SAFESTEREO: phase II randomized trial to compare stereotactic radiosurgery with fractionated stereotactic radiosurgery for brain metastases.

BACKGROUND: Stereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases. METHODS: Patients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15-24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life. DISCUSSION: Currently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure. TRIAL REGISTRATION: ClincalTrials.gov, trial registration number: NCT05346367 , trial registration date: 26 April 2022.

Withdrawal of antiepileptic drugs in patients with low grade and anaplastic glioma after long-term seizure freedom: a prospective observational study.

BACKGROUND: When glioma patients experience long-term seizure freedom the question arises whether antiepileptic drugs (AEDs) should be continued. As no prospective studies exist on seizure recurrence in glioma patients after AED withdrawal, we evaluated the decision-making process to withdraw AEDs in glioma patients, and seizure outcome after withdrawal. METHODS: Patients with a histologically confirmed low grade or anaplastic glioma were included. Eligible patients were seizure free ≥ 1 year from the date of last antitumor treatment, or ≥ 2 years since the last seizure when seizures occurred after the end of the last antitumor treatment. Patients and neuro-oncologists made a shared decision on the preferred AED treatment (i.e. AED withdrawal or continuation). Primary outcomes were: (1) outcome of the shared decision-making process and (2) rate of seizure recurrence. RESULTS: Eighty-three patients fulfilled all eligibility criteria. However, in 12/83 (14%) patients, the neuro-oncologist had serious objections to AED withdrawal. Therefore, 71/83 (86%) patients were analyzed; In 46/71 (65%) patients it was decided to withdraw AED treatment. In the withdrawal group, 26% (12/46) had seizure recurrence during follow-up. Seven of these 12 patients (58%) had tumor progression, of which three within 3 months after seizure recurrence. In the AED continuation group, 8% (2/25) of patients had seizure recurrence of which one had tumor progression. CONCLUSION: In 65% of patients a shared decision was made to withdraw AEDs, of which 26% had seizure recurrence. AED withdrawal should only be considered in carefully selected patients with a presumed low risk of tumor progression.

Clinical applicability of and changes in perfusion MR imaging in brain metastases after stereotactic radiotherapy.

To assess the applicability of perfusion-weighted (PWI) magnetic resonance (MR) imaging in clinical practice, as well as to evaluate the changes in PWI in brain metastases before and after stereotactic radiotherapy (SRT), and to correlate these changes to tumor status on conventional MR imaging. Serial MR images at baseline and at least 3 and 6 months after SRT were retrospectively evaluated. Size of metastases and the relative cerebral blood volume (rCBV), assessed with subjective visual inspection in the contrast enhanced area, were evaluated at each time point. Tumor behavior of metastases was categorized into four groups based on predefined changes on MRI during follow-up, or on histologically confirmed diagnosis; progressive disease (PD), pseudoprogression (PsPD), non-progressive disease (non-PD) and progression unspecified (PU). Twenty-six patients with 42 metastases were included. Fifteen percent (26/168) of all PW images could not be evaluated due to localization near large vessels or the scalp, presence of hemorrhage artefacts, and in 31% (52/168) due to unmeasurable residual metastases. The most common pattern (52%, 13/25 metastases) showed a high rCBV at baseline and low rCBV during follow-up, occurring in metastases with non-PD (23%, 3/13), PsPD (38%, 5/13) and PU (38%, 5/13). Including only metastases with a definite outcome generally showed low rCBV in PsPD or non-PD, and high rCBV in PD. Although non-PD and PsPD may be distinguished from PD after SRT using the PW images, the large proportion of images that could not be assessed due to artefacts and size severely hampers value of PWI in predicting tumor response after SRT.

Prognostic value of the S100B protein in newly diagnosed and recurrent glioma patients: a serial analysis.

The S100B protein is associated with brain damage and a breached blood-brain barrier. A previous pilot study showed that high serum levels of S100B are associated with shorter survival in glioma patients. The aim of our study was to assess the prognostic value in terms of survival and longitudinal dynamics of serum S100B for patients with newly diagnosed and recurrent glioma. We obtained blood samples from patients with newly diagnosed and recurrent glioma before the start (baseline) and at fixed time-points during temozolomide chemotherapy. S100B-data were dichotomized according to the upper limit of the reference value of 0.1 µg/L. Overall survival (OS) was estimated with Kaplan-Meier curves and groups were compared with the log rank analysis. To correct for potential confounders a Cox regression analysis was used. We included 86 patients with newly-diagnosed and 27 patients with recurrent glioma. Most patients in both groups had baseline serum levels within normal limits. In the newly diagnosed patients we found no significant difference in OS between the group of patients with S100B levels >0.1 µg/L at baseline compared to those with <0.1 µg/L. In the patients with recurrent glioma we found a significantly shorter OS for patients with raised levels. In both groups, S100B values did not change significantly throughout the course of the disease. Serum S100B levels do not seem to have prognostic value in newly diagnosed glioma patients. In recurrent glioma patients S100B might be of value in terms of prognostication of survival.

