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Wiener Klinische Wochenschrift Jul 2024Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder characterized by a loss of glycosyl-phosphatidyl-inositol-linked (GPI) proteins on various...
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder characterized by a loss of glycosyl-phosphatidyl-inositol-linked (GPI) proteins on various hematopoietic cells. Some GPI proteins are involved in the regulation of the complement system, and their absence renders erythrocytes susceptible to complement-mediated lysis. Current standard of care in PNH is to block the complement system at the level of C5 using ravulizumab or eculizumab; however, some patients with PNH may develop extravascular hemolysis (EVH) during treatment with C5 inhibitors. The proximal complement inhibitor iptacopan has recently been shown to be efficacious in patients with PNH. This article reports on a 43-year-old female patient with PNH who was successfully treated with iptacopan. The patient had received ravulizumab for several years and developed a clinically relevant EVH. After obtaining informed consent, the patient received oral iptacopan 200 mg twice daily and ravulizumab was discontinued. Over the next few weeks hemoglobin levels and reticulocyte counts normalized. The patient reported mild flushes with erythema, chills, and mild muscle pain, all of which resolved during follow-up. No breakthrough hemolysis occurred, and no severe adverse events were recorded.
PubMed: 38954058
DOI: 10.1007/s00508-024-02390-w -
Journal of Neurology Jul 2024To evaluate the effectiveness and safety of nusinersen for the treatment of 5q-spinal muscular atrophy (SMA) among Chinese pediatric patients.
OBJECTIVE
To evaluate the effectiveness and safety of nusinersen for the treatment of 5q-spinal muscular atrophy (SMA) among Chinese pediatric patients.
METHODS
Using a longitudinal, multi-center registry, both prospective and retrospective data were collected from pediatric patients with 5q-SMA receiving nusinersen treatment across 18 centers in China. All patients fulfilling the eligibility criteria were included consecutively. Motor function outcomes were assessed post-treatment by SMA type. Safety profile was evaluated among patients starting nusinersen treatment post-enrollment. Descriptive analyses were used to report baseline characteristics, effectiveness, and safety results.
RESULTS
As of March 2nd, 2023, 385 patients were included. Most patients demonstrated improvements or stability in motor function across all SMA types. Type II patients demonstrated mean changes [95% confidence interval (CI)] of 4.4 (3.4-5.4) and 4.1 (2.8-5.4) in Hammersmith Functional Motor Scale-Expanded (HFMSE), and 2.4 (1.7-3.1) and 2.3 (1.2-3.4) in Revised Upper Limb Module (RULM) scores at months 6 and 10. Type III patients exhibited mean changes (95% CI) of 3.9 (2.5-5.3) and 4.3 (2.6-6.0) in HFMSE, and 2.1 (1.2-3.0) and 1.5 (0.0-3.0) in RULM scores at months 6 and 10. Of the 132 patients, 62.9% experienced adverse events (AEs). Two patients experienced mild AEs (aseptic meningitis and myalgia) considered to be related to nusinersen by the investigator, with no sequelae.
CONCLUSIONS
These data underscore the significance of nusinersen in Chinese pediatric patients with SMA regarding motor function improvement or stability, and support recommendations on nusinersen treatment by Chinese SMA guidelines and continuous coverage of nusinersen by basic medical insurance.
PubMed: 38954034
DOI: 10.1007/s00415-024-12442-w -
Cancer Immunology, Immunotherapy : CII Jul 2024Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)/CD141(BDCA-3) myeloid dendritic cells (myDC) in the tumor microenvironment are... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)/CD141 (BDCA-3) myeloid dendritic cells in solid tumors.
BACKGROUND
Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)/CD141(BDCA-3) myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB.
METHODS
In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)/CD141(BDCA-3) myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS).
RESULTS
Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event.
CONCLUSION
SBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint.
TRIAL REGISTRATION NUMBER
Clinicaltrials.gov: NCT04571632 (09 AUG 2020).
EUDRACT
2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022.
Topics: Humans; Antibodies, Monoclonal, Humanized; Female; Male; Aged; Middle Aged; Radiosurgery; Dendritic Cells; Ipilimumab; Adult; Antineoplastic Combined Chemotherapy Protocols; Neoplasms; Thrombomodulin; Aged, 80 and over; Combined Modality Therapy; Myeloid Cells; Glycoproteins; Antigens, CD1
PubMed: 38954010
DOI: 10.1007/s00262-024-03751-0 -
Heart and Vessels Jul 2024Iliac artery angioplasty with stenting is an effective alternative treatment modality for aortoiliac occlusive diseases. Few randomized controlled trials have compared...
