2,890 research outputs found
Switching from natalizumab to fingolimod: an observational study
Background – Multiple sclerosis patients who discontinue using
natalizumab are at risk of a rebound in disease activity. However, the
optimal alternative therapy is not currently known. Aims of the
study – We report on clinical and MRI data and patient safety in a
group of relapsing–remitting multiple sclerosis patients who tested
seropositive for the JC virus and who have switched from
natalizumab to fingolimod because of concerns regarding PML risks.
Methods – The test for JC virus antibodies was performed in 18
relapsing–remitting multiple sclerosis patients who were being treated
with natalizumab for more than 1 year. Eight seropositive patients
switched to fingolimod while the seronegative patients continued with
natalizumab. Results – After switching to fingolimod, five of eight
patients (63%) experienced clinical relapses, and MRI activity was
detected in six of eight patients (75%). Neither clinical relapses nor
MRI activity was observed in the patients who continued with
natalizumab. No serious adverse effects were detected. Conclusions –
Natalizumab is an effective treatment for relapsing–remitting multiple
sclerosis, but its discontinuation continues to be a complex problem.
All of the therapies tried thus far, including fingolimod, have been
unable to control the reactivation of the disease. Further studies
addressing alternative therapies after natalizumab discontinuation are
necessary
Spanish multicenter real – life registry of retrievable vena cava filters (REFiVeC)
Background
The treatment of venous thromboembolic disease the treatment of choice is systemic anticoagulation. However, the interruption of the inferior vena cava with filters has been recommended when anticoagulation fails or there is a contraindication. Due to the rising inferior vena cava filter (IVCF) complications, physicians are encouraged to retrieve them when there is no longer recommended. In daily practice, it may be a difficult close follow-up of these patients. In this study, the primary objective was to evaluate the IVCF retrieval rate of all implanted filters in a Spanish registry. Secondary objectives were to analyze the causes of failed retrieval, procedure-related complications, and outcomes at a 12-month follow-up.
Results
Three hundred fifty-six vena cava filters were implanted in 355 patients. The types of filter were: Gunther Tulip (Cook Medical) 160 (44.9%), Optease (Cordis) 77 (21.6%), Celect (Cook Medical) 49 (13, 7%), Aegisy (Lifetech Scientific) 33 (9.2%), Option ELITE (Argon Medical devices) 16 (4.4%), Denali filter (BD Bard) 11 (3.08%), ALN filter (ALN) 10 (2.8%).
Removal was achieved in 274/356 (76,9%). eighty-two (23,1%) IVCF were not retrieved due to the following: 41 (11,5%) patients required ongoing filtration, 24 IVCF (6,7%) patients died before retrieval, and 17 (4,7%) impossibility of retrieval because of a tilted and embedded filter apex. There were no major complications observed.
Conclusions
The global retrieval rate of IVCF was achieved in 76.9%, and the adjusted retrieval rate was of 94.15% with no major complications. IVCF tilting was associated with failure of filter removal in less than 5% of cases. This study demonstrates that the retrieval procedure of IVCF is controlled by the clinician and not by the interventional radiologist
T-cell-derived miRNA-214 mediates perivascular fibrosis in hypertension
RATIONALE: Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood. OBJECTIVES: To study the functional role of microRNA-214 (miR-214) in the induction of perivascular fibrosis and endothelial dysfunction driving vascular stiffening. METHODS AND RESULTS: Out of 381 miRs screened in the perivascular tissues in response to Ang II (angiotensin II)-mediated hypertension, miR-214 showed the highest induction (8-fold, P=0.0001). MiR-214 induction was pronounced in perivascular and circulating T cells, but not in perivascular adipose tissue adipocytes. Global deletion of miR-214-/- prevented Ang II-induced periaortic fibrosis, Col1a1, Col3a1, Col5a1, and Tgfib1 expression, hydroxyproline accumulation, and vascular stiffening, without difference in blood pressure. Mechanistic studies revealed that miR-214-/- mice were