Interobserver variability in the radiological assessment of magnetic resonance imaging (MRI) including perfusion MRI in glioblastoma multiforme.

BACKGROUND AND PURPOSE: Conventional magnetic resonance imaging (MRI) has limited value for differentiation of true tumor progression and pseudoprogression in treated glioblastoma multiforme (GBM). Perfusion weighted imaging (PWI) may be helpful in the differentiation of these two phenomena. Here interobserver variability in routine radiological evaluation of GBM patients is assessed using MRI, including PWI. METHODS: Three experienced neuroradiologists evaluated MR scans of 28 GBM patients during temozolomide chemoradiotherapy at three time points: preoperative (MR1) and postoperative (MR2) MR scan and the follow-up MR scan after three cycles of adjuvant temozolomide (MR3). Tumor size was measured both on T1 post-contrast and T2 weighted images according to the Response Assessment in Neuro-Oncology criteria. PW images of MR3 were evaluated by visual inspection of relative cerebral blood volume (rCBV) color maps and by quantitative rCBV measurements of enhancing areas with highest rCBV. Image interpretability of PW images was also scored. Finally, the neuroradiologists gave a conclusion on tumor status, based on the interpretation of both T1 and T2 weighted images (MR1, MR2 and MR3) in combination with PWI (MR3). RESULTS: Interobserver agreement on visual interpretation of rCBV maps was good (κ = 0.63) but poor on quantitative rCBV measurements and on interpretability of perfusion images (intraclass correlation coefficient 0.37 and κ = 0.23, respectively). Interobserver agreement on the overall conclusion of tumor status was moderate (κ = 0.48). CONCLUSIONS: Interobserver agreement on the visual interpretation of PWI color maps was good. However, overall interpretation of MR scans (using both conventional and PW images) showed considerable interobserver variability. Therefore, caution should be applied when interpreting MRI results during chemoradiation therapy.

Pharmacy compounded pilocarpine: An adequate solution to overcome shortage of pilogel® discs for sweat testing in patients with cystic fibrosis.

To respond to shortage of pilocarpine discs due to CE-licensing problems a pharmacy compounded pilocarpine HCL solution was developed and validated for use in CF diagnosis. The aim of this study was to compare the results from a pharmacy compounded pilocarpine HCL solution versus Pilogel® discs for the measurements of sweat chloride concentrations. Ten pediatric and adult patients with CF underwent a sweat test using both Pilogel® discs and pilocarpine HCL solution. The average difference between both methods was -3.25 mmol/L (95% Limits of Agreement: -7.19 [95% CI: -9.19;-5.19] and 0.69 [95% CI: -1.31;2.69] mmol/L. Passing-Bablok regression showed that zero was enclosed with the 95% CI of the calculated intercept (0.15 [95% CI: -1.70;1.42] mmol/L). These data show a good agreement in chloride concentrations obtained using the two pilocarpine products. Therefore, the pharmacy compounded pilocarpine HCL solution can be used as an alternative for Pilogel® discs during times of shortage.

Is accommodation a confounder in pupillometry research?

Much psychological research uses pupil diameter measurements to investigate the cognitive and emotional effects of visual stimuli. A potential problem is that accommodating at a nearby point causes the pupil to constrict. This study examined to what extent accommodation is a confounder in pupillometry research. Participants solved multiplication problems at different distances (Experiment 1) and looked at line drawings with different monocular depth cues (Experiment 2) while their pupil diameter, refraction, and vergence angle were recorded using a photorefractor. Experiment 1 showed that the pupils dilated while performing the multiplications, for all presentation distances. Pupillary constriction due to accommodation was not strong enough to override pupil dilation due to cognitive load. Experiment 2 showed that monocular depth cues caused a small shift in refraction in the expected direction. We conclude that, for the young student sample we used, pupil diameter measurements are not substantially affected by accommodation.

Scenarios of crashes involving light mopeds on urban bicycle paths.

