Intra-fraction coverage probability of 99% can be achieved when using 5 mm isometric expansion for the left and right SV and 3 mm for the prostate. Conclusion This is the first study to investigate SV intrafraction motion during MR-guided RT sessions on an MR-Linac. We have shown that high quality 3D cine-MR imaging and SV tracking during RT is feasible with beam-on. The tracking method as described may be used as input for a fast replanning algorithm, which allows for intrafraction plan adaptation

Prostate intrafraction motion during the preparation and delivery of MR-guided radiotherapy sessions on a 1.5T MR-Linac

Purpose: To evaluate prostate intrafraction motion using MRI during the full course of online adaptive MR-Linac radiotherapy (RT) fractions, in preparation of MR-guided extremely hypofractionated RT. Material and methods: Five low and intermediate risk prostate cancer patients were treated with 20 × 3.1 Gy fractions on a 1.5T MR-Linac. Each fraction, initial MRI (Pre) scans were obtained at the start of every treatment session. Pre-treatment planning MRI contours were propagated and adapted to this Pre scan after which plan re-optimization was started in the treatment planning system followed by dose delivery. 3D Cine-MR imaging was started simultaneously with beam-on and acquired over the full beam-on period. Prostate intrafraction motion in this cine-MR was determined with a previously validated soft-tissue contrast based tracking algorithm. In addition, absolute accuracy of the method was determined using a 4D phantom. Results: Prostate motion was completely automatically determined over the full on-couch period (approx. 45 min) with no identified mis-registrations. The translation 95% confidence intervals are within clinically applied margins of 5 mm, and plan adaption for intrafraction motion was required in only 4 out of 100 fractions. Conclusion: This is the first study to investigate prostate intrafraction motions during entire MR-guided RT sessions on an MR-Linac. We have shown that high quality 3D cine-MR imaging and prostate tracking during RT is feasible with beam-on. The clinically applied margins of 5 mm have proven to be sufficient for these treatments and may potentially be further reduced using intrafraction plan adaptation guided by cine-MR imaging

Delivered dose quantification in prostate radiotherapy using online 3D cine imaging and treatment log files on a combined 1.5T magnetic resonance imaging and linear accelerator system

Background and purpose: Monitoring the intrafraction motion and its impact on the planned dose distribution is of crucial importance in radiotherapy. In this work we quantify the delivered dose for the first prostate patients treated on a combined 1.5T Magnetic Resonance Imaging (MRI) and linear accelerator system in our clinic based on online 3D cine-MR and treatment log files. Materials and methods: A prostate intrafraction motion trace was obtained with a soft-tissue based rigid registration method with six degrees of freedom from 3D cine-MR dynamics with a temporal resolution of 8.5–16.9 s. For each fraction, all dynamics were also registered to the daily MR image used during the online treatment planning, enabling the mapping to this reference point. Moreover, each fraction's treatment log file was used to extract the timestamped machine parameters during delivery and assign it to the appropriate dynamic volume. These partial plans to dynamic volume combinations were calculated and summed to yield the delivered fraction dose. The planned and delivered dose distributions were compared among all patients for a total of 100 fractions. Results: The clinical target volume underwent on average a decrease of 2.2% ± 2.9% in terms of D99% coverage while bladder V62Gy was increased by 1.6% ± 2.3% and rectum V62Gy decreased by 0.2% ± 2.2%. Conclusions: The first MR-linac dose reconstruction results based on prostate tracking from intrafraction 3D cine-MR and treatment log files are presented. Such a pipeline is essential for online adaptation especially as we progress to MRI-guided extremely hypofractionated treatments