protected against endothelial dysfunction, oxidative stress, and increased Nox2, all of which were induced by Ang II in WT mice. Ang II-induced recruitment of T cells into perivascular adipose tissue was abolished in miR-214-/- mice. Adoptive transfer of miR-214-/- T cells into RAG1-/- mice resulted in reduced perivascular fibrosis compared with the effect of WT T cells. Ang II nduced hypertension caused significant change in the expression of 1380 T cell genes in WT, but only 51 in miR-214-/-. T cell activation, proliferation and chemotaxis pathways were differentially affected. MiR-214-/- prevented Ang II-induction of profibrotic T cell cytokines (IL-17, TNF-a, IL-9, and IFN-y) and chemokine receptors (CCR1, CCR2, CCR4, CCR5, CCR6, and CXCR3). This manifested in reduced in vitro and in vivo T cell chemotaxis resulting in attenuation of profibrotic perivascular inflammation. Translationally, we show that miR-214 is increased in plasma of patients with hypertension and is directly correlated to pulse wave velocity as a measure of vascular stiffness. CONCLUSIONS: T-cell-derived miR-214 controls pathological perivascular fibrosis in hypertension mediated by T cell recruitment and local profibrotic cytokine release
Structure-based discovery and in vitro validation of inhibitors of chloride intracellular channel 4 protein
The use of computer-aided methods have continued to propel accelerated drug discovery across various disease models, interestingly allowing the specific inhibition of pathogenic targets. Chloride Intracellular Channel Protein 4 (CLIC4) is a novel class of intracellular ion channel highly implicated in tumor and vascular biology. It regulates cell proliferation, apoptosis and angiogenesis; and is involved in multiple pathologic signaling pathways. Absence of specific inhibitors however impedes its advancement to translational research. Here, we integrate structural bioinformatics and experimental research approaches for the discovery and validation of small-molecule inhibitors of CLIC4. High-affinity allosteric binders were identified from a library of 1615 Food and Drug Administration (FDA)-approved drugs via a high-performance computing-powered blind-docking approach, resulting in the selection of amphotericin B and rapamycin. NMR assays confirmed the binding and conformational disruptive effects of both drugs while they also reversed stress-induced membrane translocation of CLIC4 and inhibited endothelial cell migration. Structural and dynamics simulation studies further revealed that the inhibitory mechanisms of these compounds were hinged on the allosteric modulation of the catalytic glutathione (GSH)-like site loop and the extended catalytic β loop which may elicit interference with the catalytic activities of CLIC4. Structure-based insights from this study provide the basis for the selective targeting of CLIC4 to treat the associated pathologies
EP05.02-003 Durvalumab after Chemoradiotherapy (CRT) in Unresectable Stage III NSCLC. Comparative Study of Two Cohorts in the Real-World Setting
[EN] Introduction: Durvalumab is the new standard of care for unresectable
locally advanced NSCLC, with PD-L1 _1% and who did not
have progression after CRT treatment in the European Union. Our
study compares the effectiveness and the frequency of radiation
pneumonitis in patients treated with concurrent CRT with or without
durvalumab consolidation during the same period in real clinical
practice. Methods: A single-center retrospective study. 71 treated
patients with unresectable stage III NSCLC were included between
March 2018 and December 2021, 37 with CRT followed by durvalumab
and 34 with CRT alone. Real-world progression-free survival
(rwPFS) and real-world overall survival (rwOS) were calculated since
the date of the end CRT. Propensity score matching (PSM) 1:1 was
used to account for differences in baseline characteristics. Results:
Median age was 67 years (range 46-82). 25.4% of the patients were
_75 years old. 78.9% were men and 53.5% former smokers. 54.9%
had squamous histology and 28%, 51% and 21% stage IIIA, IIIB and
IIIC disease, respectively. The most used scheme was carboplatinpaclitaxel
(43.7%), receiving induction chemotherapy in up to 54.9%
of patients. 73.2% received between 60-66 Gy doses of radiotherapy.