In the Netherlands, cyclists have to share the bicycle path with light moped riders. These riders are allowed to ride 25 km/h and do not have to wear a helmet (Dutch regulation). Due to several trends such as traffic congestion and the introduction of the scooter model, light mopeds have become more popular, both among older and younger people. This has led to an increased traffic density on bicycle paths as well as concerns about the safety of cyclists. In response to these concerns, several Dutch cities would like to ban light moped riders (LMRs) from the bicycle path and let them ride on the carriageway. However, it is uncertain what the consequences would be for the safety of light moped riders. Moreover, it is not clear to what extent the shared use of bicycle paths leads to serious crashes between cyclists and LMRs. Therefore, an in-depth crash investigation study was carried out to gain more insight into the factors and circumstances that influence the occurrence and consequences of light moped crashes on bicycle paths. A dedicated team for in-depth road crash investigation collected and analyzed detailed information on 36 light moped crashes that occurred on an urban bicycle path. This resulted in a description of the course of events for every crash that was analyzed, including a list of factors that contributed to the occurrence of the crash and possible injuries. Crashes with a similar course of events and a comparable combination of contributory factors were grouped into (sub)types of light moped crashes. Six types of crashes were identified. Based on the contributory crash factors of the identified crash types, remedial measures can be developed to prevent similar crashes from occurring in the future. Moving the LMR to the carriageway is only advisable on 30 km/h roads. Alternative measures to improve the safety of both cyclists and light moped riders include: 1) removing obstacles such as poles from the bicycle path, 2) following guidelines on the minimum width of bicycle paths given traffic volumes, 3) improving sight distances at intersections, 4) traffic light control without conflicts between traffic flows, and 5) introducing a helmet law for light moped riders and their passengers.

Effect of physical effort on mental workload of cyclists in real traffic in relation to age and use of pedelecs.

To improve cycling safety, insight is required into the factors that contribute to road safety of older cyclists. From the wide range of possible factors, this paper addresses the role of physical effort on mental workload of cyclists with the aim to investigate whether physical effort affects mental workload of cyclists in real traffic in a field experiment. Two instrumented bicycles, a conventional bicycle and a pedelec, were used. Mental workload of cyclists in two age groups - 30-45 years and 65 years and over - was measured by means of a secondary cognitive task requiring the detection and reaction to visual stimuli on a cycle route that varied in physical effort and task complexity. We expected physical effort to impair performance on the secondary task in complex traffic sections and not in simple sections, and that this impairment would be greater for older cyclists because of age related reduced muscle strength than for younger cyclists. We expected this impairment to be smaller if a pedelec was used. If such would be the case, this would indicate pedelecs to be beneficial for this older age group, because of a lower mental workload. Our study confirmed that increased physical effort in complex traffic sections deteriorated the detection of relevant stimuli in both age groups. Overall, older cyclists had longer reaction times and lower hit rates than younger cyclists. Mental workloads of cyclists are basically the same when cycling on a conventional bicycle or on a pedelec. In theory, pedelecs may be beneficial to reduce physical effort in cycling in order to maintain enough mental capacity to handle complex traffic situations. However, this study did not demonstrate these benefits. As pedelecs are often used for longer trips, by elderly with low muscle strength, future studies should also explore the effect of higher physical effort over longer periods of time, and also specifically in elderly with low muscle strength.

Crashes involving cyclists aged 50 and over in the Netherlands: An in-depth study.

The number of seriously injured cyclists is increasing in the Netherlands. The majority of these seriously injured cyclists were involved in single-bicycle or bicycle-bicycle crashes. Little is known about the circumstances in which these crashes occur, as the police only registers 4% of these crashes. Therefore, an in-depth study was carried out to gain insight into the factors and circumstances that influence the occurrence and consequences of these crashes. The focus was on crashes involving cyclists aged 50 and over, as this group has a large share in the number of cyclist-only crashes. Detailed information on 41 single-bicycle and bicycle-bicycle crashes was collected and analysed. This resulted in a description of the course of events for every analysed crash, including a list of factors that had contributed to the occurrence of the crash and possible injuries. Subsequently, crashes with a similar course of events and a comparable combination of contributory factors were grouped into types of crashes. Results showed that cyclists aged 75 and over are more often involved in falls from a bicycle than younger cyclists. Contributory factors that played a role in a large number of crashes were behaviour of another road user, distraction and narrow cycling facilities or traffic lanes. However, which factors played a role in the occurrence of a crash depended on the type of crash. Eight types of crashes were identified. Based on the factors that played a role in the occurrence of these crashes, remedial measures can be developed to prevent similar crashes from occurring in the future.

Short-term clinical results of revision elbow arthroplasty using the Latitude total elbow arthroplasty.