Balloon-expandable cobalt chromium stent versus self-expandable nitinol stent for the Atherosclerotic Iliac Arterial Disease (SENS-ILIAC Trial) Trial: a randomized controlled trial.
Iliac artery angioplasty with stenting is an effective alternative treatment modality for aortoiliac occlusive diseases. Few randomized controlled trials have compared the efficacy and safety between self-expandable stent (SES) and balloon-expandable stent (BES) in atherosclerotic iliac artery disease. In this randomized, multicenter study, patients with common or external iliac artery occlusive disease were randomly assigned in a 1:1 ratio to either BES or SES. The primary end point was the 1-year clinical patency, defined as freedom from any surgical or percutaneous intervention due to restenosis of the target lesion after the index procedure. The secondary end point was a composite event from major adverse clinical events at 1 year. A total of 201 patients were enrolled from 17 major cardiovascular intervention centers in South Korea. The mean age of the enrolled patients was 66.8 ± 8.5 years and 86.2% of the participants were male. The frequency of critical limb ischemia was 15.4%, and the most common target lesion was in the common iliac artery (75.1%). As the primary end point, the 1-year clinical patency as primary end point was 99% in the BES group and 99% in the SES group (p > 0.99). The rate of repeat revascularization at 1 year was 7.8% in the BES group and 7.0% in the SES group (p = 0.985; confidence interval, 1.011 [0.341-2.995]). In our randomized study, the treatment of iliac artery occlusive disease with self-expandable versus balloon-expandable stent was comparable in 12-month clinical outcomes without differences in the procedural success or geographic miss rate regardless of the deployment method in the distal aortoiliac occlusive lesion (ClinicalTrials.gov, NCT01834495).
PubMed: 38953938
DOI: 10.1007/s00380-024-02431-4 -
Future Oncology (London, England) Jul 2024This is a summary of two studies that looked at the safety and effectiveness of a potential new treatment, N-803 (Anktiva), in combination with a standard treatment...
WHAT IS THIS SUMMARY ABOUT?
This is a summary of two studies that looked at the safety and effectiveness of a potential new treatment, N-803 (Anktiva), in combination with a standard treatment bacillus Calmette-Guerin (BCG) for people with .One study was a Phase 1b study that tested increasing doses of N-803 in combination with the same dose of BCG in people with NMIBC who had never received BCG previously (BCG-naive). The other study is a of N-803 and BCG in people with NMIBC whose cancer wasn't eliminated by BCG alone (BCGunresponsive).
WHAT HAPPENED IN THE STUDIES?
In the Phase 1b study, the nine participants were split into three groups of 3 participants who received a dose of 100, 200, or 400 μg N-803 along with a standard 50 mg dose of BCG. In the Phase 2/3 study, one group (cohort A) of participants with carcinoma in situ (CIS) disease and another group (cohort B) with papillary disease were treated with 400 μg N-803 plus 50 mg BCG. There was also a cohort C that received only 400 μg N-803. Treatments were delivered directly into the bladder once a week for 6 weeks in a row.
WHAT WERE THE KEY TAKEAWAYS?
N-803 plus BCG eliminated NMIBC in all nine BCG-naive participants and the effects were long-lasting, with participants remaining NMIBC-free for a range of 8.3 to 9.2 years.As reported in 2022, cancer was eliminated in 58 of 82 (71%) participants with BCG-unresponsive CIS disease and the effect was also long-lasting. Importantly, approximately 90% of the successfully treated participants avoided surgical removal of the bladder. In cohort B participants with papillary disease, 40 of 72 (55.4%) were cancer-free 12 months after treatment. N-803 used alone was only effective in 2 of 10 participants. In both studies, the combination of N-803 and BCG was found to be associated with very few adverse events.Based on results from the Phase 2/3 study, the U.S. Food and Drug Association (FDA) approved the use of N-803 plus BCG for the treatment of BCG-unresponsive bladder CIS with or without Ta/T1 papillary disease. NCT02138734 (Phase 1b study), NCT03022825 (Phase 2/3 study).