Epidemiology of extremity fractures in the Netherlands

Insight in epidemiologic data of extremity fractures is relevant to identify people at risk. By analyzing age- and gender specific fracture incidence and treatment patterns we may adjust future policy, take preventive measures and optimize health care management. Current epidemiologic data on extremity fractures and their treatment are scarce, outdated or aiming at a small spectrum of fractures. The aim of this study was to assess trends in incidence and treatment of extremity fractures between 2004 and 2012 in relation to gender and age. We used a combination of national registries of patients aged ≥ 16 years with extremity fractures. Fractures were coded by the International Classification of Diseases (ICD) 10, and allocated to an anatomic region. ICD-10 codes were used for combining the data of the registries. Absolute numbers, incidences, number of patients treated in university hospitals and surgically treated patients were reported. A binary logistic regression was used to calculate trends during the study period. From 2004 to 2012 the Dutch population aged ≥16 years grew from 13,047,018 to 13,639,412 inhabitants, particularly in the higher age groups of 46 years and older. The absolute number of extremity fractures increased significantly from 129,188 to 176,129 (OR 1.308 [1.299-1.318]), except for forearm and lower leg fractures. Incidences increased significantly (3-4%) for wrist, hand/finger, hip/upper leg, ankle and foot/toe fractures. In contrast to the older age categories from 66 years and older, in younger age categories from 16 to 35 years, fractures of the extremities were more frequent in men than in women. Treatments gradually moved towards non-university hospitals for all except forearm fractures. Both relative and absolute numbers increased for surgical treatments of clavicle/shoulder, forearm, wrist and hand/finger fractures. Contrarily, lower extremity fractures showed an increase in non-surgical treatment, except for lower leg fractures. During the study period, we observed an increasing incidence of extremity fractures and a shift towards surgical treatment. Patient numbers in university hospitals declined. If these trends continue, policy makers would be well advised to consider the changing demands in extremity fracture treatment and pro-actively increase capacity and resource

Systematic CT evaluation of reduction and hardware positioning of surgically treated calcaneal fractures: a reliability analysis

Up to date, there is a lack of reliable protocols that systematically evaluate the quality of reduction and hardware positioning of surgically treated calcaneal fractures. Based on international consensus, we previously introduced a 23-item scoring protocol evaluating the reduction and hardware positioning in these fractures based on postoperative computed tomography. The current study is a reliability analysis of the described scoring protocol. Three raters independently and systematically evaluated anonymized postoperative CT scans of 102 surgically treated calcaneal fractures. A selection of 25 patients was scored twice by all individual raters to calculate intra-rater reliability. The scoring protocol consisted of 23 items addressing quality of reduction and hardware positioning. Each of these four-option questions was answered as: 'optimal', 'suboptimal (but not needing revision)', 'not acceptable (needing revision)' or 'not judgeable'. We used intraclass correlation coefficients (ICC's) to calculate inter- and intra-rater reliability. Inter-rater reliability of the overall 23-item protocol was good (ICC 0.66, 95% CI 0.64-0.69). Individual items that scored an inter-rater ICC ae 0.60 included evaluation of the calcaneocuboid joint, the posterior talocalcaneal joint, the anterior talocalcaneal joint, the position of the plate and sustentaculum screws and screws protruding the tuber and medial wall. The intra-rater reliability for the overall protocol was good for all three individual raters with ICC's between 0.60 and 0.70. Our scoring protocol for the radiological evaluation of operatively treated calcaneal fractures is reliable in terms of inter- and intra-rater reliabilit

CYTOKINE PRODUCTION BY THE HUMAN BLADDER-CARCINOMA CELL-LINE T24 IN THE PRESENCE OF BACILLUS-CALMETTE-GUERIN (BCG)

The study was initiated as an in vitro approach to the situation existing during intravesical bacillus Calmette-Guerin (BCG) instillation in patients with superficial bladder cancer. Cytokine secretion of a human bladder carcinoma cell line T 24 treated with BCG was investigated. A 24-h treatment of T24 cells with BCG resulted in a tenfold higher secretion of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFalpha) when compared with T24 cells treated with Escherichia coli, Streptococcus faecalis or a cell wall preparation of Nocardia rubra (N-CWS). No secretion of IL-1beta and IL,2 was detected. Pre-exposing T24 cells to BCG for various periods of time indicated that a minimum exposure time of 0.5 - 1 h was required to upregulate IL-6 and TNFalpha production. Extending the BCG pre-exposure time to 2 and 3 h further increased the rate of cytokine production. No significant difference was found, however, between the rate of secretion initiated after a 2-h or 3-h pre-exposure period. The amounts of these cytokines secreted in the presence of BCG-conditioned medium did not differ significantly from the constitutively secreted amounts, excluding an effect of products possibly secreted by BCG on the upregulation of IL-6 and TNFalpha. In addition, upregulation of cytokine production appeared to be dependent on the concentration of BCG. The results suggest that cytokines may be produced by urothelial tumor cells after intravesical instillation in patients with superficial bladder cancer, which may play a role in the mode of action of BC