AIMS: Revision total elbow arthroplasty (TEA) is often challenging. The aim of this study was to report on the clinical and radiological results of revision arthroplasty of the elbow with the Latitude TEA. PATIENTS AND METHODS: Between 2006 and 2010 we used the Latitude TEA for revision in 18 consecutive elbows (17 patients); mean age 53 years (28 to 80); 14 women. A Kudo TEA was revised in 15 elbows and a Souter-Strathclyde TEA in three. Stability, range of movement (ROM), visual analogue score (VAS) for pain and functional scores, Elbow Functional Assessment Scale (EFAS), the Functional Rating Index of Broberg and Morrey (FRIBM) and the Modified Andrews' Elbow Scoring System (MAESS) were assessed pre-operatively and at each post-operative follow-up visit (six, 12 months and biennially thereafter). Radiographs were analysed for loosening, fractures and dislocation. The mean follow-up was 59 months (26 to 89). RESULTS: The ROM of the elbow did not improve significantly. The mean EFAS and MAESS scores improved significantly six months post-operatively (18.6 points, standard deviation (sd) 7.7; p = 0.03 and 28.8 points, sd 8.6; p = 0.006, respectively) and continued to improve slightly or reached a plateau. The mean pain scores at rest (Z = -3.2, p = 0.001) and during activity (Z = -3.2, p = 0.001), and stability (Z = -3.0, p = 0.003) improved significantly six months post-operatively. Thereafter scores continued to improve slightly or a plateau was reached. There were no signs of loosening. CONCLUSION: Revision surgery using the Latitude TEA results in improvement of functionality, reduced pain and better stability of the elbow. Improvement of ROM of the elbow should not be expected. Cite this article: Bone Joint J 2016;98-B:1086-92.

Mid-term clinical results of a modern convertible total elbow arthroplasty.

Unlinked, linked and convertible total elbow arthroplasties (TEAs) are currently available. This study is the first to report the clinical results of the convertible Latitude TEA. This was a retrospective study of a consecutive cohort of 63 patients (69 primary TEAs) with a mean age of 60 years (23 to 87). Between 2006 and 2008 a total of 19 men and 50 women underwent surgery. The mean follow-up was 43 months (8 to 84). The range of movement, function and pain all improved six months post-operatively and either continued to improve slightly or reached a plateau thereafter. The complication rate is similar to that reported for other TEA systems. No loosening was seen. Remarkable is the disengagement of the radial head component in 13 TEAs (31%) with a radial head component implanted. Implantation of both the linked and the unlinked versions of the Latitude TEA results in improvement of function and decreased pain, and shows high patient satisfaction at mid-term follow-up.

Colorimetric solid-phase capture hybridization assay for detection of amplified Borrelia burgdorferi DNA.

To simplify detection procedures of DNA fragments resulting from PCR, we developed a colorimetric microplate hybridization assay. This format was used for the identification of Borrelia burgdorferi sensu lato, the causal agent of Lyme disease. The system relied on the use of a specific capture probe covalently linked to polystyrene plates and a specific polybiotinylated detection probe. DNA fragments, resulting from PCR and sandwiched between these two probes, were detected by enzymatic color development. The new detection format outperformed agarose gel electrophoresis of PCR products in sensitivity and specificity Moreover, in view of its rapidity and simplicity, the system proved appropriate for the routine diagnostic analysis of clinical specimens from Lyme disease patients. The proposed detection format can be adapted easily to other DNA targets and is suitable for automation.

Rapid identification of Mycobacterium xenopi from bacterial colonies or "Bactec" culture by the polymerase chain reaction and a luminescent sandwich hybridization assay.

Oligonucleotide primers were used in the polymerase chain reaction (PCR) to amplify a specific 584-bp DNA fragment, located in the 16S RNA gene of Mycobacterium xenopi. This set of primers, X222 and X224, was able to discriminate between the pathogen and other mycobacterial species as well as non-mycobacterial strains; it detected down to 3 fg of M. xenopi DNA, i.e. about one genome equivalent. These oligonucleotide primers proved suitable for the routine identification of M. xenopi cultures, starting from one single colony on solid medium or from a liquid culture in Middelbrook 12B "Bactec" medium. In addition, a luminescent hybridization assay was designed for use on PCR-amplified DNA. This system, which, for capture, relied on a matrix-bound oligonucleotide (M30) specific for the genus Mycobacterium and, for detection, on a biotinylated xenopi-specific X221 probe, proved fully specific, highly sensitive and rapid for the evaluation of M. xenopi Bactec cultures at low growth index.

[Manifestations of histoplasmosis]. / Manifestaties van histoplasmose.

