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High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival. Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age (<60 vs ≥60 years) and institution (Berlin vs Tübingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m 2) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m 2) on days 3–5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with ClinicalTrials.gov, number NCT00153530. 551 patients (median age 63 years, IQR 55–69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8–39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5–46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80–1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6–25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3–16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%). No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors. German Cancer Aid.

Background Glioblastoma is the most common and most aggressive malignant primary brain tumor in adults. Glioblastoma cells synthesize and secrete large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Moreover, neuronal networks interconnect with glioblastoma cell networks through glutamatergic neuroglial synapses, activation of which induces oncogenic calcium oscillations that are propagated via gap junctions between tumor cells. The primary objective of this study is to explore the efficacy of brain-penetrating anti-glutamatergic drugs to standard chemoradiotherapy in patients with glioblastoma. Methods/design GLUGLIO is a 1:1 randomized phase Ib/II, parallel-group, open-label, multicenter trial of gabapentin, sulfasalazine, memantine and chemoradiotherapy (Arm A) versus chemoradiotherapy alone (Arm B) in patients with newly diagnosed glioblastoma. Planned accrual is 120 patients. The primary endpoint is progression-free survival at 6 months. Secondary endpoints include overall and seizure-free survival, quality of life of patients and caregivers, symptom burden and cognitive functioning. Glutamate levels will be assessed longitudinally by magnetic resonance spectroscopy. Other outcomes of interest include imaging response rate, neuronal hyperexcitability determined by longitudinal electroencephalography, Karnofsky performance status as a global measure of overall performance, anticonvulsant drug use and steroid use. Tumor tissue and blood will be collected for translational research. Subgroup survival analyses by baseline parameters include segregation by age, extent of resection, Karnofsky performance status, O 6 -methylguanine DNA methyltransferase (MGMT) promotor methylation status, steroid intake, presence or absence of seizures, tumor volume and glutamate levels determined by MR spectroscopy. The trial is currently recruiting in seven centers in Switzerland. Trial registration NCT05664464. Registered 23 December 2022.

Pompe disease is a rare autosomal-recessive disorder characterised by limb-girdle myopathy and respiratory weakness in the late-onset form (LOPD). Various mutations in the acid alpha-glucosidase gene lead to toxic lysosomal and extra-lysosomal glycogen accumulation in all organs due to ineffective glycogen clearance by the encoded enzyme. Only one randomized trial demonstrated beneficial effects of respiratory function and meters walked in the 6-min walking test with enzyme replacement therapy (ERT). These results were confirmed in several retrospective and prospective observations and in meta-analyses. Due to a potential lifelong therapy, moderate efficacy and high treatment costs time of ERT initiation and cessation is an ongoing matter of debate. So far, several national and international recommendations have been published with different criteria concerning diagnosis, initiation and cessation of ERT in LOPD. We therefore formally analysed recent published recommendations and consensus statements of LOPD using diagnostic nodes (DODES) as a special software tool. With DODES, an objective analysis becomes possible if the content of the recommendations is represented as algorithms using cross-compatible elements. This analysis formally disclosed both, areas of great heterogeneity and concordance for the diagnosis and management of LOPD and paved the way for a Pompe disease burden scale focussing on ERT initiation. According to this investigation further clinical research should concentrate on ERT in pre-symptomatic and severely affected LOPD patients and on cessation criteria for ERT as these issues are areas of international uncertainty and discordance.

Background The management of meningiomas is challenging, and the role of postoperative radiotherapy is not standardized. Methods Radiation oncology experts in Swiss centres were asked to participate in this decision-making analysis on the use of postoperative radiotherapy (RT) for meningiomas. Experts from ten Swiss centres agreed to participate and provided their treatment algorithms. Their input was converted into decision trees based on the objective consensus methodology. The decision trees were used as a basis to identify consensus and discrepancies in clinical routine. Results Several criteria used for decision-making in postoperative RT in meningiomas were identified: histological grading, resection status, recurrence, location of the tumour, zugzwang (therapeutic need to treat and/or severity of symptoms), size, and cell division rate. Postoperative RT is recommended by all experts for WHO grade III tumours as well as for incompletely resected WHO grade II tumours. While most centres do not recommend adjuvant irradiation for WHO grade I meningiomas, some offer this treatment in recurrent situations or routinely for symptomatic tumours in critical locations. The recommendations for postoperative RT for recurrent or incompletely resected WHO grade I and II meningiomas were surprisingly heterogeneous. Conclusions Due to limited evidence on the utility of postoperative RT for meningiomas, treatment strategies vary considerably among clinical experts depending on the clinical setting, even in a small country like Switzerland. Clear majorities were identified for postoperative RT in WHO grade III meningiomas and against RT for hemispheric grade I meningiomas outside critical locations. The limited data and variations in clinical recommendations are in contrast with the high prevalence of meningiomas, especially in elderly individuals.