Median time from end of CRT to onset durvalumab was 44 days
(range 13-120) with a median of 14 infusions (range 6-27). Of the
34 patients without durvalumab treatment, the expression PD-L1
<1% (58.8%) was the most frequent cause for rejecting consolidation
therapy. After PSM analysis, patients distributions were well
balanced. With a median follow-up of 19.7 months (range 1.4-36.6);
median rw-PFS was 9.3 months (95% CI, 5-13.5) without durvalumab
and 17 months (95% CI, 11-22.9) with durvalumab (pÂĽ0.013).
Median rw-OS was 19.3 months (95% CI, 3.8-34.8) without durvalumab
and 29.9 months (95% CI, 23.3-36.6) with durvalumab
(pÂĽ0.241) with a rw-OS% at 6, 18 and 24 months of 90%, 62% and
49% vs 100%, 86% and 74%, respectively. The rate of radiation
pneumonitis was more frequent with durvalumab consolidation
(56.8% against 44.1%), (pÂĽ0.346), especially within 3 months after
CRT. G3 pneumonitis was only observed in the consolidation therapy.
Conclusions: Our results demonstrate the effectiveness of
durvalumab consolidation after CRT in real-world patients with
unresectable stage III NSCLC. Further sample and longer follow-up
are required to obtain more accurate results. Active surveillance and
appropriate management for radiation pneumonitis are needed, in
especially in candidates for consolidation treatmentS
EP05.02-002 Who Benefits More of Durvalumab after Chemoradiotherapy (CRT) in Real-World Patients with Locally Advanced Non-Small-Cell Lung Cancer (NSCLC)?
[EN] Introduction: Durvalumab received EMA approval as consolidation
therapy (CT) for unresectable stage III NSCLC with PD-L1 _1% and
who did not have progression after CRT. Our objective was to analyze
in real clinical practice the effectiveness of durvalumab and explore the
clinical factors that may be associated with the benefit from CT.
Methods: Retrospective study was made at Hospital of Leon (Spain),
including 37 patients with locally advanced NSCLC treated with durvalumab
after CRT treatment between March 2018 and october 2021
(40.5% patients were included in the durvalumab early access program).
The neutrophil-to-lymphocyte ratio (NLR) could identified after
CRT as a factor that may be benefit from durvalumab. Results: Median
age was 67 years (range 46-82 years). 40.5% of patients were _70
years old. 78.4% were male and 51.4% smokers. 54% had non-squamous
histology. PD-L1 expression was <1% in 5% and not available in
8% patients. 2.7% ROS1 rearrangements, 5.4% KRAS mutations and
not available in 43.2% patients. Stage IIIA, IIIB, IIIC disease were
24.3%, 54.1% and 21.6%, respectively. Median time from end of CRT to
onset durvalumab was 44 days (range 13-120 days). Overall median CT
duration was 214.8 days (range 69-399 days) with a median of 14
infusions (range 6-27 infusions). With a median follow up of 19.7
months (range 1.4-34.9 months); 67.6% had stopped CT: 37.8% due to
completing treatment, 16.2% disease progression, 10.8% adverse event
and 2.7% due to COVID19 infection. Median real-world progressionfree
survival (rwPFS) was 17 months (95% CI, 11-23). Median realworld
overall survival (rwOS) was 29.9 months (95% CI, 23.3-36.6). %
rwOS at 6, 18 and 24 months were 100%, 86.9% and 74.5%, respectively.
For patients with post-CRT NLR not exceeding the cohort median
value of 6, receipt of durvalumab was associated with an improvement
in rwOS (median not reached vs 25.7 months; pÂĽ0.025). 56.8% patients
had any grade of radiation pneumonitis (median time from CRT
start: 119 days [range 36-241 days]). Of these, 19% patients developed
worsening of radiation pneumonitis with durvalumab. 54,1% developed
immune-mediated toxicity, mostly G1-2 (85.1%). Conclusions:
Our results demonstrate the effectiveness of durvalumab consolidation
in this patients population in a real-life setting. We identified low NLR
after CRT as a potentially predictive factor for the benefit of CT in
locally advanced NSCLC.S
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