71 research outputs found
Fingolimod and tumor-infiltrating lymphocytes in checkpoint-inhibitor treated cancer patients.
Immune checkpoint inhibitors (ICIs) are emerging as the new standard of care for treating various metastatic cancers. It is known that effective anti-tumor immune responses are associated with a stronger presence of tumor-infiltrating lymphocytes (TILs) in solid tumor tissue. Cancer patients with relapsing-remitting multiple sclerosis (RRMS) are often under continuous treatment with fingolimod, an immune-modulating drug that inhibits lymphocyte egress from secondary lymphatic organs. Little is known about the effect of fingolimod on ICI cancer therapy, as fingolimod may limit the number of TILs. Here we present three patients with RRMS, who developed various cancers during fingolimod treatment. Histology of all tumors consistently showed low numbers of TILs. A second biopsy taken from one of the tumors, a melanoma, revealed a significant increase of TILs after stopping fingolimod and starting pembrolizumab, indicating a surge in the number and re-invigoration of T cells. Our study suggests that fingolimod limits the number of TILs in solid tumors and may, thus, inhibit anti-cancer immune responses
Prognostic impact of meningeal dissemination in primary CNS lymphoma (PCNSL): experience from the G-PCNSL-SG1 trial
Background We evaluated the frequency and prognostic impact of meningeal dissemination (MD) in immunocompetent adult patients with primary central nervous system lymphoma treated in a randomized phase III trial. Patients and methods MD was evaluated at study entry and defined by lymphoma proof in the meningeal compartment detected by at least one of the following methods: cerebrospinal fluid (CSF) cytomorphology, detection of clonal B cells by IgH PCR in CSF or contrast enhancement of the leptomeninges on magnetic resonance imaging (MRI). Results Data on MD were available in 415 patients, of those, MD was detected in 65 (15.7%): in 44/361 (12.2%) by CSF cytomorphology, in 16/152 (10.5%) by PCR and in 17/415 (4.1%) by MRI. Major patients' characteristics and therapy did not significantly differ between patients with MD (MD+) versus those without MD (MDâ). There was a significant correlation of MD with CSF pleocytosis (>5/ÎŒl; P45 mg/dl). Median progression-free survival was 6.7 months [95% confidence interval (CI) 0-14.5] in MD+ and 8.3 months (5.7-10.8) in MDâ patients (P=0.95); median overall survival was 21.5 months (95% CI 16.8-26.1) and 24.9 months (17.5-32.3), respectively (P=0.98). Conclusion MD was detected infrequently and had no impact on outcome in this tria
Improving outcome measures in late onset Pompe disease:Modified Rasch-Built Pompe-Specific Activity scale
Background and purpose The Rasch-Built Pompe-Specific Activity (R-PAct) scale is a patient-reported outcome measure specifically designed to quantify the effects of Pompe disease on daily life activities, developed for use in Dutch- and English-speaking countries. This study aimed to validate the R-PAct for use in other countries.Methods Four other language versions (German, French, Italian, and Spanish) of the R-PAct were created and distributed among Pompe patients (>= 16 years old) in Germany, France, Spain, Italy, and Switzerland and pooled with data of newly diagnosed patients from Australia, Belgium, Canada, the Netherlands, New Zealand, the USA, and the UK and the original validation cohort (n = 186). The psychometric properties of the scale were assessed by exploratory factor analysis and Rasch analysis.Results Data for 520 patients were eligible for analysis. Exploratory factor analysis suggested that the items separated into two domains: Activities of Daily Living and Mobility. Both domains independently displayed adequate Rasch model measurement properties, following the removal of one item ("Are you able to practice a sport?") from the Mobility domain, and can be added together to form a "higher order" factor as well. Differential item functioning (DIF)-by-language assessment indicated DIF for several items; however, the impact of accounting for DIF was negligible. We recalibrated the nomogram (raw score interval-level transformation) for the updated 17-item R-PAct scale. The minimal detectable change value was 13.85 for the overall R-PAct.Conclusions After removing one item, the modified-R-PAct scale is a valid disease-specific patient-reported outcome measure for patients with Pompe disease across multiple countries
Start, switch and stop (triple-S) criteria for enzyme replacement therapy of late-onset Pompe disease:European Pompe Consortium recommendation update 2024
Background and purpose: Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late-onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT. Methods: The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in-person meeting, three rounds of discussion and voting to provide a consensus recommendation. Results: The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient-by-patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion-associated reactions. Switching of ERT should be discussed on a patient-by-patient shared-decision basis. If there are severe, unmanageable infusion-associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six-monthly European Pompe Consortium muscle function assessments are recommended. Conclusions: The triple-S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six-monthly long-term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT.</p
Secretion of Clostridium difficile Toxins A and B Requires the Holin-like Protein TcdE
The pathogenesis of Clostridium difficile, the major cause of antibiotic-associated diarrhea, is mainly associated with the production and activities of two major toxins. In many bacteria, toxins are released into the extracellular environment via the general secretion pathways. C. difficile toxins A and B have no export signature and their secretion is not explainable by cell lysis, suggesting that they might be secreted by an unusual mechanism. The TcdE protein encoded within the C. difficile pathogenicity locus (PaLoc) has predicted structural features similar to those of bacteriophage holin proteins. During many types of phage infection, host lysis is driven by an endolysin that crosses the cytoplasmic membrane through a pore formed by holin oligomerization. We demonstrated that TcdE has a holin-like activity by functionally complementing a λ phage deprived of its holin. Similar to λ holin, TcdE expressed in Escherichia coli and C. difficile formed oligomers in the cytoplamic membrane. A C. difficile tcdE mutant strain grew at the same rate as the wild-type strain, but accumulated a dramatically reduced amount of toxin proteins in the medium. However, the complemented tcdE mutant released the toxins efficiently. There was no difference in the abundance of tcdA and tcdB transcripts or of several cytoplasmic proteins in the mutant and the wild-type strains. In addition, TcdE did not overtly affect membrane integrity of C. difficile in the presence of TcdA/TcdB. Thus, TcdE acts as a holin-like protein to facilitate the release of C. difficile toxins to the extracellular environment, but, unlike the phage holins, does not cause the non-specific release of cytosolic contents. TcdE appears to be the first example of a bacterial protein that releases toxins into the environment by a phage-like system
Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.
BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma.
METHODS: Patients were treated with RT (60âGy in 2âGy fractions) combined with TMZ 75âmgâm(-2) daily, and Sb administered at three dose levels (200âmg daily, 200âmg BID, and 400âmg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200âmgâm(-2) D1-5/28) and Sb (400âmg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&Sb) (Clinicaltrials ID: NCT00884416).
RESULTS: The MTD of Sb was established at 200âmg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5âh (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6).
CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings
Improving outcome measures in late onset Pompe disease: Modified Rasch-Built Pompe-Specific Activity scale
Background and purpose
The Rasch-Built Pompe-Specific Activity (R-PAct) scale is a patient-reported outcome measure specifically designed to quantify the effects of Pompe disease on daily life activities, developed for use in Dutch- and English-speaking countries. This study aimed to validate the R-PAct for use in other countries.
Methods
Four other language versions (German, French, Italian, and Spanish) of the R-PAct were created and distributed among Pompe patients (â„16âyears old) in Germany, France, Spain, Italy, and Switzerland and pooled with data of newly diagnosed patients from Australia, Belgium, Canada, the Netherlands, New Zealand, the USA, and the UK and the original validation cohort (nâ=â186). The psychometric properties of the scale were assessed by exploratory factor analysis and Rasch analysis.
Results
Data for 520 patients were eligible for analysis. Exploratory factor analysis suggested that the items separated into two domains: Activities of Daily Living and Mobility. Both domains independently displayed adequate Rasch model measurement properties, following the removal of one item ("Are you able to practice a sport?") from the Mobility domain, and can be added together to form a "higher order" factor as well. Differential item functioning (DIF)-by-language assessment indicated DIF for several items; however, the impact of accounting for DIF was negligible. We recalibrated the nomogram (raw score interval-level transformation) for the updated 17-item R-PAct scale. The minimal detectable change value was 13.85 for the overall R-PAct.
Conclusions
After removing one item, the modified-R-PAct scale is a valid disease-specific patient-reported outcome measure for patients with Pompe disease across multiple countries
Comparative genomic analysis of toxin-negative strains of Clostridium difficile from humans and animals with symptoms of gastrointestinal disease
Background: Clostridium difficile infections (CDI) are a significant health problem to humans and food animals. Clostridial toxins ToxA and ToxB encoded by genes tcdA and tcdB are located on a pathogenicity locus known as the PaLoc and are the major virulence factors of C. difficile. While toxin-negative strains of C. difficile are often isolated from faeces of animals and patients suffering from CDI, they are not considered to play a role in disease. Toxin-negative strains of C. difficile have been used successfully to treat recurring CDI but their propensity to acquire the PaLoc via lateral gene transfer and express clinically relevant levels of toxins has reinforced the need to characterise them genetically. In addition, further studies that examine the pathogenic potential of toxin-negative strains of C. difficile and the frequency by which toxin-negative strains may acquire the PaLoc are needed. Results: We undertook a comparative genomic analysis of five Australian toxin-negative isolates of C. difficile that lack tcdA, tcdB and both binary toxin genes cdtA and cdtB that were recovered from humans and farm animals with symptoms of gastrointestinal disease. Our analyses show that the five C. difficile isolates cluster closely with virulent toxigenic strains of C. difficile belonging to the same sequence type (ST) and have virulence gene profiles akin to those in toxigenic strains. Furthermore, phage acquisition appears to have played a key role in the evolution of C. difficile. Conclusions: Our results are consistent with the C. difficile global population structure comprising six clades each containing both toxin-positive and toxin-negative strains. Our data also suggests that toxin-negative strains of C. difficile encode a repertoire of putative virulence factors that are similar to those found in toxigenic strains of C. difficile, raising the possibility that acquisition of PaLoc by toxin-negative strains poses a threat to human health. Studies in appropriate animal models are needed to examine the pathogenic potential of toxin-negative strains of C. difficile and to determine the frequency by which toxin-negative strains may acquire the PaLoc
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