Background The objective consensus methodology has recently been applied in consensus finding in several studies on medical decision-making among clinical experts or guidelines. The main advantages of this method are an automated analysis and comparison of treatment algorithms of the participating centers which can be performed anonymously. Methods Based on the experience from completed consensus analyses, the main steps for the successful implementation of the objective consensus methodology were identified and discussed among the main investigators. Results The following steps for the successful collection and conversion of decision trees were identified and defined in detail: problem definition, population selection, draft input collection, tree conversion, criteria adaptation, problem re-evaluation, results distribution and refinement, tree finalisation, and analysis. Conclusion This manuscript provides information on the main steps for successful collection of decision trees and summarizes important aspects at each point of the analysis.

Objective To evaluate predictors of ischemic stroke in patients with primary angiitis of the central nervous system after initiation of immunosuppressive therapy. Materials and methods This retrospective study included 204 MRI examinations of 23 patients with primary angiitis of the central nervous system, treated with immunosuppressive therapy between 2015 and 2020 at the University Hospital Bern and the Cantonal Hospital St. Gallen, Switzerland. Two senior neuroradiologists evaluated the MRI exams with regard to the occurrence and location of ischemic stroke and hemorrhage, as well as the following characteristics of inflamed vessels on 3D time-of-flight angiography and T1 dark-blood post contrast: signal intensity of vessel walls, length of enhancement, circular extent of enhancement, and stenosis. After matching ischemic strokes to their corresponding vessel, the temporal relationship of vessel alterations in accordance with therapy initiation and stroke onset was calculated. Results The majority (77.6%) of observed strokes were in the vascular territory of an inflamed vessel. A significant, non-linear temporal relationship between the timing of MRI and the initiation of immunosuppression was found. The highest predicted probability of ischemic stroke was observed between 10 and 20 days after the initiation of immunosuppressant therapy, reaching approximately 12%. Out of all evaluated vessel characteristics, a higher degree of stenosis (Estimate: 0.93, p  = 0.006) and a higher circularity of enhancement (Estimate: 0.76, p  = 0.01) were significantly associated with a higher likelihood of stroke. Conclusions A better understanding of unfavorable constellations (critical timeframe, characteristic vessel wall changes) in patients treated for primary angiitis of the central nervous system may help to prevent secondary ischemic strokes. Critical relevance statement A better understanding of ischemic stroke predictors in patients treated for primary angiitis of the central nervous system may prompt closer monitoring or therapy adjustment. Key Points To evaluate risk factors for ischemic stroke in patients treated for primary angiitis of the central nervous system. Higher degree of stenosis and circular enhancement are associated with a higher likelihood of ischemic strokes, which typically occur between 10 and 20 days after therapy onset. Data obtained from this may prompt closer monitoring or therapy adjustment. Graphical Abstract

In a recent publication by Klein et al., the need for real-world data on rare diseases is highlighted. We strongly support this need, and the collaboration with the patient community to collect data, as promoted in this publication. Our concern, however, is that this paper may be misunderstood as suggesting that the Sanofi-run Rare Disease Registries (RDRs) are sufficient to provide the datasets needed to evaluate current and future therapies. Industry-driven registries focus on their own product(s) and, therefore, do not provide the opportunity to compare products from different companies. Today, multiple companies produce treatments for all diseases included in the RDRs. Each company will have to run its own registry for regulatory purposes. This will lead to data fragmentation, which is prohibitive of truly understanding the effects of the various treatment options for these rare diseases. Therefore, independently funded and owned registries are essential to generate real-world evidence (RWE) unrelated to specific products. We discuss options for this for Pompe disease, including the International Pompe Survey, which has collected patient-reported outcomes independently from industry since 2002. This letter aims to raise awareness of the problem of siloed data and advocate for a new way forward where independent registries provide post-marketing surveillance data.