Two patients, a 34-year old man-to-woman transsexual and a 32-year-old man, with aids presented with pulmonary symptoms, fever, serious weight loss and an oral ulcer. A third patient, a 16-year-old boy, had signs of transverse myelitis and meningitis without immunodeficiency. All were South American citizens and had disseminated histoplasmosis. After antifungal treatment they recovered, although the third patient remained a wheelchair user. If pulmonary or miliary tuberculosis is suspected in a patient originating from South America, histoplasmosis should be considered. Oral ulcers and skin lesions can be diagnostic clues. Specific stainings of direct preparations and longer-lasting cultures of various materials, especially of biopsy samples, then provide the diagnosis.

Sex hormone binding globulin deficiency due to a homozygous missense mutation.

CONTEXT: SHBG is known as the major sex steroid binding protein in plasma, and it regulates the bioavailability of both T and estradiol levels required for effects on target tissues. We identified a man with an undetectable SHBG concentration in combination with low total T. He presented with a 7-year history of muscle weakness, fatigue, and a low libido. OBJECTIVES: To determine the cause of the SHBG deficiency, we employed both genetic analysis of the SHBG gene and transgene SHBG expression. RESULTS: Genetic analysis identified a novel homozygous missense mutation that was predicted to be deleterious for protein function. Transgene expression showed that the mutation resulted in a block in SHBG secretion accompanied by increased expression of the endoplasmic reticulum molecular chaperone HSPA5. The mutation results in accumulation of the mutant SHBG within the cell and failure to secrete the mutant protein. Screening of family members identified one sister who was also deficient for SHBG. CONCLUSIONS: We have identified a family with a missense mutation within the SHBG gene, which results in a complete deficiency of plasma SHBG in the homozygous state. Although total T level was low in the male patient, it did not interfere with normal gonadal development and spermatogenesis, suggesting a limited role of SHBG in sexual maturation and male physiology.

Automatic synthesis of multifork-like structures for multiple labeling of oligonucleotides: application to diagnosis of Lyme disease.

Multifork-like structures have been designed for multiple labelling of oligonucleotides. They rely on the synthesis of new non nucleosidic phosphoramidites which can be used in automatic DNA synthesis. The new compounds allowed tagging of any oligonucleotide and provided reactive primary amino groups for non isotopic labelling. Polybiotinylated oligonucleotides have been tested in hybridization assays using a corresponding complementary sequence covalently linked to polystyrene tubes. Detection limits ranged from 3.10(5) to 3.10(6) molecules, depending on the number of biotins. Multilabelled oligonucleotides have been included into a capture format to detect DNA of Borrelia burgdorferi, the causal agent of Lyme disease. In short, 5'-phosphate oligonucleotides were chemically condensed onto aminated microwells and served to capture PCR-amplified target DNA which, in turn, hybridized with polybiotinylated complementary oligonucleotides. Detection of the hybrids was achieved through streptavidin-conjugated peroxidase and a colorimetric substrate. The solid phase sandwich DNA hybridization assay proved highly specific, very sensitive, rapid and user friendly for the identification of spirochetal DNA in human biological specimens.

"Hairpin" and "hammerhead" ribozymes directed towards the mumps virus nucleocapsid RNA: specific cleavage of a small synthetic RNA substrate and full-length mRNA.

In an attempt to develop efficient antiviral agents against Mumps virus, we designed ribozymes targeting the nucleocapsid (NP) mRNA. Transacting catalytic RNAs of the hammerhead and hairpin types were synthesized; they contained specific motifs, shared similar flanking regions and were directed against a 5'GUC3' target immediately downstream to the initiation codon of NP mRNA. Both ribozymes were first assayed on a synthetic 16 bases target RNA and found to catalytically and efficiently cleave the substrate in a sequence specific way. No cleavage, however, occurred when mutated forms of the ribozymes were used. In addition, both ribozyme types, when tested on the full length NP mRNA, were also able to cleave the substrate although turnover could not be demonstrated. As a rule, the hammerhead ribozyme proved more efficient than its hairpin counterpart, as well on the synthetic RNA substrate as on the full length NP mRNA target.

Total elbow arthroplasty with the Kudo prosthesis.

Between 1990 and 1997 we undertook 57 Kudo type-4 total elbow replacements in 45 patients with rheumatoid arthritis. A total of 34 patients (44 elbows) were evaluated at an average of 7 (4.4-11.2) years using the Mayo Clinic Performance Index. At review 29 elbows were excellent or good and four were fair or poor. The main complications were intraoperative fractures and ulnar neuropathy. No luxations were seen. Loosening of the ulnar component and breakage of the humeral component were most frequent indications for revision. Preoperative radiographic joint destruction was not correlated with revision rate.