PubMed: 38953850
DOI: 10.1080/14796694.2024.2363744 -
Hepatology Research : the Official... Jul 2024This study aims to evaluate the efficacy and safety of lenvatinib radiofrequency ablation (RFA) sequential therapy for certain hepatocellular carcinoma (HCC) patients.
Lenvatinib radiofrequency ablation sequential therapy offers survival benefits for patients with unresectable hepatocellular carcinoma at intermediate stage and the liver reserve of Child-Pugh A category: A multicenter study.
AIM
This study aims to evaluate the efficacy and safety of lenvatinib radiofrequency ablation (RFA) sequential therapy for certain hepatocellular carcinoma (HCC) patients.
METHODS
One hundred and nineteen patients with unresectable HCC in the intermediate stage with Child-Pugh A were retrospectively recruited in a multicenter setting. Those in the lenvatinib RFA sequential therapy group received lenvatinib initially, followed by RFA and the retreatment with lenvatinib. The study compared overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs) between patients undergoing sequential therapy and lenvatinib monotherapy.
RESULTS
After propensity score matching, 25 patients on sequential therapy and 50 on monotherapy were evaluated. Independent factors influencing OS were identified as sequential therapy, modified albumin-bilirubin (mALBI) grade, and relative dose intensity (%) with hazard ratios (HRs) of 0.381 (95% confidence interval [CI], 0.186-0.782), 2.220 (95% CI, 1.410-3.493), and 0.982 (95% CI, 0.966-0.999), respectively. Stratified analysis based on mALBI grades confirmed the independent influence of treatment strategy across all mALBI grades for OS (HR, 0.376; 95% CI, 0.176-0.804). Furthermore, sequential therapy was identified as an independent factor of PFS (HR, 0.382; 95% CI, 0.215-0.678). Sequential therapy significantly outperformed monotherapy on survival benefits (OS: 38.27 vs. 18.96 months for sequential therapy and monotherapy, respectively, p = 0.004; PFS: 13.80 vs. 5.32 months for sequential therapy and monotherapy, respectively, p < 0.001). Sequential therapy was significantly associated with complete response by modified Response Evaluation Criteria in Solid Tumors (odds ratio, 63.089). Ten of 119 patients experienced grade 3 AEs, with no AE beyond grade 3 observed.
CONCLUSION
Lenvatinib RFA sequential therapy might offer favorable tolerability and potential prognostic improvement compared to lenvatinib monotherapy.
PubMed: 38953838
DOI: 10.1111/hepr.14089 -
Clinical Advances in Hematology &... 2024Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are implicated in various cancers, including those of the lung and thyroid. The prevalence of NTRK fusions is... (Review)
Review
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are implicated in various cancers, including those of the lung and thyroid. The prevalence of NTRK fusions is 0.1 to 0.3% in non-small cell lung cancer (NSCLC) and as high as 26% in pediatric papillary thyroid carcinoma. Detection methods include immunohistochemistry, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, and next-generation sequencing. Management of NTRK fusion-positive lung cancer primarily involves targeted therapies, notably the tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib. Both agents demonstrate high response rates and durable disease control, particularly in metastatic adenocarcinoma of the lung. They are preferred as first-line treatments because of their efficacy over immunotherapy. Possible adverse events include dizziness, weight gain, neuropathy-like pain, and liver enzyme elevation. Larotrectinib and entrectinib also produce robust and durable responses in NTRK fusion-positive thyroid cancer that is refractory to radioactive iodine. Second-generation TRK inhibitors that have been designed to overcome acquired resistance are under investigation.
Topics: Humans; Protein Kinase Inhibitors; Thyroid Neoplasms; Lung Neoplasms; Indazoles; Pyrazoles; Oncogene Proteins, Fusion; Pyrimidines; Receptor, trkA; Benzamides; Treatment Outcome
PubMed: 38953725
DOI: No ID Found -
Expert Opinion on Pharmacotherapy Jul 2024During menopause the majority of women experience vasomotor symptoms which may lead to several untoward effects and negatively impact quality of life. Fezolinetant, a,... (Review)
Review
INTRODUCTION
During menopause the majority of women experience vasomotor symptoms which may lead to several untoward effects and negatively impact quality of life. Fezolinetant, a, novel agent directly targeting the underlying pathophysiology of menopause-associated vasomotor symptoms offers an alternative to hormonal therapies for which many patients have a contraindication or unwillingness to take due to safety concerns.