Growth hormone treatment in growth-retarded adolescents after renal transplant

Growth failure is a psychosocial problem for many patients who have undergone renal transplantation. 18 adolescents (mean age 15.6, range 11.3-19.5) with severe growth retardation after renal transplantation were treated with biosynthetic growth hormone (GH) for 2 years. All received prednisone, administered daily or on alternate days, with azathioprine and/or cyclosporin A. 16 were blindly assigned to one of two GH doses (4 vs 8 IU per m2 per day). Growth, bone maturation, renal graft function, plasma insulin-like growth factors, serum binding proteins, and other biochemical parameters were checked regularly. Glomerular filtration rate and effective renal plasma flow were tested with 125I-Thalamate and 131I-Hippuran. Data on growth and glomerular filtration rate during GH treatment were also compared with those of matched non-GH-treated controls. Mean (standard deviation) increment in height after 2 years of GH was 15.7 (5.1) cm, significantly greater (p 25% reduction in glomerular filtration rate over 2 years was not significantly higher in GH-treated patients than in non-GH-treated controls (39% vs 32%, p = 0.97). Although a few patients had deterioration of graft function, we could not find a relation with GH treatment. Our results show that sustained improvement of height can be achieved with GH in severely growth-retarded adolescents after renal transplantatio

Computer-assisted 3D planned corrective osteotomies in eight malunited radius fractures

In corrective osteotomy of the radius, detailed preoperative planning is essential to optimising functional outcome. However, complex malunions are not completely addressed with conventional preoperative planning. Computer-assisted preoperative planning may optimise the results of corrective osteotomy of the radius. We analysed the pre- and postoperative radiological result of computer-assisted 3D planned corrective osteotomy in a series of patients with a malunited radius and assessed postoperative function. We included eight patients aged 13-64 who underwent a computer-assisted 3D planned corrective osteotomy of the radius for the treatment of a symptomatic radius malunion. We evaluated pre-and postoperative residual malpositioning on 3D reconstructions as expressed in six positioning parameters (three displacements along and three rotations about the axes of a 3D anatomical coordinate system) and assessed postoperative wrist range of motion. In this small case series, dorsopalmar tilt was significantly improved (p = 0.05). Ulnoradial shift, however, increased by the correction osteotomy (6 of 8 cases, 75 %). Postoperative 3D evaluation revealed improved positioning parameters for patients in axial rotational alignment (62.5 %), radial inclination (75 %), proximodistal shift (83 %) and volodorsal shift (88 %), although the cohort was not large enough to confirm this by statistical significance. All but one patient experienced improved range of motion (88 %). Computer-assisted 3D planning ameliorates alignment of radial malunions and improves functional results in patients with a symptomatic malunion of the radius. Further development is required to improve transfer of the planned position to the intra-operative bon

Pharmacogenetic risk factors for altered bone mineral density and body composition in pediatric acute lymphoblastic leukemia

Background This study investigates pharmacogenetic risk factors for bone mineral (apparent) density (BM(A)D) and body composition in pediatric acute lymphoblastic leukemia Design and Methods We determined the influence of SNPs in 4 genes (vitamin-D receptor (VDR: BsmI/ApaI/TaqI and Cdx-2/GATA), collagen type I alpha 1 (SpI), estrogen receptor 1 (ESR1: PvuII/XbaI), glucocorticoid receptor (BclI)) on body composition, BM(A)D and fracture risk during dexamethasone-based pediatric acute lymphoblastic leukemia treatment. Body composition and BMD were measured repeatedly during and after treatment using dual energy X-ray absorptiometry. Results Non-carriers of VDR 5'-end (Cdx-2/GATA) haplotype 3 revealed a significant larger fat gain than carriers (D%fat: non-carriers: +1.76SDS, carriers: +0.77SDS, P<0.001). At diagnosis and during therapy, lumbar spine BMD was significantly higher in non-carriers of VDR 5'-end (Cdx-2/GATA) haplotype 3 than in carriers. The other SNPs did not influence BMD or fracture risk during/after treatment. The year after treatment completion, lean body mass increased in non-carriers of ESR1 (PvuII/XbaI) haplotype 3 and decreased in carriers (D lean body mass: non-car-riers:+0.28SDS, carriers: -0.55SDS, P<0.01). Conclusions Only VDR 5'-end (Cdx-2/GATA) haplotype 3 was identified as protective factor against excessive fat gain and as a risk factor for lower lumbar spine BMD during treatment. Carrying ESR1 (PvuII/XbaI) haplotype 3 negatively influenced recovery of lean body mass after pediatric acute lymphoblastic leukemia treatment