Aim To investigate the maturation of the peripheral nervous system by analyzing the cross‐sectional area of the sciatic nerve during the first 2 years of life. Methods The sciatic nerve was examined by high‐resolution ultrasound imaging in 52 children aged 0 days to 10 years, 45 of whom were younger than 2 years. The correlation between the cross‐sectional area of the nerve and the age was statistically tested. A logarithmic regression analysis was performed to develop a logarithmic growth model of the cross‐sectional area. Results There is a highly significant correlation between the age and the cross‐sectional area of the sciatic nerve. The growth rate can well be described by a logarithmic model. Interpretation Based on the literature on the maturation of the median nerve and nerve roots and the findings of the present study, we conclude that both the proximal and the distal parts of the nerves of the peripheral nervous system increase simultaneously. What this paper adds Normative values for the size of the sciatic nerve in children. The sciatic nerve was examined by high‐resolution ultrasound imaging in children younger than two years. There is a highly significant correlation between the age and the cross‐sectional area of the sciatic nerve. The growth rate can well be described by a logarithmic model.

PurposeTo systematically analyse the time course of vessel wall enhancement and associated stenosis in patients with primary angiitis of the central nervous system (PACNS) following immunosuppressive therapy.Material and methodsTwo neuroradiologists retrospectively analysed MRIs of patients with PACNS seen at the Bern University Hospital and the St. Gallen Cantonal Hospital between 2015 and 2020. MRIs were examined for the presence of vessel wall enhancement, length of vessel wall enhancement (mm), circumferential extent of enhancement (degree) and degree of stenosis (%). Descriptive statistics and measurements of interobserver reliability were obtained. To investigate the temporal profiles of the variables following the commencement of immunosuppressant treatment, four series of Bayesian generalised multi-level models were generated.ResultsA total of 23 patients with 43 affected vessels identified from 209 MRI exams were evaluated (mean follow-up: 715 days, standard deviation ± 487 days), leading to a complete dataset of 402 entries. Vessel wall enhancement and circumferential extent of enhancement decreased for approximately 1 year after the initiation of immunosuppressant therapy. Changes were more pronounced in younger patients. Disappearance of vessel wall enhancement (in at least one vessel) was seen in about half of patients after a median of 172 days interquartile range 113–244, minimum 54 days, maximum 627 days.ConclusionsThis study evaluated the typical time course of vessel wall enhancement in patients with PACNS. Our results could be a useful reference for radiologists and clinicians interpreting follow-up imaging in patients with PACNS.Critical relevance statementRoutine clinical exams can be interpreted with more confidence when radiologists are aware of the typical temporal evolution of vessel wall enhancement in patients with primary angiitis of the central nervous system after initiation of immunosuppressive therapy.Key PointsFew data exist for vessel wall imaging of primary angiitis of the central nervous system.Following immunosuppressant therapy, vessel wall enhancement decreases for approximately one year.These results may serve as a reference for radiologists performing follow-up imaging.

Background Natural ghrelin, a peptide growth hormone secretagogue, has a therapeutic potential in cachexia. We designed a dose‐finding trial of subcutaneous natural ghrelin to improve nutritional intake (NI) in advanced cancer patients. Methods Advanced cancer patients with cachexia management (symptom management, physiotherapy, nutritional, and psychosocial support) started with ghrelin at 32 μg/kg body weight, followed by 50% dose increases. Patients self‐injected ghrelin twice daily for 4 days followed by a wash‐out period. After reaching the primary endpoint, maximal NI (minimal dose for maximal NI), a maintenance period followed during which patients injected 10 doses of ghrelin per week. Safety parameters, NI, and cachexia outcomes (symptoms, narratives, muscle mass, and strength) were measured over 6 weeks. Results Ten patients with metastatic solid tumours were included, and six (100% male, mean age 61.8 ± 8.5 SD) received ghrelin. Minimal dose for maximal NI was reached in four patients. Three patients reached the end‐of study visit. Ghrelin was well tolerated with variable results on appetite and eating‐related symptoms but a positive effect in the narratives. Mean Functional Assessment of Appetite & Cachexia Therapy score was 6.8 points lower at final measurement compared with baseline, t(5) = 5.98, P < .01. Muscle mass was stable in two patients and increased in one patient, and muscle strength was stable in three patients. Subjective tolerability was high. Patients showed a fluctuating trajectory, and median survival was 88 days (51–412 days). Conclusions Ghrelin was safe in advanced patients with cancer cachexia without dose‐limiting toxicity and well tolerated. The intervention was very complex, and the number of patients included was small. There was a positive effect on nutritional intake and patient narratives.