AREAS COVERED
This review summarizes key pharmacologic, pharmacokinetic, and pharmacodynamic parameters of fezolinetant along with efficacy and safety data derived from clinical trials. A literature search of peer-reviewed publications evaluating the efficacy and safety of fezolinetant was conducted using PubMed and EMBASE databases. A review of registered trials in clinicaltrials.gov was evaluated to identify ongoing studies.
EXPERT OPINION
Placebo-controlled studies demonstrated that fezolinetant led to a statistically significant reduction in vasomotor symptom frequency and severity among patients with moderate to severe vasomotor symptoms. The most common adverse event is headache (5-10%) and no serious safety signals have been noted. Direct head-to-head comparison with hormonal therapies and nonhormonal therapies for VMS, assessment of sleep outcomes, and evaluation of efficacy and safety beyond one year are key areas where additional data is still needed.
PubMed: 38953697
DOI: 10.1080/14656566.2024.2375039 -
Journal of Clinical Microbiology Jul 2024The clinical microbiology laboratory is capable of identifying microorganisms in clinical specimens faster and more accurately than ever before. At face value, this...
The clinical microbiology laboratory is capable of identifying microorganisms in clinical specimens faster and more accurately than ever before. At face value, this should enable patient care providers to make better-informed decisions and target antimicrobial therapies to deliver individualized care. Ironically, more complete and specific reporting of microorganisms isolated from specimens may result in overtreatment based on the presence of a pathogen, even in the absence of clear signs of clinical infection. This conundrum calls into question the role of the laboratory in contributing to care through selective or "exception" reporting whereby some results are selectively withheld when there is a low probability that laboratory findings correlate with the clinical infection. In a recent article published in the , Bloomfield et al. (J Clin Microbiol 62:e00342-24, 2024, https://doi.org/10.1128/jcm.00342-24) examine the impact and safety of an exception reporting strategy applied to wound swab specimens. Canonical pathogens associated with skin and soft tissue infections including and beta-hemolytic streptococci are withheld from the laboratory report if certain patient criteria are met that would put them at low risk of adverse outcomes if untreated, or if treated with guideline-recommended empiric therapy. Their central finding was an approximately 50% reduction in post-laboratory report antibiotic initiation without adverse events or increased 30-day admission rate (indicative of infection-related complications, e.g., disseminated disease). While effectively achieving their goal, the premise of exception reporting and other modified reporting strategies raises questions about the potential risk of underreporting and how to ensure that the message is being interpreted, and acted upon, by care providers as was intended by the laboratory.
PubMed: 38953652
DOI: 10.1128/jcm.00703-24 -
Inflammatory Bowel Diseases Jul 2024There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). This study aimed to...
BACKGROUND
There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). This study aimed to evaluate the efficacy of proactive TDM in IBD patients treated with intravenous (iv) vedolizumab (VDZ).
METHODS
This single-center retrospective cohort study included consecutive IBD patients treated with maintenance iv VDZ therapy undergoing TDM from November 2016 to March 2023. Patients were followed through June 2023 and were divided in to 2 groups: those who had at least 1 proactive TDM vs those who underwent only reactive TDM. A survival analysis was performed to evaluate drug persistence, defined as no need for drug discontinuation due to loss of response, serious adverse event, or an IBD-related surgery.
RESULTS
The study population consisted of 94 patients (proactive TDM, n = 72) with IBD (ulcerative colitis, n = 53). Patients undergoing at least 1 proactive TDM compared with patients having only reactive TDM demonstrated a higher cumulative probability of drug persistence (Log-rank P < .001). In multivariable Cox proportional hazard regression analysis, at least 1 proactive TDM was the only factor associated with drug persistence (hazard ratio, 14.3; 95% confidence interval [CI], 3.8-50; P < .001). A ROC analysis identified a VDZ concentration of 12.5 µg/mL as the optimal drug concentration threshold associated with drug persistence (area under the ROC curve: 0.691; 95% CI, 0.517-0.865; P = .049).
CONCLUSION
In this single-center retrospective study reflecting real-life clinical practice, proactive TDM was associated with increased drug persistence in patients with IBD treated with iv VDZ.
PubMed: 38953651
DOI: 10.1093/ibd/izae140